Khans Treatment Planning in Radiation Oncology 4th Edition

FOURTH
EDITION
KHAN’S
Treatment Planning in Radiation
Oncology
EDITORS
Faiz M. Khan, PhD

Professor Emeritus
Department of Radiation Oncology
University of Minnesota Medical School
Minneapolis, Minnesota
John P. Gibbons, PhD

Chief Medical Physicist
Ochsner Health System
New Orleans, Louisiana
Paul W. Sperduto, MD, MPP, FASTRO

Radiation Oncologist
Minneapolis Radiation Oncology
ERRNVPHGLFRVRUJ
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4th edition
Copyright © 2016 Wolters Kluwer
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Library of Congress Cataloging-in-Publication Data

Names: Khan, Faiz M., editor. | Gibbons, John P., Jr., editor. | Sperduto,
Paul W., editor.
Title: Khan’s treatment planning in radiation oncology / editors, Faiz M. Khan,
John P. Gibbons, Paul W. Sperduto.
Other titles: Treatment planning in radiation oncology.
Description: Fourth edition. | Philadelphia : Wolters Kluwer [2016] |
Preceded by Treatment planning in radiation oncology / editors, Faiz M. Khan,
Bruce J. Gerbi. 3rd ed. c2012. | Includes bibliographical references and
index.
Identifiers: LCCN 2016004611 | ISBN 9781469889979
Subjects: | MESH: Neoplasms—radiotherapy | Radiotherapy Planning,
Computer-Assisted | Radiation Oncology—methods
Classification: LCC RC271.R3 | NLM QZ 269 | DDC 616.99/40642—dc23
LC record available at http://lccn.loc.gov/2016004611
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Given continuous, rapid advances in medical science and health information, independent
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LWW.com
To Kathy, my wife and companion of fifty years:
Happy Anniversary, My Love.
—Faiz M. Khan
To my wife Nicole, for her continued patience and support

—John P. Gibbons
To Jody, Luke, Maria, and Will for their love and laughter and
my patients who provide me the privilege of caring for them in
times of greatest need.
—Paul W. Sperduto
Contributors
Judy A. Adams, CMD

Director of Dosimetry
Massachusetts General Hospital Cancer Center
Boston, Massachusetts
Fiori Alite, MD
Stritch School of Medicine
Loyola University
Maywood, Illinois
John A. Antolak, PhD

Associate Professor & Consultant
Mayo Clinic
Rochester, Minnesota
James M. Balter, PhD

Professor
Radiation Oncology Department
University of Michigan
Ann Arbor, Michigan
Christopher Beltran, PhD

Mayo Clinic
Rachel C. Blitzblau, MD, PhD

Assistant Professor
Duke University School of Medicine
Attending Physician, Radiation Oncology
Duke University Medical Center
Durham, North Carolina
Stefan Both, PhD

Associate Attending
Medical Physics Department
Memorial Sloan Kettering Cancer Center
New York, New York
Frank J. Bova, PhD, FACR, FAAPM, FAAPM

Albert E. and Birdie W. Professor of Computer-Assisted Stereotactic
Neurosurgery
University of Florida College of Medicine
Gainesville, Florida
Jason Chan, MD
Resident in Training
University of California San Francisco
San Francisco, California
Albert Chang, MD, PhD

Assistant Professor in Residence
Departments of Radiation Oncology and Urology
University of California, San Francisco
George T. Y. Chen, PhD

Massachusetts General Hospital and Harvard Medical School
Zhe (Jay) Chen, PhD
Professor
Department of Therapeutic Radiology
Yale University School of Medicine
Yale-New Haven Hospital
New Haven, Connecticut
Yen-Lin Evelyn Chen, MD

Instructor
Radiation Oncology
Massachusetts General Hospital
James C. L. Chow, PhD

Assistant Professor
University of Toronto
Radiation Physicist
Radiation Medicine Program
Princess Margaret Cancer Center
Toronto, Ontario, Canada
Benjamin M. Clasie, MD
Resident Physician
Radiation Oncology
Rush University Medical Center
Chicago, Illinois
Brian G. Czito, MD
Gary Hock and Lyn Proctor Associate Professor
Thomas F. DeLaney, MD, FASTRO

Andres Soriano Professor of Radiation Oncology
Harvard Medical School
Medical Director, Francis H. Burr Proton Therapy Center
Co-Director, Center for Sarcoma and Connective Tissue Oncology
Lei Dong, PhD

Director, Chief of Medical Physics
Scripps Proton Therapy Center
Professor, Department of Radiation Medicine and Applied Sciences
University of California—San Diego
San Diego, California
Bahman Emami, MD, FACR, FASTRO

Professor
Loyola University Medical Center
Chicago, Illinois
Robert L. Foote, MD, FASTRO

Professor of Radiation Oncology
Mayo Medical School
Chair
Mayo Clinic
Ryan D. Foster, PhD

Medical Physicist
Carolinas HealthCare System/Levine Cancer Institute
Concord, North Carolina
William A. Friedman, MD
Professor and Chair
Department of Neurosurgery
University of Florida College of Medicine
Gainesville, Florida
Yolanda I. Garces, MD, MS

Consultant
Assistant Professor of Radiation Oncology
Mayo Clinic
John P. Gibbons Jr, PhD

Ochsner Health System
New Orleans, Louisiana
Eli Glatstein, MD, FASTRO

Emeritus Professor
University of Pennsylvania
Philadelphia, Pennsylvania
Vinai Gondi, MD
Co-Director, Brain & Spine Tumor Center
Northwestern Medicine Cancer Center, Warrenville
Warrenville, Illinois
Aditya N. Halthore, MD
Resident
Department of Radiation Medicine
Hofstra North Shore-LIJ School of Medicine
North Shore-LIJ Health System
Lake Success, New York
Andrew Jackson, PhD
Associate Attending Physicist
Medical Physics Computer Service
Memorial Sloan-Kettering Cancer Center
New York, New York
Julian Johnson, MD
Resident in Training
James A. Kavanaugh, MS
Washington University in St. Louis
Director of Satellite Services
Siteman Cancer Center
St. Louis, Missouri
Paul J. Keall, PhD

Professor and NHMRC Australian FellowDirector, Radiation Physics
Laboratory
Central Clinical School
Sydney Medical School
The University of Sydney
New South Wales, Australia
Faiz M. Khan, PhD

Professor Emeritus
Eric E. Klein, PhD

Professor
Northwell Health
Jonathan P. S. Knisely, MD
Associate Professor
Northwell Health
Hofstra University School of Medicine
Hanne M. Kooy, PhD

Associate Professor
Rupesh Kotecha, MD
Resident
Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio
Gerald Kutcher, PhD

Professor
History Department
Binghamton University
State University of New York
Binghamton, New York
Guang Li, PhD, DABR

Associate Member and Associate Attending Physicist
Department of Medical Physics
New York, New York
Tony Lomax, PhD

Professor
Centre for Proton Therapy
Paul Scherrer Institute
Switzerland
Shannon M. MacDonald, MD
Associate Professor of Radiation Oncology
Massachusetts General Hospital/Harvard Medical School
Francis H. Burr Proton Therapy Center
Gig S. Mageras, PhD

Member, Memorial Hospital
Attending Physicist
Memorial Hospital
New York, New York
Amit Maity, MD, PhD

Professor
Charles Mayo, PhD

University of Michigan
Ann Arbor, Michigan
Minesh P. Mehta, MD, FASTRO

Professor
University of Maryland School of Medicine
Baltimore, Maryland
Loren K. Mell, MD
Associate Professor
Department of Radiation Medicine and Applied Sciences
University of California San Diego
La Jolla, California
Dimitris N. Mihailidis, PhD, FAAPM, FACMP, CAMC

Cancer Center-Alliance Oncology
West Virginia University School of Medicine
Clinical Professor
Radiation Oncology
Charleston, West Virginia
Radhe Mohan, PhD

Professor
Department of Radiation Physics
University of Texas MD Anderson Cancer Center
Houston, Texas
Yvonne M. Mowery, MD, PhD

Resident Physician
Resident Physician
Radiation Oncology
Arno J. Mundt, MD, FACRO, FASTRO

Professor and Chair
Department of Radiation Medicine & Applied Sciences
President, Radiating Hope Society Chair
American College of Radiation Oncology
Sasa Mutic, PhD, FAAPM

Professor and Director of Medical Physics
Washington University School of Medicine
St. Louis, Missouri
Colin G. Orton, PhD

Professor Emeritus
Wayne State University
Detroit, Michigan
Manisha Palta, MD
Assistant Professor
Duke Cancer Institute
Niko Papanikolaou, PhD

Professor and Chief
Division of Medical Physics
University of Texas Health Science Center at San Antonio
San Antonio, Texas
Anthony Paravati, MD, MBA

Resident in Radiation Oncology
Moores Cancer Center
University of California, San Diego
Charles A. Pelizzari, PhD

Associate Professor
Department of Radiation and Cellular Oncology
The University of Chicago Medical Center
Chicago, Illinois
Bradford A. Perez, MD
Resident
John P. Plastaras, MD, PhD

Associate Professor
Ezequiel Ramirez, MSRS, CMD, RT(R)(T)

University of Texas Southwestern Medical Center
Dallas, Texas
Mark J. Rivard, PhD, FAAPM

Professor of Radiation Oncology
Tufts University School of Medicine
Gregory C. Sharp, PhD

Assistant Professor
Daniel R. Simpson, MD
Assistant Professor
Moores Cancer Center
UCSD School of Medicine
Chang W. Song, PhD

Professor Emeritus
Paul W. Sperduto, MD, MPP, FASTRO

Medical Director, Minneapolis Radiation Oncology
Co-Director, University of Minnesota Gamma Knife Center
Kevin L. Stephans, MD
Assistant Professor
Cleveland Clinic
Cleveland, Ohio
Kenneth R. Stevens Jr, MD

Professor Emeritus and Former Department Chair
Radiation Medicine Department
Oregon Health & Sciences University
Portland, Oregon
Alexander Sun, MD, FRCPC

Associate Professor
University of Toronto
Staff Radiation Oncologist
Princess Margaret Cancer Centre
Toronto, Canada
Nancy J. Tarbell, MD, FASTRO

CC Wang Professor of Radiation Oncology
Dean for Academic and Clinical Affairs
Bruce R. Thomadsen, PhD

Professor
Medical Physics
University of Wisconsin
Madison, Wisconsin
Robert Timmerman, MD
Professor, Vice Chair
University of Texas Southwestern Medical Center
Dallas, Texas
Wolfgang A. Tomé, PhD, FAAPM

Professor and Director of Medical Physics
Institute for Onco-Physics
Albert Einstein College of Medicine
Professor and Director
Division of Therapeutic Medical Physics
Montefiore Medical Center
Bronx, New York
Jordan A. Torok, MD
Resident Physician
Jan Unkelbach, PhD

Assistant Professor of Radiation Oncology
Assistant Radiation Physicist
Jacob (Jake) Van Dyk, BSc, MSc, FCCPM, FAAPM, FCOMP, DSc(hon)
Professor Emeritus
Oncology and Medical Biophysics
Western University
Former Manager/Head
Physics and Engineering
London Regional Cancer Program
London Health Sciences Centre
London, Ontario, Canada
Gregory M. M. Videtic, MD, CM, FRPC

Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Staff Physician
Taussig Cancer Center
Cleveland Clinic
Cleveland, Ohio
Yi Wang, PhD
Instructor
Medical Physicist
Radiation Oncology
Kenneth J. Weeks, PhD

Medical Physicist
Federal Medical Center
Butner, North Carolina
Christopher G. Willett, MD, FASTRO

Professor and Chairman
Duke University
John A. Wolfgang, PhD

Physicist
Neil M. Woody, MD, MS

Resident
Cleveland Clinic
Cleveland, Ohio
Catheryn M. Yashar, MD, FACRO

Professor
Fang-Fang Yin, PhD

Professor
Duke Clinics
Darwin Yip, MD
Clinical Fellow
Sua Yoo, PhD

Associate Professor
Ellen D. Yorke, PhD

Attending Physicist and Member
New York, New York
Preface
The field of radiation oncology has advanced considerably since the

advent of Intensity-Modulated Radiation Therapy (IMRT) and related
technologies such as Image-Guided Radiation Therapy (IGRT),
Volumetric-Modulated Arc Therapy (VMAT), and Stereotactic Body
Radiotherapy (SBRT). As a result of maturation of these techniques in
the past decade or so, their application in the treatment of various
cancers has accelerated at a rapid pace. Also, parallel to these
developments, proton beam therapy has gained widespread acceptance
as an effective modality, especially in the treatment of pediatric tumors
and other malignancies where greater conformity of dose distribution is
required than possible with photons. Consequently, we invited some
leading experts to write about these latest developments in the field. It is
our hope that the fourth edition will bring our readers up-to-date with
the state of the art in the physics, biology, and clinical practice of
radiation oncology.
This book provides a comprehensive discussion of the physical,
biologic, and clinical aspects of treatment planning. Because of its
primary focus on treatment planning, it covers this subject at a much
greater depth than is the case with other books on medical physics or
radiation oncology. Like the previous editions, it is written for the
benefit of the entire treatment planning team—namely the radiation
oncologist, medical physicist, dosimetrist, and radiation therapist. A
distinctive feature of this edition is the inclusion of Key Points and Study
Questions at the end of each chapter. This is intended to make the book
useful not only for the practitioners but also residents preparing for their
board examinations.
We acknowledge Julie Goolsby, Acquisitions Editor, Emilie Moyer,
Senior Product Development Editor, and other editorial staff of Wolters
Kluwer for their support in the development and production of this
book.
Last but not the least, we wish to acknowledge the contributing
authors whose expertise and efforts are greatly appreciated. Their
valuable contributions have made this publication possible.
Faiz M. Khan
John P. Gibbons
Paul W. Sperduto
Preface to First Edition
Traditionally, treatment planning has been thought of as a way of

devising beam arrangements that will result in an acceptable isodose
pattern within a patient’s external contour. With the advent of computer
technology and medical imaging, treatment planning has developed into
a sophisticated process whereby imaging scanners are used to define
target volume, simulators are used to outline treatment volume, and
computers are used to select optimal beam arrangements for treatment.
The results are displayed as isodose curves overlaid on multiple body
cross-sections or as isodose surfaces in three dimensions. The intent of
the book is to review these methodologies and present a modern version
of the treatment planning process. The emphasis is not on what is new
and glamorous, but rather on techniques and procedures that are
considered to be the state of the art in providing the best possible care
for cancer patients.
Treatment Planning in Radiation Oncology provides a comprehensive
discussion of the clinical, physical, and technical aspects of treatment
planning. We focus on the application of physical and clinical concepts
of treatment planning to solve treatment planning problems routinely
encountered in the clinic. Since basic physics and basic radiation
oncology are covered adequately in other textbooks, they are not
included in this book.
This book is written for radiation oncologists, physicists, and
dosimetrists and will be useful to both the novice and those experienced
in the practice of radiation oncology. Ample references are provided for
those who would like to explore the subject in greater detail.
We greatly appreciate the assistance of Sally Humphreys in managing
this lengthy project. She has been responsible for keeping the
communication channels open among the editors, the contributors, and
the publisher.
Faiz M. Khan
Roger A. Potish
Contents
Contributors
Preface
Preface to First Edition
SECTION I
Physics and Biology of Treatment Planning
CHAPTER 1 Introduction: Process, Equipment, and Personnel
Faiz M. Khan
CHAPTER 2 Imaging in Radiotherapy
George T.Y. Chen, Gregory C. Sharp, John A. Wolfgang, and
Charles A. Pelizzari
CHAPTER 3 Treatment Simulation
Dimitris N. Mihailidis and Niko Papanikolaou
CHAPTER 4 Treatment Planning Algorithms: Photon Dose Calculations
John P. Gibbons
CHAPTER 5 Treatment Planning Algorithms: Brachytherapy
Kenneth J. Weeks
CHAPTER 6 Treatment Planning Algorithms: Electron Beams
Faiz M. Khan
CHAPTER 7 Treatment Planning Algorithms: Proton Therapy
Hanne M. Kooy and Benjamin M. Clasie
CHAPTER 8 Commissioning and Quality Assurance
James A. Kavanaugh, Eric E. Klein, Sasa Mutic, and Jacob
(Jake) Van Dyk
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CHAPTER 9 Intensity-Modulated Radiation Therapy: Photons
Jan Unkelbach
CHAPTER 10 Intensity-Modulated Proton Therapy
Tony Lomax
CHAPTER 11 Patient and Organ Movement
Paul J. Keall and James M. Balter
CHAPTER 12 Image-Guided Radiation Therapy
Guang Li, Gig S. Mageras, Lei Dong, and Radhe Mohan
CHAPTER 13 Linac Radiosurgery: System Requirements, Procedures, and
Testing
Frank J. Bova and William A. Friedman
CHAPTER 14 Stereotactic Ablative Radiotherapy
Ryan D. Foster, Ezequiel Ramirez, and Robert D.
Timmerman
CHAPTER 15 Low Dose-Rate Brachytherapy
Mark J. Rivard
CHAPTER 16 High Dose-Rate Brachytherapy Treatment Planning
Bruce R. Thomadsen
CHAPTER 17 Electron Beam Treatment Planning
John A. Antolak
CHAPTER 18 Proton Beam Therapy
Hanne M. Kooy and Judy A. Adams
CHAPTER 19 Role of Protons Versus Photons in Modern Radiotherapy:
Clinical Perspective
Darwin Yip, Yi Wang, and Thomas F. DeLaney
CHAPTER 20 Fractionation: Radiobiologic Principles and Clinical Practice
Colin G. Orton
CHAPTER 21 Radiobiology of Stereotactic Radiosurgery and Stereotactic
Ablative Radiotherapy
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Paul W. Sperduto and Chang W. Song
CHAPTER 22 Tolerance of Normal Tissue to Therapeutic Radiation
Bahman Emami and Fiori Alite
CHAPTER 23 Treatment Plan Evaluation
Ellen D. Yorke, Andrew Jackson, and Gerald J. Kutcher
SECTION II
Treatment Planning for Specific Cancers
CHAPTER 24 Cancers of the Gastrointestinal Tract
Jordan A. Torok, Bradford A. Perez, Brian G. Czito,
Christopher G. Willett, Fang-Fang Yin, and Manisha Palta
CHAPTER 25 Gynecologic Malignancies
Anthony Paravati, Daniel R. Simpson, Loren K. Mell,
Catheryn M. Yashar, and Arno J. Mundt
CHAPTER 26A Cancer of the Genitourinary Tract: Prostate Cancer
Jason Chan and Albert Chang
CHAPTER 26B Genitourinary Cancers: Bladder Cancer
Julian Johnson and Albert Chang
CHAPTER 26C Cancers of the Genitourinary Tract: Testis
CHAPTER 27 The Lymphomas
John P. Plastaras, Stefan Both, Amit Maity, and Eli
Glatstein
CHAPTER 28 Cancers of the Head and Neck
Yolanda I. Garces, Charles Mayo, Christopher Beltran, and
Robert L. Foote
CHAPTER 29 Cancers of the Skin, Including Mycosis Fungoides
Aditya N. Halthore, Kenneth R. Stevens Jr., James C. L.
Chow, Zhe (Jay) Chen, Alexander Sun, and Jonathan P. S.
Knisely
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CHAPTER 30 Breast Cancer
Yvonne M. Mowery, Sua Yoo, and Rachel C. Blitzblau
CHAPTER 31 Cancers of the Central Nervous System
Vinai Gondi, Wolfgang A. Tome, and Minesh P. Mehta
CHAPTER 32 Pediatric Malignancies
Shannon M. MacDonald and Nancy J. Tarbell
CHAPTER 33 Cancers of the Thorax/Lung
Gregory M. M. Videtic, Rupesh Kotecha, Neil M. Woody,
and Kevin L. Stephans
CHAPTER 34 Soft Tissue and Bone Sarcomas
Yen-Lin Chen and Thomas F. DeLaney
Index
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SECTION I
Physics and Biology of

Treatment Planning
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1 Introduction: Process,
Equipment, and Personnel
Faiz M. Khan
Every patient with cancer must have access to the best possible care regardless
of constraints such as geographic separation from adequate facilities and
professional competence, economic restrictions, cultural barriers, or methods
of healthcare delivery. Suboptimal care is likely to result in an unfavorable
outcome for the patient, at greater expense for the patient and for society.
—Blue Book (1)
INTRODUCTION
Radiotherapy procedure in itself does not guarantee any favorable
outcome. It is through meticulous planning and careful implementation
of the needed treatment that the potential benefits of radiotherapy can
be realized. The ideas presented in this book pertain to the clinical,
physical, and technical aspects of procedures used in radiotherapy
treatment planning. Optimal planning and attention to details will make
it possible to fulfill the goal of the Blue Book, namely, to provide the
best possible care for every patient with cancer.
TREATMENT PLANNING PROCESS

Treatment planning is a process that involves the determination of
treatment parameters considered optimal in the management of a
patient’s disease. In radiotherapy, these parameters include target
volume, dose-limiting structures, treatment volume, dose prescription,
dose fractionation, dose distribution, patient positioning, treatment
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machine settings, online patient monitoring, and adjuvant therapies. The
final product of this activity is a blueprint for the treatment, to be
followed meticulously and precisely over several weeks.
TARGET VOLUME ASSESSMENT

Treatment planning starts right after the therapy decision is made and
radiotherapy is chosen as the treatment modality. The first step is to
determine the tumor location and its extent. The target volume, as it is
called, consists of a volume that includes the tumor (demonstrated
through imaging or other means) and its occult spread to the
surrounding tissues or lymphatics. The determination of this volume and
its precise location is of paramount importance. Considering that
radiotherapy is basically an agent for local or regional tumor control, it
is logical to believe that errors in target volume assessment or its
localization will cause radiotherapy failures.
Modern imaging modalities such as computed tomography (CT),
magnetic resonance imaging (MRI), ultrasound, single photon emission
computed tomography (SPECT), and positron emission tomography
(PET) assist the radiation oncologist in the localization of target volume.
However, what is discernible in an image may not be the entire extent of
the tumor. Sufficient margins must be added to the demonstrable tumor
to allow for uncertainty in the imaging as well as microscopic spread,
depending upon the invasive characteristics of the tumor.
Next in importance to localization of the target volume is the
localization of critical structures. Again, modern imaging is greatly
helpful in providing detailed anatomic information. Although such
information is available from standard anatomy atlases, its extrapolation
to a given patient is fraught with errors that are unacceptable in
precision radiotherapy.
Assessment of the target volume for radiotherapy is not as easy as it
may sound. The first and foremost difficulty is the fact that no imaging
modality at the present time is capable of revealing the entire extent of
the tumor with its microscopic spread. The visible tumor, usually seen
through imaging, represents only a part of the tumor, called the gross
tumor volume (GTV). The volume that includes the entire tumor, namely,
GTV, and the invisible microscopic disease can be estimated only
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clinically and is therefore called the clinical target volume (CTV).
The estimate of CTV is usually made by giving a suitable margin
around the GTV to include the occult disease. This process of assessing
CTV is not precise because it is subjective and depends entirely on one’s
clinical judgment. Because it is an educated guess at best, one should not
be overly tight in assigning these margins around the GTV. The assigned
margins must be wide enough to ensure that the CTV thus designed
includes the entire tumor, including both the gross and the microscopic
disease. If in doubt, it is better to be more generous than too tight
because missing a part of the disease, however tiny, would certainly
result in treatment failure.
Added to the inherent uncertainty of CTV are the uncertainties of
target volume localization in space and time. An image-based GTV, or
the inferred CTV, does not have static boundaries or shape. Its extent
and location can change as a function of time because of variations in
patient setup, physiologic motion of internal organs, patient breathing,
and positioning instability. A planning target volume (PTV) is therefore
required, which should include the CTV plus suitable margins to account
for the above uncertainties. PTV, therefore, is the ultimate target volume
—the primary focus of the treatment planning and delivery. Adequate
dose delivered to PTV at each treatment session presumably assures
adequate treatment of the entire disease-bearing volume, the CTV.
Because of the importance of accurate determination of PTV and its
localization, the International Commission on Radiation Units and
Measurements (ICRU) has come up with a systematic approach to the
whole process, as illustrated in Figures 1.1 and 1.2. The reader is
referred to ICRU Reports 50, 62, and 71 for the underlying concepts and
details of the system (2–4).
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FIGURE 1.1 Schematic illustration of ICRU volumes. (From ICRU. Prescribing, Recording, and
Reporting Photon Beam Therapy. ICRU Report 50. Bethesda, MD: International Commission of
Radiation Units and Measurements; 1993.)
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FIGURE 1.2 Schematic representation of ICRU volumes and margins. (From ICRU. Prescribing,
Recording, and Reporting Photon Beam Therapy [Supplement to ICRU Report 50]. ICRU Report
62. Bethesda, MD: International Commission on Radiation Units and Measurements; 1999.)
Although sophisticated treatment techniques such as intensity-

modulated radiation therapy (IMRT) and image-guided radiation therapy
(IGRT) are now available, which account for organ motion and
positional uncertainties as a function of time, the basic problem still
remains: How accurate is the CTV? Unless the CTV can be relied upon
with a high degree of certainty, various protocols to design PTV from it
and the technical advances to localize it precisely in space and time
would seem rather arbitrary, illusory, or even make-believe. Therefore,
the need for technologic sophistication (with its added cost and
complexity) must be balanced with the inherent uncertainty of CTV for a
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given disease.
However, the above, seemingly pessimistic view of the process should
not discourage the development or the use of these technologies. It
should rather be taken as a cautionary note for those who may pursue
such technologies with a blind eye to their limitations. Technologic
advances must ultimately be evaluated in the context of biologic
advances. “Smart bombs” are not smart if they miss the target or, worse
yet, produce unacceptable collateral damage.
Treating the right target volume conformally with the right dose
distribution and fractionation is the primary goal of radiotherapy. It does
not matter if this objective is achieved with open beams or uniform-
intensity wedged beams, compensators, IMRT, or IGRT. As will be
discussed in the following chapters, various technologies and
methodologies are currently available, which should be selected on the
basis of their ability to achieve the above radiotherapy goal for the given
disease to be treated. In some cases, simple arrangements such as a
single beam, parallel-opposed beams, or multiple beams, with or without
wedges, are adequate, while in others IMRT or IGRT is the treatment of
choice.
EQUIPMENT
Treatment planning is a process essentially of optimization of
therapeutic choices and treatment techniques. This is all done in the
context of available equipment. In the absence of adequate or versatile
equipment, optimization of treatment plans is difficult, if not impossible.
For example, if the best equipment in an institution is a cobalt unit or a
traditional low-energy (4 to 6 MV) linear accelerator, the choice of beam
energy for different patients and tumor sites cannot be optimized. If a
good-quality simulator (conventional or CT) is not available, accurate
design of treatment fields, beam positioning, and portal localization are
not possible. Without modern imaging equipment, high accuracy is not
possible in the determination of target volumes and critical structures, so
that techniques that require conformal dose distributions in three
dimensions cannot be optimized. Accessibility to a reasonably
sophisticated computerized treatment planning system is essential to
plan isodose distributions for different techniques so as to select the one
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that is best suited for a given patient. Therefore, the quality of treatment
planning and the treatment itself depend on how well equipped the
facility is with regard to treatment units, imaging equipment, and
treatment planning computers.
External Beam Units

Low-Energy Megavoltage X-ray Beams
Low-energy megavoltage beams without IMRT capability (e.g., cobalt-60
and/or 4–6-MV x-rays) are principally used for relatively shallow or
moderately deep tumors such as in the head and neck, breast, and
extremities. For treatments using parallel-opposed beams, the body
thickness in the path of these beams should not exceed approximately 17
cm. This is dictated by the ratio of maximum peripheral dose to the
midline dose (5).
In addition to the beam energy, it is also important to have machine
specifications that improve beam characteristics as well as accuracy of
treatment delivery. Some of the major specifications, for example, are
isocentric capability with source-to-axis distance of 100 cm (not less
than 80 cm for cobalt-60), field size of at least 40 × 40 cm, versatile
and rigid treatment couch, asymmetrical collimators, MLCs, and other
features that allow optimization of treatment techniques.
For IMRT or IGRT techniques, a 6-MV x-ray beam is sufficient so far as
the energy is concerned. However, the unit must be equipped with a
special collimator having dynamic MLC or apertures suitable for these
techniques. Its operation must be computer controlled to allow for
intensity-modulated beam delivery in accordance with the IMRT or IGRT
treatment plans.
Medium- or High-Energy Megavoltage X-ray Beams

X-ray beams in the energy range of 10 to 25 MV allow treatment
techniques for deep-seated tumors in the thorax, abdomen, or pelvis. For
parallel-opposed beam techniques, the deeper the tumor, the higher the
energy required to maximize the dose to the tumor, relative to the
normal tissue. Again, the ratio of the maximum peripheral dose to the
midline dose is an important consideration (5). In addition, the dose
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buildup characteristics of these beams allow substantial sparing of
normal subcutaneous tissue in the path of the beams.
One may argue that the degree of normal tissue sparing achieved by x-
ray beams of 10 MV energy can also be achieved by lower megavoltage
beams using more than two beam directions, as in multiple isocentric
fields, rotation therapy, or IMRT. However, for deep-seated tumors,
high-energy beams offer greater tissue sparing for all techniques,
including IMRT.
Charged-Particle Beams
1. Electrons. Electron beams in the range of 6 to 20 MeV are useful for
treating superficial tumors at depths of 5 cm. They are often used in
conjunction with x-ray beams, either as a boost or a mixed-beam
treatment, to provide a particular isodose distribution. The principal
clinical applications include the treatment of skin and lip cancers, chest
wall irradiation, boost therapy for lymph nodes, and the treatment of
head and neck cancers.
Depth–dose characteristics of electron beams have unique features
that allow effective irradiation of relatively superficial cancers and
almost complete sparing of normal tissues beyond them. The availability
of this modality is essential for optimizing treatments of approximately
10% to 15% of cancers managed with radiotherapy.
2. Protons. Proton beam therapy has been used to treat almost all
cancers that are traditionally treated with x-rays and electrons (e.g.,
tumors of the brain, spine, head and neck, breast, lung, gastrointestinal
malignancies, prostate, and gynecologic cancers). Because of the ability
to obtain a high degree of conformity of dose distribution to the target
volume with practically no exit dose to the normal tissues, the proton
radiotherapy is an excellent option for tumors in close proximity of
critical structures such as tumors of the brain, eye, and spine. Also,
protons give significantly less integral dose than photons and, therefore,
should be a preferred modality in the treatment of pediatric tumors
where there is always a concern for a possible development of secondary
malignancies during the lifetime of the patient.
3. Carbon ions. Efficacy of charged particles heavier than protons such
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as nuclei of helium, carbon, nitrogen, neon, silicon, and argon has also
been explored. Although carbon ions or heavier charged particles have
the potential to be just as good as protons, if not better, it is debatable
whether the benefits justify the high cost of such machines. As it stands,
for most institutions, even the acquisition of protons is hard to justify
over the far less expensive but very versatile megavoltage x-ray and
electron accelerators.
Protons and heavier charged particles no doubt have unique biologic
and physical properties, but “Are they clinically superior to x-rays and
electrons with IMRT and IGRT capabilities?” The answer awaits more
experience. Clinical superiority of heavy charged particles needs to be
demonstrated by carefully conducted clinical trials.
Patient Load Versus Treatment Units

The number of patients treated on a given unit can be an important
determinant of the quality of care. Overloaded machines and
overworked staff often give rise to suboptimal techniques, inadequate
care in patient setup, and a greater possibility of treatment errors. As in
any other human activity, rushed jobs do not yield the best results. In
radiotherapy, in which the name of the game is accuracy and precision,
there is simply no room for sloppiness, which can easily creep in if the
technologist’s primary concern is to keep up with the treatment
schedule. An assembly line type of atmosphere should never be allowed
in a radiotherapy facility because it deprives the patients of their right to
receive the best possible care that radiotherapy has to offer.
A report like the Blue Book is the best forum for setting up guidelines
for equipment use. The recommendation of this document is that the
load for a given megavoltage unit should not exceed 6,000 standard
treatments (single patient visit equivalent) per year. Depending upon the
complexity of procedures performed on a machine, its calibration
checks, and quality assurance, the patient load per megavoltage machine
for full use can vary from 20 to 30 patients treated per day. Details of
calculating realistic load for a megavoltage unit and criteria for
replacing or acquiring additional equipment are given in the Blue Book
(1).
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Brachytherapy Equipment
Brachytherapy is an important integral part of a radiotherapy program.
Some tumors are best treated with brachytherapy, alone or in
conjunction with an external beam. It is therefore important to have this
modality available if optimal treatment planning is the goal. Although
electrons are sometimes used as an alternative, brachytherapy continues
to have an important role in treating certain tumors such as gynecologic
malignancies, oral cancers, sarcomas, prostate cancer, and brain tumors.
Currently, the sources most often being used are cesium-137 tubes,
iridium-192 seeds contained in ribbons, iodine-125 seeds, and
palladium-103 seeds. These isotopes can be used in after-loading
techniques for interstitial as well as intracavitary implantation.
Numerous applicators and templates have been designed for
conventional LDR brachytherapy. The institution must follow a
particular system consistently with all its hardware, rules of
implantation, and dose specification schemes. Remote after-loading
units, LDR as well as HDR, are becoming increasingly popular, especially
among institutions with large patient loads for brachytherapy.
Brachytherapy hardware, software, and techniques are discussed in later
chapters.
Imaging Equipment
Modern treatment planning is intimately tied to imaging. Although all
diagnostic imaging equipments have some role in defining and localizing
target volumes, the most useful modalities currently are the CT, MRI,
and PET.
Most radiotherapy institutions have access to these machines through
diagnostic departments. The only problem with this kind of arrangement
is that the fidelity of imaging data obtained under diagnostic conditions
is quite poor when used for treatment planning. This is caused primarily
by the lack of reproducibility in patient positioning. Besides appropriate
modifications in the scanner equipment (e.g., flat tabletop, patient
positioning aids), the patient setup should be supervised by a member of
the treatment planning staff. With the growing demand for CT, 4-
dimensional (4D) CT (respiration-correlated), and MRI in radiotherapy
and the large number of scans that 3-dimensional (3D) treatment
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planning requires, dedicated scanners in radiotherapy departments are
becoming the norm.
Simulator
There is still a role for conventional simulators in a radiation therapy
department although their presence is becoming less common. It is
important that the simulator has the same geometric accuracy as the
treatment machine. In addition, it should allow the simulation of various
treatment techniques that is possible with modern treatment machines.
With the advent of 3D treatment planning, conformal field shaping,
MLCs, 4D CTs, and electronic portal imaging, it is logical to move into
CT simulation. A conventional simulator may be useful for final
verification of the field placement, but with the availability of good-
quality DRRs and special software for CT simulation, this need no longer
exists. Final field verification before treatment can be obtained with the
portal imaging system available on modern linacs.
CT scanners have been used for treatment planning for many years
because of their ability to image patient anatomy and gross tumor, slice
by slice. These data can be processed to view images in any plane or in
three dimensions. In addition, CT numbers can be correlated with tissue
density, pixel by pixel, thereby allowing heterogeneity corrections in
treatment planning. The only drawback of diagnostic CT scans is that of
geometric accuracy of localization needed in radiotherapy. Diagnostic
CT units, with typically narrow apertures and curved tabletops, cannot
reproduce patient positions that would be used for treatment. Although
variations due to positioning can be minimized by using flat tabletops
and units with wide aperture (e.g., 70 cm or larger diameter), the
personnel operating diagnostic equipment are not trained to set up
patients accurately to reproduce radiation therapy conditions. In
addition, diagnostic simulation units are usually too busy to allow
sufficient time for therapy simulations. Because of these technical and
logistic problems, a dedicated CT scanner for radiation therapy has
gained wide acceptance.
A dedicated radiation therapy CT scanner, with accessories (e.g., flat
table identical with those of the treatment units, lasers for positioning,
immobilization, and image registration devices, etc.) to accurately
reproduce treatment conditions, is called a CT-simulator. Many types of
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such units are commercially available. Some of them are designed
specifically for radiation therapy with wide apertures (e.g., 85 cm
diameter) to provide flexibility in patient positioning for a variety of
treatment setups. The CT image data set thereby obtained, with precise
localization of patient anatomy and tissue density information, is useful
not only in generating an accurate treatment plan, but also in providing
a reference for setting up treatment plan parameters. This process is
sometimes called virtual simulation.
Positron Emission Tomography/Computed Tomography

The physics of PET is based on the positron–electron annihilation into
photons. For example, a radiolabeled compound such as
fluorodeoxyglucose (FDG) incorporates 18F as the positron-emitting
isotope. FDG is an analog of glucose that accumulates in metabolically
active cells. Because tumor cells are generally more active metabolically
than normal cells, an increased uptake of FDG is positively correlated
with the presence of tumor cells and their metabolic activity. When the
positron is emitted by 18F, it annihilates a nearby electron, with the
emission of two 0.511-MeV photons in opposite directions. These
photons are detected by ring detectors placed in a circular gantry
surrounding the patient. From the detection of these photons, computer
software (e.g., filtered back projection algorithm) reconstructs the site of
the annihilation events and the intervening anatomy. The site of
increased FDG accumulation, with the surrounding anatomy, is thereby
imaged with a resolution of about 4 mm.
Combining PET with CT scanning has several advantages:
1. Superior quality CT images with their geometric accuracy in defining
anatomy and tissue density differences are combined with PET images
to provide physiologic imaging, thereby differentiating malignant
tumors from the normal tissue on the basis of their metabolic
differences.
2. PET images may allow differentiation between benign and malignant
lesions well enough in some cases to permit tumor staging.
3. PET scanning may be used to follow changes in tumors that occur
over time and with therapy.
4. By using the same treatment table for a PET/CT scan, the patient is
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scanned by both modalities without moving (only the table is moved
between scanners). This minimizes positioning errors in the scanned
data sets from both units.
5. By fusing PET and CT images, the two modalities become
complementary.
Although PET provides physiologic information about the tumor, it

lacks correlative anatomy and is inherently limited in resolution. CT, on
the other hand, lacks physiologic information but provides superior
images of anatomy and localization. Therefore, PET/CT provides
combined images that are superior to either PET or CT images alone.
Accelerator-Mounted Imaging Systems

After the treatment planning and simulation comes the critical step of
accurate treatment delivery of the planned treatment. Traditionally,
patients are set up on the treatment couch with the help of localization
lasers and various identification marks on the patient, for example, ink
marks, tattoos, or palpable bony landmarks. Sometimes identification
marks are drawn on the body casts worn by the patient for
immobilization. These procedures would be considered reasonable, if
only the patient would not move within the cast and the ink or tattoo
marks did not shift with the stretch of the skin. Bony landmarks are
relatively more reliable, but their location by palpitation cannot be
pinpointed to better than a few millimeters. Good immobilization
devices are critical in minimizing setup variations and are discussed later
in the book.
With the introduction of 3D conformal radiation therapy (CRT),
including IMRT and IGRT, it has become increasingly apparent that the
benefit of these technologies cannot be fully realized if the patient setup
and anatomy do not match the precision of the treatment plan within
acceptable limits at every treatment session. As the treatment fields are
made more conformal, the accuracy requirements of patient setup and
the PTV coverage during each treatment accordingly have to be made
more stringent. These requirements have propelled advances in the area
of patient immobilization and dynamic targeting of PTV through
imaging systems mounted on the accelerators themselves. Thus began
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the era of IGRT.
Each of the three major linear accelerator manufacturers, Varian,
Elekta, and Siemens, provide accelerator-mounted imaging systems
allowing online treatment plan verification and correction (adaptive
radiation therapy) and dynamic targeting, synchronized with the
patient’s respiratory cycles (gating). The commercial names for the
systems are Trilogy (www.varian.com), Synergy (www.elekta.com), and
ONCOR (www.siemens.com). These products come with various options,
some of which may be works in progress or currently not FDA approved.
The reader can get the updated information by visiting the
corresponding Web sites.
The important consideration in acquiring any of these systems is
dictated by the desire to provide state-of-the-art radiation therapy. Such
a system is expected to have the following capabilities:
1. 3D CRT with linac-based megavoltage photon beam(s) of appropriate

energy (e.g., 6 to 18 MV)
2. Electron beam therapy with five or six different energies in the range
of 6 to 20 MeV
3. IMRT, IGRT, and gated radiation therapy capabilities
4. Accelerator-mounted imaging equipment to allow the treatment
techniques mentioned earlier (such as IMRT and IGRT)
Typically, such a system consists of an electronic portal imaging

device (EPID), a kVp source for radiographic verification of setup, an
online fluoroscopic mode to permit overlaying of treatment field
aperture on to the fluoroscopy image, and cone-beam CT capability for
treatment plan verification. Many of these devices and their use in
modern radiotherapy such as IGRT are discussed in the following
chapters.
Treatment Planning Computers

Commercial treatment planning computers became available in the early
1970s. Some of the early ones such as the Spear PC, the Artronix PC-12,
Rad-8, Theratronics Theraplan, and ADAC were instant hits and
provided a quantum jump from manual to computerized treatment
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planning. They served their purpose well in providing fast and
reasonably accurate 2-dimensional (2D) treatment plans. Typically, they
allowed the input (through the digitizer) of external patient contours,
anatomic landmarks, and outlines of the target volume and of the critical
structures in a specified plane (usually central). Beams were modeled
semiempirically from the stored beam data obtained in a water
phantom. Various corrections were used to apply the water phantom
data to the patient situation, presenting irregular surfaces, tissue
inhomogeneities, and multiple beam angles. However, from today’s
standards, the old systems would be considered very limited in
capability and rudimentary in the context of modern 3D treatment
planning.
With the explosion of computer and imaging technologies in the last
20 years or so, the treatment planning computers and their algorithms
have accordingly become more powerful and sophisticated. Systems that
are currently available allow 3D treatment planning in which patient
data obtained from CT scanning, MRI, PET, and so on, are to be input
electronically. Beams are modeled with sophisticated computational
algorithms, for example, pencil beam, convolution–superposition, semi
Monte Carlo, or full Monte Carlo. These algorithms for photons,
electrons, and brachytherapy sources are discussed in later chapters.
Besides major improvements in dose computational methods, there
have been revolutionary advances in software, which allow planning of
complex treatments such as 3D CRT, IMRT, IGRT, and HDR
brachytherapy. One of the most powerful treatment planning algorithms
is called inverse planning, which allows the planner to specify the desired
dose distribution and let the computer generate a plan as close to the
input specifications as possible. Again, these techniques and algorithms
are topics of discussion later in the book.
Major 3D treatment planning systems that are commercially available
are Pinnacle (www.medical.philips.com), Eclipse (www.varian.com),
and Computerized Medical Systems (CMS; www.cms.stl.com). As these
systems are constantly evolving and undergoing revisions, the reader
should be mindful of the fact that an older version of any given system
may not carry much resemblance to the newest version. Therefore,
anyone in the market for such a system needs to do some researching
and check out each system with its most current version. Also, because
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these systems and their software are frequently revised and updated, the
user is advised to carry a service contract for maintenance as well as the
option of receiving future updates as they come along.
Staffing
The 1991 Blue Book has been updated by ASTRO to a new document,
entitled Safety Is No Accident: A Framework for Quality Radiation Oncology
and Care (6). This book was published in 2012 and is available online at
https://www.astro.org/Clinical-Practice/Patient-Safety/Blue-
Book/bfp/index.html#/60. The new document provides a blueprint for
modern radiation oncology facilities in terms of structure, process, and
personnel requirements.
The basis for these recommendations is the fundamental principle that
radiation oncology practice requires a team of personnel with
appropriate educational and training background. Besides the physician
specialists, the radiation oncologists, radiotherapy requires the services
of medical physicists, dosimetrists, therapists, and nurses. The minimum
level of staffing recommended is shown in Table 1.1. In the specific
areas of treatment planning, the key personnel are radiation oncologists,
medical physicists, and dosimetrists. The quality of treatment planning
largely depends on the strength of this team.
TABLE 1.1 Minimum Personnel Requirements for Clinical Radiation

Therapya
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The radiation oncologist, who has the ultimate responsibility for the care
of the patient, heads the treatment planning team. It is his or her
responsibility to formulate the overall plan for the treatment, including
dose prescription to tumor-bearing sites of the body. Details of the actual
treatment technique, beam energies, beam directions, and other specific
details of the treatment are finalized after a number of isodose plans
have been calculated and an optimal plan has been selected. The final
plan must meet the approval of the radiation oncologist in charge of the
patient.
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The ACR standards require that the radiation oncologist be board-
certified to practice radiation oncology. In addition, the number of
radiation oncologists in a given institution must be in proportion to the
patient load (Table 1.1). No more than 25 to 30 patients should be
treated by a single physician. It is important to ensure that each patient
receives adequate care and attention from the physician and that the
treatments are not compromised because of the physician’s lack of time.
Medical Physicist
No other medical specialty draws as much from physics as radiation
oncology. The science of ionizing radiation is the province of physics,
and its application to medicine requires the services of a physics
specialist, the medical physicist. It is the collaboration between the
radiation oncologist and the medical physicist that makes radiotherapy
an effective treatment modality for cancer. Ralston Paterson (7),
emphasizing this relationship, stated in 1963: “In radiotherapy the
physicist who has given special study to this field is full partner with the
therapist, not only in the development of the science, but in the day-to-
day treatment of patients. The unit team, therefore, even for the smallest
department, consists of a radiotherapist and a physicist.”
The unit team of radiation oncologist and medical physicist must have
a supporting cast to provide radiotherapy service effectively to all
patients referred to the department. Dosimetrists, radiation therapists
(previously called technologists), nurses, and service engineers are the
other members of the team. It must be recognized by all concerned that
without this infrastructure and adequate staffing in each area of
responsibility, radiotherapy is reduced to an ineffective, if not unsafe,
modality of treatment.
Adequacy of the support of physics has been spelled out in the ASTRO
document (6). The number of physicists required in a radiotherapy
institution depends not only on the number of patients treated per year
but also on the complexity of the radiotherapy services offered. For
example, special procedures such as stereotactic radiotherapy, HDR
brachytherapy, total-body irradiation for bone marrow transplantation,
3D CRT, IMRT, IGRT, SBRT, respiratory gating, TomoTherapy,
CyberKnife treatments, and intraoperative radiotherapy are all physics-
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intensive procedures and therefore require more physicists as
recommended by ASTRO.
According to the American Association of Physicists in Medicine
(AAPM), a medical physicist involved with clinical services must have a
PhD or MS degree and be board certified in the relevant specialty; in this
case, radiation oncology physics. Also, most physicists in an academic
setting teach and do research, and therefore a doctorate degree is more
desirable for them. Such research plays a key role in the development of
new techniques and in bringing about new advances to radiation
oncology. Paterson (7) emphasized this role by stating “While the
physicist has a day-to-day routine task in this working out or checking of
cases, it is important that he has time for study of special problems.
These may include the development of new x-ray techniques, the
devising of special applicators to simplify or assist treatment, the critical
analysis of existing techniques, or research work of a more fundamental
nature.”
TABLE 1.2 Roles and Responsibilities of Physicists
A medical physicist’s role in radiotherapy is summarized in Table 1.2.

Specifically in treatment planning, the physicist has the overall
responsibility of ensuring that the treatment plan is accurate and
scientifically valid. That means that the physicist is responsible for
testing the computer software and commissioning it for clinical use. He
or she is also responsible for proper interpretation of the treatment plan
as it relates to the dose distribution and calculation of treatment
duration or monitor units.
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One important role of a medical physicist that is often overlooked is
that of a consultant to radiation oncologists in the design of the
treatment plan. Physicians working directly with dosimetrists to
generate a treatment plan without any significant input from the
physicist can often be seen. This process may be operationally smooth
and less costly but can be risky if serious errors go undetected and the
final plan is not optimal. It must be recognized that a qualified medical
physicist, by virtue of education and training, is the only professional on
the radiotherapy team who is familiar with the treatment planning
algorithm and can authenticate the scientific validity of a computer
treatment plan. It is important that he or she be actively involved with
the treatment planning process and that the final plan receives his or her
careful review. Because of the tendency of some physicians to bypass the
physicist, some institutions have developed the policy of having the
physicist present during simulation and doing the treatment planning
either personally or closely working with the dosimetrist in the
generation and optimization of the treatment plan.
Dosimetrist
Historically, dosimetrists were classified as physics personnel with a
Bachelor of Science degree in the physical sciences. They assisted
physicists in routine clinical work such as treatment planning, exposure
time calculations, dosimetry, and quality assurance. They could be called
a physicist assistant, analogous to physician assistant.
Today the dosimetrist’s role is not much different, but the educational
requirements have been formalized to include certification by the
Medical Dosimetrist Certification Board (MDCB), in addition to a
Bachelor’s Degree and graduation from an accredited Medical Dosimetry
training program.
As discussed earlier, the role of a dosimetrist is traditionally to assist
the physicist in all aspects of physics service. However, in some
institutions, dosimetrists substitute for physicists, and/or the treatment
planning procedure is made the sole responsibility of the dosimetrist
with no supervision from the physicist. Whether it is done for economic
or practical reasons, leaving out the physicist from the treatment
planning process is not appropriate and definitely not in the best interest
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of the patient. The dosimetrist’s role is to assist the physicist, not to
replace him or her. The radiation oncologist must understand that a
computer treatment plan necessitates the physicist’s input and review
just as much as it necessitates consultation of other medical specialists in
the diagnosis and treatment of a patient.
REFERENCES
1. ISCRO. Radiation Oncology in Integrated Cancer Management: Report of
the Inter-Society Council for Radiation Oncology (Blue book). Reston,
VA: American College of Radiology; 1991.
2. ICRU. Prescribing, Recording, and Reporting Photon Beam Therapy.
ICRU Report 50. Bethesda, MD: International Commission on
Radiation Units and Measurements; 1993.
3. ICRU. Prescribing, Recording, and Reporting Photon Beam Therapy
(Supplement to ICRU Report 50). ICRU Report 62. Bethesda, MD:
International Commission on Radiation Units and Measurements;
1999.
4. ICRU. Prescribing, Recording, and Reporting Electron Beam Therapy.
ICRU Report 71. Bethesda, MD: International Commission on
Radiation Units and Measurements; 2004.
5. Khan FM, Gibbons JP. The Physics of Radiation Therapy. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2014:179–180.
6. American Society for Radiation Oncology (ASTRO). Safety is No
Accident: A Framework for Quality Radiation Oncology and Care.
Fairfax, VA: American Society for Radiation Oncology; 2012.
https://www.astro.org/clinical-practice/patient-safety/safety-
book/safety-is-no-accident.aspx
7. Paterson R. The Treatment of Malignant Disease by Radiotherapy. 2nd
ed. Baltimore, MD: Williams & Wilkins; 1963:527.
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2 Imaging in Radiotherapy
George T.Y. Chen, Gregory C. Sharp, John A. Wolfgang,

and Charles A. Pelizzari
INTRODUCTION
Imaging is the basis of modern radiotherapy; it plays a major role in
disease localization, treatment planning, guiding radiation delivery, and
monitoring response. While projection radiography was the backbone of
medical imaging in the first 75 years of its existence, transformative
imaging advances in the 1970s led to visualizing patient anatomy
through computer assisted tomography. Soft tissue tumors can alter the
spatial relationships of normal organs, and with transverse 3-
dimensional (3D) maps radiation oncologists could assess target extent
and proximity to sensitive organs at risk for collateral damage. Shortly
after the introduction of computed tomography (CT) scanning in
diagnostic radiology departments, radiation oncologists explored its
potential use in therapeutic radiology. Initial studies found tumor
coverage was marginal or inadequate in nearly one-half of patients
studied (1). Advances in volumetric imaging have continued to evolve,
and today multimodality imaging provides insight into tumor
biochemistry and microenvironment normal organ function as well as
structure.
In parallel, advances in radiation delivery such as intensity modulated,
charged-particle-beam, and stereotactic body radiotherapy provided the
capability to deliver highly conformal doses to the 3D target using
personalized anatomical maps (2–4). Such delivery advances in turn
increased the interest in the development of more accurate methods to
image and treat moving targets. Advances in treatment-room imaging
have further provided the capability of image-guided radiotherapy,
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where images obtained on a daily basis before or during treatment can
be used to correct for variations in setup and organ motion. With
advances in imaging and radiation treatment, dose conformation has
provided an opportunity to safely increase tumor dose, thereby
increasing the probability of tumor control, while minimizing dose to
normal radiation sensitive organs below thresholds of serious
complications.
The general principles of medical image formation and clinical
oncologic imaging are described elsewhere (5,6). Observance of the
centennial anniversary of the discovery of x-rays has resulted in
historical reviews (7,8). This chapter provides an overview of the
imaging modalities and image processing relevant to conformal external
beam radiotherapy.
IMAGE ACQUISITION
Volumetric Imaging
Imaging in radiotherapy is broadly categorized into acquired and
processed images. Figure 2.1 diagrammatically summarizes imaging
modalities used in radiotherapy. Imaging in radiotherapy is dominated
by volumetric data sets from multiple modalities. The modalities probe
the body noninvasively, utilizing different physical interactions of tissues
and the probe modality. Each modality has its strengths and
applications, and complements the strengths of other imaging
techniques. Volumetric image acquisition is emphasized, although
projection radiography has an important role in the clinic. Use of
advanced imaging technologies was surveyed and reported in 2009 (9).
Computed Tomography
CT is the primary imaging modality used in radiation oncology. The
history and basic principles of CT image formation are discussed
elsewhere (5,10). Briefly, CT measures the linear attenuation coefficient
of each pixel in the transverse imaging plane. A fan beam of diagnostic
energy x-rays passes through the patient, and the transmitted radiation is
measured. Multiple projection views are acquired as the x-ray source
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rotates around the patient. From these projections, image reconstruction
algorithms generate a transverse digital image. Each pixel value is a
measurement of μx, the linear attenuation coefficient (relative to water
μw) at an effective diagnostic x-ray energy. At diagnostic energies, the
dominant photon/tissue interactions are the photoelectric and Compton
effects. Pixel values are quantified in Hounsfield units (HU):
For a single energy scan, the HUs associated with various body
components are: air, -1,000 HU; water, 0 HU; fat, ∼-80 HU; muscle,
∼30 HU, and bone variable up to or greater than 1,000 HU. HUs of
different tissues at diagnostic energies can be approximately
extrapolated to electron density values used for dose calculations (11).
Tissue characterization to separately unfold the atomic composition and
electron density per pixel can be performed with dual energy scanning
(12), although most radiotherapy planning scans are performed at a
single x-ray potential. A possible need for dual energy scanning is the
calculation of charged particle stopping powers used in proton and
heavy ion radiotherapy.
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FIGURE 2.1 A: Imaging modalities acquired in radiation therapy; B: Image processing performed
on acquired images to extract and integrate information needed for treatment.
Figure 2.2 shows a human abdominal cadaver section compared to the

corresponding CT image (13). While delineation of an organ on CT will
not exactly correspond to photographic ground truth (14,15), CT can be
geometrically very accurate. Early CT scanners produced a single
transaxial slice; 3D volumes were constructed by stacking images.
Multiplanar reconstruction of CT data provides the user with sagittal,
coronal, and oblique views.
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Volumetric CT studies are acquired on CT-simulators within the
department. These devices are essentially diagnostic quality scanners
with a slightly larger gantry opening to accommodate treatment
accessories. The resulting images are nearly the same quality as those
used in diagnosis, and provide images usually more than adequate for
radiation therapy planning.
CT Scan Acquisition for Treatment Planning

The volumetric CT scans are input into treatment planning, with the goal
of calculating the dose delivered at treatment. Thus, care is taken to
position the patient as he/she will be treated on the linear accelerator.
Flat treatment couches are used rather than the diagnostic scanner
curved table-tops to ensure that internal organs closely approximate
their shape and location at treatment. Treatment immobilization devices
are used during the scan. High-speed scanning reduces motion artifacts
and can capture a bolus of contrast before dissipation.
FIGURE 2.2 A: Photographic transaxial section of a human abdomen from a cadaver. B:

Corresponding CT scan (courtesy Visible Human Project).
Three-dimensional CT acquisition modes include (a) axial and (b)

helical mode. In axial mode, the patient support assembly is static an
image slice is acquired, the x-ray source is then gated off, and the couch
is advanced to the next longitudinal position. The procedure is repeated
to build a 3D image volume. In helical mode, the couch is continuously
advanced while the x-ray tube continuously rotates, leading to faster
volumetric scan acquisitions. The time to complete one rotation is ∼0.5
seconds. Tagging the x-ray longitudinal coordinate with the image
projection data and resorting as the patient advances into the gantry
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provides the information needed for helical scan image reconstruction.
A scan field of view (FOV) is selected to permit visualization of the
external skin contour, data needed for dose calculations. For sites such
as head and neck, often two FOVs are used: a smaller FOV for the neck,
and a larger FOV to fully image the shoulders. Longitudinal scan limits
are chosen to capture both the tumor extent and longitudinal extent of
organs at risk. Slice thickness of 3 mm and a total of 200 slices per
scanning study are typical in planning scans.
Convention dictates that cross-sectional images are displayed as
viewed from below; for a patient in the supine position on the table,
head first into the scanner gantry, the image left is the patient’s right
side. Icons and alphanumeric information imprinted on the scan image
provide details of pixel size, slice thickness, and radiographic parameters
used during imaging.
CT Artifacts
Artifacts can degrade CT planning studies (16). Artifacts may originate
within the patient. Beam hardening results in streaks when the photon
beam crosses particularly opaque regions, such as the bone in the
posterior fossa of the brain, or metallic fillings in teeth. Physiologic
motion can also cause streak artifacts. Intravenous or oral contract can
artificially elevate HUs. These artifacts can perturb the calculation of
radiographic path length leading to inaccurate dose calculations.
Artifacts can also originate within the scanner hardware or by choice of
imaging parameters. Partial volume sampling is an artifact resulting
from choice of slice thickness; too thick a slice influences the
detectability of small lesions. Other artifacts are introduced in helical or
cone-beam reconstructions.
Limitations of 3D Imaging of Moving Anatomy

Imaging organ motion is essential in conformally irradiating moving
targets. Quantifying motion can ensure adequate tumor coverage and
unnecessary irradiation of adjacent normal tissues. Conventional 3D
imaging of moving anatomy may result in an inaccurate depiction of
organ shape and location. A motion artifact can frequently be seen in a
thoracic CT scan of a patient breathing lightly during a scan (17). Figure
2.3 is an example of such an artifact, where the lung/diaphragm
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interface is distorted.
Phantom studies under controlled conditions illustrate this temporal
aliasing artifact (18). The first column in Figure 2.4 is a photograph of
test objects embedded in a foam block. An initial scan is taken with the
phantom stationary. Surface rendering of the scan shows life-like
realism, as seen in the second column. The phantom is then set into
motion simulating respiration, and scans are acquired in standard scan
mode. The resulting images of test objects are strikingly distorted, as
shown in the next three columns. For scale, the largest ball is 6 cm in
diameter. With a motion amplitude of 1 cm (2 cm peak to peak), this
sphere may be imaged with an inaccurate longitudinal axis dimension as
small as 4 cm. The distortion visualized is dependent on both scan and
object motion parameters as well as the respiratory phase at the instant
the imaging planes intersect the test object, which explains why
distortions vary.
FIGURE 2.3 Temporal aliasing artifacts when scanning a patient during respiration. Note distortion
at the lung/diaphragm interface, indicated by yellow.
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FIGURE 2.4 Imaging test objects in a phantom. The objects are surface rendered when the
phantom is static and undergoing respiration simulated motion. Note the geometric distortions of
the pear and balls.
4D CT Scanning
Four-dimensional (4D) CT scanning here is defined as CT acquisition at a
respiratory time scale. The objective of 4D CT scanning is to capture the
shape and trajectory of moving organs during breathing. The motion
data can then be used to design an aperture to encompass the observed
motion, or to apply motion mitigation strategies such as beam gating.
Proof of principle of 4D scanning was initially prototyped on single-slice
scanners in 2003 (19–21). A multislice 4D CT simulator system became
commercially available shortly thereafter and rapidly became the
scanner of choice for radiation therapy (22).
FIGURE 2.5 Coronal MPRs of 4D liver tumor scan. Organs move craniocaudally (yellow reference
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line) at exhale (A); at inhale (B); residual artifacts due to irregular breathing (C).
Respiration-correlated CT uses the motion of the abdominal surface,

volume of air measured by spirometry, or other respiratory surrogate
signal to correlate the respiratory state during CT acquisition of each
slice. The signals are used to re-sort the approximately 1,500 slices of
reconstructed image data to a set of coherent spatiotemporal CT data set
corresponding to specific time points of the respiratory cycle. A 4D CT
acquisition requires a few minutes, and produces 10 static CT volumes,
each with a temporal separation of ∼one-tenth of the respiratory period
(∼0.4 seconds). Details of the 4D CT acquisition methods and
applications are described elsewhere (22–24). Dose during a 4D CT scan
is approximately five times that of a conventional treatment planning
scan, although studies have shown that this may be reduced by altering
the radiographic technique without significant reduction of motion
information (25).
Figure 2.5 displays coronal images of a 4D CT scanned for a liver
tumor. The first two images represent anatomy at exhale and inhale,
showing a caudal movement of the dome of the liver by several
centimeters.
A 4D capable CT-simulator is suited for assessing organ motion at ∼1
second time scale, but has insufficient temporal resolution to image
cardiac motion. Ultrahigh-speed cardiac scanners have shown that
vessels and tumors near the heart can move by >1 cm (26) due to
cardiac pulsation.
While an important advance, 4D CT acquisition can still have residual
artifacts. Phase resorting neglects variability of lung tidal volume during
free breathing. Figure 2.5C shows an example of an artifact from phase-
based 4D CT resorting where breathing amplitude was irregular.
Respiratory variations in amplitude, periodicity, and trajectory can
perturb 4D scans. Strategies to coach breathing during 4D scanning have
included voice prompts and visual feedback but with variable success.
Physical breathing control has been attempted through abdominal
compression or active breathing control, where the patient breathes
through a regulated valve and is forced to hold his breath at a specific
respiratory phase. This interventional approach reduces the 4D problem
to a static scenario, where both imaging and treatment are performed
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with minimal motion (27,28).
Volumetric Imaging in the Treatment Room

The interest in precision radiotherapy spurred x-ray volumetric image
acquisition in the treatment room. As this topic is covered in detail in
the chapter on Image Guided Radiotherapy, we briefly cover selected
highlights of image-guided therapy.
CT scanning in the treatment room was extensively used to study
prostate and seminal vesicle volume over a protracted treatment regimen
(29). The study acquired over 360 CT scans in 15 patients at a 3-scan-
per-week rate. The patient is initially set up on the treatment couch and
CT scanned in room (with the scanner advancing along the patient’s
longitudinal axis by translating on rails). After tumor localization, the
patient support assembly is rotated into treatment position. This solution
provided a stopgap volumetric imaging capability in the treatment room
while other imaging solutions were developed and refined.
The most common implementation in use today involves adding
tomographic imaging capability to the treatment machine. Much of the
interest was spurred by investigators at William Beaumont Hospital (30).
An x-ray tube and flat panel detector are mounted orthogonal to the
treatment axis. The imaging approach is known as cone-beam computed
tomography (CBCT) because the imaging beam is divergent along the
longitudinal axis. Projection images for volumetric reconstruction are
acquired at multiple angles as the gantry is rotated around the patient in
∼1 minute. Reconstruction algorithms optimized for CBCT are used to
generate volumetric anatomical maps. While diagnostic CT scanners still
set the image quality standard, CBCT images provide clinically useful
information even in the presence of motion during acquisition, radiation
scatter, and mechanical isocenter wobble during scans. An advance in in-
room CBCT imaging was the development of 4D CBCT (31). Time-
resolved data can be obtained by sorting the acquired projection data
into different temporal bins according to respiratory motion phase in an
approach similar to standard 4D CT.
A third approach to treatment room tomographic imaging is to use the
MV treatment beam itself. The therapeutic beam serves as the radiation
source and a flat panel radiation detector to acquire image projections
(32). Although soft tissue contrast is reduced in the megavoltage CBCT
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images, there is adequate information for patient positioning. MV CT is
less susceptible to imaging artifacts due to high-density objects such as
metallic hip implants or dental fillings. As with other tomography
imaging, CBCT is affected by motion during data acquisition.
Innovative integrated imaging/treatment hardware has also been
developed. Tomotherapy (33) incorporates fundamental principles of CT
imaging into a megavoltage treatment system. IMRT is delivered slice by
slice as radiation intensity across the slice is modulated by shutters.
Rotation around the patient similar to CT acquisition produces highly
conformal MV dose distributions. An unmodulated fan beam can
generate an MVCT image before treatment for image guidance. The
Cyberknife (34) is another approach; a compact linear accelerator is
mounted on an industrial robotic arm. The robotic arm covers more
patient solid angle than a conventional linac, and enables irradiation
from noncoplanar angles. Image guidance is provided by room-mounted
x-ray tubes and digital image receptors, providing real-time 2D
fluoroscopic imaging. The system has been used to “track” motion of
tumors in the lung and abdomen by following radio-opaque markers.
Magnetic Resonance Imaging

Magnetic resonance imaging probes the body with magnetic and RF
radiation, providing a spatial map of the bulk magnetization of a voxel.
Acquisition sequences can be tailored to vary image contrast and
content. The most commonly acquired MRI scans are proton density, T1-
and T2-weighted images. T1, T2 notation refers to spin–lattice and spin–
spin relaxation times, time constant associated with nuclear magnetic
moment reorientation after excitation to an elevated energy state.
Factors that influence image appearance include the proton density
within the voxel, relaxation times, blood flow, and magnetic
susceptibility (5,6). Spin density and relaxation times of soft tissues vary
considerably depending on microenvironment, leading to images with
superior contrast resolution in comparison to CT. Figure 2.6 shows CT
and MRI scans of an abdominal scan of a patient at the same anatomical
level.
MRI contrast agents are paramagnetic materials that have unpaired
electrons, resulting in magnetic susceptibility. These materials alter the
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T1 and T2 relaxation rates. Gadolinium chelates are used as contrast
media for brain imaging when a breakdown of the blood–brain barrier is
suspected.
FIGURE 2.6 CT and proton density weighted MRI scan of patient with liver tumor, at
approximately the same anatomical level. Lesion is well visualized in the MRI due to superior soft
tissue contrast. Bone in CT (white) appears dark on MRI. Fat, due to its high hydrogen content,
appears brighter on MRI.
MRI Artifacts
Magnetic field inhomogeneity, RF field spatial distribution, and effects
associated with rapidly changing magnetic field gradients can cause
artifacts in MRI images. Artifacts due to magnetic field inhomogeneity
can result in geometric distortion, which leads to slight differences in
geometric scale along image axes. Foreign materials also result in a local
geometric distortion. On MRI, surgical clip artifacts result in loss of
signal and spatial distortion, even when the metallic fragments are
small. With patient motion, multiple ghosts in the image may appear.
Treatment planning scans using MRI must therefore pay particular
attention to geometric distortions (35,36). Phantoms may be useful to
calibrate MR scanners, but in vivo variations are difficult to correct.
Often, a CT scan is also available, and direct comparison provides a
measure of determining geometric integrity.
Target Delineation with MRI

MRI is useful in delineation of tumors and normal structures of the brain
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(35,37). In comparing CT and MRI with stereotactic biopsies,
investigations found that both CT and MRI defined gross tumor by their
contrast enhanced ring, but T2-weighted MRI detected a larger
edematous region containing infiltrating tumor.
Isotropic margins for high-grade gliomas (1 to 2 cm) are commonly
used. Diffusion tensor imaging (DTI) is an MR technique sensitive to
disruptions of white matter tracts resulting from tumor infiltration. A
current hypothesis is that such data can predict areas of potential tumor
involvement along structural pathways (37,38), increasing CTV
delineation accuracy.
Cine MRI has been used to study organ motion (39–41). Patients are
scanned every few seconds in the selected anatomical plane for up to 1
hour, during which physiologic motion in them is visualized. Advantages
of MRI over CT in studying motion include no radiation dose and direct
imaging in the plane of interest. These studies revealed information on
the range of organ motion and distortion possible over a treatment time
interval.
Functional Magnetic Resonance Imaging

Functional MRI (fMRI) reveals physiologic and neurologic activity in
contrast to structural information (42). When a task is performed,
oxygen demand in the region of the brain controlling the activity rises,
resulting in a net increase in oxyhemoglobin. Since deoxyhemoglobin is
paramagnetic, changes from increased blood flow result in changes in
the signal. Functional imaging of the brain has been used to map the
human visual system during visual stimulation, language processing
areas, and sensory and motor cortex (43,44).
If the neuropsychologic activation sites of a specific patient are
localized before treatment planning, it may be possible to avoid
irradiating these eloquent areas during focal radiotherapy. Figure 2.7A
shows an image of a patient with an astrocytoma in the left parietal
region. fMRI was used to identify an area during silent word generation,
finger movement, tactile stimulation, and other motor functions. Dose
calculations performed showed dose to certain functional areas could be
reduced (45) by shifting dose to another less critical area.
Magnetic Resonance Spectroscopic Imaging
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The dominant MR signals result from the 1H nuclei of water. Suppression
of water signals permits the measurement and analysis of other
compounds. Spectroscopy was initially limited to small regions of
interest but technology has evolved in imaging multiple voxels. For each
voxel, the MR spectrum then reveals the chemical composition.
Differences in metabolite concentrations—either observed by peak
heights or peak ratios of different peaks—can be used to characterize the
tissue. Application of MRSI imaging in radiation therapy includes
applications to characterize brain and prostate tumors (46,47).
FIGURE 2.7 A: fMRI scan showing proximity of brain tumor to eloquent areas of the brain. The
functional areas (silent word generation, motor cortex controlling finger/hand) were labeled OAR
areas and dose was optimized to spare regions. B: Metastatic lymph nodes (yellow) are mapped
on to pelvic vessels using a lymphotropic iron nanoparticle contrast agent. The prostate (green)
and seminal vesicles (gold) are also shown. Left – AP view; Right – LPO view.
An example of combining functional and spectroscopic imaging in the

treatment of brain tumors has been reported (48). This feasibility study
involved patients whose target volume was defined in part by MRSI (by
detecting voxels with a choline:creatine ratio associated with tumors)
and functional areas of the brain. This general approach was proposed
by Ling et al. (49) decades ago when the technology for studies were
evolving. The authors reported that the combination of these special
imaging procedures complemented conventional CT and MRI studies
with the potential of dose painting.
Lymph Node Visualization in the Pelvis

Nodal metastases from prostate cancer are primarily located along the
major pelvic vasculature. Defining nodal irradiation treatment portals
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based on vascular rather than bony anatomy could decrease the
irradiation of normal pelvic tissues, thereby reducing toxicity.
An experimental MRI imaging technique is visualization of lymph
nodes with iron nanoparticles. Lymphotropic nanoparticle-enhanced
magnetic resonance imaging has been shown to identify the location and
extent of the lymphatic system involved with cancer. Nanoparticles
increase contrast of the lymphatic system during optimized MRI pulse
sequences. Figure 2.7B shows lymph node distributions for prostate
cancer (50).
MRI Imaging in the Treatment Room

With MRI’s superior soft tissue imaging, it is natural to explore its
integration with treatment machines. Two devices under development
have been reported. The ViewRay System (51) employs a low field
strength MRI imaging system to provide volumetric images. Treatment is
delivered via a cobalt 60 triple headed system, capable of IMRT. Co-60
provides a nonferrous solution to avoid complexities associated with
operating a linear accelerator near a magnetic field. An alternative
approach is the union of a diagnostic MRI unit and a linear accelerator
(52).
Emission Tomography
Emission tomography probes tumor biochemistry by measuring the
biodistribution of biologically active radiolabeled pharmaceuticals.
Specific tracers can probe tumors for hypoxia, the degree of cell
proliferation, angiogenesis, apoptosis, and response to therapy. These
data complement anatomical and structural information from CT and
MRI, and may provide the data needed to identify tumor sub-volumes
for dose painting. The current status of functional and molecular
imaging for radiotherapy is described in a 2014 review (53).
Emission imaging is based on the detection of gamma rays emitted by
intravenously injected radiopharmaceuticals. Scintillators detect the γ-
rays emitted and the resulting visible light is amplified by
photomultiplier tubes. Reconstruction of these signals provides
volumetric information on the 3D and 4D biodistribution of the
administered radiopharmaceutical. In SPECT imaging, single γ-emitting
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isotopes are administered, while for PET, positron emitters are used. The
positrons annihilate nearby electrons with emission of opposed γ-rays.
PET scanners include a ring of detectors to allow simultaneous detection
of the emitted γ-rays in the transverse plane. Volumetric data sets are
acquired at several couch positions, requiring several minutes at each
position.
PET in Radiation Planning

PET is useful in staging disease and in defining the target volume. Its use
in target volume delineation in non-small cell lung cancer (54) has been
prospectively studied. Target volumes were drawn with and without the
use of PET. The most common tracer used is 18F-FDG, which identifies
regions of high glucose metabolism, often associated with tumors. In this
study, use of PET altered the treatment volume in ∼60% of cases. PET
distinguished tumor from atelectasis (CT cannot), identified nodal
disease in one-third of patients, and identified additional tumor foci.
Applications of PET in treatment planning have been studied (55,56).
Cu-ATSM is a radiopharmaceutical labeled with a positron-emitting
isotope of copper, that has been shown to identify areas of tumor
hypoxia. Identifying such regions could be used to focus an additional
boost radiation dose to control these historically radio-resistant cells.
Chao et al. (57) reported the feasibility of using Cu-ATSM in treatment
planning for head and neck tumors. By simulating hypoxic regions with
a distribution of the radiopharmaceutical localized by PET, they showed
that additional dose could be delivered by IMRT accurately after fusing
the PET data with a planning CT.
PET/CT
The role of PET in radiation oncology has increased with the
development of PET/CT scanners. A PET/CT scanner is a mechanical
union of a multislice CT scanner with a PET scanner (58). By mechanical
integration, technical image registration issues are minimized, although
data acquisition periods for the modalities differ. This significant
difference can result in ambiguities in bio-distributions that arise from
different patient positioning during scanning.
As with other tomographic imaging modalities, respiratory motion
poses a challenge to PET imaging. During the ∼20 minutes of data
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acquisition, periodic motion leads to blurring of the reconstructed
isotope distributions. Four-dimensional PET acquisition has been
reported (59,60). Data acquisition is performed in temporal correlation
to respiratory motion by labeling each detected event with the actual
motion state. Following encoded temporal data acquisition,
reconstructions are performed using temporal bins of detected events.
Imaging Response
The importance of imaging response to therapy is clear. For the
individual patient, early evidence of treatment ineffectiveness can
prompt adjustments in treatment. In clinical trials, evidence of the
effectiveness of a new agent or technique can speed its approval by
regulatory agencies. Because overall survival from a therapeutic
modality may require decades to quantify, biomarkers that indicate
response can indicate which therapeutic approaches are most promising.
Imaging both anatomical and biologic response to treatment provides a
noninvasive method to measure response. A current standard for
quantifying response is Response Evaluation Criteria in Solid Tumors
(RECIST) (61), which has been refined since its introduction 15 years
ago. RECIST applies unidimensional measurements to objectify response.
Newer quantitative methods for response evaluation (61,62) (PET,
volumetric measurements) are considered to have promise, but await
standardization and validation before widespread adoption.
Other Imaging Techniques

Projection Imaging
Thus far, the focus has been on volumetric 3D/4D image acquisition.
Two-dimensional projection imaging still has an important role in
radiotherapy. While limited in visualizing soft tissues and 3D
localization, it is useful in patient setup and quality assurance.
Simulation Images
Conventional radiographic simulators generate 2D projection images and
fluoroscopic sequences. Historically, radiation oncologists outlined the
region to be irradiated on radiographs; cerrobend blocks were fabricated
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to shield uninvolved tissues. Today, with 3D simulation, 2D simulation
workload has been reduced, and limited to simple setups (e.g., palliative
cases). A right lateral simulation radiograph for a metastatic brain lesion
is shown in Figure 2.8A. Bony anatomy and low-density areas, for
example, airways, are well visualized in projection radiography.
Typically AP and lateral images are acquired for field placement and
treatment. If more complex oblique or noncoplanar beam angles are
used, reference films still provide data useful for confirming isocenter
placement. Fluoroscopic imaging on a digital simulator produces
dynamic planar images that can be used to estimate lung tumor motion
in 2D. Conventional simulators also are used to simulate the first
treatment setup, known as a verification sim, to free linear accelerators
of lengthy first day setup.
FIGURE 2.8 A: simulator radiograph of left lateral treatment field. B: Corresponding MV port film.
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FIGURE 2.9 A: Ultrasound image to align prostate to isocenter. Contours from the planning scan
are projected onto daily ultrasound image. B: Surface imaging is used to align breast. The region
of interest (purple) on treatment day is aligned to the reference surface (acquired on first day or
from simulation). The system computes couch translation and rotation moves required to bring
surface du jour to reference surface.
Quality Assurance Images

Treatment verification images are required once per week to verify
setup. Historically, a majority of verification films were acquired
through MV planar imaging. Figure 2.8B is such an image for
verification of the port shown in the simulator film in Figure 2.8A.
Today, linacs have the flexibility to acquire verification images by 2D kV
or MV imaging or by CBCT. Critical setup verification (IMRT, SRS, SRT)
is often performed using CBCT scans on the treatment machine. Choice
of modality for QA images primarily depends on the Department’s
preference.
Ultrasound
Ultrasound imaging has been used in prostate localization for image-
guided therapy. High-frequency sound waves, in the range of 1 to 10
MHz, are generated by a piezoelectric crystal. A handheld ultrasound
probe is positioned manually over the suprapubic region. The US waves
are reflected at tissue interfaces and used to generate an anatomic image
(63). Since the position of US probe is known in the machine coordinate
system, the required correction of the target to isocenter can be
determined. A typical radiotherapy ultrasound image for prostate
alignment during external beam conformal therapy is shown in Figure
2.9A. Use of ultrasound to image the prostate prior to IMRT was a
milestone in the utilization of routine IGRT. The technique was an
improvement over laser setup and bony landmark imaging. However, as
other IGRT approaches matured, studies showed systematic differences
between US-guided setup compared to radio-opaque implanted markers
(64), leading to a shift away from its use. The skill level needed to
reproducibly identify and localize the prostate with US was also a factor.
In a 2009 study of image-guided therapy (65), approximately 20% of
radiation oncologists reported use of US in IGRT, although use over the
years has fallen.
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Surface Imaging
Video imaging to aid patient repositioning was proposed as early as
1970s (66). With digital video imaging, a 3D map of the patient surface
topology at simulation can be captured. A corresponding 3D surface
image is acquired on the treatment machine. In 3D video-guided setup,
the patient surface du jour is brought into congruence with the 3D
reference image in real time to provide setup correction. The key
assumption in surface-guided target setup is that reproducible
repositioning of external surface leads to precise subsurface target
alignment.
A 3D video generated image is shown in Figure 2.9B. In this
technology, stereo cameras view the patient during a flash exposure of a
projected speckle pattern. The system reconstructs the surface topology
to an accuracy of <1 mm (67). The surface at treatment is fitted to a
reference surface to determine the transformation needed to bring the
two surfaces into congruence. The system has been applied to the setup
of partial breast irradiation (68,69). Video also provides a nonionizing
means of patient position surveillance.
Image Processing
Acquired tomographic images undergo extensive processing to generate
new information. The data extracted from the acquired studies are
utilized to determine the size, shape, location, and motion of the target
volume relative to adjacent normal tissues. One of the most critical tasks
of image processing is image segmentation.
Segmentation Nomenclature
Image segmentation involves the process of classifying regions by
defining their boundaries. The boundaries define organs or volumes
associated with treatment planning objectives. Nomenclature is
important to ensure clear communication between members of the
treatment planning team within a department, and to facilitate
interinstitutional comparison and collaboration in clinical trials.
Nomenclature continues to evolve as more precise documentation of
delivered dose is sought (70–74).
Table 2.1 lists basic abbreviations of target and organs at risk
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originating from ICRU reports. The Gross Target Volume (GTV) localizes
the visible tumor. The Clinical Target Volume (CTV) includes a margin
around the GTV to encompass microscopic tumor extension. Planning
Target Volumes (PTV) include geometric margins to account for setup
error, tumor motion, physiologic variability (e.g., variable bladder
filling), and other uncertainties. Organs at Risk (OARs) identify radiation
sensitive structures to which dose should be minimized to avoid
collateral radiation injury. The Planning Volume at Risk (PRV) is to be
protected in dose optimization.
In an effort to more completely define volumes and sub-volumes,
groups have proposed additional nomenclature for radiation planning
(75,76). One proposal recommends additional descriptors to basic
nomenclature to simultaneously identify target and dose. For example,
PTVp1_5000 would be used to identify the planning target volume
associated with primary tumor p1, to be treated to 5000 cGy. A Level 2
node clinical target volume treated to 4,000 cGy would be denoted as
CTVn2_4000. For OARs with additional geometric expansion margins (in
case of setup uncertainty), planning organs at risk volumes (PRVs) could
be defined. For example, a left kidney could be identified as:
Kidney_L_10, denoting a 10-mm safety margin.
TABLE 2.1 Target and Normal Organ Volume Definitions
Segmentation
Volumes of interest can be segmented manually or automatically. In
manual segmentation, points are digitized by mouse on each transaxial
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CT scan and connected by a closed contour. A 3D surface is created by
tessellation. When a steep HU gradient clearly identifies a boundary,
simple threshold edge detection is used; the skin and lung/chest wall
interface are typically outlined by this method. However, threshold edge
detection fails when organ boundaries are fuzzy and indistinct, or when
an organ abuts another soft tissue. Since image segmentation is
important to many medical specialties, algorithms to perform accurate
automated segmentation have been an area of continued development in
radiology and radiation oncology as well as in computer science (77).
Newer algorithms apply more sophisticated approaches to image
segmentation. Information from anatomical atlases and databases has
been used as well as methods that apply statistical models of shape and
appearance. Studies have evaluated machine learning to teach
computers to segment. Multimodality imaging combined with image
registration can sometimes be used to enhance the performance of
automated segmentation schemes. In evaluating the efficacy and
accuracy of various automated schemes, metrics have been proposed to
compare performance with “ground truth” (78).
Segmentation variability can also be traced to the radiation oncologist,
who uses his personal experience, clinical knowledge, findings
documented in surgical notes, and other sources in addition to the
digital image data set to define the target. A study (79) involving 12
physicians were asked to delineate a tumor and target volume on five
brain tumor cases; all were given the same image data. Variations of
factors of 2 in volume and 2 to 3 cm in location were observed.
Beam’s Eye View and Digitally Reconstructed Radiographs

The segmented target and normal tissues are used to build an interactive
3D model of the patient’s anatomy. The concept of an interactive BEV
was initially proposed by McShan (80), who used planar tomography to
extract skin, lung, and internal contours. By adjusting the beam angle, it
is often possible to geometrically avoid irradiation of a critical organ.
Goitein (81) advanced the concept to contiguous volumetric CT-based
treatment planning and further proposed using digitally reconstructed
radiographs (DRRs). A DRR is generated by 3D ray tracing from the
radiation source through the volume of CT data, projecting the resulting
image onto a plane. Like a radiograph, the DRR shows bony anatomy
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and low-density anatomy (airways, lung), providing an internal anatomy
backdrop for segmented organ contours. The DRR is the reference image
against which the IGRT radiograph is compared to make final
adjustments in treatment setup. A BEV of a thoracic tumor is shown in
Figure 2.10.
FIGURE 2.10 BEV image of a thoracic tumor. Structure contours are segmented from a CT scan.
Red: primary tumor; violet: nodal areas. OARs include spinal cord (green), esophagus (yellow)
and heart (light blue). Isocenter: green crosshairs. Multileaf collimator vanes are step stair lines
within the rectangular primary jaw opening. The DRR shows bony structures and lung.
Image Registration
Image registration is the process that aligns different image data sets into
a common coordinate system. Reviews of medical image registration
have been published (82,83). We describe common approaches to image
registration and their application to radiation oncology.
Registration can be performed manually, semi-automatically, or fully
automatically. In manual registration, the user visually inspects and
adjusts images interactively, by sliding images over each other, or using
a landmark tool to define matching points. Interactive alignment in its
basic form provides image alignment with three degrees of freedom
(translation). Semi-automatic tools allow for a limited degree of
feedback from the user, such as a starting guess or an incomplete set of
matching points. Fully automated methods can generate a
transformation matrix without operator feedback, but still require
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inspection of the final alignment to validate its correctness. Ideally,
image registration defines a one-to-one mapping between the
coordinates of points in one space with a corresponding point in the
second space.
An important use of image registration is in multimodality imaging for
target delineation. Tumor extent may be more visible on MRI, but needs
to be accurately mapped into the CT coordinate system for treatment
planning. Anatomic and fMRI or PET volumes can also be defined and
mapped onto CT scans for planning. Strategies for daily IGRT also rely
on image registration to bring the planned treatment and daily setup
into alignment. Correlation of multiple serial scans of a patient provides
data on movement of internal organs needed to determine appropriate
portal margins. The variation of prostate and seminal vesicle position
during the course of fractionated external beam therapy (84–86) through
serial CT data sets first requires the serial CT coordinate systems to be
aligned relative to each other.
Automated Image Registration

In fully automatic image registration approaches, the user does not
digitize landmarks or contours, or interact with data. The images
themselves provide the necessary information. Automatic image
registration methods are characterized by a transform and cost function.
The transform defines the nature of the mapping between spaces, and is
either linear (i.e., pure translation, rigid, and affine), or nonlinear (B-
spline or free-form). The cost function is a score that defines the relative
quality of a match. The best transform for a given cost function is
selected using an optimizer that searches for the best match.
Automated image registration in radiation oncology often utilizes
maximization of mutual information (or the converse—minimization of
entropy). The utility of mutual information is based on the intuitive
assumption that while corresponding anatomical regions may have
different distributions of intensities in different imaging modalities, the
relationship between those intensities is predictable and consistent. For
example, bony anatomy is bright in a CT scan but dark in MRI; therefore
one could map very bright regions in a CT scan onto very dark regions in
MRI. Mutual information implicitly extends this idea to every location in
the image through its mathematical definition in terms of the joint
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probability density function of the matched images.
To illustrate how the joint probability distribution can characterize
image matching, consider the simplified illustration shown in Figure
2.11A, where a volumetric CT scan and MRI scan of the same patient’s
brain are to be matched. In this example, we assume there are only four
tissue types: air, bone, brain, and fat. Air is dark on both MRI and CT;
bone is bright on CT scan and dark on MRI; brain and fat are of
intermediate intensity in both modalities but their relative intensities are
reversed. Brain is brighter on CT and fat is brighter in MRI. Assume
further that there is only one intensity value associated with each tissue
type. If the entire 3D image volumes were perfectly registered, then
every bone CT voxel would map onto a bone MR voxel, brain onto brain,
and so forth. We construct a joint histogram of the CT and MR intensities
in Figure 2.11B, where each point on the plane represents a single
combination of CT and MR intensity. The histogram would contain zeros
everywhere except at the four points corresponding to (CT bone, MR
bone); (CT brain, MR brain); (CT air, MR air); and (CT fat, MR fat).
If the image volumes were to become slightly misaligned, some CT
bone voxels would map onto MR brain voxels, introducing another peak
in the joint histogram. Some MR bone voxels would likewise map onto
CT brain voxels, introducing yet another peak. In fact, some voxels from
each of the four CT tissue classes could map onto all four MR voxel
classes, leading to potentially 16 different peaks. Thus the effect of
misalignment is to reduce the sharpness of the joint histogram. The
sharpness of such a distribution can be expressed in terms of its entropy.
The details of the mathematics are covered elsewhere (87–89). Here we
state that when the images are perfectly registered, knowing that a voxel
has the bone value in the CT scan means that the corresponding voxel in
the MR scan will have the MR bone value, with no uncertainty. In this
case, the entropy would be low and the mutual information would be
high. The search for the optimal transformation involves minimizing this
score. Mutual information and its variants have been used to register CT,
MRI, PET, SPECT, and various 2D images (anatomic and functional,
radiographic, and photographic) with themselves and with each other.
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FIGURE 2.11 A: CT and MRI brain scan to be automatically registered. B: Joint intensity
histogram of simplified CT and MRI volumes when perfectly registered. Image intensities for four
tissues considered: air, bone, fat, brain. Misregistration of the scans broadens peaks in histogram.
Deformable Image Registration

An advance of image registration is the development of deformable
image registration (DIR). Applications of DIR include registration of
interfractional patient scans (where scans on different days may show
organ shift and deformation), intrafractional registration (at respiratory
time scale), and multimodality image registration. An overview of DIR
for radiotherapy applications can be found elsewhere (90). Recently a
test data set representing ground truth was used to evaluate and validate
the accuracy of various approaches to DIR (91). The best performing
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algorithms mapped landmarks to within a few millimeters of ground
truth.
A useful application of DIR is the segmentation of organs in 4D CT
data, which is impractical without significant computer assistance. With
DIR, it is feasible to propagate contours of organs from one respiratory
phase to another. Figure 2.12 shows such an example. In this example,
the liver was segmented by the physician on the T30 respiratory phase.
To study organ deformation and perform 4D dose calculations, it is
necessary to contour the liver on all 10 phases, a tedious task if
manually performed. With DIR, the vector mapping of each voxel from
one phase to all other phases is calculated. This transformation may then
be applied to the voxels that define the contour, to map the organ
outline to other phases. There are some small discrepancies, but most
contours are acceptable. Editing can be performed to the propagated
contours as needed. A full set of 3D contours at each phase permits
calculation and quantitative assessment of organ trajectories.
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FIGURE 2.12 Four-dimensional liver segmented by deformable registration. The liver was
manually contoured in 3D at T30 respiratory phase; deformable registration was applied to map at
the segmented contours to all other respiratory phases. Accuracy is best near T30, with a few
millimeter inaccuracies at phases farther from reference phase.
Volume Visualization
An alternative to ring-stack or surface display of anatomy is volume
visualization, initially described in the computer science literature (92).
In volume rendering, the opacity and hue of a voxel of the 3D image
data set can be interactively set to be a function of its CT number.
Volume-rendered displays have been used in treatment planning for
radiotherapy (93) and in radiology (94).
Figure 2.13 is a volume rendering of CT data. The image is of a patient
with a lung tumor, and the data rendered are from a high-quality
treatment planning scan (0.5-mm slice thickness, 256 slice scanner).
Low-density lung parenchyma is rendered transparent, and the
tracheobronchial tree is visualized along with bony anatomy. The
visualization software used displays regions of high gradients in HU that
essentially display interfaces. Therefore, the contents of organs (e.g.,
heart) are not visible.
An advantage of volumetric visualization in radiotherapy planning is
that this technique can display anatomic detail not normally segmented.
Nerves, vessels, and lymph nodes are difficult to identify and laborious
to segment on axial cuts. Yet these structures often may be directly seen
in a volumetric rendering from a selected BEV. The hypothesis is that
visualization of these structures may help in aperture design of the
clinical target volume.
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FIGURE 2.13 Volume visualization of a lung tumor: Lung parenchyma is rendered transparent.
The tracheobronchial tree is visible as are surface interfaces of bony anatomy and mediastinum.
Scan: 1-mm slice thickness performed on a 256 slice CT scanner.
FIGURE 2.14 Prototype visualization combines 4D volume rendered CT data with additional
quantitative parameters overlaid. Key: Brown-longer RPL; Green-shorter RPL. (A) The skin
surface with overlayed radiological path length color map from skin to distal PTV. The skin
surface/air interface is selected for display in grey level. The image can be animated to show RPL
variation during breathing. B: Left anterior oblique view indicates internal RPL between the chest
wall/lung interface and the proximal surface of the PTV. The brown region indicates the beam
grazes heart, leading to an undesirable steep compensator gradient. C: Changing to a more
oblique angle avoids this, resulting in more uniform compensator geometry. D: Overshoot image,
the amount by which each ray at chosen beam angle overshoots the distal PTV during respiration.
Green indicates overshoot is <3 mm. Dark brown areas indicate greater overshoot (>1 cm) as the
tumor moves during respiration. PTV includes upper airways, which also move during respiration,
resulting in beam overshoot. Visualizations help quantify variation of beam penetration in dynamic
situations.
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The difficulty of volume visualization is that so much anatomy,
including overlying tissues, is visualized, and some are not relevant to
the planning task. Methods to display only the relevant anatomy from a
given beam perspective are needed. Interactive tools capable of
selectively peeling away tissues obscuring the volume of interest must be
incorporated into these techniques to reveal the volumes of interest.
Scientific Visualization Challenges

We can be easily overwhelmed with the gigabytes of multimodality
image data generated by 4D volumetric images. Additional data arise
from dosimetric and imaging data in the course of treatment planning
4D dose, image-guided treatment, and follow-up. The challenge we face
is articulated by Johnson (95), who addressed the major unsolved
problems in scientific visualization. Several of the unsolved problems are
relevant to visualization of radiotherapy image data, including
(a) visualization of uncertainty, (b) displaying time dependent data sets,
(c) visualizing multidimensional data (beyond 4D anatomy, dose, etc.),
and (d) quantitatively establishing the value of scientific visualization to
decision making.
We provide an example of how advanced visualization techniques
might be used in radiation oncology. One possibility is interactive
display of 4D anatomy overlaid with quantitative data. Because charged
particle beam therapy is particularly sensitive to inhomogenities, we use
a 4D CT data set to illustrate features of a quantitative n-dimensional
visualization problem (96). Figure 2.14 shows a series of images to
extract hidden information and display it in an intuitive way. Consider
the need to understand the radiological pathlength (RPL) associated with
proton irradiation of a lung tumor. As detailed in the caption, we use
volume rendering on the fly to quantify the RPL changes during 4D
motion of a lung tumor, and explore how graphics and visualization can
aid in extending the BEV concept beyond geometric relationships. The
quantities we wish to ultimately display not only include RPL as a
function of BEV, but treatment uncertainty.
KEY POINTS
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• Multimodality volumetric imaging is the basis of modern
radiotherapy. Imaging modalities provide not only
geometric/anatomic information for treatment planning and delivery,
but important information on organ function and tumor physiology
that may be useful in designing the target and avoiding critical
structures.
• Data sets undergo extensive image processing, including
segmentation, building 3D/4D models of the patient. The
anatomical representations provide insight into beam portal design
to optimize dose delivery.
• Images are becoming an integral part of target alignment,
especially for conformal treatments that promise high conformality
of dose (IMRT, charged particle therapy, stereotactic radiosurgery).
Daily target confirmation is becoming more common.
• With vast amounts of image data available to the radiation
oncologist, new approaches to segmentation and display are
needed. Some possibilities include volume rendering in real time
and powerful graphics for scientific visualization.
QUESTIONS
1. Which of the below provides information to estimate the electron
density of each voxel needed for dose calculations?
A. MRI
B. Ultrasound
C. CT
D. SPECT
E. None of the above.
2. Functional MRI is used to locate cognitive and eloquent areas of
the brain. The detection mechanism involves measuring which of
the following?
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A. Proton density
B. Reflectivity of RF from interfaces
C. Attenuation coefficient
D. Oxygen in hemoglobin
E. SUV
3. PET has been used to determine tumor hypoxic regions through
which of the following?
A. Measurement of SUV
B. Using 18F-FDG
C. Cu-ATSM
D. Electron spin resonance.
4. Organ motion over an 1-hour interval is best measured through
which of the below types of imaging?
A. MRI
B. CT
C. PET/CT
D. Cone-beam CT
E. Fluoroscopy
5. Which of the following best completes this statement: Image
registration by maximization of mutual information
A. involves defining corresponding points and surfaces to be
matched.
B. involves interactive image alignment.
C. minimizes entropy.
D. is only applicable to deformed organs.
E. is not clinically used.
ANSWERS
1. C
2. D
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3. C
4. A
5. C
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graphics. Br J Radiol. 1979;52:478–481.
81. Goitein M, Abrams M, Rowell D, et al. Multidimensional treatment
planning: 2. Beam’s eye view, back projection, and projection
through CT sections. Int J Radiat Oncol Biol Phys. 1983;9:789–797.
82. Maurer CR, Fitzpatrick JM. A review of medical image registration.
In: Maciunas RJ, ed. Interactive Image Guided Neurosurgery. Park
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Ridge, IL: AAN; 1993:17–44.
83. Maintz JB, Viergever MA. A survey of medical image registration.
Med Image Anal. 1998;2:1–36.
84. Beard CJ, Kijewski P, Bussière M, et al. Analysis of prostate and
seminal vesicle motion: implications for treatment planning. Int J
Radiat Oncol Biol Phys. 1993;27(Suppl 1):136.
85. Roeske JC, Forman JD, Messina CF, et al. Evaluation of changes in
the size and location of the prostate, seminal vesicle, bladder and
rectum during a course of external beam radiation therapy. Int J
Radiat Oncol Biol Phys. 1995;33:1321–1329.
86. Melian E, Mageras GS, Fuks Z, et al. Variation in prostate position
quantitation and implications for three-dimensional conformal
treatment planning. Int J Radiat Oncol Biol Phys. 1997;38(1):73–81.
87. Wells WM, Viola P, Kikinis R. Multi-modal volume registration by
maximization of mutual information. Second Annual Int Symposium
on Medical Robotics and Computer Assisted Surgery. John Wiley &
Sons; 1995:55–62.
88. Viola P. Multi-modality image registration by maximization of
mutual information. 1995.
89. Pluim JP, Maintz JB, Viergever MA. Mutual information based
registration of medical images: a survey. IEEE Trans Med Imaging.
2003;22(8):968–1003.
90. Sarrut D. Deformable registration for image-guided radiation
therapy. Z Für Med Phys. 2006;16(4):285–297.
91. Sharp G, Peroni M, Li R, et al. Evaluation of Plastimatch B-Spline
Registration on the EMPIRE10 Data Set. Massachusetts General
Hospital; 2010. http://empire10.isi.uu.nl/staticpdf/article_mgh.pdf.
92. Drebin R, Carpenter L, Hanrahan P. Volume rendering. Compu
Graph. 1988;22:65–74.
93. Pelizzari CA, Ryan MJ, Grzeszczuk R, et al. Volumetric visualization
of anatomy for treatment planning. Int J Radiat Oncol Biol Phys.
1995;34(205–212).
94. Kuszyk BS, Ney DR, Fishman EK. The current state of the art in
three dimensional oncologic imaging: an overview. Int J Radiat
Oncol Biol Phys. 1995;33:1029–1040.
95. Johnson C. Top scientific visualization research problems. IEEE
Comput Graph Appl. 2004;24(4):13–17.
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96. Milos Hasan. Shadie: A Domain-Specific Language for Volume
Rendering. Boston, MA: Massachusetts General Hospital; 2010.
miloshasan.net/Shadie/shadie.pdf.
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3 Treatment Simulation
Dimitris N. Mihailidis and Niko Papanikolaou
INTRODUCTION
Treatment planning is one of the most crucial processes of radiotherapy,
through which the most appropriate way to irradiate the patient is
determined. The process is composed of several important steps, such as:
1. Reproducible patient positioning and immobilization;

2. Accurate identification of the location and shape of the tumor and
neighboring critical organs;
3. Selecting the most appropriate beam arrangement;
4. Computing the doses to be delivered and evaluation of resulting dose
distributions;
5. Transfer of the treatment planning information to the treatment
delivery system;
In today’s radiotherapy, 3-dimensional (3D) patient anatomy

visualization and target definition enables planning to conform the dose
to the target volume, delivering as high doses as possible, while avoiding
the critical organs. In order to achieve this, a process called treatment
simulation is necessary to be performed. In essence, treatment simulation
is a combination of, or requires that steps 1 to 3 (mentioned above) have
been performed successfully. There are several ways to perform a
simulation, each with a different level of complexity. The most common
ones are:
1. When clinical treatment volume can be determined via simple
radiographic and fluoroscopic images from a traditional radiotherapy
simulator (1), sometimes called the anatomical approach (clinical
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setup).
2. When only a limited number of transverse computed tomography (CT)
images are used for the target delineation along with radiographic
planar images (as above) in order to complete the treatment planning,
sometimes called the traditional approach.
3. When simulation can be performed on a CT scanner via a special
computer software that provides a full 3D patient representation in
the treatment planning position, a process called CT-simulation. Then,
a complete treatment planning strategy can be designed, a process
referred to as virtual simulation (1,2).
Radiotherapy simulation is a very important process on which
treatment planning and treatment delivery depend and are based on.
The accuracy of the entire radiotherapy treatment can be influenced by
the quality of treatment simulation on a patient-per-patient basis.
SIMULATION METHODS
Treatment simulation can also be thought of as a “feasibility study” of
the patient treatment strategy. Technologic advances of medical imaging
and computing have brought great improvement to the simulation
process and limitless capabilities.
We will describe the three most common methods of radiotherapy
simulation today, which strongly depend on the treatment strategy that
will be followed for the patient.
Simple Simulation—Anatomical and Traditional Approach

When the patient is necessary to be prepared for treatment in a short
amount of time, or there is a simple treatment to be delivered, a
conventional simulation can be performed. In this case, a radiographic
simulator, which actually operates in both the radiographic and
fluoroscopic mode, is used (Fig. 3.1A,B). It is an apparatus that uses a
diagnostic x-ray tube with an image intensifier (Fig. 3.1C) but duplicates
the radiotherapy treatment unit in terms of its geometric, mechanical,
and optical properties (3–5).
The patient is set up and immobilized on the simulator the same way
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that she will be treated in the treatment unit. The clinical borders of the
treatment area are marked on the patient skin by the physician and
radio-opaque markers are placed on skin on these borders. The selection
of the treatment isocenter is done via fluoroscopic imaging of the area,
typically with two orthogonal reference views, anterior (AP) and lateral
(LAT) (Fig. 3.2). Upon selection of the isocenter, two orthogonal
radiographic films (or digital images) are produced for further use and
comparison with the treatment setup, and documentation purposes.
Then, the beams that will be used for treatment are simulated in order to
be geographically optimized, depending on the treatment site, by
selecting gantry and collimator angles, treatment field sizes, and so
forth; all in relationship to externally placed markers and internal bony
landmarks. A crucial step is the proper marking of the patient, like the
isocenter (as a “3-point” marking) and alignment skin marks using the
simulator laser system in all planes. At the same time, other necessary
information is collected to be used for setup and dosimetry, such as
source-to-surface distances of the simulated treatment fields, patient
thickness, determination of the time-set or monitor unit calculation point
relative to the isocenter (if half-blocked or heavily blocked fields are
used, as in Figure 3.2), simple contours of the patient surface (with
contour-makers) through points of dosimetric interest, and evaluation
data for bolus or compensator.
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FIGURE 3.1 Typical radiotherapy simulator. Patient setup represented by a phantom (A), room
view (B), and geometric diagram (C).
Some simulators have a tomographic attachment (simulator-CT) that

analyzes and reconstructs the images from the image intensifier using
either analog or digital processing (6). The quality of the reconstructed
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image is inferior to the CT-based simulation. However, it is adequate for
acquiring patient contours and identifying bony landmarks. The
simulator-CT does provide a volumetric reconstruction of the patient’s
anatomy and as such could be used as a basic image data set in
treatment planning. The reduced spatial resolution of such volumetric
imaging renders this technique unsuitable for high precision conformal
radiotherapy planning where a series of many thin slices is required for
detailed volume reconstruction (7,8).
FIGURE 3.2 Typical simulation portal, lateral view for a head and neck treatment. The blocking is
represented by the black marker outlines on the film and the prescription point is denoted as “Calc
Point,” which is off-axis related to the half-blocked central-axis.
Interestingly, the concept of simulator-CT has recently re-emerged and

is referred to as cone beam CT (CBCT). Cone beam imaging is currently
used in the context of image-guided radiotherapy (IGRT) for daily
patient localization and setup verification prior to treatment. Those
images could also be used for patient re-planning in the context of
adaptive radiotherapy, although for the time being this is only a research
application. However, it is expected that once the image quality,
imaging dose to the patient, and the speed of re-planning improve, the
CBCT adaptive radiotherapy will become an integral part of advanced
radiotherapy.
CBCT imaging can be obtained using the kV imaging system of a linac
(Varian, Elekta) or the MV beam itself (Tomotherapy, Siemens).
Regardless of the implementation, CBCT is similar to and suffers from
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the same characteristics as the simulator CT.
Verification Simulation
This is a simulation approach “positioned” between the previously
described approach and the virtual simulation that will be described
next. This process starts by immobilizing the patient in the treatment
planning position with all the necessary devices, this time on the CT
scanner flat table-top. In this case, there is no laser localization system
available in the CT room. A standard treatment planning study of the
patient will be obtained throughout the clinical area, after radio-opaque
markers are placed by the physician on the patient’s skin. The simulation
team will need to place “3-point” tattoos or another type of long-lasting
markers on the patient’s skin. For CT purposes, the “3-point” locations
and the treatment area borders will be visible on the CT images. Patient
scans are typically obtained in an axial mode, 3 to 5 mm slice thickness.
Smaller slice thickness can be used for small areas, when higher
resolution and accuracy are necessary.
The CT images are reviewed and then imported to a treatment
planning system where a computer simulation will be done off-line. The
physician will define the volumes of interest and the isocenter might be
adjusted to accommodate the target volume extensions. The coordinates
of the treatment isocenter can be referenced to the original “3-point”
location marked in the CT room. Next, the remaining treatment planning
process is completed and the plan gets finalized. Two orthogonal (AP &
LAT) digitally reconstructed radiographs (DRRs) (9,10) will be produced
at the original CT point and the new isocenter (Fig. 3.3). DRRs of the
treatment fields will also be produced.
A verification simulation is scheduled in the conventional simulator,
where the patient is immobilized and set up again in the treatment
planning position. The patient is then simulated according to the
approved treatment plan. A sample simulation form is shown in Figure
3.4, where all the appropriate shifts from the original CT marks to the
final isocenter are implemented. An orthogonal set of setup ports, first at
the original CT point (“3-point” mark) and then at the treatment
isocenter, will assure the proper localization when compared to the
DRRs at the same locations. The patient will be marked appropriately to
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insure reproducibility of setup during treatment. Further on, additional
ports of the treatment fields can be obtained to increase the accuracy of
the simulation setup and for documentation purposes. The orthogonal
and treatment ports will be compared to portal images or portal films in
the treatment room, especially on the first day of treatment. A diagram
of the verification simulation process is shown in Figure 3.5A.
CT-Simulator and Virtual Simulation

This is an exciting development in the area of simulation because it
converts a CT (or other scanning modality) scanner into a simulator
(1,2,11–13). Both patient and treatment unit are virtual, the patient
being represented by CT images and the treatment unit by model beam
geometry and expected dose distributions. The simulation film is
replaced by the DRRs. The DDRs are generated from the CT scan data by
mapping average CT values computed along lines drawn from a “virtual
source” to the location of the “virtual film.” A DRR is essentially a
calculated port film that serves as a simulator film, which contains all
the useful anatomical information of the patient (Fig. 3.6). A dedicated
radiation therapy CT scanner, with the above described virtual
simulation software and simulation accessories (e.g., flat table-top,
immobilization devices, etc.), is called a CT-simulator (Fig. 3.7A). In
addition, CT-simulators are equipped with high-precision movable laser
systems to mark the isocenter location on the patient during the virtual
simulation process. The laser system is mounted on fixed pedestals on
the floor and ceiling as shown in Figure 3.7B.
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FIGURE 3.3 Breast patient CT image with two orthogonal reference fields on the treatment
isocenter-GREEN point (A), 3D reconstruction of the patient imaged area with the reference field
(B), LAT-reference field to the treatment isocenter (C), AP-reference filed to the isocenter (D). The
RED-point is the original CT point.
Modern radiotherapy CT-simulators are based on the most recent CT

scanner technology with multislice (multidetector) detector technology,
axial and helical scanning mode capabilities, rapid CT acquisition time,
and high-image quality performance and wide bore (>75 cm diameter)
to accommodate the patient immobilization devices. Further on, an
option called gating allows the scanner to perform “motion-correlated”
scanning, a process called 4-dimensional (4D) CT (the fourth being the
time information), useful for accurate treatment planning on moving
anatomy (e.g., respiratory motion in lung). The standard linear
accelerator (linac) requirements for large weight capability (up to 450 to
600 lb load), small sag (<2 mm), and hard table-top apply for CT-
simulators, too.
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A diagram that describes the CT-simulation and virtual simulation
processes is shown in Figure 3.5B.
CT-Simulation Process
The patient is immobilized on the CT table and in the treatment
planning position. At this initial stage, all special immobilization devices
(e.g., head and neck masks, pelvic shells, breast boards, etc.) are
required to be constructed and/or utilized, in order to be included in the
CT image study of the patient. These devices can be indexed on the CT
table top, the same way that later on will be indexed on the linac
treatment table (Fig. 3.8A–C). Additional planning modifiers, such as
skin bolus are also required to be included. The borders of the clinical
area marked by the physician on the patient can be outlined with CT
radio-opaque markers (Fig. 3.8C). Sometimes, initial reference skin
marks are placed in the middle of the clinical treatment area. The CT
movable lasers are used to define and mark the CT reference point on
the patient.
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FIGURE 3.4 Sample in-house simulation form for breast setup. Note the setup instructions and
appropriate shift information from the “3-point” computed tomography (CT) mark to the treatment
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isocenter. Detailed information on the treatment fields are entered in the table below. This form
can also be used for verification simulation.
A set of anterior and lateral topograms (“scout views”) will assist the
patient alignment on the CT table. The patient will be scanned based on
a preset protocol according to the disease site and the images will be
stored for virtual simulation, while the patient remains on the CT table.
FIGURE 3.5 Verification simulation process diagram (A) and computed tomography (CT)
simulation process (B).
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FIGURE 3.6 Virtual simulation as part of computed tomography (CT) simulation for a lung patient.
The user can visualize the anatomical information that will assist appropriate placement of points,
such as the treatment isocenter and the fields. In addition, tumor and other critical volumes can be
outlined at this stage. This information will be eventually transferred to the treatment planning
system.
FIGURE 3.7 A: A large (wide) bore CT-simulator accommodates the majority of immobilization
devices to be included in patient setup. B: A room view of a CT-simulator with the localization
laser system.
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FIGURE 3.8 Patient immobilization devices as integral part of computed tomography (CT)
simulation process for radiotherapy. A head and neck head holder and mask (A), indexing
grooves for the immobilization devices on the table top (B) and a breast patient on a breast board
with reference CT radio-opaque markers ready to be CT-simulated (C).
Virtual Simulation Process

There are three tasks that pertain to virtual simulation. First is the
treatment isocenter localization, which is typically placed at the
geometric center of the treatment volume; the second is the target and
critical structures volumes delineation; and the third is to determine the
treatment beam parameters via beam’s-eye-view (BEVs) (14) using
DRRs, including gantry, collimator and couch angles, field sizes,
shielding block, and so forth. This last part can also be performed at a
later time during the treatment planning and isodose computation
process.
The CT images will be utilized to render a 3D view of the patient
which will allow the more precise localization of the isocenter and later
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on, more efficient placement of the treatment fields (Fig. 3.9). The
isocenter will be marked on the reconstructed patient anatomy and two
reference fields (typically an AP and a LAT) will be assigned at that
point. The DRRs (Fig. 3.10) of the reference fields will be compared with
the equivalent port films later on, the same way simulator films have
been used at the past. Having determined the isocenter, the patient is
marked with the assistance of the movable lasers, one anterior and two
lateral marks on each side of the “3-point.” Shifts between the original
CT reference marks and the isocenter marks should be logged in the
patient’s chart.
At this stage, the patient can be removed from the CT table. The rest
of the virtual simulation process can be performed off-line via the special
simulation software or the treatment planning system software.
Connectivity between the CT scanner’s computer system and the
treatment planning computer is essential to be evaluated and tested by
the physicist on a frequent basis (13). Image format standards such as
DICOM (15) and DICOM-RT (16) (developed especially for radiation
therapy) transfer protocols between imaging devices, and the treatment
planning computer are the industry standard. One needs to keep in mind
that DICOM-RT transfer protocol can be highly complex to implement
and vary in interpretation from one manufacturer to another.
In the treatment planning system, the patient’s CT study and CT-
simulation information (reference marks, points, reference fields, etc.)
should be available for potential registration or fusion with other
imaging modalities (other CT studies, MRI, PET, etc.) that the patient
might have gone through (Fig. 3.11). The information provided by the
multiimaging studies will allow the physician to outline target and other
volumes more accurately.
Starting from the reference marks and setup ports, the treatment
isocenter is typically selected at the center of the treatment area.
Relative shifts of the isocenter from the reference CT marks are
monitored for subsequent patient setup, as described above, and shown
in Figure 3.12. The physician will outline the target areas and other
critical structures in a slice-by-slice process and will review the 3D
representation of these volumes in three major views (axial, sagittal, and
coronal). Delineation of target and critical organs is an extremely time-
consuming process, in most clinical cases. Progress has been made
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toward computer-assisted automatic contouring, pattern recognition, and
auto segmentation (17). Figure 3.13 compares manually outlined and
auto-segmented heart volumes. However, the basic problem remains that
target delineation is inherently a manual process, since the extend of
target depends on tumor grade, stage, and patterns of spread to adjacent
structures. Clinical evaluation of the contouring results by a radiation
oncologist provides the final judgment in defining the target volume.
FIGURE 3.9 Virtual simulation based on 3D reconstruction allows accurate placement of

treatment fields (top-right). In this brain treatment, for example, two lateral (top-left and bottom-
right) and a vertex (bottom-left) treatment field shaped by multi-leaf collimators (MLCs) are
shown.
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FIGURE 3.10 Isocenter placement during virtual simulation, based on reconstructed planes (top)
and orthogonal digitally reconstructed radiographs (DRRs) (bottom) for a head and neck
treatment.
With all the volumes (targets and critical structures) approved by the
physician, the treatment planning team can initiate the selection of the
appropriate treatment fields via BEVs and 3D reconstruction of internal
geometry of the patient (Fig. 3.9). Keeping in mind the clinical and setup
margins to the tumor volume, as defined by the ICRU (International
Commission on Radiation Units and Measurements) (18,19), appropriate
blocks with multileaf collimators (MLCs) can be used for 3D conformal
treatment planning. It is important to remember that each beam has
physical penumbra where the dose varies rapidly and that the dose at
the edge of the field is approximately 50% of the center dose. For this
reason, to achieve adequate dose coverage of the target volume, the field
penumbra should lie sufficiently beyond the target volume to offset any
uncertainties in PTV. Beam apertures can be designed automatically or
manually depending on the proximity of the critical structures and the
uncertainty involved in the allowed margins to the target volume (Fig.
3.14). Clinical judgment is frequently required between sparing of
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critical structures and target coverage.
FIGURE 3.11 Multiimage registration for a brain patient. MRI and CT are aligned and fused in all
three major views: axial, sagittal, and coronal. This allows the user to outline volumes that are
visualized in MR images onto the CT images and proceed with treatment planning.
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FIGURE 3.12 A diagram showing the relative shifts from the reference computed tomography
(CT) marks to the treatment isocenter. Visualization of internal body structures are essential in this
process.
All possible gantry, collimator, and couch angles can be evaluated

based on target coverage and avoidance of critical structures. Some
commercial planning systems provide software-assisted beam geometry
parameter optimization (20,21) which is important for highly conformal
treatment plans. Beam directions that create greater separation between
the target and critical structures are generally preferred unless other
constraints such as obstructions in the beam path or gantry collisions
with the treatment couch or patient preclude those choices.
Alternatively, dose–volume objectives for the target volume and critical
structures can be employed to produce an inversely optimized plan, with
the majority of commercial planning systems being capable of providing
inverse planning optimization algorithms (22). Final dose computations
take full advantage of CT-electron density information in order to
account for tissue inhomogeneities (23). The virtual simulation process
smoothly makes a transition into treatment planning and the treatment
evaluation stage, which is beyond the purpose of this chapter.
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FIGURE 3.13 Subsequent CT axial images. Compare the heart volume that has been manually
outlined (BLUE-line) and the result of auto-segmentation (GREEN-line).
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FIGURE 3.14 A field shaped around the prostate with specific margins using multi-leaf collimators
(MLCs). The BEV view (left) and the axial view (right).
A few points of precaution are in order when virtual simulation is

performed.
• Due to precise visualization of internal organ and target volumes, one

might be misled to use arbitrary small margins to the target volume in
a feeling of false confidence. Thus, other important effects such as
patient setup and target motion might not be taken into account in a
proper way, since patient and organ motion is not well visualized by
traditional 3D virtual simulation. In the absence of 4D CT imaging, an
additional fluoroscopic study, in a traditional simulator, might be of
great benefit to treatment planning, especially for moving targets such
as lung.
• The spatial resolution is generally limited by the spacing of the axial
images. Thus, within the target area it is required that smaller scanning
spacing (typically 2 to 3 mm) is used while a larger spacing (typically 1
to 2 cm) can be used further from the area of interest. One needs to
keep in mind that this will affect the quality of the reconstructed DRRs.
• Limitation of CT imaging in visualizing all treatment sites can influence
the clinical target volume (CTV) design; in other words, CT imaging do
not always provide the best method to visualize microscopic disease.
Most commonly, in the case of brain tumors, CT imaging cannot
provide clear borders of the disease. The clinician needs to keep in
mind that combination (image registration process) of the treatment
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planning CT with other modalities, such as MR or PET, will allow a
more accurate delineation of the target volume. It is important to
remember that the ability to precisely conform to a target volume has
limited value if the target is not determined accurately.
4D CT-Simulation Process
Modern CT scanners are capable of providing a high-resolution
volumetric reconstruction of the patient’s anatomy. Each image voxel
has a characteristic CT number that is uniquely related to the electron
(or mass) density of that voxel. The density information is used in the
computation of dose and accounts for the effects of tissue inhomogeneity
in treatment planning. When the anatomy that is imaged is mobile
(tumor and organs move during the imaging study due to cardiac or
respiratory motion), the image data are subject to motion artifacts.
Consequently, the resulting volumetric reconstruction of the patient is a
blurred representation of the true patient anatomy. In addition, motion
artifacts will result in erroneous CT numbers and electron density values
in the vicinity of the mobile anatomy. It is therefore important to
minimize any motion artifact as it impacts not only the image quality
and the specificity by which we can resolve anatomical changes, but also
the accuracy of the calculated dose in treatment planning.
There are three different types of motion artifacts that we can observe
during a CT acquisition (24):
• If the CT scanning speed in the superior–inferior direction is much less

than the tumor motion speed, then we observe a smeared image of the
tumor.
• If the CT scanning speed is much faster than the tumor motion speed,
then the tumor position and shape are captured on the image at an
arbitrary phase of the breathing cycle.
• If the CT scanning speed is similar to the tumor motion speed, then the
tumor position and shape can be significantly distorted.
It is evident that patient motion can cause significant artifacts during

3D CT imaging (25,26), which not only degrade the image quality and
our ability to delineate anatomical structures (27), but sometimes can
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even simulate the presence of disease (28). Figure 3.15 illustrates image
artifacts that are caused by superior–inferior motion during conventional
CT imaging of a test sphere (29).
FIGURE 3.15 Illustration of image artifacts that are caused by superior–inferior (SI) motion during
3D CT imaging. A: CT coronal section of a static sphere. B: CT coronal section of the same
sphere in oscillatory motion (range, 2 cm; period, 4 seconds) (29).
Ritchie (30) proposed a high speed (fast) scan to avoid motion

artifacts that was of limited success with the third-generation CT
scanners. The use of multislice technology (31) has significantly reduced
motion artifacts in CT images when acquired in fast scanning mode.
However, fast scans, although less susceptible to motion artifacts, do not
portray the full extent of motion of the tumor and are therefore not of
clinical use in treatment planning of mobile tumors. Multislice helical
scanning, on the other hand, can be used with a 4D CT scanning
protocol and reduces the overall scanning time while achieving the goal
of capturing the temporal position of the tumor in the imaging study.
When we consider the organ motion, we have to choose an imaging
technique that will minimize motion artifacts during the CT simulation.
Several methods have been proposed to address this problem, including:
• A breathhold CT simulation, where the patient is instructed to

voluntarily hold his breath while the scanning beam is turned on. A
similar result can be achieved using the active breathing control
technique (ABC) proposed by Wong et al. (32).
• A slow CT scan where axial images are acquired at a speed of 4 seconds
or slower per slice. A slow scan will ensure that the envelope of motion
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of any moving organ subject to respiratory motion will be captured in
the image (typical respiratory period is 4 to 6 seconds).
• A gated CT scan where the beam is turned on only when the patient’s
breathing is at a certain window of the respiratory cycle (typically 30%
to 35% of duty cycle). The respiratory-related motion is usually
monitored using an external marker. In one of the commercially
available implementations, this is accomplished by correlating the
respiration-related tumor motion to the displacement of an external
marker placed on the patient’s chest as measured using an infrared
camera. The user can specify which portion of the sinusoidal-shaped
signal obtained from the infrared camera is used to trigger the CT
scanner using the cardiac gating port. This method of imaging is also
known as prospective gated image acquisition.
• A 4D CT scan where multiple scans are obtained for each location
(oversampling) whereby the organ motion is captured at different
sampled phases of the respiratory cycle. At the end of the scan a very
large set of 3D images is produced corresponding to each of the phases
in which the breathing cycle was sampled (Fig. 3.16). The collection of
those 3D CT scans constitutes the 4D CT study for this patient. This
method is also known as retrospective image reconstruction.
FIGURE 3.16 The 4D CT phase-sorting process: the CT images, breathing tracking signal, and
“X-ray ON” signal form the input data stream. The breathing cycle is divided into distinct bins (e.g.,
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peak exhale, mid inhale, peak inhale, mid exhale). Images are sorted into those image bins
depending on the phase of the breathing cycle in which they were acquired (29).
Of all the imaging methods that aim to minimize respiration-related

motion artifacts, the 4D CT technique is the most comprehensive way to
perform the task because it not only reduces motion artifacts but also
captures the changing topography of the tumor during the respiratory
cycle. This information can be used during treatment planning to
optimally delineate treatment volumes and margins under the
assumption that the patient will be breathing the same way during
treatment as they did during the 4D CT simulation. Irregular breathing
(during imaging or treatment) is not desirable and we often coach the
patient to breath regularly and reproducibly. Coaching can be auditory,
where a computerized voice instructs the patient to breath in and out, or
visual, where for example the patient looks at the superposition of their
baseline breathing curve and their real-time breathing curve and tries to
match them as they control and pace their breathing.
Ultimately, the goal of simulation is to uniquely and reliably identify,
in the patient’s treatment position anatomy, the exact target shape and
location that can be reproducibly localized and treated during the daily
treatments. Four-dimensional CT simulation allows us to segment the
target and organ volumes with high specificity resulting in more
educated decisions on margin selection but also improved dose
calculation during treatment planning.
ACCEPTANCE TESTING AND QUALITY ASSURANCE

When it comes to conventional simulators and CT-simulators, the initial
acceptance testing is performed to verify that the unit is operating as
specified by the manufacturer and to serve as a baseline data pool for
future comparisons with periodic quality assurance (QA) testing.
Conventional Simulator
Acceptance testing of a simulator may be divided into two parts: (a)
geometric and spatial accuracies verification and (b) performance
evaluation of the x-ray generator and the associated imaging system. The
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first part is similar to the acceptance testing and evaluation of a linear
accelerator for mechanical performance. Because the simulators are
designed to mimic the treatment accelerators, their geometric accuracies
should be comparable with those of the accelerators. To minimize
differences between the simulator and the accelerator it is desired to use
the same table design and accessory holders as those on the treatment
machine.
The second part is a performance evaluation of a diagnostic
radiographic and fluoroscopic unit.
Several authors have discussed the technical specifications of
treatment simulators and the required testing procedures and have
presented comprehensive reviews on this subject (3,4,33–35). The
quality assurance for the x-ray generator and the imaging system has
been discussed by various groups (36,37). The most recent
recommendations on QA for conventional simulators are from AAPM
Task Group #40 (Table III in the report) (38). Of course a well-
established QA program requires daily and annual testing for simulators,
in addition to the monthly testing.
CT-Simulator
Acceptance testing for a CT-simulator requires the acceptance testing of
the CT scanner as an imaging device to be done first. This process is
described in detail by AAPM Report No. 39 (39). For the purpose of CT-
simulation, additional literature needs to be employed to cover the needs
of radiotherapy (see McGee and Das in Ref. 11). Due to the complexity
of the new technology scanners, the manufacturer’s acceptance testing
procedure (acceptance testing procedure (ATP) manual) provides a great
guide to suggested recommendations for testing tolerances for the
particular scanner. We recommend that the AAPM Task Group #66
report is followed for all the QA needs of a CT-simulator as it applies to
radiotherapy procedures (13). Table I in Ref. 13 outlines the
electromechanical components testing (e.g., lasers, table, gantry, and
scan localization). Table II outlines test specifications for image
performance evaluation (e.g., CT number vs. electron density, image
noise, contrast and spatial resolution). A simplified set of tests are shown
in Figure 3.17. Keep in mind that the CT-simulation process QA should
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be performed along with the treatment planning process QA where
information and data are transferred between the CT scanner and the
treatment planning computers.
When 4D CT scans are used for simulation, the quality assurance is for
the most part the same as that for the CT simulator. In addition to the
tests described previously, one could include scans of test phantoms that
are placed on a moving platform. Such motorized platforms can be
programmed to a user-defined moving cycle that is typically 1-
dimensional (1D) or 2-dimensional (2D), which is adequate for QA
purposes. Since the physical size of the phantom and any objects
embedded inside it are known, a 4D CT scan would test the ability of the
scanner and the accompanying software to build the 4D model of the
phantom and to reproduce the true dimensions of the imaged objects.
Although there is currently not much information on QA for 4D CT, such
protocols can easily be developed and incorporated in routine quality
assurance programs for CT simulation.
RECENT DEVELOPMENTS IN RADIOTHERAPY

SIMULATION
During the last decade, positron emission tomography (PET) in
combination with CT in hybrid, cross-modality imaging systems
(PET/CT) has gained more and more importance as a part of the
treatment planning procedure in radiotherapy. The fusion of PET with
CT adds anatomical information to the physiologic information of PET,
allowing for improvement in spatial resolution. The high sensitivity and
specificity of PET/CT in identifying the areas of tumor involvement in
various disease sites (40,41) attracted great interest in integrating
functional imaging with PET/CT into the radiotherapy planning process.
The aim is to better define and delineate the tumor’s extent and its
relationship to the surrounding radiosensitive vital structures and to
improve the therapeutic index (Fig. 3.18).
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FIGURE 3.17 Set of monthly QA tests for CT-simulator. This set of tests is based on AAPM TG-66
(13).
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FIGURE 3.18 PET/CT fusion of a patient with nasopharyngeal cancer with an upper left lobe lung
nodule (white arrow).
Magnetic resonance imaging (MRI) is becoming an increasingly

important tool in radiation oncology, as it can provide anatomical and
functional information regarding the tumor and normal tissues, which
may be complimentary to information from CT alone. For more than a
decade MRI has been successfully used in stereotactic radiosurgery
procedures. Thus, MRI has already been integrated into a CT-based RT
workflow, using image registration tools. Such tools are already an
inherent part of the RT workflow, for multimodality and multiphasic
image registration for radiation treatment planning (for MRI, PET, and
other imaging) and for image guidance at the treatment unit (42).
CONCLUSIONS
Treatment simulation is a crucial component of the entire treatment
planning process and guarantees successful radiotherapy practice. The
advancements of today’s technology, both in hardware and software,
allow more accurate patient setup and representation with customization
of the treatment plans to the specific patient and site. However, stringent
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QA procedures are necessary to maintain optimum and safe use of such
technologies. The introduction of multimodality imaging for RT
introduces the need for deformable image registration early in the RT
simulation process, which, as a whole, is an exciting topic to investigate.
KEY POINTS
• Treatment planning requires accurate patient data to be acquired
through the process of treatment simulation.
• Radiographic, CT, PET/CT, ultrasound, and MRI simulators are
essential in modern radiotherapy treatment planning.
• Image fusion between different simulation modalities is necessary
for complex modern radiotherapy techniques for mapping out
structural or functional anatomy of the targeted areas.
• Important components of CT-simulations and virtual simulation are
3D representation of the patient, DRRs, image registration and
segmentation, and tumor motion management.
• Treatment volume delineation, treatment portal placements, and
their directional optimization can be performed as part of the virtual
simulation process based on 3D visualization of the patient model.
• Process quality assurance and periodic testing of the radiotherapy
simulation equipment should be an integral part of the modern
radiotherapy simulation process in order to secure optimal and safe
implementation of all aspects of the simulation process.
QUESTIONS
1. What is the most common imaging modality used in radiotherapy
simulation?
A. MRI
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B. Planar imaging
C. Ultrasound
D. CT
E. PET
2. When compared with CT, MRI provides better
A. spatial resolution
B. contrast resolution
C. patient setup
D. tissue density information
E. geometrical accuracy
3. When compared with MRI, PET provides better
A. spatial resolution
B. patient setup
C. tissue density information
D. malignancy differentiation from normal tissue
E. geometric accuracy
4. During a 4D CT process,
A. the CT beam is turned on only when the patient’s breathing is
at a certain window of the respiratory cycle.
B. a slow CT scan of axial slices is acquired.
C. multiple scans for each location are obtained and are shorted
via retrospective image reconstruction.
D. a breathhold technique is used during the image acquisition.
ANSWERS
1. D
2. B
3. D
4. C
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REFERENCES
1. Sherouse GW, Bourland JD, Reynolds K, et al. Virtual simulation in
the clinical setting: some practical considerations. Int J Radiat Oncol
Biol Phys. 1990;19:1059–1065.
2. Sherouse GW. Radiotherapy simulation. In: Khan FM, Potish R, eds.
Treatment Planning in Radiation Oncology, Baltimore, MD: Williams &
Wilkins; 1998:39–53.
3. McCullough EC. Radiotherapy treatment simulators. AAPM
Monograph No. 19, 1990:491–499.
4. McCullough EC, Earl JD. The selection, acceptance testing, and
quality control of radiotherapy treatment simulators. Radiology.
1979; 131:221–230.
5. Khan FM. The Physics of Radiation Therapy. 4th ed. Baltimore, MD:
Lippincott Williams & Wilkins; 2010.
6. Galvin JM. The CT-simulator and the Simulator-CT. In: Smith AR, ed.
Radiation Therapy Physics. Berlin: Springer-Verlag; 1995:19–32.
7. Dahl O, Kardamakis D, Lind B, et al. Current status of conformal
radiotherapy. Acta Oncol. 1996;35(Suppl. 8):41–57.
8. Rosenwald JC, Gaboriaud G, Pontvert D. [Conformal radiotherapy:
principles and clarification]. Cancer Radiother. 1999;3:367–377.
9. Siddon RL. Solution to treatment planning problems using
coordinate transformations. Med Phys. 1981;8:766–774.
10. Siddon RL. Fast calculation of the exact radiological path for a
three-dimensional CT array. Med Phys. 1985;12:252–255.
11. Coia LR, Schultheiss TE, Hanks GE, eds. A Practical Guide to CT
Simulation. Madison, WI: Advanced Medical Publishing; 1995.
12. Aird EG, Conway J. CT simulation for radiotherapy treatment
planning. Br J Radiol. 2002;75:937–949.
13. Mutic S, Palta JR, Butker EK, et al. Quality assurance for computed-
tomography simulators and the computed-tomography-simulation
process: report of the AAPM Radiation Therapy Committee Task
Group No. 66. Med Phys. 2003;30:2762–2792.
14. Goitein M, Abrams M, Rowell D, et al. Multi-dimensional treatment
planning: II. Beam’s eye-view, back projection and projection
15. NEMA. The DICOM Standard. 2006.
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16. Bosh W. Integrating the management of patient treatment planning
and image data. In: Purdy JA, ed. Categorical course syllabus: 3-
dimensional radiation therapy treatment planning. Chicago, IL: RSNA;
1994;151–160.
17. Ragan D, et al. Semi-automated four-dimensional computed
tomography segmentation using deformable models. Med Phys.
2005;32:2254–2261.
18. ICRU Report No. 50. Prescribing, Recording and Reporting Photon Beam
Therapy. Bethesda, MD: ICRU; 1993.
19. ICRU Report No. 62. Prescribing, Recording and Reporting Photon Beam
Therapy (supplement to ICRU Report 50). Bethesda, MD: ICRU; 1999.
20. Rowbottom CG, Oldham M, Webb S. Constrained customization of
non-coplanar beam orientations in radiotherapy of brain tumors.
Phys Med Biol. 1999;44:383–399.
21. Bedford JL, Webb S. Elimination of importance factors for clinically
accurate selection of beam orientations, beam weights and wedge
angles in conformal radiation therapy. Med Phys. 2003;30:1788–
1804.
22. Purdy JA, Grant WH III, Palta JR, Butler BE, Perez CA, eds. 3D
Conformal and Intensity Modulated Radiation Therapy: Physics and
Applications. Madison, WI: Advanced Medical Publishing, Inc; 2001.
23. Papanikolaou N, Battista JJ, Boyer AL, et al. eds. Tissue
inhomogeneity corrections for megavoltage photon beams. AAPM Task
Group Report No. 65. 2004.
http://www.aapm.org/pubs/reports/RPT_85.pdf.
24. Jiang S. Management of Moving Targets in Radiotherapy: Integrating
New Technologies into the Clinic: Monte Carlo and Image-Guided
Radiation Therapy. AAPM Monograph No. 32; 2006.
25. Mayo JR, Muller NL, Henkelman RM. The double-fissure sign: a
motion artifact on thin-section CT scans. Radiology. 1987;165:580–
581
26. Ritchie CJ, Hseih J, Gard MF, et al. Predictive respiratory gating: a
new method to reduce motion artifacts on CT scans. Radiology.
1994;190:847–852.
27. Keall PJ, Kini VR, Vedam SS, et al. Potential radiotherapy
improvements with respiratory gating. Australas Phys Eng Sci Med.
2002;25:1–6.
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28. Tarver RD, Conces DJ Jr., Godwin JD. Motion artifacts on CT
simulate bronchiectasis. AJR Am J Roentgenol. 1988;151:1117–1119.
Phys Med Biol. 2003;48:45–62.
30. Ritchie CJ, Godwin JD, Crawford CR, et al. Minimum scan speeds
for suppression of motion artifacts in CT. Radiology. 1992;185(1):
37–42.
31. Kachelriess M, Kalender WA. Electrocardiogram-correlated image
reconstruction from subsecond spiral computed tomography scans of
the heart. Med Phys. 1998;25:2417–2431.
Oncol Biol Phys. 1999;44(4):911–919.
33. Connors SG, Battista JJ, Bertin RJ. On technical specifications of
radiotherapy simulators. Med Phys. 1984;11:341–343.
34. International Electrotechnical Commission. Functional Performance
Characteristics of Radiotherapy Simulators. Draft Report. Geneva:
1990. IEC SubC 62C.
35. Bomford CK, et al. Treatment simulators. Br J Radiol. 1989;(Suppl.
23):1–49.
36. National Council on Radiation Protection and Measurements.
Quality Assurance for Diagnostic Imaging Equipment. Report No.
99;1988.
37. Boone JM, et al. AAPM Report No. 74. Quality Control in Diagnostic
Radiology. Report of Task Group #12;2002.
38. Kuthcer GJ, et al. AAPM Report No. 46. Comprehensive QA for
Radiation Oncology. Report of Task Group #40;1994.
39. Lin PP-J, et al. AAPM report No. 39. Specification and Acceptance
Testing of Computed Tomography Scanners. Report of Task Group #2;
1993.
40. Öllers M, Bosmans G, van Baardwijk A, et al. The integration of
PET-CT scans from different hospitals into radiotherapy treatment
planning. Radiother Oncol. 2008;87:142–146.
41. Thorwarth D, Geets X, Paiusco M. Physical radiotherapy treatment
planning based on functional PET/CT data. Radiother Oncol.
2010;96:317–324.
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42. Devic S. MRI simulation for radiotherapy treatment planning. Med
Phys. 2012;39:6701–6711.
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4 Treatment Planning Algorithms:
Photon Dose Calculations
John P. Gibbons
INTRODUCTION
Computerized treatment planning systems have been utilized in
radiotherapy planning since the 1950s. The first computer algorithm
used has been attributed to Tsien (1) who used punch cards to store
isodose distributions to allow for the addition of multiple beams. Since
that time, advancements in computer speeds and algorithm development
have vastly improved our capability to predict photon dose distributions
in patients.
In an early attempt to classify computer planning algorithms, ICRU
Report 42 (2) divided photon dose calculation methods into two
categories: empirical and model-based algorithms. Early empirical
algorithms such as Bentley–Milan were developed using clinical beam
data measured on a flat water phantom as input. Corrections were then
made to incorporate various effects, such as changes in patient external
contour, blocking or physical wedges, and so forth. Eventually, patient
heterogeneity correction factors became incorporated, but these were
applied afterward, that is, after water-based calculations were performed
assuming a homogenous patient geometry. Most of this development
occurred prior to the advent of CT, or at least before the incorporation of
CT-images into the radiotherapy planning process.
However, eventually the commercial utilization of empirical
algorithms faded. In the early 1990s, 3-dimensional (3D) conformal
radiation therapy (3D CRT) began to use patient-specific CT-image data
in the planning process. Initially this was limited to virtual simulation.
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At that time computer-based algorithms which could incorporate the
newly available volumetric density information and compute true 3D
dose distributions in a reasonable amount of time were not yet available.
In order to fully utilize this new information, it was necessary to develop
new algorithms which could more accurately incorporate variations in
individual patient anatomy. As a result, most, if not all, commercial
treatment planning systems have moved to model-based photon
calculation methods.
In this chapter, we will describe three photon calculation models
currently in use in radiotherapy clinics. Photon calculation models are
an area of continuous development and it is likely that each commercial
vendor’s implementation of one or more of these models will differ in
many respects. Nevertheless, the intent is to provide a basic
understanding of the principles behind these algorithms.
This work represents an update of the chapter of Mackie, Liu, and
McCullough from the previous edition (3). Their work contained
thorough coverage of the subject and much of their description and
analyses have been reproduced here. In particular, their expertise
regarding the convolution/superposition algorithm is without equal, and
the reader is encouraged to review their work for greater details.
THE REPRESENTATION OF THE PATIENT FOR DOSE

PLANNING
Patient representation has evolved dramatically over the past 40 years.
Initially, patients were considered as a flat water phantom of a specific
SSD and depth for use in simple dose or monitor unit calculations.
Development of external contour tools aided the treatment planner in
determining patient-specific dose distributions. Such procedures resulted
in the patient being represented as a homogeneous composition (i.e.,
water) but did allow for the application of surface corrections to the
calculation. Patient heterogeneities could be represented in simple ways,
such as using internal contours with assigned densities. The electron
density to assign to the region could be inferred from CT atlases or, if
available, the mean patient-specific CT number within the contoured
structure (4). The problem with this approach was that tissues such as
lung and bone are not themselves homogeneous, and their density
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variations would not be taken into account using this approach.
All modern radiotherapy systems use volumetric imaging data to
characterize the patient in a 3D voxel-by-voxel description. The most
common imaging dataset used for radiotherapy treatment planning is a
treatment-planning CT scan, obtained using a conventional CT-simulator.
A CT dataset of the treatment region constitutes the most accurate
representation of the patient applicable for dose computation, primarily
because of the one-to-one relationship between CT number and physical
and/or electron density (4). Dose algorithms that can use the density
representation on a point-by-point basis are easier for heterogeneous
calculations because contouring of the heterogeneities is typically not
required. An exception to this occurs when data is present within the CT
scan which will not be present for the treatment. One obvious example is
the CT-simulator couch, which is either manually or automatically
removed and, in some cases, replaced with a treatment couch by the
planning system. Also relevant are temporary contrast agents that can
produce a CT number that mimic a higher density material within the
body. Usually, the contrast agent is used to aid in the tissue
segmentation, and so only the additional step of providing a more
realistic CT number in the segmented region is required to correct for
the presence of the contrast agent. The spatial reliability of CT scanners
is typically within 2%, which leads to dose uncertainties of ∼1% (4).
Other imaging modalities provide information which will aid in the
location and delineation of structures, but is of less value in the
calculation of dose. For example, the advent of cone-beam CT within the
treatment room provides invaluable information regarding patient
alignment. However, the scatter contained within the images makes
accurate determination of density difficult. Although MRI is often able to
provide superior tissue contrast, the information in MRI is not strongly
related to electron density. Furthermore, MRI images are more prone to
artifacts during image formation, which will degrade the quality of the
calculated dose distributions.
In addition to electron density, it is also necessary to determine the
tissue composition for more modern calculation algorithms. In
convolution/superposition algorithms, fluence attenuation tables are
typically computed using mass-attenuation coefficient data, which are
somewhat weakly dependent on material. Often these coefficients are
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determined for each voxel by linearly interpolating between published
results of two different materials (e.g., water and bone) based on the
density assigned to the voxel. For both Monte Carlo (MC) and Boltzmann
transport calculations, a full material assignment must be made to allow
for accurate cross-section determination for both photon and electron
transport throughout the patient volume.
Ideally, the size of the voxels in the treatment planning CT should be
close to the dose grid resolution used for calculation. A CT volume set
typically consists of 50 to 200 images with a voxel matrix dimension of
512 × 512 for each image. For a 50-cm field of view, this corresponds
to a voxel size of ∼1 mm in the transverse direction. The longitudinal
voxel size depends on the slice thickness, but is typically from 2 to 5
mm. In many planning systems, the CT slice thickness is chosen as the
voxel size of the dose grid. For these systems, it may be appropriate to
downsample the CT image set to 256 × 256. This makes the transverse
resolution more closely matched to that of the longitudinal direction,
with only a minor degradation in the image. Degrading the resolution
further from 256 × 256 may result in an unacceptable loss of detail.
BASIC RADIATION PHYSICS FOR PHOTON BEAM DOSE

CALCULATION
Here we present an introduction to the important aspects of x-ray
production and interaction to understand the capabilities and limitations
of model-based photon treatment planning algorithms.
Megavoltage Photon Production

Figure 4.1 displays a cross-sectional view of a linear accelerator
treatment head, which consists of a high-density shielding material such
as lead, tungsten, or lead-tungsten alloy. It consists of an x-ray target,
flattening filter, ion chamber, and a primary and movable collimator.
High-energy electrons are accelerated in the linac’s accelerating
structure and impinge on the x-ray target.
The production of Bremsstrahlung, or braking radiation, occurs when
the high-energy electrons strike a tungsten target located in the head of
the accelerator. The size of the focal spot of the electrons on the target is
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small, typically on the order of a few millimeters (5). This finite size
contributes to the penumbra, or the blurring of the beam near the edges
of the field.
A first, or primary collimator, fabricated from a tungsten alloy, defines
the maximum field diameter that can be used for treatment.
At megavoltage energies, Bremsstrahlung is produced mainly in the
forward direction. In most conventional C-arm accelerators, to make the
beam intensity more uniform, a conical filter positioned in the beam
preferentially absorbs the photon fluence along the central axis. The
presence of the field-flattening filter alters the energy spectrum, since
the beam passing through the thicker central part of the filter has a
higher proportion of low-energy photons absorbed by the filter. This
may not be necessary for modern treatment deliveries where modulation
is used to vary the intensity of the beam. Indeed, many treatment units
now have the option of removing the filter for these treatments (e.g.,
Varian TrueBeam, Palo Alto, CA; Elekta Versa HD, Atlanta, GA), or have
removed the flattening filter entirely (e.g., TomoTherapy, Inc. Hi-Art,
Madison, WI) when a uniform field is not needed.
Compton Scatter
Photons can inelastically scatter via three main processes: photoelectric
absorption, incoherent (Compton) scattering with atomic electrons, and
pair production in the nuclear or electron electromagnetic field. In the
energy range used for radiation therapy, most interactions are Compton
scattering events, which are discussed in more detail here.
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FIGURE 4.1 Components of the treatment head of a linear accelerator. A: A cross-sectional view
of the treatment head operating in x-ray therapy mode. B: A cut-away diagram of the linac. (From
Varian Medical Systems: www.varian.com, with permission.)
Compton scattered photons may originate in either the accelerator

treatment head or the patient (or phantom). Most of the scatter dose
generated by the accelerator head is produced within the primary
collimator and the field-flattening filter. These scattered photons and
electrons are sometimes referred to as “extrafocal radiation” which may
be added to the primary photon beam emitted from the source. As the
collimator jaws open, more scattered radiation is allowed to leave the
treatment head, which results in an increase in the machine output with
field size. This effect is known as collimator scatter (6), although the
collimator jaws themselves contribute little forward scatter. The photons
scattered in the primary collimator and field-flattening filter also add to
the fluence just outside the geometrical field boundary.
Like accelerator-produced scatter, phantom scatter primarily occurs in
the forward direction and increases with the size of the field. However,
for phantom-generated scatter, the penetration characteristics of the
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beam are also altered. As the field size increases, the phantom scatter
causes the beam to be significantly more penetrating with depth. This
effect is significant enough that this energy difference must be included
in the dose computations.
The behavior of scatter from beam modifiers such as wedges must also
be considered within the photon model. When the field size is small, a
beam modifier mainly alters the transmission and does not contribute
much scatter that arrives at the patient. However, when the field is
large, beam modifiers begin to alter the penetration characteristics of the
beam, much as phantom scatter does. This effect is exemplified by the
increase in the wedge transmission factor with increasing field size and
depth (7,8).
Electron Transport
Photons are indirectly ionizing radiation. The dose is deposited by
charged particles (electrons and positrons) set in motion from the site of
the photon interaction. At megavoltage energies, the range of charged
particles can be several centimeters. The charged particles are mainly set
in forward motion but are scattered considerably as they slow down and
come to rest. Electrons lose energy by two processes: inelastic collisions
within the media (primarily with target electrons), and radiative
interactions (primarily with target nucleus). Inelastic collisions which
ionize the target atom can lead to secondary electrons, known as delta
rays. Radiative interactions occur via Bremsstrahlung, which effectively
transfers the energy back to a photon. Equations which model these
coupled electron–photon interactions are described later on.
The indirect nature of photon dose deposition results in several
features in photon dose distributions. Initially, the superficial dose
increases, or “builds up” from the surface of the patient because of the
increased number of charged particles being set in motion. This results
in a low skin dose, the magnitude of which is inversely proportional to
the path length of the charged particles. The dose builds up to a
maximum at a depth, dmax, characteristic of the photon beam energy. At
a point in the patient with a depth equal to the penetration distance of
charged particles, charged particles coming to rest are being replenished
by charged particles set in motion, and charged particle equilibrium
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(CPE) is said to be reached. In this case, the dose at a point is
proportional to the energy fluence of photons at the same point. The
main criterion for CPE is that the energy fluence of photons must be
constant out to the range of electrons set in motion in all directions. This
does not occur in general in heterogeneous media, near the beam
boundary, or for intensity-modulated beams.
Electrons produced in the head of the accelerator and in air between
the accelerator and the patient are called contamination electrons. The
interaction of these electrons in and just beyond the buildup region
contributes significantly to the dose, especially if the field is large.
Perturbation in electron transport can be exaggerated near
heterogeneities. For example, the range of electrons is three to five times
as long in lung as in water, and so beam boundaries passing through
lung have much larger penumbral regions. Bone is the only tissue with
an atomic composition significantly different from that of water. This
can lead to perturbations in dose of only a few percent (9), and so
perturbations in electron scattering or stopping power are rarely taken
into account. Bone can therefore be treated as “high-density water.”
SUPERPOSITION/CONVOLUTION ALGORITHM
The most common photon dose calculation in use for radiotherapy
planning today is the Superposition/Convolution algorithm (9–19). This
method incorporates a model-based approach in describing the
underlying physics of the interactions, while still being able to calculate
dose in a reasonable time.
The convolution–superposition method begins by modeling the
indirect nature of dose deposition from photon beams. Primary photon
interactions are dealt with separately from the transport of scattered
photons and electrons set in motion.
Dose Calculation under Conditions of Charged Particle

Equilibrium
To begin, we consider the special case of dose determination under
conditions of CPE. In this case, the total energy absorbed by charged
particles at position r is the same as the total energy which escapes due
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to photon interactions at the same location. Thus, the primary dose Dp
and the first-scattered dose from a parallel beam of monoenergetic
photons can be computed as (3):
where YP(r) and (Kc(r))P are the primary energy fluence and collision
kerma, respectively, at point r is the mass energy absorption
coefficient, øP(r = 0) is the primary photon fluence at the surface of the

phantom, hnP is the primary photon energy, and μ is the attenuation
coefficient of primary photons. The total dose is the sum of the primary
and scatter components
where dPscat(q,r′)/dV is the probability per unit volume of a primary

photon being scattered into a solid angle centered about angle q.
These equations are complicated enough, but they do not take into
account any secondary or higher-order photon scatter. They also neglect
beam divergence and do not take into account tissue heterogeneities.
They are valid only for CPE situations, so that the dose computation is
not valid in the buildup region or near the field boundaries, and the
scatter dose is perturbed by heterogeneities lying between the scatter
site at r′ and the point r, where the total dose is being computed.
Convolution/Superposition Method
Unfortunately, Equation (4.1) is simplistic because it does not take into
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account the finite range of charged particles. In other words, the energy
fluence that was present at the point the charged particles were set in
motion upstream should replace the energy fluence in Equation (4.1).
We may think of this energy fluence as that originating upstream (i.e.,
assuming that the charged particles all moved linearly downstream), but
in reality, the particles may originate from any location around the
calculation point, as long as it is within the particles’ range. Thus, rather
than a single effective photon interaction site, this expression for dose
becomes a convolution integral about r:
where Ac(r−r′) describes the contribution of charged particle energy

that gets absorbed per unit volume at r from interactions at r′ and the
integration is over all values of r′ that make up volume dr′. The charged
particle energy absorption kernel has a finite extent because the range of
charged particles set in motion is finite.
Equation (4.3) requires knowledge of the energy fluence due to both
primary and scattered photons at all points. Time-consuming transport
methods, such as the method of discrete ordinates or the MC method
would be needed to compute the scattered component accurately. A
simpler solution is to utilize a scatter kernel that includes the scattered
photon component along with the contribution from charged particles.
The kernel is no longer finite because photon scatter (which has no
range) is included. Now only primary photons are explicitly transported.
A convolution equation that separates primary photon transport and a
kernel that accounts for the scattered photon and electrons set in motion
away from the primary photon interaction site is as follows:
where is the mass attenuation coefficient, ΨP(r′) is the primary energy

fluence, and A(r − r′) includes the contribution of scatter. The product
of the mass attenuation coefficient and the primary energy fluence is the
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primary terma (total energy released per unit mass) TP(r′). Terma, first
defined by Ahnesjo, Andreo, and Brahme (20), is analogous to kerma,
and has the same units as dose.
The convolution kernels can, in principle, be obtained by analytic
computation, deconvolution from dose distributions, or even by direct
measurement. Most often, the kernels are computed with the MC method
by interacting a large number of primary photons at one location and
determining from where energy is absorbed, that is, from primary-
generated charged particles, charged particles subsequently set in
motion from scattered photons, or both (12,13,20,21). Figure 4.2
illustrates isovalue lines for a 1.25-MeV kernel in water. As is evident
from the figure, the kernel is forward directed even at this low energy.
As the energy increases, the kernel becomes even more forward peaked.
Modeling Primary Photons Incident on the Phantom

The convolution equation is restricted to describing monoenergetic
parallel beams of primary photons interacting with homogeneous
phantoms. To model a clinical radiotherapy beam, the contribution for
each energy bin of the photon spectrum must be summed. At present,
the spectral information is derived from MC simulations benchmarked
by measurement. Using the EGS4 MC method, Mohan and Chui (22) first
quantified the spectrum of clinical accelerators using the MC method.
Since that time, several other authors have performed simulations to
calculate photon energy spectrum (18,23,24).
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FIGURE 4.2 Cobalt-60 (more precisely, 1.25-MeV primary photons) kernels for water computed
using Monte Carlo simulation (MCS). The isovalue lines are in units of cGy MeV−1 photon−1. A:
The contribution due to electrons set in motion from primary photons (i.e., the primary
contribution). B: The first scatter contribution. C: The sum of the primary and all scatter
contributions. (Reprinted from Mackie TR, Bielajew AF, Rogers DW, et al. Generation of photon
energy deposition kernels using the EGS4 Monte Carlo code. Phys Med Biol. 1988;33:1–20, with
permission.)
The spectrum will also vary with off-axis position if a field-flattening

filter is used. Figure 4.3 shows that the mean energy of primary
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radiation (directly from the target) for a Varian 2100C (flattened) 10-MV
photon beam decreases off-axis, but the extrafocal photons (primary
collimator and flattening filter) do not (18). This off-axis decrease is due
to differential hardening of the beam by the field-flattening filter. Since
the direct photon component dominates, the model must take into
account the change in the energy spectrum across the field.
FIGURE 4.3 The photon mean energy distribution in an open 40 × 40-cm field from a 10-MV
photon beam target, primary collimator, and field-flattening filter. Values are for in-air photons
arriving at the plane of the isocenter. (Reprinted from Liu HH, Mackie TR, McCullough EC. A dual
source photon beam model used in convolution/superposition dose calculations for clinical
megavoltage x-ray beams. Med Phys. 1997;24:1960–1974, with permission.)
Collimators and block field outlines are usually modeled with a

mathematical mask function, which consists of the fraction of the
incident fluence transmitted through the modifier. For a collimator, the
mask function inside the field is unity, and underneath the collimator it
is equal to the primary collimator transmission. For a block, the mask
function inside the field is the primary transmission through the block
tray, and underneath the block it is equal to the primary block
transmission. The mask function alone would not be able to model the
penumbral blurring of the field boundary. This has been modeled by an
aperture function. The mask function is convolved by a 2-dimensional
(2D) blurring kernel that represents the finite size of the source. The
blurring kernel is usually assumed to be a normal function with a
standard deviation equal to the projection of the source spot’s width
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through the collimation system (thereby accounting for magnification of
the source at large distances from the collimator system). Finally, the
mask function is multiplied by the energy fluence distribution for the
largest open field.
The energy fluence outside the field is greater than that which can be
accounted for by collimator transmission of the primary photons
generated in the target. It can be modeled by adding short, broad normal
distribution to the energy fluence. The source of this component is
mainly the extrafocal radiation produced from Compton scattering in the
field-flattening filter. The magnitude of the extrafocal radiation source
can also be used to account for the variation in the machine-generated
output factor, because the scatter outside the field and the increase in
machine-generated output are both due to scatter from the accelerator
head (18,25).
Conventional wedges and compensators cannot be accurately modeled
with primary attenuation only. These components produce scatter and
cause differential hardening of the beam. The hardening of the primary
beam can be accounted for according to the material of the wedge and
the beam spectrum as a function of radial position. Scatter from the
wedge is more difficult to account for. The increased scatter results in
the wedge factor increasing by a few percent as a function of field size.
This can be adequately modeled by a field size-dependent factor that
duplicates the effect. Alternatively, the wedge or compensator can be
included as part of the patient representation. This extended phantom
has a large heterogeneity in it, namely, the air gap between the device
and the patient. This method can predict the variation in the wedge
factor as a function of field size.
Ray-Tracing the Incident Energy Fluence Through the

Phantom
The incident 2D energy fluence distribution is ray-traced through the
patient to create a 3D distribution of energy fluence (Fig. 4.4). The
density of the rays followed and the sampling of the rays along their
path must be sufficient to represent the attenuation behavior of the
phantom. Sufficient sampling density is especially important for head,
neck, and breast tangential fields. In general, the sampling density
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required is higher than the dose resolution desired, so several rays are
traversing each calculation voxel.
FIGURE 4.4 The ray-tracing of a two-dimensional (2D) energy fluence distribution through the
patient to create a three-dimensional (3D) energy fluence distribution in the patient. SSD, source-
to-surface distance.
Terma is computed within the calculation matrix by multiplying the

primary fluence by the mass attenuation coefficient. The primary ray
attenuation coefficient, weighted to the appropriate beam spectrum, is
based on the voxel properties. The energy fluence at a sample point is
reduced from the previous sample along the ray. Hardening of the
primary energy fluence spectrum with depth and off-axis position is
accounted for by changing the attenuation coefficient with position. The
speed of the ray-tracing operation can be improved significantly by the
use of lookup tables to store precomputed results.
Electron Contamination
The electron contamination of the beam is not accounted for in the
conventional convolution method, so an additional independent
component must be added to account for this dose. The surface dose
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from megavoltage photon beams is almost entirely due to the electron
contamination component. Studies in which the electron contamination
has been removed by magnetically sweeping electrons from the field
reveal that dose from the contaminating electrons resembles an electron
beam with a practical range somewhat greater than the depth of
maximum dose. A reasonable agreement with measured depth–dose
curves can be obtained by scaling the contamination electron depth–dose
curve with the surface dose and adding this component to the
convolution-computed dose distribution.
Kernel Spatial Variance and Phantom Heterogeneities

The convolution equation assumes that the kernel is spatially invariant
in that the kernel value depends only on the relative geometrical
relationship between the interaction and dose deposition sites and not
on their absolute position in the phantom. When this is true, the
convolution calculation can be done in Fourier space, saving much time.
Unfortunately, this is not the case as the kernel varies with position.
The effects of hardening and divergence of the beam are small and can
be calculated in a number of ways. A multiplicative correction to the
terma in the patient can be used to correct for hardening of the kernel
(17,26). Alternatively, several kernels valid for different depths in the
phantom can be used as a basis for interpolation to a specific depth
(17,19). Liu et al. showed that the correction as a function of depth is
nearly linear, and not employing any correction results in ∼4%
discrepancy at 30-cm depth. Tilting the kernel to match the beam
divergence results in only a minor improvement in accuracy for the
worst-case examples (19).
Phantom heterogeneities are a more serious problem. Modeling the
transport of electrons and scattered photons through a heterogeneous
phantom would require a unique kernel at each location. Each kernel
would be superimposed on the dose grid and weighted with respect to
the primary terma. What is required to make the calculation tractable is
to modify a kernel, computed in a homogeneous medium, to be
reasonably representative in a heterogeneous situation. If most of the
energy between the primary interaction site and the dose deposition site
is transported on the direct path between these sites, it is possible to
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have a relatively simple correction to the convolution equation based on
ray-tracing between the interaction and dose deposition sites, and on
scaling the path length by density to get the radiologic path length
between these sites. The convolution equation modified for radiologic
path length is called the superposition equation:
where ρr−r′ · (r - r′) is the radiologic distance from the dose deposition
site to the primary photon interaction site and ρr · r′ is the radiologic
distance from the source to the photon interaction site.
Woo and Cunningham (15) compared the modified kernel using range
scaling for a complex heterogeneous phantom with a kernel computed de
novo for a particular interaction site inside the phantom. The results
shown in Figure 4.5 indicate that agreement is not perfect, but the
computational trends are clearly in evidence in that isovalue lines
contract in high-density regions and expand in low-density regions.
FIGURE 4.5 Comparison of Monte Carlo–generated 6-MeV primary photon kernel in a water
phantom containing a ring of air. The dashed line is a kernel modified for the heterogeneous
situation using range scaling from one derived in a homogeneous phantom. The continuous line is
a kernel computed expressly for the heterogeneous situation. It is impractical to compute kernels
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for every possible heterogeneous situation, and there is sufficient similarity to warrant the range
scaling approximation. (Reprinted from Woo MK, Cunningham JR. The validity of the density
scaling method in primary electron transport for photon and electron beams. Med Phys.
1990;17:187–194, with permission.)
MONTE CARLO
The Monte Carlo (MC) technique of radiation transport consists of using
well-established probability distributions governing the individual
interactions of electrons and photons to simulate their transport through
matter. MC methods are used to perform calculations in all areas of
physics and math for any problems which involve a probabilistic nature.
Several excellent reviews of MC calculations in radiation therapy exist
(27–31), as well as an AAPM Task Group Report which discusses its
clinical implementation (32).
Although the MC method had been proposed for some time, it was not
capable of being fully utilized until the development of the digital
computer in the 1940s. Radiation transport was one of the first uses for
this methodology at that time, and public codes, such as Monte Carlo N-
Particle Transport code (MCNP) began appearing as early as the 1950s.
In photon transport calculations, the Electron Transport (ETRAN) code,
developed by the National Bureau of Standards in the 1970s, was based
on the condensed history technique (discussed below) first introduced by
Berger in 1963. The Electron Gamma Shower (EGS4) code was originally
developed at the Stanford Linear Accelerator in the 1980s, and is now
maintained (as the modified EGSnrc) by the National Research Council
of Canada (33).
Analog Simulations
As pointed out by TG 105, an analog simulation is the random
propagation of a particle through the following four steps: (1)
determining the distance to the next interaction, (2) transporting the
particle to the interaction site, (3) selecting which interaction will take
place, and (4) simulating this interaction (32). The initial step is
performed based on the probability that the particle will interact within
the medium in question. For example, if the probability of interaction is
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represented by an attenuation coefficient m, a random interaction
distance r can be determined from a random number e (between 0 and
1) by the following (30,32):
The second step is relatively straightforward, but knowledge of the mass

density (and the corresponding changes in μ) is required for
heterogeneous materials. Another random choice will be made for step
3, weighted proportionally to the relative probabilities of interaction
choices (e.g., Compton scatter vs. photoelectric absorption vs. pair
production). Finally the results of the interaction must be randomly
simulated, including the particles of new energy (if not absorbed) and
trajectory.
Condensed Histories
While analog simulations work well for photon interactions, a practical
problem arises for the transport of electrons. The mean free path for
electrons in the therapeutic energy range is of the order of 10−5 g/cm2.
This means that a single electron of energy >1 MeV will have more than
105 interactions before stopping. To perform an analog simulation of this
event is impractical.
The condensed history electron transport technique was first
introduced by Berger in 1963. Berger noted that most electron inelastic
interactions did not lose a great deal of energy or have a significant
directional change. These “soft” interactions could be separated by more
significant “catastrophic” events, where the electron had a significant
energy loss (e.g., delta ray production, Bremsstrahlung event). The soft
interactions could be separately simulated by combining these into
single virtual large-effect interactions, while the catastrophic events can
be analog simulated as described above (30). For electrons with energies
above an energy threshold, the mean free path for catastrophic
interactions is of several orders of magnitude higher.
While this approach allows for faster computations, the step size
choice for the condensed histories has been shown to produce artifacts in
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the results (34). However, these issues have led to improved, high-
accuracy condensed history methods (34–36).
Variance Reduction Techniques

Instead of simulating individual events as in an analog simulation, one
may employ techniques to improve the MC calculation efficiency in
obtaining a particular result. Variance reduction techniques are used to
reduce the variance of a given calculation result for a given number of
histories. For example, an analog simulation of a Bremsstrahlung event
would randomly select an energy and direction (proportional to their
respective probabilities) for the resulting photon emission. Alternatively,
one could simulate the emission of a large number of photons with lower
weights to better mimic the random directional emission of these events.
This particular technique is termed Bremsstrahlung splitting (37) and is
one of many different techniques which may be employed within a
particular MC code. These techniques are important in keeping
calculation times practical for most situations. However, care must be
taken that the underlying physics is not biased by the results.
Monte Carlo Radiotherapy Dose Calculations

In principle it is possible to simulate histories for the entire radiation
therapy delivery, that is, from the initial accelerated electron’s impact
onto the target to the delivery dose. However, this would be a
tremendously inefficient process, as few of these histories would make it
beyond the accelerator head to the patient. Alternatively, it is possible to
transport the particles through the patient-independent structures (e.g.,
target, primary collimator, ion chamber), and store this information for
future use. This information is known as a phase-space file, and it
contains information including the position, energy, and direction of the
photons and electrons emitted from the accelerator.
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FIGURE 4.6 Illustration of the components of a typical Varian linear accelerator treatment head in
photon beam mode. Phase space planes for simulating patient-dependent and patient-
independent structures are also represented. (Reprinted from Chetty IJ, Curran B, Cygler JE, et
al. Report of the AAPM Task Group No. 105: Issues associated with clinical implementation of
Monte Carlo-based photon and electron external beam treatment planning. Med Phys.
2007;34:4818–4853, with permission.)
Figure 4.6 shows a cross-sectional view of a Varian linac which

demonstrates a possible location of a phase-space plane located distal to
all the patient-independent components of the accelerator head. Once
initially computed, this information may be continually used to calculate
the dose to individual patients. It may also be advantageous to create
phase-space planes further down the beam path (c.f., phase-space plane
2 in Fig. 4.6), particularly for standard collimator settings and/or beam
modifiers. Otherwise, these data can be projected directly onto the
patient for dose calculation.
DISCRETE ORDINATES METHOD

More recently several authors have reported on a direct numerical
solution of the Boltzmann transport equations (BTEs). The approach has
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been commercialized in the Varian Eclipse Treatment Planning System,
under the name Acuros. In particular, this methodology has been
proposed as an alternative to MC calculations, in order to produce
accurate dose distributions with a substantially reduced calculation time.
Derivation of the Transport Equations

The linear Boltzmann Transport Equation can be derived by assuming
particle conservation within a small volume element of phase space
(38–40). We define a quantity called the angular density of electrons,
Ne(r,Ω,E,t), which represents the probable number of electrons at
location r and direction W with energy E at time t per unit volume per
unit solid angle per unit energy. Ω represents the unit director in the
direction of motion, that is, parallel to v. Thus, Ne(r,Ω,E,t) dV dΩ dE
represents the number of electrons at time t in a volume element dV
about r, in a narrow beam of solid angle dΩ about Ω, and energy range
dE about E.
After a time Δt, these electrons have moved to position r + v Δt, and
have been reduced due to collisions within the medium by an amount e
−av∆t. Here σ is the macroscopic cross-section for electrons, and represents
1/λ, where λ is the mean free path. Although not strictly a cross-section,
σ is analogous to the photon attenuation coefficient and has units of
1/length. For very short times Δt, the number of electrons from this
packet which have reached r + v Δt is ≈ Ne (1 – σ v Δt) dV dΩ dE.
At the same time scattered electrons from elsewhere in the medium
may reach the same position (r + v Δt). This quantity may be
determined by integrating the angular density over phase space
multiplied by the probability for these interactions:
where represents the doubly differential cross-section

for electron scatter from energy E′ and direction W′ to energy E and
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direction W.
In addition, any additional sources of electrons produced during time
Δt may also reach position r + v Δt. In this case, the number of
additional electrons at r + v Δt becomes Q(r,W,E,t) Δt, where Q(r,W,E,t)
represents the rate of electron production from other sources. The total
number of electrons at position r + v Δt is now given by the following
equation:
Dividing the equation by Δt, and taking the limit Δt → 0, we obtain
The limit term represents the total time derivative of Ne for an observer
moving with the packet of electrons (i.e., from r to r + vΔt). It may be
rewritten to simplify the equation:
The first term in Equation (4.10) represents the velocity times the
directional derivative of Ne in the direction of W. It is known as the
streaming term, as it represents the difference in the time derivative
between the moving and rest frames, the latter of which also includes
the effects of electrons moving past r without any collisions.
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Upon inserting (4.10) into (4.9), the resulting equation becomes:
where we have removed the arguments for simplicity. This is the basic
form of the transport equation, which is often called the Boltzmann
equation because of its similarity to the expression derived by Boltzmann
involving the kinetic theory of gasses (39). It is more often written in
terms of the angular flux, Ye, where Ye(r,W,E,t) = νNe(r,W,E,t):
Use of the Transport Equations for Photon Beam

Calculations
In external beam radiotherapy, the time-independent form of Equation
(4.12) is used, since steady state is achieved in a much shorter time than
that when the beam is on (41). Equation (4.12) is an integro-partial–
differential equation which can be solved numerically using either
stochastic or deterministic methods. Most reports have utilized the latter,
employing some form of grid-based numerical method in which phase
space is discretized in spatial, angular, and energy coordinates
(40,42,43), although there are some differences in the literature about
which techniques are used. Finite difference and finite element methods
are used for spatial discretization, and Boman et al. reported using the
finite-element method for all variables (40). Alternatively, the method of
discrete-ordinates has been employed for angular discretization in the
Attila solver (44,45), and in the subsequent Acuros XB algorithm
currently available in the Varian Eclipse treatment planning system
(Varian Assoc, Palo Alto, CA). Energy-dependent coupled photon–
electron cross-section data are available through CEPXS, which uses the
multigroup method to discretize the particle energy domain into energy
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intervals or groups (46). This class of solvers is commonly known as the
discrete ordinates method, although technically the name only refers to
the method for numerically discretizing in angle.
Up to now, we have only discussed electron angular density (or
angular flux). However, in external beam calculations, collisions involve
photons, electrons, and positrons. In principle, Equation (4.12) then
becomes a set of coupled equations. For example, excluding positron
interactions, we have the following:
where represents the differential cross-section for the

creation of particle 2 with energy E, direction Ω, from particle 1 of
energy E′, direction W′.
Acuros XB Implementation of the Linear Boltzmann

Transport Equations
Currently the only commercial implementation of the linear BTE is the
Acuros XB dose calculation algorithm available on the Varian Eclipse
treatment planning system. Acuros XB was developed using many of the
methods employed with a prototype BTE solver developed at Los Alamos
National Laboratories called Attila, which was co-authored by the
founders of Transpire, Inc. (Gig Harbor, WA) (47). Transpire, Inc.,
established a licensing agreement to commercialize Attila, for a broad
range of applications. Acuros XB has adapted and optimized the methods
within Attila for external photon beam calculations (48).
Within the Acuros algorithm, both charged pair-production particles
are assumed to be electrons, and the contribution of electron-produced
Bremsstrahlung within the patient is assumed to be deposited locally.
As already mentioned, energy discretization is performed using a
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multigroup representation of the cross-section. However, this is difficult
for electrons where the inelastic cross-section increases rapidly when
energy losses become small. These “soft” interactions would require a
very large number of energy bins to accurately describe, which is
impractical for an efficient solution. As a result, electron interactions are
separated into large and small energy losses, the latter of which are
described by a continuous slowing-down (CSD) approximation. In this
case, the angular electron fluence is described by the Boltzmann–
Fokker–Planck transport equation:
FIGURE 4.7 Comparison of EGS4/PRESTA with Attila for a percent depth–dose calculation in a
heterogeneous phantom. (Reprinted from Gifford KA, Horton JL, Wareing TA, et al. Comparison of
a finite-element multigroup discrete-ordinates code with Monte Carlo for radiotherapy calculations.
Phys Med Biol. 2006;51:2253–2265, with permission.)
In this case σee represents larger, “catastrophic” interactions that are

represented by standard Boltzmann scattering (48).
Gifford et al. (44) first performed an evaluation of the prototype solver
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Attila for radiation therapy dose calculations. Dose calculations
performed by Attila were directly compared with those calculated using
MC codes MCNPX for a brachytherapy calculation, and EGS4 for an
external photon beam calculation. Differences in doses were compared,
along with relative calculation speeds.
The photon dose calculation comparison was made comparing Attila
versus EGS4 for an 18-MV photon beam from a Varian 2100 accelerator.
A narrow beam geometry was used to highlight any differences in
regions of electron disequilibrium. In addition, a heterogeneous
multislab phantom was used, which consisted of water, lung, and
aluminum. The Attila calculation was divided into 24 and 36 photon and
electron energy groups, respectively. A comparison of depth doses
between these two calculations is shown in Figure 4.7. The agreements
here was also good, with an RMS difference of 0.7% of the maximum
dose.
Vassiliev et al. (45) extended these comparisons to include external
beam calculations of heterogeneous patient geometries. In their work,
Attila was compared with EGSnrc MC simulations for a 6-MV photon
beam from a Varian 2100 for a prostate and a head and neck case
previously treated within their department. For both the BTE and MC
calculations, CT datasets were converted into a material map of four
materials with fixed densities: air, adipose tissue, soft tissue, and bone.
In their comparison, calculations were performed with the same beam
geometries as those used clinically, with the exception of beam
modulation which was removed for this comparison. Dose calculation
differences were investigated along with the resolution of various
discretization variables required for accurate Attila calculations.
Figure 4.8 displays the material map for an axial slice through the
center of the PTV for the head and neck case. Also displayed is the
resulting dose distribution performed using the Attila dose calculation
engine. The black areas on each image are regions where the difference
between the MC and BTE calculations exceeded 5% of the maximum
dose. A more quantitative comparison can be seen by looking at a dose
profile through the center of the PTV (Line “L1” on Fig. 4.8) and off-axis
(Line “L2”). The dose profiles for both the Attila and EGSnrc codes for
these lines are displayed in Figure 4.9. The overall agreement between
these two methods was good, with over 98% of the calculation points
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within a ±3%/±3 mm criterion.
Since the release of Acuros XB, there have been a number of planning
studies investigating the efficiency and accuracy of the discrete ordinates
method. Comparisons are made either with other planning algorithms or
with measured results for a variety of treatment sites including lung
(49,50), breast (51), and nasopharynx (52). Evaluations of Acuros for
calculations within heterogeneous media (53) or for radiosurgery
treatments (54) have also been reported. The interested reader is
referred to these works for additional information.
FIGURE 4.8 A: Dose field calculated by Attila for a head-and-neck case on the axial plane
through isocenter. Pixels, where the dose difference between Attila and Monte Carlo (EGS)
exceeds 3%/3 mm, are shown in black on A and B. B: Material map through the axial plane
containing the isocenter for the dose distribution calculated in A. (Reprinted from Vassiliev ON,
Wareing TA, Davis IM, et al. Feasibility of a multigroup deterministic solution method for three-
dimensional radiotherapy dose calculations. Int J Radiat Oncol Biol Phys. 2008;72:220–227, with
permission.)
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FIGURE 4.9 Dose line plot comparisons between EGSnrc (red) and Attila (blue) along line L1 A
and L2 B in Figure 4.8. Sharp peaks and dips in the Attila solution correspond to material
heterogeneities, which are revolved at the CT image pixel level by Attila. (Reprinted from
Vassiliev, Wareing TA, Davis IM, et al. Feasibility of a multigroup deterministic solution method for
three-dimensional radiotherapy dose calculations. Int J Rad Onc Biol Phys. 2008;72:220–227,
with permission.)
KEY POINTS
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• Modern radiation therapy planning systems have evolved
tremendously over the past few decades. A number of complex
model-based photon dose algorithms exist which calculate dose to
a 3D representation of the patient. These algorithms have been
developed in response to improvements in algorithm development,
computing power, and greater availability of volumetric imaging
data.
• Today, most commercial photon dose algorithms are a variation of
the convolution/superposition method. As algorithm development
and computing power improve, the use of MC and discrete-
ordinates methods which better incorporate nonequilibrium
dosimetry will likely increase.
• A convolution/superposition model should account for the following
characteristics:
• Off-axis energy variations
• Finite source size
• Extrafocal radiation
• Scatter and attenuation from beam modifying devices
• MC algorithms track histories of individual photons and electrons

that undergo hard (“catastrophic”) collisions. Soft electron collisions
are dealt with using condensed history methods.
• The discrete ordinates method represents a numerical solution to
the coupled Boltzmann transport equations. In this method, the
energy, position, and direction of the radiation quanta are
discretized for the numerical solution of the integro-differential
equations.
• Photon beam optimization presents additional challenges within the
planning process. The need to calculate dose rapidly under
conditions of changing incident fluence is necessary in a modern
radiotherapy clinic.
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QUESTIONS
1. Which of the following algorithms is/are measurement based?
A. Bentley–Milan
B. Convolution/Superposition
C. Monte Carlo
D. Discrete ordinates
2. Which of the following is/are used to speed up a Monte Carlo
dose calculation? Choose all that apply.
A. Variance reduction technique
B. Condensed history method
C. Kernel tilting
D. Density scaling
3. Which of the following algorithms account for nonequilibrium
conditions (e.g., at tissue interfaces)? Choose all that apply.
A. Bentley–Milan
B. Convolution/Superposition
C. Monte Carlo
D. Discrete ordinates
4. For a typical 6-MV beam, an error in CT number of 2% leads to
an error in dose of around:
A. 0.1%
B. 1%
C. 5%
D. 10%
5. The inelastic photon scattering processes which must be
accounted for include
A. Rayleigh scattering
B. Moller scattering
C. Photoelectric absorption
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D. Bremsstrahlung interactions
6. The convolution dose equation cannot be solved using Fourier
analysis primarily because
A. Scatter kernels are depth dependent
B. Patient heterogeneities
C. Beam hardening within the patient
D. Step-size artifacts
ANSWERS
1. A
2. A and B
3. C and D
4. B
5. C
6. B
REFERENCES
1. Tsien KC. The application of automatic computing machines to
radiation treatment planning. Br J Radiol. 1955;28(332):432–439.
2. Use of Computers in External Beam Radiotherapy Procedures With High-
Energy Photons and Electrons. International Commission on Radiation
Units and Measurement (ICRU): Bethesda, MD.
3. Mackie TR, Liu HH, McCullough EC. Treatment Planning Algorithms:
Model-Based Photon Dose Calculations in Treatment Planning in
Radiation Oncology. Philadelphia, PA: Lippincott Williams & Wilkins;
2012:773.
4. Sontag MR, Battista JJ, Bronskill MJ, et al. Implications of computed
tomography for inhomogeneity corrections in photon beam dose
calculations. Radiology. 1977;124(1):143–149.
5. Jaffray DA, Battista JJ, Fenster A, et al. X-ray sources of medical
linear accelerators: focal and extra-focal radiation. Med Phys.
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6. Khan FM, Gibbons JP. Khan’s the Physics of Radiation Therapy. 5th ed.
Philadelphia, PA: Lippincott, Williams & Wilkins; 2014:624.
7. McCullough EC, Gortney J, Blackwell CR. A depth dependence
determination of the wedge transmission factor for 4–10 MV photon
beams. Med Phys. 1988;15(4):621–623.
8. Palta JR, Daftari I, Suntharalingam N. Field size dependence of
wedge factors. Med Phys. 1988;15(4):624–626.
9. Sauer OA. Calculation of dose distributions in the vicinity of high-Z
interfaces for photon beams. Med Phys. 1995;22(10):1685–1690.
10. Battista JJ, Sharpe MB. True three-dimensional dose computations
for megavoltage x-ray therapy: a role for the superposition principle.
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11. Mackie TR, Scrimger JW, Battista JJ. A convolution method of
calculating dose for 15-MV x-rays. Med Phys. 1985;12(2):188–196.
12. Boyer A, Mok E. A photon dose distribution model employing
convolution calculations. Med Phys. 1985;12(2):169–177.
13. Mohan R, Chui C, Lidofsky L. Differential pencil beam dose
computation model for photons. Med Phys. 1986; 13(1):64–73.
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convolution dosimetry for stereotactic radiosurgery. Int J Radiat
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15. Woo MK, Cunningham JR. The validity of the density scaling
method in primary electron transport for photon and electron
beams. Med Phys. 1990;17(2):187–194.
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radiotherapy x-rays: analysis using a convolution/superposition
method. Phys Med Biol. 1990;35(11):1533–1549.
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the convolution method for polyenergetic spectra. Med Phys.
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19. Liu HH, Mackie TR, McCullough EC. Correcting kernel tilting and
hardening in convolution/superposition dose calculations for
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clinical divergent and polychromatic photon beams. Med Phys.
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20. Ahnesjo A, Andreo P, Brahme A. Calculation and application of
point spread functions for treatment planning with high energy
photon beams. Acta Oncol. 1987;26(1):49–56.
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energy deposition kernels using the EGS Monte Carlo code. Phys
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photon transport for radiation dosimetry. In: Kase K, Bjarngard BE,
Attix F, eds. The Dosimetry of Ionizing Radiation. New York, NY:
Academic Press; 1990:427–539.
28. Mackie TR. Applications of the Monte Carlo Method. In: Kase K,
Bjarngard BE, Attix F, eds. The Dosimetry of Ionizing Radiation. New
York, NY: Academic Press; 1990:541–620.
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physics. Phys Med Biol. 2006;51(13):R287–R301.
32. Chetty IJ, Curran B, Cygler JE, et al. Report of the AAPM Task
Group No. 105: Issues associated with clinical implementation of
Monte Carlo-based photon and electron external beam treatment
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of Electrons and Photons. New York, NY: Plenum; 1988:115–137.
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code. Intl J Appl Radiat Isot. 1991;42:917–941.
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New York, NY: Wiley; 1984.
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for Science and Technology. Berlin: Springer; 1993.
44. Gifford KA, Horton JL, Wareing TA, et al. Comparison of a finite-
element multigroup discrete-ordinates code with Monte Carlo for
radiotherapy calculations. Phys Med Biol. 2006;51(9):2253–2265.
45. Vassiliev ON. Wareing TA, Davis IM, et al. Feasibility of a
multigroup deterministic solution method for three-dimensional
radiotherapy dose calculations. Int J Radiat Oncol Biol Phys.
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2008;72(1):220–227.
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Coupled Electron-Photon Cross Section Generating Code. New Mexico:
Sandia National Laboratories: Albuquerque; 1989:110.
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element Sn methods on 3-D unstructured grids. Nucl Sci Eng.
2001;138:256–268.
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Medical Systems, Inc., Palo Alto, CA 94304. P1008611-002-B.
December 2014.
49. Liu HW, Nugent Z, Clayton R, et al. Clinical impact of using the
deterministic patient dose calculation algorithm Acuros XB for lung
stereotactic body radiation therapy. Acta Oncol. 2014;53(3):324–
339.
50. Kroon PS, Hol S, Essers M. Dosimetric accuracy and clinical quality
of Acuros XB and AAA dose calculation algorithm for stereotactic
and conventional lung volumetric modulated arc therapy plans.
Radiat Oncol. 2013;8:149.
51. Fogliata A, Nicolini G, Clivio A, et al. On the dosimetric impact of
inhomogeneity management in the Acuros XB algorithm for breast
treatment. Radiat Oncol. 2011;6:103.
52. Kan MW, Leung LH, Yu PK, Dosimetric impact of using the Acuros
XB algorithm for intensity modulated radiation therapy and
RapidArc planning in nasopharyngeal carcinomas. Int J Radiat Oncol
Biol Phys. 2013;85(1):e73–e80.
53. Kan MW, Leung LH, So RW, et al. Experimental verification of the
Acuros XB and AAA dose calculation adjacent to heterogeneous
media for IMRT and RapidArc of nasopharyngeal carcinoma. Med
Phys. 2013;40(3):031714.
54. Fogliata A, Nicolini G, Clivio A, et al. Accuracy of Acuros XB and
AAA dose calculation for small fields with reference to RapidArc(®)
stereotactic treatments. Med Phys. 2011;38(11):6228–6237.
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Brachytherapy
Kenneth J. Weeks
INTRODUCTION
Brachytherapy involves the treatment of cancer using photon, electron,
and positron emissions from radioisotopes. Brachytherapy was
developed using naturally occurring radioisotopes such as radium 226.
The history, applications, and emission details of radioisotopes are
described elsewhere (1–5). It is the goal of brachytherapy treatment
planning to determine the number of sources, their individual strengths,
and the location of each source relative to the treatment volume, so as to
treat a localized volume to a given minimum dose while respecting
tolerances of normal tissues. It is important to note that the original
brachytherapy clinical applications were developed realizing that
brachytherapy demanded 3-dimensional (3D) planning because the
sources were distributed in three dimensions. Because of this fact and
the absence of computers, these original treatment systems were all
inclusive. They were systems with rules for distributing the sources,
rules for picking and arranging source strengths, and given the latter,
precalculated dose-rate tables for determining the dose to a point. The
Manchester, Paris, Stockholm, Memorial, and Quimby systems (1–5) all
specified in alternate ways how to do this for interstitial and
intracavitary implants. See Chapter 15 for discussion of these systems.
From this history we can obtain knowledge of the range of the
radioactive source applications, which is important in devising dose
calculation algorithms. Thus, we summarize guidelines, which include
the following: When distributing lines of sources, attempt to keep them
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spaced no closer than 8 mm (smaller volumes) and no farther than 2 cm
(larger volumes) apart. The periphery of the treatment volume is
generally not much farther than 5 cm from the center of gravity of the
source distribution. The very high doses close (less than 5 mm) to the
sources are not prescribed or evaluated as to clinical significance. At
distances greater than 10 cm from the center of the implant, the dose
delivered is low and the precise dose is not considered a treatment
objective. Therefore, we conclude that dose calculation algorithms that
are very accurate from 5 mm to 5 cm and generally accurate to 10 cm
are required. The availability of computers and advanced imaging
capabilities means precalculated dose tables for predetermined patterns
of multiple sources are no longer required. Calculation of the dose
distribution for the individual patient’s source distribution is possible.
Radioisotopes decay randomly with a time independent probability
(1,3,5,6). If there are N0 radioactive atoms at time t = 0, then at a later
time t we have N(t) atoms given by
where l (0.693/T1/2) is the radioisotope’s decay constant and T1/2 is the

half-life (time it takes for half of the sample to decay). The activity (A)
at time = t, is proportional to the number of radioactive atoms present
and is defined by
where A0 is the initial activity. Throughout the following we will

consider the calculation of the dose-rate, (in cGy/h). The total dose D
delivered during an implant which lasts for time t, is found from the
initial dose-rate, , at the start of the implant from
for the case t >> T1/2, for example, a permanent implant, the total dose
(D) is simply whereas if t << T1/2, D = t . Throughout the
following, we will calculate the dose-rate at the start of the implant .
The total dose delivered in time t is then found from Equation 5.3.
The isotope emits energy (in the form of photons, electrons, and
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sometimes positrons) in all directions and that energy is absorbed in the
mass (tissue) around the isotope, giving rise to absorbed dose (absorbed
energy/mass). The calculation of dose-rate depends on the number of
radioactive atoms, the types and energies of the emitted particles, the
time rate of emission of those particles, and finally the energy absorption
and scattering properties of the surrounding media and the radioactive
material itself. In this chapter, we will begin with the simplest case of a
point source. From there we will use the point source result to determine
the dose-rate for an ideal line source and then a real clinical cylindrical
source. Finally, we will obtain the dose-rate distribution for a 3D
source/shield/applicator via numerical integration of the point source
result. Various intermediate parameterized calculation methods are
discussed. This inevitably leads to systems which explicitly model the
flow of energy from the radioactive sources. These include Monte Carlo
and Boltzmann transport theory. These latter techniques owe their
existence to the extensive computation power now available. The
advantages and disadvantages of these methods will be discussed.
CALCULATION OF DOSE-RATES AROUND A POINT

SOURCE
A point source is the simplest situation to calculate. The first
approximation, used in radiation oncology, is to ignore the charged
particle emissions and consider only the photons. The significance of this
approximation is best understood by reviewing the basic nuclear decay
data (7). Consider the well-known 192Ir which has a half-life of 73.8 days
and decays via β decay (95% of the decays) or electron capture (5%).
The decay of a single 192Ir nucleus produces on average 2.38 photons
(there are 44 possible photon energies ranging from 7.8 to 1,378 keV
which can be emitted in a single decay event) and 0.95 β-decay electrons
(with the β decay continuous energy spectrum ranging from 0 to 669
keV). In addition, atomic electrons can be emitted with various discrete
energies ranging from 11 to 1,378 keV. In a single decay, the average
total energy output from photons is 813 keV (note the average energy of
the photons is therefore 341 keV from 813 keV/2.38) and the average
electron energy output is 216 keV (7). Therefore, the total average
energy output per decay is 1,029 keV. Our decision to ignore the emitted
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electrons means we are going to ignore around 21% of the total energy
output from the source in our dose-rate calculations. Why is this
justified? The reason is that practical commercial sources used for
Radiation Oncology will be encapsulated radionuclides and that
encapsulation will scatter and slow down the electrons such that most do
not leave the source capsule itself, and for those that do escape, their
range in tissue outside the source is much smaller than 5 mm and thus
will not contribute dose at a clinical prescription distance. This
encapsulation of the source is essential for the clinical use of most
isotopes used in radiation oncology. Historically, in the early days of
radiotherapy, in the United States, a clever technique to enclose radon
gas in glass capsules was developed. The high energy of the β particles
and the light filtration led to unfavorable clinical results (4). We end this
discussion with the observation that there can be a major clinical dose
distribution difference between an encapsulated and an insufficiently
encapsulated radionuclide.
Consider a sample of radioactive material whose largest dimension is
much smaller than 0.1 mm. This will be small enough so that all atoms
can be approximately considered as located at a single point. Restricting
ourselves to the photon emissions from the point source, we will first
think about the dose-rate produced in a small volume (dV) of tissue
located at a distance (r) from the source. For simplicity, consider the
source in vacuum (so no scatter) and that in each decay it emits exactly
one photon with energy E. The situation is shown in Figure 5.1. The
dose-rate in dV must be equal to the product of the following: time rate
of emission of the photons, that is, activity A, the probability of the
photon hitting dV (we will abbreviate that as P(r,dV)), the probability
that the photon of energy E which hits dV actually interacts with dV as
opposed to just passing through (P(E,dV)), and the average amount of
energy (dEabs) that is absorbed in dV whenever a photon interacts with
it, all divided by the mass (m) of dV. The units are energy/mass/time,
which is dose-rate. Explicitly,
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FIGURE 5.1 Point source (S) emission of photons (wavy lines) in vacuum. Direction is random.
Only the photon emitted straight at dV can deposit energy in dV and only if it randomly interacts
with the material in dV.
FIGURE 5.2 Point source (S) emission of photon radiation in vacuum. Cross-sectional area (da)
of small material volume dV faces the source. dV is moved from radius r to radius R causing a
reduced probability of being hit by the photons by the factor r2/R2.
The first question is, what happens to the dose-rate in dV if we simply

change its distance from r to R (Fig. 5.2)? The two things that do not
change, at all, are the activity of the source and the mass of the tissue
that we move around. P(E,dV) and dEabs should not change if the angles
with which the photons hit the volume are similar, that is, the solid
angle subtended by dV is small. So we are left to focus on the probability
of a photon hitting dV. When a nucleus decays and gives off a photon,
that photon is emitted isotropically, which means the photon is equally
likely to go in any direction. Let the cross-sectional entrance area of the
mass m be denoted as da (Fig. 5.2). Of course, the total surface area at a
distance r is 4pr2. So the probability of a photon emitted in a random
direction hitting da after it has traveled a distance r is
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If we move dV to a larger distance R, the probability of hitting da now
equals da/(4pR2). Therefore the probability of hitting da has been
reduced by a factor of r2/R2 in moving from r to R. This suggests that we
can try and approximate Equation 5.4 as simply
where we have defined c = P(E,dV)dEabs/m and we are hoping that c is

constant, under the assumption that the factors in c do not change much
as we move the small volume around in vacuum.
In Equation 5.6, it is understood that we should not move the little
volume of tissue someplace where it makes no sense to assume that c
remains constant. A counterexample best illustrates why it is not true
that c is a constant. Suppose that we had moved the volume dV and
centered it on r = 0, so that it completely surrounded the radioisotope.
The factor P(r,dV), where we got r2 from in the first place, is now P(r =
0, dV) = 1, that is, every photon emitted from the radioisotope hits the
volume. One can easily see from Equation 5.4 that the dose-rate does not
become infinite at r = 0 (as Equation 5.6 implies); in fact, depending on
the photon energy (E) and the size of dV, the dose-rate (from the
photons emitted) could be extremely small. This example clearly shows
that the algorithms we devise to calculate dose-rate have their regions of
validity.
Historically, radioisotope emissions were first measured in air. In
particular, the concept of exposure (1,3,5,6) (amount of ionization of air
per unit mass) was used extensively because charge collection in air-
filled cavities are the easiest measurements to make. The process was:
first, measurement of exposure rate in air; second, conversion of that
exposure rate in air to dose-rate to a small amount of tissue in air; and
finally, conversion to dose-rate to a point in the patient. The result of
this process (1,3) led one to define a dose-rate to a small amount of
water at a distance r surrounded by air as
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where the single constant c in Equation 5.6 is split into two constants. Γ
is the exposure rate constant (1,3,5) (in units of R cm2/mCi/h) which
represented the conversion of photon energy to ionization of air for the
given isotope and fmed (in units of cGy/R) is the conversion constant
from exposure in air to dose to medium (water) at the average photon
energy given off by the radioisotope. Normally, people choose to express
dose to water since its radiation properties are similar to tissue and
measurements were/are made in water. Values of fmed (range 0.88–0.97
cGy/R) and Γ (range 1.45–13 R cm2/mCi/h) for various radioisotopes
are summarized in the literature (1,3,5).
FIGURE 5.3 Point source (S) emission of photon radiation in homogeneous water medium. Wavy
lines are photons, straight lines are electrons, and crosses (x) mark photon interaction points.
Three photons are followed. Photon a: Compton scatters above dV, the electron produced misses
dV, the Compton photon scatters again (just above dV). The Compton electron after slowing down
deposits its remaining energy in dV. Photon b: It was aimed right at dV coming out of S but
halfway there was scattered. Both the Compton photon and electron miss dV. Photon c: Compton
scatters below dV and the scattered photon heads right for dV and is photoelectrically captured
inside dV, its photoelectron (not shown) is absorbed in dV.
In Equation 5.7, we have the dose-rate to water in air, but what we

ultimately want is the dose-rate in water (i.e., to the patient). Let us look
again at a source radiating photons toward dV but this time in a full
water medium. Figure 5.3 shows three examples of photon histories.
First, a photon that was going to miss dV (a in Fig. 5.3) is scattered
several times; eventually, a secondarily scattered electron deposits a
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fraction of the original energy into dV. Second, a photon (b) which is
emitted from the source aimed right at dV interacts on the way there and
no part of its energy reaches dV. Finally, a photon (c) which was going
to miss dV interacts and the scattered photon from that interaction is
completely absorbed in dV.
One thing we might guess is that inverse square is not going to be
valid anymore because how dV absorbs energy is much more
complicated. However, we remember that, inverse square was not a law
anyway, and what we want is an approximation in a restricted region of
interest. In any event, we could start by describing the dose-rate to a
point r in water as
In this equation the major effect of attenuation is represented in the first

term where we exponentially attenuate the in-air dose-rate of Equation
5.7 with the linear attenuation coefficient (μ) for water for the average
energy E emitted by the radionuclide (roughly 0.1 cm–1) (1,3,5). The
exponential attenuation factor takes care of one of these effects above
(photon [b] in Figure 5.3), scatter out of the path from the radionuclide
to dV. Dscat now represents the result of all the various scatter
possibilities and is far more complicated. Equation 5.8 has merely
organized the calculation into a primary part and a secondary scatter
part. Now we note in Figure 5.3 that the attenuation scattering events
[b] reduce the dose-rate in dV but the scatter events [a and c] increase
the dose-rate relative to the (Fig. 5.1) in-vacuum case. Maybe, if we get
lucky, these will cancel out. It turns out that scatter and attenuation
effects do not cancel out at all distances from the source, but close to the
source they almost do and their change with distance farther away can
be simply parameterized. Meisberger et al. (8) showed that the measured
variation in dose-rate in water as r changed from 1 to 10 cm was such as
to establish Equations 5.9 and 5.10 as a good approximation for the
dose-rate to water
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Application of this algorithm (Equation 5.9) has, in the past, been a
popular choice in commercial computerized treatment-planning systems.
Technically, fmed should now be a function of r to account for the lower
energy of the scattered photons with greater distance in water (9,10);
however, that detail is usually ignored. Comparing the in-air Equation
5.7 with the in-phantom Equation 5.9, the difference is simply the
inclusion of the parameterized factor T(r). T(r), the attenuation and
build up factor, is a polynomial in r (Equation 5.10) which Meisberger et
al. (8) used to represent the ratio of the exposure in water to the
exposure in air. The free parameters A,B,C, and D are determined by
least squares fit to the experimental data for each isotope. One notes
(1,3,5,8) that A is close to 1.0 and that B,C,D are on the order of 10–3 or
less. Because of this, the value of T(r) is very close to 1.0 up to a certain
distance. Attenuation and in-scatter are balanced at a distance rA where
T(rA) = 1.0. Hale (11) pointed out that in-scatter cancels out the
attenuation loss, which was not obvious. For instance, if we consider
137Cs (E = 662 keV), the distance is around 3 cm. If we estimate the
reduction in dose from attenuation of 3 cm of water (using μ = 0.086
cm–1) we would expect a 23% drop off. Clinically, the fact that a simple
dose calculation such as in Equation 5.9 can be used, instead of
something as in Equation 5.8, makes calculations easy both by hand and
by early computers and has been extremely useful. The mathematical
form, Equation 5.10, which was chosen by Meisberger et al. (8) for T(r)
is not a unique parameterization of the attenuation and scatter effects.
One could use the form proposed by Evans with equal ease (12)
Kornelson and Young (13) fit the coefficients ka and kb to Monte Carlo
results (14). Venselaar et al. (15) extended the range of the fitted data to
60 cm. Other mathematical expressions (16–18) have been utilized;
there is little difference of clinical significance between them or
Equations 5.9 and 5.11. The reader should note that Equations 5.9 or
5.11 can be used to perform quick hand check verifications of clinical
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implant plans. If one looks at a dose-rate at a point 10 cm from the
implant center, all the implanted sources can be considered
approximately as one point source located at the center of gravity of the
implant. Add all the activities together and calculate the cGy/h value
expected and compare it to your treatment planning system isodose line.
One cannot use this method to determine a small error in the computer
plan result but one can use it to uncover the presence of a major error.
Comparing Equations 5.8 and 5.11, the first term is identical and is
the attenuated primary in-air dose-rate. Comparing the second terms,
one can see that Equation 5.11 assumes that is proportional to the
attenuated primary dose-rate. This is physically reasonable since scatter
comes from the attenuation that occurs in the out-of-path directions and
this should be similar to the in-path attenuation. To the extent that this
is not true, we make up for that by letting ka and kb be completely free
parameters for each different isotope. Fitting the parameters can be done
in two ways: fitting the free parameters to match measured data, or
fitting (13–15) to match a better calculation such as Monte Carlo. All the
parameters (A,B,C,D, and ki) have no direct physical meaning, they are
chosen to allow us to describe the dose-rate as accurately as possible.
Because of that, it is required to keep track over what range of data the
parameters were determined. For example, the best-fit value of D just
happens to be negative (1,3,5,8) for 192Ir, 198Au, and 137Cs. Hence, at
large distances (r > 25 cm), where the r3 term in Equation 5.10
dominates T(r), T(25 cm) is negative, and therefore Equation 5.9
predicts negative dose-rate for those isotopes at large distances. This
negative dose result arises because we have applied Equation 5.9 outside
the range of the fitted parameters and have obtained a nonphysical
(wrong) result.
CALCULATION OF DOSE-RATES AROUND A LINE

SOURCE
In Equation 5.9, we now have an expression for the dose-rate in water
due to a simple point source. We can now apply this result (we could
have just as easily used Equation 5.11 instead) to help us calculate the
dose-rate from different source geometries. The next simplest case is a
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line (length L) of radioactive material (Fig. 5.4). In the point source case,
we had spherical symmetry, which meant that the direction from the
source did not change the dose, only the distance (r) did. With a line
source we need to consider direction and distance relative to the center
of the line. There is still symmetry remaining, specifically rotational and
reflection symmetry, so if we can calculate the dose-rate to every point
in the shaded region of Figure 5.4, the dose-rate anywhere else in the
patient volume is determined without calculating. For example, the
dose-rate at P in Figure 5.4 is the same as at point B (reflection of P with
respect to Y–Z plane), C (reflection of P with respect to X–Y plane), or D
(reflection of B with respect to X–Y plane). Moreover, any point off the
plane (y ≠ 0) of Figure 5.4 that can be mapped to a point in the plane of
Figure 5.4 by a rotation about the z-axis will have the same dose-rate as
that point in the plane.
FIGURE 5.4 Line source geometry. Dose-rate calculation to point P depends on distance and
direction (r, q) of P from the source center. The active length (L) defines angles (q1 and q2) from
the endpoints of the line source to point P. β = q2 − q1 is the angle from P to the endpoints of the
active source. Results need only be calculated for the shaded quadrant, dose to points B, C, and
D will be identical to point P by symmetry, likewise for all points in 3D space obtained by rotation
of the source about the z-axis.
The solution can be found in an analytic form by defining an activity

per unit length (A/L) of source and integrating the point source
expression of Equation 5.9 along the line of the source (dl) to obtain the
dose-rate at any point P(r, q) in the plane (19). The final result
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L is the active length of source and β = q2 − q1 is the angle subtended
by the line source when viewed from point P.
CALCULATION OF DOSE-RATES AROUND AN

ENCAPSULATED CYLINDRICAL SOURCE
Most applications in radiation oncology entail the use of encapsulated
(e.g., stainless steel) cylindrical sources. Consider a cylindrical source S
(radioactive source radius rS, active length L) and enclose it (Fig. 5.5)
inside a cylinder of encapsulation material (radial wall thickness t and
end cap thickness te). Again, we will consider the active source region to
be divided up into many small point sources and determine the
contribution from each point source separately using Equation 5.9 and
add the results. Clearly the first-order effect of the encapsulation will be
to reduce the dose-rate by an amount that depends on the path lengths
through the encapsulation. As the path length through the encapsulation
from every small point source to a given dose point is different, the
reduction will be different in different directions. The solution to an
encapsulated line source was given by Sievert (20). He presented the
equivalent (T(r) was ignored in those days) of the following expression
for the dose-rate at a point P located at planar coordinates r and q
(measured from the radioactive source center, Fig. 5.5)
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FIGURE 5.5 Cylindrical encapsulated source geometry, thickness of encapsulation is t, radius of
source is rS, and the end cap thickness is te. Radioactive material in the source region is
subdivided into N tiny regions. Photons from each of the regions are attenuated by their path
length through source material and encapsulation. Dose-rate at P (located at r, q from center of
source) involves repeated application of point source calculation for all N cubes. For the ith cube,
its distance to P is ri, the path through the source material is dSi, and through the encapsulation is
dei.
where μe is the attenuation coefficient for the radioisotope’s photons

through the encapsulation material, t is the perpendicular wall thickness
of the encapsulation, and q1 and q2 are the angles from the point P to
the ends of the active length of the source. The integral expression in
Equation 5.13 is the Sievert integral, which can be numerically evaluated
with a computer. Young and Batho (21) later provided expressions for an
effective wall thickness accounting for source radius. As an aside, Γ
would be the unfiltered exposure rate constant in Equation 5.13 because
the attenuation of the source’s photons by encapsulation is explicitly
calculated. The differences between filtered and unfiltered exposure rate
constants are discussed in detail elsewhere (1,3,5,6,22,23).
Equation 5.13 is valid for points (such as P in Fig. 5.5) in the patient
where path lengths do not go through the ends of the source.
Expressions (19,20) that give the dose-rate in the other geometrically
distinct regions (through ends of the source capsule) will not be
presented here, as calculations involving numerical integration (21) can
be obtained with computers. We can present a single equation for
calculation anywhere in the region by numerical integration. We
subdivide the source volume into N equal parts. Each little source
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volume element i contributes independently to the dose-rate at P. The
dose-rate at a point P located at r, q, from the center of the source is
given by adding all N exponentially attenuated point source
contributions
where dsi (dei) (Fig. 5.5) are the individual path length distances through
the source (encapsulation) material from tiny source region i to point P.
For a clinical 137Cs source N = 100 is a fine enough subdivision. The
effects of the attenuation coefficient of the source (μs) and its path length
(dSi) are included. The numerical integration method in one form or
another has been used often in the past (21,24–28). In Equation 5.14,
the coefficients μ are either chosen to give the best fit of Equation 5.14
to experimental measurements or directly measured. If the coefficients
are directly measured, one sees that measurements (28) of attenuation
produced by materials relative to attenuation by water work better than
linear attenuation coefficients in Equation 5.14 because the material is a
perturbation of the water medium and not a perturbation of air medium.
ENCAPSULATION AND THE LOW ENERGY PROBLEM

In our discussion up to now, we have avoided details such as where we
get the activity (A) of a given source, what is the correct way of
calculating the exposure rate constant, how does one calibrate a source
and the relationship of the latter procedures to the final step, and
calculation of dose-rate. To get an idea of the ambiguities, consider a
hypothetical encapsulated source where a manufacturer makes the
encapsulation container from lead and the radioactive material emits a
photon of energy 30 keV in half of the nuclear decays and a photon of
energy 1 MeV in the other half. If we were to measure the output of this
encapsulated source we would never detect the decays wherein photons
of 30 keV are produced because the lead would absorb them. The
activity we would infer from measurement would then be less than what
it really is because we would only be aware of half the decays. We
would be in a dilemma to call that measured activity the activity,
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because the activity is essentially a measure of the actual number of
radioactive atoms (Equation 5.2). This example illustrates why there
arose a need for “apparent activity.” In short, the source manufacturer
would tell you the “apparent activity” under the assumption that you
would use the same value of Γ that he used to derive his apparent
activity. Then when you multiply A and Γ together, you will get the
correct result. Look at Equations 5.9 to 5.14; notice that what you need
to calculate the dose correctly is the value of AΓ. You do not need the
true activity A and the theoretical Γ. We emphasize that you have to
check that the value of Γ that the source manufacturer quotes it uses
matches the value in your treatment planning system in order to use the
source manufacturer’s reported activity. As an aside, it is no wonder that
the use of mg Ra eq (1,2,3,5) for quantifying activity lasted so long after
the abandonment of radium implants because everyone agreed that the
value of Γ = 8.25 (R cm2/mg Ra eq hour) for radium filtered by 0.5 mm
of Pt would be the value you would use for all isotopes.
The second problem (opposite in nature to the first) comes from the
details of calibration of the sources. It is easier to measure the emission
output of a radioisotope in air than in water. Suppose a low energy
photon is given off by the source and it gets out of the capsule or is
scattered from the capsule, giving rise to a photon even lower in energy,
and such a photon travels through air and its ionization is measured by
the detector. By everything said above, for determining the activity, that
seems like a good thing (a nucleus decayed and its effect was registered).
However, suppose that photon is so low in energy that it would be
absorbed very quickly by tissue (within an mm or so). Its effect is
included in the calibration of the source in air but clinically it is of no
significance in delivering a dose at a distance in a patient (29). Therefore
its effects should be excluded.
TWO-DIMENSIONAL DOSE CALCULATION FORMALISM

It should be noted that both these problems were present even from the
earliest days of brachytherapy using radium (1–3). The problems were
not a great enough danger to warrant rethinking the dose-rate
calculation formalism till low-energy sources such as 125I and 103Pd
came into clinical use. It has been recently decided to define a more
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consistent method. Task Group 43 (TG43) of the American Association
of Physicists in Medicine (AAPM) recommended the adoption of a new
system (30–34) for calculating the dose-rate to water for low-energy
sources. This system is designed to be consistent from calibration of the
source by the accredited calibration laboratories to the final clinical
calculation for the patient. The 2-dimensional (2D) dose-rate equation
for cylindrically symmetric encapsulated sources in the TG43 formalism
(30) is given by
This dose-rate equation is a 2D calculation as points in the plane with

coordinates r and q are calculated and all other points in 3D space are
then found by rotation about the z-axis. Equation 5.15 is really a choice
between two equations, where X = P signifies that you will use a point
source geometry factor and X = L indicates a line source is used. All
quantities in Equation 5.15 are referenced to a single reference position,
usually ro = 1 cm and qo = 90o (i.e., 1 cm from the source center in a
direction perpendicular to the symmetry axis of the source, e.g., 1 cm
along the x-axis in Figure 5.5). The product SK  is the dose-rate in water
at the reference position, ro, qo.
Two new quantities are defined in Equation 5.15. First, the air kerma
strength (1,30,33), SK, gives a measure of the absolute amount of
radionuclide available. Its source calibration unit U equals cGy cm2/h by
definition. The air kerma strength is the air kerma rate in vacuum times
d2 (due to photons of energy greater than a cutoff energy, >5 keV,
measured with a free air chamber centered at a distance d); d is usually
1 m. This energy cutoff (5 keV) is chosen so that the calibration effects
of low-energy photons (which ultimately would not contribute to tissue
dose at distances greater than 1 mm from the source) are subtracted
from the calibration result. Source manufacturers now provide both the
air kerma strength (referenced to the reference position) as well as
apparent activity (for historical comparison). Typical conversions from
air kerma strengths to “apparent activity” values (U/mCi) for isotopes
used clinically are 1.27, 1.29, 2.86, and 4.12 for 125I, 103Pd, 137Cs, and
192Ir, respectively.
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The second new quantity in Equation 5.15 is the radionuclide’s dose-
rate constant,  (units = μGy/h/U at 1 m). The dose-rate constant is the
ratio of a reference dose-rate (ro,qo) in water to SK. The dose-rate
constant is determined once and for all for each manufacturer’s source
via Monte Carlo modeling plus experimental measurements usually with
thermoluminescent dosimeters (TLDs) (30,31,35–38). There are errors in
both methods, so results are averaged to produce a “consensus” value for
 (31,35).
G(r, θ) is a new symbol for the simple geometry dependence already
seen in Equations 5.9 and 5.12, namely, point (P) source and line (L)
source (30,31,39). G accounts for the main effects of distance and
direction of source from point of measurement. TG43 defines GP and GL,
The ratio of G(r,q) to the reference value G(ro,qo) is explicitly indicated

in Equation 5.15.
In Equation 5.15, the radial dose function g(r) redefines the traditional
attenuation and scatter build-up factor. It accounts for photon
attenuation and scatter in water in the radial direction to the source
symmetry axis (qo = 90o). The radial dose function is essentially
fmed(r)T(r) renormalized so that g(ro) = 1.0. Since we know that the
parameters of Equation 5.10 can be fitted accurately, it is not surprising
that a polynomial expansion can be used to accurately represent g(r)
where X = P or L means that one compares their dose-rate data (at

varying positions r with qo = 90o) to their calculations using Equation
5.15, and determines the six coefficients ai in Equation 5.18 using point
or line source formula Equations 5.16 or 5.17 for the geometry factor.
The dose-rate data required to determine the radial dose functions come
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from Monte Carlo calculations and are verified by measurements. Each
radioisotope has its own set of ai determined (5,30,31,40,41).
The anisotropy of source distribution function F(r,q) is introduced to
account for differences in dose-rate as a function of angle from the
symmetry axis due to the specific geometry of the encapsulation of the
radionuclide source. In other words, it takes into account the different
path lengths through the source and encapsulation at various angles. If
we have information on the dose-rate in all directions (such as from
Monte Carlo modeling or numerical integration or the Sievert integral)
then the anisotropy function can be determined (5,30,42–44) from
Equation 5.15. The normalization for F is, F(r, qo = 90o) = 1.0.
In high dose-rate afterloader applications using 192Ir (Chapter 16),
there is a single high activity cylindrical source. Optimization techniques
(Chapter 16) are used to vary source dwell times at various positions in
fixed implanted catheters. Because you must localize the catheters to
plan the patient, you have the orientation of the source symmetry axis in
the patient at all possible dwell positions and therefore you can
determine the angle q in Figure 5.4 for any position P. Therefore one
uses the 2D dose calculation (X = L) of Equation 5.15. Similarly 125I
seed sources loaded into a fixed geometry eye plaque for ocular
melanoma treatment can use the line source form.
There is a practical problem in using Equation 5.15 for cylindrical
sources that are not constrained to be in a definitive geometric
orientation by the applicator which holds them. Namely, it is not always
easy to determine orientation. Consider permanent prostate implants
which use 125I seed sources. Computed tomography (CT) scans and/or
radiographs cannot easily provide the necessary resolution to determine
the line direction in 3D space for all the sources, (though methods are
being developed to do that (45,46)). So we definitely have line sources
but we cannot determine each angle q (from each and every source to
each and every point P). Thus we are forced to use the point source
geometry factor. In this event, one can use a better approximation (31).
Although the anisotropy function is a function of r and q, one can
average F over the 4p geometry and F can be approximated by a simple
radial function, fan(r), called the 1-dimensional (1–D) anisotropy
function, e.g. this results in a roughly a 5% reduction for 192Ir (5,31).
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Where a 2D calculation cannot be used for cylindrical sources, the
revised TG43 protocol (31) recommends the use of
Compare Equation 5.19 to Equation 5.15 (with X = L) with respect to

the geometry function. In Equation 5.19, the line source geometry
formula is used but regardless of what the angle q is on the left side of
the equation, we evaluate the right-hand side using q = qo = 90o. The
advantage of Equation 5.19 is that it is more accurate for cylindrical
sources at distances less than 1 cm than if we use Equation 5.15 with the
point source approximation (X = P).
It is important to understand the methodology behind the 2D dose
calculation algorithm provided by Equation 5.15. A point or line source
approximation for the geometry function is chosen (this choice is
determined by practical realities in most cases as almost all clinical
sources are cylinders). Experimental measurements and/or Monte Carlo
calculations provide the desired 3D dose distribution answer. The radial
dose-rate function in point source geometry is then determined by
choosing the parameters of Equation 5.18 so that multiplying all the
factors together at points where q = qo = 90o yields the correct dose-
rate (which you already know from the full 3D Monte Carlo result) at
those points. Once you have that, you can determine the anisotropy
factor, in the same way using the already known correct dose
distribution. One can either store a table of results (5,30,31) or create a
fitting function to reproduce the results. Furhang and Anderson (47)
proposed the functional form:
where a, b, c, and d are polynomials in r with a total of 12 free

parameters. Sloboda and Menon (48) fit those parameters to the results
of Monte Carlo calculations. Ling et al. (49) had also used a similar
parameterization to fit the dose-rate results for an 125I source.
Equations 5.9, 5.11, 5.12, and 5.14 can be converted to the more
modern formalism by substituting SKg(r) for fmed AΓT(r). For example,
Equation 5.14 for the dose-rate about a cylindrical encapsulated source
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would be
where SK would have been determined for the encapsulated source;

hence already accounting for source size and encapsulation, we subtract
the source radius, rS, and the encapsulation wall thickness, t, from the
path differences.
Finally, let us review the rationale of the change in Equation 5.15. In
the old system, calibration in air, calculation in air, and then conversion
to dose in medium was the calculation process. The new TG43 system is
more akin to external beam calculations. In Equation 5.15, SK is the
cGy/h calibration in water at a reference position (the analog of linear
accelerator calibration at dmax). The product of G(r,qo) and g(r) is like a
depth dose correction along the x-axis in Figure 5.4 normalized at ro.
Finally, F(r,q) is like external beam off axis ratios. Looked at in this way,
the new formalism does not look so foreign.
THREE-DIMENSIONAL DOSE CALCULATIONS—

ASYMMETRIC DOSE DISTRIBUTIONS REQUIRED BY
APPLICATORS AND SHIELDS
Some treatments involve the use of asymmetric metal applicators to
introduce the radioactive sources into the body. In treatment of
carcinoma of the uterine cervix (1,2) some of the applicators have
tungsten shields attached, which provide a severe asymmetry in the
measured dose-rate distribution. The measurement (27,28,50,51) of
dose-rate in the presence of these asymmetries shows that the effects are
to reduce dose-rate in particular directions (geometric shadow of the
shields) by up to 40%. These applicators clearly have an effect on the
dose-rate distribution that is different in different directions; hence the
dose-rate algorithm must calculate dose-rate over the entire 3D grid
centered on the source (25,27,28,52–54). Now because clinical use
involves a source loaded into the same applicator with shields every
single time, the calculation can be done once for the
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source/applicator/shield and the result for that dose distribution stored
on the computer. Figure 5.6 shows that the dose point P has paths from
the various source volume elements that miss or go through the shield.
Numerical integration can be extended to this case quite easily, thereby
accounting for primary attenuation for path length through source (S),
encapsulation (e), shield (Sh), and applicator housing (A). The
expression is the following:
FIGURE 5.6 Asymmetrical source/applicator/shield geometry. Radioactive material in source

region is subdivided into N tiny regions, photons from each of the regions are attenuated by their
path length through source material, encapsulation, shield material, and applicator material. Dose-
rate at P (located at r, q from center of source) involves repeated application of point source
calculation for all N regions. For the ith cube, its distance to P is ri, the path through the source
material is dSi, through the encapsulation is dei (the latter two are not shown here, see Fig. 5.5),
the path through the shield material is dShi, and the path through the applicator material is dA i.
For the jth cube, its distance to P is rj, its path misses the shield and the path through the
applicator material is dA j.
The path length intersection differences (d) have to be evaluated for

every direction and the μ are free parameters. The strength of Equation
5.22 is that it is simple and the 3D results can be obtained clinically fast.
The 3D calculation for a point P in Equation 5.22 involves numerous ray
line (the radial direction from each source subvolume piece to the point
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P) calculations. The attenuation produced by the metal structure along
each path is accounted for, which is the greatest effect. However, the
metal structure off the ray line path to point P (secondary effect) is
ignored in Equation 5.22. For example, in Figure 5.6 the evaluation of
the contribution to dose at P from source subvolume j is the same
whether there is a tungsten shield present in the applicator or not. In
Equation 5.22, it is g(r) which represents scatter, determined from the
case of a homogeneous water medium. We are assuming in Equation
5.22 that g(r) is the same when a nonwater material is lateral to the ray
line. Equation 5.22 is a very fast calculation method and comparison to
Monte Carlo calculations (53) show it works very well for 137Cs. Lower
photon energies require a method to deal with scatter.
Reasonably fast 3D methods having a scattering component, have
been developed by Williamson (52) and Russell and Ahnesjo (55). Monte
Carlo calculations of dose results for source/applicator and just source
are each separated into primary and scattered components. Monte Carlo
calculations are used to create precalculated distance-dependent scatter
ratios that are a function of distance and mean free path in the patient.
Surprisingly, scatter is shown to be fairly isotropic about each applicator,
so scatter dose can be treated as a distance-dependent but angle-
independent term. This approximation speeds up the calculations. As
Williamson (52) points out, this demonstration of the simple angle-
independent nature of the scatter also explains why formalisms such as
Equation 5.22 work very well for the high-energy photons of 137Cs. At
larger distances from the implant or for lower-energy isotopes such as
125I, the scatter separation method remains accurate.
Generalization of the TG43 2D dose calculation formalism Equation
5.15 to a form suitable for 3D dose calculation would look something
like this:
F(r,q,φ) is extended to explicitly include the angle φ dependence, 0 < φ

< 2p and includes all angular variations. F could be described by a
function such as Equation 5.20 with the 12 free parameters themselves a
function of φ. This would then involve hundreds of parameters.
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At this point, historical review helps us understand that simple
equations such as Equations 5.9 or 5.11, among others, arose because
the developers needed some simple equation to calculate or check
treatments by hand. Today, many parameter fits (such as Equation 5.23
would require) can easily be done on a computer. However, it is also
true that characterizing the dose-rate calculation directly using Monte
Carlo over a full 3D volume 20 × 20 × 20 cm3 and storing such a 3D
matrix would not be a problem either. So one could follow the historical
development and precalculate the Monte Carlo result, then fit the
parameters of Equation 5.23 to the Monte Carlo, throw away the Monte
Carlo result and use Equation 5.23 with the large number of parameters
to calculate the dose distribution. Alternatively, one could just store and
use the Monte Carlo results directly (after smoothing to minimize
statistical errors). Therefore it is unlikely that the description of the
results of 3D dose calculations will follow TG43 in describing the dose-
rate as a product of several fitted functions whose parameters were
found by comparing to Monte Carlo results. Instead “consensus” 3D
Monte Carlo generated dose-rate matrices normalized to the dose at a
reference position could be provided.
THREE-DIMENSIONAL TREATMENT PLANNING WITH 3D

DOSE DISTRIBUTIONS
If we have a precalculated 3D dose-rate distribution, how do we use it
clinically? It is necessary to determine the position and orientation of
each source’s 3D dose distribution in the patient. Figure 5.7 shows a
single source, which is arbitrarily angled in the patient. The patient
coordinate system (x, y, z) is defined by a 3D imaging device such as a
CT scanner. The 3D dose-rate distribution of the source/applicator
would have been (pre-)calculated in a coordinate system (x′, y′, z′)
centered on the source. This is the intrinsic coordinate system of the
source/applicator system. If there was cylindrical symmetry about the
intrinsic z′-axis, there would be no need to determine in what direction
the x′ and y′ axes are oriented in the CT scan coordinate system, but here
we are assuming there is no symmetry whatsoever. We define as the
calculated dose-rate distribution in its own intrinsic coordinate system
for a unit air kerma strength source. So in Figure 5.7, the dose-rate at
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point P (located at in the CT scan) produced by the source (located at
implies looking up the value for from the precalculated 3D matrix.
We therefore need to determine the vector (distance and direction) In
practice, this requires that we determine which way the x′,y′,z′ axes
point in the CT scanner. Now , the vector from S to P, is the same
vector as only expressed in the coordinates of the CT scanner. These are
shown in Figure 5.7 and related via
FIGURE 5.7 Relationship between patient coordinate system (as defined by a computed
tomography [CT] scan) and the internal dose-rate calculation coordinate system of a
precalculated 3D source, which is rotated relative to the CT system. The center of the source is at
rS (relative to the CT scan). Point P in the patient is located at rP in the CT scan but at r′p relative
to the internal source coordinate system. rPS and r′p are physically the same vector, expressed in
CT and intrinsic coordinates, respectively.
where E(α,β,g) is the rotation matrix (56) for a solid body and α,β,g are
the Euler rotation angles, which rotate the intrinsic coordinate system of
the source in correspondence with the CT coordinate system. Our
problem is to find the three degrees of rotational freedom, the Euler
angles. Finding both ends of the source defines a line in space and
decides the z′-axis orientation (equivalent to two degrees of freedom).
The last degree of freedom (rotation about that line) is found by
identifying a landmark in the CT scan not on the z′-axis. Methods and
equations for calculating the Euler angles based on this information have
been given for particular 3D source/shield/applicators (57). One last
problem is that CT scans do not determine absolute position with a
precision better than one-half the scan spacing. Three-dimensional
graphic positioning of the entire applicator can make the determination
more precise (57).
Continuing on to the case of multiple sources, in Figure 5.8, the dose
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at point P from two sources requires that the orientations of both sources
be determined. In order to look up the value for and , we have
to determine and . So the Euler angles for two coordinate systems
must be found. For N sources we use Equation 5.24, and the total dose-
rate in the patient’s 3D coordinate system for N sources is given
by
where SKi is the source strength and is the inverse of the Euler
rotation matrix for the ith source. The Euler angles (αi,βi,gi) for each
source must be determined. It is the latter task, which is the additional
work needed to implement 3D dose distributions in a clinical real-time
setting (57).
Once a dose-rate calculation algorithm has been implemented there
are two choices in calculating the total 3D dose-rate distribution in the
patient from a multitude of sources (enclosed in applicators with or
without metal shields). They are (a) dose superposition, that is, addition
of individual source/applicator dose distributions independent of the
presence of the other sources (Equation 5.25 is dose superposition), or
(b) direct dose calculation, that is, using the calculation algorithm with
all the sources and applicators accounted for in the calculation. The first
is the least computationally taxing because the dose-rate matrices ( )
may be precalculated. The second method is what would be used in real
time clinical Monte Carlo or GBBS applications using CT data.
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FIGURE 5.8 Superposition approximation. The dose-rate at P is found by adding the contribution
from source 1 (assuming source 2 is not present), to the contribution from source 2 (assuming
source 1 is not present). The internal coordinate system for each source is shown. Only two out of
three axes are shown.
Commercial treatment-planning systems currently use dose

superposition. How important is it to correct for interapplicator
shielding effects, and patient inhomogeneities? The answer depends on
the number of sources, shields, or applicators and their positions relative
to one another. At this time, it is not clear how important these effects
are to clinical applications. Let us try and estimate this for one particular
example where we have a significant amount of metal in the form of
tungsten shields in an applicator. Consider Figure 5.9, which shows just
two sources. Let the point P be at a distance of 2 cm from the center of
source 2 and 4 cm from source 1 on the left. It is reasonable to assume
that the perturbation of having source/applicator 1 to the left of
source/applicator 2 cannot affect the contribution that source 2 makes to
the dose at P very much. Therefore, that part of the total dose stays the
same for dose superposition or direct dose calculation. However, it is
obvious that having source/applicator 2 in between point P and source 1
changes the dose contribution of source 1 to the dose at P. Crudely, we
will estimate the error using inverse square considerations alone. In dose
superposition, the contribution of source/applicator 1 is roughly (2/4)2
= 1/4 of the contribution that source/applicator 2 makes to the dose-
rate at point P. So if source/applicator 1’s contribution is reduced by
33% (which would only be for points fully in the shadow of the shield),
the error in the dose-rate (caused by forgetting about interapplicator
effects, as you do for dose superposition) would be roughly 1/12 or 8%
of the total dose. In treatment of carcinoma of the uterine cervix (2)
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(Figure 5.9 is an example in a plane through the ovoids to a point lateral
to the ovoids) this 8% difference would be reduced even more by the
dose-rate contributions from the tandem sources, whose contribution to
P would be about the same in superposition or direct calculation.
FIGURE 5.9 Direct calculation of dose from multiple sources. Two radioactive source calculation
including attenuation effect of all regions. Sources 1 and 2 are subdivided into N regions each.
Dose-rate at P involves repeated application of point source calculation for all 2N regions and
calculation of path lengths through each region from both sources. For the ith cube in source 1, its
distance to P is rS1i, the path goes through source 1’s source material, encapsulation and
applicator material, it then enters and leaves source 2 on the way to point P. It passes through
source 2, shield 2 and through the second applicator (entering and leaving). For the jth cube in
source 2, its distance to P is rS2j and the path does not pass through source 1 and only intersects
its own materials.
In low dose-rate permanent implants of the prostate, one may have up

to 100 125I stainless steel clad sources in a 40 cc volume. Potentially, the
overall inhomogeneity effect caused by seed-to-seed attenuations might
be severe especially since the photon energy is low. Burns and Raeside
(58) in a Monte Carlo study of a model two plane implant showed that
the shadowing effect reduces the dose in the interior of the implant, but
this reduction was not enough to drop the dose below the reference
prescription dose. So, the significance is that very high doses here and
there inside the implant region are not really as high as one thought.
Meigooni et al. (59) also studied interseed effects for 125I and found
through measurements that variations were not only dependent on
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direction but that overall, the dose at the periphery of the implant is
reduced by 6%. Chibani et al. (60) used Monte Carlo simulation and
found similar results for 125I and 103Pd. Based on these studies it is not
easy to see the need for any correction other than possibly a 5%
reduction of predicted overall dose to the periphery. We emphasize that
these studies justify a dose documentation correction, not a 5% boost of
the seed activity/strength. The latter is a completely different question
which is beyond the scope of this chapter. At the present time, it is
unclear (61) whether these corrections are needed in permanent seed
implants.
Finally, as regards patient heterogeneities, this problem is harder still
to evaluate since the variations can be endless. Das et al. (62) found that
the dose beyond bone is most affected and that the perturbations of the
dose distribution are too complex to be modeled by simple dose
calculation algorithms, so Monte Carlo calculations must be used.
Meigooni and Nath (63) used measurements plus Monte Carlo simulation
and found in their model that lower-energy sources such as 125I and
103Pd have significant changes in dose due to patient heterogeneity
whereas 192Ir does not. Calculation methods to produce simple
corrections have been proposed by Williamson et al. (64). They used
Monte Carlo generated primary and scatter components and
incorporated empiric parameters into a scatter subtraction method to
gain the advantages of Monte Carlo computation but with a large saving
in computation time. Agreement with full Monte Carlo simulations was
within a few percent in most examples considered. Furstoss et al. (65)
studied both interseed and breast tissue heterogeneity effects for 125I and
103Pd seed permanent breast implants using Monte Carlo simulation. At
these low energies, they found that breast tissue can change D90 by 10%
relative to the homogeneous water case, interseed attenuation is not
important.
THREE-DIMENSIONAL DOSE CALCULATIONS—MONTE

CARLO AND BOLTZMANN TRANSPORT TECHNIQUES
In this section, we move away from macroscopically parameterized
calculations and calculate the dose distribution using microscopically
parameterized functions. These calculations can handle all
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inhomogeneities as straightforwardly as the homogeneous case. The
techniques require significant computer power which are now available.
The techniques are feasible for brachytherapy applications because the
distances and volumes of interest are small. The method of Monte Carlo
(66–69) involves the concepts figuratively expressed in Equation 5.4 at
the start of this chapter. Namely, a photon leaves a radioisotope in a
random direction and when it hits something, there is a chance of
something happening, or not. In Monte Carlo, a photon is randomly
created, starts off in a random direction, and each step of the way has a
probability (cross-section) of photoelectric interaction, Compton
interaction, pair production, or coherent scattering. If it spits off an
electron at a certain location headed in a certain direction determined
by a “roll of the dice,” that electron loses energy (6) as it moves through
the medium. The medium is split into small volume regions (cells), as
electrons lose energy in those cells; that energy loss is tallied as being
deposited into that cell. So after the one photon has left and all its
scattered photon and electron descendants have ended up as too low in
energy to escape any more cells and are absorbed, you say that one
history has been completed. After that first history, almost every cell
volume around the source has zero dose because most cells were either
not geometrically hit by anything or, if hit, no interaction event occurred
within them. In order to get useful results we will have to rerun this
“rolling of the dice” process over and over again. The computer is tailor
made to handle this task, many millions of times or more to finally get
smooth continuous results close to the source. We note that Monte Carlo
simulation tries to mimic what is happening in the patient. Monte Carlo
is sometimes thought (67) of as a simulated measurement process
carried out on the computer.
The errors in Monte Carlo are of two types, systematic and statistical.
The systematic errors arise from the fact that the scattering cross-
sections are themselves parameterized approximations to the real atomic
scattering. When Monte Carlo is used in Radiation Oncology to predict
average macroscopic properties such as dose distributions, these errors
are insignificant. The random statistical errors arise because of the need
to stop the calculation in some finite time, before statistical variation in
each and every volume element of the patient is rendered insignificant.
The details can be misleading. Suppose we use 50 million histories in a
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Monte Carlo modeling of a prostate HDR treatment, this seems like an
enormous number. In that case a 10 Ci source can expose the patient for
300 seconds and therefore, the actual treatment involves around 1014
photon histories. So the seemingly huge Monte Carlo computation
models 2 million times less decays than the real treatment. Looked at the
other way, the 50 million history Monte Carlo calculation represents
what we would expect from a less than millisecond HDR treatment. In
Monte Carlo, the statistical uncertainty in the dose varies in the patient.
The uncertainty is larger the farther away from the source distribution
which one considers. Near the source distribution, the 50 million
histories modeling are usually acceptable. If not, run more histories.
Monte Carlo for brachytherapy investigations has a long history
starting with Berger’s work (66), which provided analysis and insight
into Meisberger et al. results (8). The encapsulated radioactive source
can be modeled and the relationship between calibration, measurement,
and calculation of 3D distributions determined. An unequaled advantage
of Monte Carlo is in handling any case regardless of complexity. All that
is required is to determine the radionuclide spatial distribution and the
positions of the inhomogeneities, subdivide each into regions, subdivide
the entire patient region of interest into small regions, and let the Monte
Carlo program run until the results stop changing significantly. This
advantage cannot be too highly praised. Consider that the Monte Carlo
N-Particle (MCNP) (67) input used for full 3D calculations of a
source/shield/applicator (53) required typing only 100 lines of text.
Meanwhile experimental measurements of 3D dose-rate distribution for
the same and similar applications (28,50,51) involved machining of
positioning devices to allow rotation of applicators with high precision
in water tanks. Measurements are made in different orientations and the
results have to be merged together. It is obvious which is easier.
Monte Carlo is also useful even when you are not going to use it
explicitly. All the approximations for dose-rate calculation in this
chapter involve parameters. If one fits the values of the parameters of
your algorithm to best match the results of Monte Carlo simulations
(53), then one obtains a parameterization which one can have more
confidence in than from the traditional method of fitting to experimental
results (28). The reasons for this were pointed out by Boyer (70)
regarding the limitations of brachytherapy measurement, for example,
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finite size of detectors, energy response changes of detector with
distance, and so on. Monte Carlo does not have these limitations. Monte
Carlo does have the limitation or more precisely the requirement that
the source emission spectrum (7) must be precisely known and that the
exact specifications of source/applicator construction are defined
correctly. Because of that, there is still a need for measurement but only
to spot check the results at a few points for confidence that the above
requirements are correct. In summary, Monte Carlo simulation is some
part of every brachytherapy dose calculation.
Recently a new method (71–73) has been proposed for brachytherapy
dose calculation. Suppose we return to our 50 million history Monte
Carlo example and rerun it again on the computer. We would obtain a
different (albeit similar) dose distribution result. If we could (we cannot)
run the actual 1014 histories, get the results, and then rerun that
simulation once more and compare, we expect that we would have no
significant difference in results. Therefore there is an expectation that an
exact solution exists, that is, an infinite history solution. To find that
solution we turn to methods for solving the linear Boltzmann transport
equation (74) that were developed at Los Alamos National Laboratory
(75,76). The Boltzmann transport equation governs the motion of a
particle in a fluid subject to random collisions. It has no analytic
solution. To make the problem computationally feasible, the scattering
energies and angles are discretized and the equations are solved on a
grid of discrete points. The technique is called lattice or grid-based
Boltzmann solvers (GBBS) (77). We can understand this method applied
to radiation as having the radioactive source creating the driving flux of
photons (Fig. 5.10). This photon flux flows out, suffers random
collisions, and is both modified and creates electron flux. The solution
which GBBS finds is the resulting photon and electron final total flux at
every grid position throughout the patient. These fluxes are also
determined approximately in the Monte Carlo method but far faster in
GBBS, thousands of times faster. Error in GBBS is systematic not
statistical. It is said that the solution is exact (77). However, the
solutions of the differential equations can be affected by the
aforementioned discretization approximations. Hence there is a danger
that the solution could be incorrect. As in Monte Carlo, this is a
technique wherein more and more computer processing power makes
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the calculations more and more reliable in shorter times.
FIGURE 5.10 Point source S of single energy photons, photon flux ΨS in homogeneous medium.
Resulting identical photon flux Ψ at positions 1 to 3 and lower energy flux at position 4. Monte
Carlo or GBBS can do no better than equal the accuracy of simple parameterized point source
dose calculations.
FIGURE 5.11 Source distribution S and dose at five positions in the presence of bone (grey) and
air (blue). Only Monte Carlo or GBBS can accurately predict dose at all positions.
In Figure 5.10, we show the photon flux in the homogeneous case,

assuming a single energy point source emitter. As one goes away from
the source the intensity of the orange photons drops (line gets shorter),
other lower-energy photons (shades of blue) appear at different angles.
Electron flux is not shown. The assumption with GBBS is that the
resulting flux at positions 1 to 4 cannot be random and must be definite
and related to each other via the transport equations. Let us compare the
use of Equation 5.15 with Monte Carlo and GBBS to illustrate the
advantages and disadvantages. In Figure 5.10, if we used Equation 5.15,
the dose which we would calculate at equally distant positions 1 to 3
would be exactly equal and correct. Assuming position 4 is 10 cm away,
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the dose would be roughly accurate. In contrast, with Monte Carlo the
dose would be very close to correct for positions 1 to 3 but the doses
would not be exactly equal because of statistical error. With GBBS, the
dose would be exactly equal and correct for positions 1 to 3. Both Monte
Carlo and GBBS would be more accurate for position 4 especially if it
were much greater than 10 cm away. Therefore, for the homogeneous
case, really nothing is to be gained over any of the historical methods of
dose calculation by using Monte Carlo or GBBS. In Figure 5.11, we show
a source distribution S, and dose points in the presence of
inhomogeneities, grey is bone, blue is air. If we use Equation 5.15
(assume we can ignore intersource attenuation effects), the calculated
doses at a prescription point such as D5 or D1 are very accurate, while
the dose at D2 is fairly accurate (unless position 2 is very close to the
bone), the dose at D3 is underestimated, and D4 is overestimated. On the
other hand, for Monte Carlo and GBBS, all doses are accurately
predicted; moreover, intersource attenuation effects need not be ignored.
There is no question, that if inhomogeneity is present, the Monte Carlo
and GBBS are superior in dose calculation accuracy throughout the
patient.
FUTURE DIRECTIONS IN 3D DOSE-RATE CALCULATION

ALGORITHMS
At the present time, commercial treatment planning systems do not
provide 3D calculation of dose and do not allow precalculated 3D dose
matrices to be used for planning. TG43 formalism is supported for all
sources. It is clear that only Monte Carlo and GBBS can handle all
difficulties in brachytherapy dose calculation. One reason is that
heterogeneities do not hamper the accuracy of these methods. If the
Monte Carlo calculation is deciding whether a photon will randomly
scatter as it goes through bone or if it is going through water, it is all the
same for the computation procedure. A similar statement applies to
GBBS. There is not much extra computation power needed for the
interapplicator/patient heterogeneity calculation relative to a
homogeneous calculation. Of course, the calculation time plus time for
identification and accurate orientation of all sources, and applicators in
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the CT scan and definition in the Monte Carlo or GBBS calculation
framework is still not a real-time clinical reality except in special cases.
However, all these problems will eventually be addressed using
increased processing power both for calculations and image analysis. In
the future, we expect to be able to take all inhomogeneity effects into
account using full clinical Monte Carlo or GBBS calculations.
Recently, BrachyVision (Varian Medical Systems, Palo Alto, CA) has
introduced a GBBS option for their HDR treatment planning system. The
user generates an optimized plan using Equation 5.15 to calculate dose
and thereby determine all dwell times. After completion, he or she have
the option to run a GBBS calculation. This documents the dose
distribution in the patient accounting for all inhomogeneities. This
calculation takes less than 10 minutes. What the user does with that
information is not clear. That the information is now available is
noteworthy. However, it would be a mistake to think that the fact that
the inhomogeneity corrected dose is different than the homogeneous
dose, justifies changing the integral dose (1) to the patient. That is a
more complicated question.
The last paragraph indicates that (unexpectedly) GBBS has leap-
frogged Monte Carlo in regard to individual patient-specific clinical
utilization. A problem with commercial implementation of Monte Carlo
is when do you stop the calculation, that is, how many histories? That
can be a function of the geometry of the case itself. Since even the
homogeneous case takes too long, to design a software system to run
more histories than you ever expect to need is not feasible today. So the
reasons for GBBS success are increased speed and that GBBS provides an
“exact” solution. The former is easy to understand, the latter should be
accepted with caution. Since the solution is exact (and hence when it
completes, you are finished) it is a huge software design advantage.
There is one potential problem. Namely, what happens to the “exact”
solution when you have artifact in the CT scan, or misinterpretation of
the size or density of metal objects or calcifications. Since in GBBS the
dose results in all areas of the patient are linked by the differential
equations, this could result in the prescription dose result being made
inaccurate by other less important regions of the patient being
incorrectly specified. This could mean that the “exact” solution is
“exactly” wrong. Whether it is possible to be clinically significant wrong
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is unclear at this time. Having said all that, one has to be excited by this
new development as much will be learned from it, and in the current
GBBS implementation for HDR, Equation 5.15 still determines the actual
clinical treatment.
SUMMARY
The history of algorithm development was that extensive use of
measurements led to simple calculation algorithms based on a point
source. Using numerical integration these were extended to cylindrical
geometries of varying complexity. These developments were then
improved by comparison to specialized Monte Carlo studies. The rise in
computer power made available more extensive Monte Carlo
investigations. These Monte Carlo studies more precisely determined the
best parameters of the calculation algorithms to give a better agreement
with experiment and later permitted a unification of source calibration
and clinical calculation of dose. The ease of these investigations has
made extensive 3D measurement projects a thing of the past. In fact, the
GBBS literature bypasses experimental measurements and compares to
Monte Carlo for justification. The GBBS will have a greater utilization in
clinical practice as it is faster than Monte Carlo and gives definite
results. As computer power increases in the future, the power and
dominance of these two techniques in providing detailed dose
distribution results will increase. It will then seem as if all the simple
equations are no longer needed as advanced computer modeling has
superseded them. One notes that none of the governing equations for
Monte Carlo or GBBS were given in this chapter. There is no need as no
one is going to use them to check the dose in a patient. The vast
computational labor of these methods is such that only the computer can
produce the results. It is then that the historical methods reappear as the
only way to check that the computer results can be believed. One is
advised to always do exactly that.
ACKNOWLEDGMENTS
The author gratefully thanks Glenn Glasgow, Ph. D. for useful discussions,
Vania Arora, MS, for a careful reading of the manuscript and Mr. Paul
Weeks for producing the figures.
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KEY POINTS
• Historical calculations for a source calibrated to specify its activity
use Equations 5.9 or 5.11.
• Modern TG43 calculations for a source calibrated to specify its
dose-rate in water at a reference position use Equation 5.15.
• Dose at a point near a cylindrical source should be calculated using
a line source approximation.
• Monte Carlo simulation has been essential to accurately determine
the basic parameters needed for Equations 5.9, 5.11, or 5.15.
• Increasing computer power, will eventually lead to using Monte
Carlo and GBBS approaches for individual patient treatment
planning.
QUESTIONS
1. If the air kerma strength (SK) doubles and the distance doubles,
the dose-rate at a given point most nearly
A. Decreases by 50%
B. Doubles
C. Remains the same
D. Decreases by 25%
2. If a 0.5 mCi 192Ir source (Г = 4.6 Rcm2/mCi h) is replaced by a
0.5 mCi 125I source (Г = 1.45 Rcm2/mCi h), the initial dose rate
at 1-cm most nearly
A. Increases by a factor of 2
B. Decreases by a factor of 2
C. Remains the same
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D. Decreases by a factor of 3
3. If a SK = 2.0 U, 192Ir (^ = 1.12 cGy/hU) source is replaced by a
SK = 2.0 U, 125I source (^ = 1.036 cGy/hU), the dose rate at 1-
cm most nearly
A. Increases by a factor of 2
B. Decreases by a factor of 2
C. Remains the same
D. Decrease by a factor of 3
4. Consider a 192Ir source and an ion chamber separated by 10 cm
and fixated at the same height in an empty tank. As water is
poured into the tank, the ionization reading from the ion
chamber is observed in three regions. First region, water level
getting closer to the source–chamber height; second region,
water level covers the source–chamber; and third region water
level rising higher in the tank above the source and ion chamber.
Observation of the signal from the ion chamber as the tank fills
would show that the signal:
A. Remains the same, increases, increases
B. Increases, decreases, increases
C. Increases, stays the same, increases
D. Increases, decreases, decreases
5. Consider a 125I seed source with an air kerma strength of 0.6 U,
use TG43 formalism to calculate the dose rate at r = 2-cm and q
= 30° in Fig. 5.4. (Use the line source geometry factor, L = 4-
mm, gL(2) = 0.819, ^ = 0.965 cGy/hU and F(2,30) = 0.842)
A. 0.02 cGy/h
B. 0.1 cGy/h
C. 0.2 cGy/h
D. 0.4 cGy/h
ANSWERS
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1. A From Equation 5.15, air kerma strength change increases
dose by factor 2, distance change decreases dose by factor
4. Dose drops by a factor of 2.
2. d Exposure rate constant for 125I is more than three times
smaller than that for 192Ir.
3. c Dose rate constants for the two isotopes differ by less than
10%.
4. B In the first region, increasing scatter from rising water
increases the dose-rate; in region 2 as water covers the
path from source to the chamber, attenuation decreases
the dose-rate; in third region, increasing scatter from rising
water above the source increases the dose-rate.
5. B Note when you calculate the line source geometry ratio in
Equation 5.15, when L << r the result is very close (in
this case, within 2%) to simply using the point source
approximation. Far enough away, all source distributions
look like point sources.
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Wiley; 1957.
57. Weeks KJ. Brachytherapy object oriented treatment planning using
three dimensional image guidance. In: Thomadsen B, ed. Categorical
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course in brachytherapy physics. Oak Brook, IL: Radiological Society
of North America, 1997:79–86.
58. Burns GS, Raeside DE. The accuracy of single-seed dose
superposition for I-125 implants. Med Phys. 1989;16:627–631.
59. Meigooni AS, Meli JA, Nath R. Interseed effects on dose for 125I
brachytherapy implants. Med Phys. 1992;19:385–390.
60. Chibani O, Williamson JF, Todor D. Dosimetric effect of seed
anisotropy and interseed attenuation for 103Pd and 125I prostate
implants. Med Phys. 2005;32:2557–2566.
61. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant
brachytherapy: report of the American Association of Physicists in
Medicine in Medicine Task Group No. 64. Med Phys. 1999;26:2054–
2076.
62. Das RK, Keleti D, Zhu Y, et al. Validation of Monte Carlo dose
calculations near 125I sources in the presence of bounded
heterogeneities. Int J Radiat Oncol Biol Phys. 1997;38:843–853.
63. Meigooni AS, Nath R. Tissue inhomogeneity correction for
brachytherapy sources in a heterogeneous phantom with cylindrical
symmetry. Med Phys. 1992;19:401–407.
64. Williamson JF, Li Z, Wong JW. One-dimensional scatter-subtraction
method for brachytherapy dose calculation near bounded
heterogeneities. Med Phys. 1993;20:233–244.
65. Furstoss C, Reniers B, Bertrand MJ et al. Monte Carlo study of LDR
seed dosimetry with an application in a clinical brachytherapy
breast implant. Med. Phys. 2009;36:1848–1858.
66. Berger MJ. Energy Deposition in Water by Photons From Point Isotropic
Sources. MIRD Pamphlet 2. Washington, DC: National Bureau of
Standards; 1968.
67. Briesmeister JT. MCNP—A general Monte Carlo N-particle transport
code. Version 4a: Los Alamos National Laboratory Report, LA-
12625. 1993.
68. Nelson W, Hirayama H, Rogers D. The EGS4 Code System. SLAC
Report 265 Stanford University, 1985.
69. Williamson JF. Monte Carlo evaluation of kerma at a point for
photon transport problems. Med Phys. 1988;14:567–576.
70. Boyer AL. A fundamental accuracy limitation on measurements of
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71. Gifford KA, Horton JL, Wareing TA, et al. Comparison of a finite-
element multigroup discrete-ordinates code with Monte Carlo for
Radiotherapy calculations. Phys Med Biol. 2006;51:2253–2265.
72. Daskalov GM, Baker RS, Rogers DW, et al. Dosimetric modeling of
the microselectron high-dose rate 192Ir source by the multigroup
discrete ordinates method. Med Phys. 2000;27:2307–2319.
73. Zhou C, Inanc F. Integral-transport-based deterministic
brachytherapy dose calculations. Phys Med Biol. 2003;48:73–93.
74. Lewis EE, Miller WF. Computational Methods of Neutron Transport.
New York, NY: Wiley; 1984.
75. Alcouffe RE, Baker RS, Brinkley FW, et al. DANTSYS: A Diffusion
Accelerated Neutral Particle Transport Code System. Los Alamos, NM:
Los Alamos National Laboratory LA-12969-M; 1995.
76. Wareing TA, McGhee JM, Morel JE. ATTILA: a three dimensional
unstructured tetrahedral mesh discrete-ordinates transport code.
Trans Amer Nucl Soc. 1996;75:146.
77. Vassiliev ON, Wareing TA, McGhee J, et al. Validation of a new
grid-based Boltzmann equation solver for dose calculation in
radiotherapy with photon beams. Phys Med Biol. 2010;55:581–598.
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Electron Beams
Faiz M. Khan
Most commercial treatment planning systems incorporate electron beam

planning programs. However, not all programs have comparable
accuracy or limitations. In general, the electron beam algorithms are
more complex than those of the photon beams and require more careful
testing and commissioning for clinical use.
Early methods of computing dose distribution were based on empiric
data or functions that used ray line geometries assuming broad beam
depth dose distribution in homogeneous media. Inhomogeneity
corrections were determined with transmission data measured with large
slabs of heterogeneities. These earlier methods have been reviewed by
Sternick (1).
The major problem with the use of broad-beam distributions and slab
geometries is that this approach is inadequate in predicting the effects of
narrow beams, sudden changes in surface contours, small
inhomogeneities, oblique beam incidence, and so forth.
An improvement over the empiric methods came about with the
development of algorithms based on age–diffusion equation by Kawachi
(2) and others in the late 1970s. These models have been reviewed by
Andreo (3). A semiempiric pencil beam model developed by Ayyangar
and Suntharalingam (4) and based on age–diffusion equation was
adopted for the Theraplan treatment planning system (Theratronics,
Kanata, Ontario). This semiempiric algorithm, if properly implemented
for a given electron accelerator, allowed reasonably accurate calculation
of dose distribution in a homogeneous medium. Contour irregularity and
inhomogeneities were considered only in the plane of calculation, as for
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example, a computed tomography (CT) slice, without regard to the
effects of the third dimension, such as adjacent CT slices. Whereas pencil
beams placed along the surface contour can predict effects of contour
irregularity and beam obliquity, inhomogeneity corrections were still
based on effective path length between the virtual source and the point
of calculations. In these cases, bulk density of the inhomogeneity in the
given CT slices was used to determine effective depth. The main
limitation of such algorithms was that the effects of the anatomy in three
dimensions were not fully accounted for, although empirically derived
correction factors could be used in simple geometric situations (5).
PENCIL BEAM MODELS BASED ON MULTIPLE

SCATTERING THEORY
In the early 1980s, there was a significant surge in the development of
electron beam treatment planning algorithms (6–9). These models were
based on gaussian pencil beam distributions obtained with the
application of Fermi–Eyges multiple scattering theory (10). For a review
of these algorithms, see Brahme (11) and Hogstrom (12). A brief
discussion of these algorithms is presented here to familiarize the users
of these programs with the basic theory involved.
Assuming small-angle approximation for multiple scattering of
electrons, the spatial distribution of electron fluence or dose from an
elementary pencil beam penetrating a scattering medium is very nearly
gaussian at all depths. Large-angle scattering events could cause
deviations from a pure gaussian distribution, but their overall effect is
considered to be small. The spatial dose distribution for the gaussian
pencil beam can be represented thus:
where dp(r,z) is the depth dose contributed by the pencil beam at a point
at a radial distance r from its central axis and depth z, dp(o,z) is the axial
dose, and is the mean square radial displacement of electrons as a
result of multiple Coulomb scattering. It can be shown that ,
where and are the mean square lateral displacements projected into
the X, Z and Y, Z planes. The exponential function in Equation 6.1
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represents the off-axis ratio for the pencil beam, normalized to unity at r
= o.
This is another useful form of Equation 6.1.
where D∞(o,z) is the dose at depth z in an infinitely broad field with the
same incident fluence at the surface as the pencil beam. The gaussian
distribution function in Equation 6.2 is normalized so that the area
integral of this function over a transverse plane at depth z is unity.
FIGURE 6.1 A pencil beam coordinate system. Dose at point P is calculated by integrating
contributions from individual pencil beams.
In Cartesian coordinates, Equation 6.2 can be written thus:
where dp(x,y,z) is the dose contributed to point (x,y,z) from a pencil

beam whose central axis passes through (x′,y′,z′) (Fig. 6.1).
The total dose distribution in a field of any shape can be calculated by
summing all the pencil beams:
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The integration of a gaussian function within finite limits cannot be
performed analytically. To evaluate it, this function necessitates use of
the error function. Thus, convolution calculus shows that for an electron
beam of a rectangular cross-section (2a × 2b), the spatial dose
distribution is given thus:
where the error function is defined thus:
The error function is normalized so that erf(∞) = 1. (It is known that

the integral .) Error function values for o < x < ∞ can
be obtained from tables published in mathematic handbooks (13).

Although, D∞(o,o,z) in Equation 6.5 is given by the area integral of the
dose from pencil beams over an infinite transverse plane at depth z, this
term is usually determined from measured central axis depth dose data
of a broad electron field (e.g., 20 cm × 20 cm).
Pencil Beam Characterization

Lateral Spread σ
As discussed earlier, the spatial dose distribution of an elementary pencil
electron beam can be represented by a gaussian function. This function
is characterized by its lateral spread parameter σ, which is similar to the
standard deviation parameter of the familiar normal frequency
distribution function:
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Figure 6.2 is a plot of the normal distribution function given by Equation
6.7 for σ = 1. The function is normalized so that its integral between the
limits −∞ < x < +∞ is unity.
As a pencil electron beam is incident on a uniform phantom, its
isodose distribution looks like a teardrop or onion (Fig. 6.3). The lateral
spread (or σ) increases with depth until a maximum spread is achieved.
Beyond this depth there is a precipitous loss of electrons as their large
lateral excursion causes them to run out of energy.
The lateral spread parameter σ was theoretically predicted by Eyges
(10), who extended the small-angle multiple scattering theory of Fermi
to the slab geometry of any composition. Considering σx (z) in the X–Z
plane,
where q2/ρl is the mass angular scattering power and ρ is the density of
the slab phantom.
FIGURE 6.2 Plot of a normal distribution function given by Equation 6.7 for σ = 1. The function is
normalized to unity for limits −∞ < x < +∞.
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FIGURE 6.3 Pencil beam isodose distribution measured with a narrow electron beam of 22-MeV
energy incident on water phantom. (Reprinted with permission from ICRU Report 35. Radiation
Dosimetry: Electron Beams with Energies Between 1 and 50 MeV. Bethesda, MD: International
Commission on Radiation Units and Measurements. 1984:36.)
There are limitations to the Eyges’ equation. As pointed out by Werner

et al. (8), σ, given by Equation 6.8, increases with depth indefinitely,
which is contrary to what is observed experimentally in narrow-beam
dose distributions. The theory does not take into account the loss of
electrons when lateral excursions exceed the range of the electrons. Also,
Equation 6.8 is based on small-angle multiple Coulomb scattering;
hence, it underestimates the probability of large-angle scatter. This gives
rise to an underestimation of σ. Correction factors have been proposed to
counteract these problems (8,14,15).
Hogstrom et al. (7) correlated electron collision linear stopping power
and linear angular scattering power relative to that of water with CT
numbers so that effective depth and σ could be calculated for
inhomogeneous media using CT data. Effective depth calculation using
CT numbers also allows pixel-by-pixel calculation of heterogeneity
correction.
Experimental measurement of σ(z) is possible with the use of narrow
beams (1-mm to 2-mm diameter). The transverse dose distribution in a
narrow beam has a gaussian shape at each depth. The root mean square
(rms) radial displacement, σr(z), can be obtained from the profiles by a
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mathematic deconvolution of the gaussian distributions.
Several investigators (15–17) used a narrow-beam depth dose
distribution to determine σr. Some (6) used the edge method, in which a
wide beam is blocked off at the center by a lead block; σ is evaluated
from the excursion of electrons into the block penumbra.
Werner et al. (8) used strip beams 2-mm wide to obtain transverse
profiles in homogeneous phantoms of various compositions. The strip
beam profiles were then fitted by gaussian distributions at various
depths. Figure 6.4 shows the results, comparing σs calculated by Eyges’
equation, with and without correction for the loss of electrons.
FIGURE 6.4 Spatial spread parameter, σx, plotted as a function of depth in water for a 13-MeV
electron beam. Comparison is shown between σx’s calculated by Eyges’ equation (dashed line)
and Eyges’ equation modified for loss of electrons (solid lines) with measured data. (Reprinted
with permission from Werner BL, Khan FM, Deibel FC. A model for calculating electron beam
scattering in treatment planning. Med Phys. 1982;9:180–187.)
Central Axis Distribution
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As seen in Equation 6.5, the central axis depth dose for a rectangular
field of size (2a × 2b) can be derived from the measured broad-beam
central axis distribution. It is given thus:
The normalization of the dose distribution function against D∞(o,o,z) is

useful because the central axis dose distribution for a broad beam can be
readily measured and includes Bremsstrahlung as well as the inverse
square law effect. Multiplication with the error functions provides the
required field size dependence factor due to lateral scatter.
SUCCESS AND LIMITATIONS OF PENCIL BEAM

ALGORITHMS
Algorithms based on gaussian pencil beam distribution have solved
many of the problems that plagued the previous methods, which used
measured broad-beam distributions or empirically derived best fit
functions with separate correction factors for contour irregularity and
tissue heterogeneity. Analytic representation of pencil beam allows for
calculation of dose distribution for fields of any shape and size, irregular
or sloping surface contours, and tissue heterogeneities in three
dimensions. However, there are limitations to pencil beam algorithms,
and they have been discussed by several investigators (12,18–20). Most
of the inaccuracies occur at interfaces of different density tissues such as
tissue–lung, tissue–bone, and bone edges. Within the homogenous media
of any density, the algorithm has an accuracy of approximately 5% in
the central regions of the field and approximately 2-mm spatial accuracy
in the penumbra.
Central Axis Distribution

One of the essential requirements of a treatment planning algorithm is
that it calculates the central axis depth dose distribution in water with
acceptable accuracy. For broad beams, there is no problem because
measured data are input as part of the formalism (Equation 6.9). So, the
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critical test of the algorithm is to reproduce depth dose distribution for
small and irregularly shaped fields. Figure 6.5 shows such a test of the
Hogstrom algorithm.
Isodose Distribution
The next step is to check isodose distributions, especially in the
penumbra region. Figure 6.6 from Hogstrom et al. (7), shows a
reasonably good agreement. The success of the pencil beam algorithm in
this case is in part attributable to the measured broad-beam central axis
data, measured off-axis profiles at the surface to provide weighting
factors for the pencil beams, and an empirically derived multiplication
factor (1 to 1.3) to modify calculated values of σx(z) for a best agreement
in the penumbra region. This is true of most algorithms—that some
empiric factors are required to obtain a best fit of the algorithm with
measured data.
FIGURE 6.5 Comparison of measured depth dose distributions with those calculated from 10 cm
× 10 cm field size data. Electron energy, 17 MeV. (Reprinted with permission from Hogstrom KR,
Mills MD, Almond PR. Electron beam dose calculations. Phys Med Biol. 1981;26:445–459.)
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FIGURE 6.6 Comparison of calculated and measured isodose distribution. (Reprinted with
permission from Hogstrom KR, Mills, MD, Almond PR. Electron beam dose calculations. Phys
Med Biol. 1981;26:445–459.)
Contour Irregularity
A pencil beam algorithm is ideally suited, at least in principle, to
calculate dose distribution in patients with irregular or sloping contour.
Pencil beams can be placed along rays emanating from the virtual
source, thus entering the patient at points defined by the surface
contours. The dose distribution in the X–Z plane from the individual
pencil beams depends on the gaussian spread parameter, σx(z), which is
properly computed as a function of depth along the ray line. The
composite dose profile therefore reflects the effect of the surface contour
shape by virtue of the individual pencil beams entering the contour
along ray lines, spreading in accordance with individual depths, and the
contributing dose laterally. Figure 6.7 shows a schematic representation
of the pencil beam algorithm used to calculate dose distribution in a
patient correction.
Tissue Heterogeneities
As discussed earlier, the Fermi–Eyges theory is strictly valid for slab
geometry. That is, a pencil beam traversing a slab of material is scattered
with a gaussian profile, and the spread, σ, of the transmitted beam
depends on the thickness of the slab and its linear angular scattering
power (Equation 6.8). Application of this theory to the human body with
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inhomogeneities of different sizes and shapes becomes tenuous. Not only
do many different pencil beams pass through tissues of different
composition, but also each pencil with its increasing spread with depth
may not stay confined to one kind of tissue. Thus, the algorithm is bound
to fail where the cross-section of the inhomogeneity is smaller than the
pencil beam spread or at interfaces where parts of the pencil beam pass
through different inhomogeneities. Research in this area continues, but
no practical solution to this problem has yet been found.
FIGURE 6.7 Schematic representation of the Hogstrom algorithm for the calculation of dose
distribution in a patient cross-section. SSD, source-to-surface distance, SCD, source-to-collimator
distance. (Reprinted with permission from Hogstrom KR, Mills MD, Almond PR. Electron beam
dose calculations. Phys Med Biol. 1981;26:445–459.)
Figure 6.8 shows an example of how CT-based inhomogeneity
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corrections have been applied with a pencil beam algorithm. A tissue
substitute phantom simulating a nose was irradiated with a 13-MeV
electron beam and a detailed thermoluminescent dosimetry was done.
The agreement between the measured and calculated distribution was
approximately 13%. This is not an acid test for the algorithm, since
many sources of uncertainties can compound the errors in this case.
However, if the user understands its limitations of accuracy in complex
clinical situations, the pencil beam algorithm is capable of providing
clinically useful information about overall dose distribution. These
limitations must be considered in making therapeutic decisions in the
use of electrons when the target or critical structures are encountered in
the path of the beam.
FIGURE 6.8 Experimental verification of the Hogstrom algorithm. Calculated isodose contours are
compared with measured data using TLD in a tissue substitute phantom. Electron energy 13 MeV;
field size, 8 cm × 8 cm; source-to-source distance (SSD), 100 cm. (Reprinted with permission
from Hogstrom KR, Almond PR. Comparison of experimental and calculated dose distributions.
Acta Radiol. 1983;364:89–99.)
COMPUTER ALGORITHM
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Implementation of a pencil beam algorithm requires dose distribution
equations to be set up so that the dose to a point (x, y, z) in a given field
can be calculated as an integral of the doses contributed by gaussian
pencil beams. The points of calculation constitute a beam grid, usually
defined by the intersection of fan lines diverging from the virtual point
source and equally spaced depth planes perpendicular to the central axis
of the beam (X–Y planes). An irregularly shaped field is projected at the
depth plane of calculation and is divided into strip beams of width ∆X
and length extending from Ymax to Ymin (Fig. 6.9). The strip is also
divided into segments so that σ of the pencil beams and effective depths
can be calculated in three dimensions and integration can be carried out
over all strips and segments.
Starkschall et al. (18) evaluated the Hogstrom algorithm (7) for one-,
two-, and three-dimensional heterogeneity corrections. The general
equation that they set up for three-dimensional (3D) dose computation is
reproduced here to illustrate the mathematical formulation of the pencil
beam algorithm:
FIGURE 6.9 Schematic representation of an irregularly shaped field divided into strips projected
at the plane of calculation (z). (Reprinted with permission from Starkschall G, Shiu AS, Bujnowski
SW, et al. Effect of dimensionality of heterogeneity corrections on the implementation of a three-
dimensional electron pencil beam algorithms. Phys Med Biol. 1991;36:207–227.)
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where De(x,y,z) is the electron dose at point (x,y,z); N is the number of
strips; M is the number of segments; W(xk,y1) is the beam weight along
the fan line at point (xk,y1); α2 is the pencil beam spread in the medium
at depth z (obtained by integrating linear angular scattering power along
a fan line from the surface of the patient to the plane of calculation); σair
is the pencil beam spread in air at the plane of final collimation and
projected to the plane of calculation in the absence of the medium;
is the measured broad-beam central axis depth dose;
SSD is the effective source-to-surface distance; is the maximum limit
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of the jth segment of the ith strip; is the minimum limit of the jth
segment of the ith strip.
Equation 6.10 does not include the Bremsstrahlung dose. Assuming
that the dose beyond the practical range, Rp, is all due to photons, one
can back-calculate the photon dose by using attenuation and inverse
square law corrections.
MONTE CARLO METHODS

There is active interest in adopting Monte Carlo (MC) methods for
treatment planning of photon and electron beams. The MC technique
consists of simulating transport of millions of particles through matter. It
uses the fundamental laws of physics to determine probability
distributions of individual particle interactions. Each particle is followed
as it travels through the medium and gives rise to energy deposition by
interaction with the atoms of the medium. The larger the number of
simulated particles (histories), the greater is the statistical accuracy of
predicting their distribution. As the number of simulated particles is
increased, the accuracy gets better but the computational time becomes
prohibitively long. So, the challenge lies in using a relatively small
sample of randomly selected particles to predict the average behavior of
the particles in the beam. The dose distribution is calculated by
accumulating (scoring) ionizing events in bins (voxels) that give rise to
energy deposition in the medium. It is estimated that the transport of a
few hundred million to a billion histories will be required for radiation
therapy treatment planning with adequate precision.
In order to improve computational efficiency and decrease calculation
time, a number of fast MC codes have been developed in the past 15
years or so. Examples include Voxel-based MC (VMC, VMC++)
(21–23), Dose Planning Method (DPM) (24), and MCDOSE (25). Some of
these codes have been implemented commercially, for example,
Nucletron OMTPS, Varian Eclipse, and CMS Xio eMC. Before clinical
implementation, the user is advised to build an appropriate program for
commissioning and routine quality assurance of the MC-based treatment
planning system. Report of the AAPM Task Group No. 105 (26) would be
helpful in this regard.
With the continuing advancement in computer technology and
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computation algorithms, it now seems probable that full-fledged MC
code will be implemented for routine treatment planning in the not too
distant future.
KEY POINTS
• The most commonly used methods of electron beam dose
calculation include pencil beam (PB) algorithms and Monte Carlo
(MC)-based algorithms.
• The premise of a pencil beam algorithm is that the lateral spread of
an elementary pencil beam of electrons penetrating a scattering
medium can be represented approximately by a gaussian
distribution function.
• The lateral spread parameter, σ, can be theoretically predicted by
Fermi–Eyges multiple scattering theory.
• Practical implementation of pencil beam algorithm, based on
Fermi–Eyges theory, was carried out by Hogstrom et al. in 1981
and has been adopted by several commercial treatment planning
systems.
• PB algorithms have acceptable accuracy in homogeneous media
of any density (e.g., a dose accuracy of ∼5% in the central regions
of the field and a spatial accuracy of ∼2 mm in the penumbra).
• PB algorithms are not accurate at interfaces of different density
tissues such as tissue–lung, tissue–bone, and bone edges.
• MC methods consist of simulating transport of millions of particles
and statistically determining probability distributions of individual
particle interactions.
• Full-fledged MC codes for treatment planning require inordinate
amount of computational times but they are the most accurate
methods of calculating dose distribution.
• Fast MC codes have been developed to improve efficiency and
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reduce computational time. Examples include Voxel-based Monte
Carlo (VMC, VMC++), Dose Planning Method (DPM), and
MCDOSE.
QUESTIONS
1. Spatial spread of a pencil beam of electrons traversing a medium:
A. Is caused predominantly by knock on collisions
B. Increases with increase in energy
C. Is mostly due to secondary electrons ejected laterally
D. Can be represented approximately by a gaussian distribution
function
2. Pencil beam algorithms for electron beam treatment planning:
A. Usually require input of measured depth dose data as well as
lateral beam profiles for broad fields as a function of beam
energy
B. Can accurately predict surface dose
C. Are useful in predicting hot and cold spots occurring at bone–
tissue interfaces
D. Are especially useful at tissue–lung interfaces
3. Fast Monte Carlo codes for electron beam treatment planning
simulate transport of:
A. Electron beam as energy kernels
B. Electrons using age-diffusion model
C. Millions of individual electrons and their interaction
probabilities in a medium
D. A single electron per pixel in a calculation grid
ANSWERS
1. D Lateral spread of an electron pencil beam is caused
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predominantly by random small-angle Coulomb scattering
and can be represented by a gaussian normal distribution.
2. A Existing electron pencil beam algorithms cannot
accurately take into account the effect of beam collimation
on depth dose or surface dose. Input of measured central
axis depth data and lateral beam profiles takes those
effects into account and assures better accuracy.
3. C Monte Carlo is not a model-based algorithm. It simulates
individual electron interactions and statistically measures
interaction probabilities. Greater the number of electrons
simulated, better the statistical accuracy.
REFERENCES
1. Sternick E. Algorithms for computerized treatment planning. In:
Orton CG, Bagne F, eds. Practical Aspects of Electron Beam Treatment
Planning. New York, NY: American Institute of Physics; 1978:52.
2. Kawachi K. Calculation of electron dose distribution for radiotherapy
treatment planning. Phys Med Biol. 1975;20:571–577.
3. Andreo P. Broad beam approaches to dose computation and their
limitations. In: Nahum AE, ed. The Computation of Dose Distributions
in Electron Beam Radiotherapy. Kungalv, Sweden: Miniab/gotab;
1985:128.
4. Ayyangar K, Suntharalingam N. Electron beam treatment planning
incorporating CT data. Med Phys. 1983;10:525 (abstract).
5. Pohlit W, Manegold KH. Electron beam dose distribution in
homogeneous media. In: Kramer S, Suntharalingam N, Zinniger GF,
eds. High Energy Photons and Electrons. New York, NY: Wiley;
1976:343.
6. Perry DJ, Holt JG. A model for calculating the effects of small
inhomogeneities on electron beam dose distributions. Med Phys.
1980;7:207–215.
7. Hogstrom KR, Mills MD, Almond PR. Electron beam dose
calculations. Phys Med Biol. 1981;26:445–459.
8. Werner BL, Khan FM, Deibel FC. A model for calculating electron
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beam scattering in treatment planning. Med Phys. 1982;9:180–187.
9. Jette D, Pagnamenta A, Lanzl LH, et al. The application of multiple
scattering theory to therapeutic electron dosimetry. Med Phys.
1983;10:141–146.
10. Eyges L. Multiple scattering with energy loss. Phys Rev.
1948;74:1534.
11. Brahme A. Brief review of current algorithms for electron beam
dose planning. In: Nahum AE, ed. The Computation of Dose
Distributions in Electron Beam Radiotherapy. Kungalv, Sweden:
Miniab/gotab; 1985:271.
12. Hogstrom KR, Starkschall G, Shiu AS. Dose calculation algorithms
for electron beams. In: Purdy JA, ed. Advances in Radiation Oncology
Physics. American Institute of Physics Monograph 19. New York, NY:
American Institute of Physics; 1992:900.
13. Beyer WH. Standard Mathematical Tables. 25th ed. Boca Raton, FL:
CRC Press; 1978:524.
14. Lax I, Brahme A. Collimation of high energy electron beams. Acta
Radiol Oncol. 1980;19:199–207.
15. Lax I, Brahme A, Andreo P. Electron beam dose planning using
Gaussian beams. Acta Radiol. 1983;364:49–59.
16. Brahme A. Physics of electron beam penetration: fluence and
absorbed dose. In: Paliwal B, ed. Proceedings of the Symposium on
Electron Dosimetry and Arc Therapy. New York, NY: American
Institute of Physics; 1982:45.
17. Mandour MA, Nusslin F, Harder D. Characteristic function of point
monodirectional electron beams. Acta Radiol. 1983;364:43–48.
18. Starkschall G, Shiu AS, Buynowski SW, et al. Effect of
dimensionality of heterogeneity corrections on the implementation
of a three-dimensional electron pencil-beam algorithm. Phys Med
Biol. 1991;36:207–227.
19. Hogstrom KR, Steadham RE. Electron beam dose computation. In:
Paltra JR, Mackie TR, eds. Teletherapy: Present and Future. Madison,
WI: Advanced Medical Publishing; 1996:137–174.
20. Hogstrom KR. Electron-beam therapy: dosimetry, planning and
techniques. In: Perez C, Brady L, Halperin E, Schmidt-Ullrich RK,
eds. Principles and Practice of Radiation Oncology. Baltimore, MD:
Lippincott Williams & Wilkins; 2003:252–282.
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21. Neuenschwander H, Mackie TR, Reckwerdt PJ. MMC-a high
performance Monte Carlo code for electron beam treatment
planning. Phys Med Biol. 1995;40:543–574.
22. Kawrakow I, Fippel M, Friedrich K. 3D Electron Dose Calculation
using a Voxel based Monte Carlo Algorithm. Med Phys.
1996;23:445–457.
23. Kawrakow I, Fippel M. Investigation of variance reduction
techniques for Monte Carlo photon dose calculation using XVMC.
Phys Med Biol. 2000;45:2163–2184.
24. Sempau J, Wilderman SJ, Bielajew AF. DPM, a fast, accurate Monte
Carlo code optimized for photon and electron radiotherapy
treatment planning dose calculations. Phys Med Biol. 2000;45:2263–
2291.
25. Ma C, Li JS, Pawlicki T, et al. MCDOSE- A Monte Carlo dose
calculation tool for radiation therapy treatment planning. Phys Med
Biol. 2002;47:1671–1689.
Group No. 105: issues associated with clinical implementation of
planning. Med Phys. 2007;34:4818–4853.
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Proton Therapy
Hanne M. Kooy and Benjamin M. Clasie
INTRODUCTION
A clinical dose computation algorithm, a “dose algorithm,” must satisfy
requirements such as clinical accuracy in the patient, computational
performance, representations of patient devices and delivery equipment,
and specification of the treatment field in terms of equipment input
parameters. A dose algorithm has been invariably imbedded within a
larger treatment planning system (TPS) whose requirements and
behavior often affect the dose algorithm itself. Current clinical emphasis
on the patient workflow and advanced delivery technologies such as
adaptive radiotherapy will lead to different dose algorithm
implementations and deployments depending on the context. For
example, a treatment planner needs highly interactive dose
computations in a patient to allow rapid evaluation of a clinical
treatment plan. A quality assurance physicist, on the other hand, needs
an accurate dose algorithm whose requirements could be simplified
considering that QA measurements are typically done in simple
homogeneous phantoms.
A dose algorithm has two components: a geometry modeler and a
physics modeler. In practice, the choice of a physics model drives the
specification of the geometry modeler because the geometry modeler
must present the physics modeler with local geometry information to
model the local effect on the physics-model calculation. Physics models
come in two forms: Monte Carlo and phenomenologic. The latter models
the transport of radiation in medium with analytical forms and has been
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the standard in the clinic because of the generally higher computational
performance compared to Monte Carlo. Monte Carlo, in general, models
the trajectories of a large number of individual radiation particles and
scores their randomly generated interactions in medium to yield energy
deposited in the medium. Monte Carlo is considered an absolute
benchmark and much effort is expanded to produce high-performance
implementations. The accuracy of a Monte Carlo model is inversely
related to the extent and complexity of the modeled interactions and
improved performance can be achieved by limiting the model to meet a
particular clinical requirement. We describe, as an example, a basic
Monte Carlo, which outperforms a phenomenologic implementation
because of its simple model and implementation on a graphics processor
unit (GPU).
The geometry modeler creates a representation of the patient, which is
invariably derived from a CT volumetric data set and the CT voxel
coordinates are sometimes chosen as the coordinates for the points for
which to compute the dose. Dose points are typically associated to
individual organ volumes after the dose calculation proper for the
computation of, for example, dose-volume histograms. A more general
implementation allows the user to select arbitrary point distributions.
The geometry modeler also provides the physical characteristics of the
patient including, for example, electron density derived from CT
Hounsfield Units and, for protons, the stopping power ratio relative to
water (also derived from CT Hounsfield Units, albeit indirectly). The
geometry modeler also implements a model of the treatment field. For a
Monte Carlo implementation this is a two-step procedure. First, the
treatment field geometry and equipment parameters are used to create a
representative phase-space; that is, the distribution of particles in terms
of position and energy, and perhaps other parameters, of the radiation
particles that impinge on the patient. Second, the particles are
transported individually through the patient until they are absorbed in
or exit the patient volume. For a phenomenologic implementation, the
treatment field geometry forms a template whose geometric extents are
projected through the patient volume. This projection is typically
implemented by a ray tracer where individual rays populate the
treatment field to sufficiently sample the features within the patient and
where the physics model becomes a function of distance along the ray.
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Figure 7.1 shows the various computational approaches.
Proton transport in medium has been exhaustively studied and the
references in this chapter are but a minimum.
PHYSICS OF PROTON TRANSPORT IN MEDIUM

Interactions
The physics of proton interactions for clinical energies, that is, between
50 and 350 MeV, is well understood. The publication “Passive Beam
Spreading in Proton Radiation Therapy” by Bernard Gottschalk (1)
provides an in-depth, theoretical, and practical, elaboration of this
physics and this section relies significantly on that material.
FIGURE 7.1 The left panel shows a Monte Carlo schematic while the right panel shows a
phenomenologic schematic. The beam includes an aperture and a range-compensator. The beam
for both is assumed subdivided in individual pencil-beam “spots.” These spots are physical in the
case of pencil-beam scanning (see text) while for a scattered field they are a means for
subdividing the field for computational purposes. The initial spot is characterized by a spread σ′,
an intensity G, and an energy R. In the Monte Carlo, the spot properties can be used as a
generator of individual protons. Thus, there will be more “red” protons than “blue” protons than
“green” protons. The total number of protons is on the order of 106 or more. Each proton is
transported through the patient and its energy loss is scored in individual voxels (a “yellow” one is
shown). In the phenomenologic model, the spot defines one or more pencil-beams that are traced
through the patient. Each ray-trace models the broadening of the protons in the pencil-beam as a
continuous function of density ρ along the ray-trace. Dose is scored to points P, where the
deposited dose depends on the geometric location of P with respect to the ray-trace axis and the
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proton range R and pencil-beam spread σ. The latter may include the initial spot spread σ′ if the
ray-trace axis represents all the protons G in the spot. Otherwise, the spot can be subdivided into
multiple sub-spots such that the superposition of those spots equal the initial spot.
Protons lose energy in medium through interactions with orbital

electrons, scatter predominantly through electromagnetic Coulomb
interactions with the nuclear electric field, and have inelastic
interactions with the nucleus itself. Proton–electron interactions produce
delta electrons that deposit dose in proximity to the proton geometric
track. The mass of the proton is about 2,000 times that of the electron,
hence the collision is equivalent to a blue whale moving at near-
relativistic speed toward you: the proton emerges unscattered. Proton–
nucleus Coulomb interactions result in small angular deviations in the
proton direction and produce, to a very good approximation, a gaussian
diffusion profile in a narrow parallel beam of protons. The gaussian form
of this profile is a consequence of the very large number of random
scattering events, which, as described by the central limit theorem, is
approximate to a continuous gaussian function to describe the
underlying discrete random events.
Protons also have inelastic interactions with the nucleus and produce
secondary particles including secondary protons, neutrons, and heavier
fragments. The secondary protons contribute up to 10% of the dose
within a proton depth-dose (2). The secondary neutron production is of
specific concern because of their long-range effect. These neutrons
deposit dose to healthy tissues throughout the patient, far from the
target region, and impact on the shielding requirements of a proton
therapy facility. The neutron contribution to the dose distribution is only
considered implicitly through their contribution in the physics
parameters such as a depth-dose distribution. The effect of heavier
secondary particles is small and can be ignored for dose calculation
purposes.
Relative Biologic Effectiveness

Dose deposited by protons is considered to be biologically equivalent to
Co60 dose. That is, cellular response to proton and photon interactions
are considered equivalent. Clinically, though, the proton physical dose
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(in Gy) is scaled by an RBE factor of 1.1 to yield the proton biologic dose
with units of Gy (RBE) (3). Thus, a photon fraction prescription of 1.8
Gy (which implicitly has an RBE of 1 as Co60 is the “standard” dose
reference) can be delivered with a proton fraction of 1.8 Gy (RBE),
which corresponds to 1.64 Gy physical proton dose. The latter is the
value one would measure in a radiation detector and to which one
would calibrate the field to deliver 1.8 Gy (RBE).
Clinically, the RBE is assumed 1.1 throughout. Of special
consideration is the change in RBE at the distal drop-off of the Bragg
peak. In this region, the change in RBE has the effect of differentially
shifting the distal edge deeper by about 1 mm compared to
measurements. That is, the biologic dose fall-off is shifted 1 mm deeper
compared to the physical dose fall-off. This inherent uncertainty in the
distal edge is one reason why the sharp distal edge is not used to
achieve, for example, a dose gradient between a target and a critical
structure. The other reason (see below) is the uncertainty in the relative
stopping power, which is estimated on the order of 2% to 3%. These
uncertainties could result in overdose to the critical structure or
underdose to the target (Fig. 7.2).
FIGURE 7.2 An SOBP depth-dose distribution with its constituent pristine Bragg peak depth-dose
distributions scaled relative to their contribution. The deepest pristine peak is at 160 mm, which
results in a lower SOBP range of 158.4 mm because of the other peak contributions. The 90–90
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modulation width is 100.2 mm while the 90–98 is 83.1 mm. The range uncertainties create a band
of uncertainty both distally and proximally (see dashed distal fall-offs). The effect is most
pronounced at the distal fall-off and the error must be considered to ensure that the target
coverage is respected. The 80% depth, R80, of a pristine peak correlates accurately with the
proton energy in MeV. The clinical historical range is in reference to the 90% depth, which also
depends on the energy spread. The difference in practice is on the order of 1 mm. Care should be
practiced especially considering calibration and reference conditions.
The RBE, in general, depends on other factors such as dose fraction

size, number of fractions, clinical end point, and so on. These factors can
be ignored for proton radiation computations but are significant for
higher LET charged particles such as carbon. Computation algorithms for
such particles are, therefore, much more complicated and must
implement a model for the LET distributions in the patient to resolve
such dependencies.
Stopping Power
The various electromagnetic interactions transfer energy to electrons in
the medium and the proton energy is reduced as a consequence. The
proton energy loss, transferred to the medium, is quantified as the rate
of energy loss per unit length, dE/dx, where E (MeV) is the energy and x
(cm) is the distance along the proton path. The stopping power S is
defined in combination with the local material density ρ (g/cm3):
and is called the mass stopping power.

The mass stopping power in a given medium is a function of the
proton energy E and increases significantly when the proton has lost
nearly most of its energy. The proton mass stopping power in a given
material can be calculated using the Bethe–Bloch equation (4) or directly
from tables (5). For example, the mass stopping power values for protons
of energies 100, 10, and 1 MeV in water are 7.3, 45.7, and 261.1 MeV
cm2/g, respectively. Thus, a proton of 1 MeV energy cannot travel more
than 0.004 cm in water. It is this rapid increase in energy loss per unit
length, and the very localized energy deposition, that leads to the
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characteristic Bragg peak of the proton depth-dose distribution (Fig.
7.2). Note that a Bragg peak is a characteristic feature of all charged
particles, including electrons, of the energy loss along the particle track.
The feature disappears for electrons traversing a medium due to their
large scattering angle. In effect, the track becomes “tangled up” and the
Bragg peak becomes averaged out over all the entwined tracks. Thus, a
monoenergetic electron depth-dose distribution has a broad and flat
high-dose region followed by the distal fall-off.
FIGURE 7.3 Conversion from CT Hounsfeld units of the volume to relative stopping power, SWV,
for biologic tissues. Figure is adapted from Schneider et al. (7).
Water-Equivalent Depth and Proton Range, R

In a photon algorithm, the computational quantity is the radiologic path
length, that gives the density (ρ in units of g/cm3 or relative
to water) corrected depth along the ray up to the physical depth z in cm.
For a proton algorithm, the appropriate quantity is the water-equivalent
thickness, τwet in g/cm2, which is the thickness in water that produces
the same final proton energy as the given thickness in the medium. It is
calculated from relative stopping power, SWV, defined as the ratio of the
stopping power of protons in the medium over that in water. In practice,
SWV is known for the materials such as polyethylene used in range-
compensators or derived empirically from CT numbers (Fig. 7.3). The
proton water-equivalent thickness1 along a ray trace is given as
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where ρw is the density of water.
The mass stopping power ratio, is almost independent of
therapeutic proton energies for biologic materials (6). If this ratio is
unity, the radiologic path length and water-equivalent thickness are
mathematically equivalent. However, in treatment planning, the
differences between τRPL and τWET can be clinically significant.
Range, R, which is often called the mean proton range, is the average
water-equivalent depth where protons stop in the medium. This is a very
close approximation of the range in the continuous slowing down
approximation, RCSDA, and the depth at distal 80% of maximum dose,
R80, of a pristine proton Bragg peak (Fig. 7.2). These definitions of range
are often used interchangeably in proton therapy.
Dose to Medium
The dose to a volume element, of thickness t along and area A
perpendicular to the proton direction, is given by the energy lost in the
voxel divided by the mass of the voxel
where f = N/A is the proton fluence in (cm−2). Consider a fluence of

109 (1 Gigaproton [Gp]) per cm2 of 100 MeV protons in water where s/ρ
= 7.3 MeV cm2/g. The dose is
at the entrance of the water (where the proton energy is 100 MeV) and
where we used the factor 10−3 to convert from gram to kilogram and
the conversion factor is 0.1602 × 10−12 J/MeV. Equation 7.4 shows
that the number of protons to deliver a clinical dose is of the order of
gigaprotons, a number less than 10−15 of the number of protons in a
gram of water. A convenient rule of thumb is that 1 Gp delivers about 1
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cGy to a 1 L (i.e., 10 × 10 × 10 cm3) volume.
The mass stopping power only measures the energy loss from
electromagnetic interactions and does not include the energy deposited
from secondary particles. In practice, a measured depth-dose is a
surrogate for the mass stopping power and thus effectively includes all
primary and other interactions in calculational models.
A CT data representation of the patient does not provide the necessary
stopping power information; it only provides the electron density on a
voxel level. The conversion from this electron density to relative
stopping power is empirical and is based on an average for particular
organs over all patients (7). Thus, the conversion has inherent
uncertainties due to (1) the nonspecificity for a particular patient, and
(2) the lack of knowledge of precise stopping powers for particular
organs. One, therefore, assumes a 3% uncertainty in the relative
stopping power in patients (Fig. 7.2). This 3% uncertainty must be
considered by the treatment planner as is described elsewhere.
A dose algorithm may use longitudinal depth-dose distributions in
water for all available proton energies. Dose distributions in the patient
are calculated from the dose in water using the local density and relative
stopping power, both of which come from CT data. In the presence of
heterogeneities, the depth-dose distribution in the medium, TM(E, τWET),
is obtained from that in water by (following from Equation 7.3 and
assuming constant fluence)
where E is the incident proton energy, z is the geometric depth in

centimeters, and the superscript ∞ indicates that broad beam depth-dose
distributions are at infinite source-to-axis distance (SAD). The effect of
inhomogeneities is twofold. First, the physical depth of the Bragg peak is
shifted relative to a water phantom based on the water-equivalent depth
in the patient. The shift for material M with geometric thickness zM and
water-equivalent thickness τWET,M is
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Second, the dose in the heterogeneity is scaled by the relative mass
stopping powers. The latter ratio of relative mass stopping powers is
close to 1 and the scaling of the dose is typically ignored in dose
algorithm implementations. These effects are illustrated in Figure 7.4.
It was well recognized early on that protons could be used instead of
x-rays for tomography and thus measure the stopping power for a
patient directly (8). Such an image measures the energy loss, which is a
function of the integrated stopping power, along a particular proton ray
instead of an attenuation measurement along an x-ray, which is a
function of the integrated electron density. The resultant reconstructed
tomographic image is thus a stopping power distribution rather than an
electron density distribution. There is considerable interest in this
technology to achieve further precision in proton beam dosimetry and to
achieve accurate volumetric imaging at very low doses.
FIGURE 7.4 TW is the depth-dose distribution in a homogenous water phantom and TW+B is the
depth-dose distribution in a water phantom with bone at 5 cm depth. The relative mass stopping
power, of bone to water gives the ratio of the dose deposited in bone to water in the
shaded region. Bone has larger relative stopping power, , compared to water and, for 2.9 cm
geometric thickness of bone with 1.72 relative stopping power, the Δ z is −2.1 cm by Equation
(7.5b).
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FIGURE 7.5 Monte Carlo (GEANT4) generated proton and electron tracks in water with
comparable penetration range. Protons maintain near constant direction of motion while
continuously slowing down by losing energy in collisions with electrons. An electron track
becomes “tangled” up with its collision electron partner and undergoes many wide-angle
scattering events. The minimal scatter of the proton makes the dose distribution accurately
described by the gaussian pencil-beam model.
Proton Lateral Spread

The numerous multiple elastic scattering events produce, for an initial
parallel and infinitesimally narrow beam of protons, a gaussian lateral
distribution profile. The characteristic spread of this gaussian profile in
the Bragg peak region is about 2% of the range (in centimeters). Thus, a
proton beam of 20 cm penetration range in water has a spread of 4 mm
in the Bragg peak region. In comparison, an electron beam has a spread
of about 20% of its range (Fig. 7.5).
The scattering angle that underlies the widening gaussian profile was
originally described by Molière (9), who investigated single scattering in
the Coulomb field of the nucleus and multiple scattering as a
consequence of numerous interactions. A complete description of
scattering theory is beyond the scope of this chapter. In practice, the
Highland approximation (10,11), or similar readily computable variants,
are used to compute the lateral beam spread in matter. For dose
calculations in thick, heterogeneous matter, the volume is divided into N
homogeneous slabs that represent the material along the particle track.
The standard deviation of the gaussian spread σP,i at radiologic depth L
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due to the ith slab is
where pv is the product of the proton momentum and speed (in MeV), LR
is the radiation length (in g/cm2), and the ith slab extends from
radiologic depth Li − 1 to Li. The total gaussian spread, σP, is the
quadrature sum of the individual gaussian spreads from each slab
Solving Equation 7.6a at each dose calculation point is not feasible due
to computation time and two simplifications are made: the radiation
length in the patient is set to the radiation length of water (36.1 g/cm2)
and the density ρ is set to the density of water (1 g/cm3) in the
integration. The simplified equation for the gaussian spread
is only a function of the radiologic depth L in the media. The

simplifications are acceptable for most cases. Consider protons with 100
MeV energy incident on a homogeneous water phantom, then σP at the
maximum water-equivalent depth is 0.179 mm. If the same beam passes
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through 1 g/cm of compact bone (LR = 16.6 g/cm2 and ρ = 1.85
g/cm3) followed by water, then σP at the maximum water-equivalent
depth is 0.169 mm, an acceptable difference compared to the
homogeneous phantom. However, in general, one should give special
attention to treatment plans that have materials with properties
significantly different from water.
Treatment planning algorithms use tables or parameterizations of σP in
water to improve the computation time. Numerical solutions of Equation
7.6c are described by Hong et al. (6) and Lee et al. (12). Figure 7.6
shows a similar calculation in water where the momentum and velocity
of protons at radiologic depth, L, and range, R, are calculated through
range-energy tables from J. Janni (5).
FIGURE 7.6 Left: The normalized gaussian spread σP(L)/σP(R) versus normalized radiologic
depth, L/R. This relation is essentially independent of R; the width of the line gives the variation
from 0.1 g/cm2 < R < 40 g/cm2. Right: The gaussian spread at the end of range of the pristine
proton beam as a function of range.
MODELS OF DOSE DISTRIBUTIONS

Phenomenologic Models
A phenomenologic model uses analytical forms to describe the physical
processes and, typically, represents the passage of the radiation through
the medium as geometric rays or pencil beams. Ray tracing, as applied in
radiotherapy algorithms, derives primarily from computer graphics
techniques to create images of three-dimensional (3D) objects as a
consequence of light rays interacting with those objects as described by
their physical properties. Monte Carlo methods in radiotherapy, in
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essence, also implement ray tracing methods where individual rays are
the particles and their path is, in general, distorted as a consequence of
local interactions. We will refer to this technique as particle tracing in
distinction from ray tracing.
The performance of ray tracing algorithms through rectilinear volume
representations, such as a CT volume, is high and the computation time
for this part of an algorithm tends to be small compared to the
computation time needed for the physics model calculations. The ray
trace along a particular line, typically a line from the radiation source
through a point in the isocentric plane, is used to accumulate the volume
physical information along the trace.
The main computational burden in a ray-trace algorithm
implementation is the association of dose to points surrounding the ray
(Fig. 7.1). In general, at a given depth z, one has to find the points that
will receive a relevant contribution from the “particles” modeled by the
ray. In the case of a proton algorithm, this means that at a depth z, one
has to search an area of radius 3σ as this, for a gaussian distribution,
contains 99% of the laterally distributed profile. To efficiently find these
points, as opposed to explicitly checking each point at each depth for the
distance from that point to the ray axis, one can resort to sorting and
indexing algorithms before commencing the ray-trace calculation.
Original implementations of dose calculation algorithms used fan-beam
grids where the points on the calculation grid fan out along rays from
the source. Such methodologies are impractical when considering
requirements such as noncoplanar beams and arbitrary distributions of
points. A more general implementation relies on indexing and sorting
the dose points, in the beam coordinate system, in the isocentric plane,
and along the axis of the beam or ray (Fig. 7.7).
GAUSSIAN PROTON PENCIL-BEAM MODEL

The gaussian behavior of charged particle spread in medium was first
used in an electron pencil-beam algorithm described by Hogstrom et al.
(13). The use of gaussian functions has the convenient mathematical
property of yielding well-behaved integration and summation results to
describe the field profile and lateral penumbrae. In a pencil-beam model,
the radiation field is subdivided into narrow subfields, that is, pencil
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beams. The central axis of the pencil beam, the “ray,” is traced through
the medium and only density variations along the axis are considered in
the calculation of the lateral spread of particles with respect to the
pencil-beam axis. The density distribution lateral to the pencil-beam axis
is considered to be that encountered on the axis and the calculation is
thus insensitive to heterogeneity variations comparable to the width of
the pencil beam. The gaussian description for electron beams works well
in homogeneous medium but less so in heterogeneous media as a
consequence of the large scattering angle of electrons (Fig. 7.5). The
gaussian model is a good mathematical and physical representation if
the spread is much smaller such as is the case for proton beams.
FIGURE 7.7 A pencil-beam traced through the volume needs to find the points that are within its
extent. Consider all dose calculation points Z projected on the isocentric plane (“dots”), binned in
rectangles (the grid shown above) in that plane, and sorted along the central axis of the overall
field. At a particular depth at Z(d) the pencil-beam has the extent shown above (blue ellipse)
which is projected on the isocentric plane (red). The pencil-beam only needs to consider the
points in those bins within its extent and only those points Z for which Z(d) − Δ < Z < Z(d) + Δ (i.e.,
those within the thickness of the ray trace step (2Δ)). Such an algorithm can improve performance
well over 10× compared to a brute force approach.
The gaussian pencil-beam model was used by Hong et al. (6) to

describe a scattered proton field produced by a general delivery device.
Such a device contains beam scatterers, an aperture, a range-
compensator, an air-gap between the range-compensator and the patient,
and the patient itself (Fig. 7.8). A physical narrow pencil beam of
protons can be mathematically modeled even in the presence of
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heterogeneities while retaining good resolution. For example, a pure
pencil beam of 15-cm range still has better than 4-mm resolution at
depth.
The dose D to a point (x,y,z) from a pencil-beam field is
where the sum is over all pencil beam i (each of range Ri) whose central
axis at a depth at the coordinate z is at (xi,yi), Y(xi, yi) is the number of
protons at (xi,yi), σT is the total spread of the pencil beam, and T W• Ri,
τWET are broad-field depth-dose distributions in water with infinite SAD.
TW• Ri, and τWET are determined from measured depth-dose distributions
with finite SAD by correcting for inverse square.
where z is the longitudinal geometric coordinate of the measurement

with axis at z = 0.
Equation 7.7 is a general description of proton diffusion through
medium as a function of depth. Its basic form is used for describing a
scattered proton field, where a proton beam is passively scattered in the
lateral dimension and modulated in depth, and a pencil-beam scanning
field, where a narrow beam of proton pencils is scanned magnetically in
the lateral dimension and modulated in depth.
Scattered Field Implementation

A scattered proton field is not dissimilar from an electron scattered field.
The scattered field is characterized by a virtual source from which the
protons appear to emanate and diverge and which has a spread σS. The
source position and size can be determined by measuring the field width
and the penumbral width of an aperture as a function of distance from
the aperture. The field width projects back to the source position, while
the penumbral width is given by the back-projection of the measured
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penumbra through the aperture, where the penumbra is 0, to that
position (as described, e.g., in 13). The resultant “virtual” source size of
the proton beam is large with σS between 5 and 10 cm as a consequence
of the proton scatter in the scattering system (Fig. 7.8). This large source
size can only be mitigated by placing the aperture as close to the patient
as possible (as is the practice for an electron aperture) and to move the
source position as far as possible from the patient. The latter is one
reason for the size of proton gantries; the other being the bending radius
necessary to bend the proton beam toward the patient. The effective
source size (the projection of the source to Z = 0 through a pinhole at
the aperture) thus becomes
which for a typical beamline, with an SAD of 300 and an aperture

distance ZA to the patient of 10 cm, reduces the source size by a factor of
(300 − 10)/10 = 29 and the contribution of the virtual source is
reduced to 3 mm or less.
The proton beam passes through the aperture and subsequently is
modified by a range-compensator, which locally shifts the proton range
such that the distal surface of the field is beyond the distal target volume
surface (with respect to the beam axis). Passage through the range-
compensator introduces compensator thickness-dependent scatter, which
introduces a penumbral spread component in the patient at depth z
given by
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FIGURE 7.8 A schematic double-scattering nozzle (top) with a range-modulator wheel (RM,
insert) and scatterer (SS), ionization chamber IC, and a snout that holds the aperture and range-
compensator (insert). The fixed scatterer (FS) inserts thin layers of lead and ensures that the
overall mean scattering angle remains constant as a function of energy, thus maintaining a flat
lateral profile. The protons in the model are assumed to spread as a consequence from the
effective source (green profile and eq. 7.9), from the range-compensator thickness (yellow and eq.
7.10) and the scatter in patient (red profile and eq. 7.6c). The bottom shows a scanning nozzle
with a pair of scanning magnets (SM). The absence (in general) of an aperture and range-
compensator requires that the incoming pencil-beam be as narrow as possible to minimize its
contribution (green) to the in-patient spread. The SAD is defined by the bending points in the X
and Y magnets (shown here in the center of the magnets). The SAD defines the origin of the
proton pencil-beam axis. The relative widths of the pencil-beam are for illustration purposes and
do not imply that a scanning beam is, by definition, narrower. The schematics represent the core
features of the IBA nozzle (IBA LTD, Louvain la Neuve).
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where q0(t) is the scattering angle produced by the protons passing
through the local thickness t at (x,y) of the range-compensator at
position ZR.
The protons in the patient further scatter and introduce a third spread
factor, σP, to the total spread of the proton pencil beam. The derivation
of σP is computed, for example, from the Highland formula (Equation
7.6c). The total spread of the pencil beam is the quadratic sum of the
three spread factors in Equations 7.9, 7.10, and 7.6b (Fig. 7.8).
The complete algorithm thus subdivides the scattered field extent
circumscribed by the aperture into many small pencil beams, typically
spaced in a rectangular grid of 2-mm resolution. This high resolution
ensures that heterogeneities within the patient are sufficiently sampled
in the lateral extent. Each pencil beam axis is traced through the CT
volume from the virtual source through a grid point and through the CT.
The calculation points (x,y,z) are transformed to the beam coordinate
system and are sorted in z (Fig. 7.7). The ray trace evaluates the water-
equivalent depth (Equation 7.5) for the point whose z is first in this
sorted list and whose that is, those points are close
enough to the pencil-beam axis to receive sufficient dose. For those
points, the evaluation of Equation 7.7 yields the dose. The ray trace
continues and repeats the procedure for the next point z in the list.
Scattered Proton Field Composition

The general framework for the algorithm for scattered fields is the
evolution of the proton field in medium described by Equation 7.7 as a
composition of individual pencil beams i. The pencil beams for this
application should be considered mathematical constructs for the
decomposition of the field; the physical field is a laterally uniform flux
of protons at different energies. The mathematical decomposition in
depth is the weighted superposition of single Bragg peak proton fields,
typically uniform in the lateral dimension or weighted according to a
measured off-axis ratio profile, to produce a spread-out Bragg peak
(SOBP) field. The SOBP is thus a weighted sum of pristine Bragg peaks
Pi.
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The superposition of Bragg peaks is achieved by mechanically inserting
range-shifting material in the monoenergetic proton beam with the
insertion time proportional to the required contribution of a peak to the
SOBP (Fig. 7.8). The common method is to use a rotating wheel with
increasing step thicknesses and where the angular extent of the step is
proportional to the weight. A rotating wheel can produce SOBPs of
varying modulation by turning the beam off before a full rotation has
been completed.
The modulation width traditionally is specified as the distance
between the distal and proximal 90%. However, this definition leads to
modulation values larger than the range value for some fields and
becomes hard to measure in the shallow entrance dose region. Thus, in
our practice at least, we specify the modulation width between the distal
90% and the proximal 98% (Fig. 7.2).
Absolute dose calculations for SOBP models have, in general, not been
implemented and output calculations rely on empirical models (14). The
complexity, specific construction details, and large number of
mechanical components in a “modern” scattering nozzle make such a
description very difficult. This complexity increases the burden on the
physicist to establish a practical quality assurance protocol for output
calibrations (15).
Pencil-Beam Scanning Field Implementation

For pencil-beam scanning fields, we have physical beams of narrow
protons whose lateral position, quantified in the isocentric plane, is
controlled by the scanning magnets (SMs) and whose penetration depth
is quantified by the energy. This energy is nearly uniform with an energy
spread dE/E on the order of 0.5% or less. The effect of the energy spread
is a broadening of the Bragg peak width.
In principal, one could use the physical pencil beam directly as a
representation for the gaussian form in Equation 7.7. However, this will
lead to an implementation that is insensitive to patient heterogeneities.
The physical pencil beam typically has a spread of 4 to 15 mm at the
entrance as a consequence of the beam transport system and scatter in
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air and windows. Thus, considering Equation 7.7, the dose algorithm
implementation would be unable to discern inhomogeneities smaller
than that spread. Schaffner et al. (16) describe various techniques of
modeling dose distributions near lateral heterogeneities and one such
model is the Fluence-dose model. The physical pencil beam (PPB) is
decomposed at the entrance into constituent mathematical pencil beams
(MPB) to retain sufficient resolution of the proton transport inside the
patient. This can be represented by considering the spot spread σ0
separately from the in-patient spread σP in the gaussian function and
modifying Equation 7.7 to the mathematically equivalent form
where the first term (Equation 7.12a) is the number of protons GS (in
units of billions or Gigaprotons) in a PPB in the set S, the second term
(Equation 7.12b) is the apportionment of these GS protons, given the
intrinsic lateral spread (RS, z) of the PPB, over the set of MPB’s K. This
set of MPB’s K in Equation 7.12c is defined at the highest resolution (∼2
mm) necessary to accurately represent the dose in the patient. Equation
7.12c models the diffusion of the number of protons, given by the
product of Equations 7.12a and 7.12b, in the patient given the scatter
spread σP(RS,τWET) in the patient due to multiple Coulomb scattering.
The intrinsic lateral spread (RS,z) in Equation 7.12b is determined by
the scatter in air, magnetic steering, and focusing properties of the PBS
system (Fig. 7.8), and is a function of the spot range RS and position z
along the pencil-beam spot axis. The parameter ΔS, K denotes the
position of a point in the computational pencil beam area AK with
respect to the spot coordinate system. The final term (Equation 7.12c)
follows Pedroni et al. (17), where TW•(RS,τWET) (in units of Gy cm2 Gp
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−1) is the absolute measured depth-dose per Gigaproton (Fig. 7.9)
integrated over an infinite plane at water-equivalent depth τWET, τWET
σp(RS,τWET) is the total pencil-beam spread at τWET caused by multiple
Coulomb scatter in the patient (6), and is the displacement from the
calculation point to the K pencil-beam axis. Equation 7.12 is a
phenomenologic description of the distribution in the patient of protons
delivered by the set of spots S.
A Monte Carlo for Proton Transport in the Patient

The limitation of the gaussian pencil-beam model is well known:
insensitivity to lateral inhomogeneities as only variations along the
pencil-beam axis is sampled (Equation 7.2). For clinical purposes, the
gaussian pencil-beam model is a very good representation (18), given
the relatively small dispersion of the MPB (Fig. 7.5). Thus, if lateral
scatter were accurately modeled, there would be little further
improvement necessary. We describe a simple Monte Carlo that only
models lateral scatter and is implemented on a GPU, generally available
on any personal computer.
FIGURE 7.9 A set of pristine peaks in absolute dose (Gy cm2) per gigaproton. Note the change in
peak width and height as a function of range.
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The physics of proton transport is well described by considering
multiple Coulomb scatter using Molière’s theory and energy loss S along
the track. Individual protons are transported through a volume
represented by a rectangular 3D grid of voxels of dimension (dx, dy, dz)
and localized by their index (i,j,k). Each voxel has the relative (to water)
stopping power SWV. The dose to a voxel is the sum of energy
depositions along the individual proton tracks that traverse the voxel
and divided by the voxel mass.
FIGURE 7.10 Pseudocode for transporting a single proton through a voxel. The proton enters with
energy Eo and scatters by a mean polar angle q, a random azimuthal (around the proton
direction) angle φ (green line). The energy loss (Ei − Eo) depends on the energy only and is
computed as a function of energy for a mean path length ·λÒ. The dose d deposited is the
deposited energy divided by the mass of the voxel.
A proton, of energy ES, enters a voxel on one of its faces and exits on
another. We compute the (unscattered) exit point along the incoming
proton direction (u,v,w) and the distance λ between the entrance and
this projected exit point. We compute the mean polar scatter angle in the
voxel as and the azimuthal angle randomly uniform between
0 and 2p. The mean scatter angle q0(Es) is derived and quantified by
Gottschalk (10), analogous to the Highland formula (Equation 7.6c) but
more appropriate to traversal through thin layers. The azimuthal angle is
the only random variable. The proton direction is adjusted to (u,v,w),
given the scattering angles and the actual exit point are computed.
The energy loss of the proton along the mean voxel geometric track
length λ is derived from either the measured depth-dose distribution,
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TW• (R, τWET), or from range-stopping power tables as in Fippel and
Soukup (19). The energy loss in a voxel in the former model is.
In either model, the depth-dose in the Monte Carlo is tuned to match the
measured depth-dose by adjusting the energy spread at the entrance to
the phantom. The use of a mean track length ·λÒ solely serves to reduce
computational overhead. Figure 7.10 shows the pseudocode for this
simple algorithm and Figure 7.11 shows the ability of the algorithm to
model traversal through heterogeneous medium.
This algorithm is implemented on a GPU, which contains numerous
processors and where each processor can execute multiple threads of the
code in Figure 7.10. The implementation can transport on the order of
600,000 protons/s on an off-the-shelf graphics card. Such speed is
competitive to a “conventional” pencil-beam application and we,
therefore, expect that such implementations will replace the
conventional implementations.
FIGURE 7.11 Energy loss distribution of 2 physical pencil-beams traversing water with
inhomogeneous blocks (gray for “bone” and open for “air.” Note the differential lateral scatter as
expected).
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The clinical proton field is defined by a set of numerous protons
(∼106 or 107) with a mean energy E, spread ΔE/E, entry point (x, y, z)
on the surface of the voxel volume, and direction (u, v, w). This
computational set is derived from the properties of the decomposed
pencil beams as they are for either scattered or PBS field as described
above.
KEY POINTS
• Pencil-beam dose algorithms rely on the decomposition of the
radiation field into numerous smaller, pencil-beam, fields that in
aggregate represent the transport of the whole field through the
patient. Note that the term pencil-beam in proton pencil-beam
algorithm refers to the decomposition of the field—not the physical
delivery! Each decomposed pencil-beam is transported through the
patient where the local energy (dose) is considered as a function of
the radiologic depth along the pencil-beam axis and a function of
the convolution of the energy at the radiologic depth to surrounding
volume.
• The accuracy of a gaussian pencil-beam algorithm is limited by the
width of the gaussian at the calculation depth. The algorithm
assumes that all volume contained by the gaussian experiences
the “same” physics and thus becomes insensitive to lateral
heterogeneities on the order of the width of the gaussian. Thus, for
protons, this limits the algorithm to about 5 mm at depth.
• Monte Carlo dose calculations calculate dose based on the energy
losses of individual particles in a computational (voxel) volume,
which is often the smallest geometric representation of the patient.
Thus, Monte Carlo dose calculations are accurate up to the size of
a voxel.
• The definition of dose–response is based on the empirical
experience gained (primarily) from photon irradiation and as
referenced to Cobalt-60. For photon irradiation, physical dose is
therefore equated to biologic dose and its radiobiologic
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effectiveness (essentially in comparison to itself) is 1. Ions exhibit
different energy deposition along their tracks compared to
electrons, which in turn may create a difference between physical
dose and biologic dose. For example, clinical proton fields are
assumed to have an RBE = 1.1 which means that 2 Gy of Cobalt-
60 dose can be delivered by 1.8 Gy of proton dose.
QUESTIONS
1. Given a prescription dose of 2 Gy (RBE) per fraction, what is the
physical dose to be delivered by the proton field?
A. 1.82 Gy
B. 2.20 Gy
C. 2.00 Gy
2. What is the thickness of a Lucite range shifter (ρ = 1.15 g/cm3)
to shift a proton beam range of 10 cm to 8 cm?
A. 2.30 cm
B. 2.00 cm
C. 2.00 g/cm2
3. What is the gaussian spread of an infinitesimal parallel proton
pencil-beam of range = 20 cm at 10 cm in water?
A. 4.5 mm
B. 1.5 mm
C. 3.0 mm
4. In a scattered proton field, the virtual source size is (typically)
very large and on the order of σ = 5 cm. A large SAD (say 300
cm) and a short aperture-to-isocenter distance (say 20) reduce
this source size to:
A. 3.3 mm
B. 3.6 mm
C. 5.3 mm
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ANSWERS
1. A 1.82 Gy [2 Gy (RBE)/1.1 (RBE)]
2. B 2.00 g/cm2 [thickness expressed in “water” thickness]
3. B (from Figure 7.6) 4.8 mm × 0.3 = 1.5 mm
4. B 20/(300 − 20) × 50 mm = 3.6 mm
REFERENCES
1. Gottschalk B. Passive beam spreading in proton radiation therapy.
http://huhepl.harvard.edu/∼gottschalk/.
2. Paganetti H. Nuclear interactions in proton therapy: dose and
relative biological effect distributions originating from primary and
secondary particles. Phys Med Biol. 2002;47:747–764.
3. International Commission on Radiation Units and Measurements.
Prescribing, recording, and reporting proton-beam therapy (ICRU
Report 78). J ICRU. 2007;7(2):NP.
4. Amsler C, Doser M, Antonelli M, et al. (Particle Data Group). Phys
Lett. B667 2008;1.
5. Janni J. Proton range-energy tables, 1 keV–10 GeV. At Data Nucl
Data Tab. 1982;27:147–339.
6. Hong L, Goitein M, Bucciolini M, et al. A pencil beam algorithm for
proton dose calculations. Phys Med Biol. 1996;41:1305–1330.
7. Schneider U, Pedroni E, Lomax A. The calibration of CT Hounsfield
units for radiotherapy treatment planning. Phys Med Biol.
1996;41:111–124.
8. Cormack AM, Koehler AM. Quantitative proton tomography:
preliminary experiments. Phys Med Biol. 1976;21:560–569.
9. Molière G. Theorie der Streuung schneller geladener Teilchen II
Mehrfach—und Vielfachstreuung-streuung. Z Naturforsch B. 1948;
3A:78–97.
10. Gottschalk B. On the scattering power of radiotherapy protons. Med
Phys. 2010;37:352–367. arXiv:0908.1413v1 (physics.med-ph).
11. Lynch GR, Dahl OI. Approximations to multiple Coulomb scattering.
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Nucl Instrum Meth. 1991;B58:6–10.
12. Lee M, Nahum A, Webb S. An empirical method to build up a model
of proton dose distribution for a radiotherapy treatment-planning
package. Phys Med Biol. 1993;38:989–998.
calculations. Phys Med Biol. 1981;26:445–459.
14. Kooy HM, Schaefer M, Rosenthal S, et al. Monitor unit calculations
for range modulated spread-out Bragg peak fields. Phys Med Biol.
2003;48:2797–2808.
15. Engelsman M, Lu HM, Herrup D, et al. Commissioning a passive
scattering proton therapy nozzle for accurate SOBP delivery. Med
Phys. 2009;36:2172–2180.
16. Schaffner B, Pedroni E, Lomax A. Dose calculation models for
proton treatment planning using a dynamic beam delivery system:
and attempt to include density heterogeneity effects in the
analytical dose calculation. Phys Med Biol. 1999;44:27–41.
17. Pedroni E, Scheib1 S, Bohringer T, et al. Experimental
characterization and physical modelling of the dose distribution of
scanned proton pencil beams. Phys Med Biol. 2005;50:541–561.
18. Jiang H, Paganetti H. Adaptation of GEANT4 to Monte Carlo dose
calculations based on CT data. Med Phys. 2004;31:2811–2818.
19. Fippel M, Soukup M. A Monte Carlo dose calculation algorithm for
proton therapy. Med Phys. 2004;31:2263–2273.
1Proton path length is the thickness of material summed over the track
of the proton. Protons at clinical energies, however, undergo little
deviation from straight paths and path length and thickness can be used
interchangeably in proton therapy. Depth is the thickness of material
summed along a ray from the entrance of the phantom to a given
endpoint.
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8 Commissioning and Quality
Assurance
James A. Kavanaugh, Eric E. Klein, Sasa Mutic, and Jacob

Van Dyk
INTRODUCTION
Modern radiation therapy requires increasingly sophisticated
technologies to accurately deliver high doses of radiation to very specific
anatomic targets. The successful administration of a patient’s radiation
treatment is the final step of a complex process, an overview of which is
illustrated in Figure 8.1. Errors at any one of these steps can produce
deviations between the delivered radiation treatment and the intended
prescription with such deviations having the potential for markedly
inferior clinical outcomes compared with those whose treatment was
initially protocol compliant (1). On rare occasions, these deviations can
have catastrophic consequences to the patient’s health (2,3). To ensure
accuracy of the prescription and the fulfillment of treatment intent, a
rigorous quality assurance (QA) program is required at all stages of the
radiation treatment process. The purpose of a QA program is to provide
systematic evaluations and necessary corrective actions to maintain the
quality and safety of a radiation therapy program. These evaluations, or
quality controls (QC), measure a specific quality metric, compare it to an
existing standard baseline, and adjust the metric to conform to the
baseline as necessary. The baselines used within a QA program are
typically defined during the initial commissioning process (4).
Commissioning is the preparation of a new device, technique, or
procedure for clinical use.
The more darkly shaded region of Figure 8.1 highlights the stages that
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relate specifically to treatment planning. Virtual simulation combined
with the use of a computerized treatment planning system (TPS) for dose
computation and technique optimization is standard practice in the
modern radiation therapy department. Developments in automated
optimization (5), beam intensity modulation (6), the use of a variety of
imaging modalities (7), and the inclusion of biologic parameters (8) to
calculate tumor control probabilities (TCPs) and normal tissue
complication probabilities (NTCPs) have added dramatically to the
complexity of the modern TPS. More recently, developments in auto
segmentation contouring algorithms, automated/knowledge-based
planning (KBP) techniques (9), and adaptive radiation therapy (ART)
(10) have further compounded this complexity.
The continually expanding complexity of the modern TPS has made
the commissioning process one of the most challenging and error-prone
steps in modern radiation therapy (11,12). Historically, measurements
and modeling of the basic radiation dataset needed to accurately
commission a TPS have been the responsibility of the local medical
physicist. Despite comprehensive guidance documents (13–16), the
variation of skill and experience of the local physicist has produced
drastic variations in the accuracy of the calculated dose distributions
across institutions utilizing the same linear accelerator technology (12).
As modern linear accelerator technology has been shown to be
consistently stable and uniform, there has been increased discussion
regarding the use of a vendor specified standardized basic radiation
dataset for commissioning a TPS (17,18). The standardized dataset for a
specific vendor (Varian Medical Systems), known as golden beam data
(GBD), would minimize the variation in TPS commissioning and would
still require local verification measurements to ensure it matches the
dose delivery data. Utilizing GBD instead of locally measured data is
quite controversial and is mentioned here to inform the reader of the
current disagreement in the field (19).
The overall need for QA in radiation therapy is well defined (20–22).
As mentioned previously, comprehensive reports on treatment planning
QA have been developed by the AAPM (13) and, more recently, by the
International Atomic Energy Agency (IAEA) (14–16). This chapter
addresses issues related to the use of treatment planning computers in
the context of acceptance testing, commissioning, and routine clinical
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application. Although the emphasis is on commissioning and QC, there is
also some discussion on QA of the total treatment planning process. The
intent of this chapter is to be as generic as possible so that it applies to
both conventional and more sophisticated radiation treatment
techniques; however, because of page limitations, details for specialized
techniques are confined to references where indicated.
Historical Perspective, Current Status, and Future

Possibilities
Publications on computer applications in radiation therapy date back to
1951, when Wheatley (23) produced an analog computer to perform
“dosage estimation of fields of any size and any shape.” The primary
purpose was to relieve the tedium associated with dosage calculations
(24). It appears that computers were used in radiation therapy as early
as in any other field of medicine. Tsien (25) has been credited with
being the first in the application of “automatic computing machines to
radiation treatment planning.” During the past 60 years, there has been
an enormous technologic evolution of computer technology, including
microcomputers, large time-sharing systems, minicomputers, graphics
workstations, and desktop personal computers, as well as laptops,
handhelds, and tablets. During each phase of computational
development, computers provided treatment planners with faster and
more sophisticated capabilities for dosage calculations, better image and
graphical displays, and improved automated optimization capabilities
(26). The evolution of these sophisticated technologic developments can
be readily followed by reviewing the proceedings of a series of
international meetings on the use of computers in radiation therapy, the
first and last of which occurred in 1966 and 2013 (27,28).
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FIGURE 8.1 Schematic flowchart of the steps in the total radiation therapy process. The shaded
region emphasizes those steps specifically associated with treatment planning and the use of the
TPS. (Adapted from Van Dyk J, Rosenwald J-C, Fraass B, et al. Commissioning and quality
assurance of computerized planning systems for radiation treatment of cancer. Figure 1 of IAEA
TRS-430 (14), reproduced with permission.)
The advances in computer technology led to a revolution of diagnostic

imaging during the 1970s that provided a further breakthrough for
radiation therapy planning. Until then, it was difficult both to localize
the tumor with any kind of accuracy and to provide accurate dose
calculations accounting for patient-specific tissue densities. With the
advent of computed tomography (CT) it became possible for the first
time to derive in vivo density information that could be incorporated
into the dose calculation process. The combination of developments in
computers and in diagnostic imaging resulted in much research,
improving dose calculation procedures that accounted for the actual
tissue composition of the patient.
Over the past two decades, the utilization of multiple imaging
modalities and the ever-increasing computational demands has
necessitated changes in the TPS hardware and storage capabilities.
Modern fluence optimization and dose calculations require significantly
more computational power, resulting in a migration from local desktop
PCs to large local server farms. Storing the vast amount of on-treatment
and historical treatment planning data often requires utilizing picture
archiving and communications systems (PACS). While the installation of
these systems is often completed by industry experts, it is typically the
responsibility of the local physics or information technology (IT) staff to
provide management for routine data backup/restoration,
software/hardware issues, and future upgrades. While larger institutions
may have the necessary resources to fully support all components of a
modern local server-based TPS, the increased hardware/software
components may be beyond the means and expertise available for
smaller clinics.
One possible solution currently being explored is the utilization of
cloud-computing (29). The ubiquity of modern high-speed fiber optic
communications may allow clinics to outsource the dose computation,
data archiving, and other TPS functionalities to professionally managed
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server farms. Cloud-computing would allow all radiation oncology
clinics to install modern TPS functions without extensively investing in
hardware or specialized staff. Implementing cloud-computing could
provide several other advantages, including easy sharing of plan data
and a standardization of TPS parameters between institutions with
matched machines. Before being adopted clinically, several issues,
including data security/privacy and data transfer integrity, would need
to be fully resolved.
The topic of QA for TPSs has only recently received extensive
attention from national and international radiation oncology groups, as
demonstrated by the development of several reports formalizing TPS QA
(13–16,30–33). This is partly due to the nature of QA, which has not
historically been considered a major area for high-powered research and
partly in response to the increased complexity and sophistication of
technology used in the modern radiation oncology clinic. This chapter
summarizes recent developments and recommendations associated with
QA issues in radiation treatment planning, especially the implementation
and clinical use of computerized radiation TPSs.
Treatment Planning Process

In its broader sense, treatment planning includes all the steps from
therapeutic decision making to target volume and normal tissue
delineation, selection of treatment technique, determination of the
direction of radiation beams, simulation, fabrication of ancillary devices
and treatment aids, monitor unit (MU)–time calculations, treatment
verification, and finally, first treatment (Fig. 8.1). In its narrower sense,
treatment planning includes the outlining of target and critical volumes
(34); the determination of the number, directions, and modality/energy
of radiation beams; and the corresponding MU calculations. In this
narrower definition, treatment planning involves the use of image
information and the computer to perform the appropriate virtual
simulation and dose calculations. The QA considered in this chapter
primarily addresses the use of the TPS to generate appropriate beam
arrangements and dose calculations. The following specific issues are
associated with that part of the QA process.
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Patient Data
Patient data can be derived in various ways, including simple methods of
external contour determination and various imaging modalities, most
commonly CT. Image registration techniques (rigid and deformable) are
used to accurately overlay the patient’s anatomy from various imaging
modalities so that each can be fully used during contour delineation. The
important issue at this stage of planning is to ensure that the patient is
positioned identically to the eventual treatment position and that the
derived data represents this position (35). It is important that the data
be transferred accurately to the TPS. Also, any conversions of digitized
data, such as the conversion of CT numbers to electron densities, must
be handled accurately by the system.
Display of Patient and Beam-Related Information

Once the data have been transferred to the TPS, the treatment planner
can manipulate the information, look at the data on various slices or in
3-dimensional (3D), and allow the system to perform reconstructions of
images. With the patient data on the computer, the radiation oncologist
is able to outline target volumes and critical organs-at-risk (OAR) on the
appropriate slices (34). The correctness of the display of patient data is
not only important for target/OAR delineation but also for the treatment
planner to accurately design the placement and optimization of radiation
beams. Beam placement is often performed by entering parameters such
as field size, beam direction, and collimator rotation. At this stage,
various options can be used for the definition of the field shape. In each
case, the beam edges can be displayed either on a beam’s-eye-view
perspective or as perspectives of the beam edges intersecting any
specified plane. Associated with the beam edge display, information
demonstrating gantry angle, collimator angle, beam energy, and
collimator size should also be displayed on the screen.
Dose Calculation and Display

Once the beam geometry has been determined, the dose distribution can
be calculated and displayed. Displays vary from simple colored isodose
lines to color washes to individual point doses. The accuracy of the
geometric correctness of isodose lines on the display is very difficult to
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assess, although very specific phantom geometries, whereby one can
assess the position of a specific isodose line, can help with this process.
Doses calculated at individual points can be correlated to the isodose
lines as well as measured data.
Development and Implementation of Treatment Planning

Algorithms
The clinical implementation of treatment planning programs involves a
number of steps. Some are under the control of the user, and some are
not, because they depend on software developed by others. The typical
clinical implementation of treatment planning programs usually takes
the following steps.
Development of Calculation Algorithms

Dose calculation algorithms are based on the physics of radiation
interactions within tissue. Because of the complexity of the physics of
these types of interactions, the algorithms usually involve simplifications
allowing the calculations to be completed fast enough to be useful to the
treatment planner. These simplifications result in approximations to the
complicated physics, and therefore, the algorithms have inherent
uncertainties and generally work well only over a limited range of
conditions. Usually, the more complex algorithms handle the physics in
more detail, but also require longer calculation times. The extreme
example of this is Monte Carlo calculations, which can take hours to
days, depending on the mode of treatment and the complexity of the
plan, although recent commercial clinical versions for electron beams
can be calculated in minutes (36) and photon beams from minutes to
hours (37). To be practical, a clinical algorithm should generate dose
distributions nearly in real time, but usually in seconds. The details of
the algorithm implemented on a given commercial TPS are not in the
control of the user.
Development of the Computer Programs Implementing the

Algorithms
Once a developer of a TPS has determined the nature of the algorithm,
the algorithm must be coded into software. This software must include
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appropriate input–output routines, image display, and manipulation
routines, options that allow the user to define the treatment technique,
and plan optimization and evaluation routines. The development of the
software is not under the control of the user. It is the responsibility of
the developer of the software to ensure that the algorithms are properly
coded.
It is important for the user to have some knowledge of the nature of
the dose calculation algorithms to help understand their capabilities and
limitations. Furthermore, a basic knowledge will also help the user
diagnose specific TPS problems and can be of some help in developing a
QA process. A detailed description of different dose calculation
algorithms can be found in the preceding chapters. A detailed report on
external beam tissue inhomogeneity corrections for photon beams has
been produced by AAPM Task Group 65 (38). In recognizing that the
thorough description of algorithms was also beyond the scope of the
IAEA TRS-430 (14), the report provides a series of questions that users
may want to address either as part of the search process for a new TPS
or in attempting to understand the calculation algorithm(s) currently
available on their TPS. This information is provided in 14 tables
addressing different issues related to TPSs. To give an idea as to the
subjects covered, the titles of these tables are summarized in Table 8.1.
Table 8.2 is an example of one of the tables in IAEA TRS-430 (14) and
shows questions related to external beam dose calculation algorithms in
a water-like medium without any beam modifiers.
For brachytherapy, an interesting review of the evolution of treatment
planning has been provided by Rivard et al. (39).
Determination of the Radiation Database Required by the

Algorithms
All algorithms, even sophisticated Monte Carlo procedures, require a
basic radiation dataset as input. As discussed earlier in this chapter, the
data used to create a basic radiation dataset originates from two possible
sources. Traditionally, the data are independently measured for each
energy on each therapy machine in every radiation therapy department.
The quality and accuracy of such data depend on the individuals
commissioning the TPS. Alternatively, one can commission the TPS using
GBD supplied by the system manufacturer and validate the supplied data
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against a subset of beam measurements from the local radiation therapy
machines.
TABLE 8.1 Titles of Tables in IAEA TRS-430 (15). Addressing

Questions Associated with TPS Algorithms
Such data are always determined over a limited range of conditions.

Thus, calculations that extend beyond the range of the original
measurements may be subject to question, depending on the
extrapolation procedures used by the calculation algorithms.
Furthermore, measured data have their own inherent uncertainties and
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depend on the type and size of detectors used and the care taken by the
experimentalist (18). The accuracy of the measured data also depends on
the stability of the radiation therapy machine and its ability to yield the
same kind of radiation characteristics from day to day and hour to hour.
The input data required by TPSs at minimum are relative, in the form
of dose ratios, with the denominator being the dose under some
reference condition. Any TPS capable of calculating MU or treatment
times also requires absolute information in the form of MUs per gray or
grays per minute. These are all part of the input dataset required by the
TPS.
TABLE 8.2 External Beam Dose Calculation Algorithm: Dose in

Water-Like Medium without Beam Modifier
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Clinical Application
Finally, the clinical use of the TPS requires patient-specific information
in the form of patient contours, usually generated with the aid of CT,
PET, and/or MRI. Appropriate parameters must be entered to determine
the treatment configuration. Dose calculations are usually performed for
each beam independently, with the summed doses displayed on a
monitor. This clinical application of treatment planning depends entirely
on the user and his or her knowledge of the capabilities and limitations
of the TPS. Admittedly, the newer inverse planning optimization
routines (5) used for IMRT are automated and leave little in the control
of the user other than entering the dose-volume constraints as required
by the objective function for the optimization.
TREATMENT PLANNING SYSTEM COMMISSIONING AND

QUALITY ASSURANCE
Terminology Associated with QA
Four major topics that are associated with the installation of any major
piece of apparatus are specifications, acceptance testing, commissioning, and
QC. In the context of TPS, the distinction between some of these terms is
not entirely clear, and therefore they warrant special discussion.
System Specifications
In the context of treatment planning computers, specifications define the
detailed functionality criteria of how the TPS will be utilized within the
clinical workflow. Until relatively recently, there have been numerous
commercial and home-grown TPSs with each offering unique
functionality. This broad selection made it extremely important for an
end user to carefully match system specifications to their current/future
clinical workflow. Currently there are only a few commercially available
systems, each offering a standard range of functions that facilitate all
applications used within most clinical workflows. Manufacturers of these
modern TPSs provide specifications that define the capabilities of their
equipment. For TPSs, the specifications tend to include necessary
hardware, system administration software, networking software, and
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dose planning software. Software specifications include detailed
descriptions of what the software is capable of doing and how accurate
the dose calculations can be made. Networking software specifications
should detail the ability for the TPS to be fully integrated with the
electronic medical record, information management, and record and
verify software systems.
Acceptance Testing
Upon the installation of any new device, the user should assess the
device to ensure that it behaves according to its vendor-defined
specifications. For a TPS, this takes at least two forms: assessment of the
hardware and the software. The latter can also be divided into several
components, including assessment of the integrity of the operating
system, dose calculations, image transfer, and image display. Acceptance
testing is typically conducted by the vendor’s installation engineers, who
must show the accuracy of all specifications, are within preagreed upon
standards. Successful completion of acceptance testing represents the
final stage of the installation contract.
Commissioning
Commissioning is the process of putting the system into active clinical
service. This includes the production of a basic radiation database,
which is entered into the TPS, after which the user tests the system over
a range of clinically relevant conditions. Quality evaluations of the
programs’ outputs are then made. Such a process cannot test all the
system’s pathways or subroutines; however, it does provide the user with
a level of confidence over a wide variety of often-used treatment
conditions. In addition, it helps the user understand the degree of
uncertainty associated with these specific calculations. Finally, during
commissioning the user produces a baseline of performance standards to
be utilized for future QC (4).
Quality Control
As indicated earlier, QA and QC are closely related. QA is the total
process required to ensure that a certain level of quality is maintained
for a defined product or service. QC consists of systematic actions
necessary to ensure that the product or process performs according to
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specification. QC contains three components: (a) the measurement of the
performance, (b) the comparison of this performance with existing
baselines or specifications defined during commissioning, and (c) the
appropriate actions necessary to keep or regain agreement with the
baseline.
In summary, QA and QC first necessitate defining a series of
specifications. Acceptance tests ensure that the system meets the basic
requirements as defined by the specifications. Commissioning makes the
computer ready for clinical use and provides a series of baselines that
can be used for ongoing QC to ensure that the system is maintaining the
required standards. Ongoing QC must be performed at intervals to
confirm that there have been no changes in the basic radiation and
machine parameter data files, in the input–output hardware, in the CT,
MRI, or other imaging-related software or hardware, or with the transfer
of data between clinical systems. Each of these four sections will be
described in detail throughout the remainder of the chapter.
System Specifications
Sources of Uncertainties
Specifications take various forms. One form is simply a statement of
whether the TPS is capable of doing a particular function or not. Another
form is quantitative, for example, calculation speed, number of images it
can hold, and so on. A third form is a statement of accuracy. This is
particularly relevant for dose calculations. To assess the accuracy of a
TPS and to define realistic accuracy specifications, it is necessary to
understand the sources of uncertainties.
The determination of uncertainties in dose calculations is complex
because dose calculation algorithms depend on input information, which
is usually generated by measurement. Thus, the uncertainty in the
calculation output depends on the uncertainties associated with the
measurements as well as the limitations of the calculation algorithms.
Measurements are of various types, including relative doses in water
phantoms, absolute dose calibrations for MU calculations, patient
anatomy using imaging techniques or contouring devices, and thickness
profiles of compensators or bolus.
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Suggested Tolerances
Criteria of acceptability for dose calculations have been described by
various authors (21,40–42). Task Group 53 of the AAPM (13) and IAEA
TRS-430 (14) also include discussions on criteria of acceptability and
tolerances generally considered achievable. All tolerance values vary
dependent on the region of calculation. Greater accuracy can be
achieved on the central ray in a homogeneous phantom than in the
penumbra region at the beam edge. Generally, four regions can be
considered: (a) regions of low-dose gradients in the central portion of the
beam, (b) regions of large-dose gradients such as those occurring in the
penumbra or in the fall-off region for electron beams, (c) regions of low-
dose gradients in low-dose areas such as those occurring outside the
beam or under large shielded areas, and (d) doses in the buildup or
build-down regions at the entrance and exit surfaces of the patient.
Criteria of acceptability are generally quoted as a percent of the
reference dose except in regions of high-dose gradients, where a spatial
agreement in millimeters is a better descriptor, since the dose
uncertainties in such regions can be very large.
Criteria of acceptability should include a statement of confidence. For
example, we may state the criterion of acceptability is an accuracy of 2%
of the dose calculated on the central ray of the beam for a homogeneous
phantom. However, it is not clear if this statement expects all calculated
doses to be less than the criterion or if it expects only a certain
percentage, such as one standard deviation (68%) to be within the 2% of
the measured values. This is an important consideration, since
ambiguities in these criteria can generate tremendous frustration from
the user’s perspective as well as some troublesome legal interactions
with manufacturers of TPSs. By way of example, Van Dyk et al. (41)
produced some tables of criteria of acceptability clearly outlining the
system’s general capabilities. Tables 8.3 and 8.4 are similar to the Van
Dyk data, but some adjustments have been made in the numerical values
to indicate a slightly tighter range of acceptability reflecting
improvements in dose calculation algorithms available with modern
TPSs. These criteria of acceptability represent one standard deviation
about the mean. Venselaar et al. (42) have used a somewhat more
complex, but more rigorous, definition of a “confidence limit” and this
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has been discussed in IAEA TRS-430 (14). It should also be noted that
calculation accuracies depend not only on the input data and the
limitations of the algorithms, but also on the user’s performance of the
calculation, which includes issues such as the choice of grid spacing.
Grid spacing can have a large impact on the accuracy of dose
calculations, especially in regions of high-dose gradient.
TABLE 8.3 Sample Criteria of Acceptability for Photon and Electron

Dose Calculations
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TABLE 8.4 Sample Criteria of Acceptability for Brachytherapy
Calculations
For brachytherapy calculations, uncertainty estimates are more

difficult to determine because of the very short treatment distances and
the corresponding large-dose gradients. Furthermore, brachytherapy
calculations usually include absolute dose estimates, which require a
detailed understanding of absolute source output specifications. A recent
AAPM report suggests that when all uncertainties are combined, the two
standard deviation (or two sigma uncertainty, k = 2 in the report) of
dose rates used in treatment planning are approximately 9% and 7% for
low-energy and high-energy photon-emitting brachytherapy sources,
respectively (43). These stated uncertainties are for a single location, 1
cm from the source along the transverse plane. It should be noted that
the one standard deviations (or one sigma uncertainty, k = 1 in the
report) are less than 5% for both low-energy and high-energy sources.
These findings keep in agreement with the suggested criteria of
acceptability for brachytherapy calculations with a confidence of one
standard deviation given in Table 8.4.
These criteria of acceptability are based on what may be realistically
achievable. Ideally, the recommendations of ICRU 42 (40) should be
used as a goal for developers of treatment planning computer software.
For external beam therapy, ICRU 42 recommends 2% accuracy in low-
dose gradients and 2 mm accuracy in high-dose gradients. For
brachytherapy, 5% to 10% accuracy (two-sigma uncertainty) at
distances of 0.5 cm or more has been suggested (43).
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Acceptance Testing
The system specifications determine the acceptance tests that have to be
performed. As a first step upon completion of the installation of a new
system, the user should determine that all the components have been
delivered and are consistent with the specifications. This includes a
review of each component of the hardware. With rapidly changing
technologies, manufacturers often switch one piece of hardware with an
updated version or with a device from another manufacturer. It is up to
the user to ensure that the new hardware equals or surpasses the
specifications set out in the purchase document.
The next step is to ensure that each component of the hardware
functions at a simple level, that is, make an assessment of the monitor,
mouse, printer, scanner, storage media, network connection, and other
hardware items. A check that all the relevant manuals and schematics
have been delivered is also important. The next level of hardware testing
is to use the diagnostic programs provided with the system to ensure
that all the hardware components assessed by the diagnostic routines are
functioning properly. This provides both a test of the system and a
baseline for the user to understand any changes that may be observed in
the follow-up QA tests.
The next step is to run the system software and to ensure that each
component of the software listed in the specifications is actually
installed and functional. This includes third-party software (commercial
software purchased by the vendor and included in the TPS) in addition
to the treatment planning software.
The TPS software acceptance is very complex, primarily because the
testing of the software requires input data specific to the therapy
machines to allow direct comparisons of calculations with
measurements. A practical approach is to test the system’s input–output
hardware to ensure that the system is capable of providing the options as
defined in the specifications and then to assess the accuracy of the
calculations as part of the commissioning process. In the signing of the
acceptance document, the purchaser should indicate that the software
acceptance will be completed as part of the commissioning process.
It should be noted that acceptance testing for IMRT requires a special
emphasis on the system’s capability of handling the penumbra region of
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small radiation fields as well as the leakage radiation outside the field.
Small differences between measured and calculated dose in these regions
can yield relatively large dose differences when many of these small
fields are summed together. Due to the difficulty of small field
dosimetric measurements, extreme care should be taken to ensure that
the input data accurately represent the radiation delivery system.
A major component of potential error relates to maintaining the
spatial integrity of imaging datasets during input–output with the TPS.
Analysis of the spatial integrity during input–output should include
validating the consistency of size, shape, distance, and orientation of the
dataset, and the uncertainty should be <1 mm. All contours, target
volumes, normal tissue structures, CT images, beam outlines, ancillary
devices such as wedges and blocks, and isodose lines should be accurate
and consistent between screen display and hard-copy output. Scales,
distance calipers, and any other measurement routines should be
assessed for both function and accuracy. This includes autocontouring,
automatic contour expansion for target volume margins, density
assessments, automatic field shaping, and other features used by the
planning software.
A more comprehensive process for acceptance testing has been
proposed by the IAEA (15). The IAEA process is based on an earlier
document specifically made for vendors of TPSs by the International
Electrotechnical Commission (IEC) (32), which developed a series of
requirements for manufacturers in the design and construction of a TPS.
The consultants group for the IAEA has proposed that vendors should
perform a series of “type” tests for their system, the results of which
should be provided by the vendor to the user as part of the purchase
documentation (15). Type tests refer to those tests that are to be done by
the manufacturer, normally at the factory, to establish compliance with
specified criteria. The type tests proposed by the IAEA are based on an
intercomparison of photon dose calculation data (44). In addition to the
6, 10, and 18 MV data in the Venselaar and Welleweerd report, cobalt-
60 data have also been added to the IAEA dataset. These data are
provided by the IAEA to all vendors. The vendors enter the basic
radiation beam data as though they were commissioning those beams for
their dose calculation algorithms. Then, the vendors should perform all
the tests as described in the IAEA document. Once the TPS is installed at
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the user’s site, a select subset of tests should be performed to
demonstrate consistency with the vendor’s type tests. The vendors
should update the type test results, if necessary, whenever software
changes or upgrades are made, and again these should be documented
and provided to all purchasers of that software. At the time of software
updates by the user, another select subset of tests can be made to ensure
consistency of results between the vendor’s calculations in the factory
and the user’s calculations in the clinic.
Commissioning
As discussed in the introduction, there is an ongoing debate on the
utilization of GBD for commissioning a TPS (19). Supporters of the
historical customized method of using institution specific beam data
contend that manufacturing and installation variations between linear
accelerators require unique beam models developed from the beam data
produced by extensive commissioning measurements (18). In this
approach, it is the responsibility of the physicist, guided by numerous
formalized documents, to correctly commission the TPS and develop
ongoing QA processes (13,18). Proponents of using GBD contend that
variations between machines from the same vendor/series are minimal
(17) and reference of several studies indicating measurement and
modeling errors during TPS commissioning and QA produce more
extensive dose calculation inaccuracies (11,12). Furthermore,
prepackaged TPSs modeled on extensively validated GBD have the
potential to drastically reduce gross systematic errors and standardize
delivery quality across the entire radiation oncology industry (19).
Several vendors of both generalized and specialized commercial TPSs
install units using manufactured measured GBD (45–47). Validation of
GBD to the measurements made on the local linear accelerator is still
needed to ensure an accurate match between the planned and delivered
dose. Regardless of which set of beam data is used during TPS
commissioning, the same general measurement and comparison
methodology should be followed, including comprehensive end-to-end
testing for the entire treatment planning and delivery process. The
commissioning process should also incorporate the development of
treatment planning procedures, training for staff, and designating expert
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users who will be responsible for the continually TPS QA program. The
remainder of this section provides examples and highlights of tests that
should be conducted during TPS commissioning.
Photon Beams
The clinical implementation of the TPS can be divided into several
components. These include entry of basic radiation data, entry of
machine-specific parameters, entry of data related to ancillary devices
such as wedges, assessment of image transfer capabilities, assessment of
the accuracy of the electron density conversion formula, and the
validation of data transfer between all systems in the clinical workflow.
Each of these components involves data entry and then tests of the
software. For each component it is important for the user to understand
the capabilities and limitations of the software.
For TPS commissioning using unique local beam data, the data entry
for dose calculations can have various forms, including a direct entry
from data stored in the water phantom computer. The software of both
the water phantom systems and TPSs evolves with time and therefore
comes in various versions. To ensure version compatibility, it is always
important to assess that the data have been read properly by the data
entry programs.
Basic radiation data can be entered in various forms, including tissue–
air ratios, tissue–phantom ratios, tissue–maximum ratios, percentage
depth doses (PDD), and cross-beam profiles. Cross-beam profiles may
also have to be measured under a variety of conditions, including
profiles for the machine collimators, shielding blocks, wedges, and
multileaf collimators. The quality and accuracy of the measured basic
radiation data should be evaluated prior to implementation in the TPS. A
standard set of procedures for acquiring radiation beam data, along with
examples of commonly identified errors, are provided by the AAPM (18).
Limitations of physical measurements, specifically for small fields, high
gradients such as the penumbra and buildup regions, and peripheral
dose regions should be carefully evaluated. In all situations it is
imperative that the user ensures the accuracy of the entered data by
looking at the numerical values on the screen or by plotting out the data
and comparing directly with what has been entered. An independent
verification of the beam data using either Monte Carlo generated data or
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GBD should be considered.
Should GBD be used during commissioning to create dose calculation
models, the validation measurements taken on the linear accelerator
should be directly compared to the GDB values. Any discrepancies
should be evaluated and, if necessary, modifications can be made to the
delivery system.
The types of tests that should be used to assess the quality of the
algorithms are summarized through working group reports as seen in
references 13, 14, and 31. Table 8.5 provides a summary of the relevant
parameters and variables that should be included in the testing process.
This is a guide to the kinds of issues that should be considered when
assessing the calculation capabilities of the TPS.
Examples of Photon Commissioning Tests

Several examples of the types of tests that can be performed, possible
methods of evaluation, and some additional issues to consider are
provided for non-IMRT photon beam commissioning. These examples do
not represent extensive commissioning testing and primarily serve to
illustrate possible methods for completing the commissioning process.
Figure 8.2 illustrates an example of simple central axis PDD data for a
range of field sizes. A comparison is made between the calculated data
(lines) and the measured data (points). Figure 8.3 shows how the data of
Figure 8.2 can be analyzed more critically by taking the absolute
difference between the entered and the calculated data for a 10 cm × 10
cm field size. It is clear that beyond the buildup depth (40 mm) the
differences are minimal (<0.2%), but in the buildup region differences
can be as large as 9%. The reason for these differences is not clear, but
the trends are similar for all field sizes. Figure 8.4 shows a difference
comparison for cross-beam profiles and includes two different
calculation algorithms, one being a table look-up algorithm and the
other a convolution calculation. In these graphs, it is clear that there are
sizable differences in dose in the penumbra region, although spatially
these differences are quite small (1 to 2 mm).
TABLE 8.5 Initial Dose Calculation Tests: Variables to Consider
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FIGURE 8.2 Central ray percentage depth doses (PDD) for fields of dimensions 4 × 4 cm, 10 × 10
cm, 25 × 25 cm, and 40 × 40 cm. The data points entered into the treatment planning system are
labeled Meas and the calculated data are shown by the lines. The data are for the 25 MV beam
from a linear accelerator and are normalized to 100% at a depth of 4 cm.
Figure 8.5 shows a comparison of measured and calculated dose

profiles with the gantry angle at 40 degrees incident on a flat water
phantom. This comparison tests the integrity of the TPS to correct for
nonnormal incidence of the primary beam. Figure 8.6 is a demonstration
of the accuracy of the wedge calculations for a motorized wedge (a
physical wedge that is inserted by motor in the beam for a fraction of
the treatment and withdrawn for the remainder). This is a severe test of
the algorithms, since the wedge is very thick, with a wedge factor of
about 0.25. Figure 8.7 shows the difference between calculated and
measured dose for central ray PDD data under the motorized wedge for a
number of field sizes.
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FIGURE 8.3 The absolute difference between calculated and entered (or measured) percentage
depth dose (PDD) data for a 10 × 10 cm field for the 25 MV photon beam from a linear
accelerator.
FIGURE 8.4 Absolute differences in relative doses comparing measurements with calculations for
cross-beam dose profiles for two dose calculation algorithms. The beam profiles were measured
at a depth of 4 cm for the 25 MV beam of a linear accelerator. The pencil beam (convolution)
algorithm shows the largest difference, about 10% in the penumbra region, although this
difference represents a spatial uncertainty of only 2 mm (not shown in figure).
Figure 8.8 shows cross-beam dose profiles calculated for a multileaf

collimator with the three 1-cm leaves covering the central portion of the
beam to yield a central beam block. Note that one of the leaves is on one
side of the central ray and the other two are on the opposite side. At
depths of 4, 10, and 25 cm, the dose profiles agree reasonably well
except in the centrally blocked region. A more detailed comparison of
this is shown in Figure 8.9, where calculated central ray depth doses are
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shown first for an open beam and then with the three central leaves
covering the beam. Also shown are measured central ray data under the
leaves. The differences between calculated and measured data under the
leaves are about 5% to 7% except in what is normally the buildup
region, where the differences are as large as 28%. These differences may
be due to this program’s inability to handle electron contamination
under the leaves or shields. This is a physics problem that occurs in older
algorithms but has been improved in most new commercial treatment
planning programs (48,49). Differences could also be originating from
the limitations of physical measurements within these regions.
FIGURE 8.5 Calculated and measured dose profiles with a gantry angle of 40 degrees incident on
a flat water phantom for a 10 cm × 10 cm field at depths of 4 and 10 cm for the 25 MV beam of a
linear accelerator.
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FIGURE 8.6 Calculated and measured dose profiles under a motorized wedge. Profiles are
shown for the 25 cm × 25 cm at depths of 4 and 15 cm, as well as a 30 cm × 30 cm field at a
depth of 4 cm for a 25 MV beam.
FIGURE 8.7 Difference profiles comparing measurements with calculations for central ray doses
measured under a motorized wedge for 6, 10, 25, and 30 cm square fields for a 25 MV beam.
Most differences are within 0.5% except in the buildup region, where differences are as large as
3.5%.
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FIGURE 8.8 Comparison of measured and calculated cross-beam profiles under a multileaf
collimator. Three leaves are in the center of the beam, with one leaf on the left side of the central
ray and the other two on the right. The largest differences occur under the centrally shielded
region of the multileaf collimator.
FIGURE 8.9 Doses along the central ray for the same geometry as Figure 9.9. The upper curve is
calculated with no multileaves in the center of the beam. The lower curve is calculated under the
leaves, and the individual data points are the measured data under the leaves. The differences
between measured and calculated doses in the buildup region under the leaves are due to the
inadequacies of the algorithm to handle electron scatter (contamination) under shields.
IMRT
There are some unique aspects to commissioning IMRT compared to 3D
conformal radiation therapy (CRT). IMRT uses automated inverse
planning routines, which use iterative algorithms to yield acceptable
plans based on specified dose–volume constraints. The resulting dose
distribution can have steep gradients between the target and the organs
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at risk and the commissioning tests need to reflect this added
consideration. Because IMRT could involve the summation of very many
small fields or multiple field edges, it is extremely important to ensure
that the modeling of the penumbra and the low-dose region outside the
beam is handled accurately. Furthermore, the accurate calculation of the
leakage radiation through the body, side, and end of the leaves,
especially those with curved ends, is very important to yield an accurate
penumbra (50,51). Because of these small field considerations, ICRU
Report 83 (52) points out that the Van Dyk criteria of acceptability (41)
of 3% in the high-dose region and 4% in low-dose regions for 3D CRT
may be too restrictive for IMRT in the high-dose region and
insufficiently restrictive in the low-dose region.
It should also be noted that the delivered dose distribution is
dependent on the leaf sequencing algorithm that is used to convert the
TPS-derived intensity maps to a deliverable set of MLC sequences. The
results are dependent on leaf width, leaf-travel distance, interdigitization
of leaves, and maximum field size. Using smaller MLC steps and a larger
number of intensity levels can result in many segments with small field
sizes again compounding the need for accuracy in MLC positioning and
penumbra modeling. Furthermore, there may be accelerator constraints
on the delivery of many segments each with a small number of MUs.
Because of the difficulty in measuring doses in small fields and
potential accelerator constraints, the ICRU Report 83 (52) suggests that
the use of end-to-end testing is integral to the beam commissioning
process. End-to-end testing validates the entire treatment planning
process including data collection, beam modeling, treatment planning
and delivery, data transfer from the TPS to the record-and-verify system,
and QA of the delivered absorbed dose. A typical end-to-end test
involves scanning a QA phantom, creating an IMRT plan on the image
dataset, measuring the delivered dose within the phantom, and
comparing the measurements to the calculated dose distribution (33).
The AAPM Task Group 119 provides an end-to-end testing suite for
IMRT planning (33).
Automated and Knowledge-based Planning

Automated and KBP techniques have recently been developed to
improve both treatment planning efficiency and plan quality (53–57).
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Automated techniques replace repetitive steps of the manual workflow
typically completed by a planner by automatically applying predefined
site-specific parameters (structure names, beam angles, weighted
optimization objectives) to a new patient dataset. These predefined
parameters provide a standardized basis to begin the optimization
process and help minimize the variations introduced by planner. KBP is
an additional method that aims to reduce the variation in IMRT plan
quality and improve efficiency by providing achievable, patient-specific
optimization objectives derived from a model trained with a cohort of
previously treated site-specific plans (57–60). This database of existing
treatment plans is used to create a dose prediction model that correlates
patient-specific anatomic relationships (contours) with prior dose
distributions and can be applied to future patients being treated to a
similar anatomic site. Recent research for automated, knowledge-based
contour validation has also shown promise (61).
Commissioning automated treatment planning software requires a
thorough understanding of how the program takes input data and
creates treatment plans. Ideally, predefined planning parameters as
discussed above are evaluated to ensure they correlate to an institution’s
treatment planning practice. To ensure acceptable quality is achieved,
plans generated using the automated software should be evaluated at
specific dosimetric endpoints against manually generated plans for
several patients across all treatment sites for which the software will be
clinically used. If acceptable plan quality is not achieved, the predefined
planning parameters should be adjusted until the necessary quality is
met.
Additional considerations are necessary when commissioning KBP
software. Users have the option to commission their own local KBP
model or to utilize existing global models created by another institution.
KBP models are intrinsically dependent on the anatomic relationships
(contours), clinical trade-offs, and dosimetric endpoints of the initial
IMRT plans selected to train the model. Global models are sometimes
provided by the vendor with a detailed description of the parameters
associated with these dependencies and each should be carefully
compared to the clinical practice before being considered for
implementation. When creating a local model, the quality and diversity
of the plans included should reflect the intended scope for which the
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model will be clinically applied. Both local and global models should be
extensively validated against an independent validation cohort of
manually created clinical plans to ensure the model will meet or exceed
expected target and OAR dosimetric goals (9). If plans created with the
model are not consistently comparable or superior to manually created
plans, the model should not be selected for use within the clinical
workflow.
Image Registration
The utilization of multimodality imaging in the definition of anatomic
OARs and targets has become increasingly common in the modern
radiation therapy clinical workflow (62,63). While CT imaging still
remains the primary modality for radiation treatment planning, it is
often inadequate when attempting to accurately delineate the tumor
(64). Tumors located in the central nervous system, abdomen, pelvis,
breast, or head and neck may require MRI/ultrasounds to provide high
contrast between soft tissues (65). Other sites in the thorax, abdomen,
pelvis, and head and neck benefit from metabolic information provided
from PET and SPECT imaging (7,66,67). In addition, specialized CT
scans (4D CT) may be necessary to assist in the management of tumor
motion in the thorax or abdomen (68). In order for the physician to
accurately and efficiently use the information provided by all imaging
modalities, it is necessary for all imaging datasets to be geometrically
associated via a process called image registration.
Image registration creates a vector transformation that maps specific
anatomic structures in the secondary imaging dataset to the
corresponding anatomic structures in the primary imaging dataset
(typically the planning CT). This transformation may be a rigid
(consisting of a global shift/rotation) or deformable (incorporating
relative local modifications of the secondary dataset). Once the image
datasets are registered, it is possible to map information such as soft
tissue contrast, metabolic uptake, tissue boundaries, or previously
delivered dose from the secondary datasets onto the primary CT dataset.
This combination of information from various imaging modalities is
known as image fusion. Many modern TPSs have developed integrated
image registration and fusion software. Due to their role in delineating
radiation targets and healthy tissue, the accuracy and reliability of the
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registration and fusion software necessitates a thorough commissioning
process.
The process of validating image registration and fusion software is
relatively new. To thoroughly evaluate the accuracy and uncertainties of
any registration software, it is necessary to quantitatively compare the
generated coordinate system changes to known true changes within
baseline image datasets. These tests should be completed across all
imaging modalities using virtual geometric and anatomic phantoms and
include both rigid and deformable registration techniques (69). Virtual
phantoms allow for predetermined changes to an imaging set against
which registration algorithms can be evaluated (52). AAPM Task Group
132 describes a series of virtual phantoms and related tests to be used
during commissioning and proposes making this standard set of virtual
phantoms available via download in order to standardize the
commission process (70). Additional end-to-end tests using physical
phantoms, such as those supplied by the Imaging and Radiation
Oncology Core (IROC) in Houston, should also be conducted. A series of
typical clinical images should also be evaluated qualitatively and an
ongoing patient specific QA process should be developed to efficiently
evaluate image registration within the treatment planning workflow.
While no formalized guidance documents currently exist, the AAPM is in
the process of developing acceptance, commissioning, and QA guidelines
(70).
Autosegmentation
Clinical autosegmentation algorithms significantly improve the efficiency
of the contouring process but can produce contours with small to
moderate errors (71,72). Commissioning tests for autosegmentation
algorithms should identify the frequency and magnitude of consistently
occurring deviations from the clinically accepted manual contours for
each structure and all treatment planning staff should be familiar with
these deviations. Continuing patient-specific contour QA should be
incorporated into the clinical treatment planning workflow.
Adaptive Radiation Therapy

ART seeks to account for the dosimetric impact of daily anatomical
variations that occur during treatment to ensure the initial planned dose
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distribution matches the final delivered dose distribution. Online ART
requires the rapid implementation of many of the typical treatment
planning steps, including image acquisition, image registration,
anatomic contouring, dose optimization, daily/cumulative plan
evaluation, and patient-specific QA (10). While each of the hardware
and software components for the ART process may have been
independently commissioned in the normal TPS, their specific
application in the ART workflow should be evaluated (73). In order to
minimize the time needed for online ART, many of the planning steps
are automated. The accuracy and functionality of any automated tools,
such as DVH evaluation scripts, cumulative dose analysis, and
OAR/target assessment, should be validated for all treatment sites.
Finally, due to the time sensitivity of online ART, each member of the
staff should be extensively trained in each of their roles. End-to-end tests
of both the system and workflow should be conducted with the staff to
ensure the online ART can be accurately and efficiently completed under
the necessary time constraints (73). A thorough evaluation of the
integrated ART workflow using modern process improvement tools has
been shown to be useful in identifying potential sources of error and
should be conducted for each unique ART workflow during the
commissioning process (74).
Electron Beams
Good examples of specific tests for electron beams can be found in
recent working group reports (13,14,21). Tests of specific concern to
electrons relate to changes in source-to-skin distance (SSD), output factor
calculations, oblique beam incidence, and variations in output for
shaped fields. Additional tests to validate the accuracy of the calculated
dose in heterogeneous medium, such as bone, fat, and lung, should also
be conducted.
Brachytherapy
Verification of brachytherapy dose calculation should be approached
similarly to the external beam tests. In this situation, however, it
becomes much more difficult to compare measurements with
calculations because of the difficulty in performing measurements over
the short distances involved in brachytherapy. The user may have to
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resort to comparing calculations with previously published source data.
Relevant information can be found in various reports (13,14,75,76,77).
One unique test for brachytherapy is the assessment of anisotropy
calculations if these are provided by the system. A recent report by
Rivard et al. (78) provides enhancements to commissioning techniques
and QA of brachytherapy TPS that use model-based dose calculation
algorithms. Additional information regarding model-based dose
calculation algorithms has been included in a recent AAPM Task Group
186 (79). As previously noted, a recent joint AAPM-ESTRO Working
Group addressed the uncertainty in dose calculation accuracy for
brachytherapy TPSs (43).
Proton Therapy
Commissioning proton beam models within a TPS is often accomplished
through a combination of simulated Monte Carlo data and measured
beam data (80). Requirements for specific commissioning tests depend
on the type of proton system (dual passive scatter vs. active spot
scanning) and examples of each have been described thoroughly
(81–84). For dual passive scattering systems, validation will typically
include measuring longitudinal fluence, virtual source position, effective
source position, source size, Bragg peaks, and lateral beam profiles.
Active spot scanning may require validation of spot size, in air lateral
profiles, and integral depth dose data. During commissioning, the lateral
and range uncertainties associated with the accuracy of the model for
the full range of treatment conditions should be carefully evaluated and
accounted for within the clinical treatment planning process (85,86).
Consideration needs to be given to accurately correlate proton stopping
power ratios to CT numbers within a patient and difference between
phantom stopping powers and patient tissue stopping power should be
evaluated (87).
Commissioning of Other Components

Modern TPSs contain many other commissioning aspects than those
related to dose calculations. Examples of other types of issues that must
be considered and verified are shown in Table 8.6. The ability of the TPS
to accurately handle tissue heterogeneities when calculating dose is of
particular importance and validation requires the use of a specialized
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phantom (16). Other nondosimetric parameters, such as image transfer
and contouring validation, can also be evaluated using specialized
phantoms to specifically address some commissioning and QA issues
(16,88).
TABLE 8.6 Commissioning of Other Components
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TABLE 8.7 Techniques Requiring Special Workup
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Special Techniques
Special and individualized techniques require their own unique
evaluation. Examples of special techniques that require additional
workup and commissioning are summarized in Table 8.7. In addition,
there are now a number of new technologies that have specialized TPS
specifically made for that technology. Examples include helical
tomotherapy (45), robotic radiation therapy (89), onboard MRI-guided
radiation therapy (46), and multiple cobalt source, small field radiation
therapy, used mostly for neurologic sites (47).
Quality Assurance and Quality Control

QC of a product or process involves three steps: (a) the measurement of
the performance, (b) the comparison of the performance with a given
standard, and (c) the actions necessary to keep or regain the standard.
The commissioning process of the TPS provides the standard for
comparison. Once the TPS is fully commissioned, a QA program should
be implemented to ensure the system is able to remain within the
standards determined during commissioning. However, the problems
associated with maintaining consistency and quality within a TPS are
quite different from the problems associated with QA of a CT simulator
or accelerator, which have electrical and mechanical components that
can wear and change with time.
Closely associated with QA is risk management. Risk management
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consists of four components: (a) identifying the possible sources of risk
of failure or malfunction, (b) analyzing the frequency of incidents of
failure or malfunction, (c) taking corrective action to minimize such
failure, and (d) monitoring the outcome of such changes. Thus, to
develop an appropriate QA program for treatment planning computers,
an assessment of the likelihood of failure helps focus on the issues of
concern. IAEA TRS-430 (14) provides a good summary of reported errors
associated with radiation treatment planning. For the “accidents” (major
clinically significant errors) associated with TPSs, they determined that
the key contributory factors include the following:
a. A lack of understanding of the TPS
b. A lack of appropriate commissioning (no comprehensive tests)
c. A lack of independent calculation checks
The major issues related to treatment planning errors were

summarized by four key words: (a) education, (b) verification, (c)
documentation, and (d) communication.
The development of a thorough QA program is a compromise between
cost and benefit. An appropriate program has specific QCs to identify
and mitigate high probability and high impact errors without being
excessively burdensome on a facility’s resources. However, as new
technology is implemented in the clinic, it can be challenging to identify
the appropriate QC tests that provide the necessary balance. A careful
evaluation of a new process should be conducted before determining
changes and additions to any QA program.
AAPM Task Group 100 (90) is attempting to deal with the issue of
ever-increasing QA activity as new and more complex technologies
evolve. The central idea of TG-100 is to transition from traditional
device-centered QA to a more comprehensive risk-based, process-
centered approach. To implement a process-centered QA program, the
task group describes three techniques that have been historically used in
engineering circles: process tree mapping, failure mode and effects
analysis (FMEA), and fault tree analysis (FTA). Process tree mapping is a
visual illustration of all the relationships of each step for a specific
process. It tracks the physical and temporal flow of each step, from start
to finish, and is useful in easily identifying and tracking weaknesses and
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error migration. FMEA is a prospective approach to QA. When used in
conjunction with a process tree map, it assesses the potential risks
(failure modes), likelihood of errors, and impact of such errors for each
step defined within the process. For each step, there may be many
potential failure modes, and each one may have several potential causes
and outcomes. For each potential cause of failure, values are assigned in
three categories: O, the probability that a specific cause will result in a
failure mode; D, the probability that the failure mode resulting from the
specific cause will go undetected; and S, the severity of the effects
resulting from a specific failure mode should it go undetected
throughout treatment. Convention uses numbers between 1 and 10.
Category O ranges from 1 (unlikely failure, <1 in 104) to 10 (highly
likely, >5% of the time). Category D ranges from 1 (undetected only
<0.01% of the time) to 10 (undetected >20% of the time). Category S
ranges from 1 (no appreciable danger) to 10 (catastrophic if persisting
through treatment). The product of these three indices forms the risk
probability number (RPN = O × S × D). A complete FMEA applied to
an entire process helps develop a fault tree analysis, which is a
visualization of all errors at each step and associated root causes for each
error. By applying a FTA, it is possible to determine appropriate QC
measures that can be implemented at the necessary steps to accurately
mitigate identified root causes of failure. The prospective approach
described by TG-100 provides guidelines to determine an efficient
application of resources within a QA program that accurately minimize
all major sources of error. Examples of FMEA analyses have been
published for the external beam radiation therapy process (91), dynamic
MLC tracking systems (92), and intraoperative radiation therapy (93).
A necessary element in developing a prospective QA program is the
inclusion of an electronic incident event reporting system (94,95). A
department level reporting system provides a platform for all employees
to voluntarily and anonymously report events, the severity of which
range from minor miscommunication to near-miss to severe treatment
error. Submitted events can be analyzed and previously unidentified
patterns can be systematically addressed prior to the occurrence of
serious errors (96). Several major groups have recently begun
development of national/international reporting systems (ASTRO’s RO-
ILS and IAEA’s SAFRON), which will provide the possibility of shared
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learning across all participating institutions.
Program and System Documentation and Training

At the most basic level of QA, the user must be aware of what the
computer programs are doing when any specific option is requested.
Even if the programs are perfectly accurate, any error in data entry
results in an error in the output. Thus, the user must have adequate
information in terms of manuals and online help to aid in the
commissioning and operational process of the TPS. The types of
documentation that should be available are listed by Van Dyk et al. (41)
and in Table A1-1 of AAPM TG53 (13).
A significant amount of documentation occurs during the
commissioning process and encompasses all systems and software that
were tested. Appropriate documentation should include detailed
descriptions of all tests run, origin of data used in the TPS, and baselines
for the QA program. Documentation detailing with the treatment
planning procedures should also be developed during the commissioning
process and all appropriate staff should be provided training to fulfill
their roles.
User Training
Closely associated with proper manuals and information is user training.
The user must be clearly aware of normalization procedures, dose
calculation algorithms, image display and reconstruction procedures,
and program calculation capabilities and limitations. This training can
be carried out at at least three levels: (a) vendor training courses, (b) in-
house staff training, and (c) special training courses set up by user
groups or third-party software vendors.
TPS training has traditionally been formatted for dosimetrists and
physicists and often only limited training is available to physicians.
Physicians should be able to effectively operate the simple tools of any
planning system (setting beams parameters, defining field sizes, contour
tools). Beyond the basic functionality, in order to accurately evaluate a
treatment plan, physicians need to be aware of inaccuracies and
limitations of the planning system. This includes the inherent
inaccuracies of the dose calculation algorithms (central axis, buildup
region, penumbra, heterogeneities) and clinical situations in which these
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inaccuracies are a common factor. In addition, physicians should be
aware of the capabilities and limitations of IMRT optimization
algorithms to achieve organ/target specific dosimetric planning goals
and the common clinical trade-offs. Finally, physicians should be able to
evaluate the quality of image registration/fusion and understand the
processes of rigid and deformable image registration.
Reproducibility Tests
A normally functioning computer is unlikely to generate small changes
in output. Computer system hardware malfunctions are likely to be
obvious. A more probable issue of concern is inadvertent access by
treatment planners to the basic radiation or machine data files. This can
result in changes to accuracy of calculations without the user being
aware that changes have taken place.
For inadvertent software or hardware changes, a binary comparison of
all the software and data files can test whether any changes have
occurred. If changes are found, the details of the changes must be
assessed and a partial system recommissioning may have to be
implemented. Alternatively, as described in the IAEA report (15), a
select subset of the vendor type tests should be performed to
demonstrate consistency with previous results.
From a risk management perspective, other possible sources of error
include intended or unintended changes in software or data files. These
can occur within the TPS or in the computers associated with data
generation, such as CT scanners and water phantom systems. Software
upgrades in these external computer systems can result in changes to the
data entered into the TPS.
To aid in the assessment of any software changes, a series of
reproducibility tests of the dose calculation algorithms, the image
display algorithms, and the plan evaluation tools should be undertaken
on a regular basis. Examples of such reproducibility tests can be found in
Van Dyk et al. (41) and in the reports from the AAPM (13) and the IAEA
(14). Users should develop their own tests based on their particular TPS
and what components of the hardware, software, and data files have any
likelihood of being changed.
Patient-Specific Tests
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Since no system of computer programs is error-free, nor are users of such
programs perfect, routine inspection of each treatment plan is a
requirement for proper QA. Calculation of the external beam dose
usually consists of two components: (a) calculation of a relative dose
distribution, and (b) calculation of the machine output in terms of MUs.
Both of these components require a check by a participant independent
of the first calculation. For relative dose distributions, secondary checks,
either conducted manually or with a third-party software, can be
performed by choosing a specific point, usually on the central ray, and
calculating a dose estimate for each of the beams using simplified tables
to generate the results. These checks should agree to about 2% to 3% of
the computer-calculated values in regions of uniform dose delivery and
relatively simple inhomogeneity corrections (97). More complicated
plans have to be evaluated on an individual basis to assess the trends of
the numerical values. Similarly, the machine setting calculation should
be checked independently of the first calculation.
With the advent of more complex segmented or dynamic conformal
therapy and IMRT, such manual checks become very difficult if not
impossible. In these situations, the absolute dose is determined as part of
the planning process, with the MUs being defined for each component of
the treatment. QC checks must be developed for each individual
technique. Georg et al. (98) suggested action levels between ±3% and
±5% dependent on the treatment site and treatment technique. They
also conclude that independent calculations may be used to replace
experimental dose verification once the IMRT program is mature (99).
Similarly, ICRU Report 83 (52) describes the use of one or more of the
following methods for patient-specific QA:
• Measurement of the intensity pattern from individual beams for a

specific patient
• Measurement of absorbed dose in phantom of the beam-intensity
pattern planned for a specific patient
• Independent absorbed dose calculations for the patient-specific beam
intensity pattern
• In vivo dosimetry
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For brachytherapy, manual single-point calculations are more difficult,
and therefore a check can be performed with one of the conventional
systems of dosage calculations, such as the Manchester system. This
approach can be used to make crude checks to an accuracy of about
10%. Again, assessing trends is crucial in evaluating the quality of the
calculation.
In vitro and in vivo Dosimetry Checks

As a final check of the quality of the overall treatment planning process,
it is useful to perform measurements using special-purpose or
anthropomorphic phantoms (in vitro dosimetry) or to perform
measurements on or in the patient with the patient in treatment position
(in vivo dosimetry). In vitro dosimetry is an important component of the
implementation of any new treatment technique or clinical procedure.
Generally, it is performed with thermoluminescent dosimetry (TLD) in a
phantom containing human-like tissue densities and composition, such
as an anthropomorphic phantom. More recently, optically stimulated
luminescence (OSL) is being used in place of TLD (100). Diodes and
metal-oxide semiconductor field-effect transistor (MOSFET) (101)
dosimetry systems are now readily available and provide instant readout
capability. This type of dosimetry ensures that the basic procedures
associated with a new treatment technique are in agreement within a
predetermined range of accuracy. A report by Dunscombe et al. (102)
gives a good overview of the use of an anthropomorphic phantom to
evaluate the quality of treatment planning computer systems. While
providing a good indication of the accuracy of the dose delivery process
near the center of the target volume, differences between measurements
and calculations away from the central region were difficult to interpret
as to whether the calculations were off, the measurements were off, or
the beam placement was inaccurate. Thus, in vitro dosimetry must be
established in such a manner that differences between measurements
and calculations can be readily interpreted.
Similar concerns of interpretation also apply to in vivo dosimetry
(103). There is a tendency by radiation oncologists to request in vivo
measurements to give them an assurance that the dose delivery process
is accurate, especially in regions where there is concern about critical
structures such as the eyes, gonads, or a fetus. Sometimes, these regions
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are close to the edge of the radiation beams. Under such circumstances,
small changes in beam alignment can generate large changes in
measured dose, leaving ambiguity in the interpretation of the results.
These interpretation difficulties should be clearly explained to the
radiation oncologist requesting the measurements. Better comparisons of
calculations and measurements can be made in regions where doses are
not changing as rapidly—either on the entrance or exit surfaces or, if
possible, by placing dosimeters in body cavities such as the mouth,
trachea, esophagus, vagina, uterus, or rectum. In vivo dosimetry is a
recommended check under some treatment conditions and it may
provide an opportunity to mitigate treatment errors (104), but it should
not replace pretreatment in vitro phantom measurements for more
complex treatment techniques, such as IMRT. AAPM Task Group 158 has
been charged with assessing the current status of in vivo dosimetry for
nontarget, out-of-field exposures and to formulate recommendations for
methods to improve measurements and calculations for doses outside the
treatment volume (105). The IAEA has also produced a recent review on
in vivo dosimetry (106).
Quality Audits
It is always useful to review the QA activities of individual institutions.
Recent years have seen the public reporting of various errors or
“accidents” in radiation therapy. While such errors can have a
devastating effect on individual patients, the actual error rate in
radiation therapy is very low. However, it is the responsibility of
members of the radiation therapy team to ensure that proper procedures
are in place to minimize such errors. As a first approach, an institutional
self-auditing process is beneficial. This is best done in the context of a
QA committee that should exist in every radiation therapy department
(107). External audits have proven to be extremely beneficial for finding
inadvertent deviations from acceptable practice. The IROC in Houston,
Texas, has done this for years for institutions participating in clinical
trials involved with the Radiation Therapy Oncology Group (RTOG)
(12,108). Dosimetry intercomparisons are also useful especially in the
development of new techniques such as IMRT and provide a means to
standardized the quality of radiation treatment facilities (12,109).
The IAEA has developed an external audit process, which involves a
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review of the total treatment process (110). They do this through the use
of a QA team in radiation oncology (QUATRO), which consists of a
radiation oncologist, medical physicist, radiation therapist, and
sometimes a specialist in radiation protection. A similar external quality
audit has been incorporated into the ASTRO Apex and ACR radiation
therapy accreditation process (111). Dosimetric intercomparisions and
external audits provide a substantial benefit to improve the overall
quality of radiation therapy across all facilities.
QA of Total Radiation Therapy Planning Process

As indicated earlier, the total radiation therapy planning process consists
of many steps, of which computerized treatment planning is only one
component. For the computer plan to be implemented accurately, it is
important that the basic patient data and image information be derived
accurately. This requires QC of the imagers generating the data (87). It
also requires assurance that the patient is positioned precisely in a
manner that will be readily reproducible on subsequent simulation and
treatment setups.
Geometric accuracy, before planning, begins with proper
immobilization and localization of the patient in treatment position.
Accuracy during planning includes assessing uncertainties associated
with image transfer, image registration, target volume and normal tissue
localization, beam placement, and dose calculations. To ensure that the
plan can be implemented on the therapy unit, the planner must verify
the correct transfer of plan data to the electronic medical record system
and that geometric arrangements are physically achievable. QA after
planning may include the comparison of the radiographs with DRRs to
verify that the field shapes are correct, as well as confirmation that the
internal anatomy is located accurately within the fields. Finally,
accuracy can be ensured at treatment by verifying that the setup
parameters such as source-to-surface distances for each field are
consistent with the planned parameters. In addition, daily online
imaging, including kV CBCT, MVCT, and kV 2D imaging, can be used to
assure geometric accuracy of the beam positioning and provide a
confirmation of the location of the internal anatomy of the patient,
immediately before each dose fraction is delivered.
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QA Administration
An important component of any QA program is its effective organization
and administration. Any QA program should be carried out according to
a predetermined schedule and ongoing records of the activities and the
results should be maintained. Proper administration requires that one
person, usually a qualified medical physicist, be responsible for the QA
program. Although this individual does not necessarily have to carry out
all the tests and their evaluations, he or she must ensure that there is
written documentation on the QA process, that the tests are carried out
according to their specified frequency, and that appropriate actions are
taken as needed.
As TPSs become networked into clusters with various planning and
target volume delineation stations, servers, and peripheral devices,
system management becomes an integral component of the entire QA of
the TPS. This management includes maintaining an adequate check on
system security and limiting user access not only to the system, but also
to specific software and data file modifications. It is important that the
radiation data files not be inadvertently changed and that patient
confidentiality be fully maintained.
To avoid the possibility of any undesired loss of information, a regular
schedule for system backup is essential (13). This may include daily
backups of the most recent patient additions and changes, weekly
backups of all patient information, and monthly backups of the entire
TPS. Backups are also warranted immediately after any major changes to
the software of the system.
In addition to standard backups, it may also be desirable to archive
specific patient information, especially if patients are to be grouped for
study purposes. In some cases, patient data may have to be forwarded to
clinical trial groups such as the RTOG, which accepts such information
through the internet. However, patient data must also be archived in
case the patient comes back for retreatment.
Proper QA of the modern 3D TPS is a time-consuming process.
Adequate staff resources must be allocated to ensure that the QA is
completed in an appropriate manner.
SUMMARY
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QA programs for radiation therapy machines, especially with the clinical
implementation of high-energy accelerators have been well defined for
many years. Formalized (CT) simulator QA is a more recent phenomenon
(88). While redundant checks for MU and time calculations have also
been standard practice, the formalization of a QA program for treatment
planning computers occurred more recently. This is partly due to the
tremendous variation in TPSs and their algorithms and partly to the
complexity of treatment planning QA, since it involves multiple facets
and is inherently centered on the entire process and not specific
equipment. Because of these complexities, it is clear that a
comprehensive program depends on institutional procedures, the type of
planning system in use, and the entire treatment planning workflow.
Treatment planning errors can be minimized with a good QA program.
As indicated earlier in this chapter, the major issues that relate to
treatment planning errors can be summarized by four key words: (a)
education, (b) verification, (c) documentation, and (d) communication
(14). Education is required not only at the technical and professional
level in terms of the use of the TPS, but also at the organizational level
with respect to institutional policies and procedures. A very important
component of education relates to understanding the software
capabilities and limitations. Secondary dose verification of TPS produced
plans are also important as many reported errors involved a lack of an
appropriate independent secondary check of the treatment plan or dose
calculation. Clear documentation is required both of each patient’s
individual treatment plan and of departmental policies and procedures.
Finally, communication among staff members is essential for all aspects
of treatment, since various individuals at various professional levels are
involved in the treatment process. Poor communication was a key factor
in a number of the errors reported that relate to treatment planning.
A carefully executed program of treatment planning computer
commissioning and ongoing QA assessment provides users with
confidence that their work is being carried out accurately. Furthermore,
it gives the user a clear understanding of the TPS’s capabilities and
limitations. Finally, the quality of the delivered radiation dose to the
patient depends on the quality of all the steps in the treatment planning
process, including patient imaging, simulation, target volume
delineation, treatment planning, treatment verification, and quality
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factors associated with dose delivery and related to the radiation therapy
machine. Thus, it is imperative that the medical physicist, as well as all
other staff associated with the radiation therapy process, be actively
involved in the QA process at all stages. This provides both full
awareness of the capabilities and limitations of each step of the process
and a mechanism for decision making about any corrective action
deemed to be necessary.
ACKNOWLEDGMENTS
Contributions of Dr. Jacob Van Dyk to previous editions of this chapter are
still prevalent throughout the content in current edition, as his expertise in
TPS commissioning and QA is unparalleled. Editorial guidance provided by
Dr. Sasa Mutic and Dr. Eric Klein greatly aided in shaping the addition of
new content and the update of existing material. I would also like to thank
my wife, Kate Kavanaugh, my eternal ghost proof reader, for providing
suggestions of structural changes that make this chapter infinitely more
readable.
KEY POINTS
• Key contributing factors for major treatment planning system (TPS)
accidents typically involve at least one of the following:
• Lack of understanding of the TPS.
• Lack of a appropriate commissioning.
• Lack of independent calculation checks.
• A rigorous quality assurance (QA) program for TPS is necessary to

ensure an accurate delivery of the treatment intent. Such a QA
program consists of the following components:
• System specifications: definitions of the capabilities of the
software and the accuracy of the dose calculations.
• Acceptance testing: assessment of the hardware and software
to ensure the accuracy of all system specifications.
• Commissioning: acquisition of all data needed to bring the
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system into clinical service.
■ Radiation beam data can be acquired onsite for each
individual radiation producing device or be a validated
universal set of golden beam data (GBD).
■ Baselines of performance standards used for quality
controls are determined during commissioning.
• Quality controls: systematic actions to ensure specific
performance standards are maintained.
• The uncertainty of the calculated dose depends on the accuracy of

the beam data used during commissioning and the limitations of the
calculation algorithms.
• For external photon beam calculations in a homogenous
phantom, this uncertainty is typically smallest on the central
axis and largest in the buildup region.
• Criteria of acceptability should be based on what is realistically
achievable and include statements of confidence.
• Commissioning of a TPS typically requires basic radiation data,
which may include tissue–air ratios, tissue–phantom ratios,
percentage depth doses, cross-beam profiles, and output factors.
• Additional measurements are needed for any ancillary devices
such as wedges, blocks, and MLCs.
• End-to-end validation of the TPS and treatment workflow should be
conducted for each unique treatment modality. End-to-end tests
typically include:
• Acquiring a CT simulation of a QA phantom.
• Creating a treatment plan on the image dataset.
• Validating the calculated dose to the measured dose.
• Modern TPSs include new functionalities such as image

registration, autosegmentation, automated planning/KBP, and
adaptive radiation therapy. While specific commissioning and
quality assurance tasks differ for each functionality, end-to-end
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tests and validations against the existing manual workflow should
be included prior to clinical implementation.
• Quality assurance for the total radiation therapy planning process

incorporates all steps from the initial simulation to the treatment
delivery. Quality controls need to be developed for each aspect of
the treatment planning workflow. Several tools that can aid in
developing a strong QA program include:
• An FMEA analysis provides the framework to identify key steps
in the treatment planning workflow at which implementing
quality controls will provide the greatest utility.
• Reproducibility tests of the dose calculation, image display, and
plan evaluation tools are useful quality controls that easily
determine no significant changes have occurred to the
planning system hardware/ software.
• In vivo and in vitro patient specific checks provide a useful final
validation of the dose distribution and can identify gross errors
that may result in harm to the patient.
• Quality audits of treatment planning process, either conducted
internally or by an external third party, can identify weaknesses
prior to implementing a new planning system, treatment
modality, or treatment technique. Such quality audits can
incorporate end-to-end tests to validate the entire treatment
planning workflow.
• A proper training program for all staff should be developed or
re-evaluated during the commissioning process. Annual
credentialing should be considered to ensure everyone is up-
to-date on any new changes that may have been implemented.
QUESTIONS
1. Dose calculations for an enface photon beam in a homogenous
phantom exhibit the highest absolute uncertainty in which
region?
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A. Central axis after a depth of maximum dose
B. Lateral penumbra
C. Buildup
D. Out of field
2. When upgrading a TPS, it is important to complete the following
tests except:
A. End-to-end tests
B. In-phantom patient-specific dose measurements
C. Third-party linear accelerator output audits
D. Reproducibility tests of basic dose calculations
3. Implementation of effective quality controls with the treatment
planning process is aided by a prospective quantitative technique
that assesses potential risks, likelihood of errors, and impact of
such errors. This technique is known as:
A. Process Tree Mapping
B. Fault Tree Analysis
C. Risk Management
D. Failure Modes and Effects Analysis
4. The advantages of using golden beam data when commissioning a
treatment planning system include all of the following except:
A. GBD accounts for the inherent differences that exist between
individual linear accelerators.
B. GBD allows for much of the TPS commissioning process to be
“pre-packaged” and minimizes the chance of gross systematic
errors arising from the input of incorrect data.
C. GBD standardizes the delivery quality of all linear accelerators
from a specific vendor.
D. GBD eliminates the possibility of poor quality commissioning
measurements being used for the basic radiation data needed
to define beam models.
booksmedicos.org
ANSWERS
1. C Uncertainties in the dose calculation are dependent on the
accuracy of the measured data used to create the beam
model and the inherent accuracy of the dose calculation
algorithm. Both exhibit the lowest uncertainty on the
central axis. Measurements in the buildup region are
inherently challenging and vary greatly with detectors
typically available to the physicist acquiring the basic
radiation data. In addition, many dose calculation
algorithms do not handle the physics of electron
contamination very well.
2. C End-to-end tests, patient specific QA, and reproducibility
tests all validate either the integrity of the dose calculation
algorithms or the planning workflow. As a TPS system
upgrade does not impact the linear accelerator output and
reproducibility tests will confirm minimal changes to the
basic beam data, third party output audits are
unnecessary.
3. D While process tree mapping and fault tree analysis can be
useful in determining effective quality controls, FMEA
provides the quantitative framework to examine the
balance between risks, probability of occurrence, and
impact.
4. A Golden beam data is intended to standardize the delivery
basic radiation data used during commissioning, thus it
does not account for small local variations that may exist
between linear accelerators. Validation measurements of
the basic radiation data should be conducted and
compared to the GBD to determine if any differences exist.
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9 Intensity-Modulated Radiation
Therapy: Photons
Jan Unkelbach
INTRODUCTION
The Rationale for IMRT: Concave Target Volumes
The development of intensity-modulated radiation therapy (IMRT) was
preceded by two important technologic developments: computed
tomography (CT) and multi-leaf collimators (MLCs). Before the
widespread availability of CT scanners, radiotherapy planning was based
on 2D x-ray images. In these images, the projection of the target volume
could be delineated, which lead to the design of 2D treatment fields.
With the development of CT imaging, a 3D model of the patient became
available. The target volume as well as organs at risk could be
delineated in three dimensions and their spatial relation became known.
This led to the development of 3D conformal radiotherapy. Conforming
the radiation dose to the target volume required improved ways of
collimating the radiation field. The solution to this problem was the
MLC. 3D conformal radiotherapy is still the standard for many treatment
sites today. However, conforming the dose distribution to the tumor is
limited to round or convex shapes of the target volume. In 3D conformal
radiotherapy, the tumor is treated with one radiation field from each
incident beam direction, where the shape of the radiation field is the
projection of the target volume in beam’s eye view. The incident fluence
is homogeneous over the field. This makes it impossible to carve out
concavities in the target volume. The problem is illustrated in Figure 9.1,
which shows a patient treated for a spinal metastasis. The target volume
shown in red includes the entire vertebral body, which surrounds the
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spinal cord. An emerging treatment paradigm for such cases consists in
delivering a single fraction dose of 18 to 24 Gy to the target volume.
This treatment approach requires that the dose to the spinal cord is
limited to approximately 10 Gy. With 3D conformal radiotherapy, it is
impossible to spare the spinal cord. As a first approach, the projection of
the spinal cord in beam’s eye view could be removed from the treatment
field, and the area to the right and to the left would be treated as two
separate fields. However, this strategy would yield an inhomogeneous
dose distribution to the target volume and would underdose the target
volume near the spinal cord. More specifically, in order to deliver the
prescribed dose to the target, the fluence at the edge of the spinal cord
has to be increased. Anders Brahme has studied this phenomenon for a
stylized geometry in his 1982 paper (1). The work can be considered as
one of the first papers illustrating the need for inhomogeneous fluence
distributions across the treatment field when treating concave target
volumes. This eventually led to the development of IMRT.
Typical Applications of IMRT

The treatment of spinal metastasis in hypofractionated regimens is a
recent application of IMRT. However, over the past years, IMRT has
become the standard of care for a variety of treatment sites. Two of the
established applications are prostate cancer and head-and-neck tumors,
which are illustrated in Figures 9.2 and 9.3. The prostate lies in the mid-
sagittal plane between the bladder and the rectum. In radiotherapy
treatments of prostate cancer, the target volume contains the entire
prostate gland. The main dose-limiting normal tissue is the anterior
rectal wall. In many patients, the lateral lobes of the prostate partially
wrap around the rectum, as illustrated in Figure 9.2. Only millimeters
separate the prostate gland from the radiosensitive lining of the rectal
wall. Historically, the prescription dose was therefore limited by rectal
toxicity as the anterior rectal wall received the full prescription dose.
Today, in the era of IMRT, a commonly used prescription dose is 79 Gy
using standard fractionation, which is among the highest prescriptions
throughout radiotherapy. This necessitates that the high-dose region
carves out the concavity formed by the rectum, which became possible
with IMRT.
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Tumors in the head-and-neck region represent a third example in
which IMRT has replaced 3D conformal techniques for the most part.
This includes tumors arising in the oral cavity, the nasopharynx, and the
oropharynx. These tumors are often inoperable and are close to a variety
of radiosensitive structures. These include the saliva secreting glands as
well as structures related to swallowing and speech. Thus, radiotherapy
to cancers of the head and neck is associated with acute und long-term
side effects that seriously impact quality of life. Examples of these side
effects are mouth dryness, dental decay, and swallowing dysfunction.
IMRT allows for sparing of the parotid glands and carefully distributing
dose in normal tissues. Furthermore, IMRT allows for complex dose
prescriptions that are standard of care today. Nowadays, treatment
protocols often use three dose levels, in which 70 Gy is delivered to the
gross tumor volume (GTV), 60 Gy to high-risk lymph nodes, and 54 Gy
to low-risk nodal stations. This type of dose painting approach would be
very difficult to mimic using forward planning techniques and 3D
conformal radiotherapy.
FIGURE 9.1 A: Geometry of a spinal metastasis treated with IMRT. The target volume (red)
entirely surrounds the spinal cord (dark green), which is to be spared. Additional organs at risk are
the kidneys (orange). B: IMRT provides the means to spare the spinal cord while delivering a high
dose to the target volume, as shown in the dose distribution.
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FIGURE 9.2 A: Prostate cancer represents a typical application of IMRT. The prostate (red) abuts
the rectum (orange) and the bladder (yellow). B: IMRT has the ability to conform the high dose to
the prostate while carving out the concavity formed by the rectum.
FIGURE 9.3 A: A head-and-neck cancer patient treated with IMRT. The target consists of multiple
volumes prescribed to different doses: GTV (brown), high-risk clinical target volume (CTV)
(purple), and low-risk CTV (red). Radiosensitive structures including the parotid glands (blue), the
submandibular glands (yellow), and the spinal cord (light blue) are near the target volume. B:
IMRT allows for conformal dose distribution to complex-shaped target volumes.
The examples above illustrate problems in oncology in which the

technical development of IMRT had profound impact on the way
patients are treated. In the case of prostate cancer, the widespread
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availability of IMRT causes a shift from radical prostatectomy toward
radiotherapy as the mainstay of therapy. In the case of spinal metastasis,
IMRT offers the option of high single fraction doses with the intent of
local control, where the role of radiotherapy was limited to palliative
treatments before.
Scope and Organization of This Chapter

This chapter focuses on the concepts of IMRT, the treatment planning
process, and the mathematical methods used. It discusses steps in the
planning process and the user interface between treatment planner and
planning software, and it provides an understanding of the algorithms
used behind the scenes by modern treatment planning systems (TPS).
For a review of the history of IMRT, the reader is referred to the paper
by Bortfeld (2) and references therein. For a comprehensive review of
IMRT including the physics and technology aspects, we recommend the
book by Webb (3). The remainder of this chapter is organized as follows:
• The section IMRT–concepts and planning process introduces the main

concepts in IMRT and illustrates the planning process step-by-step
using a head-and-neck cancer example.
• The section Fluence map optimization discusses fluence map
optimization (FMO) in more detail, which represents the most
important concept in IMRT planning. In that context, the formulation
of IMRT treatment planning as a mathematical optimization problem is
discussed.
• The section Leaf sequencing describes the leaf sequencing problem, that
is, the method to deliver intensity-modulated radiation fields using
MLCs.
The above-mentioned sections reflect the historical development of

IMRT, and thereby the functionality and algorithmic foundation of the
first-generation IMRT planning systems. In recent years, IMRT TPS have
evolved to more advanced planning algorithms and support more
complex delivery techniques. To that end, the remaining sections
describe recent developments in IMRT planning.
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• The section Direct aperture optimization describes methods for direct
aperture optimization (DAO), which aims to overcome problems of the
traditional two-step approach of FMO plus leaf sequencing.
• The section Arc therapy describes treatment planning for volumetric-
modulated arc therapy (VMAT), that is, a delivery technique where the
gantry continuously rotates around the patient while radiation is
delivered.
• The section Specialized topics in IMRT planning addresses current areas
of research and development in IMRT including new approaches to
deal with inherent tradeoffs between conflicting planning goals.
Pareto-surface navigation methods are introduced as a means for
interactive planning, which provide the treatment planning with a
graphical user interface to navigate in a database of treatment plans to
determine the treatment plan with the most desirable tradeoff.
IMRT—CONCEPTS AND PLANNING PROCESS

This section demonstrates the concepts of IMRT planning step-by-step for
an example case. We consider the head-and-neck cancer patient shown
in Figure 9.3, which represents a typical application of IMRT. The target
consists of multiple volumes, the GTV and adjacent lymph nodes, which
are prescribed to different dose levels. In addition, several radiosensitive
structures are located in proximity of the tumor. This includes the saliva-
producing parotid glands, the spinal cord, and the larynx. Radiotherapy
in the head-and-neck region is typically related to acute and long-term
side effects, such as swallowing dysfunction. Reducing dose to all normal
tissues is of great importance.
The Fluence Map

IMRT refers to radiotherapy delivery methods for which the fluence
distribution in the plane perpendicular to the incident beam direction is
modulated. To that end, the radiation beam is divided into small beam
segments, which are in principle deliverable by an MLC, as further
described in the leaf sequencing section. The lateral fluence distribution
of the beam is thereby discretized into small elements, which are
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commonly referred to as beamlets or bixels. For an MLC with 1-cm leaf
width, the fluence distribution is represented by the intensities of 1 × 1-
cm beamlets. Nowadays, modern MLCs with a smaller leaf width often
allow for a finer discretization into 5 × 5-mm beamlets. The discrete
representation of the fluence is commonly referred to as the fluence map.
In IMRT planning, the goal is to find the fluence maps of all incident
beam directions that yield the best possible dose distribution in the
patient. This problem is referred to as FMO and is the topic of this
section and the following one.
The definition of the fluence map is illustrated in Figure 9.4. Similar to
3D conformal therapy, this starts with the definition of the isocenter. For
IMRT planning, we subsequently determine the set of all beamlets that
are potentially helpful in finding the most desirable treatment plan.
Loosely speaking, this corresponds to all beamlets that contribute a
significant dose to the target volume. A common method for initializing
the fluence map consists in including all beamlets for which the central
axis of the corresponding beam segment intersects the target volume.
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FIGURE 9.4 Illustration of the fluence map definition for IMRT planning for a head-and-neck
cancer patient. The figure shows the digitally reconstructed radiograph (DRR) for one of the
incident beam directions. The contours show the projections of the three target volumes in
beam’s-eye-view. The fluence map consists of all beamlets that cover the projection of the target
volume.
The Dose-Deposition Matrix

The quality of a treatment plan is primarily judged based on the dose
distribution in the patient. Thus, we would like to determine the fluence
maps of the incident beams as to best approximate a desired dose
distribution. To that end, we have to relate the incident fluence to the
dose distribution in the patient. The dose-deposition matrix concept,
which is frequently used in IMRT planning, provides this link.
For dose calculation, the patient is discretized into small volume
elements referred to as voxels. A dose calculation algorithm is used to
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calculate the dose distribution of every beamlet in the fluence map in
the patient. Let us denote the dose that beamlet j contributes to voxel i
in the patient as Dij, and let us denote the intensity of beamlet j as xj.
The total dose di delivered to voxel i is then simply given by the
superposition of all beamlet contributions:
Here, the matrix of dose contributions Dij of beamlets j to voxel i is

referred to as the dose-deposition matrix. In practice, the fluence is
commonly quantified in monitor units (MU). In this case, the natural
unit of the dose influence matrix is Gy/MU, such that the resulting dose
distribution in the patient is obtained in Gy. The dose-deposition matrix
concept is convenient since it allows for a separation of the
mathematical optimization of beamlet intensities xj from the dose
calculation algorithm. In IMRT planning, the dose-deposition matrix is
often calculated up front and held in memory. Subsequently, the dose
distribution is obtained by a simple matrix multiplication d = Dx.
Formulation of IMRT Planning as an Optimization Problem

In order to determine the optimal fluence map for every incident beam
direction, we have to specify the desired dose distribution. In other
words, we have to characterize what a good treatment plan is. In the
example case in Figure 9.3, treatment planning aims at different goals
including:
1. A prescribed dose dpres should be delivered to all parts of the target
volume. In this case, the target volume consists of multiple parts. The
GTV is often prescribed to 70 Gy; adjacent lymph nodes which are
likely to contain microscopic tumor and are prescribed to an
intermediate dose of 60 Gy; and more distant lymph nodes that may
contain tumor cells but are less likely to do so are prescribed to 54 Gy.
The lymph node targets essentially consist of normal tissue such that
treatment planning aims at a homogeneous dose in the target,
avoiding both under- and overdosing.
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2. The dose distribution should conform to the target volume. Outside
the target volume, a steep dose falloff is desired and unnecessary dose
to all healthy tissues should be avoided.
3. The dose delivered to the parotid glands is to be minimized to avoid
or reduce side effects such as xerostomia (mouth dryness).
4. The dose to the spinal cord has to be limited. The maximum dose
delivered to any part of the spinal cord has to stay below a maximum
tolerance dose dmax.
For IMRT planning, these goals have to be translated into
mathematical terms. This is done by defining functions, which represent
measures for how good a treatment plan is, and whether it is acceptable
at all. In this context, we distinguish objectives and constraints:
Constraints are conditions that are to be satisfied in any case. Every

treatment plan that does not satisfy the constraint would be
unacceptable.
Objectives are functions that measure the quality of a treatment plan.
They may represent measures to quantify how close a treatment plan
is to the ideal or desired treatment plan.
In the above example, the first three goals can be formulated as

objectives; the fourth goal of enforcing a strict maximum on the spinal
cord dose represents a constraint. The goal of delivering a homogeneous
dose to the target volume can be formulated via a quadratic objective
function:
Ideally, every voxel that belongs to the target volume receives the
prescribed dose dpres, which corresponds to a value of zero for the
function fT . Otherwise, fT yields the averaged quadratic deviation from
the prescribed dose. The larger the objective value is, the more the dose
deviates from the prescription dose, corresponding to a worse treatment
plan.
Similarly, the goal of minimizing the dose to the parotid glands can be
formulated as an objective function. For example, we can define the
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objective fP as
which aims at minimizing the mean dose to the parotid glands. The goal
of conforming the dose distribution to the target volume can for example
be described via a piecewise quadratic penalty function
where the + operator is defined through (di − dimax)+ = di − dimax if di

≥ dimax, and zero otherwise. Thus dimax is a maximum dose that is
accepted in voxel i; dose values exceeding dimax are penalized
quadratically. Clearly, in normal tissue voxels directly adjacent to the
target volume, high doses are unavoidable, whereas at large distance
from the target volume, treatment planning should aim at avoiding
unnecessary dose. Therefore, dimax can be chosen based on the distance
of voxel i to the target volume. For example, dimax is set equal to the
prescribed dose in voxels directly adjacent to the target volume, and to
half the prescription at 1 cm distance.
Finally, we would like to ensure that the dose in all voxels that belong
to the spinal cord does not exceed a maximum tolerance dose dsmax. If
we do not accept any treatment plan that exceeds the maximum dose,
this can be implemented as a constraint, not an objective. In this case we
can formulate the constraint as
where S is the set of all voxels belonging to the spinal cord.

Treatment planning simultaneously aims at minimizing all of the
above objective functions, that is, ideally we would like each tumor
voxel receive the prescribed dose while no dose is delivered to the
normal tissues. It is clear that the objectives associated with different
structures are inherently conflicting. Thus, the treatment planner will
have to weight these conflicting objectives relative to each other and
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accept a compromise. The traditional approach in IMRT planning
consists in manually assigning importance weights w to each objective,
using a high weight for the most important objective, and a smaller
weight for less important goals. The best treatment plan is then defined
as the one that minimizes the weighed sum of objectives
IMRT planning uses mathematical optimization algorithms in order to

determine the fluence map x, corresponding to the dose distribution d =
Dx, which minimizes the weighted sum of objectives, subject the all
constraints on the dose distribution, and under the condition that all
beamlet weights have to be positive. We will further discuss
optimization algorithms in the section Fluence map optimization. Below,
we first look at the result of such an optimization for a specific choice of
optimization parameters.
Solution to the IMRT Problem: The Optimal Treatment Plan

Figure 9.5 illustrates an IMRT treatment plan using 11 incident beam
directions. It shows the dose distribution overlaid on a coronal slice of
the patient’s CT. Also shown are the 11 beams together with the
effective fluence that is incident from each direction. One of the
radiation fields is illustrated in more detail in Figure 9.6, in which the
fluence is overlaid on the digitally reconstructed radiograph (DRR). The
figure illustrates the modulation of the intensity over the radiation field.
The resulting dose distribution of the IMRT plan is shown in Figure
9.7. The middle panel shows the cumulative dose distribution of all
beams. IMRT allows for dose distributions that conform to complex-
shaped, concave target volumes. A single IMRT plan allows for different
dose levels in high- and low-risk lymph node targets, as well as a
simultaneous integrated boost (SIB) to the GTV. The peripheral images
in Figure 9.7 show the dose contributions of 6 of the 11 incident beams.
Controlling Tradeoffs
Different objectives in IMRT planning are inherently conflicting. Clearly,
there is a tradeoff between delivering dose to the tumor and reducing
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dose to healthy tissues. In the above example, the target volume is
directly adjacent to the parotid glands. Sparing the parotid glands from
radiation will lead to a dose reduction in the adjacent part of the target
volume. Ensuring coverage of the target will in turn lead to higher doses
to the parotid glands. In addition, there are tradeoffs between different
normal tissues. In order to deliver the prescribed dose to the target
volume, some dose to the normal tissues is unavoidable. However, using
intensity modulation and enough beam directions, the dose distribution
in the normal tissue can be shaped according to the physician’s
preference.
FIGURE 9.5 Illustration of an IMRT plan for the head-and-neck cancer patient generated in the
RayStation planning system, version 4.0. The dose distribution is shown on a coronal slice of the
patient’s CT scan. The blue circle indicates the isocenter. The 11 beam directions are displayed
with their respective fluence. Red color indicates a low fluence, white a high fluence.
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FIGURE 9.6 Illustration of a single intensity-modulated field, overlaid on the DRR. The figure
shows the effective fluence that is incident on the patient surface for the final treatment plan. This
includes modification of the optimized fluence map through leaf sequencing (Leaf sequencing
section) and refinement of MLC leaf positions (Direct aperture optimization section). The same
applies to Figure 9.5.
In most TPS that are in use today, treatment planners control the
tradeoffs between different planning goals manually by manipulating the
relative weights w of objective functions. This can lead to a time-
consuming trial-and-error process. Different approaches have been
suggested to improve the interaction of the treatment planner with the
TPS, including interactive Pareto-surface navigation methods, which are
discussed in the section Specialized topics in IMRT planning.
Delivery of Intensity-Modulated Fields

In order to deliver an intensity-modulated field, the fluence map is
decomposed into a number of smaller radiation fields that can be
delivered using an MLC. This process is called sequencing and is
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described in more detail in the Leaf sequencing section. As an outlook to
subsequent sections, Figure 9.8 illustrates how the fluence shown in
Figure 9.6 is delivered as a sequence of three MLC openings.
FLUENCE MAP OPTIMIZATION*

The previous section illustrated the main concepts in IMRT planning for
an example case. In this section we take a more formal look at IMRT
planning as a mathematical optimization problem. We first discuss some
of the frequently used objective and constraint functions, in particular
the handling of dose–volume effects (section on Dose–volume effects). The
subsequent section briefly outlines the use of outcome models in IMRT
planning and their limitations. Finally, the section on Optimization
algorithms introduces basic mathematical optimization algorithms used
in IMRT planning to solve IMRT problems.
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FIGURE 9.7 IMRT dose distribution for the head-and-neck case example, demonstrating the
ability of IMRT to conform the dose distribution to complex target volumes (middle panel). Also
shown are the dose contributions of 6 (out of 11) beam directions (surrounding images).
In mathematical terms, a general FMO problem can be formulated as

the following mathematical optimization problem:
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FIGURE 9.8 Delivery of an intensity-modulated field through a sequence of MLC openings. Each
figure shows the incident total fluence overlaid on the DRR, together with the leaf positions of the
multi-leaf collimator that define the field opening. Also shown are the positions of the Y-jaws that
reduce transmission through closed MLC leaves (blue).
Treatment planning involves balancing different clinical objectives.

Therefore, the objective function f is a weighted sum of individual
objectives:
Here, wn are positive weighting factors, which are used to control the
relative importance of different terms in the composite objective
function.
The objective function that may be the most commonly used in
current TPS is a piece-wise quadratic penalty function:
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Here, dmax is a maximum tolerance dose for an organ, which is usually
specified by the treatment planner through the graphical user interface
in the TPS. Similarly, for target volumes dmin is a minimum dose that is
to be delivered to the target volume.
The functions gs(d) correspond to hard constraints on the dose
distribution. Common constraints are maximum dose values in organs at
risk and minimum doses in target volumes. In this case, cs is the
maximum dose in a structure, s is an index over all voxels in the
structure, and gs(d) is simply the dose in voxel s. In the subsection Dose-
Volume effects, additional commonly used objectives and constraints are
discussed.
Dose–Volume Effects
An organ at risk will typically receive an inhomogeneous dose
distribution. The question arises whether it is better to irradiate a small
part of the organ to a large dose while sparing the remaining parts to a
large extent; or whether it is better to spread out the dose and avoid
large doses in all parts of the organ. In that context, one distinguishes
parallel organs and serial organs. For organs with a serial structure, the
function of the whole organ will fail if one part of the organ is damaged.
One prominent example for a serial organ is the spinal cord. For serial
organs it is therefore crucial to limit the maximum dose delivered to the
organ, rather than the mean dose. For a parallel organ, the function of
the organ as a whole is preserved even if a part of the organ is damaged.
The lungs are an example of a parallel organ. The dependence of a
clinical outcome on the irradiated volume of an organ is commonly
referred to as a volume effect or dose–volume effect. For IMRT planning,
clinical knowledge on dose–volume effects are to be translated into
appropriate objective functions. Today, mainly two types of
objective/constraint function are being applied: dose–volume histogram
(DVH) constraints and the concept of equivalent uniform dose (EUD).
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Equivalent Uniform Dose
One approach to quantifying dose–volume effects consists of using
generalized mean values of the dose distribution:
where the exponent α is larger than 1 for OARs. For the special case α =
1, EUD(d) is equivalent to the mean dose in the organ. In the limit of
large α values, the value of EUD(d) approaches the maximum dose in the
organ. Thus, parallel organs are described via a small value of α close to
1, whereas serial organs are described via large values of α
(approximately 10). The generalized mean value is commonly referred to
as EUD. The generalized mean value can also be applied to target
volumes by using negative exponents. For a large negative value of α,
the EUD approaches the minimum dose in the target volume. In practice,
exponents in the range of α = –10 … –20 are considered. The EUD can
be used as both an objective function and a constraint function.
DVH Objectives and Constraints

The clinical evaluation of treatment plans often uses the DVH. A typical
evaluation criterion for the target volume is: at least 95% of the target
volume should receive a dose equal to or higher than the prescription
dose. Similarly, a criterion for an OAR could be: at most 20% of the
organ should receive more than 30 Gy. From an optimization
perspective, it is not straightforward to handle DVH constraints in a
rigorous way. In practice, DVH constraints are therefore handled
approximately using a quadratic penalty function. We consider the
example that no more than 20% of an organ should receive a dose
higher than dmax. Given an initial dose distribution, one can identify the
fraction of voxels that exceed the dose level dmax. If this fraction is
smaller than 20%, the DVH constraint is fulfilled. Otherwise, a quadratic
penalty function is introduced that aims at reducing the dose to those
voxels that exceed dmax by the least amount. For example, if 30% of the
organ receives a higher dose, the 20% of voxels receiving the highest
dose are ignored. For the 10% of voxels a quadratic penalty term as in
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Equation 9.2 is added to the objective function.
The Use of Clinical Outcome Models in IMRT Optimization

Since the beginning of the IMRT era, the question regarding the
adequate objective function has persisted. Intuitively, we would like to
translate the notion of “maximizing the tumor control probability (TCP)”
while “minimizing the normal tissue complication probability (NTCP)”
more directly into mathematical terms.
One of the most common methods for relating treatment outcome to
the dose distribution consists in performing logistic regression. As an
example, we consider NTCP models, however, the same methodology
can be applied to TCP models. The severity of a radiation side effect is
clinically assessed in discrete stages. Typically, one is interested in
avoiding severe complications. For example, in the treatment of lung
cancer, treatment planning may aim at minimizing the probability for
radiation pneumonitis of grade 2 or higher. This converts the observed
clinical outcome into a binary outcome label. NTCP modeling can thus
be considered as a classification problem, which aims at estimating the
probability of a complication given features of the dose distribution.
Standard statistical classification methods, such as logistic regression,
can be applied to this problem. In logistic regression, the NTCP model is
given by:
Here, f is a function of the dose distribution d and the model

parameters q. The central problem in statistical analysis and modeling of
patient outcome consist in determining the function f, that is, selecting
features of the dose distribution that are correlated with outcome. One
of the most commonly used representations of f is given by:
In this case, f is a linear function of a single feature of the dose

distribution, namely the EUD. For EUD(d) = TD50, the value of NTCP
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evaluates to 0.5, that is, TD50 corresponds to the effective dose that leads
to a complication probability of 50%. The parameter γ determines the
slope of the dose-response relation. The NTCP model has three
parameters (TD50, γ, and the EUD exponent α) which can be fitted to
outcome data, for example, through maximum likelihood methods. This
NTCP model is equivalent to the Lyman–Kutcher–Burman (LKB) model,
except that the LKB model traditionally uses a different functional form
of the sigmoid.
Although phenomenologic outcome models play an increasing role in
treatment plan evaluation, their capabilities from a treatment plan
optimization perspective have remained limited so far. One reason for
that is the uncertainty in outcome models. A second reason is that
currently used models are not more powerful than dose-based objective
functions. In particular, the NTCP model above represents an increasing
function of the EUD, that is, independent of the parameters TD50 and γ,
higher EUD always leads to higher NTCP. As a consequence, the dose
distribution that minimizes EUD is the same as the dose distribution that
minimizes NTCP. Hence, from an IMRT optimization perspective,
minimizing EUD and NTCP is equivalent (5).
Optimization Algorithms
Our goal in this chapter is to provide the reader with an understanding
of the most basic optimization algorithms, which do not require
advanced knowledge of optimization theory. We start with a geometric
visualization of the IMRT optimization problem. Subsequent, the
gradient descent algorithm is described, which is in principle sufficient
to optimize fluence maps. Afterward, extensions of gradient descent
methods toward quasi-Newton algorithms are outlined. Certainly, the
field of IMRT optimization has advanced significantly, and increasingly
complex algorithms for constrained optimization are being applied.
These algorithms require knowledge of optimization theory, which is
beyond the scope of this chapter. The interested reader is referred to the
optimization literature (6,7). Ehrgott et al. (8) provide a review of
radiotherapy planning from a mathematical optimization perspective.
Visualization of The Fluence Map Optimization Problem
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Due to the large number of beamlets (optimization variables) it is not
possible to directly visualize the objective and constraint functions for a
full IMRT planning problem. Nevertheless, it is helpful to understand the
structure of the IMRT optimization problem. To that end, we consider a
simplified version of an IMRT planning problem in which only 2
beamlets and 4 voxels are considered. We consider the following dose-
deposition matrix:
where the first two columns correspond to the tumor voxels, and
columns 3 and 4 correspond to OAR voxels. We further assume that we
aim to deliver a dose of 2 to both of the tumor voxels, and we impose a
maximum dose constraint on OAR voxel of 0.8 and 1.0, respectively.
The goal of delivering the prescribed dose to the tumor voxels is
expressed via a quadratic objective function. The optimization problem
for this illustrative example can be formulated as:
Since we only have two optimization variables, the objective and

constraint functions can be visualized explicitly. This is done in Figure
9.9. The objective function is illustrated via isolines. Since we consider a
quadratic objective function, it represents a two-dimensional parabola.
The minimum of the objective function is located at beamlet intensities
x1 = 1 and x2 = 1. At this point, both tumor voxels receive the
prescribed dose and the objective function is zero.
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We now consider the constraints on the OAR voxels. Since the dose in
each voxel is a linear function of the beamlet intensities, the constraints
represent hyperplanes in beamlet intensity space, that is, lines in two
dimensions. In Figure 9.9 we show the lines where the constraints d3 =
0.8 and d4 = 1.0 are met exactly. For all beamlet intensity beyond these
lines, the maximum dose to an OAR voxel is exceeded. All beamlet
intensity combinations below the lines form the feasible region. Thus,
the optimal solution to the IMRT planning problem is given by the point
within the feasible region that has the smallest value of the objective
function. In this example, this is given by x1 = 0.7 and x2 = 1.2 and is
indicated by the red dot in Figure 9.9. By multiplying this solution with
the dose-deposition matrix, we obtain the corresponding optimal dose
distribution.
In this case, the constraint for OAR voxel 3 is binding, that is, the OAR
voxel receives the maximum dose we allow for. We further note that the
minimum of the objective function is outside of the feasible region,
which means that, in order to fulfill the maximum OAR dose constraint,
we have to accept a compromise regarding target dose homogeneity.
FIGURE 9.9 Visualization of the IMRT optimization problem for two beamlets. The quadratic
objective function is shown via isolines; the linear maximum dose constraints of OAR voxels are
shown as thick black lines (with permission reproduced from (4)).
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FIGURE 9.10 Visualization of the composite objective function containing quadratic penalty
functions to approximate maximum dose constraints. For increasing weights w for the penalty
function, the minimum of the composite objective function moves closer to the optimal solution of
the constrained problem (with permission reproduced from (4)).
Approximate Handling of Constraints Via Penalty Functions

In IMRT planning, maximum dose constraints in OARs are often
approximated via penalty functions. More specifically, we can consider
the composite objective function where a quadratic penalty function,
multiplied with a weight w is added to the original objective for target
dose homogeneity:
Adding the penalty function does not change the objective function
within the feasible region, only the objective function values outside of
the feasible region are increased. This is shown in Figure 9.10 for
penalty weights of w = 5 and w = 20. While w is increased, the
unconstrained minimum of the function f moves closer to the optimal
solution of the constrained problem.
The Basic Gradient Descent Method

In this section we introduce the most generic optimization algorithm,
which can in principle be used to generate an IMRT treatment plan. To
that end, we assume that we want to minimize an objective function f,
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subject to the constraint that all beamlet intensities are positive. We do
not consider additional constraints g on the dose distribution, that is, all
treatment goals are included in the objective function.
The gradient of the objective function is the vector of partial
derivatives of f with respect to the beamlet intensities xj:
The gradient vector is oriented perpendicular to the isolines of the

objective function; it points in the direction of maximum slope in the
objective function landscape. Thus, taking a small step into the direction
of the negative gradient yields a fluence map x that corresponds to a
lower value of the objective function, that is, an improved plan. This
gives rise to the most basic nonlinear optimization algorithm: In each
iteration k, the current fluence map xk is updated according to:
where α is a step size parameter, which has to be sufficiently small in

order for the algorithm to converge.
Gradient Calculation. The gradient of the objective function with

respect to the beamlet intensities can be calculated by using the chain
rule in multiple dimensions: Given that the objective is a function of the
dose distribution we have
The partial derivative of the voxel dose di with respect to the beamlet
weight xj is simply given by the corresponding element of the dose-
deposition matrix:
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The partial derivative of the objective function with respect to dose in
voxel i describes by how much the objective function changes by varying
the dose in voxel i. For the quadratic objective function
the components of the gradient vector are given by
which has an intuitive interpretation. The total change in the objective

function value due to changing the intensity of beamlet j is obtained by
summing over the contributions of all voxels. The contribution of a voxel
is given by the dose error (di − dpress) multiplied by the influence Dij of
beamlet j onto the voxel i. If the dose di exceeds the prescribed dose, the
voxel’s contribution is positive; voxels that are underdosed yield a
negative contribution to the gradient component. If the gradient
component is negative after summing over the contributions of all
voxels, the impact of the underdosed voxels dominates. A step in the
direction of the negative gradient corresponds to increasing the beamlet
weight xj, thus reducing the extent of underdosing.
Handling the Nonnegativity Constraint. So far, only the objective

function f was considered, not taking into account the nonnegativity
constraint on the beamlet intensities. Applying the gradient descent
algorithm without accounting for the nonnegativity constraint leads to
negative intensities for some of the beamlets, which is not meaningful.
Different extensions of the gradient descent algorithm exist in order to
ensure positive beamlet weights.
One method consists in simply setting all negative beamlet intensities
to zero after each gradient step. Formally, this corresponds to a
projection algorithm for handling bound constraints. An alternative
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approach is based on a variable transformation. In this case, a new
optimization variable is introduced for every beamlet, which is defined
as the square root of the intensity. Thus, the beamlet intensity, given by
the squared value of the variable, is always positive, while the
optimization variable can take any value. This way, the constrained
optimization problem is converted into a fully unconstrained problem.
Improvements to Gradient Descent

The generic gradient descent algorithm shows slow convergence in
practical IMRT optimization problems. Improvements to the generic
gradient descent algorithm can be made mainly in three aspects:
1. Selecting an appropriate step size using line search algorithms.

2. Improving the descent direction by including second derivative
information.
3. Improve the handling of constraints using more advanced algorithms
for constrained optimization.
For the first and third aspects, the reader is referred to the advanced
optimization literature. The second aspect is outlined below.
Including Second Derivatives. The generic gradient descent algorithm

considers the first derivative of the objective function at the current
fluence map x. This can be interpreted as finding a hyperplane that is
tangential to the objective function at x. The convergence properties of
iterative optimization algorithms can be improved by including second
derivative (i.e., curvature) information. This can be interpreted as
finding a quadratic function that is tangential to the objective function at
x. The iterative optimization algorithm, known as the Newton method,
then performs a step toward the minimum of the quadratic
approximation.
To formalize this concept, we consider a second-order Taylor
expansion of the objective function f at the fluence map x:
By defining the Hessian H as the matrix of second derivatives, this can
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be written as:
The idea of the Newton method consists in taking a step Δ x such that
we reach the minimum of the quadratic approximation. For the special
case that the original objective function f is a quadric function, the
approximation is exact, and thus the Newton method finds the optimal
solution in a single step. Generally, f will not be a purely quadratic
function. However, it is assumed that a Newton step will approach the
optimum faster than a step along the gradient direction.
To calculate the Newton step Δx*, we set the gradient of f with respect
to Δx to zero, which yields the condition
Thus, the Newton step is given by
This leads to a modified iterative optimization algorithm in which the

beamlet intensities are updated according to
We can further note that the Newton method has a natural step size α
= 1.
In practical IMRT optimization, the pure Newton method is not
applied. A naïve computation of the Newton step involves the
calculation of the Hessian matrix at point x, inverting the Hessian
matrix, and multiplying the inverse Hessian H(xk)−1 with the gradient
vector. In IMRT optimization, the size of the Hessian matrix is given by
the number of beamlets squared. Therefore, the explicit calculation and
inversion of the Hessian is often computationally prohibitive. Thus,
IMRT optimization employs the so-called quasi-Newton methods, which
rely on an approximation of the Newton step. One of the most popular
methods that is applied in IMRT planning is the limited memory L-BFGS
quasi-Newton algorithm. In this algorithm, the descent direction H(xk)
−1∇f(xk) is approximated based on the fluence maps and gradients
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evaluated during the previous iterations of the algorithm, which avoids a
costly matrix inversion. The comprehensive description of the L-BFGS
algorithm can be found in the textbook by Nocedal and Wright (6).
Convexity
Many objective functions commonly applied in IMRT planning are
convex. This is in particular the case for the piecewise quadratic
objective, linear objectives, and the generalized EUD for exponents |α|
> 1. The convexity property of objective and constraint functions has
important implications for the optimization of fluence maps. An
optimization problem defined through a convex objective function f and
convex constraint functions gs has a unique global minimum, that is,
there are no local minima, which are not the global minimum. Thus,
gradient descent–based optimization algorithms do reliably find the
optimal fluence map. The only nonconvex objectives commonly applied
in practice are DVH constraints. However, practical experience suggests
that the nonconvexity of DVH constraints does not cause severe local
minima-related issues in IMRT planning.
LEAF SEQUENCING
In this section, we discuss ways to deliver intensity-modulated radiation
fields. The section is focused on IMRT delivery using conventional Linacs
equipped with an MLC. This represents, by far, the most widely used
IMRT technique, although it is not the only possible form of IMRT.
Historically, IMRT delivery with compensators has been performed in
many centers. In that technique, an intensity-modulated field is created
using an absorber placed in the beam path in the Linac head. The
absorber causes an exponential attenuation of the fluence. By varying
the thickness of the absorber across the beam profile, the desired
intensity-modulated field can be created. Compensators had to be
custom made for every patient and every field, and where typically cast
in lead. This required a machine shop connected to the radiotherapy
department. Nowadays, the use of computer-controlled MLCs, which
eliminates the need for patient-specific hardware, has replaced
compensator-based IMRT delivery.
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FIGURE 9.11 Illustration of beam collimation for IMRT delivery using multi-leaf collimators and
jaws.
Beam Shaping and Multi-Leaf Collimators

This section briefly introduces MLCs. We focus on the main aspects of
MLCs that are relevant for IMRT planning and delivery as described in
the remainder of this chapter. For details on the mechanical and
technical aspects, the reader is referred to the literature (3). Figure 9.11
illustrates of the main components used to collimate the radiation beam:
the jaws and the MLC. The MLC is the primary collimation device that
defines the shape of the beam. It consists of thin sheets of tungsten,
which are moved in and out of the beam using computer-controlled
electric motors. Each leaf has a considerable height (measured in beam
direction) of approximately 5 to 10 cm in order to keep the transmission
of radiation through closed leaves low. In contrast, each leaf is only a
few mm thick to yield a projected beamlet size of 5 mm or 10 mm at the
isocenter. The jaws represent rectangular field collimators upstream of
the MLC. Figure 9.12 illustrates the use of the MLC for beam collimation
in beam’s-eye-view. A variety of terms are used to refer to a radiation
field produced by an MLC. In this chapter, we use the term aperture;
other common terms are segment or MLC opening.
Depending on the MLC model, there are a number of constraints on
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leaf motion and leaf positioning. This limits the set of apertures that can
be delivered by an MLC. With the latest generation of MLCs some of
these restrictions are eliminated or mediated, but especially for older
models some of the following restrictions may apply:
• Interdigitation: For some MLCs it is not possible for neighboring leaf

pairs to cross, that is, the tip of the left leaf cannot move past the tip of
a neighboring right leaf. The leaf configuration of leaf pairs 7 and 8 in
Figure 9.12 would be prohibited. The interdigitation constraint has
been eliminated for most modern MLCs.
FIGURE 9.12 Illustration of beam collimation in beam’s-eye-view using an MLC and jaws. The
MLC leaves (gray bars) are used primarily for beam shaping. The jaws (red and yellow blocks)
are typically placed in a post-processing step to irradiate the smallest rectangular field that covers
the MLC aperture. The jaws reduce transmission through closed MLC leaves. In addition, for
MLCs that require a finite gap between the left and right leaf tip, closed leaf pairs can be hidden
behind the jaws, as illustrated in rows 1 and 8.
• Maximum overtravel: Most linear accelerators have a 40 × 40-cm field

of view at the isocenter. However, for some MLCs it is not possible for
the left leaf to travel all the way the right side of the field of view. The
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maximum distance that the leaf tip can travel beyond the isocenter
projection is called the maximum overtravel. The constraint implies
that the MLC cannot deliver small apertures far away from the
isocenter.
• Minimum leaf gap: For some MLCs a leaf pair cannot fully close, that
is, a minimum gap between the right and left leaf tips has to remain.
• Maximum leaf speed: In addition to restrictions on leaf positioning,
MLCs have dynamic constraints. Leaves cannot move faster than a
maximum speed; typical values are 3 cm/s or 6 cm/s.
Aperture Decomposition of Fluence Maps

It is intuitively clear that the superposition of multiple distinct radiation
fields formed by an MLC may yield an intensity-modulated field. This is
schematically illustrated in Figure 9.13.
In IMRT planning, the inverse problem needs to be solved, that is,
given an optimized fluence map, we have to determine a set of apertures
that closely reproduce the fluence map. This is called the leaf sequencing
problem. We assume for now that the fluence map is discretized into
evenly spaced fluence levels. A closer look at Figure 9.13 demonstrates
that the leaf sequencing problem does not have a unique solution, that
is, a given fluence map can be decomposed into a set of apertures in
many different ways. We consider MLC rows 3 and 4 in Figure 9.13,
which yield the same fluence, created with a distinct sequence of leaf
openings. MLC row 3 uses a sliding window decomposition, in which the
right and left leaves move unidirectionally from left to right. In contrast,
MLC row 4 uses a close-in technique, in which case the first aperture
corresponds to the largest field opening. Subsequent apertures shrink the
field and deliver additional fluence at the beamlets that have higher
intensity. In Figure 9.13 and throughout this section, we assume that the
fluence over an open field is homogeneous, which is applicable to Linacs
with flattening filter. Although not discussed here, leaf sequencing
methods can be extended to flattening filter free (FFF) delivery of IMRT,
which has the advantage of higher dose rates.
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FIGURE 9.13 Schematic illustration of the decomposition of a fluence map (right panel) into
apertures. The positions of MLC leaf ends are indicated by the green bars. It is assumed that
each aperture delivers one unit of fluence; the colors yellow, orange, and red indicate one, two,
and three units of fluence, respectively.
Sliding Window Sequencing

We consider the sliding window decomposition of fluence maps in more
detail (9). To that end, we consider a single leaf pair. The upper panel in
Figure 9.14 shows an example of one row of a fluence map for a single
leaf pair. The bottom panel shows the sliding window type aperture
decomposition. In the example, both leaves move unidirectionally from
left to right.
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FIGURE 9.14 Illustration of sliding window sequencing. The upper panel shows the fluence map
(vertical bars) corresponding to a single leaf pair. The bottom panel shows the set of apertures
(horizontal bars) to realize the fluence map.
It is intuitive that the gradients in the fluence map, that is, changes in
the intensity between neighboring beamlets, determine the leaf
positions. In the example, the fluence increases by 4 units between
beamlet 1 and beamlet 2. This determines that, during the delivery of 4
units of fluence, beamlet 1 has to be blocked by the left leaf while
beamlet 2 is exposed. Likewise, the fluence decreases by 1 unit between
beamlets 2 and 3, which determines that during the delivery of 1 unit of
fluence, beamlet 3 has to be blocked by the right leaf while beamlet 2 is
exposed. We call an increase in the fluence from one beamlet to the next
higher numbered beamlet a positive gradient, and a decrease a negative
gradient. It is clear that the sum of positive gradients (SPG) equals the sum
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of negative gradients. In sliding window sequencing, the positive
gradients uniquely determine the left leaf positions, while the negative
gradients uniquely determine the right leaf positions. In the first
aperture, the left leaf is positioned to the left of beamlet 1, the right leaf
is positioned where the first negative gradient occurs, which is between
beamlet 2 and 3. For the second aperture, the left leaf stays in the same
position while the right leaf moves to the next negative gradient
position, which is between beamlets 3 and 4.
It is intuitive that an irregularly shaped fluence map with several
peaks and valleys requires more apertures to deliver than smooth fluence
maps. It can be shown that the minimum total number of MU to deliver
a fluence map is given by the SPG. Sliding window sequencing is
therefore optimal regarding the total number of MU since it always
reproduces a fluence map with the shortest possible beam-on time.
Sequencing as an Optimization Problem

As illustrated in Figure 9.13, the leaf sequencing problem does not have
a unique solution. The degeneracy of the problem provides some
freedom that can be exploited, that is, the sequencing step can aim at
determining apertures that have desirable features. Criteria for good
aperture sets are:
• The total number of MU to be delivered is small, which corresponds to

the total beam-on time.
• The total number of apertures is small.
• Leaf travel is minimized, that is, the MLC leaves move as little as
possible
• Apertures should have regular shapes and very small apertures are
avoided.
• The fluence map is reproduced exactly or as closely as possible without
prior discretization.
• All MLC constraints are satisfied.
The sliding window sequencing method is optimal regarding the total
number of MU. However, other sequencing methods can potentially
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reduce the total number of apertures needed. To that end, the
sequencing problem can be formulated as an optimization problem.
While the FMO problem is a continuous optimization problem for which
gradient-based optimization methods are applied, the sequencing
problem is discrete and requires different optimization techniques. The
interested reader is referred to the literature. For example, the work by
Engel (10) describes a sequencing algorithm that yields the minimum
number of MU and simultaneously approximately minimizes the number
of apertures.
Step-and-Shoot Delivery Versus Dynamic Delivery

In IMRT, two types of delivery are distinguished: step-and shoot delivery
and dynamic delivery. In step-and-shoot IMRT, the fluence map is
sequenced into a set of apertures as described above. Each aperture is
irradiated individually, that is, the MLC leaves move to the desired
position, and the beam is turned on to deliver the specified number of
MU. Subsequently, the beam is turned off while the MLC leaves are
moved to shape the next aperture. In dynamic delivery, the MLC leaves
move while the treatment beam is on. In this case, the sequencing task
consists in determining the trajectories of MLC leaves, that is, the leaf
positions as a function of time.
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FIGURE 9.15 Illustration of dynamic IMRT delivery using a sliding window technique. The red
lines in the upper panel show the positions of the left and right leaf as a function of time. The
green line in the bottom panel shows the corresponding fluence profile.
Dynamic delivery is frequently associated with a sliding window type

delivery, because this gives rise to a constructive method to determine
the leaf trajectories (11). To that end, we consider a generalization of
the sliding window aperture decomposition in Figure 9.14. Figure 9.15
schematically illustrates continuous trajectories of the left and right leaf
in one MLC row. The horizontal axis shows the position of the leaf end,
while the vertical axis shows the time when the leaf end traverses a
given position. At every beamlet position in the MLC row, the effective
fluence of the beamlet is given by the exposure time. Initially, both
leaves are positioned on the left side and the right leaf covers the
beamlet. At time t1 the right leaf end traverses the beamlet and opens
the radiation field at that position. At a later time point t2 the left leaf
traverses the beamlet and closes the radiation field. The fluence of the
beamlet is proportional to the time interval t2 – t1 during which the
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beamlet is exposed. Thus, the distance of right and left leaf on the
vertical axis determines the corresponding fluence profile (green line in
the bottom panel).
In practice, the MLC leaves cannot move arbitrarily fast and have to
respect a maximum leaf speed. In Figure 9.15, the maximum leaf speed
constraint corresponds to a minimum slope of the leaf trajectory. To
allow a leaf to move a certain distance on the horizontal axis, a
minimum amount of time has to pass. This is indicated by the black
dashed line in the upper panel.
Dynamic delivery is frequently associated with sliding window type
delivery and used synonymously by some people. However, dynamic
delivery is not per se tied to sliding window trajectories. In principle,
other sequencing methods that allow for bidirectional leaf motion could
be developed and used. In fact, delivery of VMAT can be considered as
dynamic delivery with bidirectional leaf motion.
DIRECT APERTURE OPTIMIZATION

Historically, IMRT planning was developed as the two-step approach of
FMO plus sequencing. However, there are a number of disadvantages
related to the two-step approach. For example, in step-and-shoot IMRT, a
large number of apertures may be required to faithfully reproduce a
fluence map. Other problems relate to dose calculation accuracy during
the FMO step. In order to cope with the limitations of the two-step
approach, DAO methods are being developed and integrated into
commercial TPS. In this section, we first summarize some of the
limitations of the two-step approach. Subsequently, approaches to DAO
are discussed, which directly determine the shapes and intensities of
apertures.
Limitations of the FMO + Sequencing Approach

Limitations of the two-step approach can broadly be categorized into
three types:
1. The fluence map is not accurately reproduced by the set of apertures.
This is primarily a problem in step-and-shoot IMRT if the total number
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of apertures is kept small.
2. In step-and-shoot IMRT, the leaf ends are positioned at the boundary
between two beamlets after the sequencing step. Especially for large 1
× 1-cm beamlets, the dose distribution can be improved by
positioning the leaves at intermediate positions.
3. Even if the leaf sequencing step reproduces the fluence map exactly,
there will still be a discrepancy between the FMO dose distribution
used during plan optimization and the dose that is actually delivered
by the set of apertures.
While the first two limitations are quite apparent, the third aspect is
more complex. There are multiple reasons for dose discrepancy. Some
are inherent to the dose-deposition matrix concept, which does not take
into account higher-order effects on the incident fluence that the MLC
causes. Others are related to compromises being made between accuracy
and computational performance in the FMO stage.
Dose calculation accuracy: The calculation of the dose-deposition
matrix often uses a simplified dose calculation algorithm to speed up the
computation. For example, the dose-deposition matrix may be based on
a pencil beam algorithm while the final dose distribution of the
apertures may be calculated with a convolution-superposition algorithm.
In addition, the dose-deposition matrix may not store small scatter dose
contributions far away from the central axis of the beamlet in order to
reduce memory requirements. This leads to dose discrepancy between
the sequenced FMO solution and the final dose distribution. This issue is
not an inherent limitation of the two-step approach, and using accurate
dose calculation methods for computing the dose-deposition matrix
could mitigate the problem. However, in practice fast treatment plan
optimization is desired, which requires compromises.
Tongue-and-groove effect: Other dose calculation problems are
inherent to the dose-deposition matrix concept. For mechanical reasons,
two neighboring MLC leaves cannot be arbitrarily close to each other.
However, a small gap between MLC leaves would lead to radiation
leaking through. In order to avoid such inter-leaf leakage, many MLCs
adopt a tongue-and-groove design, which is schematically illustrated in
Figure 9.16. Let us consider an aperture consisting of two neighboring
beamlets in adjacent leaf pairs. The dose-deposition matrix concept used
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in FMO assumes linearity. This means, if both beamlets are combined to
a single aperture, the resulting dose distribution is predicted to be the
same compared to the situation in which both beamlets are delivered
individually as separate apertures. However, for MLCs with tongue-and-
groove design, this is not true. The regions where both leaves overlap
are now blocked as soon as one of the two leaves is closed. This leads to
an underdosage of the region of the beamlet boundary if both beamlets
are delivered as separate apertures.
FIGURE 9.16 Illustration of MLC leaves with tongue-and-groove design.
Leaf transmission: During the FMO step, the fluence of beamlets may
be zero if the beamlet is not beneficial for the treatment plan. Also, the
sequencing method typically assumes that the fluence for closed leaves is
zero. In reality this is only approximately true as there is some
transmission of radiation through closed MLC leaves. The effect is
mitigated by the jaws and is small when considering a single aperture.
However, the leaf transmission effect can add up for treatment plans
consisting of a large number of irregularly shaped apertures.
Mitigation of dose discrepancies: There are approaches to mitigate
the effects that lead to discrepancies between the dose distributions at
the FMO stage and after sequencing. One approach consists in adding
regularization terms to the FMO problem to favor smooth fluence maps
that require fewer apertures to deliver. In this context, the L1-norm
regularization term is of particular interest, which has edge-preserving
properties and favors piece-wise constant fluence maps (12,13).
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Furthermore, enhancements to the sequencing algorithm have been
devised, which for example, aim to reduce tongue-and-groove effects
(14).
Direct Aperture Optimization for Step-and-Shoot IMRT

In light of the above-mentioned limitations of the two-step approach of
FMO plus sequencing, it appears desirable to directly optimize the
shapes and intensities of apertures based on the dosimetric objective
function f(d). As a modification of the FMO problem in the section on
Fluence map optimization, the DAO problem can be stated as follows:
Determine the intensities and shapes of K apertures that minimize the
objective function f(d) subject to the constraints gs(d) ≤ cs. Optimizing
shapes of the apertures refers to optimizing the positions of all MLC leaves.
In order to appreciate the inherent difficulties in DAO, we recall the
favorable properties of the FMO problem. For FMO, the optimization
variables are the beamlet intensities, while the objective is a function of
the dose distribution. Given the dose-deposition matrix elements as fixed
parameters, the dose distribution is a linear function of the beamlet
intensities. A small change in the intensity of one beamlet leads to a
small linear change in the dose to a voxel. Thus, the objective function
can be written explicitly as a function of the optimization variable. In
addition, if the objective is a convex function of dose, the overall
optimization problem is convex and gradient-based algorithms can be
used to determine the global optimum reliably.
The DAO problem does not have this favorable property. The dose
distribution is a more complex and nonconvex function of the
optimization variables (the MLC leaf positions), which cannot easily be
stated in closed form. If we consider the dose in a voxel as a function of
the position of an MLC leaf, the dependence is given by a smoothed step
function. While both leaves are fully open, the leaf pair contributes its
maximum dose to the voxel. While one leaf moves to close the field, the
leaf pair’s dose contribution goes to zero. However, for most parts, a
change in the leaf position has little impact on the dose to a particular
voxel. Only in a small region that corresponds to the projection of the
voxel onto the MLC plane, a small change in the leaf position yields a
steep change in the voxel’s dose.
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In addition, there is a combinatorial aspect to the DAO problem. An
IMRT plan typically consists of 5 to 11 beam directions. Some beams
contribute more dose than others, and not all beam directions require
the same amount of intensity modulation. Therefore, the best
distribution of a limited number of apertures over the incident beam
angles is unclear a priori. Assigning the same number of apertures to
every beam may not yield the best treatment plan.
All approaches to DAO have to cope with these intrinsic difficulties.
DAO approaches can broadly be categorized into three types:
1. Stochastic search methods

2. Aperture generation methods
3. Gradient-based leaf position optimization
Stochastic Search Methods

Stochastic search methods for DAO include simulated annealing (15) and
genetic algorithms (16,17). These approaches typically start with a
geometry-based initialization of aperture shapes, that is, apertures that
conform to the target volume, possibly excluding projections of the
OARs. Subsequently, random perturbations of leaf positions are
generated and dose distribution d and objective function f (d) are
evaluated. If the treatment plan improves, the modification of the
aperture set is accepted; otherwise it is rejected with some probability.
Stochastic search methods have a number of advantages. First, random
perturbations of leaf positions can be restricted such that all MLC
constraints are fulfilled. In addition, these methods can in principle
escape from local optima of the objective function. Simulated annealing–
based DAO has been commercialized by PROWESS in the Panther TPS
for step-and-shoot IMRT. Furthermore, the method has been adapted to
VMAT (section on Arc therapy) and is used in the RapidArc module in
the Eclipse TPS marketed by Varian.
Aperture Generation Methods

The second class of methods refers to techniques that iteratively
generate new apertures that are added to a treatment plan. Such an
approach has been suggested by Romeijn et al. (18) and Carlsson (19).
Here, we illustrate the main idea behind the approach. We assume that
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the current treatment plan consists of n – 1 apertures and we are
interested in generating the nth aperture that yields a large improvement
to the current treatment plan. To that end, we consider the partial
derivative ∂f/∂xj of the objective function f with respect to the intensity
of a beamlet j. If the derivative is negative, adding the beamlet with a
small positive intensity reduces the objective function, that is, improves
the treatment plan. Furthermore, if |∂f/∂xj | is large, the beamlet
promises a large improvement to the treatment plan. Therefore, a
plausible approach to identifying a valuable new aperture consists in
finding a deliverable aperture that contains many beamlets j for which
∂f/∂xj < 0 and |∂f/∂xj | is large. Romeijn et al. (18) describe an efficient
algorithm to identify the aperture A for which
is minimized. The aperture is added to the treatment plan and the

intensities of all n apertures are optimized. The problem of optimizing
the aperture intensities is formally identical to the FMO problem and can
be solved using the algorithms described in the section on Fluence map
optimization. The dose distribution of an aperture Ak in the patient is
obtained by summing the dose-deposition matrix elements over the
beamlets contained in the aperture,
and the dose distribution is simply given by summing the contributions

of all apertures,
where yk is the intensity of aperture k. The iterative generation of new

apertures can be stopped once a maximum number of apertures is
reached or the plan quality is sufficiently high.
Local Leaf Position Optimization*
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In the remainder of this section, we describe the third approach of
gradient-based leaf position optimization in more detail. The reason is
that this approach is implemented in several of the widely used
commercial TPS including Pinnacle (Philips) (20), RayStation (Raysearch
Laboratories), and Monaco (Elekta).
In this approach to DAO, we assume that we are given an initial set of
apertures. This set of apertures can, for example, be obtained by
sequencing a fluence map solution, or from the aperture generation
method discussed above. Due to the nonconvex nature of the problem,
the initial set of apertures should represent a good starting point for leaf
position refinement, that is, ideally forms a decent treatment plan
already. The set of K apertures, indexed by k, is characterized by
• aperture intensities yk.

• leaf positions for the left and right leaf edges: Lkn and Rkn where n is
the index of the MLC leaf pair.
The goal of gradient-based leaf refinement is to optimize the objective

function f (d) with respect to the leaf positions and aperture weights. In
particular, we allow the leaf positions to change continuously, that is,
the leaf edge does not have to be positioned at a beamlet boundary.
Approximate Dose Calculation

We first formulate the dose distribution as a function of the optimization
variables, that is, leaf positions and aperture intensities. The dose in
voxel i is given by the sum of the contributions of the individual
apertures, weighted with their intensity yk. Furthermore, the dose
contribution of each aperture is given by the contributions of each
MLC leaf pair:
To proceed, we have to further characterize the function . For

that purpose, we consider a particular MLC row n in aperture k. We first
imagine that the left leaf is located at the left-most position at the edge
of the field; and we consider the dose contribution of the MLC row as a
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function of the right leaf position, which we denote by the function
. Let us further assume that the voxel i is within the beam’s-eye-
view of the MLC row such that the MLC row contributes a significant
dose to voxel i. We know that the function has the shape of a
smooth step function: If the right leaf is located at the left most position,
the MLC row is closed and the dose contribution is zero. While the right
leaf is moving to the right, the dose contribution increases
monotonically. This is illustrated in Figure 9.17.
We now consider the dose-deposition matrix representation of the
dose to further characterize the function . We note that we know
the function at discrete points, namely when the right leaf is
positioned at an edge of a beamlet. Let Δx denote the size of a beamlet,
and let j denote the beamlet index in leaf motion direction. At position
jΔ x, the dose contribution is simply given by the sum over the exposed
beamlets, that is,
where we introduce the dose-deposition matrix notation to denote the

dose contribution of beamlet j in MLC row n to voxel i. For a continuous
leaf position in between, we consider a linear interpolation (Figure
9.17). This corresponds to the assumption that the dose distribution of a
beamlet that is half exposed is given by the beamlet dose distribution
with half the intensity. This approximation will break down for large
beamlet size Δx, however, for practical beamlet sizes of 5 mm, the
approximation yields adequate results. Using the function we can
express the dose contribution of an MLC row as
The first term represents the beamlets that are exposed by the right
leaf; the second term subtracts the beamlets that are blocked by the left
leaf.
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FIGURE 9.17 Illustration of the function , representing the dose contribution of an MLC row
to a voxel as a function of the right leaf position. The function is known at discrete position where
the right leaf is positioned at a beamlet boundary and the dose contribution can be expressed as
a sum of dose-deposition matrix elements. In between, the dose contribution is interpolated
linearly (with permission reproduced from (4)).
Optimizing Leaf Positions

To optimize leaf positions and aperture intensities we can utilize
gradient descent–based algorithms for nonlinear optimization. To apply
the generic gradient descent algorithm described in the section on
Fluence map optimization, we have to evaluate the gradient of the
objective function with respect to leaf positions and aperture intensities.
This can be achieved with the help of the function ø. Let us consider
the derivative with respect to one of the right leaves, Rkn:
The calculation of the partial derivatives ∂f/∂di is identical to the case

of FMO as described in the Fluence map optimization section. Using the
linear approximation illustrated in Figure 9.17, the derivative of the
dose contribution function only depends on the beamlet where the
leaf edge is currently located. If we further assume that the leaf position
is measured in units of beamlets (i.e., moving a leaf by the width of one
beamlet corresponds to a distance of 1), the derivative of is simply
given by
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where jkn is the index of the beamlet where the leaf edge is located. The
derivative of the voxel dose with respect to the aperture intensity is
simply given by the dose contribution of the aperture for unit intensity:
Evaluating the dose gradient of the objective function with respect to

the optimization variables provides the prerequisites for the use of a
gradient-based nonlinear optimization algorithm. In contrast to FMO,
DAO considers two types of optimization variables simultaneously, that
is, leaf positions and aperture intensities. Therefore, the use of second
derivatives in the optimization algorithm is important. In particular, the
quasi-Newton methods like L-BFGS can be used. Variations of gradient-
based leaf position optimization are described by De Gersem et al. (21)
and Cassioli and Unkelbach (22).
DAO provides the opportunity to directly account for restrictions of
the MLC. These can be integrated into the optimization problem in the
form of bound constraints and linear constraints. In addition, DAO
provides better ways of mitigating dose calculation inaccuracies
compared to FMO. For example, at an intermediate stage of gradient-
based leaf position optimization, the dose distributions of the current
aperture set can be calculated using a convolution-superposition
algorithm. In subsequent iterations, changes can be approximated by a
pencil beam–based dose-deposition matrix. If leaf position changes
remain small, the error in the dose distribution is minor.
ARC THERAPY
In IMRT, the patient is irradiated from discrete beam directions.
Typically between 5 and 9 beam directions are used. While the gantry
moves from one angle to the next one, the treatment beam is off. Arc
therapy refers to a radiotherapy delivery mode in which the treatment
beam is continuously on while the gantry rotates around the patient.
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Conformal arc therapy has long been used as a delivery mode for
conformal therapy, especially for small spherical lesions that do not
require intensity modulation. In conformal arc therapy, the treatment
field is fixed during gantry rotation or conforms to the projection of the
target volume. VMAT refers to an extension of IMRT to a rotational
treatment mode, delivered at conventional Linacs equipped with an
MLC. The treatment field does not necessarily conform to the target at
every angle. Instead, an effectively intensity-modulated field is delivered
over an arc sector.
The motivation for VMAT has been twofold: First, the patient is
irradiated from all gantry angles rather than a relatively small number of
discrete angles. This bears the potential for better and more conformal
treatment plans. Second, VMAT bears the potential for shorter treatment
times because the treatment beam is continuously on. The idea of
delivering intensity-modulated fields through arc therapy was suggested
by Yu as early as 1995 (23). However, a clinical implementation of
VMAT was delayed in part by the lack of TPS that support this
technique. In 2008, Varian introduced the RapidArc planning module in
the Eclipse planning system and provided a commercial VMAT solution.
Around the same time, Philips Medical Systems provided the SmartArc
module in the Pinnacle planning system to support VMAT. Today, most
treatment systems including Monaco (Elekta) and RayStation (Raysearch
Laboratories) support VMAT planning.
Before the clinical adaptation of VMAT, specialized hardware to
deliver intensity-modulated fields in a rotational mode was developed.
The device has been proposed by Mackie (24) and was commercialized
as Tomotherapy, resulting in the first patient treatment in 2002. The
design of Tomotherapy machines resembles a serial CT scanner in which
the x-ray tube is replaced by a Linac that produces a therapeutic MV
treatment beam. The radiation source continuously rotates while the
patient is shifted through the device. The patient is irradiated slice-by-
slice using a fan beam, whose intensity is modulated using a customized
binary MLC. From a treatment planning perspective, Tomotherapy can
build on the FMO concepts described in the Fluence map optimization
section. The leaf sequencing problem is simple compared to MLCs at
conventional Linacs. In this section, we therefore focus on VMAT, which
poses new challenges for treatment planning. For further details on
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Tomotherapy, we refer the interested reader to the review by Mackie
(25) and references therein. A more extended review of treatment plan
optimization approaches to VMAT is provided by Unkelbach (26). For
further information on the clinical implementation of VMAT, we suggest
the review by Yu (27).
The VMAT Treatment Planning Problem

VMAT can be thought of as a dynamic MLC technique to deliver IMRT,
with the modification that the gantry does not stand still at discrete
angles but continuously rotates while radiation is delivered. The dose
distribution delivered by a VMAT plan is determined through three types
of variables:
1. The MLC leaf trajectories, that is, the positions of the left leaves Ln
and the right leaves Rn as a function of time;
2. The gantry angle φ(t) as a function of time;
3. The dose rate δ(t) as a function of time.
In principle, the jaws, collimator and treatment couch also could

move. However, here we assume that the collimator and couch are at
fixed angles, and that the jaws can be positioned in a post-processing
step with minor impact on the treatment plan. For dose calculation, a
VMAT arc is discretized into small arc sectors. For example, a 360-
degree arc is divided into 180 arc sectors of 2-degree length. For
treatment planning, a dose-deposition matrix can be calculated at the
center of each arc sector.
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FIGURE 9.18 Relation between leaf trajectories and effective fluence in VMAT delivery. The red
area corresponds to the exposure time of the beamlet in arc sector φ and is proportional to the
beamlet’s effective fluence.
Given the trajectories for leaves, gantry, and dose rate, a VMAT plan
delivers an effective fluence at any gantry angle φ. The relation
between effective fluence and leaf trajectories is illustrated in Figure
9.18 for a single leaf pair n. Let us for simplicity assume that the dose
rate is constant over the arc sector φ. Then the effective fluence is
determined by the time that beamlet j is exposed by the MLC leaves. In
Figure 9.18, the red-colored area enclosed by the leaf trajectories and
the beamlet boundaries corresponds to the effective exposure time. This
method to relate leaf positions to fluence involves the common
approximation made in Figure 9.17: If at time t, a beamlet is partially
exposed by the MLC leaves, the time point’s contribution to the
beamlet’s effective fluence is proportional to the exposed fraction of the
beamlet. The dose distribution is obtained by multiplying the effective
fluence with the dose-deposition matrix at each arc sector.
VMAT planning aims at determining short trajectories that lead to
high plan quality, that is, VMAT plans that only take a short amount of
time to deliver. Thereby, the trajectories have to satisfy a number of
machine constraints. In particular, the MLC leaves have to satisfy the
maximum leaf speed constraint. In addition, the gantry speed is limited
to one full rotation per minute. Limitations on the dose rate are highly
machine dependent. Some Linacs allow for continuously varying dose
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rates while others allow for discrete values only. All machines have a
maximum dose rate.
DICOM Specification of a VMAT Plan

VMAT planning approaches differ in the way that the leaf trajectories
are parameterized. The most common representation is driven by the
DICOM specification of a treatment plan, which is used to communicate
the plan between the TPS and the treatment machine control system.
Using DICOM standard, the treatment plan is defined via a sequence of
control points. Each control point is defined through a set of leaf
positions, a gantry angle, and the total number of MU that is delivered
up to that control point. Thereby, the DICOM specification gives rise to
formulating VMAT planning as a DAO problem. For example, a prostate
patient may be treated with a single 360-degree arc, which is divided
into 90 arc sectors of 4-degree length. For VMAT planning, one control
point (i.e., one aperture) is assigned to the center of each arc sector.
Subsequently, the DAO methods discussed in the Direct aperture
optimization section can be applied for plan optimization.
The DAO algorithm will return the aperture shapes and aperture
intensities for each control point along the arc. It is apparent that a
given aperture intensity yφ, which corresponds to the number of MU
delivered over the arc sector, depends on the gantry speed sφ, the dose
rate δφ, and the length of the arc sector Δφ and is given by
Large aperture intensities can be realized by a large dose rate or a

slow gantry speed. Since the motivation for VMAT treatments is in part
the reduction in treatment time, the machine controller should select the
largest possible gantry speed.
In principle, a DAO algorithm applied to VMAT planning yields a
deliverable plan if the gantry speed can vary between the maximum and
very small values. However, without modifications, the resulting
treatment plan may be inefficient regarding delivery time. As an
example, we assume that we want to deliver a 360-degree arc in 90
seconds at constant gantry speed. Then, the gantry sweeps over each 4-
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degree arc sector in 1 second. If the maximum leaf speed of the MLC is 3
cm/s, the MLC leaves can only move by 3 cm between two neighboring
control points. Otherwise, the gantry speed has to be reduced, leading to
longer delivery times. Hence, VMAT planning typically aims at limiting
the leaf travel between adjacent control points—in the interest of
treatment time and also dose calculation accuracy. For gradient-based
leaf position optimization methods, constraints on leaf travel correspond
to linear constraints on the leaf positions.
Illustration of a VMAT Plan

Figure 9.19 illustrates a VMAT plan for a prostate cancer patient treated
with a single 360-degree arc, delivered by moving the gantry counter-
clockwise from 180 to –180 degrees. The arc is evenly divided into 90
arc sectors that are assigned one aperture each. The circle around the
patient indicates the coplanar incident beam directions. The yellow bars
depict the number of MU that is delivered over each arc sector. In the
foreground, one of the apertures along the arc is shown.
FIGURE 9.19 Illustration of a VMAT plan for a prostate cancer patient generated in RayStation
4.0. The treatment plan consists of a single 360-degree arc divided into 90 sectors. The dose
distribution is shown on a coronal slice of the patient’s CT.
Approaches to VMAT Plan Optimization

The VMAT implementations in commercial systems heavily build on the
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concepts that were previously developed for IMRT planning. Bzdusek et
al. (28) suggest a three-step approach to VMAT, using all three concepts
of IMRT planning.
1. In the first step, FMO is performed at discrete, equi-spaced beam
angles. In practice, 15 to 20 beam angles are used.
2. In the second step, the resulting fluence maps are converted into
apertures that are distributed over the corresponding arc sector.
Assuming 15 beam angles are considered in the FMO step, leading to
24-degree arc sectors, each fluence map can be segmented into six
apertures, which results in one control point every 4 degrees. In this
arc sequencing step, it is desired that neighboring apertures are similar.
For that reason, most arc sequencing methods use a sliding window
type decomposition, which leads to a natural ordering of the
apertures.
3. In the third step, DAO methods are applied to refine the leaf positions
and aperture intensities. Assuming that the first two steps yield a good
starting point, local gradient-based DAO methods can be used in the
third step.
Such a three-step approach is implemented in several commercial

systems including the SmartArc module in Pinnacle (Philips Medical
Systems), the RayArc module in RayStation (Raysearch Laboratories),
and in Monaco (Elekta). Planning systems differ in the exact
implementation of each step and not all details are disclosed.
The work by Otto (29) is the basis for the RapidArc module in the
Eclipse planning system (Varian). This approach primarily depends on
DAO using simulated annealing as described by Shepard et al. (15), and
uses a geometry-based initialization of aperture shapes. Other VMAT
optimization approaches proposed in the literature are based on sliding
window delivery of a fluence map over an arc sector (30–32). An
overview of VMAT planning approaches can be found in the review by
Unkelbach et al. (26).
SPECIALIZED TOPICS IN IMRT PLANNING

Multi-Criteria Planning Methods
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IMRT treatment planning has to find a tradeoff between inherently
conflicting clinical goals. The traditional approach to explore these
tradeoffs consists in manually choosing relative weights for different
objectives. This can lead to a time-consuming trial-and-error process.
Several methods have been proposed to improve the planning process in
that regard.
Prioritized Optimization
One approach is referred to as prioritized optimization (33) or
lexicographic ordering (34). It is motivated by the assumption that the
clinical objectives can be ranked according to their priority. For
example, in the prostate cancer example shown in Figure 9.2, the main
planning goal may be to deliver the prescribed dose to the target
volume. The second planning goal is the sparing of the anterior rectal
wall. Additional objectives are related to bladder dose and conformity,
but are considered of lower priority.
A prioritized optimization scheme performs a sequence of IMRT
optimizations. In the first step, we obtain the treatment plan that yields
the best possible plan only considering the highest ranked objective. In
the prostate example, we may minimize a quadratic objective function
for the target volume:
where gs(d) ≤ cs represents the hard constraints on the dose distribution.

This yields an optimal value fT* for the quadratic objective function for
the target volume. In the next step, the target objective is turned into a
constraint, while minimizing the objective with the second highest
priority, which could be the EUD in the rectal wall:
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In this formulation, the EUD in the rectal wall is minimized, subject to
the constraint that the target dose homogeneity deteriorates by at most ε
compared to the optimally achievable value fT*. Solving this
optimization problem yields the optimal rectal wall EUD fR* that is
achievable under the given constraints. In the third step, the objective
function for dose conformity can be minimized as the only objective,
subject to the constraints that the target and rectum objectives only
deteriorate by a small ε from their optimal values fT* and fR*.
Pareto-Optimality
Prioritized optimization schemes rely on a ranking of the objectives, and
make the assumption that higher ranked objectives are not compromised
to improve lower ranked objectives. This is a potential drawback in
situations where a large improvement in one objective can be achieved
by only a minor degradation of a higher ranked objective, or if the
ranking is unclear a priori.
For simplicity, we consider only two objectives below, for example,
target dose homogeneity and rectal wall EUD in a prostate case. By
varying the tolerance level ε in the prioritized optimization scheme, one
can generate a sequence of treatment plans as illustrated in Figure 9.20.
The plans obtained in this manner define the set of Pareto-optimal
treatment plans that form the Pareto surface. A treatment plan is Pareto-
optimal if it is not possible to improve the plan in one objective without
worsening at least one other objective.
Interactive Pareto-Surface Navigation Methods

For radiotherapy planning, we are interested in choosing a treatment
plan from the Pareto surface. However, it may depend on the patient’s or
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physician’s preference which treatment plan to pick. Especially for
difficult cases such as the head-and-neck cancer example in Figure 9.3,
the physician or treatment planner may want to explore the tradeoffs
between different planning goals. Both tasks are straightforward in a
two-dimensional tradeoff as illustrated in Figure 9.20. In this case, the
Pareto surface can be approximated with a few treatment plans that are
evenly spaced on the one-dimensional Pareto surface in the clinically
relevant range. The treatment planner can then choose one of these pre-
computed treatments plans. However, IMRT planning typically involves
tradeoffs between more than two objectives (say, 5 to 10). It is apparent
that in higher dimensions the approximation of the Pareto surface is
more challenging due to the curse of dimensionality. In addition,
exploring the tradeoff space is nontrivial. The development of a
treatment planning framework has to address two problems:
1. Developing methods to efficiently represent the Pareto surface with a

small number of Pareto-optimal treatment plans, which are called
database plans. One method to achieve this is the so-called Sandwich
method described by Craft et al. (35).
2. Providing a graphical user interface and the underlying mathematical
methods that allow the treatment planner to interactively explore and
visualize the tradeoffs between conflicting planning goals.
FIGURE 9.20 Schematic illustration of the Pareto surface for the tradeoff between target dose
homogeneity and rectal wall EUD. All treatment plans below the Pareto surface are impossible to
achieve; treatment plans above the Pareto surface are undesirable because they can be
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improved in one objective without worsening the second objective. Points on the Pareto surface
can be generated using the constrained method, that is, by minimizing the rectal wall EUD,
subject to different target homogeneity constraints (with permission reproduced from (4)).
One goal of Pareto-surface navigation methods is to allow for a

continuous exploration of treatment plans. To that end, not only the
discrete database plans are considered but also linear combinations of
plans. We assume that a treatment plan is defined through the fluence
map x. Given two treatment plans with fluence maps x1 and x2, we can
form a convex combination of the two treatment plans by considering
the averaged fluence map
which is obtained by averaging the beamlet intensities beamlet-by-

beamlet, using a mixing parameter q ∊[0,1]. If x1 and x2 are Pareto-
optimal treatment plans, the convex combination of two plans is
expected to be also a “good” treatment plan (although not strictly
Pareto-optimal).
In a TPS, the planner has to be provided with tools to navigate in the
space of convex combinations of database plans. In a practical scenario,
the planner may have evaluated a current treatment plan, and would
like to improve the treatment plan regarding one particular objective,
say the rectum dose. The TPS has to provide a user interface to express
this request. Figure 9.21 shows the Pareto-surface navigation interface in
the RayStation TPS (version 4.0), distributed by RaySearch Laboratories.
Each objective is associated with a slider. By moving the slider, the user
can request an improvement of the treatment plan with respect to the
chosen objective. In the background, the TPS translates the slider
movement into a new convex combination of database plans.
Beam Angle Optimization

IMRT planning primarily refers to determining the fluence maps of
incident beam directions and their delivery with MLCs. In this context it
is assumed that the incident beam directions are given. In practice,
treatment planners often use a template of standardized beam directions
for a given treatment site. For example, for prostate treatments a set of 7
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evenly spaced coplanar beam directions is used. For treatment sites that
exhibit relatively little geometric variation across patients, such
templates often provide satisfying plan quality. However, treatment
planning studies suggest that some treatment sites, for example
intracranial lesions may benefit from individualized noncoplanar beam
directions. Despite this benefit, current TPS have very limited support
for automated selection of optimized beam directions. Typically, the
treatment planner selects beam angles manually based on experience
and the patient’s geometry.
Approaches to automated beam angle optimization (BAO) in the
literature can broadly be categorized in two types:
• Beam angle selection and FMO are considered jointly. That means, the
quality of a treatment plan is judged by an objective function f (d) as
used for FMO. The goal of BAO is then to simultaneously select a set of
beam angles and their associated fluence maps such that the objective
function f is minimized.
• Beam angle selection is separated from the FMO problem. In the first
step, beam angles are selected based on simplified measures to score
the quality of a beam direction. This is done mostly based on geometric
features. In the second step, FMO is performed for the fixed set of beam
angles.
Approaches in the first category are typically formulated as a

combinatorial optimization problem. In that setting, BAO aims to select
a small subset of n beams from a larger pool of N candidate beam
directions. This yields a very large number of possible beam ensembles
given by the binomial coefficient. No computationally efficient
algorithms exist to determine the optimal beam ensemble, and it is in
part this combinatorial nature of BAO that has prevented a practical
implementation in commercial TPS. Most approaches to combined FMO
and beam angle selection amount to solving a large number of FMO
problems for different beam ensembles. This includes stochastic search
methods like simulated annealing (36) as well as integer programming
methods (37). For a review of BAO from a methodology perspective we
suggest the paper by Ehrgott et al. (8). BAO research suffers from the
lack of shared patient data sets. Works that compare different BAO
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algorithms on a common patient data set using the same objective
functions are scarce. The work by Bangert et al. (38) is an exception and
compares three stochastic search methods and an iterative beam
selection heuristic, observing similar performance of the investigated
methods.
FIGURE 9.21 Graphical user interface for multi-criteria IMRT planning in the RayStation treatment
planning system (version 4.0). Each objective is associated with a slider. The user can drag
sliders to improve the treatment plan regarding the corresponding objective. The user request is
translated into a new convex combination of database plans and the corresponding DVH and the
dose distribution are displayed. By locking sliders (visible as the check boxes to the left of each
slider) the user has additional control over the navigation process. For example, by locking the
slider for target dose homogeneity, the user can request that the navigation is restricted to
treatment plans for which the target homogeneity is no worse than indicated by the current slider
position.
Integrating Uncertainty and Organ Motion in IMRT Planning

Setup uncertainties and organ motion in radiotherapy is traditionally
handled via a safety margin approach. The clinical target volume (CTV)
is expanded by a margin to form the planning target volume (PTV).
Radiotherapy planning aims at delivering the prescribed dose to the
PTV. As long as the CTV stays within the PTV, it can be assumed that the
CTV receives the prescribed dose despite variations of the CTV location.
IMRT planning is formulated as a mathematical optimization problem,
which provides the possibility of incorporating a model of patient
motion directly into the IMRT treatment planning problem. In this case,
the manual definition of the PTV becomes obsolete and, in some cases,
better sparing of normal tissues can be achieved.
Accounting for Respiratory Motion

As an example, we consider the handling of respiratory motion in the
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lung. Tumors located close to the diaphragm that are not attached to the
chest wall may move approximately 2 cm in superior–inferior direction
between exhale and inhale. Nowadays, the magnitude of motion can be
assessed using 4D CT, which provides snapshots of the patient geometry
at 10 phases during the respiratory cycle. Traditionally, motion is
accounted for using the internal target volume (ITV) concept. The ITV
represents the union of the target volume defined on each individual
phase. Treatment planning aims at delivering the prescribed dose to the
entire ITV to ensure that the target volume receives the prescribed dose
in any phase of the breathing cycle.
The dose delivered to the surrounding lung tissue can be reduced via a
nonuniform dose distribution within the ITV. Rather than irradiating the
ITV homogeneously with the prescription dose, the dose can be higher in
regions that are covered by the tumor most of the time. Thereby, the
dose can be reduced in regions that are occupied by lung tissue most of
the time, and only rarely by the tumor. The dose inhomogeneities are to
be designed such that the tumor eventually receives the prescribed dose
while accumulating dose contributions from different phases in the
respiratory cycle. IMRT optimization provides the means to formalize
this idea.
We assume that a 4D CT provides a CT image for each respiratory
phase s. Typically, the exhale phase is used as a reference phase, which
is used to define OAR voxels and tumor voxels. IMRT planning can be
based on the cumulative dose that a voxel accumulates over the
breathing cycle, which can be approximated as
Here, dis is the dose received by voxel i in phase s, Dsij is the dose-
deposition matrix in phase s, and ps is the relative amount of time that
the patient spends in phase s. The calculation of the dose-deposition
matrices in phase s represents a substantial practical difficulty. Dsij
represents the dose that the anatomical voxel i defined on the reference
phase receives from beamlet j in another phase s. Its calculation requires
a dose calculation on phase s, but also a deformable registration of the
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dose distribution to the reference phase.
In the respiratory motion case as described so far, the motion is
assumed to be predictable in the sense that the cumulative dose
distribution can be calculated. Although this involves practical
challenges, it does not require conceptual changes in terms of the
optimization method used. IMRT planning can be performed by
minimizing the objective function f that is evaluated for the cumulative
dose.
Handling Uncertainties
The presence of uncertainty is different from the case of predictable
motion. For example, a systematic setup error implies that the dose
distribution delivered to the patient is not predictable and is inherently
uncertain. This requires conceptual changes regarding the formulation of
the treatment planning problem.
To illustrate the handling of uncertainty, we consider systematic setup
errors. For example we can consider six patient shifts of ±5 mm in
anterior–posterior, superior–inferior, and left–right direction. For each
patient shift a separate dose-deposition matrix Dsij can be calculated,
leading to different dose distributions d s (where s is now an index for
the error scenario). Since we consider a systematic error, only one of the
dose distributions dis can be realized, not an average. Generally, the goal
is to obtain a treatment plan that is good or acceptable for any error
scenario that is accounted for. There are mainly two approaches to
translate this notion into mathematical terms for IMRT planning: the
probabilistic approach and the worst-case approach.
In the probabilistic approach, a probability ps is assigned to each
scenario s. For example, a higher probability can be given to the nominal
scenario (i.e., no setup error occurs), and a lower probability is assigned
to setup error scenarios. IMRT treatment plan optimization is performed
by minimizing the expected value of the objective function f:
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In words, the composite objective function is a weighted sum of
objectives evaluated for each error scenarios, where a higher weight may
be given to likely scenarios, and a lower weight to less likely scenarios.
While the probabilistic approach can be seen as optimizing the average
plan quality, the worst-case approach aims at finding the treatment plan
that is as good as possible for the worst error scenario that is accounted
for. Formally, this can be formulated as
Methods to incorporate motion and uncertainty in IMRT planning

have been investigated in the literature. For example, Trofimov et al.
(39) consider respiratory motion for lung tumors, and Heath et al. (40)
extend this work to include uncertainties in the breathing trajectory.
Bohoslavsky et al. (41) consider random and systematic setup errors for
prostate treatments. In recent years, these methods have been applied to
intensity-modulated proton therapy (IMPT) to handle range
uncertainties. In IMPT, the PTV concept is fundamentally limited (42)
and cannot generally ensure robust treatment plans. The need for
methods to incorporate uncertainty directly into IMPT planning has led
to the first commercial implementations. The RayStation planning
system (version 4.5) implements a worst-case approach for handling
systematic setup errors (and range errors when applied to IMPT).
KEY POINTS
• Illustrate the need for intensity-modulation when treating concave
target volumes such as head-and-neck tumors, prostate cancer, or
spinal metastasis.
• Discuss fluence map optimization (FMO) and the formulation of

IMRT planning as a mathematical optimization problem.
• Review the traditional two-step approach of IMRT planning, that is,

FMO plus leaf sequencing.
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• Understand gradient-based methods for direct aperture
optimization (DAO) to optimize MLC leaf positions.
• Provide an overview of treatment plan optimization approaches for

volumetric-modulated arc therapy (VMAT).
• Provide an introduction to advanced topics in IMRT planning

including multi-criteria optimization (MCO) and the incorporation of
uncertainty and organ motion.
QUESTIONS
1. How is a VMAT plan communicated between the treatment
planning system (TPS) and the Linac?
A. The TPS determines the optimal MLC leaf positions as a
function of time as well as the gantry speed and dose rate.
B. The TPS generates a sequence of control points defined
through leaf positions, gantry angle, and cumulative monitor
units.
C. The TPS optimizes incident fluence maps and the Linac control
system converts these into MLC apertures.
2. What are advantages of the sliding window leaf sequencing
method?
A. The conversion of a fluence map into a sliding window leaf
trajectory can be performed analytically without the need for
time-consuming optimization.
B. Sliding window sequencing yields the smallest number of
apertures.
C. Sliding window sequencing yields the smallest total number of
monitor units.
3. Which statement about direct aperture optimization (DAO) is
appropriate?
A. DAO is an important component of many VMAT planning
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algorithms.
B. DAO has been developed for step-and-shoot IMRT and is
therefore not applicable to dynamic delivery techniques such
as VMAT.
C. DAO eliminates the need for mathematical optimization
methods in IMRT planning and hence makes IMRT planning
faster and better.
D. DAO can in part overcome the problem of dose degradation
that may occur in the leaf sequencing step following fluence
map optimization.
E. The DAO problem can be solved much more reliably compared
to the traditional fluence map optimization approach and
therefore leads to better treatment plans.
4. What is the motivation for multi-criteria optimization (MCO)?
A. MCO potentially provides better treatment plans because the
traditional planning approach does not yield Pareto-optimal
plans.
B. Allowing the treatment planner to assess tradeoffs is one of the
main motivations for MCO.
C. In MCO, direct aperture optimization or VMAT planning can
more easily be integrated compared to the traditional
planning approach.
D. MCO is a way to overcome the cumbersome tweaking of
objective weights, which can be time-consuming in traditional
planning.
ANSWERS
1. B VMAT plans are communicated via DICOM standard, that is,
via a sequence of control points. Gantry speed, dose rate, and
MLC leaf trajectories are determined by the machine controller
based on the sequence of apertures generated by the TPS.
2. A and C It is the main disadvantage of sliding window
sequencing that it may generate a large number of small
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apertures.
3. A and D DAO addresses the shortcomings of the traditional
fluence map plus sequencing IMRT planning approach.
Although DAO was originally developed for step-and-shoot
IMRT, it is widely used in VMAT algorithms, in parts due to the
DICOM specification of a VMAT plan as a sequence of
apertures.
4. B and D The main motivation for MCO is to provide methods for
an efficient and interactive exploration of tradeoffs between
planning goals. This may in turn translate into improved
treatment plans. It is a common misconception that the
traditional planning method of assigning importance weights
does not yield Pareto-optimal plans. In fact, the same
optimization methods are used in MCO, except that importance
weights are determined by an algorithm rather than manually.
Incorporating DAO or VMAT into an MCO framework is
difficult and subject to ongoing research.
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4. Boyer A, Unkelbach J. Intensity-modulated radiation therapy
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5. Romeijn HE, Dempsey JF, Li JG. A unifying framework for multi-
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6. Nocedal J, Wright SJ. Numerical Optimization. 2nd ed. Springer;
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Scientific; 1999.
8. Ehrgott M, Güler C, Hamacher HW, et al. Mathematical optimization
in intensity-modulated radiation therapy. Ann Oper Res.
2010;175:309–365.
9. Bortfeld TR, Kahler DL, Waldron TJ, et al. X-ray field compensation
with multileaf collimators. Int J Radiat Oncol Biol Phys.
1994;28(3):723–730.
10. Engel K. A new algorithm for optimal multileaf collimator field
segmentation. Discrete Appl Math. 2005;152(1):35–51.
11. Stein J, Bortfeld T, Dorschel B, et al. Dynamic x-ray compensation
for conformal radiotherapy by means of multileaf collimation.
12. Li R, Xing L. Bridging the gap between IMRT and VMAT: Dense
angularly sampled and sparse intensity modulated radiation
therapy. Med Phys. 2011;38(9):4912–4919.
13. Kim H, Li R, Lee R, et al. Dose optimization with first-order total-
variation minimization for dense angularly sampled and sparse
intensity modulated radiation therapy (DASSIM-RT). Med Phys.
2012;39(7):4316–4327.
14. Kamath S, Sahni S, Palta J, et al. Optimal leaf sequencing with
elimination of tongue-and-groove underdosage. Phys Med Biol 2004;
49(3):N7–N19.
15. Shepard DM, Earl MA, Li XA, et al. Direct aperture optimization: a
turnkey solution for step-and-shoot IMRT. Med Phys.
2002;29(6):1007–1018.
16. Li Y, Yao J, Yao D. Genetic algorithm based deliverable segments
optimization for static intensity-modulated radiotherapy. Phys Med
Biol. 2003;48:3353–3374.
17. Cotrutz C, Xing L. Segment-based dose optimization using a genetic
algorithm Phys Med Biol. 2003;48:2987–2998.
18. Romeijn HE, Ahuja RK, Dempsey JF, et al. A column generation
approach to radiation therapy treatment planning using aperture
modulation. SIAM J Optim. 2005;15:838–862.
19. Carlsson F. Combining segment generation with direct step-and-
shoot optimization in intensity-modulated radiation therapy. Med
Phys. 2008;35:3828–3838.
20. Hardemark A, Liander H, Rehbinder H, et al. Direct machine
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parameter optimization with RayMachine in Pinnacle. Ray-search
Laboratories White Paper. 2003.
21. De Gersem W, Claus F, De Wagter C, et al. Leaf position
optimization for step-and-shoot IMRT. Int J Radiat Oncol Biol Phys.
2001;51:1371–1388.
22. Cassioli A, Unkelbach J. Aperture shape optimization for IMRT
treatment planning. Phys Med Biol. 2013;58(2):301–318.
23. Yu CX. Intensity-modulated arc therapy with dynamic multileaf
collimation: an alternative to tomotherapy. Phys Med Biol. 1995;
40(9):1435–1449.
24. Mackie TR, Holmes T, Swerdloff S, et al. Tomotherapy: a new
concept for the delivery of conformal radiotherapy. Med Phys. 1993;
20:1709–1719.
25. Mackie TR. History of tomotherapy. Phys Med Biol. 2006;51:R427–
R453.
26. Unkelbach J, Bortfeld T, Craft D, et al. Optimization approaches to
volumetric modulated arc therapy planning. Med Phys.
2015;42(3):1367–1377.
27. Yu CX, Tang G. Intensity-modulated arc therapy: principles,
technologies and clinical implementation. Phys Med Biol. 2011;
56(5):R31–R54.
28. Bzdusek K. Friberger H, Eriksson K, et al. Development and
evaluation of an efficient approach to volumetric arc therapy
29. Otto K Volumetric modulated arc therapy: IMRT in a single gantry
arc. Med Phys. 2008;35:310–317.
30. Craft D, McQuaid D, Wala J, et al. Multicriteria VMAT optimization.
Med Phys. 2012;39:686–696.
31. Papp D, Unkelbach J. Direct leaf trajectory optimization for
volumetric modulated arc therapy planning with sliding window
delivery. Med Phys. 2014;41(1):011701.
32. Wang C, Luan S, Tang G, et al. Arc-modulated radiation therapy
(AMRT): a single-arc form of intensity-modulated arc therapy. Phys
Med Biol. 2008;53(22):6291–6303.
33. Wilkens JJ, Alaly JR, Zakarian K, et al. IMRT treatment planning
based on prioritizing prescription goals. Phys Med Biol.
2007;52:1675–1692.
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34. Jee KW, McShan DL, Fraass BA. Lexicographic ordering: intuitive
multicriteria optimization for IMRT. Phys Med Biol. 2007;52 1845–
1861.
35. Craft D, Halabi TF, Shih HA, et al. Approximating convex Pareto
surfaces in multiobjective radiotherapy planning. Med Phys. 2006;
33(9):3399–3407.
36. Stein J, Mohan R, Wang XH. Number and orientations of beams in
intensity-modulated radiation treatments. Med Phys.
1997;24(2):149–160.
37. Lee EK, Fox T, Crocker I. Integer programming applied to intensity-
modulated radiation treatment planning. Annals of Operations
Research. 2003;119:165–181.
38. Bangert M, Ziegenhein P, Oelfke U. Comparison of beam angle
selection strategies for intracranial IMRT. Med Phys.
2013;40:011716.
39. Trofimov A, Rietzel E, Lu HM. Temporo-spatial IMRT optimization:
concepts, implementation and initial results. Phys Med Biol.
2005;50(12):2779–2798.
40. Heath E, Unkelbach J, Oelfke U. Incorporating uncertainties in
respiratory motion into 4D treatment plan optimization. Med Phys.
2009;36:3059–3071.
41. Bohoslavsky R, Witte MG, Janssen TM, et al. Probabilistic objective
functions for margin-less IMRT planning. Phys Med Biol.
2013;58(11):3563–3580.
42. Unkelbach J, Bortfeld T, Martin B, et al. Reducing the sensitivity of
IMPT treatment plans to setup errors and range uncertainties via
probabilistic treatment planning. Med Phys. 2009;36(1):149–163.
*This section was in parts adapted from the book chapter Boyer A, Unkelbach
J. Intensity-modulated radiation therapy planning. In: Brahme A, ed.
Comprehensive Biomedical Physics, Vol 9, Chapter 17, Elsevier; 2014.
*This section was in parts adapted from the book chapter Boyer A, Unkelbach
J. Intensity-modulated radiation therapy planning. In: Brahme A, ed.
Comprehensive Biomedical Physics, Vol 9, Chapter 17, Elsevier; 2014.
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10 Intensity-Modulated Proton
Therapy
Tony Lomax
INTRODUCTION
Proton therapy is becoming an increasingly relevant modality in
radiation therapy. In a recent review of proton therapy facilities
worldwide, it was reported that there are more than 50 particle therapy
facilities now in operation, with at least another 50 being built or in an
advanced stage of planning. Consequently, by the end of 2018, the
number of particle therapy facilities will be quickly approaching 100 or
more, with this trend being very likely to continue. In addition, by the
end of 2015, it is also predicted that, for the first time, the number of
treatment rooms having the capability of delivering pencil-beam
scanning (PBS) will overtake those delivering passive scattering (PS)
(1,2), with the number of PBS rooms being predicted to expand
exponentially in the next years. Thus, it is becoming increasingly clear
that not only will proton therapy become a mainstream cancer
treatment, but that PBS will be the particle therapy modality of choice in
the future.
There are two main reasons for this paradigm change in proton
therapy. First is the inherent automation of the PBS approach in
comparison to PS, and second is the ability of PBS to deliver the so-
called intensity-modulated proton therapy (IMPT). The treatment
planning aspects of PBS and IMPT will be the focus of this chapter.
BASIC PHYSICS OF PROTON INTERACTIONS
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Before looking at the treatment planning process for PBS, it is first
necessary to briefly review the physics of proton interactions with
matter and the basic characteristics of the PBS approach.
Energy Loss and Scattering

Typical depth dose curves for quasi monoenergetic proton beams are
shown as red curves in Figure 10.1. As can be seen, in contrast to the
depth–dose curve for photons, this is characterized by a relatively low
entrance dose, which gradually increases with penetration and
culminates in the well-known Bragg peak. At the distal (far) end of this
peak, the dose drops off very quickly. This characteristic is determined
by the inverse square relationship of dose deposition as a function of
particle velocity, which can be analytically described by the Bethe–Bloch
equation
where dE/dz is the rate of change of energy of the proton (equivalent to

the deposited energy to tissue) and β is the velocity of the particle
represented as the fraction of the speed of light (3). As such, in
comparison to photon beams, where the depth dose characteristics are
predominantly determined by photon absorption, the proton curve is
characterized by energy loss of the protons, which leads to the well-
defined range and shape of the Bragg peak in tissue. Thus, the higher the
initial energy, the deeper the Bragg peak, while the lower the energy,
the shallower its range, at least if both are applied to the same medium.
However, the absolute range of the Bragg peak is also dependent on the
physical characteristics of the medium, and is determined by the
medium’s stopping power to protons. Typically, this is defined relative to
water (when it is then referred to as the relative proton stopping power).
Indeed, to a good approximation, this is a linear relationship, with the
geometric range in a medium with a relative stopping power of two
being half that of the range in water.
In reality of course, it is impossible to deliver perfectly monoenergetic
proton beams, with most clinical beams having an energy spectrum
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(usually referred to as the momentum band) of about +/–1%. This will
tend to broaden the Bragg peak above that of the pure energy loss curve
given by the Bethe–Bloch equation. In addition, as energy loss is a
statistical process, there is an additional broadening of the Bragg peak
due to statistical smearing, an effect referred to as range straggling.
Although a complex process, the amount of range straggling is
dependent on the range of the proton beam (and therefore the energy)
and can be approximated as broadening the width of the Bragg peak by
about 1% of its range (4).
In addition to energy loss, protons also undergo scattering processes,
mainly due to multiple Coulomb scattering (MCS) events (electrostatic
deflection of the protons as they pass close to the positively charged
nuclei of atoms). For instance, the additional broadening of a proton
pencil beam with an initial energy of 177 MeV (range in water ∼21 cm)
due to MCS will be about 4 mm (σ) at the BP. However, due to the
resulting divergence of the beam after such scattering, this broadening
can be much larger if the beam subsequently passes across air gaps (5)
or through regions of low density in the patient (6). This is an important
characteristic that needs to be taken into account during the treatment
planning process.
FIGURE 10.1 The concept of the “Spread-Out-Bragg-Peak,” showing how range (energy) shifted
Bragg peaks can be modulated in order to deliver a homogeneous depth–dose profile.
This angular-spatial divergence of a proton beam is generally

represented using Fermi–Eyges transport theory. Although quite
involved mathematically, in its simplest form, the doubled spatial
variance of a narrow proton beam can be represented in the form (5):
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where A′2,x describes the doubled spatial variance of the beam width in
the lateral x direction at position z (beam width in air plus MCS
scattering in the medium) and A0, A1, A2 are the moments of the
angular-spatial distribution of the beam in air. The term in brackets and
the integral represent the additional scattering due to MCS in the
medium. From these, the width (σ) of the beam in the medium, at
distance z, is then given by:
A similar equation is used for the y direction. For a detailed

description of scattering theory of protons, the reader is referred to
Gottschalk et al. (7) and Safai et al. (5).
NUCLEAR INTERACTIONS
Whereas energy loss and scattering are the primary interactions of
protons with matter, there are also secondary processes that can have a
significant effect on calculated and delivered PBS fields. As protons
penetrate tissue, there is a small, but finite probability that they will
interact directly with an atomic nucleus, either in an elastic or inelastic
way. In the first, this will lead to a potentially wider deflection of the
proton, whereas in the second process, the proton will be absorbed from
the beam and secondary particles produced. This loss of proton fluence
as a function of depth is small (about 1% per centimeter of penetration
in water (4)), but nevertheless leads to a 20% loss of proton fluence at
the Bragg peak for an initial energy of 177 MeV. In addition, the
secondary particles and their trajectories can lead to an “extension” of
the lateral, low-dose tail of the beams profile, together with a generally
forward projected background of secondary neutrons. For a more
detailed description of proton interactions with matter, the reader is
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referred to the publications of Gottschalk (3) or Lomax (8).
LET and RBE

Before moving on to the technicalities of PBS, two more, somewhat
related properties of proton beams should be mentioned, namely linear
energy transfer (LET) and relative biological effectiveness (RBE). Let’s
first look at RBE.
There is plenty of evidence from in vitro cell experiments, that the
biological effectiveness of protons for the same applied physical dose is
somewhat higher than for photons. The reader is referred to the papers
by Paganetti et al. (9,10) for an excellent review of this. This enhanced
biological effect is defined as the RBE, and depending on the cell line
and end point can vary from 0.9 to 1.8 or even higher. It has also been
demonstrated that RBE tends to be highest for the lowest energies (i.e., in
the Bragg peak) and also increases as dose reduces. Despite this, most
proton centers still assume a global RBE of 1.1 to biologically “scale”
proton doses to allow for an average RBE effect.
In contrast to RBE, LET is a physical quantity that is, in principle
directly measureable. As such it can be more precisely defined and
related back to the underlying physics. In short, LET is a measure of the
local linear energy deposited to tissue and has the units of keV/μm. In
regions where protons are losing (depositing) energy rapidly, the LET
will be higher than where energy deposition is less intense. Thus, LET is
higher in the Bragg peak and distal fall-off region than in the plateau,
mainly due to the inverse relationship of energy deposition with particle
energy. In addition, although the relationship between LET and RBE is
complex, there is a clear correlation between higher LET and increased
RBE, and thus LET can be considered a good surrogate (but not a direct
predictor) for RBE.
PENCIL BEAM SCANNING

Pencil-beam scanned (PBS) proton therapy is a conceptually simple
technique (11,12), and is shown schematically in Figure 10.2. As protons
(and other particles used for therapy such as carbon and helium ions)
have a charge, they can be easily deflected by magnetic fields. Thus, if a
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narrow beam of particles can be produced (a pencil beam), this can be
scanned laterally to the incident field direction such as to paint dose over
the target volume. If this is performed using a near monoenergetic beam,
this will deliver what is called a single energy layer, or a surface of Bragg
peaks, all with the same range in a uniform medium such as water.
However, as should be clear from Figure 10.1, the delivery of a single
monoenergetic layer will not necessarily ensure the delivery of a
homogeneous dose throughout the whole tumor. Thus, a full PBS field
will typically consist of a number of such layers, each modulated in
energy in order to “fill-in” the missing dose along the field direction.
FIGURE 10.2 Schematic representation of the pencil-beam scanning approach. Energy

modulated Bragg peaks are scanned across the tumor volume, with the delivered fluence at each
BP also being modulated.
In a one-dimensional sense, such a combination of individual, energy-

modulated Bragg peaks, combined in such a way as to deliver a
homogeneous dose in depth across the tumor volume, is called a
“Spread-Out-Bragg-Peak” (SOBP) (1), an example of which is shown as
the blue curve in Figure 10.1. Although a key aspect of passive scattered
proton therapy, the SOBP concept actually has little meaning in PBS
other than to indicate that, typically, the Bragg peak weights (fluences)
at the distal end of the field will tend to be higher than those at the
proximal end. Instead, it is much more meaningful to think of a PBS field
as a set of three-dimensionally distributed, individually weighted Bragg
peaks, the position and calculation of which are free variables which can
all be manipulated to define PBS treatment fields and plans.
In the rest of this chapter we will use both pencil beam and Bragg peak
to describe the individual elements delivered as part of a PBS proton
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field. However, Bragg peak (BP) will be used to specifically refer to the
“spot of high dose” in and around the Bragg peak, whereas pencil beam
will refer to the whole pencil beam, from the exit of the nozzle to the
Bragg peak.
THE TREATMENT PLANNING PROCESS

In common with other forms of radiotherapy, the goal of the treatment
planning process is to design clinically acceptable treatments by
predicting a three-dimensional distribution of the delivered dose in
relation to patient anatomy. As such, the overall planning process for
PBS and IMPT is identical to that of conventional therapy, and will be
briefly outlined here, if only to define the subsequent structure of this
chapter.
From the physics point of view, a fundamental basis for any treatment
planning system is a succinct and accurate description of the
characteristics of the treatment system to be modeled (beam model). This
will be used as input into a dose calculation engine, which can then
calculate a three-dimensional prediction of the delivered dose to the
patient. In addition, modern treatment planning is unimaginable without
a physical model of the patient in the form of volumetric x-ray CT data.
For reasons discussed below, this is even more important for proton
therapy. However, as with conventional treatments, it is more or less
standard of care in proton therapy to also use MRI and, if available, PET
to help with the delineation of the tumor and organs at risk (OAR). As
such, once all relevant imaging data has been imported into the planning
system, the task of target/organ delineation is essentially the same as for
conventional approaches, even if there may be some differences in the
definition of the PTV or ITV, as discussed in more detail below.
Once all structures have been defined, the next task is to define one or
(more usually) multiple fields such as to best “focus” the high-dose
volume on the target, while ensuring that dose constraints to critical
organs are likely to be met and that any physical limitations on field
directions are, where possible, observed. Once the fields have been
defined, then each field needs to be shaped and optimized. Finally, when
a full plan has been calculated, the quality of the plan needs to be
evaluated, both clinically and also from the point of view of its
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robustness to potential delivery uncertainties. Each of these steps will be
discussed in more detail in the following sections.
Beam Modeling
Before any form of predicted dose in a phantom or patient can be
calculated, a parameterization of the characteristics of the delivery
machine and radiation modality must be performed. Typically, this is
called beam modeling and can be broken down into two main
components; the definition of a set of energy-dependent depth dose
curves and a corresponding representation of the angular-spatial
distribution of the beam for each energy (see Equation 10.2).
For the dose calculation, the energy-dependent depth dose curves are
usually represented as integral depth dose curves. That is, the dose at any
depth is the integral dose deposited at that depth in an infinite plane
perpendicular to the incident direction of the beam. Although based on
measured data, such depth dose curves are generally converted into a
numeric representation (such as a depth-dependent look-up table) using
analytical or empirical fitting algorithms (13,14). In contrast, the beam
width is dependent on two components—a model for MCS in the
medium (represented by the integral part of Equation 10.2) and an
analytical representation of the beam width in air (the A0, A1, A2
parameters in Equation 10.2). Although beam broadening due to MCS is
determined solely by physics considerations, the beam width in air will
need to be measured and the A parameters then derived from these
measurements using data fitting techniques. However, in addition to
being dependent on energy, for scanning gantries, beam width in air
could well be also dependent on both the beam deflection and gantry
angle.
Dose Calculations
Analytical Calculations—Primary Dose
Although it is likely that Monte Carlo (MC)–based dose calculations will
become more prevalent in the future, most dose calculations for
treatment planning of PBS proton therapy are analytically based.
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Although such approaches are inherently limited in their accuracy, they
are also inherently fast. Even with today’s computer power, this is still a
big advantage over MC techniques, especially when being used for
optimization (see below).
All analytical dose calculations for the primary dose for PBS proton
therapy (we will return to approaches for incorporating the distribution
of secondary particles resulting from nuclear interactions later) are
based on a parameterization of a physical, or calculational, pencil beam
in the following form:
where d(x, y, z) is the dose at calculation point x, y, z, with x and y

being the distances of the dose calculation point away from the central
axis of the pencil beam, z is the coordinate of the dose calculation point
along the beam direction, D(WER(0,0,z)) the integral dose deposited at
depth WER(0,0,z), 0, 0, z is the WER at distance z along the central axis
of the pencil beam and σx(z) and σy(z) are the beam widths in the two
directions orthogonal to the beam direction at distance z along the beam
direction. σx(z) and σy(z) can be derived from Equations 10.2 and 10.3.
In essence, the first quotient gives the central axis dose at position z,
whereas the two exponents correct for the off-axis position of the point
away from the central axis (x and y), and can therefore be considered as
providing the off-axis ratios for the pencil-beam dose.
Equation 10.4 is all that is really needed for calculating primary dose
in water and is remarkably accurate, as long as the beam model
parameters (depth dose curves, in-phantom MCS and phase space) are
correctly parameterized. However, when calculating in patient
geometries, methods of dealing with density heterogeneities also have to
be included.
Perhaps the simplest method of dealing with density heterogeneities is
the ray casting approach described in the paper by Schaffner et al. (15).
In this, Equation 10.4 is slightly modified such that D(WER(0,0,z))
becomes D(WER(x,y,z)), indicating that the WER of the dose calculation
point itself determines the depth at which the integral dose is extracted
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from the depth dose curve, rather than that of the central axis of the
pencil beam. Thus, off-central-axis density heterogeneities can be
incorporated into the calculations, allowing for estimations of the
distorting effects of density heterogeneities on the pencil beam. In fact,
as this approach neglects the effects of proton scattering after the density
heterogeneities, it actually overestimates the effects of these.
Nevertheless, this algorithm is still the one used clinically at PSI, and all
dose distributions in this chapter (Fig. 10.3) have been calculated using
this approach.
A more sophisticated approach (but not necessarily more accurate in
all circumstances) is to decompose the physical pencil beam into a set of
smaller, calculational pencil beams and then apply Equation 10.4 to
each individual calculational beam. This approach has been proposed by
both Schaffner et al. (15) and Soukup et al. (16). In the Schaffner
approach, the total fluence contribution from the sum of all pencil
beams for a given energy layer is first calculated, with this fluence
envelope then being decomposed into a set of narrow, calculational
beams for the calculation. This approach has the advantage of efficiency,
but is not convenient for the optimization, as the correlation between
calculational and physical pencil beams is lost. Soukup’s approach then,
although less efficient, is more appropriate for the optimization step. In
addition, Soukup et al. also proposed the calculation of the multiple
scattering angle on a voxel by voxel basis along the beam direction,
rather than using a precalculated look-up table of beam broadening in
water, in order to better model the effect of the position of density
heterogeneities along the beam direction. Similarly, Szymanowski and
Oelfke (17) have proposed to mitigate this problem using a material-
specific lateral scaling factor.
Analytical Calculations—Secondary Dose

As discussed above, a small but clinically relevant component of a
proton dose distribution is due to secondary particles resulting from
interactions of the primary protons with atomic nuclei. As such, a
number of corrections to the basic primary dose algorithms described
above have been proposed.
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FIGURE 10.3 Example cases treated with PBS at PSI. (A) Skull base chordoma. (B)
Ependymoma. (C) Meningioma. (D) Sacral chordoma. Arrows indicate the field directions. Green
are coplanar, yellow noncoplanar.
The earliest of these is that of Pedroni et al. (13), who attempted to

represent this secondary component using a two Gaussian model of the
following form:
where d(x,y,w) is the dose at point x, y with depth w, D(w) is the integral
dose at depth w, fNI is the fraction of the total integral dose at depth w
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resulting from secondary particles, Gp is the Gaussian distribution of the
primary beam, σp is the beam width of the primary beam, GNI is the
Gaussian distribution of the secondary particle distribution and σNI is the
width of the secondary distribution. In this work, values for fNI and σNI
were determined experimentally using a series of “frame” fields of
different sizes with a thimble detector in the middle of each frame to
measure the resulting peripheral dose. From these, values for fNI and σNI
could be deduced. Soukup et al. (16) proposed a similar approach, but
based on MC simulations of the secondary dose in water, from which
they could then deduce an analytical model of this distribution.
Although the fraction of dose delivered by secondary particles is small,
their contribution is nevertheless important for correctly predicting
absolute dose (as reported in the paper by Pedroni et al.), and if
neglected, can lead to an overestimation of the dose at the edge of a
homogeneous field or an underestimation of the dose in “dose-valleys”
in highly modulated IMPT fields, as shown in Figure 10.4.
Monte Carlo Dose Calculations

It is undisputed that the most accurate dose calculations available are
MC methods. In short, these model the transport and interactions of
individual protons, that are tracked through the patient geometry (and
sometimes the whole-beam line and gantry), using knowledge about the
underlying physics, together with probabilities of the various
interactions that protons can undergo. As they track individual,
simulated protons, MC calculations do not have many of the limitations
of analytical calculations, and as such can be considered to be the gold
standard for the calculation of dose for PBS proton therapy.
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FIGURE 10.4 The effects of secondary particles. Primary dose calculation (solid line) and the
corrected dose taking into account secondary particle distributions. Note the reduced dose at the
field edges (left) and increased doses in dose “holes” (right).
There are currently a number of different MC codes available that

have been used for proton therapy calculations, the main ones of which
are FLUKA (18), GEANT4 (20), MCNPX (21), VMCPro (22), and Shield-
HIT (23). All have their advantages and disadvantages, with some
having more accurate modeling of various interactions than others.
Nevertheless, none of these codes are necessarily easy to use without
considerable knowledge of the code and underlying physics, and as such,
MC calculations have been slow to get into clinical use, except in
departments with specialized staff. This is changing somewhat now with
the development of MC tool kits specifically designed for RT applications
and with simplified interfaces for ease of programing and specification.
Perhaps the most widespread of these at the time of writing is the
TOPAS system (24), which is based on GEANT4 and has been widely
validated for proton therapy applications by the group at Massachusetts
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General Hospital and elsewhere (25).
The drawback of MC calculations is still the time required for accurate
calculations, with MC calculations typically taking many hours to run.
However, methods are being developed to improve efficiency through
the use of, for example, track repeating algorithms (26) or
implementation on graphical processing unit (GPU) hardware. With such
measures, full MC calculations are now being performed in a few
seconds with clinically acceptable statistics (18,27).
Imaging for Treatment Planning

Although MRI, PET, and other imaging modalities can all be of great use
for helping to define target volumes and other anatomical structures for
the treatment planning process, the core dataset for treatment planning
for PBS proton therapy is x-ray CT. This is currently the only imaging
modality that can be accurately converted into the relative proton
stopping powers required for accurate dose calculations in the patient.
As such, it is important that the CT data set to be used for dose
calculations is as good a quality as possible. This does not necessarily
mean that the CT has to have the best resolution, but more that the
Hounsfield units (HU) of the CT are correct.
X-ray CT gives a three-dimensional model of the patient in terms of x-
ray attenuation, and as such needs to be converted into relative proton
stopping power. This is a nontrivial and nonunique process. Although a
number of methods of performing this calibration have been reported
(28–30), the most widely used calibration procedure is that of Schneider
et al. (29), referred to as the stoichiometric calibration. As the name
implies, this approach is based on knowledge of the densities and
chemical composition of the mediums to be calibrated. Unfortunately,
there is no unique and one-to-one relationship between HU and proton
SP, with different materials with the same HU value having different
proton SP and vice versa (29). As such, clinically applied calibration
curves are defined based on biologically relevant tissues (29–31) and are
thus, strictly speaking, only valid when applied to patient tissues.
Although on first site this may appear not to be a problem, it can be an
issue when treating through nonbiological materials such as the table
couch or metal implants (6,32). In such cases, it may be necessary to
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override the HU or SP values in the planning CT in order to ensure that
the correct SP is used for the dose calculations. More details on this issue
can be found in Lomax et al. (6) and Kruse (32).
Thus, planning CTs for proton therapy should be acquired under strict
imaging protocols, such that the acquisition parameters for the images
are exactly those used for the calibration curve to be used in the
planning system. Under these conditions, the HU–SP calibration can be
accurate to about 1% in soft tissues and 2% to 2.5% in bones (31,33).
However, allowing for other imperfections in CT data (beam hardening,
partial volume effects, etc.), it is generally recommended that a range
uncertainty of 3% to 3.5% be assumed from the CT imaging/calibration
process alone.
Such range uncertainties are what can be assumed in the case of high-
quality CT data, that is, CT data that is well calibrated and “clean.” In
this context, “clean” refers to CT datasets that are free of substantial
reconstruction artifacts. For CTs in which high-density implants are
present, however (e.g., postsurgical implants, teeth fillings, implanted
fiducial markers), reconstruction artifacts can be substantial and thus
cannot be ignored (34,35). Simply put, artifacts resulting from
reconstruction problems provide the wrong HU values for the underlying
tissues, and will obviously then provide the wrong stopping powers for
proton range and dose calculations. As such, it is imperative that the
degrading effects of such artifacts are mitigated as much as possible for
treatment fields which pass through them.
There are two main ways of doing this. The first, and the
recommended approach, is to try to reduce such artifacts at the imaging
stage. This can be done for instance by using dual-energy CT, which has
been shown to reduce reconstruction artifacts around metal implants
substantially (36,37) or by using artifact reduction methods during the
image reconstruction process (38,39). The second approach is to
manually correct the artifacts in the planning CT, by outlining the most
obvious regions of corrupted HU values and manually setting these
regions to average HU or SP values appropriate for the presumed
underlying tissue. Although certainly not optimal, this approach has
recently been shown to significantly improve the agreement between
planned and delivered doses when measured in an anthropomorphic
phantom (40) and is considered as the absolute minimal approach to
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artifact mitigation for proton therapy. Indeed, as artifact reduction
algorithms and dual energy acquisitions are not perfectly effective, it
may still be necessary to perform manual stopping power corrections to
correct for residual artifacts even when using these techniques.
Structure Definition
The definition of both target and normal tissue structures for PBS proton
therapy is an essential part of the treatment planning process and is, to a
large extent, the same across all external-beam radiotherapy techniques.
Certainly, there is no reason why GTVs or CTVs for a given indication, as
well as OAR and other anatomical structures, should be any different for
PBS proton therapy than for conventional therapies. However, given the
potentially different lateral penumbra of proton fields, together with the
additional uncertainty in range, there may be good reasons why PTVs
could be different for PBS proton therapy.
PTV margins should be determined based on the estimated magnitude
of random and systematic errors during the delivery. For proton therapy,
these need to be determined both from positioning errors (which will
mainly determine the lateral margin) and range uncertainties, which
should ideally determine the distal margin. Given that these
uncertainties will not necessarily have the same magnitude, and are
likely to be of a different nature (e.g., positioning errors will likely be
random, whereas the main sources of range uncertainty will be
systematic (41,33)) it can be argued that PTVs for PBS should be field
rather than target specific, with different margins being defined laterally
to those defined distally and proximally (42,43). In practice, however,
this may not be a practical approach, particularly if field-specific
margins are not easily supported in the treatment planning system.
Indeed, at our institute, conventional, isotropic PTV margins of 4 to 7
mm are routinely used. These have been calculated based on an analysis
of our positioning uncertainties for different sites (44), and using an
estimated uncertainty in range of 3% (see above). As it turns out, this
leads to lateral and distal/proximal margins of similar values, at least for
centrally located tumors in the brain. Nevertheless, field-specific PTVs
may become more prevalent in the future as more sophisticated and
automated tools become available.
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Beam Selection and Plan Design
Due to its ability to deliver a more or less homogeneous distribution to
the target from a single direction (see Fig. 10.1), it is not absolutely
necessary to treat with multiple fields, even if this is highly
recommended. This characteristic of proton therapy has a number of
consequences. First, the number of fields for a typical proton plan can be
quite small, and second, there is a lot of flexibility in the choice of these
directions as all can, at least theoretically, deliver a homogeneous dose
to the target. In practice, however, there are a number of issues that
should be taken into consideration when selecting field directions, which
will be briefly outlined in this section.
The most obvious consideration is the avoidance of critical structures.
Although all normal tissues in a patient can be considered “critical” in
one way or another, some tissues are more critical than others, and one
of the easiest ways of ensuring that dosimetric constraints are met is to
avoid bringing treatment fields through these. This can be achieved by
avoiding the structures with the lateral edge of the field and, given the
stopping characteristics of protons, also by use of the distal dose fall-off.
Due to worries about range uncertainty and increased LET/RBE at the
distal end of the field however, it is currently considered bad practice to
directly stop a proton field against critical structures which may be
sensitive to small volumes of large dose, such as the spinal cord or
brainstem. On the other hand, if there is a reasonable distance between
the distal edge of the field and the critical structure (in this context a
“reasonable distance” is difficult to precisely define, but will depend on
the estimated range uncertainty for the field), using the distal field edge
to “shield” a critical organ is perfectly acceptable, and is often the best
way of realizing the power of proton therapy.
The second consideration is the avoidance of coarse and complex
density heterogeneities. These should be ideally avoided for the
following three reasons; potential problems with the dose calculation
accuracy, limitations with dose homogeneity and conformity, and
sensitivity to potential set-up errors.
The Bragg peaks and SOBP shown in Figure 10.1 are that expected for
proton beams delivered to a perfectly homogenous medium such as
water. However, if delivered to a material that is density
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inhomogeneous, then these curves can look quite different. For instance,
when a pencil beam partially intersects with a density heterogeneity,
then different portions of the beam will “see” different material
densities, thus affecting the range of those portions of the beam. As such,
the beautiful, sharp Bragg peaks shown in Figure 10.1 becomes degraded
and distorted into a broader, more irregular shape with often a much
degraded distal fall-off.
FIGURE 10.5 Degradation of the distal fall-off for a PBS proton field passing through complex
density heterogeneities.
Such an effect is shown in Figure 10.5. For this field, one can observe
that the distal end of the field does not conform well to the distal end of
the target due to the distorting effect of the density heterogeneities. In
addition, as shown by the color bar on the right side showing the dose
banding, the maximum dose in this field is quite high (138% of the
mean dose delivered to the target). This is also a consequence of the
distortion of the Bragg peaks for this field, which the optimization
process cannot fully compensate. Indeed, the dose conformity and
homogeneity of this field should be compared to that of the single field
shown in Figure 10.6B. The field in the latter figure is traversing a
particularly homogeneous part of a patient’s anatomy (only skull and
brain), and thus the shape of the Bragg peaks are preserved, leading to a
much more homogeneous (a maximum dose in the field of only 106% of
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the mean target dose) and distally conformal distribution. This distorting
effect of density heterogeneities on pencil beams is one reason why they
should ideally be avoided.
The second reason is the sensitivity of such field directions to potential
positioning and set-up errors. To explain this, once again consider Figure
10.5. Clearly, the position of the “tongues” of dose extending beyond the
distal edge of the target volume are correlated with the position of the
density heterogeneities and as such, their position in relation to the
patient’s anatomy will change due to any misalignments, particularly
rotational, of the patient in relation to the delivered beam.
In summary then, it is advisable to try to avoid field directions that
avoid complex density heterogeneities, while picking directions that
avoid critical structures. In practice however, following these guideline
religiously is simply not possible, and one or other (if not all) guidelines
may have to be compromised depending on the case and anatomy.
Nevertheless, they are worth keeping in mind in plan design wherever
possible.
FIGURE 10.6 Optimization for PBS proton therapy. (A) Optimized Bragg peak positions and
fluences (colours) for a single field planned to an Ependymoma case. (B) The corresponding,
optimized dose distribution.
Field Shaping and Optimization
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In this section, we will delve a little deeper into the planning process for
PBS proton therapy, by discussing the details of how the individual fields
are defined and shaped such as to efficiently deliver a clinically relevant
dose to the target volume. This process is termed “field shaping,” and
has been recently described in detail by Zhu et al. (45).
Bragg Peak Placement

The basic process of field shaping for PBS proton therapy is shown in
Figure 10.7. This shows the stages of shaping a PBS field planned to a
central brain ependymoma using the in-house treatment planning system
developed at our institute (46,47). Figure 10.7A shows the originating
planning CT and defined structures for this case, with the PTV displayed
as the green contour, whereas Figure 10.7B shows a three-dimensionally
distributed set of BP positions (the red crosses) for a posterior field
applied to this patient before any field shaping has been applied, with
this distribution of BPs essentially providing the starting conditions for
the field-shaping process.
In order to get the distribution of BPs shown in Figure 10.7B, at least
two parameters for the field and/or delivery machine must be known or
defined. These are the spot spacing and energy resolution or spacing. For
the case shown in the figure, spot separation refers to the spacing
between BPs/pencil beams in the two directions orthogonal to the beam
direction—so along the horizontal (lateral) axis in this case, as well as in
and out of the plane of the image. The energy resolution then determines
Bragg peak separation along the beam direction. For the case shown,
energy resolutions of 3.5 MeV and a spot spacing of 5 mm have been
used. Such a lateral spacing is the standard spot spacing used for our
treatments at PSI and, although a field-specific parameter in our
planning system, is more-or-less a standard for all types of treatment at
our institute. This separation has been determined such that there is a
sufficient overlap between the narrowest spots deliverable by our
machine (about 3 mm σ) such as to deliver a homogeneous (ripple free)
lateral profile. Using the definition of spot spacing defined by Zhu et al.
(45), this corresponds to an α of about 0.7 for the narrowest beam
dimension (where the spot spacing, s, is related to the full-width-half-
maximum (FWHM) of the beam by the relationship s = α FWHM, see
Zhu et al.)
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The next step in field shaping is to define the sub-set of BPs that will
deliver useful dose to the tumor volume, by selecting just those BPs that
are within the target volume, or a short distance outside. This sub-set of
BPs is shown in Figure 10.7C, where all BPs internal to the selected PTV
(green contour) have been selected, together with BPs within 5 mm of
the PTV surface. This reduced set of BPs is what can now be referred to
as the shaped field. As a note, the extra, external BPs are required in
order to ensure that the high-dose area of the final dose distribution
extends to the target volume surface. In addition, the sub-set of BPs
shown in Figure 10.7C has also been assigned an initial weight (fluence)
as indicated in the figure by the color coding of the BPs and the color
bar on the right-hand side. As we will see in the following section, this
initial set of weights will not typically provide a homogeneous dose to
the field, necessitating an optimization step in the planning process.
Fluence Optimization
The BP fluences shown in Figure 10.7C have been assigned using a
precalculated, one-dimensional weighting scheme based on the SOBP
concept (see Fig. 10.1). Such fluences, if assigned to a PBS field planned
to a rectangular box in water, would then provide a homogeneous dose
across the target, and indeed such fields are a way by which a PBS
machine can emulate PS (48). However, when applied to an irregular
target in a nonhomogeneous patient with a nonflat skin surface, then
this simple fluence assignment approach is insufficient, as can be seen in
Figure 10.7D. This shows the dose distribution resulting from the set of
BP and fluences shown in Figure 10.7C, calculated using the ray-casting
analytical approach (see above). Although the 95% isodose covers most
of the PTV in the slice shown, there are clear areas of under-dosage
(<<95%) at the edge of the PTV. In order to improve this situation, an
optimization of the fluences is required, by which the fluence of each
selected BP in the field is iteratively modified, with the goal of making
the resultant dose distribution as homogeneous as possible across the
target volume.
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FIGURE 10.7 Field shaping for PBS proton therapy. See main text for details.
The optimization process used for this step is essentially the same as
that used for other applications in radiotherapy (e.g., IMRT) and is based
on minimizing the following function:
where N is the number of dose calculation points and Pi and Di are the
prescribed and calculated doses at point i.
There are numerous ways of going from this simple relationship to the
actual update functions applied to each pencil beam per iteration (49),
but the one we will show here is that used in our planning system at PSI
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and that was originally derived for IMPT optimization (50). This has the
following form:
In this, wj,k and wj,k-1 are the weights of the jth pencil beam at
iterations k and k -1 respectively and di,j is the dose delivered by pencil
beam j at dose calculation grid point i. Pi and Di are as in Equation 10.6.
As noted by Lomax (50), this formulation has the advantage that pencil-
beam weights can never go negative as part of the optimization process.
For a detailed derivation of Equation 10.7, the reader is referred to
Albertini et al. (51).
The result of applying Equation 10.7 to the case shown in Figure 10.7
is shown in Figure 10.6. Figure 10.6A shows the fluences, modified as a
result of the optimization process, after 60 iterations, while Figure 10.6B
shows the final dose distribution. The 95% dose now almost perfectly
encompasses the PTV, and there are no regions with doses above 106%.
When applied (as in this case) to a single field with the sole constraint
of obtaining a homogeneous dose across the target volume, this
approach is called “Single Field, Uniform Dose” or SFUD. This does not
however mean that this approach only ever uses one field for a plan, but
rather that multiple field plans can be designed by combining one or
more such fields, each optimized individually as described above. As an
example, a three-field, SFUD plan for the same case is shown in Figure
10.8. About 60% of all PBS treatments at our institute are planned and
delivered using such an SFUD approach.
An alternative approach is to perform the optimization for all pencil
beams of all fields simultaneously, a technique called IMPT or multiple
field optimization (MFO). In this case, additional constraints are also
typically added to the optimization, such as dose constraints to one of
more critical structures, and Equation 10.6 above is then expanded a
little to the following (see Unkelbach et al. (52)):
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Now, WPTV and WOAR are weighting factors defining the relative
importance of target coverage and critical structure sparing, and PPTV
and POAR are constraint doses for the target and critical structures,
respectively. Note that in this formulation, the last (OAR specific) sum is
only performed over the dose calculation points where the dose
constraints for the organ are exceeded (so over the sub-set of N′OAR
points only). An update function similar in form to that of Equation 10.7
can then be derived that will optimize all pencil beams of all fields
together, under the constraints of both maximizing target dose coverage
and homogeneity, and reducing doses to critical structures to below the
predefined dose constraints.
An example of a four-field IMPT plan to a skull base chordoma is
shown in Figure 10.9, once again showing the dose distributions for the
individual fields, together with the full plan doses. Note the difference in
the form of the individual fields of Figure 10.9 to those in the SFUD
example above (Figure 10.8). The “single field, uniform dose” constraint
of SFUD has now been relaxed, with the result that the dose distributions
of the individual fields have become very inhomogeneous and complex,
but with the advantage that the dose can be selectively “carved-out” of
neighboring critical structures such as the brainstem and optic nerves. As
examples of the type of SFUD and IMPT plans that can be achieved using
PBS proton therapy, a selection of cases treated at our institute in the
last years are shown in Figure 10.3.
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FIGURE 10.8 The individual fields (A-C) and full SFUD plan (C) for an example ependymoma
case.
FIGURE 10.9 The individual fields (A-D) and full IMPT plan (E) for an example skull base
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chordoma case.
Field-Modifying Devices
In all PBS treatment gantries, there is a lower limit on the transportable
beam energy. This is typically about 70 MeV, but can be as high as 100
MeV on some machines. The range of 70 MeV protons is roughly 4 cm in
water, and thus this determines the minimum range of BP that can be
delivered to a patient without additional modulation of the beam.
A minimum range of 4 cm is extremely limiting. For instance, for some
pediatric cases (e.g., orbital rhabdomyosarcomas), the maximum required
range may only be of the order of 4 to 5 cm, thus making such tumors
untreatable with PBS proton therapy without measures for reducing the
minimal deliverable energy. In addition, in an analysis of over 3,800
delivered fields at our institute, covering a whole range of treatment
sites and tumor types, it was found that over 30% of all BPs in these
fields were delivered with a range of 5 cm or less. Thus, the delivery of
low-energy/low-range pencil beams is an important issue. And it is for
this reason that all PBS proton treatment facilities have the ability to
insert a preabsorber into the beam.
Unfortunately, the use of such a preabsorber is not without its costs.
As with any medium through which protons pass, MCS will occur,
broadening the beam as it passes through the preabsorber. If the
preabsorber could be placed directly on the patient surface, this
wouldn’t be a major problem, as the broadening of the beam due to the
4 cm of preabsorber alone is relatively small. However, when the
preabsorber is mounted in the treatment nozzle, it is extremely difficult
to get it very close to the patient, and inevitably there will be a gap of a
few centimeters between it and the patient. Indeed, depending on the
geometry of the nozzle, the anatomy of the patient and the type of
fixation devices used (which in the worst case can limit how close the
nozzle can be brought to the patient), gaps of 20 cm or more are not
uncommon. As MCS in the preabsorber doesn’t just broaden the beam,
but also adds an angular divergence as well, the beam geometrically
broadens across this gap, and thus, the larger the gap, the larger the
pencil-beam size on entry into the patient. As an example, for the PSI
Gantry 2, the beam width (in air) at iso-center for a 70-MeV proton
pencil beam (the lowest energy that can be transported through the
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gantry) is about 4.5 mm (σ). However, with a 4-cm preabsorber and a
distance of 31 cm from the exit of the preabsorber to the iso-center, this
increases to over 10 mm (σ) in air. As the lateral penumbra of pure PBS
plans can never be sharper than the lateral fall-off of a single pencil
beam, the consequences on plan quality are hopefully clear. A more
detailed discussion on the problem of treating superficial tumors, and
the use of preabsorbers, can be found in Titt et al. (53), Zhu et al. (45),
and Lomax et al. (6).
Advanced Optimization
Up to now, we have looked at two modes of optimization for PBS plans;
SFUD and IMPT. However, given the number of pencil beams available
to the optimizer (typically thousands to tens of thousands of pencil
beams per field), the optimization problem is inherently degenerate. That
is, there are many different sets of PBS fluences that could give quite
similar dosimetric results. This aspect of SFUD/IMPT optimization is
discussed in detail elsewhere (51,55) and won’t be elaborated on here.
However, the degenerate nature of the optimization process means that
other aspects of field definition and design may be something that can
be exploited.
In Figure 10.6A, one sees that the majority of BPs have generally very
low fluences after the optimization process. Based on this, the question
arises whether these BPs are required, or whether clinically acceptable
plans could be delivered with less pencil beams per field. Indeed, this
idea has been proposed very early on in the work of Deasy et al. (56)
and Lomax (50). In the original paper by Deasy et al., the concept of
distal edge tracking (DET) was proposed, in which BPs are only deposited
at the distal edge of the PTV. Although there is no way that such a
reduced number of BPs in a field can deliver a homogeneous dose from
one field, the use of multiple DET fields, together with IMPT type
optimization, have been shown to be able to deliver clinically acceptable
plans in which the integral dose to normal tissues can also be somewhat
reduced, at least for centrally located tumors (56,57). An expansion of
this work has also been reported by Albertini et al. (51), in which a so-
called “spot-reduction” method was incorporated into the optimization
loop that automatically switches low-weighted pencil beams off,
sequentially reducing the number in the plan as the optimization
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progresses. This approach has been shown to be able to reduce the
delivered BPs for plans with a small number of fields (where the pure
DET approach has too few degrees of freedom) while approaching the
DET approach (and further) for plans with many fields. However, due to
fears about the robustness of such plans to delivery errors (55,58), at the
time of writing, such “spot-reduction” techniques are not used clinically.
Indeed, robustness itself is a parameter that can also be included into
the optimization process, either indirectly or directly. In the work by
Albertini et al. mentioned above, an indirect approach was taken in
which the starting conditions of the optimization “force” the optimizer
to a robust solution. Direct robust optimization methods, on the other
hand, use robustness criteria and measures as additional constraints in
the optimization procedure. More details on this approach can be found
in the literature (52,59–61).
As a last example, it has recently been proposed that LET could also be
an interesting parameter to include in the optimization process (62). In a
way, this is also a type of robust optimization, as the idea is to try to
mitigate the potential effects of enhanced RBE by modulating the LET
and thus make the resulting plan more robust to potential biological
effects.
So there are many additional criteria that could be optimized in
addition to target and critical structure doses, and the optimization
process in PBS proton therapy is clearly a multiple criteria problem. It
should be of no surprise, therefore, that one of the main areas of
optimization research in this area is into multiple criteria optimization
(MCO) techniques (60).
Plan Evaluation
The final stage of the treatment planning process is the clinical and
physics review of the plan, before being released for delivery to the
patient.
For the most part, the clinical review will be very similar to that for
conventional therapy. Certainly, target coverage and doses to critical
structures will need to be reviewed, through both a visual assessment of
the dose distribution in all relevant slices and DVHs. However, given the
potential for increased RBE values in some parts of the plan, then
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perhaps an additional clinical assessment of the plan from the point of
view of RBE should be performed. For instance, are highly weighted
fields stopping directly against a critical structure? If so, is this
acceptable, or should the dose constraints to the structure be reduced to
allow for this? The differences are somewhat more when assessing a plan
from the physical point of view, however.
One area, which we have not discussed in this chapter up to now, is
the effects of delivery uncertainties on PBS proton plans. This has been
an area of considerable research in recent years, and has recently been
reviewed by Mohan and Sahoo (63). We will not go into details here,
other than to outline the two main uncertainties; positional and range.
Positional uncertainties are of course present in any form of external
beam radiotherapy, but are a particular problem for fractionated
treatments. Inevitably, the accuracy of patient set-up over many days
cannot be as accurate as that of a single treatment, despite image-guided
techniques to improve this. In practice, therefore, positioning
inaccuracies of a few millimeters day-to-day have to be expected.
Typically, such uncertainties are managed through the use of a PTV (see
above), with estimation of the potential effects of positional
uncertainties being restricted to evaluating dose coverage of the PTV.
However, more sophisticated approaches to this are now being
developed, allowing for more direct visualization of dosimetric
uncertainties in three dimensions and in relation to the patient
geometry.
Although some of the first work in analyzing treatment uncertainties
was for photon treatments (64), much of the more recent published work
has concentrated on proton therapy, either as a metric for robust
optimization (61,65–67) or for evaluating the robustness of plans outside
of the optimization process (68–71). Many of these provide uncertainty
distributions, estimated by recalculating dose on a number of instances
of the nominal geometry shifted in space to simulate potential treatment
set-up errors. The uncertainty distribution is then calculated at each
point by generating dose error bars at each dose calculation point
through the combination of the multiple dose values into a uncertainty
band, typically by displaying the difference in the maximum and
minimum values of all calculated doses at each point (65,66,68,69).
Although this approach can be used for comparing the robustness of two
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different plans, it is a very conservative approach which basically
assumes that positional errors will be systematic in nature. As such Lowe
et al. (72) have recently modified this approach to also allow for
fractionation under the assumption that set-up errors will generally be
random, which has the effect of reducing the error bars considerably
(Fig. 10.10). In the author’s opinion, this approach provides a more
realistic approximation of likely dose uncertainties resulting from daily
set-up uncertainties and thus provides a more clinically relevant tool for
evaluating (and optimizing) PBS proton plans from the point of view of
robustness.
FIGURE 10.10 Robustness analysis for positional uncertainties for an IMPT treatment to a sacral
chordoma (A). Robustness analysis without fractionation (B) and for 14 fractions (C). Note the
substantial reduction of uncertainty, particularly in the PTV and around the cauda equina.
(Courtesy of Matthew Lowe.)
In additional to positional uncertainties, there are many potential
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sources of uncertainty in the proton range in vivo, as reviewed by Lomax
et al. (6) and Paganetti (33). These include inherent uncertainties in the
CT calibration, potential extensions to the Bragg peak range due to RBE
enhancement, CT artifacts (e.g., metal implants) and anatomical changes
to the patient anatomy during the course of treatment. In contrast to
positioning errors, all these are systematic in nature and thus have a
potentially larger impact on the quality of the treatment than set-up
errors. As such, their incorporation into the optimization procedure (60),
as well as any robustness analysis tools, could be more important than
those of set-up errors. Indeed, IMPT (see Section 8.2) was first used at
our institute in order to make the plan more robust to range
uncertainties (73). It is thus interesting to see that robust optimization
can lead to similar results automatically (60). However, we have found
now that our standard optimization algorithm (i.e., without robustness
criteria) anyway leads to range robust results in many cases, as discussed
by Albertini et al. (58,74). A good example of this is also shown in
Figure 10.9. Although each individual field of this complex plan is
highly inhomogeneous, there are no sharp gradients ranging out on the
brainstem (the main constraining organ in this case), with dose sparing
of this organ being achieved with lateral gradients only. In summary,
there is much still to be done in the understanding and quantification of
plan robustness for PBS proton therapy.
SUMMARY
In this chapter, we have described the main principles of treatment
planning for PBS proton therapy. Given the three-dimensional nature of
the delivery system (i.e., that individual Bragg peaks can be delivered
anywhere in the three dimensions from any single-field direction), PBS is
an inherently flexible and automated method which requires treatment
planning tools that can best exploit its potential. The techniques and
examples in this chapter hopefully do justice to its power.
However, it should be remembered that PBS proton therapy is still
very much in its infancy, with only a few thousand patients having been
treated worldwide. As such, much experience still has to be gained into
optimizing its planning and delivery, and many developments, both
technical and clinical, remain to be done.
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The main areas of such developments in the coming years are likely to
be in exploiting the degeneracy of the optimization problem. The very
fact that this is a degenerate problem implies that the problems we are
currently giving the optimizer to solve are maybe not demanding
enough, and thus there is scope for adding more and more criteria into
the optimization step.
A simple approach is to start using PBS proton therapy for “dose
painting,” the first analysis of which has just been published by our
group (75). Given the number of variables available to the optimization
process, there is a considerable potential for IMPT to more precisely
form deliberately nonhomogeneous dose distributions. Likewise, and as
we understand more about normal tissue responses, and/or have more
access to functional imaging, it could well be that the concept of
“conformal avoidance” becomes more important. That is, the idea of
more precisely “carving-out” dose not from complete organs but from
the main functional parts of the organs. The flexibility and power of
IMPT should have considerable potential for such approaches as well.
Finally, much work still needs to be done in not just optimizing pencil-
beam fluences, but in also optimizing the field-shaping process such as
to either more efficiently deliver treatments, or to use more sophisticated
combinations of pencil beams, such as in the form of, for example, fan-
beams or nonregular distributions of pencil beams that directly follow
the contours of the target volume (76).
These are just some of the possibilities of PBS proton therapy that are
waiting to be discovered.
KEY POINTS
• Beam modeling and dose calculations.
• Field shaping and plan design.
• Optimization of single-field uniform dose and intensity-modulated

proton therapy plans.
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• Plan evaluation and robustness.
QUESTIONS
1. Please select the answer choice that best completes the sentence.
Pencil-beam scanning (PBS) . . .
A. Relies on collimators and compensators for conforming the
dose to the target
B. Delivers individually weighted proton Bragg peaks distributed
in three dimensions throughout the target volume
C. Is dependent on the SOBP concept
D. Is not capable of delivering individually homogeneous field
doses across the target
Dose calculations for PBS proton therapy . . .
A. Have to be performed using Monte Carlo techniques
B. Can be analytical, but only for the primary dose component
C. Can be analytical, but only for the secondary dose component
D. Can be analytical, but at the cost of accuracy
PBS plans…
A. Require many field directions to achieve a high level of
conformity
B. Can achieve good dose homogeneity across the target with just
a few treatment fields
C. Are inherently robust to delivery uncertainties
D. Allow for the same amount of normal tissue sparing as IMRT
Optimization in PBS treatment planning…
A. Can only be performed using MC dose calculations
B. Is far more complex than for IMRT planning
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C. Is a degenerate problem
D. Is not required.
Accurate dose calculations for PBS proton therapy…
A. Can only be performed on MRI data
B. Cannot be performed based on CT data, as it provides the
wrong information
C. Should be performed on good quality CT data using a scanner-
specific calibration curve
D. Requires PET data for calculating range.
ANSWERS
1. B Pencil-beam scanning magnetically scans individual proton
pencil beams across the target volume in combination with
energy changes. As only Bragg peaks within (or very close to)
the target volume are delivered, no collimators or
compensators are needed. In addition, as the fluences of the
Bragg peaks are individually optimized in order to best cover
the target with a homogeneous dose, then the concept of the
fixed, one-dimensional SOBP required for passive scattering is
no longer valid. Finally, as mentioned, in the so-called SFUD
(Single-Field Uniform Dose) mode, the optimization process
ensures that the dose across the target volume is homogeneous.
Therefore, the only correct answer is (B).
2. D All commercial (and noncommercial) treatment planning
systems use analytical calculations for both primary and
secondary dose components rather than Monte Carlo, due to
the substantial advantages in computational speed. Although
there is in doubt the Monte Carlo calculations are more
accurate, no proton therapy facility at the moment is using MC
calculations for their routine treatment planning (other than in
a few centers as an independent check of the calculated plan).
Therefore, the only correct answer is (D).
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3. B For both passive scattering and PBS, it is possible to achieve
homogeneous doses across the target with a single field,
therefore answer (A) is wrong. Due to the problem of range
uncertainties, however, proton plans are not inherently robust
unless specifically designed to be, through careful selection of
beam angles and/or robust optimization. Thus answer (C) is
also wrong. Finally, on average, proton plans reduce the doses
to normal tissues by a factor of 2, and therefore allow for more
normal tissue sparing than for IMRT. Thus, answer (D) is also
wrong. This leaves answer (B) as the only correct answer.
4. C As with Question 3, Monte Carlo calculations are not standard
approaches to proton planning, and may be too slow for the
optimization process. Thus, answer (A) is wrong. Optimization
algorithms for proton therapy are the same as for IMRT, as are
the way in which target doses and OAR dose prescriptions are
defined. Therefore, answer (B) is also not correct. Finally,
optimization is essential for PBS proton therapy, thus answer
(D) is also incorrect. However, the optimization problem is
highly degenerate (due to the number of free variables (pencil
beams) per field that are available to the optimizer), and thus
answer (C) is the correct one.
5. C CT is the only imaging modality currently from which proton
range can be accurately calculated. Thus, the only correct
answer is (C).
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34. Newhauser WD, Giebeler A, Langen KM, et al. Can megavoltage
computed tomography reduce proton range uncertainties in
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35. Jaekel O, Reiss P. The influence of metal artefacts on the range of
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40. Dietlicher I, Casiraghi M, Ares C, et al. The effect of metal implants
in proton therapy: Experimental validation using an
anthropomorphic phantom. Phys Med Biol. 2014;59:7181–7194.
41. Lomax AJ. Intensity modulated proton therapy and its sensitivity to
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treatment uncertainties 1: The potential effects of calculational
uncertainties. Phys Med Biol. 2008;53:1027–1042.
42. Cabal GA, Jäkel O. Dynamic Target Definition: A novel approach for
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45. Zhu XR, Poenisch F, Heng Li, et al. Field shaping: Scanning beam.
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conformal voxel scanning. Radiat Environ Biophys. 1992;31:251–256.
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48. Zenklusen SM, Pedroni E, Meer D, et al. Preliminary investigations
for the option to use fast uniform scanning with compensators on a
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49. Bortfeld T, Buerkelbach J, Boesecke R, et al. Methods of image
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50. Lomax A. Intensity modulated methods for proton therapy. Phys
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51. Albertini F, Gaignat S, Bosshard M, et al. Planning and Optimizing
Treatment Plans for Actively Scanned Proton Therapy. In: Censor Y,
Jiang M, Wang G, eds. Biomedical Mathematics: Promising Directions
in Imaging, Therapy Planning and Inverse Problems. Madison, WI:
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52. Unkelbach J, Craft D, Gorissen BL, et al. Treatment plan
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optimization in proton therapy. In: Das I, Paganetti H, eds. Principle
and Practice of Proton Beam Therapy. Madison, WI: Medical Physics
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53. Titt U, Mirkovic D, Sawakuchi GO, et al. Adjustment of the lateral
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54. Bues M, Newhauser WD, Titt U, et al. Therapeutic step and shoot
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H, eds. Proton and charged particle radiotherapy. Boston, MA:
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starting conditions on the robustness of intensity-modulated proton
therapy plans. Phys Med Biol. 2010;55:2863–2878.
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of IMPT treatment plans to setup errors and range uncertainties via
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76. Meier G, Leiser D, Besson R, et al. Contour scanning for pencil beam
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11 Patient and Organ Movement
Paul J. Keall and James M. Balter
INTRODUCTION
The driving tenet of external-beam radiotherapy is the precise delivery
of focal radiation doses to the target, so that an effective dose can be
delivered while limiting concomitant normal tissue irradiation and
related toxicity risk. Technical advancements, such as intensity-
modulated radiation therapy (IMRT), volumetric-modulated arc therapy
(VMAT), and image-guided radiotherapy (IGRT) have provided
significant gains in specifying means to provide such dose distributions.
Accurate delivery, so that intended and actual doses agree, is a more
complicated matter.
The problems of patient positioning and motion have been studied
extensively. Although there are currently areas that need further
exploration, it is possible to consider the magnitude of various
uncertainties in dose delivery due to patient position variation and organ
movement, and to discuss rational strategies for dealing with these
uncertainties in the context of precision radiotherapy.
DESCRIPTION OF THE PROBLEM OF GEOMETRIC

VARIATION
The International Congress on Radiological Units (ICRU) has addressed
the relative problem of geometric variations. In reports 50 (1), 62 (2),
and 83 (3), concepts are evolved to attempt to standardize means of
reporting doses. Some of the concepts presented in these reports have
served as the basis for numerous investigations over the past few years,
and have been adopted as standards for clinical trials. A brief discussion
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of the key concepts as they apply to geometric variation follows.
The key structures that are delineated are the gross tumor volume
(GTV) and organs at risk (OARs). The GTV is generally defined as the
“visible” target, that is, that can be delineated from imaging or related
information. The OARs are tissue structures that are dose-limiting due to
risk of radiation-induced toxicity.
The next volume of interest is the clinical target volume (CTV). This
target volume ideally expands about the GTV to include a reasonable
expectation of the true target extent on a (static) patient model. The CTV
expansion includes a reasonable expectation of the extent of disease
below the sensitive range of the imaging modality.
The planning target volume (PTV) adds a margin to the CTV to
account for organ motion or setup error. Margins, allowing for
positioning, motion, and anatomical changes, may also be required for
the OAR to arrive at the planning organ-at-risk volume (PRV). A margin
provides a buffer in the delineation of tissues to account for
uncertainties (3). These structures are used for the treatment planning
process.
When the patient is imaged to define the CTV and critical structures,
the position is sampled. In general, this sample occurs once, specifically
during the computed tomography (CT) scan for treatment planning. To
obtain this sample, the patient is immobilized and positioned with
typical reference marks placed on the skin and/or immobilization device
at the principal axes of the CT scanner for verification of position and
orientation. The sample of the patient serves as the model for treatment
planning, and all subsequent targeting and density modeling are based
on the information obtained during this session. With the advent of
broadly available in-room imaging modalities, such as cone beam CT
(4–7) and the emerging integrated MRI-radiotherapy systems (8–10),
adaptive strategies which can account for inter and potentially infraction
anatomic changes are emerging.
Multiple samples of patient position will form a distribution. If we set
the position at the initial (treatment planning) CT scan as the “true”
patient position, then a reasonable method of describing this distribution
of subsequent positioning is by the translation necessary to make the
patient position match that of the treatment planning CT scan.
Conventionally, the average coordinate of this distribution is considered
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as the “systematic” error, in that it is the effective transformation that
persists throughout the samples (multiple CT scans in the above
example, or multiple patient positions over a course of treatment). The
spread of sampled positions about this average coordinate represents the
random setup variation. It is important to note that the average
coordinate may never be sampled. An excellent overview of margins in
radiotherapy is given by van Herk (11).
MINIMIZING THE IMPACT OF SETUP VARIATIONS ON

TREATMENT
Obviously, these setup variations require margins to create the PTV to
ensure proper coverage of the CTV. Reducing the margins yields a
smaller volume of tissue irradiated to high doses, and can potentially
reduce the toxicity to normal tissues. As such, significant efforts have
been made to minimize the range of variations and their resulting
impact on treatment.
Positioning Systems
A significant variety of equipment is in use to aid in repeat setup of
patients. This equipment attempts to address a dual role: immobilization
and localization. These dual roles are not necessarily compatible for any
given piece of technology.
Immobilization
Quite simply, the process of immobilization involves limiting or
eliminating movement for the time period of imaging or treatment. The
primary objective is to limit target movement, although critical normal
tissue movement also needs to be considered. There is a large amount of
literature on immobilization; however, as the technology is evolving, it
is important to consider a number of key aspects in deciding on a
technology and strategy for use of an immobilization system.
The advantage of a given immobilization method may be
compromised by the complexity of use. If an immobilization system has
many degrees of freedom, improper configuration of the device may lead
to systematic errors in patient position or shape at treatment. Examples
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of complex systems are multiuse boards for fixation, in which the angles
and positions of arm supports, angle of the upper thorax, shape of neck
support, and other components are adjustable. These devices are very
cost-effective, and can be used effectively, but special care must be taken
to properly verify the patient configuration, including notation of all
configuration parameters and documented photographs of proper setup.
Some systems (e.g., alpha cradle and vacuum loc) form directly to the
patient’s shape. This can be beneficial in positioning, but it is important
to separate comfort from immobilization. Formed immobilization that
extends to distal regions from the target has been shown to be beneficial
in reproducing position (12). However, studies have shown that simple
or no immobilization, when used well, can be as effective as more
complex systems (13). Therefore the training, use, protocols,
documentation, and in-house expertise are as important as the systems
themselves and there is no substructure for qualified expert staff.
Localization Technology
A wealth of technology has been applied to localization in radiation
therapy. At present, the most prevalent technology includes in-room
lasers, gantry-mounted kilovoltage x-ray imaging systems and electronic
portal imaging devices (EPIDS) though in-room localization is a very
fast-changing field.
In-room diagnostic radiography is, in fact, a very old concept. Film-
based radiographic systems have existed on linear accelerators for over
30 years (14). Room-based digital systems have been used for
radiographic (15–18) and fluoroscopic (19) procedures.
A number of different localization technologies have been used to
treat radiotherapy patients. These include dedicated systems such as the
real-time tracking radiotherapy system (20), tomotherapy, (21),
CyberKnife (22), and Vero (23) linear accelerators. A number of
additional localization methods have been develop based on markers
including Calypso (24), Navotek (25), and Raypilot (26). Emerging
localization technologies include ultrasound (27) integrated MRI-
radiotherapy systems (10, 28–30) and kilovoltage intrafraction
monitoring (KIM) (31,32). Given the reduction in the cost of camera-
based surface imaging for recreational (typically gaming) applications,
surface imaging (33) is anticipated to grow rapidly in use to assist with
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both setup reproducibility and intra-treatment patient monitoring.
STRATEGIES FOR POSITION CORRECTION

Online Correction
Generally, online position correction refers to the processes of measuring
and correcting setup error at the start of each treatment fraction. This is
the area in which the vast majority of technical developments have
focused recently. The process of online correction includes three steps:
measurement, decision, and adjustment. A fourth step (verification) may
also be used.
Measurement systems include data collection and analysis. Data can
be from imaging (e.g., radiographs, CT scan images, ultrasound, and
video) or other markers (e.g., electromagnetic and external fiducial).
Analysis is the comparison of reference image or position information to
that gathered at treatment.
Decision is the process of choosing to act or not on information from
measurements. It is valuable to consider that the measurement systems
as well as correction technology are not perfect, and therefore the errors
in these systems may increase errors in certain circumstances. The use of
thresholds for corrections allows a trade-off between the cost (frequency
of adjustment) and benefit (actual reduction of errors). Figure 11.1
shows the cost versus threshold for setup adjustment in prostate patients.
Of course the definition of cost in setup adjustment is important here. If
integrated, for example, real-time adaptation, the cost of correction is
very low. If the setup adjustment involves a manual procedure, including
treatment pause, reimaging, position shift, and verification, then the
time is long and the cost is high. Automation can substantially reduce
the cost of radiotherapy. Figure 11.2 shows the impact of positioning
strategy on margins under assumptions of systematic error versus none.
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FIGURE 11.1 Cost (frequency of adjustment) versus threshold for online setup adjustment (based
on 6-mm σ for pelvic patients).
Off-Line Correction
One of the earlier forms of position correction was off-line correction.
Studies of the dosimetric impact of setup error (34–37) demonstrate that
systematic error has the largest impact on margin needed to adequately
dose a target, and that the geometric expansion to account for random
error is generally small (less than one standard deviation). Given this
observation, it can be seen that, as long as random errors are not
exceedingly large, the most significant patient benefit comes from
strategies that rapidly reduce the magnitude of systematic setup
variation.
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FIGURE 11.2 Benefit (margin) versus threshold for adjustment (4-mm σ setup, 1.5-mm σ
measurement uncertainty, and 1.0-mm σ setup correction uncertainty).
A number of strategies have been used to minimize systematic error.

Two strategies are the shrinking action level (SAL) and no action level
(NAL) methods (38–40). In the SAL protocol, setup is verified daily for
the first few fractions, and adjustments are made with tolerances that
reduce in magnitude as the fractions progress. This strategy has shown
promising results.
The NAL protocol has also been used. In this method, images from
setup are acquired for n (typically 3 to 5) fractions. These images are
analyzed off-line (thereby minimizing the delay needed to analyze and
act on images at the treatment unit), and the best prediction of the
systematic error (typically the average position of the fractions analyzed)
is corrected before the next fraction treated. This protocol has been
tested, and shown to dramatically reduce systematic errors.
ADAPTIVE RADIOTHERAPY STRATEGIES

Adaptive strategies for position adjustment were first proposed by Yan et
al. (41). The adaptive process extends the concept of off-line and online
strategies. Essentially, the patient position variability is assumed to
follow a population model before patient-specific measurements. As
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information about that patient’s variation is acquired (e.g., through
multiple CT scans or daily portal images), the model of variation is
refined, and predictions from this refined model can be used to adjust
position and margins. The frequency of further measurement can be
similarly adjusted as increased confidence in the patient variation is
gained, and similarly increased frequency of measurement can be
reinstated if, for example, an unexpected outlying measurement occurs
during the treatment course. Such strategies form a basis for plan
modification, which is a topic of active research and development in
radiation therapy.
Organ Movement
Internal organ movement is a further, sometimes significant, factor in
dose-limiting geometric uncertainty. The most studied forms of organ
movement have been prostate movement and breathing-induced
movement in (primarily) the thorax and abdomen. Langen and Jones
have published an excellent review of the magnitude of organ movement
as studied by several investigators (42). With the availability of real-time
localization systems, rich datasets of tumor position are now available
(24,43,44).
Prostate position variability is a combination of pelvic setup variation
(mentioned above) with internal movement of the prostate within the
pelvis (45–54). The primary factors affecting prostate movement are
rectal and bladder filling, with differential influence of these forces in
prone versus supine patients. The vast majority of prostate patients are
positioned supine, both for patient comfort and owing to observed
improvements in setup variation of the pelvis. Prone positioning has
been reported advantageous due to a separation of the rectal wall from
the prostate, although both setup variation and (breathing-related)
internal movement have been observed to increase in these patients.
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FIGURE 11.3 Graphic representation of the dominant modes of prostate movement (bladder
—yellow, rectum—brown, prostate—pink, intraprostatic implanted markers—white stars). The
major translation axes (black arrows) about the left–right and anterior–posterior axes have also
been significantly attributed as rotation about the left–right axis (white arrow).
Internal movement of the prostate has generally been observed in the

anterior–posterior (AP) and cranial–caudal (CC) directions. Furthermore,
a significant component of this movement has been correlated to
rotations of the prostate about the left–right (LR) axis, with a pivot at or
near the prostatic apex (7) (Fig. 11.3). The magnitude of this movement
(of the prostate relative to the pelvic bones) is typically 1 cm or less in
the AP and CC directions, and, 5 mm in the LR direction.
Although most prostate movement studies have examined
interfractional position changes (i.e., on the order of days), some
measurements have been made of intrafractional movement. Breathing
has been shown to impact prostate movement, most notably during deep
breathing and in prone patients (55,56). Peristalsis, gas in the rectum,
and bladder filling have a more significant influence on prostate position
and potentially short-term movement. The complexity of prostate motion
is shown in Figure 11.4. In most cases, there is little motion, but motion
of over 15 mm can be observed with a variety of motion types.
Prostate movement has been addressed by attempts at reducing
motion by diet as well as immobilization through a rectal balloon. Most
common attempts at managing prostate movement, however, have
focused on localization. Radiographic localization and tracking of
implanted markers, studied by several investigators, are routine
practices, with initial localization (before subsequent movement)
accuracy of better than 2 mm. Ultrasound and in-room CT scan have also
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been used for prostate localization before treatment.
FIGURE 11.4 Prostate motion exhibits a variety of different motion characteristics. From Ng JA,
Booth JT, Poulsen PR, et al. Kilovoltage intrafraction monitoring for prostate intensity modulated
arc therapy: first clinical results. Int J Radiat Oncol Biol Phys. 2012;84(5):e655–e661.
Vast efforts have recently been focused on the problem of breathing-

related movement in radiation therapy. An AAPM Task Group has been
dedicated to this topic (57). Breathing influences movement and shape
change primarily in the thorax and abdomen, although, as noted above,
breathing-related movements can also be seen in pelvic structures.
Breathing is a complex process. It is controlled both voluntarily and
automatically. Various combinations of thoracic and abdominal muscles
(including the diaphragm) can be used to control breathing, and
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therefore the shape of a patient can vary for the same estimated “phase”
of breathing when evaluated sequentially.
A few general observations have been made about breathing in
population studies. A typical breathing cycle lasts around 4 seconds for
lung cancer patients (58). During normal breathing, patients tend to
spend more time to (or near) exhale than inhale. Tumors near the apices
of the lungs tend to move less than those near the diaphragm. Although
these general observations represent a reasonable population summary,
numerous studies have shown that individual patients may violate any of
the above observations. The need for patient-specific motion assessment
has been demonstrated (59,60). The advent of four-dimensional (4D) CT
techniques (61) provides data that help further elucidate patient-specific
movement. 4D CT is now a widely used method in radiotherapy.
A very thorough summary of the ventilatory movement patterns of
intrathoracic tumors was published by Seppenwoolde (43). In addition
to the above observations, this study further showed the influence of
heartbeat on some tumors, especially those near the mediastinum. An
observation of complex, elliptical movement (“hysteresis”) was also
noted in this study and observed by several other investigators. This
elliptical movement can be attributed to the complex elastic properties
of lung tissue, coupled with the different interactions of muscles and
force between the inhale and exhale portions of the breathing cycle.
Lung tumor motion induced by respiration changes with time. The daily
variation of lung tumor motion traces over 4 consecutive treatment days
is shown in Figure 11.5. A large variation in motion within and between
fractions is observed, which challenges the ability to determine suitable
treatment margins.
Motion has been studied in breast cancer as well. In general, the
breast and chest wall move <1 cm within a single treatment fraction.
Such small movements may not demand significant intrafraction
intervention for motion management. Larger interfraction variation of
chest wall position has been seen in portal imaging studies. Of note,
however, is the potentially significant advantage of deep-inspiration
breathhold (62–67), not only for immobilizing the chest wall
temporarily, but also, more importantly, for reducing lung density and
separating the heart from the medial high-dose region.
The abdomen has demonstrated significant breathing-related
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movement with typical amplitudes of 1.5 cm or more. The superior
region of the liver moves with strong correlation to the diaphragm,
while more caudal regions of the liver may move differentially due to
deformation (68–71).
Technology to Manage Organ Motion

A number of technologies have been introduced to manage breathing
movement. The most common method currently employed involves
using larger margins to account for the expected inter- and intrafraction
motion variation, though as shown in Figure 11.5 this motion is variable
and difficult to estimate. Another system involves gating (turning on and
off) the treatment beam. The feedback for gating has generally been
from the monitoring of an externally placed reflective marker on the
patient’s abdomen, although fluoroscopic tracking systems have also
been used with tolerance windows for gating (72). Gating involves a
trade-off of residual motion versus efficiency. The narrower the
acceptance range for motion, the less frequently the beam is on. The
most significant concern with external gating is the relationship between
the external marker position and the tumor location. While targets near
the skin surface (e.g., breast) may have significant correlation with
external references, other targets, especially those in the thorax, have
been shown to vary in location at the same phase (as estimated from
external motion) over multiple breathing cycles (73–76).
FIGURE 11.5 Calypso-measured lung tumor motion traces over 4 consecutive days. Note the
large changes within and between fractions. From Shah AP, Kupelian PA, Waghorn BJ, et al.
Real-time tumor tracking in the lung using an electromagnetic tracking system. Int J Radiat Oncol
Biol Phys. 2013;86(3):477–483.
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FIGURE 11.6 Components of an active breathing control (ABC) system.
Another commonly used technology is active breathing control (ABC)

(Fig. 11.6). First introduced by Wong (77), this concept involves using a
system that monitors breathing, and occludes breath at a given phase of
the breathing cycle and/or volume of air relative to exhalation. Various
studies have shown excellent short-term reproducibility of target
position in the thorax and abdomen using this technology (15), (78–82).
Decreased accuracy in long-term reproducibility suggests the advantage
of image-guided localization at the start of a treatment fraction in
combination with ABC-aided ventilatory immobilization.
More complex technology for managing breathing movement involves
tracking. In this process, an estimate of the target’s trajectory is used to
adjust the couch, linear accelerator orientation, or field aperture. The
available systems to perform real-time adaptation, along with the year
they were first implemented clinically are shown in Figure 11.7. Of the
four systems shown, the most widely available are the multileaf
collimator (MLC) and couch. The MLC is the lightest and as each leaf can
be controlled individually, higher order corrections such as rotation (83)
and deformation (84) can be performed.
Some breathing management systems rely on the relationship of a
surrogate to estimate tumor position at any given time or patient state.
Various surrogates have been employed, including implanted fiducial
markers, external fiducials (usually tracked in real time by video
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systems), external surface monitoring, and lung volume and air flow.
The relationship between surrogate state/position and tumor position
may be variable, and the influence on this variability on geometric
accuracy of target position prediction should determine the extent of
additional verification needed or residual error expected. Two
commercial systems, the CyberKnife and Vero, currently employ a
hybrid approach to tracking, in which implanted radiopaque fiducials
are periodically localized using biplanar radiographs, and their position
is used to update a correlation with the constantly monitored external
surface of the patient.
FIGURE 11.7 The four systems investigated to realign the radiation beam and tumor due to
intrafraction motion.
SUMMARY
The influence of geometric variations in radiation therapy increases in
significance with the conformality of the planned treatment. Our
understanding of motion and its effects is growing. Interventions to
better reduce these movement-related uncertainties are evolving rapidly.
A fundamental understanding of the limitations of any given monitoring
or tracking system, coupled with the impact of uncertainty in target
position on dose, will yield efficient strategies for implementing
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technology to limit the impact of patient and organ movement on
treatment outcome.
KEY POINTS
• Organ structure nomenclature has been standardized by the ICRU
in reports 50, 62, and 83. The visible gross tumor volume (GTV)
may be expanded into a clinical target volume (CTV) to include
microscopic disease, and further expanded into a planning target
volume (PTV), to account for organ motion or setup error. Similarly,
the organs at risk (OARs) may be expanded to planning organs at
risk (PRVs) to account for patient position and organ motion.
• Patient positioning systems are designed to immobilize the patient

and/or improve the localization of the treatment site. Immobilization
devices should limit target movement, but not so complex that
systematic setup errors could be introduced. A number of in-room
localization technologies have been introduced in the past few
years to assist with setup reproducibility and intrafractional target
monitoring.
• Patient positioning corrections can be made online or off-line.

Online corrections include measurement, decision as to whether to
shift, adjustment, and in some cases verification. Off-line
corrections are important in minimizing systematic errors, which
have a significant impact on the margin necessary for adequate
treatments. Adaptive strategies can serve to modify the above
corrections, based on the variations observed with individual
patients.
• Organ motion within the patient represents another source of

positional uncertainty. Several site-specific studies of interfractional
organ motion have been performed, many of which have focused
on the prostate gland. Intrafractional organ motion may also be
significant, especially for diseases within the lung, which has
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motivated the development of a number of techniques to manage
treatment of this site.
QUESTIONS
1. ICRU 50 first introduced which of the following nomenclature?
A. Gross treatment volume (GTV)
B. Off-axis ratios (OARs)
C. Clinical target volume (CTV)
D. Normal tissue complication probability (NTCP)
2. Which of the following is/are used to immobilize patients?
A. Alpha cradle and/or vacuum loc
B. Calypso
C. Electronic portal imaging systems
D. ABC systems
3. Two strategies for performing off-line corrections to minimize
systematic error are:
A. Inter- and intrafractional motion management
B. Adaptive and non-adaptive margin adjustments
C. System gating and/or tracking
D. Shrinking action level and no action level
4. The magnitude of the interfractional movement of the prostate
relative to the pelvic bones is typically:
A. 1 cm or less in the anterior–posterior direction
B. 1 to 2 cm in the cranial–caudal direction
C. 5 mm or less in the left–right direction
D. <5 mm in any direction.
5. The following technologies was/were developed to help manage
breathing movement:
A. Ultrasound
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B. In-room CT
C. Treatment beam gating
D. Tracking using multileaf collimator
ANSWERS
1. C
2. A
3. D
4. A and C
5. C and D
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Group 76. Med Phys. 2006;33(10):3874–3900.
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tumors. Int J Radiat Oncol Biol Phys. 2004;58(4):1251–1257.
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12 Image-Guided Radiation
Therapy
Guang Li, Gig S. Mageras, Lei Dong, and Radhe Mohan
INTRODUCTION
The aim of external beam radiation therapy (EBRT) of cancer is to target
localized disease noninvasively with radiation that conforms to the
target while minimizing dose to surrounding organs at risk (OAR).
Radiation dose is often delivered with inadequate visualization of the
regions being irradiated. Therefore, imaging guidance is crucial at every
step of the process, including cancer diagnosis, staging and delineation;
treatment simulation and planning; patient setup, tumor localization,
and motion monitoring; and treatment response assessment, efficacy
evaluation and strategy refinement. In fact, most of the significant
advances in radiation oncology over the last three decades have been
made possible by advances in medical imaging. Using three-dimensional
(3D) images of patient anatomy from computed tomography (CT) and
magnetic resonance imaging (MRI), as well as visualization of viable
tumor extent from MR spectroscopic imaging (MRSI), positron emission
tomography (PET), and single photon emission computed tomography
(SPECT), treatment target and OARs can be delineated with precision,
thus reducing the likelihood of marginal misses in tumor and minimizing
the exposure of normal tissues to high radiation dose. Multimodality
imaging has become an integrated component throughout the treatment
process, providing the ability to localize and visualize the tumor in space
and time to ensure an accurate delivery of a highly conformal treatment
plan.
Image-guided radiation therapy (IGRT) is composed of a multitude of
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major innovations in radiation oncology to address the problems arising
from inter- and intrafractional target variations. IGRT aims to deliver a
treatment as it is planned based on 3D images acquired at treatment
simulation. These images establish a 3D reference frame of patient
anatomy (with possible inclusion of motion) for both image-based
treatment planning and image-guided treatment delivery. The former
process follows the exact 3D patient anatomy (the tumor and nearby
OARs) for dosimetric planning, while the latter focuses mostly on tumor
alignment between the planning image and images at the treatment unit
prior to and during treatment, thereby aligning to the radiation fields.
The variations of tumor position in the image-guided interfractional
setup (between treatment fractions) and intrafractional (within a
treatment fraction) patient and organ motion can be corrected for more
accurate delivery. The variation of normal tissue positions is often
assessed in terms of proximity to the irradiated volume in the current
image-guided approach, but is also a focus of adaptive IGRT research to
assess dosimetric and clinical consequences under various clinical
scenarios. Examples of image guidance in various stages of radiation
therapy are illustrated in Figure 12.1.
Increasing evidence has shown that there are substantial inter- and
intrafractional variations, in contrast to the “snapshot” planning
anatomy of a patient. The causes of such variations include voluntary
motion (body shift, rotation, and deformation), involuntary motion
(respiratory, cardiac, and digestive), disease-related changes (tumor
growth and weight loss), and radiation-induced changes (tumor
shrinkage). The variation in respiratory-induced tumor motion during
treatment may substantially deviate from the one-cycle motion extent
quantified by 4DCT at simulation, owing to breathing irregularities.
These variations could have a significant impact on the outcome of
treatments, as they may result in underdosing the target or overdosing
the OAR (1–3). In the current practice of treatment planning and
delivery, it is assumed implicitly that patient’s anatomy remains static
throughout the course of the radiation therapy. To account for statistical
variations, wide treatment margins derived from population-based
studies are used to ensure coverage of the disease at the expense of
exposing considerable OAR volumes to or near full prescribed radiation
dose. A large margin limits the ability to safely deliver higher tumor
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doses because of increased risk of OAR toxicity, especially for
hypofractionated stereotactic body radiotherapy (SBRT), in which the
high dose per fraction exceeds the normal tissue’s capacity for sublethal
repair. Furthermore, the margin needed for some patients exhibiting
large target variations may exceed the population-based margin,
potentially leading to marginal misses, especially with the use of highly
conformal modalities, such as 3D conformal radiotherapy (3DCRT),
intensity-modulated radiotherapy (IMRT), volumetric-modulated arc
therapy (VMAT), and proton therapy (4–6). Treatment planning and
delivery techniques that do not correct for such daily volumetric
variations adequately may lead to suboptimal treatments. These factors
may, in part, be responsible for the poor outcome and high toxicity in
radiation therapy for some cancers (7). IGRT has the potential to target
gross and microscopic diseases accurately, to individualize treatments to
reduce margins, and to allow dose escalation to higher levels with the
expectation of improving local control and reducing toxicity (8–10).
Therefore, IGRT can help to improve the therapeutic ratio, namely the
ratio of tumor control probability (TCP) and normal tissue complication
probability (NTCP) (1,7). The recent efforts to introduce MRI, PET, and
optical surface imaging (OSI) into the treatment room can further
improve the ability to assess the accuracy of treatment delivery by direct
viewing of the target during treatment (11), imaging proton beam path
(12), and visualizing photon Cherenkov scattering (13), respectively.
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FIGURE 12.1 Image guidance at various stages of the radiotherapy process.
This chapter focuses on IGRT technologies related to treatment

planning and delivery of EBRT. The second and third sections introduce
various imaging forms of IGRT technologies and their commercial
implementations for inter fractional patient setup and intrafractional
motion monitoring, respectively. The fourth section reviews
requirements and considerations for IGRT, including quality assurance
(QA). Various possible IGRT strategies, margin assessment and
reduction, and clinical implications are described in the fifth section.
Finally, the sixth section looks into the future and speculates on new
processes coming into this field.
INTERFRACTIONAL IGRT IMAGING MODALITIES FOR

PATIENT SETUP
In this section, we focus on in-room IGRT imaging modalities for daily
patient setup. Images acquired immediately prior to treatment are used
to reposition the patient so as to align the target or its surrogate (such as
implanted radiopaque fiducials in or near the tumor) with the planned
radiation isocenter. Digitally reconstructed radiograph (DRR) images
derived from the planning CT are used as the reference. A couch
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positional adjustment is typically used to realign the patient. This is the
simplest form of IGRT without modification of the original treatment
plan.
2D Radiographic Imaging
Two-dimensional (2D) radiographic (projection) imaging is typically
used in treatment rooms to align the patient relative to the radiation
beams. Megavoltage (MV) imaging uses therapy x-ray beams and an
amorphous-silicon (a-Si) flat-panel imager, known as electronic portal
imaging device (EPID), to verify patient’s setup, defined as the position
of the skeletal anatomy (14). Other uses of MV imaging are to verify
treatment beam apertures prior to treatment and in vivo portal
dosimetry during treatment (15,16). Because imaging uses the therapy
beam, it provides direct in-field verification of treatment delivery, and
therefore serves as a “gold standard” for validating new IGRT
techniques. Disadvantages of MV imaging include higher radiation dose
to the patient (typically 1 to 5 cGy) and poorer image quality owing to a
large Compton scattering contribution from the higher x-ray energies
and high-energy electrons reaching the detector.
Two general categories of 2D kilovoltage (kV) x-ray imaging are
frequently used for IGRT. One is a gantry-mounted kV imaging system
on a linear accelerator (linac), orthogonal to the therapy MV x-ray beam.
The kV x-ray source and flat-panel imager are mounted on retractable
arms, providing near-diagnostic quality images. The second category of
kV imaging is room-mounted systems: the x-ray source and detector are
mounted on the ceiling or the floor. These systems provide an oblique
orthogonal image pair for stereoscopic imaging at a wide range of
treatment couch angles. Most kV x-ray imaging systems have a
companion fluoroscopic imaging mode, which is useful for observing
motion of the internal anatomy or implanted fiducials. Since kV imaging
systems are distinct from the MV beam line, the kV–MV isocenter
coincidence must be established within a clinical tolerance through
initial and periodic QA processes.
kV radiographs are often not sufficient for detecting soft tissue targets
but are more successful in aligning skeletal landmarks or implanted
radiopaque fiducials as target surrogates. In-room kV imaging represents
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a major improvement over MV imaging due to its superior image quality
and its low imaging dose (0.01 to 0.1 cGy), facilitating its use for daily
image-guided patient setup (17). The different appearance of kV and MV
thoracic images is shown in Figure 12.2.
FIGURE 12.2 The appearance of anatomy kV (top row) and MV (bottom row) radiographs can be
quite different. At kV x-ray energies, the bony structures are enhanced; at the therapeutic (MV)
energies, the air cavity is enhanced.
Tomographic Imaging
CT imaging inside the treatment room provides 3D anatomical
information and improved soft tissue visibility, thus providing
advantages over radiographic imaging with higher imaging dose (18).
In-room CT images are the standard for six degrees-of-freedom (DOF)
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patient setup and can be used to estimate the delivered dose
distributions based on the anatomy captured at treatment. The planning
CT image is used as the reference for patient alignment on skeletal
anatomy, fiducials, or tumors in some disease sites.
kV Helical CT and kV Cone-Beam CT

Helical multislice CT systems have been widely used in diagnostic
imaging and radiation treatment planning for many years. The first
integrated CT-linac clinical system was designed for noninvasive,
frameless stereotactic radiotherapy of brain and lung cancers with
reduced uncertainty between fractions (19). Another integrated system
with a rail system to transport the patient between treatment and CT
couches was assembled at the Memorial Sloan Kettering Cancer Center
for treatment of paraspinal lesions and prostate cancer (20,21).
FIGURE 12.3 A: An Elekta Synergy unit (Elekta Inc., Sweden). B: A Varian TrueBeam unit (Varian
Oncology Systems, Palo Alto, CA) (Photograph courtesy of Yingli Yang, PhD). Both linear
accelerators have a kV imaging system orthogonal to the therapy beam direction. Both systems
provide 2D radiographic, fluoroscopic, and CBCT modes.
A commercial CT-linac system was introduced in the clinic in 2000

(22). It consists of a medical linac and a movable CT scanner that slides
along a pair of rails (“CT-on-Rails”). A similar “CT-on-Rails” commercial
system (EXaCT, Varian Oncology Systems, Palo Alto, CA) has the
mechanical accuracy of within 0.5 mm (23,24). The biggest advantage of
an in-room CT scanner for IGRT is the similarity of image quality and
field of view (FOV) with planning CT images.
Gantry-mounted kV imaging systems are capable of radiography,
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fluoroscopy, and cone-beam CT (CBCT), providing a versatile solution
for IGRT applications (25,26). CBCT imaging involves acquisition of
projection images of the patient as the gantry rotates through an arc of
at least 180 degrees plus a so-called cone-beam angle subtended by the
imaging panel (∼200 degrees total). A filtered back-projection
algorithm is used to reconstruct the volumetric images. Geometric
calibration of the CBCT system is needed periodically to maintain image
quality and geometric accuracy. Corrections on the order of 2.0 mm may
be required to compensate for the gravity-induced flex in the support
arms of the source, detector, and gantry. Submillimeter spatial resolution
and accuracy have been demonstrated in phantom. The volumetric
image with nearly isotropic spatial resolution is useful in frameless
stereotactic radiosurgery (SRS) (27).
Since 2005, major manufacturers have offered CBCT capabilities
(Elekta Synergy and XVI, Elekta Inc., Sweden; Varian On-board Imager
[OBI] and TrueBeam Imaging, Palo Alto, CA), as shown in Figure 12.3.
Elekta’s system uses a slightly larger flat panel detector (41 × 41 cm),
compared to Varian’s detector (40 × 30 cm), which limits the scan
length to 15 cm when using the full-fan scan mode. A half-fan scan
method displaces the detector vertically to capture half projection
images and requires 360-degree rotation to have the axial FOV to at
least 40 cm (28).
Limitations of CBCT image quality include elevated x-ray scatter,
which reduces image contrast and introduces cupping artifacts. Scatter
can be reduced by using both anti-scatter grids and post-processing
methods (29,30). To further improve the image quality, Kim et al. have
proposed to use orthogonal dual-source and dual-detector “in-line” with
MV beam to produce 2D and 3D images with tetrahedral collimation
(31). Because of regulations on gantry rotation speed (1 rpm), CBCT
image quality is adversely affected by the breathing motion. The IGRT
setup process may add 5 minutes (∼2 minutes acquisition and ∼3
minutes registration/approval) to the regular treatment schedule.
MV Helical CT and MV Cone-Beam CT

Tomotherapy (Accuray Inc., Sunnyvale, CA) is an integrated technology
that combines a helical megavoltage CT (MVCT) with a linear
accelerator (Fig. 12.4A) as x-ray source, which is specially designed for
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delivering intensity-modulated radiation in a slit geometry (32–34).
Low-dose (1 to 2 cGy), pretreatment MVCT images are obtained from the
same treatment beam line but with a nominal energy of 4 MV. The CT
detector uses an array of 738 channel xenon ion chambers and an FOV
of 40 cm can be reconstructed.
MV CBCT uses the therapy MV x-ray and the EPID detector (35,36).
With the a-Si flat panel EPID (37), it has become possible to rapidly
acquire multiple, low-dose 2D projection images with treatment beams,
as shown in Figure 12.4B. There is no effective MV scatter-reduction
mechanism for EPID, which limits image quality. The amount of scatter
reaching the detector depends on the photon energy, field size, and
thickness of the imaged object; however, the imaging system can be
optimized by calibrating the system using site-specific phantoms (38).
The MVCT and MV CBCT images provide sufficient contrast to verify
patient position and to delineate many anatomic structures (38,39). It is
interesting to note that the MVCT numbers are linear with respect to the
electron density of material imaged, yielding accurate dose calculations
(40). Another advantage is the reduced influence of implanted metal
objects on image quality, in contrast to kV CT, which exhibits strong
artifacts when high-Z material is present (Fig. 12.5).
FIGURE 12.4 A: A picture of tomotherapy unit (TomoTherapy Inc., Madison, WI) (Photograph
courtesy of H. Ning, PhD). Tomotherapy is an integrated IGRT system, which combines a linear
accelerator with an MVCT image guidance system. B: A Siemens MV CBCT imaging system
using a conventional linac and a flat-panel EPID. Reprinted from Morin O, Gillis A, Chen J, et al.
Megavoltage cone-beam CT: system description and clinical applications. Med Dosim.
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2006;31:51–61.
Hybrid Cone-Beam CT and Digital Tomosynthesis

A hybrid CBCT can be achieved by combining orthogonal kV and MV x-
ray projection images with a partial arc gantry rotation as little as 90
degrees (41) while maintaining projection images span an arc of 180
degrees. Acquisition requires only 15 seconds, making it optimal for
breath-hold imaging (42).
FIGURE 12.5 Images showing the artifacts due to the presence of metal objects in the
conventional kV CT images (left panels). Artifact-free images were obtained with an MV CBCT
(right panels). Reprinted from Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam CT:
system description and clinical applications. Med Dosim. 2006;31:51–61.
Digital tomosynthesis (DTS) is a special situation of tomographic

reconstruction with limited arc (20 to 40 degrees) of projection images
(43–45). The DTS scan has short time (<10 seconds), less radiation, but
sacrifices spatial resolution in the direction perpendicular to the x-ray
beam. When necessary, a second DTS can be added quasi-orthogonal to
the first.
Respiration-Correlated (4D) Computed Tomography
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Imaging
Respiration-induced motion is an important consideration in some
disease sites, in which tumor motion up to 4 cm has been observed (46).
CT scans acquired synchronously with the respiratory signal can be used
to reconstruct a set of CT scans, representing the 3D anatomy typically at
10 respiratory phases. This collection of 3DCT datasets is called
respiration-correlated CT (RCCT), or 4DCT, which describes the
snapshots of patient’s 3D anatomy over one breathing cycle.
Respiration-Correlated 4DCT
Respiration-correlated 4DCT can be acquired in either cine or helical
mode. In cine mode, repeat CT projections are acquired over slightly
more than one respiratory cycle with the couch stationary while
recording patient respiration; the couch is then incremented and the
process repeated. Following acquisition, the images are sorted with
respect to the respiratory signal, leading to a set of volume images at
different respiration points in the cycle (47,48). Helical scan uses a low
pitch and adjusts the gantry rotation period such that all voxels are
viewed by the CT detectors for at least one respiratory cycle (49,50).
Both techniques have been widely characterized and applied clinically
for estimating the extent of moving tumors in lung and abdomen
(51,52).
The selection of the type of respiratory signal can vary, and
commercial systems commonly use one of the two types of breathing
monitors. One such monitor (Real-time Position Management, RPM,
Varian Oncology Systems, Palo Alto, CA) captures the anterior–posterior
motion of an infrared-reflective block placed on the patient’s abdomen
or chest using an infrared camera. The other is a “pneumo bellows”
system (Philips Medical Systems, Milpitas, CA) that records the digital
voltage signal from a differential pressure sensor wrapped around the
patient’s abdomen. Periodic motion is assumed in the binning approach
and breathing irregularity adversely affects the quality of 4DCT images,
leading to anatomical distortions (53,54). Phase-based binning assumes
repeatable breathing cycles and often produces 4DCT images with
greater motion artifacts than amplitude-based binning (55,56).
Reduction of motion artifacts in 4DCT is an active area of investigation
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and numerous methods have been proposed (57–59).
Respiration-Correlated 4D CBCT
As CBCT is acquired with limited gantry speed at 1 rpm, motion artifacts
are different and more pronounced in CBCT than CT. Respiration-
correlated 4D CBCT has been developed similar to 4DCT (60,61). A
slower gantry rotation is required to acquire sufficient projections in
each phase bin, resulting in scan times of 3 to 6 minutes. The limited
number of projections per phase reduces the contrast resolution and
introduces image artifacts; thus, the method is more suited to detecting
high-contrast objects such as tumor in parenchymal lung (60–62).
Respiratory-correlated DTS has also been reported (45). An alternative
approach is to process the CBCT images with motion correction using a
patient-specific motion model (63,64). Most of the methods use
deformable image registration (DIR) to deform the images to a common
motion state. Motion-corrected CBCT allows normal scanning time and
accurate tumor positioning (65,66).
Magnetic Resonance Imaging

MRI is well known for its nonionization radiation imaging, high soft
tissue contrast, flexible image orientation, and versatile image
appearance. The appearance of the soft tissue can be manipulated with
different pulse sequences, such as T1-weighted or T2-weighted. The
tumor visibility can be further enhanced by administrating a contrast
agent, such as a gadolinium-chelated compound. The magnetic field
strength is 0.2 Tesla (T) for open-field MRI and 1.5 T or 3 T for a closed-
field whole-body (≤70 cm bore) MRI scanner.
MRI may suffer from geometric distortion due to nonuniformity of the
magnetic field strength. This scanner-specific factor can be corrected by
imaging a large grid phantom (67). The geometric integrity is also
affected by susceptibility differences at tissue interfaces. MRI yields
limited visibility of bone owing to its fast relaxation time. Recently, MRI-
based treatment planning has been studied (68,69); an important area of
investigation is the conversion of MRI voxels to a CT number or electron
density for dosimetric calculation.
MRI-guided treatment delivery systems are an active area of
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development. An integrated MRI-cobalt (60) machine (MRIdian System,
ViewRay, Inc., Gainesville, FL) was commissioned at several radiation
oncology clinics in the United States in 2014 (70). An integrated MRI-
linac system is under development by Philips and Elekta and a prototype
has been installed at the University Medical Center Utrecht in the
Netherlands (71). A third MRI-guided system that has been installed in
Princess Margaret Cancer Center nearing clinical implementation enables
a rail-mounted 1.5-T MR scanner to operate in three different rooms: MR
simulation, MR-guided brachytherapy, and MR-guided radiotherapy
linac (72). Such in-room systems offer both soft tissue–based 3D target
alignment and near real-time 2D tumor motion monitoring (73). The
goals are to provide online treatment guidance, adaptive replanning, and
monitoring of treatment response.
2D, 3D, and 4D MRI

MRI can produce 2D planar, 3D volumetric, and 4D temporal images
(74), which are scanned and reconstructed slice by slice. When a fast
scan pulse sequence is applied, such as TrueFISP (true fast imaging with
steady-state precession), cine 2DMR images, or 2D(t), can be acquired at
4 fps without parallel imaging. At this acquisition speed, respiration-
induced tumor motion can be monitored for respiratory gating or real-
time tumor tracking.
A 3D volumetric MR image is potentially useful for MRI-based
treatment planning (68,69,75,76) with high soft tissue contrast without
ionizing radiation. It is important to minimize MRI geometric distortions
(77), obtain the electronic density of MRI voxels for dose calculation
(69), and generate pseudo-DRRs as reference images to align with 2D
radiographs for patient setup (78).
Four-dimensional MRI imaging provides time-resolved (TR) (79,80) or
respiration-correlated (RC) (76,81) volumetric images during respiration.
TR-4DMRI requires parallel imaging with multi-channel coils and
parallel computing to achieve a temporal resolution of 1 to 2 fps, while
RC-4DMRI is achieved based on respiratory correlation. Hu et al. (80)
introduced an amplitude-based triggering system to acquire prospective
T2-weighted 4DMRI for abdominal tumor tracking. Tryggestad et al.
(81,82) proposed a method with two-step reconstruction to produce
deblurred 4DMRI images and a method to track tumor centroid motion
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using orthogonal cine 2DMRI to achieve local volumetric information
and sufficient patient-specific breathing statistics.
Positron Emission Tomography

PET is used increasingly for tumor delineation in treatment planning and
for assessment of tumor response to radiation treatment. Using a
positron-emitting biologic tracer, tumor metabolic, proliferating, and
hypoxic conditions can be probed. A well-established PET tracer is 18F-
fluoro-deoxy-glocose (18F-FDG), a sugar-like molecule, which
accumulates in tumor cells owing to their high metabolic activities. In
the event of positron emission, the positron annihilates with an electron
to emit a pair of 511 keV photons in opposite directions. A PET scanner
with a band of scintillation detectors around the gantry detects the two
coincident events and determines the event location by the times of
flight of the two photons. Similarly, SPECT uses gamma-emitting tracers
to image a tumor by detecting independent gamma-decay events.
Hybrid PET/CT, SPECT/CT, and PET/MRI scanners are commercially
available, which provide coregistration of viable lesions in a patient
anatomy. Recently, in-room PET and SPECT have been studied as a
direct means for tumor positioning and tracking for IGRT (12,83–85).
For proton therapy, PET has been applied to directly image the by-
products of positron emitters, such as 15O, in the beam path and assess
the geometric accuracy of treatment delivery (84).
Ultrasound Imaging
Ultrasound is useful in soft tissue targeting in the abdomen for
radiotherapy. Fontanarosa et al. have recently reviewed ultrasound
guidance for external beam radiotherapy (86).
The ultrasound transducer is both a sound source and detector. It
transmits brief pulses that propagate into the tissues and receives the
echo that is bounced back at tissue interfaces where acoustic impedance
changes, owing to differences in tissue density or elasticity. The round-
trip time of the pulse-echo wave is used to determine the transducer-to-
object distances. A scan line converter constructs a 3D image of the
patient using 1D (with sweeping) or 2D transducer. Poor ultrasound
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image quality, unfamiliar image appearance, and anatomy distortions
due to applied pressure have limited its utility for precise image
guidance. The inter- and intrauser variability is large for ultrasound-
guided setup (87) and more pronounced for fiducial alignment (88).
Optical Surface Imaging

Stereoscopic OSI provides real-time imaging, primarily used for aligning
superficial tumors (the breast) or immobile tumors (the brain). A
commercial OSI system (AlignRT, Vision RT, Ltd., London, UK) is
composed of two to three ceiling-mounted stereo-camera pods, each
having two cameras and a speckle projector. The triangulation among
the two cameras and a skin point identified by the cameras from the
speckle pattern is used to calculate the location of the point in space. A
skin surface image is reconstructed from all visible surface points with
the accuracy within 1.0 mm.
Validated with x-ray imaging, OSI provides a quick and nonradiologic
means for image-guided setup. Early studies of surface imaging in
radiotherapy were reported by Massachusetts General Hospital (89) and
Johns Hopkins University (90) in 2005. It has been applied in breast,
lung, brain, and head and neck. Patient setup requires to register the
surface image to a reference region of interest (ROI) defined on the
delineated patient body surface in a simulation CT. The discrepancy
between OSI and CBCT setup in brain cases is usually about 1 to 2 mm
(27).
A different type of OSI is Cherenkov video imaging to visualize
radiation delivery relative to patient anatomy, such as the breast
(13,91). The optical detection is gated with the radiation pulse from a
linac, providing a direct evidence of radiation delivery.
Patient Position Correction

Rigid body position correction has 6 DOF, including 3 translational (3T)
and 3 rotational (3R) adjustments. Usually the alignment correction
based on rigid registration is performed in 3 DOF (3T), 4 DOF (3T + 1R
for couch rotation), or 6 DOF (3T + 3R) if a 6D couch or rotationally
adjustable couch extension is used. Translational correction is essential
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to align the tumor or tumor surrogate, while correction for rotation may
not be necessary. Deformable/mobile target position may be corrected
using the centroid position and 3 DOF position correction. The centroid
of the visible GTV in the thorax could be used for patient setup
alignment (92,93), but may result in substantial uncertainty in CTV
alignment (94). This is still an area of investigation.
INTRAFRACTIONAL REAL-TIME IMAGING AND MOTION

COMPENSATION
The main goal of real-time tumor tracking is to minimize the effect of
target motion not only at setup, but also during a treatment fraction.
Tumor tracking usually requires real-time motion monitoring (detection)
and motion compensation (execution) with the minimal time delay.
Although implanted markers are primarily used as surrogates for target
position using x-ray fluoroscopy, markerless approaches are emerging,
including MRI (82), EPID (95), fluoroscopy (96), CBCT projection images
(97), and OSI (27,98). In the following sections, we review different
approaches for real-time monitoring and tracking in photon
radiotherapy.
Fluoroscopic Imaging with Implant Fiducials

Two commercially available room-mounted systems, as shown in Figure
12.6, are CyberKnife (Accuray Inc., Sunnyvale, CA) and ExacTrac
(BrainLAB AG, Feldkirchen, Germany). Both are integrated IGRT systems
for target localization, setup correction, and the delivery of high-
precision frameless SRS and SBRT. The image guidance uses two distinct
imaging subsystems: kV stereoscopic x-ray imaging and real-time
infrared (IR) marker tracking. CyberKnife provides fluoroscopy for target
tracking, external marker tracking, and can perform adaptive beam
gating or real-time target tracking (99). ExacTrac is designed for
intracranial SRS or extracranial SBRT and can acquire x-ray images at
nonzero couch angles for verifying patient position (100). The 6 DOF
patient position adjustment is possible using 2D/3D image registration
(section “Image Registration and Fusion”).
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FIGURE 12.6 Two room-mounted kV image-guided IGRT real-time tracking systems. A:
CyberKnife system (Photograph courtesy by Accuray Inc., Sunnyvale, CA). B: ExacTrac system,
BrainLAB AG, Feldkirchen, Germany (Photograph courtesy of BrainLAB AG.)
Gantry-mounted kV imaging systems usually have only one kV x-ray

imager and acquire an orthogonal image pair by rotating the gantry,
including Varian’s OBI and TrueBeam Imaging systems and Elekta’s
Synergy and Infinity systems. The kV imaging beam lines are orthogonal
to the MV treatment beam line, sharing the same isocenter of gantry
rotation, as shown in Figure 12.3. The kV–MV configuration provides a
possibility to acquire images during treatment with alternated beam on
time (101–103). Studies have shown that EPID can capture at least one
fiducial marker 40% to 95% of the time in VMAT prostate treatment,
while kV imaging can be used as needed for the rest (104,105). VERO
(BrainLAB AG Feldkirchen, Germany) is another gantry-mounted linac
system (Fig. 12.7), equipped with two orthogonal kV imaging and one
optical tracking systems (106). It provides CBCT, simultaneous
orthogonal 2DkV imaging and fluoroscopic imaging. Fast gantry tracking
by a gimbal-based gantry system has a latency less than 50 ms (107).
Poels et al. have reported tumor tracking using both orthogonal kV and
planar MV imaging to achieve 0.3 mm accuracy on phantom (108).
Clinical applications of VERO for SRS and SBRT have been reported
(106,108,109).
Optical Fiducial Motion Surrogates

Optical tracking determines the position of an IR-emitting or reflecting
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marker via triangulation from two stereoscopic cameras. Owing to its
clean stereoscopic marker images and simple calculation, it is capable of
high spatial (0.1 mm) and temporal (<0.05 s) resolution in marker
tracking. Multiple markers can be tracked simultaneously in real-time
allowing continuous correction of patient position during treatment.
Meeks et al. have reviewed this technology in several implementations
for intracranial and extracranial SBRT (110). Markers can also serve as
fiducials; but variation in marker placement between simulation and
treatment cause uncertainty.
FIGURE 12.7 A VERO system (BrainLAB AG Feldkirchen, Germany and Mitsubishi Heavy
Industries, Tokyo, Japan) (Photograph courtesy of Dirk Verellen, PhD). The system offers quick
gantry movement aiming to a moving tumor, guided by gantry-mounted stereoscopic x-ray
imaging systems. Two rotations of the radiation beam and 5 DOF couch are available in the
system.
Video-Based Optical Surface Imaging

OSI utilizes the same principles as above to determine the position of a
surface point, which is identified with the assistance of a texture image
projected onto a patient skin. High spatial resolution is achievable
although temporal resolution is limited by the substantially increased
number of points to track. The speed of 3D surface image reconstruction
depends on the size of the ROI and image resolution: for facial area with
high resolution, 2 to 5 fps is achievable (27). AlignRT (Vision RT,
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London, UK) is a commercial optical surface monitoring system (OSMS)
that has been integrated with the Varian Edge system (Fig. 12.8A).
For surface alignment, a ROI should be created with sufficient reliable
landscape on a reference surface, which is either an OSI image acquired
at simulation or an external surface rendered from the planning CT
image imported via DICOM-RT. The image registration algorithm is
based on an iterative-closest-point method leading to an efficient and
robust surface alignment of the ROI. Clinical setup time can be less than
2 minutes with high accuracy and reproducibility (27).
The real-time surface matching capability has been applied to head
motion monitoring during frameless SRS (27,98). Using an OSI image
captured at treatment as reference, systematic errors of the OSI system
can be cancelled, yielding 0.2 mm accuracy for rigid motion detection.
For nonrigid anatomy, an OSI-based spirometry has been reported (111),
aiming to utilize all respiration-induced external motion to predict tumor
motion via physical relationships (112).
Real-Time Electromagnetic Localization and Tracking

Tracking of implanted fiducials without ionizing radiation imaging is
possible with a technology that uses radiofrequency (RF)
electromagnetic fields to induce and detect signals from implanted
“wireless” transponders (Calypso, Varian Medical Systems).
Electromagnetic tracking is now an integrated component of Varian’s
Edge treatment machine, as shown in Figure 12.8. The system consists of
a console, optical tracking system, and tracking station. The console is
situated near the treatment couch with a magnetic array panel extended
above and close to the patient surface. The array panel contains RF
source coils to excite the transponders and sensor coils to detect the
transponder response signals, each at a different resonant frequency for
unique identification at 10 Hz and submillimeter accuracy (113,114).
The Calypso system can be implanted in soft tissue throughout the body
except in lung, which is currently under clinical studies (115).
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FIGURE 12.8 Two nonionizing motion-tracking systems equipped for the Edge System (Varian
Oncology Systems, Palo Alto, CA). A: Photograph of the system with the OSMS and Calypso
systems. B: A diagram showing the prototype AC electromagnetic field tracking system with the
detector array and the infrared cameras (Calypso, Varian Oncology Systems, Palo Alto, CA). The
Beacon transponder is shown in the inset.
FIGURE 12.9 Two integrated MRI-guided treatment units. A: A schematic of a prototype MRI-
guided real-time tracking system for IGRT (MRIdian, ViewRay, Inc., Gainesville, FL). The system
is designed to have a low-field open MRI for real-time imaging and three-headed Cobalt source
for intensity-modulated gamma ray irradiation (Photograph courtesy of James Dempsey, PhD). B:
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A prototype of MRI-Linac system (by Philips Medical Systems, Milpitas, CA and Elekta Inc.,
Sweden) with a 1.5T split magnet and a 6MV Linac (Photograph courtesy of Jan Lagendijk, PhD).
MRI Real-Time Cine Imaging

An integrated MRI-guided cobalt machine (Fig. 12.9A) is commercially
available as an IGRT system (70), which consists of a low-field open MRI
system and three cobalt irradiation sources. Three computerized double-
focused multileaf collimator systems provide intensity-modulated
gamma-ray beams, which have lower energy and larger penumbra than
a linac. The technology emphasizes the MRI-guided, near real-time (4
Hz) imaging system, which can track soft tissue targets and OARs
without interrupting treatment delivery.
Integrated MRI-linac systems are an active area of development
(71,116,117). It has a design similar to the MRI-cobalt system in that the
radiation beam is perpendicular to the magnetic field between two split
magnets (Fig. 12.9B). The linac waveguide is shielded from the magnetic
field (1.5 T) and RF signal of the MRI unit. However, the magnetic field
interacts with secondary electrons generated in the patient, thereby
affecting the dose distribution (118). The effect is most pronounced at
tissue-air interfaces, where exiting electrons return to the tissue as a
result of the Lorentz force and locally deposit additional dose. On the
other hand, the beam modifiers, such as MLC, can affect the
homogeneity of the magnetic field (119).
A fast scan sequence, such as balanced steady-state free precession, is
required for cine 2DMRI (∼4 Hz) and TR 4DMRI (2 Hz) that uses
parallel imaging and approximation in image reconstruction
(79,120,121). Respiratory-correlated 4DMRI is also available (80,81).
MRI can sample more respiratory cycles without ionizing radiation for
treatment simulation and planning.
PET Real-time Imaging

In PET/SPECT imaging, the radiation source is the viable tumor, which
is also the target of radiation therapy. In principle, in-room PET/SPECT
imaging could provide tumor position in real time. Fen et al. proposed
emission-guided radiotherapy (EGRT) that combines a PET scanner with
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a linac (85). In this study, dose delivery was simulated using Monte
Carlo computation in a digital patient. Yang et al. investigated the
feasibility of using list-mode PET imaging to guide beam tracking of
tumor motion in a phantom study with 1D or 3D motion tracers (122).
The current method requires 10 seconds to determine tumor centroid
position; thus needs further improvement for motion tracking. Yan et al.
investigated the construction of an in-room SPECT system for functional
image guidance (83). The studies are in early stages of preclinical
research.
Real-Time Tumor Motion Compensation

Real-time tumor tracking refers to continuous adjustment of the
radiation beam or patient position during treatment so as to follow the
changing position of the tumor or its surrogate. In principle, real-time
tracking provides a combination of increased normal tissue sparing
relative to motion-encompassing methods by reducing the treatment
margin, and more efficient treatment with near 100% duty cycle relative
to gated treatment. In the following sections, we summarize three
strategies in various stages of development involving motion tracking of
a linac system.
Dynamic Multileaf Collimator Approach

Keall et al. have demonstrated motion tracking using dynamic MLC
(DMLC) (123). The Calypso system provides a near real-time motion
signal in prostate with better than 2 mm accuracy and 220 ms system
latency (114). One concern of this motion compensation method is the
anisotropic tracking resolution owing to MLC characteristics: Depending
on whether target motion is along or perpendicular to the leaf motion,
the spatial resolution for tracking is either <1 mm (the leaf motion) or
2.5 or 5 mm (the leaf width). Different strategies to optimize leaf
trajectories have been studied (124,125). Zimmerman et al. have
demonstrated motion tracking with intensity-modulated arc therapy
(126). Motion-tracking radiation delivery has been demonstrated using
cine 2DMRI for image guidance in motion phantom experiments (127).
Keall et al. have reported the first clinical experience on DMLC tracking
of Calypso transponder for a prostate treatment (128).
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Mobile Treatment Couch Approach
D’Souza et al. have proposed compensation of the tumor motion using a
robotic couch (129). Unlike the DMLC approach, this method can
compensate for 3D tumor motion with isotropic system responses;
however, there may be patient-related physical and medical concerns.
For instance, couch motion could induce a counter-reaction from the
patient, body shift, or tissue deformation when changing motion
directions, especially for obese patients. Varian 6D couch is capable of
motion tracking but has not released for clinical use, while developments
on mobile couch/extension have been shown (130). Menten et al. have
illustrated comparable motion compensation between the mobile couch
tracking and DMLC tracking (131).
Movable Gantry Approach

The CyberKnife has a 6D robotic arm to position a light-weighted linac
and a 6D robotic couch to align a patient and provides the first clinical
solution for tumor tracking (99). The robotic arm can move at speeds of
several centimeters per second, which makes it compatible with tracking
respiration-induced tumor motion. The VERO system is designed for
image-guided tumor tracking (Fig. 12.7). Based on a gimbaled design,
the beam can rotate transversely (panned) or longitudinally (tilted) to
track implanted fiducials in or near the tumor with the maximum
motion range of 4.4 cm (or 2.5 degrees) at the treatment isocenter and a
latency of 50 ms for 4DRT (107,132,133). The latency effect will be
discussed in “Management of Intrafractional Tumor Motion”.
IGRT REQUIREMENTS AND CONSIDERATIONS

IGRT Commissioning and Quality Assurance
Commissioning and QA of IGRT-enabled technologies are essential. The
American Association of Physicists in Medicine (AAPM) has issued
several task group (TG) reports, covering in-room kV x-ray imaging for
patient setup/target localization (TG#104) (134), QA for
nonradiographic imaging for patient setup/target localization (TG#147)
(135), QA for CT-based IGRT technologies (TG#179) (136), QA for
medical accelerators (TG#142) (137), SBRT procedures (TG#101) (138),
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and management of respiratory motion (TG#76) (46). These reports
provide guidelines for clinical use and QA of the IGRT imaging systems
and procedures. In the following, we summarize three important aspects:
geometric accuracy, image quality, and motion detection.
Coincidence of Imaging and Treatment Isocenters

One of most important tasks in commissioning an in-room imaging
modality is to compare the imaging isocenter with the treatment
isocenter. Conventionally, it is paramount to check the alignment of
radiation isocenter, mechanical isocenter, and laser isocenter. When
using IGRT, coincidence of imaging and treatment radiation isocenters
must be initially and periodically checked to ensure that discrepancies
are within clinically acceptable tolerances. The MV-EPID is used as the
gold standard as it provides direct reference to the treatment beam. For
stereotactic procedures, the discrepancy must be within 1.0 mm;
otherwise, it should be within 2.0 mm (137) for conventional
treatments. A calibration procedure is required to correct mechanical
sagging for kV imaging and EPID detectors (38,139). Customized QA
phantoms have been developed for different IGRT systems, including kV
and MV imaging systems of C-arm linacs (137,140) and MVCT imaging
of tomotherapy units (141). To determine the geometric accuracy of
IGRT for SRS/SBRT, an end-to-end (from simulation to delivery) test is
recommended, by comparing the alignment of the center of the
delivered MV dose distribution with the planned isocenter (106,142).
Image Quality
Bissonnette et al. have established a QA program for CBCT image quality
with the Elekta Synergy and Varian OBI systems (29,30,74). The report
evaluates flat-panel detector stability, performance and image quality of
10 linac imaging systems over a 3-year period. Details for correcting
background (dark current) and pixel-by-pixel gain uniformity (flood-field
image) of the plat-panel detector are also described. The CatPhan 500
phantom (The Phantom Laboratory, Salem, NY) is used to quantify
image quality (143). A comprehensive QA program by Yoo and Yin
describes safety, functionality, geometric accuracy, and image quality for
the Varian OBI system (144). Image quality characterization and QA
procedures for EPID (145), MV CBCT (146), and MVCT in helical
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tomotherapy (141) have also been reported. A stereotactic head
phantom (Model 605 Radiosurgery Head Phantom; CIRS, Norfolk, VA)
or equivalent is used for imaging QA of the CyberKnife system (147).
Motion Detection
Clinical motion management guidelines have been published in AAPM
TG#76 (46), pertaining to respiration-induced motions of the target and
normal tissue. For fluoroscopic imaging, temporal resolution should be
100 ms or less, which produces a uncertainty of <2 mm for an object
moving at speeds up to 2 cm/s. Jiang et al. have outlined major clinical
challenges in respiratory-related procedures, including respiratory
gating, breath hold, and 4DCT (148). As external surrogates are used in
many respiratory gating and breath-hold procedures, the biggest
challenge is to ensure treatment accuracy. Indeed, many have reported
the limited reliability of internal–external correlation using external
fiducials. When external monitoring is used, verification of internal–
external correlation using image guidance prior to each treatment
session is needed.
Image Registration and Fusion

In IGRT context, image registration serves to align daily 3D or 2D
patient setup images with the planning CT or DRR images, respectively.
Uncertainty in image registration increases when the underlying
anatomy changes, including motion, deformation, or physical changes.
To minimize the uncertainty, image registration often focuses on the
vicinity of the tumor using surrogates, such as the bone and fiducials.
Visual verification with necessary manual adjustment is essential after
automatic image registration. The three orthogonal views of fused 3D
images are evaluated using color blending, checkerboard, or split
windows. Direct evaluation of 3D volumetric image rendered by GPU-
based, real-time computation is also possible (149,150). QA of the image
registration and fusion methods should be performed using an
appropriate phantom (151).
Rigid Image Registration

Most image registration tools used for IGRT are rigid registration using a
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rigid transformation. In addition to deformation-related uncertainty in
rigid image registration, uncertainty may come from interobserver
variation during manual alignment. Registration accuracy, couch
adjustment accuracy, kV–MV isocenter discrepancy, couch walk for
noncoplanar beams, and patient motion after image acquisition
determine the overall setup accuracy for tumor localization.
Rigid image registration in a volume of interest (VOI) is more
clinically relevant in the presence of tissue or patient setup deformation.
Zhang et al. (152) and van Kranen et al. (153) have reported using
multiple VOIs for rigid registration to evaluate the local deformation
among the three-to-nine different VOIs in the head-and-neck region.
Park et al. have developed a spatially weighted image registration
method to allow users to define the structure of interest (154).
Mencarelli et al. developed an automatic detection system with multiple
VOIs to account for posture variation during head-and-neck setup (155).
A 3D/3D (CBCT/CT) registration is the standard to achieve 6 DOF.
Registration of an orthogonal pair of 2DkV to CT (2D/3D) can also
achieve 6 DOF by using multi-DRRs with small rotational increments.
This technique has been employed in CyberKnife, BrainLab, and Varian’s
OBI with accuracy of 1 mm/1 degree or less in 6 DOF alignment of bony
structure or fiducial markers (100,156).
Deformable Image Registration

DIR may not be suitable for setup correction using couch adjustments, as
rigid transformation cannot effectively compensate for tissue
deformation. Nevertheless, DIR is essential for contour propagation and
delivered-dose estimation: it is a useful tool for adaptive IGRT. Since
2007, DIR has been intensively studied focusing on deformation
algorithms, physical constraints, self-consistency, and accuracy
assessment (157,158). The uncertainty of DIR is 2 to 3 mm on average.
DIR can track deformed anatomy voxel by voxel between two 3D
images, producing a deformation vector field (DVF) useful in the
following three IGRT areas (92,159–161).
First, the DVF provides complete motion transformation matrix
between two stages of motion and useful for motion modeling. To
simplify and expedite calculation, Zhang et al. have shown that the
combination of DIR with principal component analysis (PCA) provides a
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patient-specific motion model (162). The 4DCT-derived DVF has been
applied to generate motion-compensated CT, CBCT, DTS, and PET with
reduced motion artifacts (58,66,163).
Second, the DVF can be used for contour propagation, which is
essential for 4D and adaptive IGRT, as illustrated in Figure 12.10.
Wijesooriya et al. have studied the accuracy of automated segmentation
among different phase CT images in 4DCT by comparing 692 pairs of
automated and physician-drawn contours. The surface congruence of the
GTV and OARs was within 5 mm in >90% cases (161). Wang et al. have
applied DVF to propagate planning contours to daily CBCT in lung and
head-and-neck cancer patients, and found the volume overlap index to
be 83% with reference to physician-drawn contours (164). Physician
evaluation of these propagated contours is highly recommended,
especially in the presence of motion and metal artifacts (160).
Third, the DVF can be applied to map a dose distribution. This method
has been applied to 4D planning using 4DCT (123) and for estimating
delivered dose using daily setup CBCT (165), which is essential for
adaptive IGRT (166,167). The mapped dose is only an estimate as tumor
shrinkage and weight loss make the mapping unreliable (168,169). Li et
al. compared energy/mass transfer and direct dose mapping in 10 lung
patients and found noticeable dose differences (11% in PTV) (169).
Calculation based on deformed anatomy should provide more accurate
dose distribution (170,171).
IGRT Concerns in Simulation and Planning

Although IGRT focus on target alignment in treatment delivery, they are
strongly related to simulation and planning (172,173). As mentioned
before, the planning CT acquired is a snapshot of patient anatomy and
may not be representative at treatment. The variation can be mitigated
by preparatory procedures such as hydrogel spacer placement. Qi et al.
(172) have shown an adaptive multi-plan method, in which nine
treatment plans for each patient were produced to cover the most
probable prostate positions relative to the nodes. An alternative method
is to perform online (immediately prior to treatment) reoptimization of
the treatment plan (174).
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FIGURE 12.10 Automated image segmentation of multiple repeat CT datasets. In this head-and-
neck example, contours drawn manually on the planning CT were deformed to obtain contours for
repeat CT scans obtained during the course of radiotherapy. Deformations were carried out using
transformation matrices based on deforming planning CT image to match each of the repeat CT
images. Such automatic segmentation tools, once validated by clinical studies, would make
adaptive replanning practical.
Information Technology Infrastructure for IGRT

Implementation of IGRT into routine clinical workflow requires tighter
integration of imaging and treatment systems and more efficient
information flow. IGRT represents a shift from a traditionally static
treatment planning process to a more dynamic, close-loop process with
multiple feedback check/control points. To meet the technical and
logistical needs, the following infrastructure and software tools are
considered important to IGRT applications:
IGRT Data Management:
• Picture Archival and Communication Systems specifically designed for

radiotherapy (RT-PACS) are needed that integrate IGRT workflows,
data management, user interfaces, and statistical tools among different
imaging and treatment procedures.
• The Integrated Health Enterprise in Radiation Oncology (IHE-RO)
(175) endeavors to specify and address specific clinical problems and
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ambiguities including those for IGRT. It aims to overcome the
shortcomings of the Digital Imaging and Communications in Medicine
(DICOM) in radiotherapy (RT), which is the current industry standard
(176).
• Treatment management systems play a central role in integrating
image guidance and treatment delivery systems. With more frequent
use of 2D, 3D, and 4D multimodal images and possible adaptive
replanning during the course of treatment, data storage requirements
can increase one to two orders of magnitude.
IGRT Facilitating Tools:
• Tools for both rigid and DIR are necessary for implementing various
IGRT approaches (92) (159).
• Automatic treatment planning and optimization are needed to perform
plan adaptation to changing anatomy or altered target volumes (177).
• Cross-platform treatment plan comparison tools are needed for multi-
institutional studies. The computational environment for radiotherapy
research (CERR) (178) and deformable image registration for adaptive
radiotherapy research (DIRART) (159) provide a common platform for
treatment plan database and tools for clinical outcome research and
analysis.
Selection of IGRT Technology

The selection of an appropriate image-guidance solution is a complex
process that may involve a compromise among clinical objective,
product availability, existing infrastructure, manpower, and resources
(9,179). The implementation of an IGRT technology in the clinic
requires a thorough understanding of the complete clinical process and
the necessary infrastructure to support data collection, analysis, and
intervention. The four considerations: clinical, technical, resource, and
administration, suggested by the AAPM TG#104 report (134), may
evolve with industry trend.
IGRT CORRECTION STRATEGIES AND APPLICATIONS
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Online Versus Offline Corrections
The establishment of a particular clinical process for correcting patient
position based on the data from various clinical studies is referred to as a
correction strategy. Strategies are broadly divided into online and offline
approaches. The online approach makes adjustment to the current
session of treatment based on data acquired. This may be as simple as
couch position adjustment or as complex as a full-plan reoptimization for
adaptation. The offline approach is to intervene treatment at a later
time, such as weekly physician review of portal images and replanning
in response to patient changes (180). The online approach has a greater
capacity to increase precision than offline strategies, but at the cost of a
higher workload. A hybrid correction strategy is often used clinically
with different error thresholds and time allowance (9,10,177,179).
In an accuracy-demanding procedure, such as frameless SRS, IGRT
patient setup and motion management can take a large portion of
treatment time (27). The overhead associated with the alignment tools
and decision rules can be prohibitive unless properly integrated. The
adaptive radiotherapy program at William Beaumont Hospital
(166,167,181) was made possible only through in-house software
integration efforts. For 4D tumor tracking, additional automatic tools are
necessary to support online correction in the intrafractional intervention.
Correction of Interfractional Setup Error

Various techniques have been developed for pretreatment setup
corrections. Without loss of generality, we consider an in-room CT-
guided IGRT system (Fig. 12.11). Following patient immobilization and
alignment of skin marks with room lasers, or using OSI for alignment, a
CBCT is acquired and aligned with the planning CT. The primary means
of intervention is correction of translational deviations, since rotational
corrections are small for single lesions enclosing the isocenter. For
multiple lesions with a single isocenter, rotational deviations may be
important and can be corrected using a 6 DOF couch with isocentric
rotation. The second level of intervention may be dose based. Ideally,
the treatment goal would be based on the delivered dose distribution.
The CBCT images of the patient’s treatment anatomy make it possible to
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estimate the delivered dose distributions and to calculate accumulated
dose. Accumulated dose deviations can be corrected infrequently using
an offline adaptive correction scheme (177,181).
FIGURE 12.11 An in-room volumetric CT-guided radiotherapy process. CT images of patient’s

setup and anatomy information are acquired and sent to an alignment workstation where the
images are compared and aligned to match with the planning CT. An interventional decision is
made based on the magnitude of anatomic variations to assess the need for an online or off-line
correction. If necessary, dose tracking may be enabled and used for replanning.
Management of Intrafractional Tumor Motion

In the presence of significant intrafractional motion, additional
geometric and dosimetric variations should be taken into account, which
will increase treatment complexity. Not surprisingly, most motion
managements are related to the treatment of lung and abdominal
cancers (46,74,177). In patient setup with a mobile tumor, localization
of implanted fiducials using fluoroscopy can be achieved by aligning the
track of the implanted marker with the track discerned from the
reference 4DCT. Bony landmarks may not be used for setup alignment
since the tumor motion trajectory relative to the bony landmark may
change (182). Soft tissue imaging with direct target alignment using 4D
CBCT or cine 2DMRI would be more preferable.
Real-time monitoring of implanted fiducials, or of the tumor directly,
is needed for accurate gating of radiation treatments. Respiratory gating
used at simulation may be used to control dose delivery during the
quiescent period around end expiration. MLC motion is intermittent
during gated IMRT, thereby reducing possible interplay effects between
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MLC and respiratory motions (183). Audiovisual feedback may improve
breathing regularity and breath-hold reproducibility (184,185), and can
be used in respiratory-gated treatment. In voluntary breath-hold, the
beam is enabled when the inspiration level is within tolerance of the
planned level (186). Reproducible involuntary breath hold may be
achieved using active breathing control developed by Wong et al. (187).
There will be a time delay from motion detection to the action of
beam hold or motion tracking, usually 100 to 400 ms (188,189). This
latency can cause a targeting error of 1 to 2 mm (104), critical to tumor
tracking. A predictive model can be used to anticipate the tumor
position to reduce the latency-caused error to gain submillimeter
accuracy (127,190). Tumor motion can be predicted using external
markers based on a motion correlation model, and such a model needs
initially calibration and periodic verification and update by frequent
imaging measurements (133,191).
Population-Based and Individualized Margins

The relative importance of systematic and random errors in the
determination of PTV margins should be considered in the design of a
clinical strategy. Geometric errors in radiation field placement are
typically characterized by distributions of nonzero mean and variance.
The mean represents the systematic discrepancy while the variance
represents the random component. The relative importance of these two
categories of errors may vary in determining appropriate PTV margins
(192,193). The reported margin formula may not completely general, as
the number of fractions is not concerned, especially for SBRT cases with
five treatment fractions or less.
A treatment margin depends not only on the imaging modality chosen
and tumor surrogate used, but also on the type of patient immobilization
and motion management technique employed. For respiratory motion,
breath hold, abdominal compression, respiratory gating, or motion
tracking manage tumor motion at different levels. As a consequence, the
margin added to form the internal tumor volume (ITV) will be reduced
relative to that for a motion-encompassing ITV (166,194). The overall
margin is the sum of uncertainties from inter- and intrafractional
motions.
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In lung, patient-breathing irregularities add another level of
uncertainty and complexity for the treatment. Grills et al. proposed a
margin formula that contained components of both population-based
and patient-specific systematic and random errors (195). Such a margin
formula was applied to CT-guided setup of lung cancer cases, resulting in
a 65% to 75% margin reduction. To compensate for baseline drift, Pepin
et al. have reported using a dynamic-gating window (196). As the tumor
motion is patient specific and determined using 4DCT, individualized
ITV margin is often applied in lung cancer treatment (195). However,
4DCT-based motion simulation is based on single respiratory cycles and
thus could be statistically unreliable (197). Motion simulation for ITV
derivation based on 4DMRI or cine 2DMRI have been proposed and
investigated (81,82,198).
In prostate cases, IGRT margin reduction is one of the most dramatic
examples in all anatomic sites. With in-room CT guidance, a 3-mm
margin was reported adequate for prostate dose coverage, but may lose
some of the seminal vesicles coverage due to daily variation in rectal and
bladder filling that causes local deformation (199). A comparative study
using four different IGRT setup methods, skin marks, 3D bony
landmarks, 3D fiducial markers, and Calypso transponders has shown
that the last two methods can achieve 4 mm and 3 mm margin
requirement, respectively (200). Another study has compared four setup
techniques using skin marks, 2D bony registration, ultrasound guidance,
and in-room 3DCT (201). A recent Calypso study has shown that a
margin of 2 mm would produce sufficient CTV dose coverage based on
1,267 tracking sessions of 35 patients (202). Figure 12.12A demonstrates
that the alignment accuracy increases along with the complexity of the
alignment technology: from skin to bone to ultrasound and to CT (8).
The dosimetric result for one patient exhibiting large organ motion is
shown in Figure 12.11B.
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FIGURE 12.12 A: Patient setup accuracy of prostate cancer using different in-room imaging
modalities. Generally, the accuracy increases with imaging frequency, dimension, and use of
fiducial. The skin mark and ultrasound setup have largest variation, as indicated by the error bars.
The margin could be reduced from 8 to 2 mm based on this finding. Reprinted with permission
from Mageras GS, Mechalakos J. Planning in the IGRT context: Closing the loop. Semin Radiat
Oncol. 2007;17:268–277. B: Target coverage based on various types of image-guided setups for
treatment. In this example, 24 treatment-time CT scans of a prostate cancer patient were used to
compare the effectiveness of four alignment techniques for patient setup using a fixed-margin
IMRT plan. The minimum target dose is lowest (59.3 Gy) for skin marks–based setup and highest
(76.0 Gy) for the CT-guided setup. The day-to-day variations in the minimum dose (represented
by the error bars) are smallest for CT-guided technique and largest for skin-mark and ultrasound-
guided techniques.
Anatomic Variations and Dosimetric Consequences

Inter- and Intrafractional Variations in Anatomy
Substantial inter- and intrafractional organ variations and setup
uncertainties of lung, liver, diaphragm, gynecologic, prostate, seminal
vesicles, bladder, and rectum have been reviewed by Langen and Jones
(203). Even with careful immobilization and alignment of the patient,
significant changes occur because of the nonrigidity of anatomy, bowel
gas movement, and variable fillings of the bladder (204). Li et al.
reported interfractional anatomic variations for all major sites based on
daily CT assessment (205). Target and OAR variations may follow
certain trends, including tumor volume shrinkage up to 12 months after
initial hormone treatment (206), radiation-induced tumor shrinkage, and
disease-related weight loss. Figure 12.13A shows a side-by-side
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comparison of a head-and-neck target volume that has shrunk
significantly during the course of treatment. The skin contour no longer
matches well with the immobilization mask. Changes in target volume
and OAR position could have significant clinical consequences
(152,153). During a prostate IMRT treatment, changes in bladder filling
can cause prostate and OARs to move away from the planning position,
as demonstrated in Figure 12.14.
FIGURE 12.13 A: An example of setup error for a patient immobilized with a thermoplastic
facemask due to tumor shrinkage as treatment progresses. Approximately half-way through the
treatment course (right panel), the lower neck was not centered on the headrest, presumably due
to the relatively “roomier” mask. B: Dosimetric impact of interfractional variations in head-and-
neck anatomy. The solid lines show the volumes of the parotid glands (left and right) decreased
as the treatment progressed. At the same time, the centers of both parotid glands also moved
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medially due to tumor shrinkage and weight loss. As a result, the percent of parotid volume
exceeding 26 Gy increased by least 10% over the course of radiotherapy.
Dosimetric Effects due to Interfractional Motion

The common approach to evaluating a delivered dose is to use the daily
setup 3DCT images and actual dynamic leaf sequence from a treatment
log file for dose reconstruction (207). To generate a cumulative dose
distribution over multiple fractions, dose mapping based on DIR is
applied to a reference image for final dose evaluation (161).
In prostate cases, it is reported that 25% (8/33) of patients would
have geometric or dosimetric miss without daily MVCT guidance to
improve prostate localization (208). Obese patients and patients with
large daily rectal motion would be most subject to such marginal miss.
van Herk has pointed out that the systematic uncertainty is more
important and should be minimized (192). Langen et al. have
investigated the dosimetric consequences of prostate motion during
helical tomotherapy for 16 patients with 515 daily MVCT scans (209).
The study finds that the mean change in target D95% is 1 ± 4% and the
average cumulative effect is smeared out after five fractions. In
individual fractions, the D95% may be off by up to 20%. For normal
tissues such as the rectum, Chen et al. have reported that daily dose
variation caused by rectal volume changes is significant and 27% of
treatments would benefit from adaptive replanning (210). Wen et al.
have calculated actual accumulated doses with three PTV margins of 10
mm (6 mm at anterior rectum), 5 mm (3 mm) and 3 mm (isotropic)
(211). With calculated TCP and NTCP values in eight early prostate
patients, they suggested that margin reduction resulting from IGRT was
an effective means to improve the therapeutic ratio. Clinically, Sveistrup
et al. compared 388 IG-IMRT with 115 non-IG 3DCRT treatments and
shown grade 2 or higher toxicity of 5.8% versus 57.3%, respectively (7).
Zelefsky et al. conducted a clinical study with 186 IGRT and 190 non-
IGRT treatments and demonstrated significant improvement in
biochemistry control at 3 years among high-risk prostate patients with
IGRT versus non-IGRT (97% vs. 77%, p = 0.05) (212).
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FIGURE 12.14 Intrafractional variations of anatomy observed in a prostate patient in the span of
20 minutes. CT images were acquired just prior and immediately after an IMRT treatment fraction.
The contours of pelvic anatomy before treatment (left) are overlaid on the CT image of the patient
acquired immediately after the treatment (right). Prostate target (red) was displaced anteriorly for
>5 mm.
In head-and-neck treatments, it is desirable to reduce the dose to the

parotid glands in order to minimize the incidence of late xerostomia
(213). Unfortunately, the parotid glands can decrease in volume and
move medially during the course of treatment (214). As a result, parotid
mean dose increased by 10% and exceed 26 Gy (Fig. 12.13B). A single
mid-course correction to adapt the treatment plan to the anatomical
change can help reduce the dose for both parotid glands (215).
Dosimetric Effects of Intrafractional Motion

The dosimetric consequence of intrafractional breathing motion for lung
tumors can be demonstrated by 4DCT-based planning. Figure 12.15A
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shows a case study that used a free-breathing CT image to design a
treatment plan with an inadequate 8-mm margin to cover the CTV
(shown in yellow). The actual dose distribution does not cover the entire
target volume in some of the breathing phases due to respiratory motion,
which is not detected in the free-breathing CT. Using DIR, the
cumulative dose distribution from the 10 individual phases is calculated
and mapped to a free-breathing fast CT scan (near phase 7). The
resultant cumulative dose distribution summed from the entire breathing
cycle shows a dose deficiency in the CTV (red arrow), as illustrated in
the bottom row of Figure 12.15B. In this case, the cumulative dose
distribution when using the ITV derived from the 10-phase 4DCT does
not underdose the target but results in treatment to a larger volume. Wu
et al. have compared three delivery techniques, 3DCRT, IMAT, and
IMRT, in five treatment cases in liver, with tumor motions ranging from
0.5 to 1.75 cm. The variation in CTV D95% is largest (−8.3%) for IMRT
and smallest (<2%) for 3DCRT, with negligible dose–volume histogram
variations for normal tissues (216). Kuo et al. have found that with an
adequate margin for motion, D95% variation is <2% in the CTV (217).
However, the representation of respiratory motion during treatment
using the one-cycle 4DCT simulation has been questioned, and a longer
4DMRI simulation has been suggested (82,198).
Adaptive Approaches for Correcting Dosimetric Deviations

William Beaumont Hospital has pioneered the adaptive radiotherapy
strategy by using a purpose-built treatment planning system to facilitate
offline dosimetric evaluation and replanning (167,181). Without the
support from a more automated planning system, routine replanning is
not feasible. Recently, studies from several groups have focused on
implementing an automated treatment planning system (218,219) and
an automatic CT simulation optimization strategy (220). Predictive
treatment planning (221), incorporating tumor regression model from
the start, represents a new approach to adaptive radiotherapy, which
may yield more flexibility in accounting for variations.
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FIGURE 12.15 A: Potential consequence of respiratory motion on target coverage. An IMRT plan,
developed using conventional CT, was applied to the patient’s 4DCT. Dose distributions were
calculated in each of the 10 phases of the breathing cycle. A portion of the CTV, shown in thick
yellow line, was not covered by the 70 Gy prescription dose line (red) in phases 1 through 4. B:
Comparison of a treatment plan as perceived on a free-breathing CT (top row) and as realized
after accounting for breathing motion in all 10 phases (bottom row). The latter was obtained by
summing dose distributions computed on individual phases of the 4DCT image (A), and mapped
to a reference CT image using deformable image registration (DIR).
Mageras and Mechalakos have discussed treatment planning in the
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IGRT context and the various challenges to treatment-plan adaptation
strategies in various disease sites (8). An alternative planning approach
to evaluating a PTV is to simulate motion and other uncertainties
directly in the dose calculation, resulting in dose distributions of not
only the CTV but also OARs.
The adaptive concept as applied to radiotherapy practice derives from
modern informatics and control theory. Offline adaptation has been
implemented for various disease sites in various institutions (180,222),
and online replanning has been reported, with computation time within
5 to 8 minutes (174). Oh et al. have reported on a hybrid adaptive
approach (online MRI guidance and offline replanning) applied to 33
cervical cancer cases to overcome the substantial organ motion and
tumor shrinkage (180). The knowledge gained from geometric and
dosimetric variations via clinical IGRT research will be useful for guiding
the treatment planning in certain clinical scenarios. Four-dimensional
MRI should provide an advantage in this respect.
Future Directions
Image-guided radiotherapy is commonly considered in the context of
treatment delivery, but it is more appropriate to broaden its scope to
include imaging at other stages of the radiotherapy (10). We, therefore,
briefly discuss future directions as they apply to this broader definition.
We believe that further advances in IGRT rely on the innovation and
integration of automated technologies to facilitate evaluation and
decision-making processes. Automation in treatment simulation,
planning, and delivery will be active areas of investigation, allowing
standardization of treatment planning based on a planning library with
optimal plans of all anatomical sites and planning techniques.
Technologies such as graphics processing unit (GPU) (97,149) and cloud
computing (223,224) allow online 3D/4D image reconstruction, online
plan reoptimization, and real-time tumor tracking. A new clinical
workflow for adaptive IGRT would be implemented with focus shifting
from routine planning process to personalized plan tailoring, plan QA,
and treatment assessment and adaptation.
Further employment of multimodal imaging in both simulation room
and treatment room will be an active area of development. Functional
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imaging provides viable tumor volumes for planning and biologic image
guidance for treatment. In-room MRI has visualized a moving tumor and
OAR during treatment for the first time and could assist to minimize the
chance of a marginal miss. Treatment verification may be augmented
with in-room PET, SPECT, MRI, or Cherenkov OSI. Cine 2DMRI and
4DMRI with visualization of tumor and OAR is more clinically desirable
for tumor motion assessment at simulation and tumor motion
monitoring during treatment. MRI-based treatment planning can change
the radiotherapy paradigm, especially in conjunction with the integrated
MRI-cobalt or MRI-linac units, realizing adaptive IGRT clinically.
Treatment response evaluation using multimodality imaging will
continue to be an active area of investigation. Due to complexity of
radiation response, a multilevel approach at molecular, cellular, organ,
and physiologic levels is more likely to yield useful information.
Different biologic tracers could be designed to probe proper biologic
attributes, such as DNA double-strand breaks or cellular membrane
rupture. Ideally, response assessment within the treatment course would
be most beneficial for individualized treatments, while the reality is lack
of an effective assessment index even after treatment. A response-driven,
biologically adaptive radiotherapy is still distant from clinical practice.
The dosimetric feedback loop, which is within reach and will ensure that
the treatment process goes along the intended course, can provide more
reliable clinical data to tune prediction models of treatment outcome.
Radiation therapy has gone through a series of technologic revolutions
following several breakthroughs in imaging in the past three decades.
We have witnessed the growth of IGRT, which has provided improved
geometric and dosimetric accuracy in radiation therapy of localized
cancers. We expect that more technologic advances are forthcoming at
all levels of IGRT, and will further close the physical, biologic, and
clinical feedback loop for radiation therapy.
KEY POINTS
• In the application of IGRT to treatment delivery, we have a better
understanding of various uncertainties, correction strategies, and
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technical limitations. Geometrically, a large body of evidence has
shown the improved accuracy of IGRT in patient setup and motion
management. Dosimetrically, IGRT improves treatment delivery in
treatment plans that contain sharp dose gradients or mobile
targets. Clinically, increasing evidence has revealed associations of
local failure with marginal miss and high-grade toxicity with organ
motion.
• In this chapter, we have discussed the importance of image-guided

radiation therapy (IGRT) and many in-room imaging modalities,
which serve as visual and quantitative guidance for 3D/4D
treatment simulation, accurate treatment planning, and image-
guided treatment delivery. Using 2D radiologic imaging, 3D
tomographic imaging, 4D respiration-correlated imaging, or 4DOSI,
the setup image before treatment is aligned to the planning image
with reference to the radiation isocenter, so that the treatment can
be delivered as planned. Tumor-tracking images during treatment
serve to align the target with radiation beam so that the mobile
tumor is irradiated continuously or within a gating window.
• Implementation of IGRT requires various tools, QA procedures, and

resources to achieve clinical objectives for radiotherapy. IGRT has
been successfully implemented for all major anatomical sites and
has been demonstrated to improve treatment accuracy with
reduced uncertainty and margin requirements.
• In the past three decades, the evolution of IGRT has been

punctuated with major technologic advancements. In the future,
IGRT will continue to evolve as emerging technologies and clinical
challenges motivate investigations into new areas.
QUESTIONS
1. On all isocentric linac machines, the kV and MV radiographic
imaging are available commercially. Which of the following
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statements is incorrect in regard to kV and MV imaging?
A. The kV and MV images can be used together to produce a
hybrid CBCT.
B. The alignment of the kV and MV imaging isocenters should be
periodically checked.
C. The quality of kV imaging is better than that of MV imaging
due to a large component of Compton scatters in the MV
beam.
D. The kV image quality can be improved by using metal grid in
front of imager and post-acquisition image processing, the
same techniques can be applied to MV image quality.
E. Both kV and MV CBCT images can be used for evaluating
delivered dose, while MV CBCT has the advantage of less
metal artifacts and no need for CT number conversion.
2. A variety of in-room imaging modalities has been developed for
IGRT procedures. Which of following imaging modalities or
nonimaging tools can be used for intrafractional real-time motion
monitoring as a direct or indirect tumor motion surrogate?
(1) 4DCT or 4D CBCT imaging
(2) Gantry-mounted orthogonal 2DkV imaging
(3) Room-mounted orthogonal 2DkV imaging
(4) Infrared marker tracking system
(5) Calypso electromagnetic transponder system
A. (1) only
B. (2) + (3)
C. (2) + (4) + (5)
D. (2) + (3) + (4) + (5)
E. All of the above
3. A CBCT scan is acquired during a paraspinal SBRT procedure and
ready for approval. However, the attending physician, who is
with another patient, approves the image alignment 10 minutes
later. The physicist on duty requests that the therapists take a
verification orthogonal 2DkV image pair. Is the physicist’s action
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correct and why?
(1) No; there is no need for 2DkV verification since 2DkV
alignment is inferior to CBCT.
(2) No; there is no need for 2DkV verification since physician has
approved the CBCT.
(3) No; there is no need for 2DkV verification since the patient is
immobilized in a mask.
(4) Yes; the 2DkV verification is necessary since the patient may
have moved out.
(5) Yes; the orthogonal 2DkV images can provide 6 DOF
registration via 2D/3D registration, so they can be used for
verification of CBCT alignment.
A. (1) + (2) + (3)
B. (2) only
C. (3) only
D. (4) only
E. (4) + (5)
4. In a radiation oncology clinic, a frameless SRS (fSRS) procedure is
implemented for clinical use. An end-to-end test is conducted
using an anthropomorphic head phantom with inserted
orthogonal films to deliver an fSRS plan and shows a 2-mm
difference between the center of the delivered spherical dose
distribution and the planning isocenter marked on the films.
Which of the following factors could be the major causes to the
observed discrepancy?
(1) A misalignment of the isocenter of the gantry-mounted kV
and the MV beamlines.
(2) Couch walk that causes misalignment of the couch isocenter
and radiation isocenter.
(3) Image registration error between the CBCT and planning CT.
(4) Couch sag at the setup position, since a 100-lb object was
placed on the couch inferior to the phantom to mimic patient
body weight.
(5) The film placed inside the head phantom with a small angle
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relative to the CT slices.
A. (1) + (2)
B. (1) + (3)
C. (1) + (2) + (3)
D. (1) + (2) + (3) + (5)
E. All of the above
5. When treating SBRT for a mobile tumor such as lung lesions, it is
important to first align the target during patient setup and then
to consider intrafractional motion management. Which of the
following methods would introduce the largest uncertainty in
tumor alignment?
(1) Using free-breathing CT for planning with the ITV delineated
based on 4DCT and free-breathing CBCT for setup.
(2) Using respiratory-gated CT at full exhalation for both
planning and CBCT setup.
(3) Using respiratory-gated CT at full inhalation for both
planning and CBCT setup.
(4) Using motion compensated mid-ventilation CT for planning
and motion-compensated mid-ventilation CBCT for setup.
A. (1)
B. (2)
C. (3)
D. (4)
E. (1) and (3)
ANSWERS
1. D The MV image quality cannot be improved using the septa
grid, as the MV photon can be further scattered by the metal
grid, causing more scatters.
2. D (1) 4DCT or 4D CBCT are retrospective reconstructed and
cannot be used in real-time; (2) Varian and Elekta linac can
only take orthogonal 2DkV one at a time, but VERO can take
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orthogonal fluoroscopic imaging simultaneously; (3)
CyberKnife uses fluoroscopy for tumor tracking, (4) and (5) can
be used as external and internal tumor tracking systems.
3. E After CBCT imaging, the alignment approval should be done
immediately to avoid patient motion, even with an
immobilization device. The orthogonal 2DkV imaging qualifies
as a verification means to conform the correctness of CBCT
alignment.
4. C The kV and MV isocenter discrepancy and couch walk are
transparent to image registration but will affect the setup
accuracy. Couch sag and film angle are minor factors, since
they only cause rotational misalignment, which is a secondary
to translational misalignment.
5. C The full-inhalation phase is known to be irreproducible and
therefore unreliable for tumor alignment.
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Radiat Oncol. 2010;20(2):94–106.
223. Na YH, Suh TS, Kapp DS, et al. Toward a web-based real-time
radiation treatment planning system in a cloud computing
environment. Phys Med Biol. 2013;58(18):6525–6540.
224. Xue H, Inati S, Sorensen TS, et al. Distributed MRI reconstruction
using gadgetron-based cloud computing. Magn Reson Med.
2015;73(3):1015–1025.
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13 Linac Radiosurgery: System
Requirements, Procedures, and
Testing
Frank J. Bova and William A. Friedman
Over the past four decades, the practice of radiosurgery has undergone a
broadening in the underlying algorithms used for localization, planning,
and treatment delivery. These changes have come about for both linear
accelerator– and GammaKnife-based treatments. For planning, geometric
solutions have given way to solutions that are more algorithmically
based. For treatment delivery, new approaches have aimed at decreasing
the overall time required to deliver the optimized dose distribution. For
immobilization and localization, approaches aimed at replacing
neurosurgical-specific equipment, such as stereotactic head-frames, with
methods familiar across all of radiation oncology, such as thermoplastic
immobilization and orthogonal and cone beam–based localization, have
gained acceptance at some institutions. As always, there are no hard and
fast rules as to when some of these new techniques will provide a
clinical advantage or when they will inadvertently negatively impact
safety and efficacy. Target size, location, prescribed dose, and pathology
all contribute to the effect. As these new techniques are applied to an
ever-increasing array of clinical targets, the radiosurgeon must ensure
that each new innovation maintains the accuracy and precision
responsible for Radiosurgery’s established clinical results.
Chapters on radiosurgery traditionally begin by exploring the
background of radiosurgery followed by a discussion of the special
parameters that are considered responsible for the clinical success of this
treatment paradigm. We often forget that these treatments were not
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derived from a perfectly understood set of interactions. The relationship
between effective doses and complications are reported observations
from carefully controlled clinical trials. While underlying principles are
understood the accurate prediction of clinical effect still lies beyond our
understanding. The radiosurgeon needs to be particularly careful not to
accept that therapeutic equivalence for short-term results, a few months
or a year, will be representative of the results’ safety and efficacy when
measured in decades. As new techniques are discussed, an attempt to
relate the relevant parameters responsible for radiosurgery’s acceptance
as a valuable clinical tool will be discussed.
HISTORIC DEVELOPMENT OF RADIOSURGICAL

PRINCIPLES
In the mid-20th century, the advent of cobalt teletherapy units, and
subsequently linear accelerators, helped radiation therapy play an
increasingly important role in cancer treatment. During this time,
external beam radiation therapy relied heavily upon the fact that normal
cells are better than cancer cells at repairing sublethal radiation damage.
Typically, a course of therapy would be divided into small fractions,
each delivering a sublethal dose of radiation to a specified target
volume. In the time between therapeutic fractions, the normal tissues
would recover more quickly than the cancerous cells, and by the end of
a course of treatment, the targeted cancer cells would have amassed
significantly more radiation damage (Fig. 13.1).
This delivery technique was necessary for two reasons. First, in the
mid-20th century, neither computed tomography (CT) nor magnetic
resonance imaging (MRI) were yet available, limiting the clinician’s
ability to map out and plan three-dimensional (3D) conformal radiation
distributions. Second, the relative ratio of normal tissue cells to cancer
cells varies considerably through the volume being targeted by the
therapeutic radiation beams. This ratio is lowest at the site of the
primary tumor, somewhat larger at the tumor’s margin, and largest in
those regions only suspected of microscopic disease that are included in
the targeted volume. It was necessary to develop a therapeutic tool that
resulted in more cancer cell death relative to normal tissue cell death for
a given course of therapy across this spectrum of tumor burden. Dose
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fractionation provided such a tool.
Radiosurgery, defined as a single-fraction stereotactically targeted
radiation therapy, proposed a paradigm shift in the art of radiation
delivery. This new approach would not attempt to leverage differential
repair of sublethal cell damage, but instead deliver a highly concentrated
dose of radiation exclusively to the tumor. The normal tissue cells would
be excluded from the target volume as a result of a very steep dose
gradient, significantly reducing the dose to normal tissues. The result of
these two changes would allow an unprecedented escalation in safe and
effective radiation delivery.
FIGURE 13.1 Figure shows the effects of a single dose therapy versus that of a fractionated
therapy. After each fraction cell repair sublethal damage before the next fraction is administered.
The term “radiosurgery” was initially conceived by a neurosurgeon,

Lars Leksell (13,14). Leksell’s first attempt at a delivery scheme was to
provide a concentrated radiation dose by attaching an x-ray tube onto an
arc-centered stereotactic head-frame system, allowing a target volume to
be placed at the center of two orthogonal arc systems (Fig. 13.2). For
surgical interventions, the normal stereotactic arc allowed a probe
holder to point toward the intersection of the two arcing planes. The
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probe holder could then be moved along either arc while maintaining a
trajectory that pointed to the target. Mounting an x-ray tube in place of
the probe holder provided a method of delivering a radiation beam that
would remain focused at the targeted tissues. This, in turn, provided a
means to deliver multiple noncoplanar beams, with separate entrance
and exit pathways that all intersected over the target. This technique
was based upon orthogonal target definitions, which, as will be
discussed later, is insufficient to define irregular 3D structures.
FIGURE 13.2 The two bi-centered arc geometry with the focal point shown at the center of two
arcs. The user can move along each of the arcs maintaining a trajectory that will always go
through the focal point.
In the 1950s, teletherapy was still in its infancy, but a transition from
delivery with x-ray tubes and radium systems to cobalt-based units was
underway. Leksell undoubtedly had a thorough knowledge of state-of-
the-art radiation delivery devices. Due to limited specific activity and the
resultant self-shielding, tele-radium sources had a very low-dose rate,
leading to extended treatment times, but novel approaches to increase
the dose rate were being developed. One such approach was a device
that could simultaneously focus multiple radium sources at a target (27)
(see Fig. 13.3). These tele-radium beams were focused at a specific
depth, converging at a point in space and then diverging as they left the
target volume. This geometric focusing technique is very similar to the
approach Leksell first used in his arc-mounted orthovoltage x-ray tube
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design and later in his 179 Cobalt-60 source GammaKnife design
(21,26). Leskell’s primary contribution to radiation delivery was the
realization that the coupling of a multi-focused radiation-beam delivery
system to a stereotactic reference system could enable a highly focused
high dose of radiation to be delivered to a defined target while providing
significant sparing of adjacent normal tissues, a development that
preceded isocentric teletherapy designs.
FIGURE 13.3 Tele-radium device for increasing dose rate over a target volume. Multiple sources
are focused at a distance providing unique entry and exit pathways while only overlapping at the
target volume.
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FIGURE 13.4 A: Image of Dr. Raymond Kjellberg fitting a stereotactic adapter for proton beam
treatment. B: Adaption of the Kjellberg’s proton therapy data relating volume to complication
demonstrating that as the treatment volume increases the safe dose must decrease to remain
below the 1% probability of radiation necrosis.
Prior to the development of the GammaKnife unit, Leksell and

Kjellberg, in separate efforts, had adapted fixed-port proton beam units
for stereotactic radiosurgical applications (Fig. 13.4). These pioneering
systems treated significant numbers of patients and provided early data
on appropriate clinical doses for malignant, as well as benign, targets.
The fact that proton units were retrofitted for patient application and not
readily available to the therapeutic community at large limited their
widespread application. Leksell’s development of the self-contained Co-
60–based teletherapy unit, GammaKnife, provided the first practical
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commercial unit to offer dose distributions that rivaled the dose
concentration and dose gradient of particle-beam therapy (see Fig. 13.5).
The GammaKnife’s concentration of dose simply relied upon the
geometric convergence of a fixed array of Co-60 sources. With a half-life
over 300 times shorter than Ra-226, Co-60 allowed for the fabrication of
a device made up of small pencil-beam sources with high-dose outputs.
A large number of these pencil-beam sources could be packed into a
focused array. Spreading out the sources over approximately a
hemisphere and ensuring a focus accurate to within 0.3 mm at the
sphere’s center created a spherical dose pattern with relative uniform
dose across the sphere’s diameter. The convergence and divergence of
the beams caused the dose at the edges of the sphere to quickly decrease
(Fig. 13.6). While Leksell’s initial intent was to provide a means to
produce functional lesion, the anatomic atlases available in the 1950s
proved insufficient as the primary means for image guidance and
targeting. CT and MRI, the tools required for such a target definition,
would not be available for several decades.
Techniques for CT-based stereotactic frame localization developed in
the 1980s and the MR-CT image fusion techniques of the 1990s began to
provide a novel solution to the problems of 3D target definition (44).
Combining these imaging techniques with a new dose computation
algorithm allowed for a paradigm shift in the treatment of intracranial
targets. For the first time, the ability to deliver a high dose of radiation
that conformed to a 3D target shape and provided an exceedingly steep
dose gradient along the entire target-to-normal tissue interface would
become widely available to clinicians.
Over the past two decades, Radiosurgery has gone from a novel
treatment approach limited to a few academic centers to a treatment
modality available in most communities. Systems capable of delivering
these precise conformal doses with steep gradients have been developed
on multiple platforms. Joining the isotope-based GammaKnife is a
multitude of linear accelerator-based systems. These include traditional
gantry-based linac approaches as well as robotic arm-mounted systems
(5,31). These newer devices can provide for not only intracranial but
extracranial radiosurgical treatments. While each of these delivery
platforms presents unique challenges, the underlying principles for
targeting and the desired characteristics of the prescribed dose
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distributions remain the same.
FIGURE 13.5 GammaKnife with dose distribution for an 18-mm helmet. The distribution and
gradient is relatively symmetric about the vertical axis of the displayed dose distribution.
FIGURE 13.6 The intersection of multiple trajectories on a target point showing the pattern of
interesting and diverging pathways. As can be seen from the blowup in the upper right, the
number of interesting beams (1 through 5 are indicated) provides a steep geometric defined dose
gradient. The lower-right diagram shows the resultant dose intensity profile of 36 beams each 1
cm in diameter.
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PRIMARY OBJECTIVES OF RADIOSURGICAL
LOCALIZATION, PLANNING AND TREATMENT
The combination of stereotactic localization and the ability to produce a
highly focused dose distribution with exceedingly high gradients
provided a radical change from the existing fractionated treatment
paradigm. This new imaging/treatment technique could successfully
address intracranial targets in a single-fraction therapy, eliminating the
dependence upon the rate of radiation repair in normal tissue cells
versus cancerous cells. This paved the way for clinicians to think of
radiation as a tool of target elimination similar to a surgical procedure
but in an outpatient setting.
Radiosurgery allowed ionizing radiation to be applied to targets
previously resistant to fractionated therapy. Dose distributions
developed with an ever-evolving set of tools for high conformality and
with steep dose gradients provided new optimization parameters that
were effectively leveraged against both benign and malignant targets.
Radiosurgery treatment of arteriovenous malformations is an example:
when differential repair did not provide a sufficient therapeutic
advantage relative to normal tissues, single-fraction conformal
distributions with high-dose gradients provided an effective therapy.
It is difficult to separate the effects of conformality and gradient on
the success of radiosurgery treatments. The GammaKnife allowed for the
treatment of spherical and irregular targets with a planning/delivery
tool commonly referred to as “sphere packing.” An array of collimators
provides a means for the creation of spherical distributions of varying
diameters. For round targets, a sphere is simply fitted to the target
volume. For nonspherical targets, the technique fits the largest possible
sphere inside the target, removes the volume covered by that sphere and
repeats the process with the remaining volume. The result is an
alignment of the target-normal tissue interface with the dose-sphere’s
steep gradient.
While eliminating normal tissue from the prescription volume is
generally accepted as a necessary parameter for an effective therapy
with few complications, a high-dose gradient has not been universally
recognized as an equally important parameter (6). When radiosurgery
gradients are examined, special attention is paid to the portion of the
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distribution where the dose decreases from the prescribed target dose to
one-half the target dose (9,12,20,30). As the volume of treated target
increases, the volume contained in the rim of normal tissue rapidly
expands. Therapies for both malignant and benign disease have shown
limitations on the safe maximum target volume of a single fraction. As
the volume of the targets increases, the dose that can be safely delivered
decreases. It is thought that this expansion of the volume of the high-
dose rim is at least partially responsible for the dose–volume limit placed
on radiosurgery treatments.
The importance of gradient can be appreciated by examining the
volume enclosed in the high-dose gradient, a shell defined by the edge of
the prescribed isodose volume to one-half the treatment volume. The
first evidence of a volume-limiting normal tissue threshold was the safe-
dose threshold versus target size published for particle beams (12). This
curve demonstrates the relationship between complications and
increasing target volume. Many other reports have provided clinical
evidence demonstrating the correlation between increasing volumes and
complications. Several reports have associated an increase in the 12 Gy
volume with an increase in complications. As can be seen in Figure 13.7,
the high-dose shell exposing normal tissue exponentially increases in
volume as the target linearly increases. The lower curve in Figure 13.7
demonstrates the increase in this shell’s volume if the steep dose
gradient, defined as the volume between the prescribed isodose surface
and the isodose surface of one-half the prescribed dose, is maintained at
3 mm. The upper curve is the volume of this shell if the gradient is
allowed to degrade from 3 to 6 mm. The net effect of the lower-dose
gradient is that the limiting dose volume is reached at smaller target
volumes. For example, assume that it is safe to expose a rim of normal
tissue, 2.0 cc in volume, to a gradient that is decreasing from 20 to 10
Gy. If a plan has a high-dose gradient, 3 mm, as described above, this
volume will not be reached until targets of ∼4 cc (2.0 cm average
diameter) are treated. However, if the high-dose gradient is allowed to
degrade to 6 mm, then the 2.0-cc rim of normal tissue volume is reached
when a target of only 0.9 cc (1.2 cm average diameter) is treated. Paying
careful attention to the high-dose gradient is critical to the delivery of a
safe and effective therapy.
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FIGURE 13.7 Volume of steep dose shell for 3- and 6-mm gradients. Left: Demonstrates the
increase in volume of the encompasses by the 80% to 40% isodose shells for a 3-mm gradient
and a 6-mm gradient. Right: Shows the effect of this change on a metastatic target.
Early radiosurgery literature was based on particle-beam treatments.

For these treatments, the Bragg peak provided a delivery tool that
allowed for both high conformality and little exit dose. The absence of
an exit dose provides for a smaller integral dose to be delivered. Due to
the necessary broadening of the proton’s Bragg peak, the proximal,
upstream dose is approximately equal to that of a photon beam. When
this upstream dose is coupled with the smaller number of beams used in
a routine proton plan, it becomes difficult for protons to outperform
photons within the abovementioned gradient zone.
The literature that established the long-term efficacy and safety of
intracranial radiosurgery, using both GammaKnife and Linac, has several
treatment techniques in common. The first is the optimization of dose
through the use of sphere packing. The second is that in order to create
the spherical dose distribution for each intracranial dose volume, the
target was placed at the center of the teletherapy system’s isocenter. The
third is the alignment of the patient through the use of a rigid
stereotactic headring system (10). Placing the treatment’s focus at the
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isocenter eliminated all but a few of the delivery machine’s mechanical
parameters. Under these conditions, the rotation of the collimator and
gantry only produce a spherical dose distribution, resulting in little to no
effect on the delivered dose. However, if multiple targets are treated
simultaneously, coupled with image-based alignment of the patient’s
anatomy through treatment unit-based imaging, these parameters can
affect both accuracy of beam placement and the distribution’s resultant
dose gradient (1,7,38). Take, for example, the treatment of two targets 8
cm apart. Instead of treating each target separately at isocenter, assume
that the first target is set at the unit’s isocenter and the other is targeted
off-axis. If one assumes a 1-degree resolution in the teletherapy unit’s
readouts and 1 degree in image-based patient alignment accuracy, errors
of half a degree (an error below that of the system’s readouts) can more
than double the isocentric error of a linac. It is therefore recommended
that before such “efficient” approaches are applied, the individual
clinical situation is carefully evaluated and the potential and
consequence for such inadvertent errors are considered.
IMAGING: BI-PLANAR IMAGE–BASED TARGET

DEFINITION
To provide a highly conformal treatment with steep dose gradients, the
system must be able to provide a spatially accurate description of the
tissues to be targeted. While suffering from a lack of true 3D target
descriptions, plane film fiducial–based systems can provide the position
of a point within a stereotactic reference frame to within a few tenths of
a millimeter (Fig. 13.8). The overly defined fiducial system and solution,
as described by Siddon (39), not only provides high-precision spatial
accuracy but also removes the previously required orthogonal geometry.
As late as the 1980s and early 1990s, images used to define intracranial
targets, such as arteriovenous malformations (AVMs), were obtained on
plane film x-rays. These systems utilized flat-imaging planes that in turn
provided the clinician with spatially undistorted projections. The
temporal resolution was limited to the speed at which film changers
could shuffle film in and out of cassettes, approximately two images per
views per second. As x-ray film gave way to higher speed image
intensifiers, these unwarped projections were lost. The image
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intensifier’s distortions were not only complex in any single orientation
but could vary nonlinearly with the orientation of the image intensifier.
With the adoption of solid-state detectors, these projections are again
able to be presented without spatial distortion.
FIGURE 13.8 Showing stereotactic system for plane films and target localization data. A: Siddon’s
description of the mathematic solution. B: Showing variable phantom that allows for targets to be
set throughout the entire stereotactic volume. C: Showing data from nine experiments that
examine the results along individual axis and in combinations.
Simple orthogonal image sets are not capable of providing 3D

descriptions of such vascular targets. Figure 13.9 shows a series of
objects for which the orthogonal projections do not provide the
information required for true 3D reconstructions. While such views have
been used for decades to reconstruct implanted radiation sources, the
vascular images differ in that unique points in each projection cannot be
matched. Although these solid-state imaging systems provide clinicians
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with the perception of the 3D nature of the vasculature, the systems
have not attempted to format and map this data relative to a stereotactic
reference system.
While angiography remains the gold standard for detection of most
vascular targets, due to the above limitations, computed tomography
angiography (CTA) and magnetic resonance angiography (MRA) became
the stereotactic targeting modalities of choice. This has resulted in many
commercial stereotactic systems abandoning radiographic fiducial
frames. Newly introduced imaging platforms capable of rapid rotation
during angiographic image acquisition and cone-beam reconstructions,
CBCT-A, have begun to compete with MRA and CTA as viable
stereotactic imaging modalities (18). Currently, the unavailability of the
required fiducial systems make it difficult for CBCT-A to gain a clinical
foothold as a primary stereotactic data source. However, if this 3D
dataset can be mapped and fused to a stereotactic dataset, such as a CT
dataset, then cone-beam computer angiographic targeting can be
incorporated into a conformal radiosurgical planning pathway.
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FIGURE 13.9 Series of objects for which a 2D projection are inadequate for an accurate 3D
description.
IMAGING CT
The first significant advance in the ability to define a true 3D
intracranial target volume relative to a rigid reference system was the CT
fiducial rod system (Fig. 13.10) (10,16). The addition of the CT fiducial
reference to a stereotactic frame provided a means by which imaged
target tissues could be accurately and precisely mapped to a stereotactic
reference platform (15). The stereotactic frame provided a method of
analyzing each CT slice by mapping CT pixels to stereotactic-based
voxels (10,33,35,41). By analyzing the rods on each image, it also
provided a framework for image-by-image quality assessment. These
systems removed scanner-dependent parameters from the required image
analysis and subsequent mapping. No longer was it necessary to obtain
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an individual image’s relationship based upon the CT table’s index or the
scanner’s alignment to the stereotactic frame. All such parameters could
now be derived from information contained in each individual CT image.
FIGURE 13.10 A fiducial cage is shown with three transaxial plains. Each image intersects all nine
fiducial rods. The right-most figure shows the fiducial cage attached to a headring with the
stereotactic grid mapped onto the upper projection.
FIGURE 13.11 Image of effects of severe CT gantry tilt (30 degrees).
Not all scanner misalignments are controllable or easily observed

during the scanning process. As CT tables are made more radio
translucent, they begin to lose the rigidity needed to provide alignment
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of the patient and reference system to the scan plane. The patient may
be rotated along several axes and the scanner gantry may not remain
perfectly aligned as the scan progresses and the table is extended
through the scanner portal.
While a severe gantry tilt (shown in Fig. 13.11) can be readily
identified at the time of image acquisition, small tilts may be more
difficult to detect by casual visual inspection of the dataset. For example,
if a patient’s stereotactic frame is tilted 0.5 degrees relative to the CT
gantry, an error of 2.6 mm in the superior–inferior axis across a 300-mm
diameter scan will result. Similar errors will result from misalignments
between the reference system and the scanner’s imaging plane. If the
stereotactic mapping algorithm is not capable of detecting these
misalignments, errors of several millimeters can quickly accumulate.
Some systems have approached stereotactic mapping by simply setting
the axial coordinate of a given CT slice to the axial coordinate at the
center of the scan. This procedure can result in millimeters of error as
more anterior and posterior targets are localized. The ability to
guarantee such small misalignments during clinical applications is
difficult. It is therefore critical for the stereotactic localization system to
be rigorously tested for accurate identification and correction of such
possibilities.
It is advisable to incorporate detection of misalignment into
radiosurgical image-processing algorithms. This can be done with a high
degree of certainty when a fiducial array is incorporated into the
imaging procedure. When, however, such systems are not present, as is
the case in many mask-based procedures, these subtle errors become
difficult to detect and correct. One potential solution is to place a known
rigid object in the imaged volume (24,25,34). Figure 13.12 shows a CT
scan for a masked-based system. Prior to treatment, an algorithm is
executed that analyses the reconstructed geometry of the sphere array
and provides an estimate of the error in the volumetric dataset. If
submillimeter precision is to be maintained, the solutions to these
potential problems must be incorporated into the stereotactic image
processing—planning–treatment algorithms.
The ability to perform a local test of stereotactic localization requires
assessment of computed stereotactic coordinates relative to a known
standard. It is important not only for the stereotactic coordinates of the
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test object to be known, but also that the test points are distributed
through the defined stereotactic volume, not only at the center of the
imaging volume. As with the above example, a small tilt may correctly
calculate the center of the defined stereotactic space. However, as the
stereotactic mapping moves away from the center of the volume to the
outer edges, the errors are magnified.
A simple test object has been developed initially for frame-based
quality assurance (29). This object contains spherical targets spaced
throughout the frame’s defined stereotactic volume, allowing a series of
tests to be performed by the user that verifies the correct computation of
these known stereotactic coordinates under varying patient–scanner
alignments. Misalignments that can be individually tested or tested in
combination are: (1) gantry tilt, (2) patient frame tilt, and (3) patient
frame rotation.
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FIGURE 13.12 Optical target system with a known geometry can be used to detect CT scan error
or patient inter-scan movement. A: Left shows an acceptable scan with the reconstructing of the
known fiducial system predicting errors less than a pixel in dimension at 10 cm from the array and
right shows a failed test with the errors predicting approximately a two pixel error at 10 cm from
the array. B: Shows the localization of a spherical fiducial marker best fitted to a circular template
helping to minimize pixelation error.
Figure 13.13 shows two types of phantoms: a fixed absolute phantom

and a variable phantom. Each phantom can be attached to a fixture that
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allows for the attachment of a CT localizer as well as to a fixture that
allows the system to be mounted onto the treatment unit. This provides
a system that can examine the alignment of the stereotactic process from
imaging through planning and treatment. The fixed phantom has six
targets at known stereotactic positions. Figure 13.14 shows the results of
a series of tests. In these tests the phantom was first aligned as precisely
as possible to the CT scanner. Then tilts, spins, and gantry tilts were
introduced. The CT scans were then processed by the program that
automatically found the fiducial rods in each image and then processed
the image set, mapping the voxels to the stereotactic ring’s reference
coordinate system. The results of this test show that the center of each of
the known targets was correctly mapped to within one pixel,
demonstrating the system’s ability to correct for such misalignments
during routine scanning. Figure 13.15 shows the absolute phantom being
used with an optical alignment system. If a ring-based system and known
fiducial device is not available, then a hidden phantom test can be
utilized. The hidden target test provides for a test of the entire imaging–
planning–treatment delivery process. If an error is found then more
testing of sub system can be conducted. The availability of 3D printers
makes the manufacture of special phantoms for such testing within the
reach of many clinics. Figure 13.16 shows a skull printed in a 3D printer
within which hidden targets can be placed. This allows the full effect of
a masked-based teletherapy image-based alignment treatment delivery
system to be tested on a realistic anatomic model to better replicate the
real-world situation.
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FIGURE 13.13 Lower images show variable Winston–Lutz phantom and angiographic with and
without fiducial system, upper images show fixed 6 target absolute phantom with CT with and
without localizer attached.
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FIGURE 13.14 Table shows results of scanning the absolute phantom (see Figure 13.11) with CT
localization. Separate runs for phantom spin, tilt and combination spin, and tilt and gantry tilt are
shown.
FIGURE 13.15 Absolute phantom and optical positioning system used for end-to-end testing, from
image acquisition through delivery.
One important factor in calculating stereotactic coordinates is the

ability to account for errors inherent in the pixilation of fiducial systems.
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With a routine CT image matrix of 512 × 512 pixels and a scan
diameter of approximately 350 mm to encompass a stereotactic fiducial
reference system, the in-plane pixels have dimensions of 0.67 × 0.67
mm. A fiducial rod of 4 mm in diameter that is randomly aligned in the
field of view can demonstrate significant sampling errors. Using prior
knowledge that the rod is straight and that the rod images must
therefore fit a straight line, many of the errors introduced by the pixel
dimension can be corrected. For the optical system shown in Figure
13.15, the knowledge that the passive fiducials are round can also be
used to help correct for these pixilation effects.
MR IMAGING
Over the past three decades, MRI has become the dominant imaging
modality for soft tissue target definition. A host of sequences have been
developed that assist in the differentiation between normal tissues and
target tissues. Most systems rely heavily upon MRI to provide the target-
to-normal tissue contrast necessary for targeting definition. While the
superior contrast of MR scanning for most solid targets is critical for
planning, MRI has limitations in providing pristine spatial uniformity.
The perturbations in the magnetic fields introduced by the patient result
in susceptibility errors that warp the MR image. These errors are most
dominant at the interface of changes in soft tissue and bone, and again
at the interface of tissue and air and in the vicinity of any materials that
introduce magnetic perturbations (17). A second set of errors in direct
fiducial-based MR stereotactic imaging are introduced by the positioning
of the fiducial systems at the outer most diameter of the image, an area
where magnetic fields are least uniform. A third issue that arises when
direct MR stereotactic imaging is attempted is that the size of the
fiducial system and the stereotactic ring system often do not fit into head
coils that have been optimized to provide the best tissue contrast and
image uniformity.
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FIGURE 13.16 Two skulls reproduced using a 3D printer. The use of such devices allows the user
to reproduce anatomic structures providing a means of testing image based time-of-treatment
positioning system.
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FIGURE 13.17 Image demonstrating successful CT-MR image fusion. Image alignment is
inspected in all three anatomic planes. Bottom image demonstrating alignment at target location.
Many systems have adopted MR-CT image-registration techniques,

also referred to as “Image Fusion Techniques.” These approaches allow
the best MR images to be obtained, often requiring head coils that
cannot accommodate a stereotactic localizer. Image Fusion Techniques
register these images with the spatially more accurate, but often lower
contrast, CT dataset, thereby providing the best of both systems and
compensating for each system’s limitations. Figure 13.17 shows a typical
MR-CT dataset aligned. The structures identified on both scanning
systems provide images of common tissue boundaries, thereby allowing
clinicians to judge the acceptability of the fusion-alignment process.
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One other advantage of nonstereotactic MR scanning is that the
imaging of the target tissues can be obtained hours or days before the
radiosurgical procedure is to be carried out. For procedures where
stereotactic rings are used, this allows for consultation and planning
without the constraint of a patient waiting on the day of procedure.
DOSE PLANNING
As previously mentioned, the criteria of conformality and gradient have
been the primary focus for plan optimization. For historical sphere
packing and target shapes that are not spherical, planning moves to the
procedure of filling the target volume with spheres (Fig. 13.18). The
resultant hotspots within the target have not been shown to be
associated with increased complications. This is supported by numerous
GammaKnife-based studies in which targets were treated with anywhere
from 80% of the maximum dose to 50% of the maximum dose. These
same sphere packing techniques were adopted by early linear accelerator
Radiosurgery systems. Due to the near uniform sensitivity of intracranial
tissues, a uniformly steep gradient is most times considered optimal. A
notable exception is for targets near the optic processes, which are
considered more sensitive for both single and fractionated treatments. In
these cases, gradients can be altered to produce a steeper gradient. For
example, gradient alteration is often used in the optimization of
treatments involving pituitary targets. In the case of the pituitary, the
optic chiasm lies just superior. Producing a steeper gradient in the
direction of the optic chiasm, at the sacrifice of more lateral tissues, is
often considered beneficial (Fig. 13.19).
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FIGURE 13.18 A hypothetical target being progressively covered, starting in the upper left and
progressing to the lower right, by varying diameter spherical dose projections.
FIGURE 13.19 Left image shows arcing planes distributed symmetrically the right image shows
the most superior beams eliminated increasing the dose gradient in the anterior–posterior
direction, decreasing the dose to the optic chiasm, while decreasing the gradient in the lateral
direction.
Many systems that approach dose planning from other perspectives

have been introduced. Dynamic conformal planning and inverse
planning have been applied to radiosurgical treatment. Dynamic
conformal planning, a technique that uses multiple nonconformal arcs
and beam’s eye collimation, has difficulty providing a high degree of
conformality when addressing very small, irregular targets (42,43). The
issue of conformality is better addressed by inverse planning and
intensity-modulated radiotherapy (IMRT), a technique that generally
employs a more limited set of beam paths. While directed gradients
against specific adjacent critical tissues can be accommodated, the
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gradient over 4 pi provides special IMRT challenges that must be
carefully evaluated. The gradient over the entire surface of the target
volume is particularly critical in most intracranial radiosurgery.
While sphere packing and intensity modulation are often seen as
competing technologies, they are in fact one in the same. Early
publications proposing intensity modulation as a potential approach to
dose optimization actually suggested packing the target volume with
spheres of differing intensities (Fig. 13.20) (2). To appreciate the
similarities of these approaches, one needs to examine the relative
output of the circular cones used to create the spheres. Figure 13.21
shows the output for a set of 6 MV radiosurgical cones. As can be seen,
the relative efficiency of monitor unit to dose begins to fall off toward
the smaller cone apertures. Let’s assume that the target volume to be
treated can be covered by two spheres, one 24 mm in diameter and one
10 mm in diameter. The output of the 24-mm collimator is 0.94 and the
10-mm collimator is 0.84, relative to that of the reference field. If one is
to deliver 15 Gy to the target volume, the 10-mm sphere would require
1.12 times the number of monitor units as the 24-mm collimator
(0.94/0.84 = 1.12). This is easily achieved if the spherical dose
distributions are delivered one at a time, as they are in a sphere packing
approach. However, if they are to be treated on one beam, as with
conformal therapy, then there are four options: (1) under dose the 10-
mm spherical volume, (2) overdose the 24-mm spherical volume, (3)
increase the 10-mm sphere to sacrifice conformality for increased
output, or (4) temporally modulate the beam to compensate for the
output factors. Figure 13.22 shows a series of distributions for treating
an acoustic neuroma where the degree of modulation for each of the
beams is shown.
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FIGURE 13.20 Diagram showing the potential creation of an intensity-modulated plan by packing
the target volume with spheres.
FIGURE 13.21 Relative output of spherical collimators with three potential scenarios of covering a
target volume. A: Covering the volume with two different spheres allowing for the required monitor
units of each segment to be separately calculated. B and C: The under- and overdose resulting
from treating the entire target with one conformal field allowing for only one monitor unit setting to
be selected.
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PRESCRIPTION ISODOSE
Because the goal of dose planning is to deliver an effective dose across
the target volume while minimizing the dose to normal tissues, the
selection of the prescription isodose shell has criteria that differ from
those used in routine fractionated therapy. Figure 13.23 shows a dose
distribution for a metastatic lesion using a conical collimator and five
noncoplanar arcs. Cross-plots of the dose along the lateral axis are
shown in Figures 13.23A–D. The first plot in Figure 13.23A shows that
the distance required for the dose to decrease from a target isodose shell
of 90% of max to 45%, half the target value, is 5.7 mm. Figure 13.24B–D
denotes the distance required if the 80%, 70%, and 60% isodose shells
are selected as the target isodose. As shown, the minimum distance, 3.8
mm, along with selecting the 80% isodose shell, provides the lowest
integral dose to normal tissue (36). This essentially selects a prescription
point just past the high-dose shoulder of the dose profile. If a lower
prescription isodose shell is selected, then the high-dose fall-off in
normal tissue encounters a lower plateau of the distribution. If sphere
packing is employed, and more than one isocenter is combined over an
irregular target volume, a small hot spot is often produced and the
resultant normalization can shift the optimized prescription shell down
to a lower value. Although tools are available to help dampen the extent
of these hotspots, prescription isodose shells of 70% through 50% are
commonly encountered. As previously mentioned, the target volume has
no normal tissue, and such hot spots, when confined to the target, have
not been correlated with increased complications.
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FIGURE 13.22 A skull-based tumor that was planned with sphere packing. Table shows the
sphere diameters and relative intensities.
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FIGURE 13.23 Dose cross-plot of a single isocenter, multiple non-coplanar arcing plan. The effect
of selecting the prescription isodose of 95%, 90%, 80%, 70% of maximum dose, demonstrating
that the dose falls most rapidly to one-half the dose when 80% of maximum dose shell is selected.
This provides maximum normal tissue sparing for near target doses.
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FIGURE 13.24 Plans for a simple acoustic neuroma two-isocenter plan for sphere packing and
VMAT plan. Also a more complex plan showing favorable VMAT planning.
Other planning techniques, such as volume modulation arc therapy

(VMAT), have also been applied to intracranial radiosurgery planning.
While these systems show excellent conformality, the ability to maintain
exceedingly tight gradients must be carefully evaluated. Figure 13.24
shows the conformality of a simple two-isocenter sphere packing plan for
an acoustic neuroma and one from several VMAT plans. As has been
observed, the optimal degree of VMAT can be difficult to judge. The
number of noncoplanar VMAT arcs, like the number of noncoplanar arcs
in a sphere packing plan, has been shown to affect the overall, 4 pi,
(1,40) dose gradient. While both provide excellent conformality, VMAT
plans have often produced a less steep dose gradient for small and
midsize targets, thereby increasing the volume of tissue exposed to near-
target dose levels. For larger targets, 2.4 to 3.0 cm average diameters,
the ability of sphere packing to rapidly converge and then diverge
becomes less effective and techniques such as intensity modulation begin
to compare favorability in the arena of dose gradient.
Because of the rapid development in treatment planning, the above
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comparisons are in a constant state of flux. However, the primary
objectives of the planning process remain the same: a high degree of
conformality and exceedingly steep dose gradients. Many groups have
suggested both conformality and gradient as critical planning parameters
(4,28,42). Wagner introduced a conformality gradient index (CGI) for
both conformality (CGIc) and gradient (CGIg) (42). For the gradient score
(CGIg), the formulation converts the volume of the prescription isodose
and the volume of the isodose that encompasses one-half the treatment
isodose into effective spherical volumes and then uses the radii of these
effective spheres to compute an average effective radius. Assigning a
score of 100 to an average radius of 3 mm, from prescription to one-half
the prescription isodose, the score is calculated as
Other conformality indexes have also been defined by the ICRU 62

(11) as the volume of the prescription of the isodose volume to that of
the planning target volume (PTV).
Another suggested conformality index utilizes the volume that

encompasses 95% of the PTV divided by the PTV. In yet another
conformality index formulation, suggested by Paddick, the volume of the
treatment isodose that does not include target volume is not counted in
the denominator (28) to ensure that the planning volume counted
overlaps with the target volume.
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The goal of radiosurgery is to mimic a surgical resection. The coverage
of the PTV is set equal to the imaging target volume. The goal of the
planning process is to ensure that the full-imaged target is covered.
Because of the steep dose gradient, the omission of any portion of the
target volume is analogous to a subtotal surgical resection. It is therefore
common for the prescribed plan to encompass the entire imaged target
volume. The sensitivity of the intracranial tissues requires that safe and
effective treatments result in conformality indexes between 1.0 and 1.3.
With average target volumes in the order of 4 to 5 cc, these plans result
in less than 1 cc of normal tissue being exposed to the prescription dose.
The steep dose gradient also minimizes the exposure of normal tissue
adjacent to the target volume. Some typical treatment plans with
conformality indexes and dose gradients are shown in Figure 13.25.
TREATMENT MARGIN, PTV VERSUS GTV

Historically, for both benign as well as malignant targets, the
prescription isodose has been set to coincide with the enhancing volume.
This sets the clinical, or imaging, target volume, CTV, equal to the
planning target volume, PTV. As with the discussion of gradient,
increasing target volume ultimately results in the lowering of the safely
administrable, although less effective, dose. With submillimeter
localization and treatment delivery, nearly all centennial studies
establishing safety and effectiveness have adopted setting the PTV equal
to the CTV (23,37).
TREATMENT DELIVERY
The above imaging and highly conformal planning with steep dose
gradients requires a highly accurate delivery system. This necessitates
that stereotactic targets be aligned with delivery systems, and that
delivery systems be able to deliver multiple noncoplanar beams while
maintaining accurate alignment.
The early GammaKnife units provided the gold standard for
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stereotactic delivery. The design of the rigid source alignment with the
system’s stereotactic reference provided a stereotactic target to isocenter
alignment of 0.3 mm (19). Early linear accelerator systems had trouble
maintaining such critical alignments (3,8). Winston and Lutz introduced
a system that allowed for the evaluation of stereotactic target alignment
to the delivery system (22). This design provided a means by which
noncoplanar delivery accuracy could be measured. In 1988, Friedman
and Bova introduced a system to correct the linear accelerator’s gantry
and patient support “wobble” (9). Redesigned linear accelerators,
capable of maintaining submillimeter delivery alignments, were also
introduced in the mid-1990s. For such systems, the Winston–Lutz
delivery testing procedure remains the standard for certifying accuracy
in delivery.
The phantoms shown in Figure 13.13 can be used with the Winston–
Lutz test to provide end-to-end system testing. After evaluation of the CT
mapping program, the computer stereotactic coordinates can be used to
“treat” the phantom. This provides a process by which the entire image-
planning–treatment chain can be evaluated. Figure 13.26 shows the
results of such a test. Again, as with previous evaluations, it is critical
that targets throughout the volume of the definable stereotactic space be
evaluated. Only testing at the center of the defined volume can mask
errors in both image mapping and treatment delivery.
The beams used in radiosurgery treatment are often significantly
smaller than those used in routine radiation therapy. The complement of
beams usually does not exceed 40 mm and usually includes beams as
small as 5 mm. The measurement of these small beams poses special
problems and requires very small detectors (32). If routine “Farmer
style” chambers are employed for such small beams, then significant
errors in both beam profiles as well as output factors can be made (Fig.
13.27). Figure 13.28 shows beam profiles using numerous high spatial
resolution/small cross-section detectors as well as the effects of a large
volume detector. Figure 13.29 shows first how a set of small beams
behaves when plotted against off-axis distance and again how they agree
when plotted against percent beam diameter. Such cross tests should be
carried out to ensure that detector sizes are not affecting measurement
results. Figure 13.30 shows the output factors for a set of circular beams
as well as a set of small square fields. Again, cross checking using
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multiple detectors is critical in ensuring that errors can be identified as
these exceedingly small beams are measured.
Services such as those provided by calibration and quality assurance
laboratories are critical in the commissioning of each radiosurgery
system to ensure that all such parameters have been correctly measured
and correctly incorporated into the system’s treatment planning and
delivery system services. The ability to localize, plan, and treat a test
phantom and to have an independent laboratory verify the end result in
both accuracy and prescribed dose is critical. Utilizing such services
should be part of each new instillation’s calibration and certification
procedure.
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FIGURE 13.25 A: Six isocenter meningiomas, B: single isocenter for acoustic neuroma, C: two
isocenter plans for acoustic neuroma showing gradient (prescription to half prescription) of 2.28
mm, D: two isocenter plans for meningioma showing gradient of 2.16 mm, one isocenter 24-mm
collimator for metastasis showing gradient of 3.06 mm, and F: five isocenter plans for metastasis
showing gradient of 4.9 mm.
FIGURE 13.26 Left: Shows the results of a hidden target test. Targets are CT imaged, planned,
and Winston–Lutz films are taken and analyzed for total vector error. Right: Experiment setup for
Floorstand and optical guidance systems.
SYSTEM CRITERIA
While it is difficult to define absolute accuracy or precision in
stereotactic imaging or treatment delivery, it is possible to examine and
provide perspective on the effect of misalignments and errors. Figure
13.31 shows the addition of treatment errors to imaging errors and how
these added errors can quickly dominate the overall system accuracy.
Accuracy and precision can be affected by (1) incorrect mapping of
stereotactic coordinates during image analysis, (2) planning that does
not provide sufficient conformality or gradient, and (3) delivery systems
that do not maintain sufficient rigidity and precision during noncoplanar
beam delivery. These first two effects have been discussed previously.
The third can be simulated in the radiosurgery planning system.
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FIGURE 13.27 Beam profiles using small diode detector and larger ion chamber demonstrating
the errors possible when detectors of large size are used on small radiosurgical beams.
During treatment planning, a simulated radiation source is

maneuvered to deliver beams from various directions. The mathematic
model is designed to point at a specific stereotactic coordinate without
error. This specific error is referred to as the teletherapy unit’s isocentric
accuracy. This accuracy is determined by different design and
manufacturing parameters that vary with each type of delivery system.
In every case, the first critical alignment is the system’s ability to place a
specific stereotactic coordinate at the unit’s nominal isocenter or
reference point. In the case of the GammaKnife, the unit’s delivery
accuracy is then determined by how accurately the collimators are
aligned within the treatment head. For a linear accelerator delivery
system, it is the system’s ability to accurately rotate the gantry and
patient support unit about this isocenter. For robotic systems, it is the
robot’s ability to maintain alignment of the beam to a point in space.
And for tomographic units, it is the combination of the isocentric
rotation of the source and the system’s ability to accurately translate the
patient through the gantry.
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FIGURE 13.28 Beam profile of a 10-mm circular beam data taken with three high spatial
resolution detectors. (AAPM TG 42.)
FIGURE 13.29 Beam cross-plots for absolute distance from central axis and again as percentage
of off-axis distance that can be used to check for effects of detector size.
To help understand how isocentric accuracy can affect dose delivery,

one can simulate isocentric inaccuracy in the planning system. The
resultant dose distributions can then be compared to those derived from
perfectly aligned simulations. For an arcing linear accelerator delivery
system, dividing the arc into several segments and allowing each
segment to aim at a different stereotactic coordinate can accomplish this
simulation. Such a simulation was conducted with the gantry and patient
support rotation maintaining a plus or minus 1-mm isocenter accuracy
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along each orthogonal axis. For a typical mid-size target of 18 mm
diameter, the effects of this degree of inaccuracy result in a shrinking of
the 80% prescription isodose shell’s volume by 15% and an 80% to 40%
isodose fall off to decrease the sharpness of the gradient by 33%. While
it is difficult to translate these effects into treatment failures or
treatment complications, they do demonstrate the striking effect of small
errors in isocentric accuracy on the delivery of the prescribed dose as
well as the maintenance of the steep dose gradient.
FIGURE 13.30 Output factors for cones and small square fields.
FIGURE 13.31 Demonstrating the effects of treatment errors when added to imaging errors
(AAPM report 42).
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FIGURE 13.32 Checklist for time-out prior to initiation of the radiosurgical procedure.
THE TREATMENT PROCEDURE

Unlike routine fractionated radiation delivery, Radiosurgery requires
more of a surgical mindset (1). With a single-fraction therapy, all QA
and checking must be completed prior to the initiation of the first and
only treatment. This places special demands on the radiation oncology
department’s teletherapy delivery team, who are more aligned with an
incremental treatment technique.
To assist in the procedure, many departments have adopted a rigid
checklist to help ensure that each critical step is performed and verified
by more than one member of the clinical team. For a ring-based SRS
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procedure, this checklist would begin when the clinical team meets the
patient and continue until the treatment is complete and the ring is
removed. The procedure would include:
• A “time out”: Prior to ring placement, a “time out” is used to ensure

that the team is focused on the correct radiosurgical target for that
individual patient. Figure 13.32 shows a typical “time out” checklist
with the accompanying MR image showing the radiosurgical target.
• Specific written orders to accompany the patient to CT scanning
• A signoff by the treatment team on the quality of image fusion
• A signoff by the treatment team on the final plan
• The development of a treatment checklist that includes:
• A check of the plan’s transfer to the treatment systems record and
verify system
• The pretreatment QA ensuring:
• The correct patient and prescription has been transferred
• The unit’s accuracy is verified prior to each treatment
• A step-by-step procedure to ensure that every step is documented
and verified, including:
• Verification of the stereotactic coordinate
• The cone and/or the collimator settings
• The monitor unit setting for each treatment segment
An example checklist, automatically generated by the treatment
planning system, is shown in Figure 13.33. The use of such a checklist is
usually accompanied by a minimum of one double-check and often with
a third “blind check” to ensure that each parameter is properly set prior
to the initiation of each treatment segment.
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FIGURE 13.33 Checklist for SRS procedures automatically produced by treatment planning
system.
It is also critical to provide an atmosphere that allows the treatment

team to concentrate on delivery and not be distracted by phone calls,
scheduling questions or any other unrelated task. While an awareness of
the distraction of cell phones during tasks such as driving a motor
vehicle are being realized, similar distractions during complex
procedures, such as radiation delivery, are often not appreciated.
Forwarding the phones at the treatment unit’s console and inside the
treatment vault, prohibiting the use of cell phones, texting and voice,
throughout the procedure and minimizing any discussions that distract
the treatment team from the delivery process should be enacted.
Providing the proper environment as well as a thoroughly planned
procedure and post-procedure reviews are critically important to the
reduction of human errors and the identification of general system
failures.
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KEY POINTS
• Radiosurgery does not depend upon the differential sensitivity
between health and diseased tissue.
• Radiosurgery requires extremely high conformality.
• Radiosurgery requires very steep dose gradients over the entire 4

pi of the target’s surface.
• The radiosurgery process is perhaps the most demanding radiation

treatment process and requires redundancy throughout the
process.
• From imaging through planning and delivery it is essential to

provide end-to-end testing of all components and processes.
• Radiosurgery requires 3D targeting. Two-dimensional targeting can

lead to either over or under coverage of target structures.
• Prescription isodose is chosen to provide the maximum gradient at

the target to normal tissue interface.
QUESTIONS
1. Which of the following imaging techniques is not recommended
for defining the 3D shape of a vascular intracranial target?
A. Computed tomographic angiography
B. Magnetic resonance angiography
C. Cone-beam angiography
D. Orthogonal angiography
2. Which of the following is usually part of a radiosurgery quality
assurance testing procedure?
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A. CT slice–thickness assessment
B. MR uniformity assessment
C. Hidden target testing
D. Field flatness assessment
3. Which of the following factors limit the application of dynamic
conformal dose optimization?
A. The size of multileaf collimators
B. The rapid change in output factor for small field sizes
C. The isocentric accuracy of teletherapy units
D. The nonlinearity of film dosimetry
4. Which of the following radiation detectors are not used in small
field measurements?
A. Parallel plate buildup detectors
B. Diamond detectors
C. Diode detectors
D. Radiochromic film
5. Why do most radiosurgery treatment units utilize either Co-60 or
6 MV as opposed to 18 MV photons?
A. 18 MV has lower penetration
B. 18 MV has a greater penumbra
C. 18 MV has a steeper dose fall-off at the edge of the field
D. 18 MV beams are more polychromatic
ANSWERS
1. D
2. C
3. B
4. A
5. B
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automated radiosurgery planning. Int J Radiat Oncol Biol Phys.
2000;48(5):1599–1611.
44. Wu A, Lindner G, Maitz AH, et al. Physics of gamma knife approach
on convergent beams in stereotactic radiosurgery. Int J Radiat Oncol
Biol Phys. 1990;18:941–949.
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14 Stereotactic Ablative
Radiotherapy
Ryan D. Foster, Ezequiel Ramirez, and Robert D.

Timmerman
INTRODUCTION
Stereotactic body radiation therapy (SBRT) or stereotactic ablative
radiotherapy (SAbR) has been established over the last few years as a
highly effective local therapy for a wide variety of tumor sites. SAbR
requires accurate targeting, effective immobilization, and tumor motion
management to deliver an ablative dose to tumors in a few fractions
(typically less than 5), while sparing surrounding normal tissues via a
steep dose gradient outside the target. SAbR can be performed on a
variety of radiation delivery platforms provided the required mechanical
accuracy can be achieved and the system has the appropriate image
guidance for the disease sites that will be treated. SAbR has become the
standard of care for certain patient populations, including inoperable
early-stage lung cancer, inoperable liver metastases, inoperable primary
liver cancer and lung metastases. The goal of SAbR is to deliver a large
conformal dose per fraction to the tumor while using geometric
avoidance and an isotropic dose fall-off to spare normal tissue. SAbR is
an extension of cranial stereotactic radiosurgery (SRS) and has many of
the same characteristics, including a heterogeneous dose inside the
tumor, sharp dose gradients outside the tumor, highly effective patient
immobilization, and the use of many beams. Since the seminal
publications of Lax and Blomgren (1,2) describing extracranial
stereotactic irradiation using a linear accelerator in the mid-1990s, the
number of publications related to SAbR has increased by more than
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fivefold based on PubMed search results, indicating the intense interest
in and rapid adoption of this evolving therapy. While the early SAbR
treatments made use of an external stereotactic coordinate system,
which was usually embedded in a body frame, the advancement and
improvement of in-room imaging has made the need for a stereotactic
coordinate system largely unnecessary (Fig. 14.1).
FIGURE 14.1 Fusion of the planning CT scan to a Cone-Beam CT scan acquired on the treatment
machine allows for accurate repositioning of lung targets.
Since the previous edition of this textbook was published, SAbR has
blossomed into a well-established therapy for localized disease and is
considered standard of care for some disease subsites, thanks to
impressive local control results. SAbR is being investigated as a potential
therapy in an increasing number of disease sites and patient populations
and techniques to optimize this therapy are still being explored. This
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chapter guides the reader through all aspects of SAbR, including patient
simulation, quality assurance and treatment planning, and recent clinical
results for a variety of disease sites will be summarized.
RATIONALE AND GOALS

Historically, radiation therapy has been fractionated because spreading
out a large dose over many treatments is easier on normal tissue and
allows time for damaged cells to repair. Fractionation was necessary in
the early days of radiation therapy because it was the only way to give
tumoricidal doses to deep seated tumors with the available technology.
The disadvantage of fractionation is that tumor cells also can repair and
repopulate over a protracted course of therapy. The underlying reason
for the success of SAbR is still the subject of much debate. Postulations
of a “new biology” have taken root whereas others have made the case
for increased cell kill using the linear-quadratic (L-Q) model due to an
increased biologic equivalent dose (BED) (3–6). The hypothesis that
devascularization leads to indirect cell death is well accepted and it has
been shown that extensive tumor cell death can lead to an immune
response which may promote further cell death (7). Modifications to the
L-Q model have been proposed and shown to fit clinical data for both
conventionally and hypofractionated treatment regimens (8).
The initiation of an antitumor immune response as a result of focal
irradiation is particularly exciting, and SAbR could play a role in therapy
for patients with widespread metastatic disease, with the belief that
systemic therapy is unable to eradicate gross deposits of cancer and local
therapy could be of benefit. There is reported evidence of an abscopal
effect in a patients with metastatic melanoma treated with local
radiotherapy (9,10). In the initial case reported in the New England
Journal of Medicine, the patient was treated to a paraspinous lesion to
28.5 Gy in three fractions while tumors in the hilum and the spleen were
not treated with radiation. The patient also received ipilimumab, a
monoclonal antibody. The untreated tumors underwent a partial
response 3 months after radiotherapy and the response was durable out
to 9 months postradiation. The combination of SAbR and
immunotherapy is a novel application of this highly focused form of
radiation therapy and this application will certainly be studied
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extensively in the coming years.
SAbR has been made possible by technologic advances such as 3D
treatment planning, tumor motion assessment and visualization, highly
accurate dose calculation algorithms and in-room image guidance. The
goal of delivering an ablative dose to noncranial lesions while sparing
nearby normal tissues was not possible previously. Due to the
technologic advances and impressive clinical results, SAbR has rapidly
become an important tool for clinicians and patients in their fight
against cancer.
SIMULATION
The SAbR process starts with patient simulation, which includes several
key elements that will determine the success of the course of therapy.
Those elements include patient immobilization, motion management,
and accurate patient imaging. The first aspect of the patient simulation
that must be optimized is patient immobilization. Patients must be
immobilized in an effort to minimize voluntary motion but the method
used must be comfortable and reproducible. Various methods of
immobilization have been shown to be effective. Body frames (11,12),
vacuum fixation (13), and alpha-cradles (14) have all been used
successfully for patient immobilization during SAbR. The main goal of
patient immobilization is to ensure that the patient is in a reproducible
“state” at the simulation and, subsequently, in the same state at each
treatment. Patient immobilization aids typically consist of a custom-
formed cushion which molds closely to the patient surface (Fig. 14.2).
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FIGURE 14.2 The vacuum cushion and the stereotactic body frame used for SAbR patient
immobilization at UT Southwestern.
In most cases, the arms are positioned over the patient’s head and
must also be supported by a custom-formed cushion. If possible, the
patient should be supported on three sides, with the molded cushion
wrapping up along the sides of the patient. Patients may become
uncomfortable and be unable to remain still for the long treatment times
that accompany SAbR if the immobilization aids are poorly designed.
Effective immobilization can allow smaller PTV margins at the time of
planning, thus reducing the amount of normal tissue receiving a high
dose.
At the time of simulation, the tumor motion must be assessed for
patients receiving treatment to the lung or abdomen. For tumors in these
locations, motion due to respiration can be as large as several
centimeters and must be minimized or accounted for. Motion assessment
can be in the form of fluoroscopy, 4DCT or cine MRI. Motion assessment
provides the clinician with information about how the tumor moves
(period, amplitude, direction, regularity) and should guide the use of
motion management. The goal of the motion management should be to
reduce the motion envelope of the GTV to no more than 5 mm larger
than the GTV itself in any one direction. As with patient immobilization,
there are several strategies available for motion management, including
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abdominal compression (11,13), breathhold (15,16), gating (17), and
tumor tracking (18–20). Abdominal compression is the simplest method
for motion management in that it utilizes a compression plate to inhibit
diaphragm motion and forces the patient to use the intercostal muscles
for respiration and in the majority of cases, reduces tumor motion (21).
At UT Southwestern, tumor motion is assessed via fluoroscopy before the
CT to determine if compression is necessary. Our current threshold for
using compression is tumor motion more than 1 cm in the superior–
inferior direction. The major disadvantage of compression is patient
discomfort. If compression is to be used, the patient must be simulated
with the compression applied.
Breathhold has been used successfully for limiting respiratory motion
during the treatment of lung and liver tumors. Patients take a deep
breath and hold it either voluntarily or are assisted with a device that
prevents expiration for a short period of time. Patients receive training
at the time of simulation. The patient is treated only during the time
they are holding their breath and the breathholds typically last for 15 to
30 seconds, depending on the patient. Patients with poor lung function
are not good candidates for breathhold techniques because they are
unable to hold their breath for a significant length of time. Another
method for motion management is to gate the delivery of the radiation
so that the beam is delivered only during specific parts of the patient’s
respiratory cycle. Gating thresholds are determined during treatment
planning and the beam is on when the tumor (or more typically, its
surrogate) is inside the gating limits. The gating can be performed
manually or can be interfaced with the accelerator, allowing automated
gating. The major disadvantage of beam gating is that it has a low duty
cycle and increases treatment times. Another concern is the validity of
the correlation between tumor and surrogate motion. The final method
for motion management, tumor tracking, is technically challenging and
is not currently a widely used technique (22). However, it has
advantages over the other techniques in that it is not uncomfortable for
the patient and does not require the beam to turn off during delivery.
Currently available tracking methods track either an external tumor
surrogate or markers implanted in or near the tumor.
Accurate patient imaging is an absolute must for SAbR treatment
planning. Considering the small fields, sharp dose gradients and high
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doses characteristic of SAbR, the geometric and density information
acquired with the simulation CT must be highly accurate. Scan length
should be sufficient to include any potential organs at risk and the
entrance point of all noncoplanar beams. For accurate contouring of
small lesions, CT slice thickness less than 3 mm is recommended. 4D CT
is recommended for imaging moving tumors and organs in order to
account for residual motion after the motion management techniques, if
any, are used. 4D scans can be reconstructed into minimum, maximum,
and average intensity projection datasets. The maximum intensity
projections (MIP) reconstruction is useful for contouring the internal
target volume (ITV) for lung SAbR because it provides the motion
envelope for the tumor. The 0% and 50% phase reconstructions
represent the limits of respiration and can be used to help determine the
craniocaudal limits of the ITV. The minimum intensity projections
(MinIP) reconstruction should be used when contouring the ITV for liver
tumors because those lesions are typically less dense than the
surrounding liver. The average dataset is used for dose calculation and
as the reference for the cone-beam CT (CBCT) localizations at the time of
treatment.
Additional imaging may be required to accurately delineate the tumor
for certain disease sites. For example, tumors in the liver and spine will
be easier to contour on magnetic resonance imaging (MRI) than on CT
and MRI allows the spinal cord itself to be contoured, as opposed to the
entire spinal canal. Additional imaging that will be fused with the
treatment planning CT should be acquired in treatment position to allow
for more accurate fusion and contouring. Positron emission tomography
(PET) has limited usefulness during treatment planning for SAbR due to
motion artifacts that obscure the tumor size and location, but is
frequently used for evaluation of posttherapy response. Any registration
between a secondary image set and the planning CT must be evaluated
for accuracy before contouring begins.
TREATMENT PLANNING AND DOSIMETRY

One of the most important steps in treatment planning is contouring of
targets and critical structures. In general, any critical structure that is
within 10 cm of the target should be contoured to help obtain accurate
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dose to these structures from the planning system. An example of what is
contoured for lung cases at UT Southwestern Medical Center is as
follows:
1. ITV—contoured by the physician using the MIP (or MinIP for liver
tumors), 0%, and 50% (when requested). Represents the envelope of
motion of the GTV. Isocenter is placed in the geometric center of the
ITV for planning.
2. PTV—5-mm expansion around ITV in all dimensions.
3. Proximal bronchial tree—the most inferior 2 cm of the distal trachea
as well as the bilateral proximal airways.
4. Proximal trachea—contoured beginning 2 cm above the carina and
extends 10 cm superior to the PTV.
5. Spinal cord—contoured based on the bony limits of the spinal canal
and extends at least 10 cm above and below the PTV.
6. Esophagus—contoured at least 10 cm superior and inferior to the
PTV.
7. Heart—contoured along with pericardial sac. The superior aspect
begins at the aorta–pulmonary window and extends inferiorly to the
apex.
8. Total lung—contoured to include both lungs subtracting out the ITV.
9. PTV + 2 cm—PTV expanded by 2 cm in all dimensions (uniform
expansion)
10. Body—contoured as the patient’s body at least 10 cm superior and
inferior to the PTV.
11. Body–PTV + 2 cm—The PTV + 2 cm structure will be subtracted
from the body and the remaining structure is used to evaluate dose
fall off 2 cm in every dimension of the PTV (D2 cm).
12. Brachial plexus—contoured from the spinal nerves exiting from C5–
T2. This contour extends along the subclavian and axillary vessels to
the level of the second rib.
13. Skin ring—contoured to evaluate the skin dose and is a 0.5 cm ring
inside body.
14. Ribs—contoured as all ribs in close proximity to PTV.
There are several delivery techniques that can be used in SAbR
treatment planning and the choice of technique often depends on an
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individual patient’s tumor location and magnitude of motion, but most
often SAbR is delivered using 3D conformal beams. The use of IMRT or
VMAT for SAbR is typically reserved for tumors that exhibit limited
motion and when intensity modulation is necessary for critical structure
sparing, such as spine lesions. The 3D conformal beam arrangement for a
right-sided lung lesion is shown in Figure 14.3 and the gantry and couch
angles for right and left lung SAbR treatments are found in Table 14.1.
FIGURE 14.3 Reconstructed simulation CT of a lung patient showing the use of noncoplanar
beams and the bellows used for phase binning of the 4DCT.
TABLE 14.1 SAbR Couch and Gantry Angles for Right- and Left-
Sided Lung Lesions
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SAbR dose distributions are characterized by a highly conformal high-
dose volume and a very compact intermediate dose region which can be
achieved by using many noncoplanar nonoverlapping beams, which
insures a rapid isotropic dose fall off outside the target (23). The
intermediate dose is the most challenging aspect of SAbR treatment
planning and achieving this compactness separates a good plan from a
bad plan because the intermediate dose is responsible for normal tissue
toxicity. RTOG 0236 specified a max dose at 2 cm outside the PTV(D2
cm) and a ratio of the 50% isodose volume to the PTV volume (R50%) and
on average 10 beams were required to meet these compactness
constraints (24). There was no relationship found between PTV size and
number of beams needed. Due to the large number of beams, SAbR dose
distributions are also characterized by a large low-dose region.
In addition to the number and arrangement of the beams, the beam
apertures can be made smaller than the PTV to reduce the volume of
normal tissue treated. At our institution, the MLC aperture is 2 mm
smaller in the radial direction and 2 mm larger in the superior–inferior
directions, as shown in Figure 14.4.
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FIGURE 14.4 Beams eye view (BEV) for a lung SAbR 3D conformal MLC aperture. The aperture
is 2 mm smaller than the PTV in the radial direction and 2 mm larger in the superior–inferior
directions.
The dose distribution within the PTV will be highly heterogeneous and
the edges of the PTV will likely be underdosed if “negative margins” are
used. To cover 95% of the PTV with the prescription isodose line, the
plan will be normalized to the 60% to 90% (usually around 80%)
isodose line, resulting in a large hot spot in the tumor. The planner must
balance the need for a conformal dose distribution with the mechanical
limitations of the radiation delivery equipment and treatment delivery
efficiency. Beam weighting is chosen so that dose fall off is isotropic
unless an adjacent organ at risk makes isotropic fall off undesirable.
Beam energies used for lung SAbR plans are typically 6 MV and no
higher than 10 MV for beams that must traverse more than 10 cm of
tissue. Lower-energy beams have a sharper penumbra, which is
especially important in the low-density lung and for the small fields used
for SAbR due to the lateral electron disequilibrium (25). Higher-energy
beams can be used for targets in the liver and spine, where tumors and
the surrounding tissues are of similar density. Flattening filter free (FFF)
beams have been shown to decrease treatment times with the efficiency
improvements most significant for larger doses per fraction, such as
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those delivered with SAbR (26–29). By removing the flattening filter,
there is much less attenuation of the beam between the target and the
patient and dose rates as high as 2,400 cGy per minute at dmax can be
achieved. These beams are also more peaked and softer (lower beam
quality) than their flattened counterparts.
When planning lung SAbR, accurate heterogeneity corrections in the
planning system become extremely important. An analysis of patients
treated on RTOG 0236, which required homogeneous calculations, found
that the true delivered dose was approximately 10% lower than the
homogeneous dose (24). Task Group 101 from the American Association
of Physicists in Medicine recommends against using pencil-beam
algorithms for lung SAbR planning because of the over-prediction of the
dose in low-density tissues (30). Studies have shown the differences in
pencil-beam algorithms and more sophisticated heterogeneity
corrections to be quite significant (31,32).
Plan evaluation is a critical component of SAbR planning and all
contours should be reviewed by the radiation oncologist to ensure that
the contours are accurate and that dose being reported to critical
structures as well as the PTVs meet expectations. Table 14.2 contains
updated normal tissue constraints for 1, 3, and 5 fraction SAbR regimens
used at UTSW. The spinal cord and brachial plexus constraints take
priority and are always met, even if it requires the tumor to be
underdosed. Occasionally, the brachial plexus constraint can be
exceeded if informed consent is given by the patient. As mentioned
previously, 95% of the PTV should be covered by the prescription dose
and 99% of the PTV should be covered by 90% of the prescribed dose.
Hot spots should ideally be inside the PTV, but any volume receiving
105% of the prescription dose should be no larger than 15% of the PTV
volume. Guidelines for the use of D2 cm and R50%, which are used to
evaluate the compactness of the intermediate dose, can be found in the
RTOG guidelines (www.rtog.org). The conformality of the prescription
dose can be determined by calculating the ratio of the volume covered
by the prescription dose to the volume of the PTV. Ideally, this ratio will
be close to 1.
TABLE 14.2 Normal Tissue Dose Constraints for SAbR Delivery
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The critical volume dose is also an important tool in plan evaluation
for parallel tissues, such as the liver and lung. The critical volume
represents the volume of an organ that must be spared in order to avoid
toxicity. In these tissues, the amount of tissue damaged or the severity of
the damage is not as important as the remaining functional volume. The
traditional DVH has been used to determine how much dose a structure
receives. Shifting this concept to evaluate a structure based on how
much of the structure is spared a certain dose is the goal of critical
volume max dose as illustrated in Figure 14.5. By definition, critical
volume max dose is an absolute volume of an organ that is spared a
specific dose in order to avoid an endpoint effect. Dose–volume
constraints for parallel organs can be found in Table 14.2.
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FIGURE 14.5 DVH showing the concept of the critical volume maximum, which is the volume of
an organ that must be spared to avoid dysfunction.
COMMISSIONING AND QUALITY ASSURANCE

While the key difference in SAbR and conventional radiation therapy is
the dose per fraction, the safe and accurate delivery of that dose would
not be possible without the technology that has been developed over the
last several decades. The quality assurance activities of the medical
physicist ensure that this advanced technology is functioning properly
and will be instrumental in ensuring the success of an SAbR program.
Initially, the physicist will be responsible for commissioning new
equipment that will be used for SAbR, such as immobilization devices,
planning systems, and linear accelerators. If existing equipment will be
used, the medical physicist should evaluate its suitability for use in
SAbR. AAPM Task Group 142 provides test tolerances for linacs that will
be used for SAbR (33). As expected, mechanical tolerances for these
linacs are stricter than those that will be used for conventional
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treatments. Planning systems must be commissioned to accurately
calculate dose distributions and monitor units for small fields in
heterogeneous tissues. Errors made in commissioning of small fields
have led to serious overdoses (34,35). Guidance for small field
measurements is provided in AAPM Task Group 101 (30) and an average
set of small field output factors have been published by the Imaging and
Radiation Oncology Core (IROC), formerly the Radiological Physics
Center, for several linac models (36,37). Institutions can compare their
measurements to the RPC dataset to ensure that there are no major
errors in their data. End-to-end tests using anthropomorphic phantoms
such as those available from the IROC quality assurance centers (Fig.
14.6) for institutions participating in clinical trials can provide an
independent evaluation of the entire SAbR process, including the
simulation, the treatment planning, the image guidance, and the
delivery.
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FIGURE 14.6 Phantoms from the Imaging and Radiation Oncology Core (IROC) provide an end
to end test for the SAbR process.
Ongoing treatment-specific quality assurance should be aimed at

reducing systematic errors and deviations from normal processes.
Analysis of the uncertainties in the end-to-end process will aid in
developing PTV expansions needed to cover targets reliably. The
physicist will also be responsible for developing the patient-specific QA
process to ensure that the entire process proceeds as planned. Items in
the SAbR process that should be part of the patient-specific QA process
include verification that normal tissue constraints are met, that the
treatment planning and patient positioning parameters have been
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independently verified and the correct patient is treated. Guidelines for
implementing a safe and high-quality SAbR program can be found in a
recent white paper (38) endorsed by the American Society for Radiation
Oncology, the American Associate of Physicists in Medicine, the
American Society of Radiologic Technologists, and the American
Association of Medical Dosimetrists. This white paper also includes
recommendations on personnel, training, and technology requirements
and provides example checklists and forms than can be amended for use
according to the individual institution’s needs.
LUNG CANCER
More than 25% of all cancer deaths every year can be attributed to lung
cancer, making it the leading cause of cancer-related death in the United
States (39). Lung was one of the first sites treated using SAbR (1) and it
continues to be the site most frequently treated with this technique (40).
Clinical use of lung SAbR has increased in recent years, with more than
half of surveyed radiation oncologists reporting that they began using
SAbR after 2008 (40). The most common reported fractionation scheme
was 18 to 20 Gy × 3 (43%), likely due to the success of RTOG 0236,
which showed a 3-year primary tumor control rate of 98% and overall
survival of 56% (41) in medically inoperable patients with early-stage
nonsmall cell lung cancer (NSCLC). Recently reported long-term results
from the trial found rates for 5-year primary tumor control and overall
survival to be 93% and 40%, respectively (42). Excess late toxicities
have not been observed, dispelling fears of such late toxicities with
hypofractionation. Results from RTOG 0236 and similar results from
other countries have cemented SAbR as the standard of care for
medically inoperable early-stage NSCLC.
For patients who are medically operable and treated with 54 Gy in
three fractions, RTOG 0618 found that 2-year progression-free survival
and overall survival were 65.4% and 84.4%, respectively (43). Only four
patients on the trial experienced treatment–related grade 3 adverse
events while no patients had grade 4 to 5 toxicity.
A more definitive examination of SAbR as a lung cancer therapy was
published in an analysis of a Dutch cancer registry (44). They examined
the time trend pattern of treatment for elderly patients with stage I
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NSCLC from 1999 to 2007. They divided this period into a pre-SAbR era
(1999 to 2001), some SAbR availability era (2002 to 2004) and a fully
available SAbR era (2005 to 2007). They found that the introduction of
SAbR coincided with a 12% decrease in the number of untreated patients
and an increase in overall survival for patients treated with radiation
therapy, an increase that was not seen in patients treated with surgery or
those receiving no treatment. While not a randomized trial and no
definitive link can be proved, it is plausible to believe that the
introduction of SAbR offered a more curative treatment option for this
population of patients.
RTOG 0915 investigated less potent fraction schemes for stage I
peripheral NSCLC, with the goal to identify a more favorable
fractionation scheme based on the rate of grade 3 or higher toxicities at
1 year. The trial compared 48 Gy delivered in four fractions and 34 Gy
delivered in one fraction. Results found similar overall survival,
progression-free survival and primary tumor control rates (45) for both
arms and the 34 Gy arm met the adverse event criteria and was chosen
as the experimental arm for a planned phase III trial comparing it
against 54 Gy in three fractions.
Optimal regimens for centrally located tumors continue to be an area
of active investigation (Fig. 14.7). RTOG 0813, a phase I/II trial to
determine the maximal tolerated dose for central lung tumors in a five-
fraction regimen recently closed after meeting the accrual goal. Efficacy
of SAbR for controlling centrally located tumors has been shown to be
nearly equivalent to control of peripheral tumors (46,47), demonstrating
that SAbR is indicated for these tumors when appropriate fractionation
schemes are used.
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FIGURE 14.7 Stereotactic body radiation therapy (SAbR) of a central lung tumor treated on
protocol. Panel A shows the isodose plan. Follow-up scans are shown at 3 months, 6 months,
and 1 year in panels B, C, and D, respectively. There was an excellent initial response with
eventual collapse of the downstream lung.
In addition to stage I patients, use of SAbR is being expanded to other

patient populations who historically did not receive radiation therapy or
received no therapy at all. Results from a phase II trial investigating
SAbR and erlotinib for patients with metastatic (stage IV) NSCLC who
progressed after chemotherapy were recently published (48). Patients
with fewer than six metastatic extracranial lesions were treated to all
sites of disease with SAbR to a modest tumor debulking equivalent dose.
With median follow-up of 16.8 months, progression-free survival was
14.7 months and overall survival was 20.4 months, both superior to
patients historically treated with systemic therapy alone. The pattern of
failure also changed, from predominantly existing sites to new sites.
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LIVER METASTASES
Approximately 150,000 Americans are diagnosed with colorectal cancer
annually, making it the third most common cancer diagnosed (49).
Approximately one-third of these patients die from the disease, with
liver metastases a leading cause of death (50,51). The liver receives
nutrient-rich blood from the digestive system (stomach, intestines,
spleen, and pancreas) via the portal vein, making it a common site for
trafficking and growth of metastases from gastrointestinal cancers. Other
primary cancers including lung, breast, and melanoma also frequently
metastasize to the liver. Surgery is the treatment of choice because it
offers the most established chance of long-term survival. However,
despite advances in surgical techniques, only 10% to 25% of patients
have metastases that are considered resectable due to existing liver
disease, number, and size of the lesions, liver damage from
chemotherapy and location of the metastases within the liver as well as
coexisting patient medical comorbidities (52,53). As a result, there is
great interest in minimally invasive ablation technologies to include
radiofrequency ablation (RFA), cryosurgery, and laser-induced
thermotherapy (54–60). However, these treatments are all invasive,
efficacy rates are dubious and patients are frequently not eligible for
these procedures for various reasons. RFA, a commonly used ablation
method, is limited in efficacy by tumor size as well as vascular heat sink
effects common in larger tumors (61). Cryosurgery can cause significant
morbidity and has a high local recurrence rate (62). No studies have
shown that any one of these therapies has clear advantages over the
others.
Historically, the use of whole or large volume liver radiation therapy
has been limited due to the risk of radiation-induced liver disease
(RILD), a variably defined condition marked by ascites, rapid weight
gain, elevated liver enzyme levels, and anicteric hepatomegaly.
Histologically, RILD appears as a form of veno-occlusive disease (VOD)
(63,64) with venous congestion of the central portion of the liver
lobules. RILD can lead to liver failure. The whole liver tolerance of 30 to
35 Gy is insufficient to achieve reasonable tumor control. In contrast to
conventional radiotherapy, SAbR has allowed radiation oncologists to
focally target lesions and deliver high doses of radiation very accurately
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to the tumor while sparing the healthy tissue around it. SAbR provides
certain advantages relative to thermal ablations technologies, chief
among them the noninvasive nature of the treatment as well as the lack
of a heat-sink problem. Several groups have published studies using
SAbR for tumors in the liver (65–73). Overall, SAbR has shown to
provide excellent local control for patients with liver metastases with
little toxicity. However, patients with larger tumors or treated with
lower doses have been shown to have worse local control and survival
(67,74,75), indicating that increasing the dose in general, but especially
to larger tumors, may improve outcomes.
Although prior studies established dose limits for irradiation of the
entire liver, dose–volume limits for partial liver irradiation are less well
established. Schefter et al. from the University of Colorado and Indiana
University performed a prospective dose escalation trial where the
maximum tolerated dose (MTD) was not found in the high-dose ranges
investigated (76). Patients treated in this study had tumor diameters less
than 6 cm and at least 700 mL of normal liver (the presumed critical
volume) was restricted to receiving a total dose less than 15 Gy (the
presumed tolerated dose). Total dose was escalated to 60 Gy in three
fractions without any RILD or grade ≥3 dose limiting toxicities. The
median gross tumor volume (GTV) was 18 cc and the median planning
target volume (PTV) was 41 cc. Phase II results of this trial using the 20
Gy × 3 dose regimen have been encouraging; actuarial local control two
years after SAbR was 92% and for lesions less than 3 cm in diameter, it
was 100% (72). At UT Southwestern, we have conducted two dose-
escalation SAbR liver studies, one using three to five fractions (73) and
another using a single fraction, the preliminary data for which was
presented at the American Society of Radiation Oncology’s annual
meeting in 2014 (77) and has been submitted for publication. The
multifraction trial found that 60 Gy can be safely delivered in five
fractions as long as normal liver constraints were met and local control
rates at 12 and 24 months were both 100%, respectively (Fig. 14.8). The
single fraction study found 40 Gy in a single fraction to be a tolerable
dose and at 1.8 years median follow-up, no patients had experienced
local progression and 50% of the imaging-evaluable tumors had
undergone a complete response. In general, it’s been determined that
local control increases with increased dose, particularly for larger
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tumors, and larger tumors can be treated so long as the critical volume is
respected.
FIGURE 14.8 Axial, coronal, and sagittal isodoses from liver stereotactic body radiation therapy
(SAbR) treated to 60 Gy are shown in panels A to C, respectively. Panels D to F show 3-month, 6-
month, and 1-year follow-up.
Patients with tumors at or near the hilum of the liver (central liver
zone) and thus near major vessels, such as the portal vein and hepatic
artery as well as large-caliber bile ducts, are ineligible not only for
invasive treatments, but are also often excluded from treatment with
thermal ablation and single fraction SAbR courses, including our own
phase I single fraction trial. The tissue at the liver hilum likely has a
lower tolerance to ablative radiation doses, similar to that seen in SAbR
treatment of central lung tumors (78). Biliary sclerosis and jaundice
requiring stenting have been seen in patients treated with SAbR to the
central zone of the liver. A better understanding of the central zone
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tolerance to ablative radiation doses will be important in order to make
this treatment option available for patients with tumors in the central
zone of the liver.
HEPATOCELLULAR CARCINOMA
Experience with SAbR for hepatocellular carcinoma (HCC) is certainly
more limited than that for liver metastases due to the underlying liver
disease that accompanies HCC. Patients with HCC often are not eligible
for curative treatments due to disease stage or poor liver function (79).
However, SAbR is emerging as a potential definitive therapy or as a
bridge to transplant. Researchers from Indiana University published their
experience for Child–Turcotte–Pugh (CTP) Class A and B patients treated
with median of 44 Gy in three fractions and 40 Gy in five fractions,
respectively (80). Their median follow-up was 27 months and the 2-year
local control, progression-free survival and overall survival were 90%,
48%, and 67%, respectively. The reported 2-year local control was better
than that from a previously reported study (81), likely due to the larger
tumor volumes treated in the earlier study. All ≥grade 3 toxicity was
hematologic, but 7 of 36 patients with CTP Class A progressed to CTP
Class B and 5 of 24 patients with CTP Class B progressed to CTP Class C.
The authors found that pretreatment CTP Class and development of
toxicity were related. Another study treated patients with more
advanced liver disease to a median dose of 34.4 Gy in six fractions (82).
Median survival was 7.9 months and overall survival at 1 year was
32.3%. During follow-up, no patients experienced progression of
irradiated HCC and there were no grade 3 or higher acute toxicities. In
general, studies for SAbR as a definitive treatment for HCC have found
that tumor size and liver function should be carefully considered before
treating these patients. Hypofractionation is also being explored as a
bridge to liver transplants. Radiotherapy can be used to downsize or
stabilize tumors prior to liver transplant. A 10-fraction regimen
delivering 50 Gy was found to be very effective with 12 patients
receiving liver transplant or resection following irradiation and were
alive at a median follow-up of 19.6 months (83).
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SPINE
The spine is a frequent site of metastases from primary cancers of the
prostate, lung, breast, and kidney. Spine metastases can cause pain and
lead to fractures and spinal cord compression. Historically, spinal
metastases have been treated with 30 Gy in 10 fractions for palliation
and this dose regimen has provided good pain relief. However, higher
dose are needed to provide durable pain and tumor control. There are a
variety of fractionation schemes being used including single and
multifraction regimens. Figure 14.9 illustrates a spine SAbR plan
prescribing 20 Gy in one fraction. A recently published study of a three-
fraction regimen with total doses ranging from 27 to 30 Gy found
significant reduction in patient reported pain at 6 months post-SAbR,
progression-free survival was 80.5% at 1 year and 72.4% at 2 years (84).
A study of spine SAbR for renal cell metastases to a median dose of 24
Gy in two fractions found 1-year overall survival and local control rates
of 64% and 83% with oligometastatic disease status a positive
prognosticator for overall survival. The phase II portion of RTOG 0631
demonstrated that spine SAbR/SRS was feasible, safe, and could be
performed at a high level by a cooperative group (85). The phase III
portion of the trial will compare 3-month pain relief and quality of life
for patients treated with single fraction 16 to 18 Gy SAbR versus patients
treated conventionally with 8 Gy in a single fraction.
FIGURE 14.9 Panel A shows a stereotactic body radiation therapy (SAbR) isodose plan of a
patient treated to 20 Gy in a single fraction with IMRT used to create a sharp dose gradient toward
the spinal cord. Panel B shows follow-up at 6 weeks with radiation pneumonitis corresponding to
the 10-Gy line.
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Spine SAbR is being used increasingly in the reirradiation setting for
patients who progress through conventional palliative courses (86) but
the optimal dose and fractionation scheme for the reirradiation has been
confounded by a poor understanding of the spinal cord tolerance and its
ability to repair previous radiation damage. Sahgal et al. analyzed
myelopathies that occurred after reirradiation with SAbR and provides
guidelines for presumed tolerant SAbR following conventional treatment
for spinal metastases. Preclinical studies in a large animal model have
shown that reirradiation 1 year after a conventional course of radiation
therapy had the same ED50 for paralysis as those that received single
fraction therapy alone (87). While animal data may not be directly
applicable for human spinal cord tolerance, it can be useful in guiding
the development of clinical trials. The most common toxicities following
spine SAbR are myelopathy (88) and iatrogenic vertebral compression
fracture (VCF) (89,90) and both are associated with higher doses while
probability of VCF is also correlated with pre-existing tumor-related VCF
(90,91).
PROSTATE
Prostate cancer accounts for 27% of new cancer cases diagnosed in men
in the United States and is the second leading cause of cancer-related
death in men (39). Prostate cancer is often diagnosed early due to
effective screening programs. Prostate cancer is conventionally treated to
79.2 Gy in 40+ fractions with IMRT and image guidance, with the
bladder, urethra, erectile tissues, and rectum serving as the most
important organs at risk. Other options for early-stage prostate cancer
include watchful waiting, surgery, and brachytherapy. While all options
have excellent survival in low-risk disease (Gleason <7, PSA <10),
cancer death rates increase with intermediate and high-risk patients.
SAbR is an attractive option for these patients because it can be
delivered in fewer fractions, is noninvasive and has been shown to be
more cost-effective than a protracted course of conventional IMRT,
provided that outcomes and quality of life are similar (92), though
longer follow-up and more mature data are needed to determine if that
is the case. A recent analysis of Medicare beneficiaries treated with SAbR
for prostate cancer found more frequent GU toxicity for patients treated
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with SAbR when compared to IMRT (93). However, their retrospective
analysis was confounded by a lack of information on grade of toxicity
experienced, differences in baseline function, SAbR dose, or treatment
technique. In contrast, a multi-institutional report on quality of life after
prostate SAbR found that at 3-year median follow-up SAbR is well
tolerated and that after a decline shortly following completion of
therapy, urinary and GI quality of life returns to baseline and remains
high long term (94). These patients received a median dose of 36.25 Gy
in four or five fractions. The same group retrospectively reported the
clinical outcomes of nearly 1,100 patients treated at 8 centers between
2003 and 2011 (95). They reported that with median follow-up of 36
months, 40 patients experienced PSA failure. Their reported 5-year
biochemical relapse–free survival for Gleason score ≤6, 7, and ≥8 were
95%, 83%, and 78%, respectively and 93% for all patients. Updated
follow-up from a multi-institutional phase I/II trial reported excellent
PSA control of 99% at median follow-up of 42 months for all patients
(phases I and II) and 54 months for patients treated on the 50 Gy arm in
the phase I study (96). Figure 14.10 shows a sample treatment plan from
this trial. The grade 3 late GI toxicity reported from this trial has been
correlated with the volume of rectal wall receiving greater than 50 Gy
and greater than 35% circumference of the rectal wall receiving 39 Gy,
related to vascular and mucosal stem cell injury (97). The grade 2+
acute rectal toxicity was related to treatment of more than 50% of the
circumference of the rectal wall to 24 Gy. It should be noted that the
strongly correlated indicator for rectal toxicities to percent of
circumferential irradiation cannot be determined from the standard
dose–volume histogram constraints; rather, prudent examination of the
actual treatment isodose lines is required. This analysis provides the
planner with guidance for plan optimization and organ at risk sparing.
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FIGURE 14.10 Representative treatment plan for prostate SAbR patients treated to 50 Gy in five
fractions on the UT Southwestern phase I/II protocol. A rectal balloon was used to reduce the
surface area of the rectum exposed to the high dose.
PANCREAS
Prognosis for patients diagnosed with pancreatic cancer is extremely
poor as it remains the fourth-leading cause of cancer related death in the
United States, and together with lung cancer, has seen the least
improvement in survival over the last three decades (39). Five-year
survival remains below 10%. Surgery is the only potentially curable
treatment, but unfortunately very few patients present with resectable
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disease. Several recently published studies have found that SAbR for
locally advanced pancreatic cancer is promising. Potential advantages of
SAbR for pancreatic cancer include shorter treatment courses, better
local control, and earlier start of chemotherapy. In as single institution
study, patients were treated with three fractions of 8, 10, or 12 Gy,
depending on the proximity of the tumor to organs at risk, which was
followed 1 month later with 6 months of weekly gemcitabine (98). With
median follow-up of 24 months, local control was 78% and median
overall survival was 14.3 months. Eight percent of patients experienced
acute grade 3 toxicities and two patients experienced late toxicity. A
multi-institutional trial examined a single fraction of 25 Gy preceded by
three cycles of gemcitabine and followed by three to five cycles (99). All
20 enrolled patients completed SAbR and received a median of five
cycles of systemic therapy. No grade 3 or greater nonhematologic acute
toxicities were seen and one late grade 3 toxicity occurred. Median
survival was 11.8 months and 1- and 2-year survival was 50% and 20%,
respectively.
A single institution retrospective review of locally advanced and
borderline resectable patients treated with three cycles of gemcitabine-
based chemotherapy followed by SAbR was recently published (100).
SAbR was delivered in five consecutive daily fractions to a median dose
of 25 to 30 Gy to the GTV and a simultaneous integrated boost of 35 to
50 Gy to the region of vessel abutment/encasement. For the borderline
resectable patients, 77.2% underwent an exploratory laparotomy and
56.1% underwent resection, with 96.9% of those resected having
negative margins. Two of the locally advanced patients underwent
surgical exploration but neither was found to be resectable. Median
overall survival and 1-year progression-free survival for borderline
resectable patients was 16.4 months and 42.8% and for locally advanced
patients was 15 months and 41%, respectively. Patients who were
resected had significantly better median overall survival and median
progression-free survival compared to all patients who remained
unresectable. No acute grade 3 or greater toxicities occurred but four
patients experienced late grade 3 adverse events. The effect of SAbR on
local control was clearly demonstrated in that 37% of patients had
distant failure only, indicating the need for improved systemic therapies
for pancreatic cancer. Another multi-institutional phase II trial using a
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33 Gy in five-fraction regimen found 1- and 2-year overall survival rates
of 59% and 18% with low toxicity (101).
METASTASES
Patients with metastases are often treated with systemic therapy in an
effort to improve survival and quality of life. Systemic therapy is
necessary to reach all sites of known metastases and to treat microscopic
disease that is assumed to be present. However, certain patients with
limited metastatic disease can have excellent long-term outcomes with
surgical resection, even without systemic treatment (102) leading many
to believe that similar results could be achieved with ablative
radiotherapy. Long-term follow-up of a prospective study treating
patients with five or fewer metastases from any primary site found 6-
year overall survival and freedom from distant metastasis rates of 20%
and 21%, respectively and approximately one-third of patients survived
more than 4 years (103). Doses were determined by the adjacent organs
at risk, with a preferred schedule of 50 Gy in 10 fractions. Patients with
metastatic breast cancer experienced significantly better outcomes than
those who had metastases from nonbreast cancer and nonbreast cancer
tumor burden was significant for worse overall survival and local
control.
A dose escalation study from the University of Chicago reported 1- and
2-year survival rates of 81.5% and 56.7%, respectively for patients
receiving SAbR to one to five metastatic sites (104). They began with
24 Gy in three fractions and escalated 2 Gy per fraction to a total of 60
Gy. They found that patients tolerated this treatment regimen and 27%
of patients developed no new metastatic lesions during the reported
median follow-up of 20.9 months for all patients and 31.3 months for
living patients. A retrospective review of 14 patients with 74 lung
metastases from soft tissue sarcomas treated with SAbR reported
excellent 3-year local control of 82% with a preferred treatment scheme
of 50 Gy in five fractions (105). The median number of lesions treated
per patient was 4 and the median GTV was 5.1 cc. Excluding a single
patient treated with 30 Gy in three fractions, the local control rate was
97%. These results are promising, but determining which patients will
benefit the most from local ablative therapies is still challenging and
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better systemic treatments are needed.
KEY POINTS
• SAbR requires optimal patient immobilization, motion management,
and accurate targeting to deliver an ablative dose to tumors while
sparing surrounding normal tissues.
• The biology of SAbR is not well understood, but the excellent local
tumor control is believed to be a result of vascular damage and
abscopal effects are likely a result of an antitumor immune
response to massive cancer cell death in the irradiated tumor.
• A successful SAbR program requires careful commissioning and a
comprehensive quality assurance program developed by the
medical physicist.
• SAbR dose distributions are characterized by a highly conformal
but heterogeneous high-dose volume, a compact intermediate dose
volume, and a large low-dose volume.
• Treatment plans should be scrutinized carefully to ensure that the
attending physician’s goals are being met for organs at risk and
targets.
• SAbR is the standard therapy for early-stage inoperable lung and
liver cancer and lung and liver metastases.
• SAbR is being studied under clinical trials for prostate and
pancreatic cancers and for metastatic disease.
QUESTIONS
1. According to the RTOG 0236 guidelines, which parameters
determine the quality of the dose distribution for a lung SAbR
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treatment plan?
A. The mean lung dose
B. The maximum lung dose and the volume of lung receiving 20
Gy
C. R50% and D2 cm
D. The PTV volume and the number of beams used
2. Lung tumor motion assessment provides all of the following
information except
A. Tumor motion amplitude
B. Tumor size
C. Tumor motion period
D. Tumor motion regularity
3. The concept of the critical volume of an organ that must be
spared to prevent dysfunction would apply to which pair of
organs?
A. Lung and liver
B. Lung and spinal cord
C. Lung and esophagus
D. Liver and spinal cord
4. In low-density tissues such as the lung, simplistic treatment
planning heterogeneity corrections such as the pencil-beam
algorithm
A. Under-predict the actual delivered dose
B. Calculate the correct delivered dose
C. Over-predict the delivered dose
D. Are recommended by the AAPM Task Group 101
5. RTOG 0915 compared the rate of grade 3 or higher toxicities in
stage I peripheral NSCLC patients treated with two different
fractionations. The doses in the trial were
A. 60 Gy in 3 fractions and 54 Gy in 3 fractions
B. 60 Gy in 5 fractions and 60 Gy in 3 fractions
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C. 48 Gy in 4 fractions and 60 Gy in 3 fractions
D. 48 Gy in 4 fractions and 34 Gy in 1 fraction
ANSWERS
1. C
2. B
3. A
4. C
5. D
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with MR imaging-guided laser-induced thermotherapy: experience
with complications in 899 patients (2,520 lesions). Radiology.
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61. Haas RJ, Wicherts DA, Adam R. Oncosurgical Strategies for
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63. Reed GB, Jr., Cox AJ, Jr. The human liver after radiation injury. A
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64. Yannam GR, Han B, Setoyama K, et al. A nonhuman primate model
of human radiation-induced venocclusive liver disease and
hepatocyte injury. Int J Radiat Oncol Biol Phys. 2014;88(2):404–411.
65. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single-dose
radiation therapy of liver tumors: results of a phase I/II trial. J Clin
Oncol. 2001;19(1):164–170.
66. Hoyer M, Roed H, Traberg Hansen A, et al. Phase II study on
stereotactic body radiotherapy of colorectal metastases. Acta
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67. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized
stereotactic body radiotherapy of liver metastases. J Clin Oncol.
2009;27(10):1585–1591.
68. Mendez Romero A, Wunderink W, Hussain SM, et al. Stereotactic
body radiation therapy for primary and metastatic liver tumors: a
single institution phase i-ii study. Acta Oncol. 2006;45(7):831–837.
69. Milano MT, Katz AW, Muhs AG, et al. A prospective pilot study of
curative-intent stereotactic body radiation therapy in patients with 5
or fewer oligometastatic lesions. Cancer. 2008;112(3):650–658.
70. Zhang Y, Xiao J, Li Y, et al., Hypofractionated stereotactic body
radiotherapy for primary and secondary liver tumors. Int J Radiat
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71. Katz AW, Carey-Sampson M, Muhs AG, et al. Hypofractionated
stereotactic body radiation therapy (SBRT) for limited hepatic
metastases. Int J Radiat Oncol Biol Phys. 2007;67(3):793–798.
72. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional
phase I/II trial of stereotactic body radiation therapy for liver
metastases. J Clin Oncol. 2009;27(10):1572–1578.
73. Rule W, Timmerman R, Tong L, et al. Phase I dose-escalation study
of stereotactic body radiotherapy in patients with hepatic
metastases. Ann Surg Oncol. 2011;18(4):1081–1087.
74. Milano MT, Katz AW, Schell MC, et al. Descriptive analysis of
oligometastatic lesions treated with curative-intent stereotactic body
75. McCammon R, Schefter TE, Gaspar LE, et al. Observation of a dose-
control relationship for lung and liver tumors after stereotactic body
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radiation therapy. Int J Radiat Oncol Biol Phys. 2009;73(1):112–118.
76. Schefter TE, Kavanagh BD, Timmerman RD, et al. A phase I trial of
stereotactic body radiation therapy (SBRT) for liver metastases. Int J
77. Meyer JJ, Foster RD, Lev-Cohain N, et al. Toxicity and efficacy
results from a phase I dose-escalation study of single-fraction
stereotactic radiation therapy for liver metastases. Int J Radiat Oncol
Biol Phys. 2014;90(Suppl 1):S51.
78. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity
when treating central tumors in a phase II study of stereotactic body
radiation therapy for medically inoperable early-stage lung cancer. J
Clin Oncol. 2006;24(30):4833–4839.
79. Bruix J, Sherman M; Practice Guidelines Committee, American
Association for the Study of Liver Diseases. Management of
hepatocellular carcinoma. Hepatology. 2005;42(5):1208–1236.
80. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body
radiotherapy for primary hepatocellular carcinoma. Int J Radiat
Oncol Biol Phys. 2011;81(4):e447–e453.
81. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of
individualized stereotactic body radiotherapy for hepatocellular
carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol.
2008;26(4):657–664.
82. Culleton S, Jiang H, Haddad CR, et al. Outcomes following
definitive stereotactic body radiotherapy for patients with Child-
Pugh B or C hepatocellular carcinoma. Radiother Oncol.
2014;111(3):412–417.
83. Katz AW, Chawla S, Qu Z, et al. Stereotactic hypofractionated
radiation therapy as a bridge to transplantation for hepatocellular
carcinoma: clinical outcome and pathologic correlation. Int J Radiat
Oncol Biol Phys. 2012;83(3):895–900.
84. Wang XS, Rhines LD, Shiu AS, et al. Stereotactic body radiation
therapy for management of spinal metastases in patients without
spinal cord compression: a phase 1-2 trial. Lancet Oncol. 2012;
13(4):395–402.
85. Ryu S, Pugh SL, Gerszten PC, et al. RTOG 0631 phase 2/3 study of
image guided stereotactic radiosurgery for localized (1-3) spine
metastases: phase 2 results. Pract Radiat Oncol. 2014;4(2):76–81.
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86. Sahgal A, Ames C, Chou D, et al. Stereotactic body radiotherapy is
effective salvage therapy for patients with prior radiation of spinal
metastases. Int J Radiat Oncol Biol Phys. 2009;74(3):723–731.
87. Medin PM, Foster RD, van der Kogel AJ, et al. Spinal cord tolerance
to reirradiation with single-fraction radiosurgery: a swine model. Int
88. Sahgal A, Weinberg V, Ma L, et al. Probabilities of radiation
myelopathy specific to stereotactic body radiation therapy to guide
safe practice. Int J Radiat Oncol Biol Phys. 2013;85(2):341–347.
89. Cunha MV, Al-Omair A, Atenafu EG, et al. Vertebral compression
fracture (VCF) after spine stereotactic body radiation therapy
(SBRT): analysis of predictive factors. Int J Radiat Oncol Biol Phys.
2012;84(3):e343–e349.
90. Thibault I, Al-Omair A, Masucci GL, et al. Spine stereotactic body
radiotherapy for renal cell cancer spinal metastases: analysis of
outcomes and risk of vertebral compression fracture. J Neurosurg
Spine. 2014;21(5):711–718.
91. Sahgal A, Atenafu EG, Chao S, et al. Vertebral compression fracture
after spine stereotactic body radiotherapy: a multi-institutional
analysis with a focus on radiation dose and the spinal instability
neoplastic score. J Clin Oncol. 2013;31(27):3426–3431.
92. Hodges JC, Lotan Y, Boike TP, et al. Cost-effectiveness analysis of
SBRT versus IMRT: an emerging initial radiation treatment option
for organ-confined prostate cancer. Am J Manag Care.
2012;18(5):e186–e193.
93. Yu JB, Cramer LD, Herrin J, et al. Stereotactic body radiation
therapy versus intensity-modulated radiation therapy for prostate
cancer: comparison of toxicity. J Clin Oncol. 2014;32(12):1195–
1201.
94. King CR, Collins S, Fuller D, et al. Health-related quality of life after
stereotactic body radiation therapy for localized prostate cancer:
results from a multi-institutional consortium of prospective trials. Int
95. King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy
for localized prostate cancer: pooled analysis from a multi-
institutional consortium of prospective phase II trials. Radiother
Oncol. 2013;109(2):217–221.
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96. Kim DW, Straka C, Cho LC, et al. Stereotactic body radiation
therapy for prostate cancer: review of experience of a multicenter
phase I/II dose-escalation study. Front Oncol. 2014;4:319.
97. Kim DW, Cho LC, Straka C, et al. Predictors of rectal tolerance
observed in a dose-escalated phase 1-2 trial of stereotactic body
radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys.
2014;89(3):509–517.
98. Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body
radiotherapy and gemcitabine for locally advanced pancreatic
99. Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction
stereotactic body radiation therapy and sequential gemcitabine for
the treatment of locally advanced pancreatic cancer. Int J Radiat
Oncol Biol Phys. 2011;81(1):181–188.
100. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body
radiation therapy for locally advanced and borderline resectable
pancreatic cancer is effective and well tolerated. Int J Radiat Oncol
Biol Phys. 2013;86(3):516–522.
101. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-
institutional trial evaluating gemcitabine and stereotactic body
radiotherapy for patients with locally advanced unresectable
pancreatic adenocarcinoma. Cancer. 2014;121(7):1128–1137.
102. Ollila DW, Caudle AS. Surgical management of distant metastases.
Surg Oncol Clin N Am. 2006;15(2):385–398.
103. Milano MT, Katz AW, Zhang H, et al. Oligometastases treated with
stereotactic body radiotherapy: long-term follow-up of prospective
study. Int J Radiat Oncol Biol Phys. 2012;83(3):878–886.
104. Salama JK, Hasselle MD, Chmura SJ, et al. Stereotactic body
radiotherapy for multisite extracranial oligometastases: final report
of a dose escalation trial in patients with 1 to 5 sites of metastatic
disease. Cancer. 2012;118(11):2962–2970.
105. Dhakal S, Corbin KS, Milano MT, et al. Stereotactic body
radiotherapy for pulmonary metastases from soft-tissue sarcomas:
excellent local lesion control and improved patient survival. Int J
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15 Low Dose-Rate Brachytherapy
Mark J. Rivard
INTRODUCTION
Brachytherapy is a form of radiation therapy in which the source of
radiation is placed close to or within the patient. The origin of the word
brachytherapy is from the ancient Greek word βραχύς or brachys, which
means short distance as relating to the proximity of the radiation source
to the patient. As a co-discoverer of radium with Marie Curie (née
Skłodowska) in 1898, Pierre Curie suggested to a fellow Frenchmen,
Henri-Alexandre Danlos, to use the radioactive material for therapeutic
purposes. With the assistance of the physicist Bloch, Danlos proceeded to
treat a patient with tuberculosis—this was the first brachytherapy
treatment (1). This form of treatment would be termed radiumtherapy
until Forssell associated the term brachyradium (2), and later simplified
as brachytherapy with the availability of other radiation sources.
Aronowitz has researched much of the early history of brachytherapy,
and the interested reader may examine these readily available
summaries (3–16).
Clinical applications of brachytherapy may be applied with the
radiation source on the patient’s skin surface, sometimes referred to as
plesiotherapy in historical documents (think of the plesiosaurus dinosaur
that lived on the water’s surface). Other means of treatment delivery can
place the source within a naturally occurring cavity within the patient
(referred to as intracavitary brachytherapy), into a naturally occurring
channel or lumen such as the esophagus (referred to as intraluminal
brachytherapy), into a blood vessel (referred to as intravascular or
endovascular brachytherapy), percutaneously into the tumor volume via
a needle (referred to as interstitial brachytherapy), and within the tumor
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volume via an open surgical procedure (referred to as intraoperative
brachytherapy). All these delivery methods require (semi)invasive
placement techniques and contrast with teletherapy, nowadays
commonly referred to as external-beam radiotherapy (EBRT), where the
radiation source is positioned relatively far from the patient.
Brachytherapy may be further portioned in terms of the means of
delivery. The first treatments were delivered with 226Ra sources directly
inserted into the lesion. This is now referred to as manual loading. 222Rn
sources were subsequently developed to provide sources with higher
specific activity, that is, Ci/g, and allow implantation of thinner needles.
After physicians and surgeons exhibited toxicities such as blackened
digits and subsequent amputations, an alternate method of implantation
was developed, now referred to as manual afterloading. Here, the lesion
was implanted with needles during surgery with the sources implanted
afterward. This approach allowed careful needle positioning without
rush, especially important at the academic centers where brachytherapy
was most active at the time. Further, radiation exposure to hospital
personnel was minimized since patients located in recovery rooms were
not emitting radiation. A further advancement was implemented with
remote afterloading, where the placement of the radiation source within
the patient was done through electromechanical means instead of
manually, with radiation exposure to hospital personnel.
All these delivery methods utilized low dose-rate (LDR) brachytherapy
sources, which are classified to administer radiation at a dose rate of 0.4
to 2 Gy/h (i.e., 0.67 to 3.33 cGy/min). High dose-rate (HDR) sources are
classified to administer radiation at a dose rate exceeding 12 Gy/h (i.e.,
20 cGy/min). This categorization of dose rate was established in Report
38 (17) by the International Commission on Radiation Units and
Measurements (ICRU). ICRU 38 categorization also includes medium
dose-rate sources that administer radiation at a dose rate of 2 to 12 Gy/h
(i.e., 3.33 to 20 cGy/min), or pulsed dose-rate brachytherapy (using
HDR sources positioned within the target for a short time as an in-
patient procedure with the treatment course extending over a few days),
but these intermediary approaches have all but stopped and are used
now only in a handful of clinics in the United States.
Key issues with the clinical delivery of brachytherapy is patient safety
and implant quality (18). The European Society for Radiotherapy &
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Oncology (ESTRO) Booklet 8 established quality standards for
brachytherapy equipment and quality assurances practices (19), but did
not offer much guidance on the quality measures governing the practice
of clinical brachytherapy. This topic is covered in greater detail within
societal reports such as the TG-56 (20) and the TG-64 (21) reports by the
American Association of Physicists in Medicine (AAPM), and also the
book by Thomadsen (22) dedicated to the subject of achieving quality in
brachytherapy.
LDR BRACHYTHERAPY SOURCES

So what is a brachytherapy source? Brachytherapy sources differ from
other internally placed sources of radiation used in medicine, for
example, nuclear medicine, in that the radiation source does not
chemically interact with the patient. Brachytherapy sources will often
have a single or double-layer of encapsulation to contain a radionuclide
whereas nuclear medicine has a radionuclide bound to a chemical that
will preferentially locate within the body after being injected. This
difference even applies to 90Y microspheres (23), where the radionuclide
is contained within a resin or glass matrix (24), approximately 30 μm in
diameter, and injected for permanently lodging within the micro vessels
of an organ such as a lobe of the liver. Radionuclides used in nuclear
medicine will typically clear the body based on a biologic half-life
related to metabolism and plumbing.
The radiation source for brachytherapy may also be generated through
electricity, such as through an internally or externally positioned x-ray
tube (25–27). However, these radiation sources are designed to deliver a
therapeutic dose within a matter of minutes and are categorized as HDR
brachytherapy sources.
This leaves the most popular type of brachytherapy source, which is a
radionuclide contained within an inert encapsulation for temporary or
permanent implantation within a patient. Due to concerns for shielding
hospital personnel and the general public from untoward radiation
emitted by patients implanted with LDR brachytherapy sources, either
implanted permanently or in a temporary manner, LDR sources today
contain radionuclides that emit radiation described as low-energy
radiation, typically photons with a mean energy ≤50 keV (28). Some
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radiologic properties of common low-energy photon-emitting
brachytherapy sources are included in Table 15.1. These three
radionuclides decay via electron capture, in which a proton-rich nucleus
absorbs an electron from an inner atomic shell, subsequently
transforming a proton into a neutron. As the atom relaxes to its ground
state, energy is releases as photons are emitted through x rays generated
by electrons from outer atomic shells filling the void of the inner shell
and sometimes also with nuclear relaxation (as is the case for 103Pd and
125I) with gamma-ray emission from the excited nucleus. These x-ray and
γ-ray photons have discrete energies and intensities for a given
radionuclide disintegration. Auger electrons may also be emitted by the
excited atom, but these low-energy electrons are blocked from exiting
the brachytherapy source due to the encapsulation.
TABLE 15.1 Some radiologic properties of low-energy photon-

emitting brachytherapy sources. X-ray transitions are listed after the
elemental symbols for the daughter nuclides. The lower probability
x-ray transitions, x-ray transitions <10 keV, and Auger electrons are
not listed
Some examples of low-energy LDR brachytherapy sources are included

in Figure 15.1 with images adapted from Rivard et al. (28,29). These
images depict the various designs that have been developed to provide
source localization with imaging from x-ray computed tomography (CT)
scans, as well as to facilitate a number of novel features such as
localization with ultrasound imaging, thinner diameters to minimize
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tissue trauma following interstitial implantation, and source flexibility.
FIGURE 15.1 Examples of low dose–rate brachytherapy sources containing 125I, 103Pd, and
131Cs, as adapted from Rivard et al. (28,29).
LDR brachytherapy sources have been used, and may still be in use in
some clinics, which contain other radionuclides that emit higher-energy
photons. These sources contained 198Au, 137Cs, or 192Ir. However, their
use in LDR brachytherapy sources has greatly diminished over the past
decade due to limited availability from manufacturers and excellent
clinical results using low-energy brachytherapy sources, which greatly
restrict the radiation exposure to the patient. Further, high-energy
photon-emitting brachytherapy sources may have higher doses in
contact with their encapsulation than low-energy sources due to
electrons escaping (30).
DOSIMETRY
The following section describes the current means in which dose
distributions are determined in the vicinity of LDR brachytherapy
sources and how these dose distributions are integrated into clinical
treatment planning systems (TPSs). Historical dosimetry systems (31–34)
that came to light before the advent of computerized treatment planning
are available to the interested reader for gaining insight on general
principles that still apply today. Currently, dose specification to water is
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the standard for which brachytherapy prescriptions are generally based.
This is due to historical reasons as the earliest brachytherapy sources
(i.e., 226Ra, 222Rn, 60Co, and 192Ir) were high-energy photon emitters and
the radiologic equivalence of water and soft tissue was within about 1%
of unity due to similarities in the mass-attenuation coefficients (i.e., μ/ρ,
governing attenuation in medium) and mass-energy absorption
coefficients (i.e., μen/ρ, governing dose deposition) for water and soft
tissue (35). For the low-energy photon-emitting LDR sources, differences
between water and soft tissue for μ/ρ and μen/ρ can exceed a couple
percent, such as for 103Pd (36), causing differences between prescribed
and administered dose by over 10% in some instances.
However, a key point to note is that current prescriptions are
generally based on trial-and-error with years of historical data (37,38).
The doses prescribed as standard-of-care are based on the assumption of
the water equivalence of human tissue (39). One cannot simply update
the medium for dose calculation without also coordinating a thoughtful
change in the prescription paradigm to correct for the radiologic
differences between water and soft tissue—often a 3D phenomenon and
not simply a scalar value.
Given the prevalence of computerized TPSs, the current worldwide
standard method is the AAPM TG-43 formalism, based on the seminal
report from 1995 (40), the most cited publication in the scientific
journal Medical Physics (41). This approach sets water as the reference
medium, with a fixed dose calculation formulism, and parameters within
the formulism that are specific to each brachytherapy source model. The
TG-43 formalism is based upon prior approaches that also parameterized
source-specific terms (42–47). For clinical dose calculations to occur, the
dose distribution must first be determined in the vicinity of a given
brachytherapy source model. From the measured or calculated dose
distributions, brachytherapy dosimetry parameters are obtained. The TG-
43 formulism relies on widespread adoption of dosimetry parameters for
a given source model, resulting in consistent dose calculation for all that
utilize accepted dosimetry parameters. The AAPM is the professional
society that establishes consensus data on brachytherapy dosimetry
parameters as they are invested in the safe and uniform implementation
of clinical brachytherapy.
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But how are radiation dose distributions around brachytherapy
sources determined in the first place? These are often performed by
dosimetry investigators, who use measurement techniques or
computational methods to derive the dose distribution around a given
model for a single brachytherapy source. The dose gradients are
smoother in EBRT than with brachytherapy, where changes in dose
exceeding a factor of two can occur within 1 mm (48). In EBRT, there
also is an established infrastructure of measurement devices and
measurement protocols for evaluating the dose distribution under
reference conditions from a linear accelerator (49); brachytherapy
dosimetry requires larger detector corrections than for EBRT (50), where
the photon energy is usually a factor of 100 or more higher than that
measured in brachytherapy dosimetry. Prescriptions in brachytherapy
are sometimes at a distance of 5 mm from the source, where a
positioning uncertainty of just 0.5 mm can result in a change in dose at
that location of 20%. Issues on the methods of measuring brachytherapy
dose distributions are discussed in detail by Williamson and Rivard
(51,52).
The practice of measuring radiation doses in EBRT radiation fields is
also supported due to the electrical nature of radiation generation and
the beam tailoring devices that can alter the dose delivered within the
patient. In brachytherapy, the radiation is almost always generated via
radionuclide decay, which is a predictable process that lends itself to
determination through strict computational methods (53,54). Due to the
low-energy photons prevalent in LDR brachytherapy, assumptions of
charged particle equilibrium and the approximation of absorbed dose
equivalence to collisional kerma can simplify the calculations while
introducing minimal errors.
Monte Carlo (MC) methods for radiation transport calculations are a
crucial component for brachytherapy dosimetry evaluations performed
recently and expected for the foreseeable future. MC methods have been
used for over four decades for this purpose (55,56). A thorough
description of the process is described by Williamson and by Thomadsen
et al. (57,58). Briefly, the dose distribution around a given model for a
single brachytherapy source is determined. Using attributes describing
the spatial distribution of the radionuclide, the brachytherapy dosimetry
parameters for that particular source model are determined. These
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brachytherapy dosimetry parameters are then entered into a
brachytherapy TPS and used for all subsequent clinical applications so
that there is uniformity in the dosimetry of patient treatments with that
source model.
In practice, one of the following two equations (28,29,59,60) is used
for clinical dose calculations:
where the dose rate at any location is simply the product of a few
brachytherapy dosimetry parameters. If the source orientation is
unknown, then Equation 15.1 is used. This 1D dose calculation
formalism is the most popular means of determining dose distributions
for LDR brachytherapy sources, which results in a spherically symmetric
dose distribution.
For the 2D dose calculation formalism, the source is assumed to be
designed cylindrically symmetric with a resultant cylindrically
symmetric dose distribution. Almost always, the source is assumed to be
designed with further symmetry about the transverse plane bisecting the
source length. Dose rate is determined as a function of radial distance r
from the source center to the point of interest and the polar angle q as
measured from the source long axis. The polar coordinate system of the
TG-43 formalism is depicted in Figure 15.2. Note that the relevant length
for dose calculations is the radioactivity extent and not the length of the
encapsulation. The reference position is at a distance of r0 = 1 cm and a
polar angle q0 = 90 degrees.
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FIGURE 15.2 TG-43 brachytherapy dosimetry coordinate system for dose calculations, adapted
from Rivard et al. (28).
The source strength is specified in terms of air-kerma strength, SK. It

has units of “U” where 1 U = 1 μGy·m2· h−1 = 1 cGy·cm2·h−1. For a
given source model, this is the only dosimetry parameter specific to the
source inventory within the clinic. Source strength is reported by the
source manufacturer and measured in the clinic. This is discussed in
greater detail in the next section.
The dose-rate constant Λ is specific to a given source model, and is the
ratio of the dose rate at the reference position, , to the source
strength. The units of Λ are cGy·h ·U . Low-energy LDR
−1 −1
brachytherapy sources have Λ values near equal to unity, with Λ
approximately equal to 0.68 cGy·h−1·U −1 for 103Pd sources, 0.93 cGy·h
−1·U−1 for 125I sources, and 1.06 cGy·h−1·U −1 for 131Cs sources.
The geometry function is the most important dosimetry parameter
toward approximating the dose-rate distribution using the TG-43 dose
calculation formalism. It can account for a factor of 10,000 gradient in
the dose distribution between near and far positions from the source,
that is, positions 0.1 to 10 cm from the source. Use of the geometry
function (and typically coarse evaluation matrices) obscures the fact that
doses exceeding 10,000 Gy may occur at the surface of LDR
brachytherapy seeds following clinical implantation. For the 1D dose
calculation formalism, a simple inverse-square relationship is used to
approximate the dose falloff. A complementary term r0 is in the
numerator to balance the units of 1/r2. For the 2D dose calculation
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formalism, the spatial distribution of the radionuclide is approximated as
a line segment that typically covers the physical extent of the
radioactivity within the encapsulation. The active length (or effective
length for sources containing multiple pellets of radioactivity) is used for
derivation of the 2D geometry function, G(r, q). The geometry function
takes the following form based on polar angle:
The term β is the angle (in radians) subtended by the ends of the
radioactive part of the source and the point of interest. When the point
of interest is more than three times the distance from the center of the
source than the active length, any differences between the 1D and 2D
dose calculation formalism results amount to less than 5% (61). For
sources with an active length of about 0.3 cm, this occurs at a distance
of about 1 cm.
The radial dose function, g(r), is the dosimetry parameter used to
obtain the dose rate in water at positions on the source transverse plane
beyond the trend expected by correcting dose rate at the reference
position by the geometry function. For instance, if the medium were not
water but a more attenuating material, the radial dose function would
fall off more steeply than in water due to increased radiation
attenuation. While the radiologic properties associated with this
dosimetry parameter are radiation attenuation and scatter, it is used
simply to permit replication of the dose-rate distribution on the
transverse plane beyond any corrections provided by the geometry
function.
In the original (1995) TG-43 report (20), a single radial dose function
g(r) was introduced to account for the deviation from the geometry
function on the transverse plane. However, since there are differences
between the 1D and 2D geometry functions, there should consequently
be different radial dose functions for each formalism to reproduce the
original dose-rate distribution. These radial dose functions, gP(r) and
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gL(r), were introduced in the 2004 report update (TG-43U1) by Rivard et
al. (59). Because there may be 1D or 2D geometry functions used based
on knowledge of source orientation, it is imperative that the correct
radial dose function, either gP(r) or gL(r), respectively, be used to
properly replicate the original dose-rate distribution. Especially at
locations near the source, use of a radial dose function for the wrong
formalism can cause errors in dose by more than a factor of two.
I like to think of the remaining term as “every else” for addressing
what is not accounted for by the combination of the geometry function
and the radial dose function to reproduce dose rates away from the
transverse plane. This concept is explained elsewhere in greater detail
(62). Like the geometry function and radial dose function, the anisotropy
function can be for either the 1D or 2D formalism. For the case of the 1D
formalism, the 1D anisotropy function, øan(r), is the ratio of the solid-
angle weighted dose rate, averaged over the entire 4π steradian space, to
the dose rate at that same distance r on the transverse plane. Due to the
anisotropy of dose as a function of polar angle at large distances from
low-energy LDR brachytherapy sources (primarily due to photon
attenuation by the encapsulation), values for øan(r) are typically slightly
less than unity. However, the dose rate is higher at locations close to the
source off the transverse plane for a given r value due to the
nonspherical geometry of the source. Consequently, volume averaging of
dose over the entire 4π steradian space at these close distances tends to
produce values for øan(r) that are typically greater than unity. In fact, the
volume averaging will include locations within the source for positions
closer than half the encapsulation length. Care must be made by
dosimetry investigators to exclude these locations for øan(r) derivation.
The 2D anisotropy function, F(r,θ), is slightly more complicated in that
it is the ratio of the dose rate at any location off the transverse plane to
the dose at the same r on the transverse plane, after accounting for the
geometry function. Consequently, the perturbing effect on the dose
distribution by the spatial distribution of radioactivity will alter
calculations of øan(r) but not F(r,θ). In the end, if properly derived, this
difference does not matter as use of the appropriate geometry function
and radial dose function in combination with the anisotropy function
will reproduce the original dose distribution.
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Once all the dosimetry parameters are available for a given model of a
brachytherapy source, the AAPM, in concert with other professional
societies such as the ESTRO, will review the literature to evaluate
candidate datasets and then establish consensus brachytherapy
dosimetry parameters based on robust and unbiased methods (28). These
data will then become available to clinical users through publication in
AAPM reports, posting on the Brachytherapy Source Registry as
managed jointly by the AAPM and the Imaging and Radiation Oncology
Core Houston Quality Assurance Center (IROC Houston, formerly the
Radiological Physics Center), through web-based resources under
development, or through inclusion in vendor-provided software by TPS
manufacturers. It is always the responsibility of the clinical medical
physicist to evaluate any data used for clinical applications and to
document this evaluation in a methodical manner. Implementation of
new dosimetry parameters can have a profound influence on the
resultant dose distribution that the patient would receive (63–65).
SOURCE CALIBRATIONS
Source strength is typically the only dosimetric quantity measured by a
clinical medical physicist. The practice for establishing calibrations
traceable to the US primary standard laboratory (the National Institute
of Standards and Technology) and making calibrations of clinical
instrumentation traceable to the NIST standard is covered in depth in the
AAPM-approved reports by DeWerd et al. (66) and by Butler et al. (67).
The report by the Calibration Laboratory Accreditation subcommittee
of the AAPM set practice standards for LDR brachytherapy source
manufacturers and dosimetry investigators (66). Source manufacturers
are to establish internal standards for source calibrations as used for
providing calibration certificates to customers. These calibrations are to
be traceable to NIST on an ongoing basis. Further, measurements of the
dose-rate constant (as performed by brachytherapy source dosimetry
investigators) are taken from a subset of the sources used to establish the
calibration standard at NIST. In this way, the dosimetry parameters used
in clinical applications and the seeds used in patients are both connected
through NIST-traceable calibrations. This process has extended the
dosimetric prerequisites (68) necessary for sources to satisfy the AAPM
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criteria for placement on the Brachytherapy Source Registry.
The report by the Low Energy Brachytherapy Source Calibration
Working Group of the AAPM set standards for clinical medical physicists
on the practice standards for assaying brachytherapy sources (67).
Specific to brachytherapy source strength measurements, these practice
standards supersede those of the AAPM TG-56 report (20). The
responsibility for such calibrations was clearly identified as being that of
the clinical medical physicist. This clarified ambiguity where some
source manufacturers offered calibrations from third-party services
where seeds were placed in strands or prepared with spacers into needle
assemblies. Clinical medical physicists are required to assay sources
preceding clinical use because there sometimes is a lack of NIST-
traceability, as well as the increased uncertainties associated with using
third-party calibration services. The report outlined standards for the
number of sources to be assayed, the permissible tolerances between
measurements performed by the clinical medical physicist and the
source manufacturer calibration certificate, and actions to be taken by
the end-user medical physicist based on the level of agreement between
the two values of the brachytherapy source strength. Interestingly, the
tolerances in this report can be extended to account for statistical
variations in the reported source strength for a batch of seeds, where the
number of sources to be assayed in a given batch can be derived based
on the desired level of agreement with the manufacturer calibration
certificate (69–72). However, this statistical approach was deemed too
complicated for setting widespread use and clinical practice standards.
For the low-energy photon-emitting radionuclides included in Table
15.1, the LDR brachytherapy seeds should have a primary calibration
standard established by NIST. This calibration standard is made through
measurements performed using the NIST wide-angle free-air chamber
(WAFAC) as described by Seltzer et al. (73), which has been extended
beyond 125I and 103Pd to include 131Cs seeds. A schematic diagram of the
NIST WAFAC device is given in Figure 15.3, where it is indicated that
the source rotates during measurements, radiation is filtered through an
aluminum foil, and the chamber can collapse in length to remove
measurement artifacts. As there are photons emitted by brachytherapy
sources with energies less than 5 keV, such as characteristic x-rays from
the frequently used titanium encapsulation, the measurement of source
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strength includes corrections to remove these low-energy photons that
do not significantly contribute to absorbed dose in tissue, yet
significantly contribute to source strength measurements (74,75).
FIGURE 15.3 Schematic depiction of the wide-angle free-air chamber (WAFAC) at the National
Institute of Standards and Technology, as adapted from Rivard et al. (28).
The source strength is measured in air at a distance of 30 cm from the

source with an 8-cm diameter tungsten aperture that collimates the
photons before reaching the ionization chamber. This collimation results
in a high signal due to the sampling angle (explaining use of the words
“wide-angle” in the WAFAC designation), which is about 90 ± 7.6
degrees from the seed long axis. Corrections to the reported source
strength (in terms of air-kerma rate in vacuum) are made for radiation
attenuation by the aluminum filter, attenuation in air, radiation scatter,
and several other effects. All these corrections total to approximately 5%
for 125I, 11% for 103Pd, and 4% for 131Cs sources.
It is important to recognize the robust processes in place for
establishing traceable calibrations of brachytherapy sources,
requirements of manufacturers to have their products included on the
Brachytherapy Source Registry, and the clinical practices standards
developed for clinical medical physicists. An example of how the dose
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delivered to a patient may vary based on nonrobust calibration methods
is given in Figure 15.4, adopted from Williamson et al. (64), where
undesirable dose variations of up to 17% occurred.
FIGURE 15.4 Variations in the delivered dose as a function of time when prescribing either 125
Gy or 115 Gy with the model 200 103Pd source using the 1D dose calculation formalism in
Equation 15.1, as adapted from Williamson et al. (64). The solid line indicates a prescribed dose
of 115 Gy, which initially delivered a dose of 117 Gy in May of 1988. Through changes in the
109Cd calibration source at Theragenics, Corp. (Buford, GA), the delivered varied from 113 to 125
Gy preceding the establishment of the National Institute of Standards and Technology (NIST)
wide-angle free-air chamber (WAFAC) calibration standard. After implementation of this
calibration standard and correction for a detector response anomaly, a prescribed dose of 115 Gy
corresponded to a delivered dose of 115 Gy through use of the AAPM TG-43U1 brachytherapy
dosimetry parameters. For those physicians that changed their prescription dose from 115 to 125
Gy in the year 2000, as indicated by the dashed line, the delivered dose ranged from 116 to 125
Gy at present.
There are still some clinics in the United States that use the antiquated
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unit of apparent activity (Aapp) for specifying brachytherapy source
strength (76). Another antiquated unit of source strength is the source
equivalence to milligrams of radium (i.e., mg Ra eq). These units of
source strength are not traceable to NIST and must not be used for
clinical applications. As a requirement for transportation paperwork to
ship sources to and from the manufacturer to the clinic, the contained
source strength in units of MBq or mCi is specified. However, the clinical
medical physicist should not use this information for the derivation of
dose in the patient—this is the role of SK with units of U. Confusion by
clinical medical physicists on this issue has resulted in numerous
medical errors in brachytherapy, with the patient receiving 27% higher
dose than intended for treatment with 125I seeds (64,77), surely resulting
in patient harm in some instances. While the radiation oncologist will be
familiar with concepts like standards of care, he/she will likely not be
familiar with concepts like calibration traceability and it is the
responsibility of the clinical medical physicist to convey the importance
of following the long-standing recommendations of the AAPM (78) for
only using SK with units of U for brachytherapy source when ordering
sources, independently measuring their source strength, and using this in
clinical treatment plans.
TREATMENT PLANNING
The treatment planning process for brachytherapy has advanced
considerably over the past decade. Modern brachytherapy treatment
planning relies on computer-based approaches for dose calculation
(58,79,80). Optimization of source strength is not typically used for LDR
brachytherapy, where it is most helpful for HDR brachytherapy using
192Ir sources when a single source traverses the implant with varying
dwell times. Even with modern computational tools and technologic
advances such as the ability to perform intraoperative brachytherapy
treatment planning without a preimplant plan, all participants in the
process must recognize that a poorly executed brachytherapy implant
cannot be salvaged afterward.
Use of film or other 2D means of identifying the spatial relationship
between the brachytherapy sources and the patient is discouraged given
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the widespread availability of CT scanners used in the clinic primarily
for EBRT treatment planning (81,82). Image-based, 3D treatment
planning for brachytherapy will produce a more realistic representation
of the implant conditions (83,84). 3D imaging is now used for both
identification of structures within the patient as well as guiding the
prescription in a volumetric manner instead of simply prescribing dose
to an arbitrary point (85,86). While CT remains the gold standard in
general for brachytherapy imaging, use of magnetic resonance imaging
(MRI) is becoming more prevalent due to its ability to discern soft issues
better than ∼100 kV x-rays (87–90). Ultrasound (US) also has a strong
role for source delivery and postimplant treatment planning in
permanent prostate implants given its nonionization nature and ability
to discern soft tissue. However, probe placement during transrectal US
imaging displaces the anatomy and produces differences in implanted
dose distributions and related plan evaluation metrics. It is now standard
practice to perform image fusion of CT with any pertinent and available
dataset(s), for example, MRI or positron emission tomography (PET).
There are many dosimetric uncertainties associated with clinical
brachytherapy. The joint AAPM + ESTRO report TG-138 estimated the
total dose calculation uncertainty (k = 1) to be about 4.4% for a single
125I source (91). The propagation of uncertainties from source
measurement to utilization in the brachytherapy TPS is given in Table
15.2.
TABLE 15.2 Propagation of best practice uncertainties and a

standard uncertainty of k = 1 (unless stated otherwise with a
coverage factor of 2) for derivation of dose at 1 cm on the
transverse plane for an LDR 125I brachytherapy source (91). The
measured source strength SK is added in quadrature with the Monte
Carlo-derived brachytherapy dosimetry parameters and the
uncertainties associated with treatment planning system (TPS)
interpolation uncertainties, yielding a total dose calculation
uncertainty of 4.4%. The expanded uncertainty (k = 2) is simply
double the standard uncertainty, and differs slightly from 8.8% due
to rounding of the preceding values.
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These uncertainties increase markedly once other sources of
dosimetric uncertainty are included from the clinical process of source
implantation. In a joint ESTRO + AAPM report, Kirisits et al. (92)
described the various uncertainty components. A standard uncertainty of
7% was associated with contouring structures using CT for permanent
prostate brachytherapy using 125I and postimplant day-0 CT. In
combination with all other uncertainty components, a total uncertainty
(k = 1) of 11% was estimated.
The 1985 ICRU Report 38 (17) established criteria for reporting doses
and volumes used in intracavitary brachytherapy for gynecologic
disease. This report was later updated to be generalized to other disease
sites requiring interstitial brachytherapy in the 1997 ICRU Report 58
(93). The AAPM updated these recommendations by providing specifics
for reporting criteria for permanent prostate brachytherapy in the TG-
137 report (39).
As part of its 2009 initiative to update all brachytherapy-related
guidelines (94), the American Brachytherapy Society (ABS) provided
updated guidelines in 2012 on transrectal US-guided permanent prostate
brachytherapy (38). These guidelines included criteria for treatment
with brachytherapy as well as contraindications, as well as an expansion
of treatment options for patients stratified by risk grouping. Where
patients were categorized as high risk, the ABS recommended use of
brachytherapy in combination with EBRT and androgen deprivation
therapy. Only the three radionuclides included in Table 15.1 were
recommended for this treatment modality. Disappointingly, the report
included recommendations for source strength in terms of apparent
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activity, requiring a leap of faith for the clinician to utilize an outdated
conversion factor to correlate apparent activity with the brachytherapy
dosimetry parameters. Prescription doses of 140 to 160 Gy were
recommended for 125I, not accounting for the prescription reset from
160 to 144 Gy due to traceable calibrations excluding titanium K-edge
characteristic x-rays (75,95,96). Similarly, prescription doses of 110 to
125 Gy were recommended for 103Pd, not accounting for a prescription
reset due to changes in source calibration standards (63,96,97).
The ABS provided guidelines for LDR brachytherapy of cervical cancer
in 2012 (98). These guidelines updated the prior ABS guidelines by Nag
et al. (99,100) to expand the role of brachytherapy to include patients
with disease stages IB2 to IVA of the International Federation of
Gynecology and Obstetrics. For definitive treatments using temporary
implants, a cumulative dose of approximately 80 to 90 Gy was
recommended, with two applications to allow for tumor reduction and
improved tumor coverage with the second brachytherapy application.
Prescriptions should require dose delivery to point A or to the 100%
isodose line. The D90 and V100 for the high-risk clinical target volume
receiving greater than 90% of the prescribed dose. Sources of LDR 137Cs
are recommended for intracavitary treatments while LDR 192Ir sources
are recommended for interstitial treatments.
In 2013, the ABS provided new guidelines for brachytherapy of cancer
of the penis (101) and for sarcomas (102). The majority of patients for
these two diseases have historically been treated with temporary LDR
192Ir brachytherapy implants. As use of HDR 192Ir brachytherapy is
becoming more prevalent, LDR brachytherapy for these diseases is not
viewed as a procedure that will be common in the future.
While breast cancer was historically treated with LDR 192Ir wires and
ribbons, this practice has fallen out of favor given the dose modulation
possibilities with HDR 192Ir and its outpatient treatments. However,
Pignol et al. have examined the feasibility of treating breast cancer with
permanent implantation of LDR 103Pd seeds (103,104). Dose to breast
tissue differed from dose to water by up to 36% (105). They also
examined feasibility of permanent LDR 125I brachytherapy for the breast,
but ruled it out due to concerns for radiation exposure from this higher-
energy photon-emitting radionuclide (106,107). However, Jansen et al.
did not observe the same concerns for radiation exposure (108).
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Other sites of disease that may receive permanent LDR brachytherapy
include the brain (109–111) and the lung (112,113). Cancers of the
head-and-neck region, anal canal, rectum, and skin are all regions that
have received LDR brachytherapy over the years, but have been treated
more recently with HDR 192Ir brachytherapy. LDR brachytherapy of the
ocular choroid within the eye is an interesting application where the
patient is often discharged following surgery to return back to the
hospital a few days later for surgical explant of the brachytherapy
plaque (114,115). Given the plaques shielding of the radiation (116),
there are radiologic effects that prompt advancements in clinical practice
so that radiation doses are more accurately known (117–121).
FUTURE DEVELOPMENTS
While this chapter covers the current standards for LDR brachytherapy,
it is also beneficial to the reader to know what lies around the corner as
the field of brachytherapy will continue to advance in a dependable
manner as it has over the last century.
In addition to the three radionuclides included in Table 15.1, several
other radionuclides are being investigated for LDR brachytherapy. 169Yb
(122) has a 32-day half-life and has been considered as a source for both
LDR and HDR applications. Radionuclides such as 170Tm (123,124) with
a 129-day half-life, 57Co (125) with a 272-day half-life, and 153Gd (126)
with a 240-day half-life all have mean photon energies of <0.1 MeV.
Sources have even been considered to purposefully contain more than
one radionuclide (127,128). Improved understanding of radiobiology
may indicate the optimal decay in dose (i.e., half-life) needed for a given
disease site (129,130).
In the past, there had been advancements with other novel
radionuclides for LDR brachytherapy such as 252Cf, which emits both
neutrons and photons. Since its proposal as a clinical source in 1965
(131), a couple thousand patients had been treated worldwide with LDR
252Cf brachytherapy (132). However, concerns for radiation exposure to
hospital personnel and increased controls for special by-product
materials have eliminated its use as a brachytherapy source following
the tragedies in the United States on September 11, 2001.
LDR brachytherapy sources have been designed to provide directional
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radiation (133), without the azimuthal symmetry required by the TG-43
dose calculation formalism. However, this attribute would require a new
approach to brachytherapy treatment planning and the ability to control
and monitor the source orientation. Sources have also been designed
(134,135) to be thinner (i.e., 0.5-mm O.D.) than conventional 0.8-mm
O.D. seeds, more flexible through plastic encapsulation and elongated
brachytherapy sources (136–140), and even for the entire LDR source to
be dissolvable within the patient and leave no radiographic trace after 1
year.
The scope of LDR brachytherapy is expanding through development of
new applicators such as for the treatment of disease within the brain
(141–143). For the GliaSiteTM balloon brain brachytherapy applicator, a
liquid solution of 125I or 131Cs is injected into the balloon for a
temporary implant of cranial disease.
To remove the variability in human skills for interstitial implantation
of brachytherapy sources, robotic means of delivery (144,145) are being
developed. The AAPM TG-192 report provides an excellent review of the
field (146). Algorithms for automatic identification of LDR seeds are
already available (147). Further automation of the brachytherapy
process has focused on the segmentation or contouring of structures
(148) following image acquisition. This is important as structure
contouring has been identified as being the most important contributor
to the dosimetric uncertainties associated with clinical brachytherapy
(92,149). Given that brachytherapy is generally an invasive procedure
and perturbs the natural state of human anatomy, algorithms are being
developed in the field of deformable image registration (150–152) to
alter the shape of the imaged anatomy and permit accurate dose
summation of the brachytherapy dose distributions. These algorithms
may also work in combination with results from EBRT treatment plans to
estimate the total dose distribution.
While the current standard for specifying brachytherapy source
strength is air-kerma strength, a more intuitive metric would be the dose
rate at some distance in a reference medium (153). One proposal that is
gaining ground in Europe is to calibrate LDR brachytherapy source
strength in terms of the dose rate to water at a specified time (154–156).
A potential advantage of this approach would be lower overall
dosimetric uncertainties since there would be no need to measure the
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dose-rate constant (153). However, there would need to be a significant
change to the clinical TPSs and to the calibration traceability available
to the clinical medical physicist. Changing to this new metric would
require societal coordination and regulatory changes for this to go
smoothly.
Another advancement in dose calculations for LDR brachytherapy
sources is through improvements in the TG-43 dose calculation
formalism (157). Differences between liquid water and soft tissue can
amount to more than 30% (158–161). A simple approach is to replace
the dosimetry parameters for liquid water with the dosimetry parameters
for soft tissue, which can drastically improve the accuracy of dose
determination. As a way to further adjust the means of dose calculation,
precalculated MC-based dose distributions may be used in conventional
TPSs for a particular applicator type (62). Again, these advancements
would require societal coordination for widespread implementation,
along with extensions to the current tasks used to commission
brachytherapy dose calculation algorithms preceding clinical use (162).
CONCLUSIONS
The field of LDR brachytherapy was established over a century ago, and
there are established clinical practice standards for the safe and
consistent delivery of this radiation-based treatment modality. The
current standard for dose calculations is the TG-43 formalism, where
dosimetry parameters and prescriptive criteria have dose to water as its
foundation (due to its heritage of 226Ra and 222Rn dosimetry). Source
strength is specified in terms of air-kerma strength, the only traceable
quantity for clinical use as recommended by the AAPM. Brachytherapy
has been applied to every disease site, and the clinical medical physicist
should learn proficiency for this manual, multidisciplinary procedure
where the dose gradients and clinical uncertainties are greater than for
EBRT. There are many exciting developments underway to enhance and
extend the field of brachytherapy.
KEY POINTS
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• Brachytherapy has been used since the early 1900s
• Brachytherapy is typically an invasive treatment modality with
potential for more conformal dose distributions than other radiation
sources
• The AAPM TG-43 dose calculation formalism has been adopted
worldwide for consistent dose calculations
• Air-kerma strength (SK) is the only traceable quantity of
brachytherapy source strength
• Clinical brachytherapy requires well-positioned sources for
delivering the desired dose distribution
• Advancements in brachytherapy will further enhance and extend
the field
QUESTIONS
1. Which listing of radionuclide (and half-life) is correct?
A. 125I (59.4 days), 103Pd (9.7 days), 131Cs (17 days)
B. 125I (59.4 days), 103Pd (17 days), 131Cs (9.7 days)
C. 125I (17 days), 103Pd (9.7 days), 131Cs (59.4 days)
D. 125I (17 days), 103Pd (59.4 days), 131Cs (9.7 days)
2. Which is the correct format for the 1D format for the TG-43 dose
calculation formalism?
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3. Using the 1D dose calculation formalism, approximately what is
the total dose delivered to the surface of a 1 U 125I seed after 1
year?
A. 11,955 Gy
B. 5,744 Gy
C. 498 Gy
D. 120 Gy
4. Which metric for brachytherapy source strength is recommended
for clinical use?
A. Apparent activity (Aapp)
B. MBq
C. mCi
D. SK
E. Dose rate to water at a distance of 1 cm from the source
transverse plane
5. For which disease site is LDR brachytherapy most prevalent?
A. Eye
B. Breast
C. Prostate
D. Cervix
E. Lung
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ANSWERS
1. B The other answers are incorrect since the half-lives are
given in Table 15.1. Section on “LDR Brachytherapy
Sources” covers this question.
2. C The other answers are incorrect since calculation of the
dose rate would not replicate the original calculated or
measured dose-rate distribution since the dosimetry
parameters are inconsistent. Section on “Dosimetry” covers
this question.
3. A The half-life of 125I is 59.4 days. After 1 year, this
amounts to over 6 half-lives and the source may be
assumed to have infinitely decayed. Using Equation 15.1
with a dose-rate constant value of 0.93 cGy·h-1·U-1 for 125I,
r = 0.04 cm for the capsule radius, and assuming gP(0.04)
equals unity, the initial dose rate in contact with a 1 U
seed is about 581 cGy/h. After infinite decay, this amounts
to 1,195,460 cGy or 11,955 Gy. The other answers are
incorrect, where (B) is low by a factor of 2.08 based on
incorrectly inverting the ln(2) factor for deriving infinite
decay, where (C) is low by a factor of 24 based on
incorrectly converting the half-life for infinite decay, and
where (D) is low by a factor of 100 for tricking the reader
when converting dose to Gy. Sections on “LDR
Brachytherapy Sources and Dosimetry” cover this
question.
4. D The other answers are incorrect since only air-kerma
strength (SK) is a quantity traceable to NIST for
determination of brachytherapy source strength. Section
on “Source Calibrations” covers this question.
5. C LDR brachytherapy is most frequently performed for the
prostate. The other disease sites have either lower
incidence or are treated more frequently with HDR
brachytherapy. Section on “Treatment Planning” covers
this question.
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161. Landry G, Reniers B, Pignol JP, et al. The difference of scoring dose
to water or tissues in Monte Carlo dose calculations for low energy
brachytherapy photon sources. Med Phys. 2011;38:1526–1533.
162. Rivard MJ, Beaulieu L, Mourtada F. Enhancements to
commissioning techniques of brachytherapy treatment planning
systems that use model-based dose calculation algorithms. Med Phys.
2010; 37:2645–2658.
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16 High Dose-Rate Brachytherapy
Treatment Planning
Bruce R. Thomadsen
GENERAL CONSIDERATIONS OF HIGH DOSE RATE

BRACHYTHERAPY TREATMENTS
High dose rate (HDR) brachytherapy forms a special method of
delivering brachytherapy where the treatment session lasts a short time.
What constitutes “a short time” is considered below, but in the overview,
the treatment session takes from 20 minutes to a couple of hours, as
opposed to a day to several days for conventional, low dose rate (LDR)
brachytherapy. Most of treatment planning for HDR brachytherapy
remains identical to that for general brachytherapy, which is covered in
Chapter 15. This chapter will only consider those aspects of treatment
planning that are either unique for, or of much greater importance to,
HDR planning. The discussion that follows does not go in order of steps
to perform for an HDR application. For example, planning a
brachytherapy procedure, which constitutes the first step, comes late in
the chapter. One reason for not following the procedural order is that
the order varies depending on the nature of the procedure. However, the
main reason is that the principles covered early in this chapter must be
understood before applying them in planning.
Several methods have been used in the past to deliver the treatment in
the short time, but all units currently use the same principle—a very
intense radioactive source on a computer-controlled cable steps through
the target volume, pausing for specified periods at particular locations
along the way. The pausing locations are referred to as dwell positions,
and the duration for which the source pauses are dwell times. Often, the
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dwell times are normalized to a particular dwell time location or the
maximum, in which case the normalized values are called dwell weights.
A unit that operates in such a manner is called a stepping source device.
The radioactive source for most units is 192Ir, although some new models
use 60Co. The operation of HDR units is discussed in detail in many texts
(1,2). Since this chapter deals with the treatment-planning aspect of
HDR brachytherapy, further description of the units properly is left to
the reader’s initiative.
HDR brachytherapy offers several advantages over LDR
brachytherapy.
1. Improved dose optimization capability. In an HDR brachytherapy
application, the dwell positions perform the same role as the source
positions do for LDR brachytherapy. For example, the same locations
where individual iridium sources would fall in an LDR gynecologic
implant, the single HDR source would pause for a dwell position. Such
an LDR implant could, and should, be “optimized.” “Optimization,” in
this context, means adjusting the strength or positions of the sources
to obtain a dose distribution with specified, desired characteristics (3).
One optimization goal often is simply that a specified isodose surface
covers a target volume. Other optimization criteria might include a
specified required homogeneity for the dose through the target
volume, or the maximum dose allowed to other anatomical structures.
Optimization of a medium size LDR implant often requires 8 to 10
different source strengths, which sometimes becomes difficult to
obtain from a supplier. For a similar HDR unit, the dwell times at each
dwell position, on the other hand, commonly may vary in increments
of 0.1 second from 0 to 999 seconds. Thus, satisfying the optimization
requirements becomes easier with the great flexibility in relative
strength at each dwell position. Optimization plays such an important
part in HDR treatment planning that a section of this chapter is
devoted to this topic.
2. More stable positioning. For intracavitary insertions, HDR
applicators usually lock into their treatment positions through fixation
to the treatment couch. With the patient essentially immobilized (e.g.,
in stirrups and strapped to the table), the applicator moves little
between imaging for dosimetry calculations and the completion of the
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treatment session. One series studying the movement of HDR tandem
and ovoid applications reported an average movement based on
skeletal anatomy of 2 mm (4). This compares with an average of 2 cm
movement for LDR tandem and ovoids (5).
3. Adding distance to normal tissue. For some HDR treatments—
notably gynecologic intracavitary insertions or head and neck
interstitial implants—normal tissue structures can be pushed away
from the path of the source during the treatment, reducing their dose.
While not every treatment site can use this technique, in those for
which it applies the dose reduction to normal structures can be
marked. In general, the discomfort that similar tissue displacement
would cause over the multiple-day treatments for LDR brachytherapy
would be intolerable.
4. Outpatient treatment. The driving force that led to the wide use of
HDR brachytherapy was the economic shift in reimbursement it
produced from the inpatient hospital to the clinical facility that
delivers the HDR treatments. This occurs because most HDR
treatments are delivered on an outpatient basis. In addition to
changing the revenue patterns, outpatient treatments usually are
much more convenient and comfortable for the patients than
confinement in a hospital room in radiation isolation.
5. Smaller applicators. For gynecologic intracavitary applications, the
tandem used for HDR treatment of uterine cancer has only a 3-mm
diameter compared with the 7-mm diameter tandem used for LDR
brachytherapy. The dilation required to insert the LDR tandem forms
the most painful part of the treatment procedure. By comparison, the
sound used to measure the length of the uterine cavity before dilation
takes place is also 3 mm in diameter and often requires no anesthesia.
6. Intraoperative and perioperative treatments. For interstitial cases,
HRD brachytherapy treatment can commence immediately following
insertion of the applicator or catheters, localization imaging, and dose
calculations. LDR brachytherapy cases usually require ordering the
sources, or if sources were ordered ahead, performing the implant as
planned without the possibility of modifications based on new
information noted during the operative procedure. This ability to treat
immediately after placement, along with the short duration of
treatment, opens the possibility of using HDR brachytherapy during
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operative cases (intraoperative) for irradiation of tumor beds during
resection or for wider use of image-guided implants (6).
7. Reduction of radiation exposure to health care providers. The
final advantage of HDR brachytherapy is that all personnel leave the
treatment room for the actual delivery of the radiation, and with
adequately shielded walls and doors, the radiation exposure to staff
should remain minimal.
HDR brachytherapy also has disadvantages compared with LDR
brachytherapy.
1. Treatment unit complexity. Compared with the usual LDR

brachytherapy situation of sources manually inserted into an
applicator, the HDR situation seems much more complicated. With the
treatment unit, transfer tubes to guide the source between the unit
and the applicator, transferring treatment programs between the
treatment planning computer and the treatment unit computer, HDR
brachytherapy entails a host of considerations not applicable to LDR
brachytherapy.1
2. Compressed time frame. Adding to the complexity of HDR
brachytherapy, much of the action takes place in time frames short
compared with LDR brachytherapy. For example, after insertion of a
tandem and ovoids for cervical cancer therapy, making images and
calculating the treatment program, the actual delivery of the
treatment frequently takes 10 to 30 minutes. If there were an error in
the treatment program, it would be easy for the error to be executed
before detection. The situation with LDR treatments provides some
latitude for detecting errors. The long duration of the treatment gives
more opportunity to spot and correct errors well before the end of
treatment, when corrective actions could prevent serious injury.
3. Radiobiologic disadvantage. The most serious disadvantage for HDR
brachytherapy results from radiobiology. Radiobiology is such an
important aspect of HDR brachytherapy that it has its own section
below. In the current discussion, it suffices to say that compared with
LDR brachytherapy, radiation delivered at a HDR produces a greater
increase in damage to normal tissue compared to cancerous tissue.
4. The potential for very high radiation doses resulting from
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mechanical failure. The HDR source cable can become stuck or
snagged, or the source can break free from the cable. In either case,
the patient could receive an injurious amount of radiation in about 1
minute. While the operator is unlikely to receive an injurious amount
of radiation removing the stuck source from the patient, there is a real
potential for receiving exposures in excess of allowed limits.
RADIOBIOLOGIC CONSIDERATIONS
Therapeutic Ratio
Accomplishing the goal of radiotherapy requires inflicting more damage
to diseased cells than to normal tissue cells. The therapeutic ratio is an
important measure involved in the planning for the goal of
uncomplicated cure of disease. The therapeutic ratio could be defined as
the ratio of the damage to tumor cells to that to normal cells for the
same delivered dose, or
Since it becomes difficult to grade damage, and the damage to cells is

not linear with dose, a more common equivalent expression often forms
the basis for the calculation of this ratio, determining the ratio of the
doses required for the same biologic endpoint, for example, five logs of
cell kill. The equation becomes
The more effective the radiation is at killing a certain type of cell, the
lower the dose required to reduce a population of cells to a given level.
Figure 16.1 shows a typical curve relating the survival of cells to dose
of radiation. In general, the relationship between cell survival, S, and
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cell killing can be modeled as
FIGURE 16.1 A cell survival curve, plotting the fraction of cells surviving a single exposure to
radiation as a function of the dose delivered. The curves are based on α = 0.25 Gy−1, βtumor =
0.025 Gy−2, βnormal tissue = 0.083 Gy−2, μrepair = 1.5 h−1. Cell proliferation has been ignored.
where D indicates the dose delivered. Equation 16.3 is just a model, and
should not be taken as the true description of the physical and biologic
process. In the figure, the lines labeled “Normal Acute” and “Tumor
Acute” indicate the response of typical normal tissue and typical tumor
cells to a single dose of radiation. For any dose level, the tumor cells
show an increased survival—not a desirable feature for radiotherapy.
The other curves indicate responses for a conventional LDR treatment
regimen, delivering the dose at approximately 0.5 Gy/h. For both tissue
types, the survival increases due to repair of sublethal damage during
the radiation delivery. However, the difference in survival between the
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two curves at any dose decreases compared with the acute curves.
Looking at it the other way, compared to LDR delivery, the difference in
response between normal tissue and tumor tissues becomes worse for
HDR delivery.
Figure 16.2 illustrates the loss in therapeutic ratio with an increase in
dose rate, and the loss in therapeutic ratio can be significant. Figure 16.2
also shows another interesting feature. The therapeutic ratio changes
slowly with dose rate over the LDR portion of the curve (0.4 to 0.8
Gy/h, shown as green vertical lines in the figure), which accounts for
historic LDR treatments giving similar results regardless of the exact
dose rate. In that region, the therapeutic ratio does not change with
absolute dose, only dose rate. At dose rates, above 20 Gy/h, the
therapeutic ratio again varies little with the actual dose rate. Most HDR
units deliver a dose at 1 cm at a rate of 100 to 500 Gy/h, but because
much of an implant lies farther away than 1 cm at least some of the
treatment time, the dose rate can fall well below that, but seldom below
12 Gy/h. Over any realistic HDR application, the dose rates anywhere in
a volume of interest remain in the flat region of the curve. However, the
biological dose distribution for an HDR application depends on the
absolute dose level, and so differs from the physical dose distribution.
FIGURE 16.2 Relative therapeutic ratio as a function of dose rate, normalized to a dose rate of
0.5 Gy/h. Each line assumes a particular ratio for the α and β in Equation 16.3 for tumor cells and
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normal cells. The blue line represents a typical situation, with α/β = 10 Gy for the tumor and 3 Gy
for normal tissue. The red line applies to aggressive tumor, with an α/β of 20 Gy and normal tissue
with α/β or 2 Gy. The vertical green lines indicate the LDR region. The blue dot indicates the
normalized therapeutic ratio for fractionated HDR treatments for typical tumors.
A very different situation obtains in the middle, transition region. In

this case, the biologic effectiveness of the radiation varies greatly with
the actual dose rate, and the biologic effectiveness of a given amount of
dose varies with position in the treated volume. Often, treatments using
nominally LDR remote afterloaders actually deliver doses at this middle
dose rate range. High precision is required with these devices to avoid
exceeding tolerance of normal tissues.
The flat response in the HDR region of the curve traces back to the
definition of “high dose rate.” In Equation 16.3 the term α in the
exponent does not depend on the rate of dose delivery. This term is often
associated with single-track killing, that is, one charged particle passing
near the DNA strand produces sufficient ionization in the right location
to break both sides of the DNA “ladder.” Such a double-sided break can
produce a biologic effect, including cell death.2 The term β can be
thought of representing the situation where the break on each side
results from different charged particles. The cell can repair a single-sided
break because the remaining side provides the template for the missing
side. Tr, the half-time for repair of sublethal damage, characterizes this
repair giving the time required to repair half of single-sided breaks.
Measured values of Tr vary widely, but a typical value is 1 to 2 hours for
both normal and tumor cells. Some normal tissues exhibit repair with
two components, one with a half-time of approximately the value above
but also a shorter component of about 20 minutes (7), although other
models of repair kinetics fit the data better (8). Tumor cells seem not to
have this faster component of repair, which gives another therapeutic
advantage to the use of LDRs. For the simple, single-component model
for repair, the repair coefficient, μ, can be calculated as
Because the breaks repair over time, the probability for a second-sided
break at the same location as the first depends how compact in time the
radiation is delivered. When all the radiation passes through the DNA in
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a short period, the likelihood that the second side will break before the
first side repairs increases compared with a long delivery. In this case, a
“short” time relates to the half-time for repair of sublethal damage.
Regardless of the actual dose rate, HDR treatment refers to a treatment
where essentially all the breaks occur before any significant repair takes
place. In general, HDR treatments should be completed within a half
hour of commencement.
Fractionation
While reducing the dose rate is one method to improve the therapeutic
ratio, another is fractionation. Figure 16.3 shows survival curves for the
same parameters as Figure 16.1, but includes the survival curves for
delivering the doses in 2-Gy fractions. The fractionation reduces the
effectiveness of the radiation at killing cells, but it also reduces the
differences between the responses of the tumor and the normal tissues.
FIGURE 16.3 Survival curves using the same parameters as in Figure 16.1 for acute (single
fraction) exposures and for 2-Gy acute fractions.
HDR brachytherapy generally fractionates the treatment course to

mitigate the problem of loss of therapeutic ratio with the increase in
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dose rate. Figure 16.4 shows the improvement in the therapeutic ratio by
using one more fraction. For example, if a plan is called for the use of
three fractions, the therapeutic ratio would improve by 4.7% by using
four fractions instead. If five fractions were used instead of four, the
therapeutic ratio would improve another 4% above the 4.7%
improvement from increasing from three to four. As can be seen, each
additional fraction improves the therapeutic ratio, but by less than the
addition of the fraction before. In external-beam treatment, which is
definitely HDR therapy, the number of fractions is approximately 35,
which would provide a great benefit in the therapeutic ratio, and the
addition or deletion of one or two fractions would not make much a
difference. Brachytherapy is both taxing on the patient and a drain on
the personnel and resources of the facility, and the use of a high number
of fractions such as common in external-beam therapy, is not an option.
Thus, a compromise must be made between improved therapeutic ratio
and practicality. The number of fractions selected for curative cases
depends on the amount of work involved and patient discomfort for each
fraction. For interstitial cases with needle-like catheters in place, such as
a prostate implant, three fractions are common. On the opposite
extreme, breast implants with soft catheters and little patient discomfort
often use 10, twice-a-day fractions. Intracavitary insertions involving the
placement of a treatment appliance at each fraction often use five or six
fractions. Tandem and ring applications using an indwelling Smit sleeve
(a sheath for the tandem) in the uterine canal simplifies the procedure to
the point to which 12 fractions have been used (9).
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FIGURE 16.4 The percentage improvement in therapeutic ratio by the addition of one more
fraction than the number on the abscissa. See the text for an example.
Prescription Doses
Because the biologic effectiveness of radiation changes going from LDR
treatments to fractionated HDR treatments, the absolute dose prescribed
also has to change to obtain the same therapeutic endpoint. As Equation
16.3 shows, cell survival has complicated exponential relationship to
dose, so dose proper is not the best variable to use when evaluating or
predicting biologic effects. Of several approaches, one of the most
practical begins by taking the log of both sides of the dose response
curves from Equation 16.3,
and then divided by −α to have at least the first term in dose alone, to
give
BED stands for biologic equivalent dose. An equivalent term seen in

the literature is the RDE, radiologic dose equivalent. Equation 16.6 holds
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for acute, single exposures. For multiple HDR exposures of n fractions of
d Gy/fraction, the BED becomes
Equation 16.7 holds when each fraction is short compared with the
half-time for repair for cellular sublethal damage, and the time between
fractions is long compared with this same half-time. As above, the
duration of the treatment should be less than a half-hour, and the time
between should be about 4 half-times, or about 6 hours. The newly
included last term in Equation 16.7 gives the effect of cellular
proliferation on the BED, where T is the total duration of the n fractions
and Tpot is the potential doubling time for the cells. The equation shows
that proliferation decreases the effectiveness of the radiation. This latter
factor often is not known well; however, a compilation of values gleaned
from the literature has been published (10). Conventionally, due to the
uncertainty in this parameter, the proliferation is often ignored. For
interstitial cases, the total therapy duration often remains the same; and
therefore also the proliferation effect, whether the treatment chosen is
HDR or LDR brachytherapy, as discussed below.
Protracted LDR therapy with some repair of sublethal damage taking
place during treatment follows Equation 16.8 (11),
where is the dose rate.

Assuming that the dose has been established for LDR treatments, the
equation to produce the same biologic effect with HDR brachytherapy
can be calculated. The first step entails selecting the number of HDR
fractions to use. As discussed above, this selection is an arbitrary
compromise between improving the therapeutic ratio and practical
utilization of resources. The next step sets the BED for each modality
equal:
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or
If the total times are similar, then the last terms on each side cancel.
Even if they are not similar, since the values needed for their calculation
are not well known, they often are simply ignored, giving
The remaining unknown term in Equation 16.11 is the dose per

fraction, d. Solving for d gives
BED depends on the tissue characteristics, as embodied in the values

for α and β. Thus, the equivalence between LDR and HDR brachytherapy
only applies to a single type of tissue—tumor or normal tissue. The dose
cannot be equivalent for both simultaneously. An equivalent regimen
must be selected to produce the same cure rate (equivalent for tumor) or
the same normal-tissue reaction (equivalent for normal tissues). If the
choice becomes too difficult, a compromise can be made—but at the cost
of not being equivalent to the LDR regimen in any way. In general,
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making the HDR regimen equivalent to the LDR regimen for tumor tends
to be the more common choice, since sacrificing cure rate would argue
strongly against performing HDR brachytherapy, and physical
techniques often can mitigate the increased effects on the normal
structures. Early in HDR brachytherapy experience, Orton (12) suggested
that doses not exceed 7 Gy/fraction to avoid normal tissue
complications. The suggestion came from the review of a survey asking
practitioners about their HDR experience. While the responses did
indicate that complications increase with fraction sizes exceeding 7 Gy,
the total doses for the cases in the survey were not controlled based on
the linear-quadratic equations given here and commonly accepted in the
present.
Complicating further the attempt to make an HDR brachytherapy
treatment similar to one performed with LDR brachytherapy, notice that
in Equation 16.12 the dose per HDR fraction, d, depends on the LDR
dose to which it should be equivalent. This means that an HDR
brachytherapy dose distribution can never be biologically equivalent to
an LDR brachytherapy dose distribution. Thus, to achieve a similar
biologic dose distribution, an HDR treatment should not duplicate the
LDR physical dose distribution.
With interstitial implants, higher doses require more fractions to
maintain normal tissues within tolerance doses. If the treatment
catheters remain in place for the whole therapy, treatments frequently
are given twice a day (BID). Table 16.1 relates LDR doses delivered at
the rate of 0.5 Gy/h with the equivalent regimen with two HDR fractions
per day. In general, the overall treatment duration—time with the
catheters in place—remains about the same. The patient, however, need
not be in radiation isolation with the HDR treatments.
TABLE 16.1 Equivalent Treatments for LDR and HDR Brachytherapy
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For intracavitary insertions, the prescribed dose often falls at an
unambiguous (although often arbitrary) location; for example, Point A
for cervical cancer, the surface of a cylinder for vaginal cancer, or 1 cm
from the center of the applicator for esophageal applications. Interstitial
implants are sometimes less well determined. Take, for example, a post-
tylectomy breast implant with a seroma visible on computer tomography
(CT). The clinical target volume (CTV) might be the seroma plus a 1.5-
cm margin, limited to remain 5 mm deep to the skin and not enter the
pectoralis major. During the dosimetry process, the prescription-dose
(100%) isodose surface ideally is set at the CTV. All these seem very
straightforward. However, depending on where the source tracks fall
with respect to the CTV, the 100% isodose may lie on the edge of the
more or less uniform dose plateau of the implant or in the rapidly
decreasing gradient. (It should be assumed that the 100% isodose
surface would never fall beyond the rapidly decreasing gradient to
where the dose decreases more slowly; that would be a poor plan
indeed.) Thus, in actual cases, some of the CTV may not receive the full
dose and some of the prescription isodose surface may fall outside the
CTV. Some guidelines for specifying the prescription dose are given in
the section on “Evaluation.”
OPTIMIZATION
In brachytherapy, “optimization” generally connotes determination of
some aspects of an application in order to achieve particular goals. For
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example, optimization may have the goal of delivering a minimum dose
to a target volume with a specified homogeneity. With permanent
implants of the prostate, optimization usually generates a pattern for
locations of the sources to deliver 90% of the prescription dose to the
entire CTV,3 limit the volume raised to 300% of the prescription dose,
and avoid doses to the rectum and urethra that exceed their respective
tolerances. In HDR brachytherapy, the most common optimization
process determines the dwell times that produce the desired dose
distribution—rarely does the process determine catheter location, which
usually is given. The assumption is that the planning of the implant, that
is, where catheters or appliances should lie, occurs at a previous stage.
This forms the basic difference between the HDR brachytherapy and the
permanent implant cases—for permanent implants, optimization is a
part of planning, while for HDR brachytherapy optimization is simply a
part of dose computation.
The optimization problem in HDR brachytherapy tends to be simpler
than for permanent implants with a single source strength, and can
usually come closer to achieving the goals of the optimization. While the
permanent implant problem can only decide whether or not to place a
source in a given location, the HDR brachytherapy problem can begin
assuming activation of all possible dwell locations, and then simply
determine each dwell time. Sometimes, the easiest approach determines
the dwell times relative to either the maximum time or some specific
time (dwell weights) for each dwell position in order to achieve some
uniformity, and then set the times in proportion to the dwell weights
required for the dose. If solution for the problem does not require a
particular dwell position, the optimization routine (optimizer) needs
only set the weight to zero. There are several, very different approaches
to optimization. Ezzell (13) and Ezzell and Luthmann (14) present
excellent discussion on optimization theory and characteristics.
The optimization problem usually specifies a goal. A simple goal might
be to deliver a particular dose to a particular location. More specific
goals might include delivering the same dose to a set of points or a
surface. Even more complex goals not only specify the dose to a surface,
but the homogeneity of the dose through the bounded volume and
maximum doses allowed to neighboring sensitive normal structures.
With the more involved goals, one of the features of the optimization
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approach includes how to specify the problem and determine the
importance of all the varied, and often conflicting, requirements. Many
of the optimization approaches use an objective function (OF) to wrap all
the goals into a single measure. An example of an OF for a prostate
implant could be
where D stands for doses and w for weighting for the term. The first term
considers the target voxels, denoted by subscript t. The first goal would
be to deliver the prescribed dose to the target. Any voxels falling below
the prescribed dose would add to the OF. Homogeneity, indicated by the
subscript h, also applies to the target voxels, and in the second term,
voxels exceeding twice the prescribed dose add to the OF. The last two
terms address dose to the rectum and urethra, and increase the OF for
voxels that exceed a specified limit for the respective organ. The goal of
an optimization could be to minimize this OF. OFs (sometimes called
cost functions) can be simpler or more complicated, and can be set such
that the goal may be to minimize or maximize the function.
Considering the function above, there may be many combinations of
dwell times that satisfy all the requirements, so there would not be a
unique solution. In the subset of all solutions, some may be better than
others. If the differences in solutions make a difference in the perceived
quality of the treatment plan, then the OF should be modified to reflect
the additional requirements or tighten the specifications. If the
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differences in the solution remain unimportant, then the first solution
found could be used.
While there are many approaches to optimization, they tend to fall in
general categories. The actual distinctions between the categories seldom
are as clear as it seems they should be, and into which category a given
approach falls often remains debatable. Nevertheless, the discussion
below considers the characteristics of some of the major categories.
Deterministic Approaches
Deterministic approaches to optimization always find the same solution
to the same problem, and generally solve equations to find the dwell
times.
Heuristic Approaches
Heuristic approaches use pragmatic search techniques to construct
solutions to the optimization problem. The search techniques may use
surrogates for the optimized quantities if they are useful. Optimization
purists might maintain that heuristics are not true optimization
approaches because they tend not to produce a true optimum but merely
a satisfactory result. For clinical problems, satisfactory results often serve
the patient needs well. In any case, the results of the optimization must
be evaluated for appropriateness.
For HDR brachytherapy, one of the most widely used heuristic
approach is geometric optimization, developed by Edmundson (15).
Geometric optimization assumes the goal is a uniform dose distribution,
and further assumes a distribution of dwell positions through the volume
to receive the uniform dose. The first step in the optimization process
recognizes that the dose to the region of the target around a dwell
position results not only from the radiation emanating from that dwell,
but from all the other dwell positions as well. Looking first at what dose
is received at a given dwell position from all the other dwell positions,
the weighting of the dwell under consideration should be inversely
proportional to the dose from the other positions. Thus, dwell positions
that receive large doses from the other dwell positions should have
shorter dwell times and those with little contribution from other dwells
should have long times. Mathematically,
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where Dj→i is the dose from dwell position j delivered to dwell position i.
The commercial versions of the programs approximate Dj→i with the
inverse square relationship, using Equation 16.15,
Such an approximation is expedient but not necessary.

One problem with geometric optimization in the form of Equation
16.14 is that the optimization assumes equal dwell times during the
calculation of the dwell weights, but then uses the calculated weights for
the treatment. Thus, the treatment does not match the conditions for the
optimization. This problem could be rectified through an iterative
procedure, where the dwell weights for current iteration used those
calculated in the last, such as
The iteration would continue until the dwell weights changed less
than some specified percentage. Geometric optimization tends to
underweight the periphery of implanted volumes. The iterative
procedure could rectify this shortcoming.
A refinement of the approach ignores the contribution of those dwell
positions within a specified radius of the one being calculated, assuming
that the influence of very close dwells may unduly influence the
resultant weights. Applying this technique of ignoring the nearby dwell
positions is known as volume optimization. In practical implementation,
often the calculation of the dose to a dwell position ignores the
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contributions from dwells along the same catheter track. When
optimizing few source tracks, such as single catheters for esophageal
treatments or a tandem and ovoid, all dwell positions would be included
in Equation 16.14—a process then known as distance optimization.
Convergent Searches
Also called “downhill searches,” convergent searches minimize the OF
iteratively (16,17). At each iteration, the program decides which
direction to make changes and how much change to make, based on the
differential of the OF with respect to the parameter being optimized in
that pass. These methods tend to get stuck in local minima if they occur
between the starting condition and the true minimum. At the time of
writing, no commercial brachytherapy planning system uses this
technique, although given the popularity of downhill searches in
optimization for intensity-modulated radiotherapy the method may
move into HDR brachytherapy.
Point-Dose Optimization
Geometric optimization works without reference to an actual dose
distribution. Point-dose optimization forms the most direct optimization
approach actually to address doses. For this approach, the operator
specifies doses to deliver to particular points (optimization points). The
process then straightforwardly establishes a set of equations for the
doses to the optimization points, of the form
where fi→a denotes the function that describes the dose at optimization
point a resulting from the source at dwell position i per unit dwell time.
The dwell time, ti, becomes the unknown in the equation. Each
optimization point forms one equation, and each dwell time an
unknown. Together they form a set of simultaneous equations.
Unfortunately, solution of the set of equations presents two problems.
The first problem is nonphysical solutions. Consider the situation with
the same number of unknown dwell times and optimization points—a
determined system. Consider a very simple case, as shown in Figure 16.5
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with 12 dwell positions, separated by 1 cm, and 12 optimization points,
where each point falls 3 cm above the dwell position. Further, to
simplify the problem, approximate the source as a point so the dose rate
only depends on the source strength, SK, the dose-rate constant, Λ, and
the inverse of the distance, r. (For 192Ir the other factors are minor and
could be ignored for the example.) Assume that all the optimization
points should receive the same dose. The system of equations becomes
FIGURE 16.5 An example for optimization: a single catheter with 12 dwell positions at 1 cm
intervals, and 12 optimization points, each 3 cm below every dwell position.
where every Di = the dose at point i = the prescribed dose, and j

indicates the source dwell position. Solving this system gives relative
dwell weights of:
1.00, 0.08, −0.18, 0.26, 0.50, −0.02, −0.02, 0.50, 0.26, −0.18,
0.08, 1.00.
The negative dwell weights are necessary to satisfy the dose
requirements. Simply deleting those dwell times, or increasing all the
times by the amount of the most negative fails to produce the uniform
dose.
A method to deal with the potential negative values for the dwell
times developed by van der Laarse adds a constraint to reduce the
variation between adjacent dwell times (18). With control of the
variation of dwell times, the equation for optimization becomes
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where wt is the dwell-time gradient weighting factor, a measure of the
importance of minimizing the differences between adjacent dwell times,
and n is the number of dwell positions along a catheter. The first term
aims to minimize the differences between the desired doses at the
optimization points and the calculated doses. The optimization process
then becomes minimizing the chi-square, χ2. Delivery of any dose
requires the net dwell time summation to be positive, so there is no
concern that the process might yield all negative times. Minimizing the
differences between adjacent dwell times only makes sense locally, that
is, along a catheter. Each catheter starts a new comparison of times. The
best correlation between desired and calculated doses comes with the
smallest value of wt that eliminates negative dwell times. The values for
wt have no limiting range, although increasing the value above
approximately 0.8 has little effect on the dose distribution.
Adding a dwell-time gradient control factor to the problem in Figure
16.5 and Equation 16.19 produces the dwell weight pattern of:
1.00, 0.31, 0.04, 0.10, 0.37, 0.22, 0.22, 0.37, 0.10, 0.04, 0.31, 1.00.
All the dwell weights have become positive. The value for the dwell
weight gradient control factor in this example was just 0.01. A small
amount of control makes a marked difference. The uniformity suffered
slightly in this case. With the negative dwell weights, the dose at the end
optimization points fell −4% below the average dose to the points, but
the remaining points were within ±1%. With the control of the dwell
times, the end points improved to −3%, but the rest of the points varied
between −1% and +3%. The results of any optimization always require
evaluation to assure that the clinical needs are met.
Approaching the problem as a minimization of chi-square also
addresses another problem. While the single catheter example above had
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the same number of dwell positions and optimization points, real cases
often have more dwell position than optimization points (making an
underdetermined system of equations) or fewer (overdetermined)—
either posing a situation that cannot be solved exactly just by
manipulating the equations. The chi-square approach gives the best
approximation to a solution. Underdetermined cases have many possible
solutions. A useful criterion for selecting the best of the solutions
controls the overall treatment time. While simply selecting the solution
that minimizes the sum of the dwell times provides a straightforward
method to achieve this, minimizing the sum of the squares of the dwell
times tends to provide a more uniform distribution of dwell times, and
likely of dose (19).
The results from optimization algorithms always need evaluation. The
algorithms, of course, do what they are instructed, but the instructions
may not be exactly the operator’s intention. Consider the simple example
of three dwell positions around a point, as shown in Figure 16.6, based
on an example of van der Laarse. Point optimization simply specifying
the dose to the point could result in the use of only one of the dwell
positions, when the intention probably was to use all three and cover a
larger volume. Either using a high value for the dwell-time gradient
weighting factor or adding optimization points at locations where the
dose is actually desired would solve the problem.
FIGURE 16.6 Three dwell positions around a point, based on an example case from van der
Laarse.
A further reason to review the results of the optimization carefully is

that the optimization requirements may not have a solution. The line
problem of Figure 16.5 had no solution that produced the prescribed
dose at each of the optimization points. Depending on the problem, the
solutions may or may not be close to the specifications. Particularly for
underdetermined problems, where the number of optimization points
exceeds the number of dwell positions, the probability of obtaining the
desired dose at all points becomes low. Evaluation procedures are
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covered in the section on “Evaluation.”
Modern brachytherapy, as with external-beam radiotherapy, tends to
specify doses to the surface of a target volume rather than a few points.
Programs often approximate surfaces with a collection of closely spaced
points. Controlling the dose within a volume often requires more points.
This proliferation of optimization points (equations) takes a greatly
increased amount of computer resources. Direct algebraic approaches
become less appealing.
Polynomial Optimization
A typical (not large) interstitial implant may have 25 catheters, each
with 15 dwell positions, resulting in a total of 375 dwell positions. As
noted at the end of the last paragraph, the number of optimization
points in this case may also become exceedingly large—likely
approximating the number of dwell positions. Thus, the system could
have 375 equations—each with as many unknowns. This could take
some time to solve. Van der Laarse proposed that with the dwell-time
gradient weighting factor, the dwell times in a catheter could be
constrained to the point that a polynomial could describe their pattern
(19). The advantage of fitting the dwell times along a catheter is the
reduction in parameters from the number of dwell times to the fitting
parameters. Van der Laarse suggests that for n dwell positions in a
catheter, a polynomial of order p could model the dwell times, where
Using the polynomials, the dwell time at position i along a catheter, at

the distance xi from the beginning of the catheter, becomes
The optimization then substitutes Equation 16.21 in Equation 16.19,

and sets to find the optimum fit for the polynomials.
Polynomial optimization as implemented in the Elekta Nucletron4

planning systems uses geometric optimization to give a first-pass value
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for the dwell times for volume implants, sums the resulting dwell times
along each catheter, and divvies that time to each dwell position in
proportion to the values resulting from Equation 16.21 divided by the
total of the ti(xi) for the given catheter.
Stochastic Approaches
Stochastic approaches to optimization search for solutions by starting
with a possible solution to the problem (in this case, the dwell times for
all dwell positions), but not necessarily (or likely) the optimum solution.
The OF is calculated for this solution. Then changes are made to the
solution, and the OF calculated for the new solution. Another new
solution would then be formed—guided by whether the value for the OF
improved or degenerated. The nature of the search pattern differs for the
various optimization programs, but all the stochastic approaches have
some element of randomness in the search pattern. Because of this
randomness, the programs may find different solutions with each run.
The only stochastic approach currently used in commercial HDR
brachytherapy treatment planning are simulated annealing (20–22) and
the genetic algorithm (23,24). Ezzell (13) and Pouliot (25) present more
detail on optimization techniques. For simulated annealing, the search
makes somewhat random changes in the dwell times. The changes are
not truly random, however. At first the changes may be large. With each
iteration, the sizes of the changes decrease. If after the change the OF
improves, the next change pushes toward that same direction. On the
other hand, if the OF becomes worse, a more random change is made.
This process hones in on a “best” solution, but can get stuck in a local
optimum, rather than the global optimum. To prevent a local trapping,
occasionally, the program makes a very large change. If the new region
of solutions does not seem promising after some tries, the program goes
back to the place it left off before the big jump. Even though the process
is computationally intensive because of the iterative nature of the
search, as implemented commercially at the time of writing,
optimization for a HDR prostate implant only takes a few seconds.
Manual Reoptimization
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Optimization programs often satisfy the specified criteria but fail to
produce the dose distribution that the operator had in mind. Manual
reoptimization remedies such a situation. Each commercial planning
system for HDR includes a tool for adjusting the path of the isodose
surfaces. With these tools, an isodose curve on a particular image slice
can be grabbed by the cursor and moved to the desired position. The
program then changes the dwell times to produce the change. The
operator can choose to have the changes adjust just a single dwell
position (local), all of the dwell positions (global), or any amount
between. Global changes actually just renormalize the dose distribution
to make a new dose as the prescription dose. Figure 16.7 shows manual
optimization in action. Figure 16.7A shows the isodose distribution
before adjustment, where the 100% isodose exceeds the target region of
interest. Figure 16.7B shows the result of moving the 100% isodose
curve to the target. For this example the change level was set to “local.”
Even though the change is local, it still affects the dose distributions in
other image cuts. Manual reoptimization must always be practiced
iteratively, changing the dose distribution through a series of images and
going back and adjusting them again, correcting the first cuts changes
for the effects of the later. At some point, the changes become small
enough that further reoptimization becomes unnecessary.
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FIGURE 16.7 An example of manual optimization. A: The isodose distribution before adjustment.
B: The result of the movement. The arrows follow the 100% isodose line (outer of the two darker,
thin lines) as it moves to the edge of the target.
Reoptimization requires caution. Increasing the size of the 100%

isodose also increases the size of all the other isodose surfaces. In
particular, the high-dose region can become large as a result. Manual
reoptimization should only be performed with the high-dose isodose
lines visible on the images—following changes in one image, other
images must be checked for unintended consequences.
Cervical Cancer Intracavitary Applications

While interstitial implants may vary in approach between facilities, for
the most part the optimization follows extremely similar criteria.
Approaches to optimization for gynecologic applications very much
more widely. Early work in HDR cervical applications attempted to
duplicate the loading of LDR applications (26). As noted in the
discussion above on radiobiology, duplicating the physical dose
distribution does not duplicate the biologically effective dose distribution.
Figure 16.8 shows two approaches. The one on top (from Jason
Rownd, Medical College of Wisconsin) using the tandem and ring starts
with the first optimization point 12 mm lateral to the first dwell
position. The remaining optimization points each fall successively 0.5 cm
more inferior: the second, the third, and the fourth lateral to the tandem
14 mm, 16 mm, and 18 mm, respectively. From the fifth point on
through Point A, the points lie 20 mm lateral to the tandem. The ring
optimization points fall 6 mm from the source track at the surface of the
cap, specified as 140% of the dose to Point A. This optimization point
pattern produces a slowly tapering pear shape with a narrow base.
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FIGURE 16.8 Two examples of optimization for cervical cancer intracavitary applications. Top:
narrow-top pear shaped (Courtesy of Jason Rownd, Medical College of Wisconsin). Bottom:
squared-off pear (University of Wisconsin).
The optimization pattern on the bottom (modified from the Madison

System (4) as practiced at the time of writing) usually leaves the first
centimeter of possible dwell positions inactive to provide space to reduce
the dose to the superior bowel, depending on the patient’s presentation.
The first optimization point falls 1 cm below and 18 mm lateral to the
first activated dwell position. From there, the optimization points fall
successively 1 cm more inferior, and all at 20 cm lateral to the tandem.
Regardless of the distance from the previous optimization point, points
are added at the position of Point A and 0.25 cm inferior to Point A.
Optimization points are added lateral to the ovoids at the surface. This
optimization pattern produces a more squared-top dose distribution that
is used at the Medical College of Wisconsin that also reaches further
laterally at the position of the ovoids.
The two distributions represent different treatment philosophies. HDR
intracavitary treatments require deciding on the shape of the desired
dose distribution before determining the dwell times. The treatment
planning system needs to know the doses to the optimization points for
the dwell time calculation. To perform that optimization, sufficient
number of optimization points need to be entered for the optimization
routine to know how to shape the distribution.
Inhomogeneity Correction
Until recently, the effect of inhomogeneities in brachytherapy had been
ignored, mostly because the effectiveness of heterogeneity corrections in
brachytherapy treatment planning has always lagged behind that of
external beam radiotherapy. However, for several forms of intracavitary
treatments, the effects of inhomogeneities have shown to be important.
Sometimes the inhomogeneities result in erroneous dose calculations,
such as from bone or resulting from the shields in vaginal ovoids
(27–29). In other cases, the inhomogeneity may perturb the geometry of
the application, such as air pockets trapped on the surface of a vaginal
applicator or on or within intracavitary breast applicator (30–32). While
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for many years the hope had been for incorporation of full Monte Carlo
simulations into brachytherapy treatment planning systems, for various
reasons this has not happened. However, recently a discrete-ordinate,
grid-based solver for the Boltzmann’s transport problem became
available in a commercial treatment planning system.5 The evaluations
of this program indicate that it compares well with Monte Carlo
simulations and differs importantly from calculations that ignore
heterogeneities (33–35). Figure 16.9 compares treatment plans with and
without correction for heterogeneities. Such programs likely will become
common in brachytherapy as they are in external-beam radiotherapy
treatment planning. The use of correction software requires imaging
with CT or magnetic resonance, which also has become more common.
The report of Task Group 186 of the American Association of Physicists
in Medicine give a very comprehensive discussion of inhomogeneity
correction in brachytherapy treatment planning (36).
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FIGURE 16.9 An illustration of inhomogeneity correction using a discrete-ordinates algorithm. A:
A plan performed assuming all space is water. B: The same plan but corrected for the shielding in
the ovoids using the Acuros program. The plans differ in the dose to the rectum due to the rectal
shields. Images courtesy of Firas Mourtada.
A Final Word on Optimization

Optimization assists a planner in achieving the goals of treatment. The
first step to achieving the goals is to place the treatment appliance in the
ideal position. While optimization can sometimes compensate for a less-
than-ideal placement, optimization cannot make a good treatment from
a bad placement. Poor placement of an appliance results in poor
homogeneity of the dose distribution, even with the best optimization.
EVALUATION
The generation of a treatment plan involves many steps—some fairly
complicated—presenting many pathways and opportunities for errors to
creep into the planning and be propagated into a treatment error. The
next section on “Quality Assurance” addresses error prevention. The
complexity of the treatment plan also presents situations where choices
have to be made or data entered, and on occasion, an entry, while not
obviously wrong, may possibly be less than ideal. As noted in the section
on “Optimization,” the results of the optimization program may not be
quite that expected. For all these reasons, careful evaluation of an HDR
treatment plan becomes very important. A fine line separates quality
management and treatment plan evaluation, and the evaluation serves as
the first step in quality assurance (QA).
Dose Prescription
The items to check do not have an unambiguous order. This discussion
addresses the items from the more obvious to the more subtle.
The Absolute Dose to a Reference Location

Often, the dose distribution for brachytherapy shows isodose surfaces of
particular dose. During evaluation, however, considering the absolute
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dose to a point or a set of points, and then the isodose distribution as
doses relative to the absolute point clarifies the two-step process
involved with most dose prescriptions. Assessing the absolute doses to
specified points forms one of the first checks to perform. For the most
part, if the operator entered particular points for dose specification, the
programs will set the absolute dose to those points accurately. Problems
that can arise include the following:
a. Selecting the wrong point from among those entered for dose
specification, for example, accidentally selecting the rectal point
instead of Point A for a cervical treatment.
b. Having entered the specification point incorrectly, either through poor
digitization or through misinterpretation of the anatomy.
c. Specifying the dose to a set of points with a wide variation in dose
between.
While the first two problems represent errors, the last may be either a
poor judgment or a bad presentation in the patient. A very simple
example would be a treatment with a tandem and ovoids in a patient
with a severely tipped uterus. The dose at Point A on the right and left
side will be very different, and simply specifying the dose to the average
of the two points could result in excessive dose on one side and too little
dose on the other. A more involved situation would be specifying the
dose to a set of points on the surface of a tumor with catheters running
through. Depending on the geometry, the points may have too wide a
variation in doses to provide a good basis for the absolute dose
specification.
In most situations, the reference location should relate to the dose
target, rather than regions of concern for normal tissues. Consideration
of normal structures comes later.
Part of checking the prescribed dose includes review of the
fractionation schema. The dose for the fraction should correspond to the
total dose divided by the number of fractions. As part of this verification,
the dose should also be checked against any relevant protocol that may
change the dose based on concomitant external-beam therapy (in an era
of satellite facilities and specialty referrals, such concomitant treatments
may not be obvious to the treatment planner) or chemotherapy.
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Relative Doses to Specified Volumes
The optimization process required some specification of locations that
should receive some faction of the prescription dose. In intracavitary
cases, this may be a few points, for example, along an esophageal
applicator or along a tandem and lateral to a vaginal ring. For a volume
implant, it may be the target volume surface. In any case, these points
define the goal for the treatment and satisfaction of the prescription
requires conformance of the dose distribution to these specifications. For
the simpler cases, review of each optimization point may be performed,
but volume implants probably require a dose–volume histogram (DVH),
as discussed below.
The dose to all the optimization points likely will not equal the
specified dose, as noted above, but should be within some defined
tolerance of that specified. Failure to adequately shape the dose
distribution raises three possibilities: accepting the results if compatible
with the treatment objectives; changing the optimization parameters and
optimizing the plan again; or manually intervening, as discussed in the
section on “Optimization.”
Limitations
The doses to limiting normal structures should be checked to assure that
they remain below tolerance. Assessment of the doses to normal
structures falls under the next section.
Visual Evaluation of Dose Distributions

Adequate coverage of the target usually involves visual inspection of the
isodose lines on multiple cuts or projections. While a DVH (see
subsequent text) shows failure to include all target within the
prescription isodose surface, the DVH does not show where the failures
occur or whether the volumes that fall below the prescription dose are
contiguous (a potentially serious problem) or widely dispersed (often not
significant). The same can be said for high dose volumes (HDVs). When
possible, the inspection of the isodose lines should be superimposed on
images, such as from CT.
Much of the evaluation of the dose homogeneity comes in the next
section using DVH. However, two tools that assess the uniformity of the
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doses only apply when visually evaluating the isodose distribution for
implants. The maximum significant dose (MSD) refers to the highest-level
isodose surface that encompasses more than one needle track. The dose
very near the source track can be very high, but the body seems to
tolerate these local HDVs. The MSD provides a convenient criterion for
when small HDVs become “significant” and likely to produce biologic
consequences. For an implant taken to normal tissue tolerance, the MSD
corresponds to the tolerance dose. For what fraction of the prescription
isodose surface the MSD becomes limiting depends on several factors.
The first is the volume of the implant—the tolerated level for the MSD
decreases with volume. The second factor is where in the gradient
around the implanted volume the prescription dose falls. Much of the
modern experience with implants comes through the use of the Paris
System (discussed below). With that system, the prescription dose
(Reference Dose (RD) in the System’s parlance) equaled 85% of the Basal
Dose (BD), that is, the mean of the local minima between needle tracks
in the central plane. The Paris System further defined a HDV as that
volume raised to 200% of the prescription dose (170% of the Basal
Dose), and suggested that this dose tightly conform to the needle tracks.
Thus, for Paris System implants, the MSD would be somewhat less than
200% of the prescription dose. Translating this MSD to HDR treatments
requires a few steps. First, assume an LDR treatment of 60 Gy delivered
at 0.5 Gy/h. From Equation 16.8 the BED using an α/β = 10 Gy−1,
appropriate for tumor cells, would be 72.8 Gy10.6 The limitation on high
doses in the target volume likely applies to normal tissue tolerances,
since it is normal tissue breakdown that results in complications.
Assuming the MSD is 200% of the prescribed dose, using α/β = 3 Gy−1,
the BED for normal tissue equals 290 Gy3. Many HDR regimens could be
used for this treatment, but this example assumes six fractions of 5.25
Gy each, which gives the same biologic effect for the tumor. The
physical dose that gives the same biologic effectiveness for normal tissue
as the MSD above is 8.45 Gy, or 160% of the prescription dose. This
result highlights a general rule of HDR brachytherapy: the variation in
dose through the treated volume must remain markedly less than with LDR
brachytherapy. That rule just restates the relative increase in the
sensitivity of normal tissue with the change to HDR treatments. The
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value of MSD of 160% matches well experience with breast implants
that use the 150% isodose surface for the MSD, and that exceeding this
level increases the probability of complications. This also agrees well
with experience with large gynecologic implants that the MSD should
stay below 125% of the Basal Dose (3,37). For small implants, the
percentage of the prescription dose selected for the MSD can increase,
but there is not as much data for small volume implant complications as
for the large.
Another tool, developed by Neblett, considers the other boundary of
the isodose distribution, finding the maximum contiguous dose (MCD), or
the highest value for an isodose surface that completely surrounds the
implanted needle tracks (38). Isodose levels higher than the MCD break
into small islands of high dose with lower doses separating volumes
enclosed. The prescription dose should not exceed the MCD, but should
not fall much outside the MCD isodose surface.
Evaluation of dose distributions for intracavitary insertions, for the
most part, remains as visual inspection of isodose plots. The concepts
that measure uniformity or HDVs find little relevance in intracavitary
applications because the dose always becomes high near the sources and
falls continuously with distance. The question in evaluating the dose
distribution becomes simply whether or not an adequate dose covers the
target or targets and avoids excessive doses to limiting structures. One
exception to this is intracavitary breast treatments with multilumen
applicators. In these cases, tailoring the distribution to the patient often
reduces the uniformity of the dose through the defined target volume,
and measures of the homogeneity of the dose, as discussed below,
provide insights into the quality of the treatment.
For intracavitary and interstitial cases, target evaluation should be
considered a 3-dimensional (3D) process. However, 3D views often
become difficult to interpret. Figure 16.10 shows the target for a breast
implant and the 100% isodose surface as a veil draped over the target.
This presentation clearly shows where the 100% isodose surface fails to
cover the target (indicated by the white arrows). In many cases,
however, the 3D images may seem confusing to those with little
experience looking at them, and sometimes to those with experience.
Limiting the number of structures shown to a region of interest and one
isodose surface helps during the interpretation.
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FIGURE 16.10 A three-dimensional view of the target and the 100% isodose surface for a breast
implant.
Quantitative Assessment of Implants

The discussion below relates mostly to interstitial implants. For a much
more detailed discussion of evaluation parameters, see Thomadsen (39).
Assessment requires precise terminology. For interstitial implants, the
International Commission on Radiation Units and Measurements (ICRU)
defines the following (39):
Recommendations for Interstitial Implant Reporting by the International

Commission on Radiation Units and Measurements
For interstitial implants, the International Commission on Radiation

Units and Measurements (ICRU) defines the following (40):
The Mean Central Dose is defined as the arithmetic mean of the local
minimum doses between all adjacent sources in the implant. This
concept is well known in the Paris System (approximating the basal
dose), but is less well known in the USA.
Peripheral Dose is the minimum dose at the periphery of the CTV, and
should be the minimum dose decided upon by the clinician as
adequate to treat the target. This dose is similar to the typical
“prescribed dose” used by many American clinicians.
A Low-Dose Region is a region within the CTV where the dose is less than
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90% of the peripheral dose. The maximum dimensions of this volume
are reported. This obviously relates to an underdosed volume of the
target, and so should correlate with treatment failure.
A High-Dose Region should correlate with complications. The high-dose
region is defined as the volume encompassed by the isodose line equal
to 150% of the mean central dose. The maximum dimensions of this
volume in all planes calculated should be reported.
The ICRU also suggests reporting on the homogeneity of the dose by

specifying the following:
1. Spread—the difference between the maximum and the minimum local
minimum doses divided by the mean central dose
2. Peripheral-mean ratio (PMR)—the ratio of the peripheral dose to the
mean central dose
Hanson points out that the first gives a measure of nonuniformity

within the implant and may be a measure of how well the implant was
accomplished (41). The second is related to proper spacing of the source
lines relative to the peripheral reach of the implant.
Another useful quantifier is the mean peripheral dose (MPD), which
equals, as it says, the mean dose on the periphery of the target volume.
The capital “M” differentiates this from the minimum peripheral dose,
simply called the peripheral dose by the ICRU, which is often denoted by
mPD. Neither of these quantities should be confused with the matched
peripheral dose, which was a concept used before imaged-based
dosimetry was available that specified the dose for a distribution of
radioactive sources compared with the dose it would deliver to the
periphery of an ellipse with the same average diameter as the volume
implanted (42).
Dose–Volume Histograms
The first step in quantitative evaluation calculates the DVH. Several very
different presentations of very different information fall under the
category of DVH. The histograms in all cases display some function
related to volume on the ordinate with dose (or a function of dose) on
the abscissa. Many of the presentations apply to dosimetry of implants
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performed without correlation to volume imaging information (i.e., CT,
MR, or ultrasound), and thus have no information regarding the
treatment relative to any target or normal structures. Such DVH consider
the implant as a whole, and are called “unlimited” because they make no
reference to a limiting region of interest. Because the current standard of
care would discourage brachytherapy implants in the absence of imaging
information, unlimited DVH will not be considered further. While they
still prove interesting for evaluating the technical execution of an
implant, they find little application in treatment planning. For more
information of such DVH, the reader should consult Thomadsen (39).
Figure 16.11 shows a relative, cumulative DVH for an HDR prostate
implant for a boost following external-beam therapy. The ordinate
records the fraction of a structure that receives at least that dose shown
on the abscissa. The normalization of the volume to the total volume of
the region of interest makes the histogram “relative.” Ideally, the curve
labeled “prostate” would run along the top of the graph at 1.0 for all the
doses until the prescription dose, indicating that the entire target
receives at least the target dose, and then the curve rapidly falls. Of
course the fall cannot be very sharp because there will always be HDVs
around the source path. The entire prostate may not receive the
prescription dose either. Depending on the limitations on dose to the
rectum, and potentially on the placement of the catheters due to the
pelvic arch, some regions of the prostate may fall shy of the prescription
dose.
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FIGURE 16.11 A cumulative, relative, dose–volume histogram (DVH) for an HDR prostate
implant.
Figure 16.11 also shows a curve for the rectum. Unlike the target, only
part of the rectal contour usually is entered into the computer. Thus, the
histogram actually shows the fraction of the contoured volume that
receives the given dose. Some organs may be completely contoured
during planning, and the fraction of the whole organ receiving particular
doses may relate to complications or other treatment limitations. For
long tube-like organs, complete contouring not only may be unlikely, but
unnecessary. Some evidence indicates that rather than the fraction of the
rectum being the critical variable, that the absolute volume may be
important. Various volumes have been proposed from 0.1 to 5 cm3
(43–48). The value of interest for these volumes would be the minimum
dose, since the maximum dose would be just a point, and not change for
any of the volumes. For volumes less than 5 cm3, it makes little
difference if the contour simply encircles the whole rectal cross section
or specifically just outlines the wall, as in Figure 16.12 (46).
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FIGURE 16.12 Examples of contouring the rectal wall: (A) for planning systems that can
designate the region between the outer wall and the inner wall and (B) for systems that cannot.
Figure 16.13A shows an example of a relative differential DVH. In this

case, the ordinate gives the change in the percent of the volume per
dose, which is closely related to the fractional volume of the region of
interest that actually receives the dose on the abscissa. The differential
DVH sometimes proves useful in selecting the prescription dose,
assessing whether the prescribed dose adequately covers the target and
the uniformity of the dose through the target. Figure 16.13B shows the
cumulative DVH for the same implant as figure 16.13A. Information on
dose rate is lost but coverage is clearer.
Figure 16.13 A: A relative, differential dose–volume histogram (DVH) for a breast implant. This
presentation shows the volume that receives a particular dose. B: The cumulative DVH for the
same implant.
DVH assists in evaluation of implants by calling attention to the

fraction of the tumor that may receive less than the treatment dose or
whether a neighboring structure exceeds tolerance. They can also help
distinguish between plans that would better concentrate the dose in the
target. However, as noted above, while presenting this information for
rapid detection, DVH loses special information, such as where the target
dose may be low.
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Figures of Merit
The DVH distills the information from the isodose distributions to
simplify some evaluations. The DVH still presents much of the data in a
2-dimensional (2D) format, sometimes complicating some assessments.
Figures of Merit provide numerical values for particular aspects of
implants, and can assist in evaluations and facilitate communication
about the treatments. More detailed discussions can be found in Saw and
Suntharalingam (49) and Thomadsen (39). Below are some of the
quantities most useful for HDR treatment planning.
Target Coverage. The first assessment should be whether the plan

adequately covers the target. Several measures for that exist, each telling
a slightly different story.
Dx, Vx − Dx% refers to the dose that covers x% of the target volume.
Ideally, the prescription dose covers 100% of the target, although as
mentioned before, that often cannot be the case. Recognizing this, many
protocols call for the prescription dose to cover some particular fraction
of the target volume, such as 95%. In such cases, D95% becomes a value
of great interest since it often defines the prescription. The companion
quantity, Vx gives the volume receiving a dose equal or to x. This
quantity assumes different forms depending on the conventions used for
a treatment protocol. Most often the volume refers to the fraction of the
CTV receiving the dose x, but at other times it is the absolute volume.
The dose, x, may refer to the absolute dose, or it may be a fraction of the
prescribed dose. The convention in use requires clarification. Again,
ideally V100% should equal 1 in an ideal implant if V equals the fraction
of the target volume with x normalized to the prescribed dose. For the
remainder of this discussion, the convention will specify doses explicitly
as either a percent of the prescription dose labeled with “%” or an
absolute labeled with “Gy.” Reference volumes will be percent, again
labeled as “%” or absolute with units of cm3. Finally, the volume to
which the quantity refers will be a leading subscript, to give quantities
such as CTVD90% or rectumV60 Gy. Figure 16.11 shows with red arrows
some of the DX and VX values.
The Coverage index (CI) specifies the fraction of the target volume
receiving a dose equal to, or greater than, the target dose (50). The CI
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corresponds to the value on the relative, cumulative DVH for the CTV at
the prescription dose. Thus, CI = CTVV100%.
Dose Uniformity. After assessing the adequacy of target coverage, the

next question focuses on the uniformity of the dose through the target
volume. As discussed above, the MSD must be controlled, but other
measures also can help in this evaluation.
The section on “Quantitative Assessment of Implants” introduced the
ICRU term high-dose region as the volume encompassed by the 150%
isodose surface. This concept came from the HDV of the Paris System,
which used a cut-off of 200% of the prescription dose. Zwicker makes
the factor a variable, p, used during optimization (51). In the discussion
above, converting from the LDR treatments to an HDR regimen, the Paris
System’s factor of 200% becomes 160%. Using an LDR factor of 150%
leads to an HDR factor of 123%. Limiting the MSD to 123% is seldom
possible in a real implant. The rest of this discussion uses a value of
150% to define the HDV for HDR implants. Figure 16.14 shows a
schematic of a section through the CTV, a prescription isodose surface as
the V100% and the surface corresponding to 1.5 times the prescription
dose, V150%. In this figure much of the V100% and the CTV coincide, but
some of the CTV remains below the prescribed dose while some of the
prescribed dose falls outside the target. Some of the target and normal
tissues receive in excess of 150%, which is very undesirable for the
normal tissue and uselessly high for the tumor. Thus, the most desirable
region has the CTV receiving doses between the 100% and the 150%.
This figure may be helpful during the following discussion.
FIGURE 16.14 A schematic showing a section of a clinical target volume (CTV) (light green,) and
two isodose surfaces corresponding to 100% (dark green) and 150% (orange) of the prescribed
dose.
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The relative dose homogeneity index (HI) measures the uniformity of the
dose through the target volume as the fraction of the target volume
receiving a dose between the target dose and the high dose level, or (52)
In Equation 16.22, both volumes are the fraction of the CTV raised to
at least the percent of the prescription dose given. Originally, the HI
referred only to the prescription isodose volumes without regard to the
target, dating from when target information usually was not available.
Most often nowadays, Equation 16.22 is used.
A very similar index, the dose nonuniformity ratio (DNR), equals the
ratio of the HDV to that volume taken to at least the target dose (53),
This quantity indicates the price paid (in HDV) to set the prescription
dose to cover the target. Obviously, the DNR and HI are related as HI =
1 − DNR, so specification of both quantities becomes duplicative.
Yu defines a somewhat more comprehensive quantity, the uniformity
number (UN) (54). The derivation begins with defining the harmonic
treatment dose (HTD) as
where D(v) is the dose to a voxel element dv, giving a quantity related to
the mean dose through the target, and the harmonic peripheral dose
(HPD) as
with D(s) being the dose in a small element on the surface of the CTV,
ds. From these, Yu determines the UN as
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The UN tends toward greater stability and robustness in the face of
small variations in the geometry of an implant.
Dose Outside the Target. As a measure of the dose outside the target,
the external volume index (EI) equals the volume of nontarget tissue
receiving doses equal to or greater than the target dose, as a fraction of
the target volume (50,55). Thus,
Here, V100% indicates the entire volume enclosed by the prescription

isodose surface and CTVV is the absolute volume of the CTV. Since
CTVV100% is the fraction of the CTV volume raised to at least 100% of the
prescription dose, the product CTVV100% . CTVV gives the absolute volume
of the CTV raised to at least 100% of the prescription dose.
Since is the fraction of the CTV volume raised to at least 100% of the
prescription dose, the product, gives the absolute volume of the CTV
raised to at least 100% of the prescription dose.
Conformity. The conformation number (CN) measures the conformance

of the prescription dose to the target (56,57),
The numerator of each factor gives the total volume of the CTV within
the 100% isodose surface, as the volume of the CTV times the fraction of
the CTV raised to the 100% dose. The first factor gives the dose within
the CTV as a fraction of the whole 100% dose volume, a measure of the
efficiency of the dose deposition. The second factor is related to the
coverage of the target. Together they indicate how closely the
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prescription dose matches the target.
The peripheral uniformity number (PUN) also addresses the conformity
at the target but at the periphery, specifying (54)
Figure of Merit Summary. Each of these figures of merit provides

useful information about the implant. Several of them are redundant and
which should be used becomes the user’s preference. None of these
quantities tells the entire story for a given implant. No single index or
quantity perfectly characterizes any implant—evaluation requires
consideration of many different aspects, not all of which optimize for the
same conditions. Final decisions and the quality of an implant require
consideration of the large overview of the implant.
QUALITY ASSURANCE
QA for the treatment plan assesses first the adequacy of the generated
treatment plan—the measures which were addressed in the section on
“Plan Evaluation.” The evaluation process includes verification that the
plan delivers the right dose to the right location. The other purpose for
QA is to detect and correct errors in the treatment plan before treatment
delivery. QA, by definition, provides indication that the plan contains no
errors and is of the quality intended.
Before performing QA, quality control (QC) works to keep errors from
happening in the first place. For HDR brachytherapy treatment planning,
the most useful and effective QC tool is a form for recording and
transmitting the important and requested information. Such a form may
serve as the prescription, since it should contain the information of the
dose—fractionation and normal structure limitation—as well as a
description of the application and any other relevant information. A
treatment planning protocol serves as the other very important QC tool.
The protocol is a standard operating procedure that dictates routine
planning decisions for most cases. Examples of information contained in
a protocol include the definition used to find Point A for cervical
intracavitary insertions and the step size for breast implants.7
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Independent verification forms an invaluable part of QA. Having
someone other than the person who generated a treatment plan check it
increases greatly the probability of detecting errors. In addition, just as a
form for recording and transmission of information helps prevent errors,
forms to guide the plan evaluation also prevent omissions during the
verification. Guidance for developing forms can be found in Thomadsen
(39). If having an independent person check the plan is not an option at
a facility, the use of forms and a fixed verification protocol becomes
even more important.
Indicators of Reasonableness
One major challenge in QA is to judge whether the planner made a
significant error. One approach to assess the plan for errors compares
some value related to the plan with standards or expectations. The
standards derive from previous experience or from the literature. The
sections below consider some examples. For a more detailed discussion,
again see Thomadsen (39).
Intraluminal Tests
Intraluminal cases generally use a single catheter, such as for
endobronchial, endoesophageal, or biliary treatments. Some of the tests
discussed below also apply for vaginal cylinder applications. Thomadsen
reported an index (58)
where the index should fall between 0.133 and 0.167 ([Gy m2 s]/[Gy
cm2 h]). Obviously, the index actually has no true units since with
multiplying by appropriate constants, the units cancel. However, for
convenience, the equation keeps the units most likely used for each
variable. This index increases above these limits for short treatment
lengths compared to the prescription distance.
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Kubo (59) and Kubo and Chin (60) calculate the approximate total
treatment time (±2%) based on a linear fit as
where “length” equals the active length along the catheter. They also
derived a quadratic fit for the treatment duration for lengths (L) between
50 and 200 mm and prescription distance, d (61):
Ezzell calculates the dose to points 10 cm distant from the

approximate center of the sources, along a line approximately
perpendicular to the catheter, in opposite directions (62). He calculated
a dose index, defined as
which should fall between:
• 0.95 to 1.10 for long treatment lengths (such as esophagus)

• 1.10 to 1.20 for short treatment lengths (such as vaginal cylinders)
• 1.05 to 1.20 for endobronchial treatments (lower if highly elongated,
higher if curved)
For any of these checks, the source strength should come from a
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separate table rather than from the treatment plan.
Tandem and Ovoids

Indices similar to those discussed above have been used in gynecologic
applications, but because the constraints for optimization vary greatly
between facilities, the actual values used with any such index must be
developed locally. Two indices developed for use with the Madison
System (4) assess whether a given tandem and ovoid application falls
within the normal range (58):
and
The location for the first index dwell falls far from the ovoids to
consider mostly the loading of the tandem. The dwell times for the tip-
most position vary greatly between patients, and thus do not serve well
for measures of application consistency. The dwell 1 cm inferior to the
first dwell position used becomes quite stable. Index 1 tells whether this
one position falls within a normal range. Index 2 considers the
application as a whole. The numerator simply gives the integrated
reference air kerma (IRAK, which numerically equals the total reference
air kerma, TRAK, of the ICRU (63)). The use of IRAK parallels the
conventional mgRaEq.h customary for evaluating the normalcy of LDR
applications. Following the Madison System optimization pattern, the
limits for the indices in units of ([Gy m2 s]/[Gy h]) become:
• Index 1—0.139 to 0.180

• Index 2
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• For small ovoids—0.098 to 0.123
• For medium ovoids—0.123 to 0.147
• For large ovoids—0.135 to 0.180
The indices also apply to applications using tandem with cylinders in

the vagina, where Index 2 values become:
• For 2.0 cm diameter—0.098 to 0.139

Interstitial Implants
Common optimized HDR implants conceptually tend to follow a cross
between Manchester and Paris implants. The implants behave much like
Manchester implants in that the differential source-strength distribution
pattern varies much like in the Manchester rules. However, unlike the
Manchester System, where the dose tends to correspond to the Paris
System’s Basal Dose, most practitioners specify the prescription to a
Reference Dose outside the limits of the implant, much like the Paris
System. With this in mind, the Manchester implant tables can be
modified to apply to 192Ir HDR implants by multiplication of the source
strengths by 1.11 to set the Reference Dose to 90% of the Basal Dose,
and converting from mgRaeq.h to 192Ir IRAK. For a given treatment plan,
the total duration of the treatment calculated by the planning computer
can be compared with the time given by
where in this equation RV = 0.00321 ManchesterRV, where ManchesterRV is

the RV in the original Manchester tables, so
where E is the longest dimension/shortest orthogonal dimension.
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Experience with breast implants shows that this formula generally agrees
with the time calculated by the treatment-planning computer within 5%.
A similar approach holds for modifying the RA values from the
Manchester table to verify the calculations for planar implants.
Alternatively, Ezzell (64) developed a formula that gives the expected
time for a dose at a specified distance from an implant plane as:
where r is the distance from the plane where the prescribed dose falls, E
is the equivalent square of the planar area = 4·area/perimeter, and a, b,
and c are fitting parameters that depend on the distance, r, given in
Table 16.2.
TABLE 16.2 Fitting Parameters for Equation 16.38
Unified Index
Das et al. considered predicting the treatment duration based on the
volume of the prescription isodose surface, V100 (65). Beginning with a
point source approximation, he derived the equation
where EC is the elongation correction, approximated as 1 + 0.06(E −

1)1.26, and K is a constant depending on the number of catheters:
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• 1 catheter, K = 1,267 U s/(cGy cm2)
• 2 or 3 catheters, K = 1,182 U s/(cGy cm2)
• More than three catheters, K = 928 U s/(cGy cm2)
Treatment Unit Programming and Pretreatment Checks

Once the treatment plan passes the evaluation and QA tests, the
treatment plan must be passed to the treatment unit in the form of a
treatment program specifying all the treatment information: channel
lengths (distance to the first dwell position), step size or sizes, and the
dwell time pattern for each channel. Verification of the program checks
the items most likely to be in error.
The most likely error is selecting the wrong program for a given
patient if there is more than one program under the patient’s identity.
This situation frequently arises in regimens where new plans are
generated at each fraction, such as gynecologic intracavitary
applications. Such plans may differ subtlety, so checking the plan entails
verifying each dwell position. Fortunately, intracavitary plans generally
contain few dwell positions. Large volume implants with more catheters
than treatment unit channels form another common treatment with
multiple files under a patient’s identity. In this case, enough details of
the file must be checked to assure selection of the correct file for the
treatment underway. To prevent using the wrong patient’s file for a
treatment, the name on the program must be matched with the patient’s
identity.
Regardless of the number of files a patient has, the first fraction for
any file must include a verification of the length for each catheter,
particularly if the length differs from the default value. The most
common error with HDR brachytherapy is unintended treatment with
the default length when a customized length was intended. The step size
also forms a simple but very important parameter to check. Once these
have been verified, and a sampling of the dwell time pattern checked,
the program can be approved. On subsequent treatment fractions, the
checks to verify programming with the correct file suffice.
PLANNING AN IMPLANT
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Planning is actually what goes before the action, or at least, what should
go before. In the context of brachytherapy, before performing an implant
or an insertion, planning entails determining the desired location of the
treatment appliance. Optimization can often (but not always) make the
prescription isodose surface cover the target in many cases following a
less-than-optimum implant; however, the price paid becomes larger
HDVs, increasing the probability of complication.
The initial steps for planning a brachytherapy procedure follow the
same pattern as for any type of radiotherapy treatment: determining the
target volumes. Earlier chapters discuss target delineation, so it will not
be addressed here, other than to say that in brachytherapy the expansion
from the CTV to form a planning target volume (PTV) usually remains
small. Such an expansion needs to consider the ability to place the
applicator in the desired location, and, for implants, the constraints
placed on the location of needles by the implant pattern to conform to
the CTV. As an example of the latter constraint, consider a template
guided implant where the edge of the CTV falls between needle rows.
Covering the CTV may require an additional needle in the row outside of
the CTV, thus effectively expanding the CTV to a PTV.
Appliance Selection and Placement

Planning where to place the treatment appliance depends heavily on the
form of the brachytherapy.
Intracavitary Insertions
Intraluminal insertions allow little selection in the treatment appliance
or location. For example, the only variable in endobronchial applications
would be how far past the target to insert the tip of the treatment
catheter. Possibly the diameter of the catheter may be selectable from
two sizes, and in some cases the stiffness of the catheter. More
applicators are available for endoesophageal applications because of the
size of the lumen. These applicators have various thicknesses of the walls
and number of channels, running from one in the center (giving a more
penetrating dose distribution) to many around the periphery (allowing
some tailoring of the dose distribution to the CTV).
Gynecologic applications present a greater opportunity to select the
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appliance most appropriate to the patient from a wide variety. For
cervical cancer, the standard approach places a long tube (a tandem) in
the uterus and channels for the source in the vagina, just as with the
LDR treatments. While the tandem for all applicators remains mostly the
same, the vaginal source channels differ greatly between applicators.
The vaginal part of the appliance for four applicators will be compared
for examples—ovoids, a ring, cylinders, and custom molds. Figure 16.15
shows examples of these applicators. The source travels through ovoids
in a tube running axially through either ellipsoidal (from which the term
ovoid derives) or cylindrical piece of plastic. Some ovoids contain
shielding in the direction of the rectum and bladder, as do LDR ovoids,
and some do not. Ovoids come in three sizes, generally 1 cm, 1.25 cm,
and 1.5 cm radius, sometimes with a “mini” size that maintains the 1-cm
radius laterally but only a few millimeters medially to fit a smaller
vagina. Some of these applicators have no fixed relationship between the
tandems and ovoids while others do. The nonfixed applicators allow
better conformance with the patient’s anatomy, while the fixed systems
maintain a standard geometry. The best dose distribution comes from
using the largest size ovoids that fit in the vagina. This gives the greatest
distance between the source track and the vaginal mucosa and thus, the
greatest depth dose, just as increasing the source to surface distance in
external-beam radiotherapy increases the fractional depth dose.
Spreading the ovoids should be avoided because that leads to reduced
doses to the cervix proper.
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FIGURE 16.15 Applicators for cervical cancer intracavitary insertions: A: Tandem and ovoid, on
the left the conventional and on the right for CT or MR localization. B: A tandem and ring. C: A
tandem and cylinder. D: A tandem and custom vaginal mold (Picture courtesy Erik Van
Limbergen).
In the ring applicator, the vaginal source path follows a circle centered
on the tandem. The ring comes in several diameters (26 to 34 cm).
Typical cases only use the dwell positions in the lateral parts of the ring
—somewhat simulating the dwell positions used in the ovoids. A plastic
cap about 5 mm thick slips over the ring to provide spacing between the
source track and the vaginal mucosa, reducing the local dose. Because
the cap provides only half the spacing as the smallest ovoid, the ring
projects the dose less deeply laterally. The fixation to the tandem make
insertion easier than ovoids.
Patients with very narrow vagina—not uncommon after high doses of
radiation therapy—may not accommodate a tandem and ovoids. One
approach places plastic cylinders around the tandem where it passes
through the vagina. While this approach allows for treatment, the dose
distribution fails to provide the coverage of tandems and ovoids. The
difference results from constraining the source track to the tandem
instead of spreading the tracks laterally, with a concomitant reduction in
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the coverage to the lateral aspects of the uterus.
Custom vaginal moulds have been used to provide applications
tailored to individual patients. These applicators use an impression of
the patient’s vagina with tracks drilled to accommodate catheters for the
source tubes (60–70). Figure 16.15D shows such a mould. In concept,
these mould applicators should provide improved fit and stability for the
applicators compared with standard ovoids or a ring. The advantage
comes at the price of increased time commitments for construction of the
mould.
Postoperative endometrial cancer treatments form one of the most
common brachytherapy procedures in the United States. The treatment
delivers radiation to the anastigmatic site at the superior end of the
vagina following removal of the uterus, with the goal of preventing
tumor recurrences in the surgical site. HDR treatments generally use
either ovoids (without the tandem, since the uterus is gone) or cylinders.
The ovoids tend to produce a dose distribution that conforms closely to
the target at risk, while maintaining relatively low doses to the bladder
and rectum. Cylinders give more dose to the rectum and the bladder
than ovoids partially because of the orientation of the source places
these organs near the perpendicular bisector of the sources and the
maximum of the anisotropy of the source. Using cylinders, the axis of
the source, where the anisotropy function is relatively low, points
toward the target at the end of the cylinder. For ovoids, the situation is
reversed, with the low values of the anisotropy toward the bladder and
the rectum and the maximum toward the target. However, Pearcey and
Petereit report that relatively low doses (50 Gy10 or an LDR equivalent
of 44 Gy) to the target produce control rates of greater than 98%, with
complications not appearing until normal tissue doses of 100 Gy3 (LDR
equivalent of 60 Gy) (71). Uncomplicated control is the norm with this
form of treatment. Thus, the differences between the applicators mean
little with regard to the treatment outcome. There are, however,
cylinders with source pathways forming a circle at the top, and rings
without the tandem, that can combine the beneficial orientation of the
source with the simplicity of the cylinder.
Interstitial Implants
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Determining the needle pattern for an implant can be the most
important decision for an implant. Many of the older systems developed
rules for needle placement that still provide good guidance (72–77).
Most of the rules that apply for LDR implants also apply for HDR
procedures.
Many of the conventional, LDR brachytherapy approaches give rules
for implants with uniform source distribution, that is, source material
not differentially distributed. The Manchester System forms the
exception. It becomes more difficult to achieve relative dose uniformity
when all sources have the same strength per centimeter along a needle
track, and rules for needle track placement were developed to produce a
dose as uniform in a plane of volume as possible given that constraint
(76,77). Beginning the planning for needle placement by following these
rules generally requires less modulation of optimized dwell times to
achieve the uniformity goals for the plan. Minimizing the required
modulation of the dwell times reduces the likelihood of large high-dose
regions. For most HDR multiplanar and volume implants, a needle
separation of 1.5 cm results in a HDV lower than 1 cm spacing, but
larger separations increase the HDV again.
Most commonly, an approach similar to the Paris System (77,78) is
followed assuming that the prescription dose, as the Reference Dose,
falls outside of the actual implanted volume. The change to optimized
HDR treatments carries also the need to adjust the Paris System’s
specifications a bit. Optimization reduces the higher doses that occur in
the interior of the implant, although it also increases the high doses near
the ends of needle tracks. While the Paris System used an RD equal to
85% of the BD, reducing the higher doses in the interior reduces the
variations of the dose minima inside the implant and lowers the mean.
The lower mean requires that the percentage relating the BD and the RD
must increase to maintain the same location and value of the RD.
Further, the change to HDRs accentuates differences in dose, so the
percentage must increase further. For a typical optimized HDR implant
to give a similar biologic Reference Dose as an LDR implant, the RD =
93% BD (37). The higher ratio of BD to RD implies that the needles
should be placed slightly closer to the edge of the target volume for HDR
implants.
For planar implants or volumes made from planes, following a strict
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grid pattern with uniform loading often results in a region of low dose
between the outlying needles and the rest of the implanted volume,
essentially wasting the space implanted near the outliers, as
demonstrated in Figure 16.16A, from Neblett (79). Optimization can fill
in this region but at the cost of increasing the HDV. Neblett recommends
moving the corner needles closer to the main body of the implant than
the regular spacing pattern would dictate, as demonstrated in Figure
16.17—a practice called tight-end loading (79). Figure 16.16B shows the
resultant dose distribution, with the prescription isodose surface
encompassing the whole implant. Tight-end loading increases the MCD,
reducing the HDV.
FIGURE 16.16 A: A planar implant with evenly spaced, uniformly loaded needles showing the
failure of the prescription isodose surface to include the volume between the main body of the
implant and the corner needles. B: The same implant as in (A) except with the corner needles
moved inward slightly, eliminating the low-dose region. (From Neblett D. Clinical techniques and
applicators available for interstitial implantation. In: Williamson JF, Thomadsen BR, Nath R, eds.
Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995, with permission from
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Medical Physics Publishing.)
Figure 16.17 A demonstration of the process for tight-end loading. (From Neblett D. Clinical
techniques and applicators available for interstitial implantation. In: Williamson JF, Thomadsen
BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995, with
permission from Medical Physics Publishing.)
Unfortunately, some implants, particularly those with irregular shapes,

require needles outside the target volume to assure adequate coverage.
Figure 16.18 shows one CT image of a breast implant. This implant uses
needles outside the target volume to boost the dose near the edge of the
implant in several locations. Optimization would not need these needles
to cover the target except for the restriction to hold the MSD to 150%.
Without that restriction, the dwell times near the boundary would
simply increase to extend the dose to the target edge. This case trades
the extension of dose to tissue outside the implant for reducing the HDV
inside the implant.
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Figure 16.18 A breast implant, showing the necessity for needles outside the target volume in this
image.
Dwell Position
Optimization often allows keeping the dwell positions all inside the
target volume. The Paris System and all the derivative systems for LDR
treatments using uniform strength sources require that the sources
extend beyond the target volume to assure adequate coverage.
Optimization increases the relative dwell times on the ends of source
tracks so the end dwell positions project the dose to the edge of the
target. Increasing the dwell times at the ends of the tracks does require
vigilance to prevent large HDV. This process simulates the crossing
needles of the Manchester System.
For those with experience with linear sources, such as 192Ir wire or
137Cs needles, placing seed-type sources, such as an HDR brachytherapy
source to give dose distributions similar to those from linear sources,
requires some care. Figure 16.19 demonstrates that, for equivalency, the
dwell positions should not start and stop at the same location as the ends
of the line source. Going to the stepping source, the activity of the line
would be cut into the small pieces that become the dwell positions.
Because the total length of source is smaller with the dwell pattern
because of the gaps between positions, the linear activity density for the
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dwells has to be greater than for the wire. Thus, the strength of the wire
is condensed into the dwells. Each dwell could be thought of as having a
sphere of influence that commands the space around it until halfway to
the next dwell. For the end dwells, this sphere also projects outward, and
it is the edge of this sphere that should fall at the location equivalent to
the end of the wire. While this concept is well oversimplified and does
not account for the fact that all of the wire’s length contributes to the
dose everywhere as do all of the dwell positions, the rapid gradient in
the dose from an element of source does make this learning presentation
useful.
Figure 16.19 Placement of seeds or dwell positions to simulate a line source.
Although an HDR plan can be made equivalent to an LDR plan with

continuous wire or 137Cs needles, usually that would not be desirable. In
wire-based implants or those with uniform linear strength such as used
in the Paris System, the sources must extend beyond the target due to
the low doses near the ends. With optimization, the source material can
remain within the target while delivering the dose to the periphery. As a
general guidance for a starting point in planning dwell positions for an
optimized implant, the distance from the surface of the target to the first
dwell position in the target should be half the space between dwell
positions (58).
KEY POINTS
• Treatment delivery with HDR brachytherapy occurs over a time that
is very short compared with the half-time of repair of sublethal
damage, usually with dose rates in excess of 12 Gy/h. HDR
brachytherapy offers several advantages over LDR brachytherapy
including improved dose optimization capability, more stable
positioning, ability to treat as an outpatient, and reduction in
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radiation exposure to health care providers. HDR brachytherapy
also has disadvantages to LDR brachytherapy, including a
reduction in the therapeutic ratio and the potential for very high
radiation dose errors.
• The therapeutic ratio, defined as the ratio of the damage to tumor
cells to that to normal tissue cells for the same dose, is lower for
single-fraction HDR brachytherapy than for LDR brachytherapy.
Fractioning the HDR treatment delivery will increase the therapeutic
ratio. The optimum number of fractions for an HDR course of
treatment is selected for practicality.
• HDR brachytherapy allows for improved treatment optimization in
that source dwell times can be adjusted for all possible dwell
positions. Two types of computerized optimization algorithms,
deterministic or stochastic, are employed to minimize an objective
or cost function, which represents the difference between the
planned and the desired dose distribution. HDR dose distributions
may also be manually optimized by moving an isodose curve to its
desired location, causing the planning system to adjust dwell
time(s) accordingly to produce the change.
• The HDR plan should be evaluated to ensure it meets the
treatment objectives. This evaluation should include verification of
the dose prescription (both to the reference location and to other
specified volumes) and of isodose coverage of the target.
Additional quantitative evaluation tools include dose-volume
histograms, dose uniformity metrics, conformity and external
volume indices.
• Quality assurance is performed for HDR to detect and correct
errors in the treatment plan before delivery. Independent
verification of the plan by someone other than the planner is an
effective method of error detection. A number of indicators have
been developed for simple single-catheter to more complex
implants, to ensure the treatment plan is reasonable.
• Applicator selection and placement is an important component of a
successful implant. This is particularly true for gynecologic
intercavitary implants, where a number of different applicators and
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sizes exist. For interstitial implants, many of the rules governing
needle placement for LDR implants also apply to HDR procedures.
QUESTIONS
1. High dose rate (HDR) brachytherapy typically involves dose rates
greater than
A. 100 Gy
B. 0.5 Gy/h
C. 0.5 cGy/h
D. 12 Gy/h
2. Compared to LDR brachytherapy, HDR brachytherapy offers the
advantage(s) of:
A. Improved therapeutic ratio for a single-fraction treatment
B. Higher energy radiation sources with better tissue penetration
C. Less applicator movement over the course of the implant
D. Reduction of radiation exposure to personnel
3. The cell survival curves for HDR brachytherapy:
A. Show a larger variation between tumor and normal tissues
than those for a conventional LDR treatment regimen.
B. Are substantially changed with considering normal tissue and
tumor repair.
C. Become closer to LDR cell survival curves when increasing
fractionation
D. Demonstrate a therapeutic ratio which is very dependent on
dose rate.
4. Compute the biologic equivalent dose (BEDHDR) to point A for a
five-fraction tandem and ovoid implant delivering 6 Gy/fraction
over a period of 28 days. Assume α = 0.35 Gy-1, α/β = 10 Gy,
and Tpot = 7 days.
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A. 25 Gy10
B. 30 Gy10
C. 35 Gy10
D. 40 Gy10
5. Repeat the calculation in question 4 for a LDR tandem and ovoid
implant delivering 0.5 Gy/h to point A for a period of 80 hours.
Assume Tr = 1 hour:
A. 27 Gy10
B. 33 Gy10
C. 39 Gy10
D. 45 Gy10
6. Which of the following figures of merit may be used to evaluate
the quality of an HDR implant?
A. Relative dose homogeneity index
B. Coverage index
C. Peripheral uniformity number
D. Harmonic peripheral dose
7. Which of the following QA measures should be performed prior
to initiation of each HDR treatment delivery?
A. Failure mode and effects analysis
B. Independent verification of the plan, ideally by someone other
than the planner
C. Room shielding and barrier survey
D. Verification of the treatment unit plan information
ANSWERS
1. D
2. C and D
3. A and C
4. D
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5. C
6. A, B, C, and D
7. B and D
REFERENCES
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Med Phys. 2001;28(5):773–779.
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planning simulated annealing and geometrical optimization for
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23. Yu Y, Schell MC. A genetic algorithm for the optimization of
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25. Pouliot J, Lessard E, Hsu I-C. Advanced 3D planning. In: Thomadsen
BR, Rivard MJ, Butler W, eds. Brachytherapy Physics, 2nd ed.
26. Houdek PV, Schwade JG, Abitbol AA, et al. Optimization of high
dose-rate cervix brachytherapy; Part I: dose distribution. Int J Radiat
Oncol Biol Phys. 1991;21(6):1621–1625.
27. Mohan R, Ding IY, Martel MK, et al. Measurements of radiation
dose distributions for shielded cervical applicators. Int J Radiat
Oncol Biol Phys. 1985;11(4):861–868.
28. Mohan R, Ding IY, Toraskar J, et al. Computation of radiation dose
distributions for shielded cervical applicators. Int J Radiat Oncol Biol
Phys. 1985;11(4):823–830.
29. Watanabe Y, Roy JN, Harrington PJ, et al. Three-dimensional
lookup tables for Henschke applicator cervix treatment by HDR
192IR remote afterloading. Int J Radiat Oncol Biol Phys.
1998;41(5):1201–1207.
30. Richardson S, Palaniswaamy G, Grigsby PW. Dosimetric effects of
air pockets around high-dose rate brachytherapy vaginal cylinders.
31. Huang YJ, Blough M. Dosimetric effects of air pocket sizes in
MammoSite treatment as accelerated partial breast irradiation for
early breast cancer. J Appl Clin Med Phys. 2009;11(1):2932.
32. Richardson S, Pino R. Dosimetric effects of an air cavity for the
SAVI™ partial breast irradiation applicator. Med Phys.
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2010;37(8):3919–3926.
33. Gifford KA, Price MJ, Horton JL Jr, et al. Optimization of
deterministic transport parameters for the calculation of the dose
distribution around a high dose-rate 192Ir brachytherapy source.
Med Phys. 2008;35(6):2279–2285.
34. Zourari K, Pantelis E, Moutsatsos A, et al. Dosimetric accuracy of a
deterministic radiation transport based 192Ir brachytherapy
treatment planning system. Part I: single sources and bounded
homogeneous geometries. Med Phys. 2010;37(2):649–661.
35. Mikell J, Mourtada F. Dosimetric impact of an 192Ir brachytherapy
source cable length modeled using a grid-based Boltzmann transport
equation. Med Phys. 2010;37:4733–4743.
36. Beaulieu L, Carlsson TA, Carrier J-A, et al. Report of the Task Group
186 on model-based dose calculation methods in brachytherapy
beyond the TG-43 formalism: Current status and recommendations
for clinical implementation. Med Phys. 2012;39(10):6208–6236.
37. Thomadsen BR. Clinical implementation of remote-afterloading,
interstitial brachytherapy. In: Williamson JF, Thomadsen BR, Nath
R, eds. Brachytherapy Physics. Madison, WI: Medical Physics
Publishing; 1995.
38. Neblett DL, Syed AMN, Puthawala AA, et al. An interstitial implant
technique evaluated by contiguous volume analysis.
Endocurietherapy/Hyperthem. 1985;1:213–221.
39. Thomadsen BR. Achieving Quality In Brachytherapy. London: Taylor
& Francis; 1999.
40. Chassagne D, Dutreix A, Ash D, I.C.O.R.U.A.M. ICRU Report 58: dose
and volume specification for reporting interstitial therapy. Report No. 58.
Bethesda, MD: International Commission on Radiation Units and
Measures; 1997.
41. Hanson WF, Graves M. ICRU Recommendations on dose
specification. In: Williamson JF, Thomadsen BR, Nath R, eds.
Brachytherapy Physics. Madison, WI: Medical Physics Publishing;
1995.
42. Hilaris BS, Nori D, Anderson LL. Atlas of brachytherapy. New York,
NY: Macmillan Publishing Company; 1988.
43. Schoeppel SL, LaVigne ML, Martel MK, et al. Three-dimensional
treatment planning of intracavitary gynecologic implants: analysis
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of ten cases and implications for dose specification. Int J Radiat
Oncol Biol Phys. 1994;28(1):277–283.
44. Saarnak AE, Boersma M, van Bunningen BN, et al. Inter-observer
variation in delineation of bladder and rectum contours for
brachytherapy of cervical cancer. Radiother Oncol. 2000;56(1):37–
42.
45. Fellner C, Potter R, Knocke TH, et al. Comparison of radiography-
and computed tomography-based treatment planning in cervix
cancer in brachytherapy with specific attention to some quality
assurance aspects. Radiother Oncol. 2001;58(1):53–62.
bladder reference point. Radiother Oncol. 2003;68(3):269–276.
47. Kirisits C, Potter R, Lang S, et al. Dose and volume parameters for
MRI-based treatment planning in intracavitary brachytherapy for
cervical cancer. Int J Radiat Oncol Biol Phys. 2005;62(3):901–911.
48. Van den Berg F, Meertens H, Moonen L, et al. The use of a
transverse CT image for the estimation of the dose given to the
rectum in intracavitary brachytherapy for carcinoma of the cervix.
49. Saw CB, Suntharalingam N. Quantitative assessment of interstitial
implants. Int J Radiat Oncol Biol Phys. 1991;20(1):135–139.
50. Saw CB, Waterman FM, Ayyangar K, et al. Quantitative evaluation
of planar 192Ir implants [Abstract]. Med Phys. 1986;13:580.
51. Zwicker RD, Schmidt-Ullrich R. Dose uniformity in a planar
interstitial implant system. Int J Radiat Oncol Biol Phys.
1995;31(1):149–155.
52. Wu A, Ulin K, Sternick ES. A dose homogeneity index for evaluating
192Ir interstitial breast implants. Med Phys. 1988;15(1):104–107.
53. Saw CB, Suntharalingam N, Wu A. Concept of dose nonuniformity
in interstitial brachytherapy. Int J Radiat Oncol Biol Phys.
1993;26(3):519–527.
54. Yu Y. A nondivergent specification of the mean treatment dose in
interstitial brachytherapy. Med Phys. 1996;23(6):905–909.
55. Saw CB, Suntharalingam N. Reference dose rates for single- and
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double-plane 192Ir implants. Med Phys. 1988;15(3):391–396.
56. van’t Riet A, Mak AC, Moerland MA, et al. A conformation number
to quantify the degree of conformality in brachytherapy and
external beam irradiation: application to the prostate. Int J Radiat
Oncol Biol Phys. 1997;37(3):731–736.
57. Baltas D, Kolotas C, Geramani K, et al. A conformal index (COIN) to
evaluate implant quality and dose specification in brachytherapy.
58. Thomadsen BR. Clinical implementation of HDR intracavitary and
transluminal brachytherapy. In: Williamson JF, Thomadsen BR,
Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics
Publishing; 1995.
59. Kubo HD. Verification of treatment plans by mathematical formulas
for single catheter HDR brachytherapy. Med Dosim. 1992;
17(3):151–155.
60. Kubo HD, Chin RB. Simple mathematical formulas for quick-
checking of single-catheter high dose rate brachytherapy treatment
plans. Endocurietherapy/Hypertherm Oncol. 1992;8:165–169.
61. Rogus RD, Smith MJ, Kubo HD. An equation to QA check the total
treatment time for single-catheter HDR brachytherapy. Int J Radiat
Oncol Biol Phys. 1998;40(1):245–248.
62. Ezzell GA. Acceptance testing and quality assurance for high dose-
rate remote afterloading systems. In: Martinez AA, Orton CG, Mould
RF, eds. Brachytherapy HDR and LDR. Columbia, MD: Nucletron
Corporation; 1990:138–159.
ICRU Report 38: dose and volume specification for reporting
intracavitary therapy in gynecology. Bethesda, MD: International
Commission on Radiation Units and Measures; 1985.
64. Ezzell GA. Quality assurance of treatment plans for optimized high
dose rate brachytherapy–planar implants. Med Phys. 1994;
21(5):659–661.
65. Das RK, Bradley KA, Nelson IA, et al. Quality assurance of treatment
plans for interstitial and intracavitary high-dose-rate brachytherapy.
Brachytherapy. 2006;5(1):56–60.
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vagina in cases of carcinoma of the uterine cervix. Cancer. 1955;
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8:1016–1020.
67. Chassagne D. La plesiocurietherapie des cancers du cavum avec
support-moule et Yridium 192. Annales de Radiologie. 1963;6:719–
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69. Peracchia G, Salti C. A simple method of preparing custom molds
for intracavitary treatment of gynecological cancer. Int J Radiat
Oncol Biol Phys. 1982;8(1):141–143.
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71. Pearcey RG, Petereit DG. Post-operative high dose rate
brachytherapy in patients with low to intermediate risk endometrial
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72. Paterson R. A dosage system for gamma ray therapy: Part I
[Clinical]. Br J Radiol. 1934;7:592–612.
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aspects. Br J Radiol. 1934;7:612–632.
74. Meredith WJ. Radium Dosage. Edinburgh, London: E. & S.
Livingstone; 1967.
75. Kwan DK, Kagan AR, Olch AJ, et al. Single- and double-plane
iridium-192 interstitial implants: implantation guidelines and
dosimetry. Med Phys. 1983;10(4):456–461.
76. Zwicker RD, Schmidt-Ullrich R, Schiller B. Planning of Ir-192 seed
implants for boost irradiation to the breast. Int J Radiat Oncol Biol
Phys. 1985;11(12):2163–2170.
77. Pierquin B, Marinello G. A Practical Manual of Brachytherapy.
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system of Paris (endo- and plesioradiotherapy with non-radioactive
preparation). A preliminary note. Ann Radiol (Paris). 1966;9(9):757–
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1The exception to this generalization is the use of a LDR remote afterloader—
a device that moves LDR sources into applicators while the patient lies in a
hospital bed. Since marketing of these units recently terminated, remote
afterloading LDR brachytherapy will not be considered in this chapter.
2For more information, the reader may consult any basic radiobiology
textbook, such as Hall EJ, Giaccia AJ. Radiobiology For Radiologists, 6th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
3Definitions for the CTV and related terms can be found in Chapter 1.
4Elekta Nucletron BV, Veenendaal, The Netherlands.
5The program Acuros in BrachyVision, Varian Associates, Palo Alto, CA,

based on Attila, Transpire Inc., Gig Harbor, WA.
6Convention dictates that the units for BED indicate the α/β as a following
subscript.
7The step size becomes very important in many implant cases. Large step sizes
give less ability to optimize the dose distribution. Small step sizes with very
short dwell times cause some unit to void a treatment plan following a source
change if the automatically recalculated dwell times become shorter than the
shortest time programmable.
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17 Electron Beam Treatment
Planning
John A. Antolak
High-energy electron beams were first available for use in radiotherapy

in the 1930s using Van de Graaff generators (1). In the 1940s, the
betatron became the machine of choice because higher energies allowed
more than just the treatment of skin lesions (1,2). Electron linear
accelerators became commercially available in the 1950s, but were not
commonly used until about a decade after their introduction (1,2).
Adding electron beam capability to a medical linear accelerator added to
the expense and complexity of the machine, and the use of electron
beams for radiotherapy was not well understood for many years. Cobalt
irradiators, which were used starting in the 1950s, were widely available
and very reliable, so it took many years for the use of medical linear
accelerators to gain traction in the radiotherapy clinic. It took even
longer for groups such as the one at MD Anderson Hospital and Tumor
Institute (3,4) to demonstrate the usefulness of megavoltage electron
beams, which gradually led to their increased use in the general
radiotherapy community. Currently, most medical linear accelerators are
purchased with electron capabilities and it has become an expected
capability in the modern radiotherapy clinic.
The most common energy range for electron beams in current medical
linear accelerators is 6 to 20 MeV, which can treat tumors up to
approximately 6 cm in depth. Primary clinical applications for electrons
include skin cancers, chest wall irradiation for breast cancer,
administration of boost treatments (i.e., breast, head, and neck), and
intraoperative radiation therapy (IORT). All of these regions can be
successfully treated with x-rays, however, electrons offer the distinct
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advantage of sparing dose to deeper, possibly critical, tissues, as well as
delivering higher surface doses.
The purpose of this chapter is not to provide a comprehensive review,
but to provide a practical understanding of the properties of electron
beams used in radiation therapy so that the reader can confidently apply
that knowledge in the clinic to plan electron beam treatments. In order
to limit the scope of this chapter, it will be assumed that the reader has a
modern 3D treatment-planning system (TPS) and uses it for electron
beam treatment planning, or that they are considering making better use
of the TPS for electron beam treatment planning. The next section on
basic physics and beam properties provides an overview of the most
important properties of electron beams as applied to patient treatments.
An understanding of electron beams is key to being able to apply them
effectively in the clinic. The next section on basic treatment-planning
builds on that understanding to provide a qualitative description of how
electron beams can be used to solve some basic treatment-planning
problems. The next section on advanced treatment planning discusses
more advanced techniques, which may not be easily accomplished using
most commercial planning systems. For a more comprehensive review of
clinical electron beam dosimetry, the reader is encouraged to consult the
two AAPM reports available on the subject (5–7), and the excellent
review article by Hogstrom and Almond (1).
Electrons are arguably under-utilized in the modern radiation therapy
clinic (8), for a variety of reasons. Electron beam radiotherapy is a
minority technology, and therefore some training programs give little
thought to teaching about the utility of electron beams. In the 1990s,
intensity-modulated radiation therapy (IMRT) and image-guided
radiation therapy (IGRT) technology started to become readily available.
Until then, one of the more common treatment sites for electron beams
was treating the posterior neck region for head-and-neck tumors, after
the spinal cord had received its tolerance dose from the lateral photon
fields. This created a dose distribution that wrapped around the spinal
cord. Using IMRT, it was possible to create a similar dose distribution
without the additional complexity of the added electron fields. The
addition of IGRT technology contributes to even better accuracy and
precision, so it is doubtful that older patched-field approaches will make
a comeback.
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BASIC PHYSICS AND BEAM PROPERTIES
Electrons are negatively charged fundamental particles with a small
mass, approximately 2,000 times lighter than a nucleon (proton or
neutron). Because of the electric charge, they readily interact with
positively charged atomic nuclei and the negatively charged electrons
that orbit the nuclei. The electric field of the nucleus can change the
direction of the incident electron, which is called Coulomb scattering.
Because this scattering occurs on a microscopic scale, it is not practical
to try to follow each scattering event. If we look at this effect on a
macroscopic scale, it is called multiple Coulomb scattering since we are
including multiple scattering events at each step. The material that the
electrons are passing though can be characterized by a scattering power,
which is a measure of how easily a given material can change the
angular distribution of the electrons passing through the material.
Occasionally, the nuclear scattering interaction is strong enough that the
incident electron loses energy in addition to scattering, and the lost
energy is emitted as an x-ray. This is called bremsstrahlung production,
and is the primary process for producing x-rays in the anode of a
diagnostic x-ray tube or in the target of a linear accelerator.
Bremsstrahlung events remove energy from the beam, but this energy is
not deposited locally and hence contributes very little to the deposited
dose.
Incident electrons also interact with atomic electrons. This generates
heat and causes ionization of the atoms in addition to scattering. This is
where the majority of the energy deposition occurs. The material that
the electrons are passing through can be characterized by a mass
collisional stopping power, which is the energy lost to collisional
interactions per unit length divided by the density of the material. The
dose deposited is the product of the electron fluence (number of
electrons per unit area) and the mass collisional stopping power. For
biologic materials, the mass stopping power is relatively constant, so the
energy deposition is determined primarily by the electron fluence, or the
number of electrons passing through a given volume. The scattering
power of the materials that the beam passes through determines how the
electrons redistribute themselves, so calculating the dose deposition due
to electron beams is primarily a problem of calculating the fluence
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distribution of the electrons in the material. While this is a somewhat
simplified description of the electron interactions in matter, it is good
enough to be able to qualitatively understand some of the basic
properties of electron beams used in radiation therapy.
Percent Depth Dose

Most of the energy loss for an incident electron beam involves transfer of
energy to orbital electrons in the medium (e.g., patient), and the rate of
collisional energy loss depends primarily on the electron density of the
material, which is closely related to the physical density for low-Z
(biologic) materials. For the energy range used in electron radiation
therapy, the energy loss is approximately 2.0 MeV per cm of water.
Figure 17.1 shows percent depth dose (PDD) curves for a Varian
TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA).
The practical range is at the depth of the intersection of the linear
portion of the distal dose falloff and the line representing the level of
bremsstrahlung contamination. At depths shallower than the practical
range, the dose is primarily due to the electrons, and it is readily
apparent that the energy of the beam is approximately double the
practical range. Very few electrons are able to reach the depth of the
practical range due to multiple Coulomb scattering deflecting the
electrons, and this gives rise to the distal slope of the electron PDD. The
therapeutic depth of the electron beam increases with energy almost
linearly, and a general rule of thumb is that the energy of the beam is
approximately 3.3 times the depth of R90.
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Figure 17.1 Electron central-axis percentage depth dose profiles for a Varian TrueBeam linear
accelerator, 10 × 10 cm2 applicator, 100-cm SSD. The practical range, Rp, and therapeutic depth,
R90, for the 20-MeV beam are illustrated.
Ideally, we would like to select the electron energy such that the
target is shallower than R90, and the critical structures are deeper than
Rp. This implies that as the energy is increased, the separation between
the target and critical structures also needs to increase if full sparing of
the critical structures is to be maintained. Using the above rules of
thumb for R90 and Rp, the optimal separation in depth (in cm) between
the target and critical structures is approximately the beam energy (in
MeV) divided by 5 (e.g., for the 20-MeV electron beam, this separation is
about 4 cm). If the target to critical structure separation is less than that,
an alternative might be to use IMRT with x-rays to get a sharper distal
falloff. If particle therapy (e.g., protons) is available, the distal falloff can
be even sharper.
The central-axis depth dose curve, for the same nominal stated energy,
may be different depending upon equipment manufacturer. Factors
contributing to these differences include, but are not limited to,
differences in the materials used in the construction of scattering foils
and ionization chambers, location of the scattering foils, and the
geometry and materials of the tertiary collimation system (applicator or
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cone). Therefore, the depth dose curves and associated isodose
distribution should be measured for each clinical treatment unit.
The surface dose for electron beams is higher than for x-ray beams,
which can be an advantage for targets near the skin surface. The primary
reason that the dose increases in the buildup region between the surface
and R100 (dmax) is increased path length per unit depth caused by
multiple Coulomb scattering. Since lower-energy electrons scatter more
readily than higher-energy electrons, the slope in the buildup is steeper
for lower energies and the surface dose is lower as well. This is contrary
to the case for megavoltage x-rays, where the relative surface dose is
lower for higher energies. As shown in Figure 17.1, the surface dose for
the 6-MeV beam is less than 90%. If full dose at the skin surface is
desired, approximately 0.5 cm of additional bolus is needed to have 90%
dose at the surface. As a consequence, the therapeutic depth (in the
patient) is reduced, in this case to 1.2 cm.
The bremsstrahlung tail (or x-ray contamination) is what is left over
after all of the electrons have stopped in the patient. In a modern
medical linear accelerator, about half of the bremsstrahlung tail is due to
x-rays generated in the high-Z components of the treatment head (e.g.,
scattering foils) and about half is due to x-rays generated in the patient.
Because the relative dose in the bremsstrahlung tail is generally smaller
than 5% of the maximum dose, it has little effect on how the electron
beams are used clinically.
Isodose Distributions
Figure 17.2 shows isodose distributions for 9-MeV and 16-MeV beams at
100-cm SSD and 110-cm SSD. On the phantom surface, the penumbra
width is proportional to the width of the angular distribution of the
electrons at the level of the final collimation (cutout is at 95-cm SSD)
multiplied by the gap between the final collimation and the phantom.
Because lower-energy electrons are more readily scattered in the
treatment head and air above the cutout, the width of the angular
distribution of the 9-MeV electrons at this level is larger (more diffuse)
than the 16-MeV electrons and hence the penumbra at the surface is
larger for the 9-MeV beam. Comparing the 100-cm SSD isodose curves to
the 110-cm SSD isodose curves, you can easily see that the penumbra at
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the surface is approximately three times larger because the gap between
the final collimation and the surface is three times larger. However,
there is less effect at R100 and R90 because the scattering in the phantom
dominates relative to the contribution of the air gap.
Figure 17.2 Isodose distributions for a 10 × 10 cm2 applicator. (A) 9 MeV, 100-cm SSD. (B) 9
MeV, 110-cm SSD. (C) 16 MeV, 100-cm SSD. (D) 16 MeV, 110-cm SSD.
Figure 17.3 Isodose distribution for a 10 × 10 cm2 applicator, 100-cm SSD, 12-MeV electron
beam. Distance measurement is shown from the projected beam edge to the 90% isodose line.
Similar to x-ray beams, the beam edge in the lateral direction does not
correspond to the therapeutic region (e.g., 90% isodose volume). When
drawing the beam portal in the TPS, a good starting point is to add 1.0
cm to the PTV in the beam’s eye view. For a 12-MeV electron beam,
Figure 17.3 shows that the distance between the 50% and 90% isodose
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lines at R100 is 0.8 cm. After computing the dose in the planning system,
the difference between the prescription isodose line and the target
volume can then be used to adjust the beam portal if needed for better
conformality. For a clinical setup, where the TPS is not used, it is
important to remember to include this dosimetric margin when creating
the beam portal. For example, if the clinical target measures 8 cm in
dimension on the skin surface, the beam portal should be a minimum of
10 cm, depending on what other structures might be present and must
be avoided.
Field Shaping and Shielding

Field shaping on most modern medical linear accelerators is
accomplished using a combination of an electron applicator (or cone)
and a field-defining insert (or cutout). Figure 17.4 shows an example of
a 10 × 10 cm2 applicator for a Varian 2100C linear accelerator (Varian
Medical Systems, Palo Alto, CA) and a patient-specific insert. The
applicator is usually constructed as a series of two to three scrapers with
apertures that gradually shrink down to the size of the final collimation.
The size of the opening of the photon jaws for each specific energy is
integral to the proper functionality of the device, so specific jaw
openings are automatically set when the applicator is inserted and a
given energy is chosen. The thickness of the final insert must be enough
to stop the highest-energy electrons. The AAPM Task Group #25
tabulated the thickness of lead required to stop various energy electrons
and found a linear relationship with the minimum required thickness of
lead in millimeters being equal to half of the energy in MeV (5). They
also recommended adding 20% to the thickness if a lead alloy was used
instead. Adding 1 mm of lead for uncertainty is prudent, so the
recommended thickness of lead as a function of energy is
For a linear accelerator with a maximum energy of 20 MeV, the

thickness required to stop the electrons is approximately 11 mm of lead,
or 13 mm of lead alloy. It is not an accident that the standard thickness
of lead alloy electron inserts is approximately 13 mm. It is also possible
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to have these inserts commercially made to order from a copper alloy by
sending the block outline from the treatment-planning computer to the
vendor (.decimal, Inc., Sanford, FL), where they are manufactured using
computerized machining and shipped to the customer.
Figure 17.4 Electron applicator for cutouts up to 10 × 10 cm2, and a patient insert made from low
melting point alloy.
In addition to being used for field shaping, lead and other high-density
materials can be used for shielding normal tissues that need to be
spared. For example, when treating a lesion near the eye, shielding the
eye might be desirable. As shown in Figure 17.2, the penumbra of the
beam is sharper when the applicator is placed closer to the patient.
However, because of the size and shape of the applicator device, it is
often necessary to treat at extended distances. In this case, shielding in
the form of lead sheets can be placed on the patient surface. This usually
requires making a positive mold of the patient so that the lead sheets can
be formed to fit the patient surface. The required thickness is given by
the above formula. Eye shields are commercially available (Civco
Medical Solutions, Coralville, IA) that are fabricated from tungsten and
coated with dental acrylic. The thickness of the tungsten is sufficient to
shield up to 9-MeV electrons. The coating serves two purposes; one is to
provide a smoother surface less prone to scratching sensitive tissues, and
the other to absorb some of the backscattered electrons. Klevenhagen et
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al. (9) measured electron backscatter as a function of atomic number and
showed that the amount of backscatter increases for higher atomic
number materials and lower-energy electrons. These backscattered
electrons generally have a spectrum of energies with a very low mean
energy, and therefore, a relatively thin layer of lower atomic number
material will absorb much of the backscattered energy. If the eye shields
are placed under the eyelid, for example, the dental acrylic coating of
the shield will greatly reduce the backscattered dose on the inside of the
eyelid. Whenever shielding is placed inside the body to shield distal
tissues, it is a good idea to place a layer of lower atomic number
material upstream of the higher atomic number shielding.
Field Size Effects

When field sizes are smaller than the lateral scatter equilibrium field
size, the percentage depth dose can change shape, and the dose output
(dose per monitor unit) can change significantly. Understanding lateral
scatter equilibrium is key to understanding how depth dose and dose
output change as a function of field size. We will use a TPS to
understand lateral scatter equilibrium. The planning system allows us to
create very accurate block openings, and to create complementary island
blocks (even though they are not physically realizable). In this case, the
treatment-planning algorithm being used is Eclipse Electron Monte Carlo
(EMC 10.0.28, Varian Medical Systems, Palo Alto, CA), which has been
shown to accurately calculate doses in heterogeneous materials under a
variety of conditions (10). Figure 17.5 shows the dose distributions for a
3 × 3 cm2 field in a 10 × 10 cm2 applicator, the same field with a
central block (instead of an opening), and the summed dose distribution.
The summed dose distribution shows a dose distribution that looks very
much like the normal open applicator dose distribution, other than a
little bit of extra leakage dose through the block material (same number
of electrons put into the phantom with double the monitor units).
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Figure 17.5 Isodose distribution for a 12-MeV electron beam at 100-cm SSD. The horizontal
dashed line shows the location of R100 for the 10 × 10 cm2 applicator field. (A) 3 × 3 cm2 field in a
10 × 10 cm2 applicator. (B) 10 × 10 cm2 applicator with 3 × 3 cm2 central block. (C) Sum of (A)
and (B).
Another way to look at the same data is shown in Figure 17.6, where
the central-axis depth dose profiles are shown for the blocked fields and
complementary central-blocked fields. Looking at the depth dose profiles
for the 6 × 6 cm2 field in a 10 × 10 cm2 applicator and its
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complementary central-block field, you first see that the depth dose for
the 6 × 6 cm2 field is almost the same as the 10 × 10 cm2 field. This is
indicative of almost having lateral scatter equilibrium. Looking at the
central-axis depth dose profile for the 6 × 6 cm2 central-block field, the
amount of dose on the central axis is very small, indicating that very few
electrons from the outer part of the field contribute to dose on the
central axis. Looking at the data for the 3 × 3 cm2 field and the 3 × 3
cm2 central-block field, the situation is not quite the same. The depth
dose in the initial part of the buildup for the 3 × 3 cm2 field follows the
depth dose for the 10 × 10 cm2 field for only about 1 cm before it starts
deviating significantly. At shallow depths, electrons from outside the 3
× 3 cm2 central area do not contribute dose on central axis. As you go
deeper, more of the dose on central axis is due to electrons that started
outside the 3 × 3 cm2 central area. At 4-cm depth, which is past R100 for
this energy, the contribution from electrons outside the 3 × 3 cm2
central area reaches a maximum. It is easy to see that re-normalizing the
depth dose for the 3 × 3 cm2 field will give a depth dose that looks
quite different from the original 10 × 10 cm2 field. The surface dose
will be higher relative to the maximum dose, and the therapeutic depth
will be about 1-cm shallower. The curves for the 1 × 1 cm2 field and the
1 × 1 cm2 central-block field clearly show that lateral scatter
equilibrium is not present at any depth.
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Figure 17.6 Calculated central-axis electron depth dose profiles for 12-MeV electron beams at
100-cm SSD. Thicker lines are for open-field sizes of 1 × 1 cm2, 3 × 3 cm2, 6 × 6 cm2, and 10 ×
10 cm2. Thin lines are for the corresponding open fields with central blocks, and the dashed line is
the sum of the open field and centrally blocked field. All fields use the same monitor units and the
dose axis is in cGy per MU.
Figure 17.7 shows the same open-field depth dose data normalized to
the maximum dose on central axis. Other than very small differences in
the buildup region, there is very little difference between the 6 × 6 cm2
field and the 10 × 10 cm2 field. The output in dose per monitor unit is a
little bit lower, but using the same PDD for both fields would be very
reasonable. For the 3 × 3 cm2 field, the relative surface dose has
increased, the depth of maximum dose has shifted toward the surface,
and the therapeutic depth has decreased. In this case, we no longer have
lateral scatter equilibrium. It is very important to keep this in mind
when deciding on the energy to use. If the field size is smaller than the
lateral equilibrium field size, the therapeutic depth may shift far enough
toward the surface that a higher energy may be needed to treat to the
desired depth. For circular fields, the minimum radius for lateral scatter
equilibrium is approximately , where is the most probably
energy of the electrons at the patient (phantom) surface (11). If we
approximate the most probably energy with the nominal energy, the
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minimum radius is approximately 3.0 cm for 12 MeV. This is
approximately the same size as the 6 × 6 cm2 field, which is consistent
with the observations made about Figures 17.6 and 17.7.
Figure 17.7 Calculated electron central-axis depth dose profiles for 12-MeV electron beams at
100-cm SSD, for open-field sizes of 1 × 1 cm2, 3 × 3 cm2, 6 × 6 cm2, and 10 × 10 cm2 in a 10 ×
10 cm2 applicator.
For the 6 × 6 cm2 field in the 10 × 10 cm2 applicator (Fig. 17.7), the
percent depth dose is almost same as the open 10 × 10 cm2 field, so the
depth coverage is about the same. However, as shown in Figure 17.6, the
output (maximum dose per monitor unit) of the 6 × 6 cm2 field is not
the same. Figure 17.8 shows measured dose output (output factors) for
cutouts in three different size applicators for the 12-MeV beam on a
Varian TrueBeam linear accelerator (Varian Medical Systems, Palo Alto,
CA). Each curve is in dose per monitor unit, so the difference in dose
output of the open applicator is included in this graph. Because the 15
× 15 cm2 applicator has larger openings, the x-ray jaw opening for this
applicator is also larger to ensure that the electron field profile is
uniform. Therefore, more electrons get through the x-ray jaws and larger
applicators tend to have slightly greater dose output. Similarly, the jaw
opening for the 6 × 6 cm2 applicator is smaller, which tends to give less
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dose output. The actual magnitude of the output of the open applicator
is a complicated function of the design of the applicator, the energy of
the beam, and the x-ray jaw opening. The x-ray jaw openings for each
energy-applicator combination are usually fixed by the vendor to
provide good dose uniformity for the open applicator and, in general,
should not be changed by the end user. The dose output should be
measured and entered into the TPS.
Figure 17.8 Measured output factors for 12-MeV electron beams at 100-cm SSD. For each
electron cone, the dose output (cGy/MU) for the cutout field size is plotted.
There are two features that can be seen in Figure 17.8 that are
consistently seen in measured output factor data. The first is the slight
rise in dose output, as the field size gets slightly smaller than the open
applicator field size. As the field size gets smaller, the field edges get
closer to central axis. Electrons scattering from the edges of the aperture
are able to reach central axis more easily and the dose output rises
slightly. When the field size gets smaller than the field size required for
lateral scatter equilibrium (about 6 cm for 12 MeV), the dose output
drops quite dramatically as electrons that would normally contribute
dose to central axis are removed from the beam. In addition, the shape
of the depth dose is also changing, as seen in Figure 17.7. If planning
clinical electron treatments (without the planning system), the change in
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dose output can be accounted for using tabulated output factors.
However, the change in percent depth dose is not so easy to deal with.
Therefore, when dealing with field sizes smaller than the equilibrium
field size, a good TPS is recommended to ensure that the treatment goals
are met.
When delivering an electron beam, it is generally possible to deliver
the same field shape using different applicators. The shape of the dose
distribution primarily depends on the shape and size of the final
collimation, as shown by Shiu et al. (12), and the dose output depends
on the chosen applicator. Referring to Figure 17.8, the dose output for a
5 × 5 cm2 field in a 6 × 6 cm2 applicator is approximately 3.5%
smaller than the dose output for the same field size in a 10 × 10 cm2
applicator. Most TPSs are able to model the change in depth dose as the
field size changes, either using tables of percent depth dose as a function
of field size or an appropriate physics model. For the former (PDD
tables), changes in dose output with different applicators may or may
not be included and it is important for the radiotherapy team to be
aware of how to convert the planning data to monitor units at the
machine, if necessary. For the latter (physics model), the absolute dose
output and percent depth dose for each applicator is usually entered as
part of the beam data, and the physics model takes care of modeling
changes to the dose deposition as the field size is changed. While it is
preferable for the TPS to provide the monitor units directly, it is not
crucial as long as the radiotherapy team is aware of how the treatment-
planning data needs to be transferred to treatment and this is done
correctly. In both cases, the formalism to calculate monitor units should
be consistent with AAPM recommendations (6,13). The AAPM also
recommends that a second check of the monitor units be carried out
prior to treatment (preferable) or before 10% of the treatment has
elapsed (14,15).
Extended SSD
In addition to changes in penumbra shown in Figure 17.2, increasing
SSD can affect the shape of the depth dose distribution as well as the
dose output (per monitor unit). To account for the change in the depth
dose distribution, AAPM TG-25 (5) recommended using a divergence
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factor (F-factor or Mayneord factor) to calculate the relative depth dose
at extended SSD from the relative depth dose at the nominal SSD. As
pointed out by Shiu et al. (12), these changes in relative depth dose are
expected to be relatively small because the electron penetration is small
compared to the SSD. They evaluated this approach for a 20-MeV
electron beam at 110-cm SSD for a 15 × 15 cm2 field and a 6 × 6 cm2
field. For the larger field size, they found the divergence factor worked
well, but there were significant differences for the smaller field size.
They hypothesized that these differences were due to a large number of
low-energy electrons scattered from the edges of the final aperture. The
number of scattered electrons depends on the design of the applicator.
Modern applicators tend to simply remove electrons at the field edge,
while older applicator designs had walls that contributed scattered
electrons.
As shown in Figure 17.9, there are a few competing factors that affect
the shape of the depth dose curve as the SSD is changed. For the 15 ×
15 cm2 field, the therapeutic depth (R90) of the electron beam is hardly
affected, but there is a deficit of electrons in the buildup region, which is
consistent with the hypothesis of Shiu et al. (12). For the smaller 6 × 6
cm2 field, we can see a few competing effects. First of all, the
therapeutic depth of the 6 × 6 cm2 field is smaller than the therapeutic
depth of the 15 × 15 cm2 field, as would be expected because of the loss
of lateral scatter equilibrium (discussed previously). If we do an inverse
square (divergence) correction for the 6 × 6 cm2 field to get to 110-cm
SSD (as recommended by AAPM TG-25), then you can see that the depth
dose does not change significantly. However, in reality, the shape of the
depth dose and the magnitude of the dose output do change
significantly. We no longer have side scatter equilibrium for the 6 × 6
cm2 field, so the simple inverse square correction, which assumes side
scatter equilibrium, is not sufficient to calculate the change in depth
dose with SSD. In addition to the small reduction in dose output, we can
see a small increase in the therapeutic depth, which is consistent with
the slightly larger field size at the extended SSD. Similar to the case with
x-ray beams, a simple divergence correction is inadequate for smaller
fields because of differences in scatter conditions, and lateral scatter is
arguably more important for electron beams.
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Figure 17.9 Calculated electron central-axis depth dose profiles for 20-MeV electron beams at
100- and 110-cm SSD, for open applicator field sizes of 6 × 6 cm2, and 15 × 15 cm2. The vertical
axis is absolute dose in cGy, and the monitor units for beams at 100-cm SSD were set to obtain
100 cGy maximum dose on central axis. For the beams at 110-cm SSD, the monitor units were
increased using an inverse square factor and an effective source distance of 90 cm (scattering foil
position for this linear accelerator). The curve labeled “inverse square” is the PDD for the 6 × 6
cm2 field size at 110-cm SSD, calculated from the 100-cm SSD depth dose using just an inverse
square correction.
Virtual Point Source

The virtual point source, as defined by AAPM TG-25 (5), is a useful
concept for calculating the divergence of the electron beam. The basic
idea is to determine the 50% width of the electron beam under
conditions of lateral scatter equilibrium. The task group recommended a
field size of 20 × 20 cm2 or larger. For most linear accelerators, the
virtual source position is close to the position of the primary scattering
foil, which is not necessarily at the same position as the x-ray target.
While useful for calculating beam profiles using a pencil-beam algorithm
(Hogstrom et al. (16)), it is less useful for calculating the dose variation
with SSD (5).
Effective Point Source
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The effective SSD concept was introduced by Khan (17) to facilitate
calculation of the dose output as a function of SSD. There is no
assumption of lateral scatter equilibrium in this case. The dose output is
tabulated as a function of the air gap between the final collimation and
the phantom surface. A plot of the inverse square root of the output as a
function of the gap is fit to a straight line and extrapolated to an
effective point source where the inverse square root of the output is zero
(or the output is infinite). The range of air gaps used for the
measurement should be representative of those used in the clinic. In
practice, the effective point source is usually tabulated as a function of
square or circular field size. The effective point source position and can
vary systematically from 50 cm (for very small fields) to approximately
the position of the primary scattering foil (90 cm for Varian, and 100 cm
for Siemens). The output at the nominal SSD (100 cm) is corrected by an
inverse square correction factor, ISCeff, to give the output at the
treatment SSD.
where r is the field size, d0 is the normalization depth for the electron
beam, and g is the air gap difference between the nominal (calibration)
SSD and the actual SSD. If the air gap is larger than what was used to
determine the effective point source, a measurement of the dose output
may be needed since the inverse square dependence of the dose output is
only approximate and may not hold for larger air gaps.
Effective Versus Virtual Point Source

For larger field sizes, where lateral scatter equilibrium exists, the
effective point source and virtual point source are approximately the
same. The electron beam appears to be emanating from a point near the
primary scattering foil in the linear accelerator. As the size of the beam
is reduced and lateral scatter equilibrium is lost, the effective source
position of the electron beam appears to move toward isocenter. It is
important to note that the effective source is not a true electron source
position; it is only a result of the fact that the output of the beam is
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varying with distance as if the source was at a different location than the
primary scattering foil. This is purely a product of the loss of lateral
scatter equilibrium. In fact, one can show theoretically that the electrons
in the middle of the beam are still diverging from a position near the
primary scattering foil; it is just the output that is being reduced more
quickly. In other words, the beam is geometrically diverging from the
primary scattering foil, but the output is decreasing as if the source was
closer to isocenter.
In Equation (17.2), g is the additional air gap between the nominal
SSD (usually 100 cm) and the actual treatment SSD. It is not important
how these effective source positions are measured, only that they exist
and can be used for distance corrections. A drawback of this method is
that finding (interpolating) the SSDeff for an irregular field is not well
defined.
Air Gap Factor

One of the more significant issues with the effective point source method
of correcting the dose output is that the effective SSD quickly moves
toward isocenter for small field sizes because of the loss of side scatter
equilibrium. Small uncertainties in field size may lead to relatively large
uncertainties in effective SSD and dose output. If the field shape is not
the same as those used to measure the effective point source, then the
field size used in the inverse square correction has even more
uncertainty.
An alternative approach for determining the output of the electron
beam at extended distance is to use the virtual SSD method from AAPM
TG-25, which uses the virtual SSD, SSDvir , and an air gap factor, fair , to
calculate the output at extended SSD.
It is important to note that this is an alternative to the effective point

source method, and must not be used in addition to the effective point
source method. The physical interpretation of this equation is that the
electrons are diverging from the virtual point source (inverse square
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term), and the air gap factor, fair , describes the deviation between
inverse square dependence from the virtual point source and the true
dose output. Note that the inverse square term no longer depends on
field size, and that the field size dependence is fully contained in the air
gap factor.
The effective point source and air gap factor methods have both been
shown to give clinically acceptable results, provided the calculations are
not made beyond the range of measured commissioning data. Either
method is acceptable for determining electron beam monitor units in
accordance with TG-71 (13), although the author prefers the air gap
factor method.
Irregular Fields
In general, data for square or circular fields is collected when
commissioning linear accelerators, but clinical electron fields are
irregularly shaped. If data is collected for square fields, which is
probably more common, it is useful to approximate the clinical irregular
field by a rectangular field size (13,18). Similar to what is done for x-ray
beams, the basic idea is to find a rectangular field with approximately
the same amount of scatter as the irregular field. Small portions of the
irregular field that are more than from the point of interest
(the minimum radius for lateral scatter equilibrium as given by Khan et
al. (11)) can be ignored. For a more detailed explanation of the rules for
constructing equivalent rectangular fields for electrons and some
examples, see the description by Hogstrom and Steadham (19), which is
reproduced by Gibbons et al. (13).
Multiple Coulomb scattering theory (16) gives several useful results
that can be used to calculate dosimetric quantities for rectangular fields,
given the same data for square fields. For percent depth dose, the PDD
for a rectangular X × Y cm2 field is given by the geometric mean of the
PDD for the square X × X cm2 field and the square Y × Y cm2 field.
Mills et al. (20) showed that a similar equation for output factors was
more accurate than using 4A/P for the effective field size.
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Similarly, there is a similar rule for the air gap factor (12).
There is no similar rule for the effective point source method.

However, if you acknowledge that both methods should give the same
result, the following equation can be derived for the effective source
inverse square correction for the rectangular field.
Similar to sector integration methods for x-ray beams, Khan et al.

(11,21–23) developed methods to be able to predict changes in depth
dose and output factors for irregular fields. When applying these
methods, it is more natural to use input data for circular fields, although
square field sizes can be converted to equivalent circular field sizes to
get the necessary input data. The methods presented are more suitable
for computer implementation than for hand calculations, and will not be
discussed here.
Sloping Surfaces
When the electron beam is incident on a sloping surface, the isodose
curves are affected in several ways. Figure 17.10 shows isodose curves
for 12-MeV electron beams at normal incidence and 40° oblique
incidence. The SSD along central axis and monitor units are the same for
both beams. There are three main effects on the dose distribution as the
beam angle is moved away from normal incidence. First, the penetration
of the electron beam relative to the phantom surface is reduced,
reducing the therapeutic depth. Second, the maximum dose along the
central axis is increased. This is due to electrons being scattering toward
central axis by the phantom material upstream of the beam entry point
(patient left in the figure). The last major effect is that the penumbra of
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the beam on the upstream side (patient left in the figure) is sharper
(isodose lines are closer together) than the penumbra on the downstream
side. The last effect is basically the same as what was shown previously
in Figure 17.2 for normally incident beams with different source to
surface distances.
Figure 17.10 Calculated dose for 12-MeV 10 × 10 cm2 fields at 110-cm SSD for (A) 0° incidence
(perpendicular) and (B) 40° angulation. The beam weights were set to obtain 100% at the depth
of maximum dose for the beam at 0° incidence.
Figure 17.11 shows calculated central-axis depth dose profiles for 12-
MeV electron beams at different angles of incidence. The therapeutic
depth along central axis is reduced, the maximum dose along the central
axis is increased, and the practical range of the electron beam increases.
On one side of the beam, we have phantom material upstream of the
central-axis beam entry point, and on the other side the phantom
material is further away than the central-axis beam entry point. The
upstream portions of the phantom scatter electrons toward the central
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axis that contribute more dose at shallower depths on the depth dose
curve. The downstream portions are not scattered until farther distances
(relative to central axis) and those scattered electrons contribute dose at
deeper depths along the beam’s central axis, which leads to what
appears to be an increased range. Figure 17.12 shows depth dose data
for the same beams, but in this case, the depth dose is perpendicular to
the phantom surface. In this case, you see an increase in dose at
shallower depths as the angle of incidence increases, as well as a
decrease in the depth of penetration relative to the skin surface. Because
it maximizes the penetration of the electron beam, we generally try to
place the electron beams at normal incidence relative to the skin surface.
Figure 17.11 Calculated central-axis electron depth dose profiles for 12-MeV electron beams at
110-cm SSD. The beam weights were set to obtain 100% at the depth of maximum dose for the
beam at 0° incidence. The entry point of the beam is fixed, and the depth dose is along the beam
axis.
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Figure 17.12 Calculated electron depth dose profiles for 12-MeV electron beams at 110-cm
SSD.The beam weights were set to obtain 100% at the depth of maximum dose for the beam at
0° incidence. The entry point of the beam is fixed, and the depth dose is perpendicular to the
phantom surface, or the depth from the phantom surface.
Surface Irregularities
Real patient surfaces are not flat. That can be rounded (e.g., extremities
or skull) or very irregular (e.g., nose or surgical defect). The former is
basically a more complicated sloping surface; the beam penetrates
further where it has normal incidence, and less where the surface is
sloping away from perpendicular incidence. The latter is perhaps more
interesting in that it introduces us to heterogeneity effects.
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Figure 17.13 Calculated dose for 16-MeV 8 × 8 cm2 field at 100-cm SSD incident on a nose
phantom, (A) without and (B) with heterogeneity corrections. The monitor units were set to deliver
100% dose for a water phantom at the same SSD.
Figure 17.13A shows the dose distribution for a nose phantom

irradiated with an 8 × 8 cm2 field of 16-MeV electrons at 100-cm SSD.
The monitor units were set to deliver 100% maximum dose on central
axis for the same field incident on a water phantom at the same SSD.
The density of the external contour was set to unity to highlight the
effect of the surface geometry. The resulting dose distribution looks very
different compared to an open-field dose distribution (see Fig. 17.2),
with hot spots of up to 120% of the dose for the open field on a water
phantom. To explain why this is happening, let’s look at the situation a
small distance into the nose portion of the phantom. The electrons in the
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nose are scattered away from the nose. The electrons in the air tend to
stay in the air, so the number of electrons just lateral to the nose
increases as the electron beam penetrates the nose. As described earlier,
more electrons means more dose, which is the primary reason why there
are significant hot spots just lateral to the nose. Because the electrons
have been redistributed laterally from the nose, there are fewer electrons
directly behind the nose, which leads to a cold spot. In general, any time
there is a hot spot due to electron scattering, there will be a
corresponding cold spot in the dose distribution.
Figure 17.14 Calculated dose for 16-MeV 19 × 12 cm2 field at 100-cm SSD incident on a water
phantom with 1-cm cylindrical bone (patient right) and air (patient left) heterogeneities. The
heterogeneities are at 1-cm depth and the monitor units were set to deliver 100 cGy at the depth
of maximum dose for a uniform water phantom.
Heterogeneities
Electron dose distributions can also be significantly affected by tissue
heterogeneities such as bone, lung, and air cavities. Figure 17.13B shows
the dose distribution for the same nose phantom as Figure 17.13A,
except that the dose calculation now includes the effect of the CT
densities (same electron field and monitor units). Compared to the
homogeneous calculation, you can see that the hot spots just lateral to
the nose are slightly reduced in magnitude. Inside the nose, we have air
cavities and some of the electrons in the tissue portions of the nose are
scattered into the internal air cavities and so fewer electrons scatter out
of the nose and hence the hot spot lateral to the nose is slightly reduced.
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Just behind those hot spots, there is another air cavity. The large
number of electrons in the lateral hot spots can now penetrate deeper
into the phantom because of the air, in addition to other electrons
scattering into those air cavities. Directly behind the nose, the electrons
tend to scatter into the long, narrow air cavities and hence are able to
penetrate much further. Overall, the electron beam is able to penetrate
much further into the phantom because of the air cavities.
It is not easy to see in Figure 17.13, but electrons in bone tend to
scatter more readily (because of the higher density). Figure 17.14 shows
the calculated dose distribution for cylindrical bone and air
heterogeneities in a water phantom, and the hot spots streaming off the
side of the bone are readily apparent. In most patient cases, the
difference in density between the bone and normal tissue gives hot spots
on the order of 3% to 5% as shown in the figure. For air cavities, the
density difference is much larger, so hot spots of 10% or greater, as
shown in the figure, are not uncommon.
Figure 17.15 Dose for a 9-MeV chest wall boost field (A) calculated without heterogeneity
corrections and (B) calculated with heterogeneity corrections.
Another common situation is shown in Figure 17.15, where we have

an electron boost field on the chest wall. Without heterogeneity
corrections, the dose appears to not penetrate very far in the lung tissue.
However, once the reduced density of the lung tissue is accounted for, it
is readily apparent that the electron beam penetrates much farther into
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the lung tissue. Fortunately, this is just a boost field so relatively little of
the total dose is given using this field.
Bolus
Bolus is a specifically shaped material, which is usually tissue equivalent
and is normally placed either in direct contact with the patient’s surface,
close to the patient’s surface, or inside a body cavity. In electron beam
radiotherapy, the most common uses for bolus are to flatten out an
irregular surface, reduce the penetration of the electrons in all or part of
the field, and/or increase the surface dose.
A very common type of bolus material available in most clinics is
superflab, which is a synthetic oil gel with a density very close to that of
water. It is available in a variety of thicknesses from 0.2 to 3.0 cm in
sheets that are typically 30 × 30 cm2 in size. It can be easily cut using
scissors or a utility knife and conforms reasonably well to patient
surfaces. As seen in Figure 17.1, lower-energy electron beams may have
a surface dose less than 90% of the maximum central-axis dose and this
dose may be lower than desired, depending on the location of the target
relative to the skin surface. In this case, adding superflab (or equivalent)
to the skin surface over the entire treatment field increases the surface
dose. The desired bolus thickness depends on the desired skin dose and
the energy of the beam being used for treatment. The penetration of the
beam into the patient will be reduced by the thickness of the bolus, so
higher electron energy may be needed depending on the depth of the
target. Using a higher energy has the disadvantage that the slope of the
distal dose falloff is not as steep, which means more radiation dose to
underlying normal tissues. Another reason to use constant thickness
bolus is to reduce the range of the beam in the patient. For a typical
linear accelerator, the energy spacing is such that the therapeutic depth
spacing is approximately 1 cm. Combining these energies with 5-mm
sheets of superflab bolus material, it is relatively easy to achieve 0.5-cm
spacing in therapeutic depth.
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Figure 17.16 Calculated dose for a 16-MeV 19 × 12 cm2 field at 100-cm SSD incident on a water
phantom with 1-cm unit density bolus in only a portion of the field. The edge on the patient right is
cut square, and the edge on the patient left is cut at a (A) 45° angle, or (B) 30° angle.
When using superflab bolus to reduce the overall range of the beam or
increase the skin dose, it is important that the bolus cover the entire
electron field with some margin. Similar to what was seen with the nose
phantom (Fig. 17.13). Figure 17.16 shows that sharp bolus edges within
the field (or close to the field edge) will lead to significant hot and cold
spots. If only partial coverage is desired (e.g., target depth variable
across the field), then it is recommended that the edge of the bolus that
is inside the electron field be tapered to not have a sharp edge as this
will reduce the magnitude of the hot and cold spots. As shown in Figure
17.16, shallower angles (e.g., 30°) are preferable; the dose calculation
shows almost no difference between cutting the bolus material square or
at a 45° angle. As noted by Gerbi et al. (6), the minimum width of the
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bolus for a scar boost treatment should be at least 2 cm to ensure dose
buildup occurs instead of getting a cold spot due to out-scattering (e.g.,
as seen with the nose phantom).
Figure 17.17 Calculated dose for a 16-MeV 8 × 8 cm2 field at 100-cm SSD incident on a nose
phantom with customized bolus, (A) without heterogeneity corrections and (B) with heterogeneity
corrections. The monitor units were set to deliver 100% dose for a flat phantom at the same SSD.
Figure 17.17A shows the dose distribution for the same nose phantom
as shown in Figure 17.13A, again with CT density set to unity. The bolus
was shaped to conform to the shape of the nose and provide a flat
surface for the electron beam using algorithms developed by Low et al.
(24). In years past, similar results were achieved by molding beeswax (or
similar material) around a positive impression of the patient. There are
some residual hot spots remaining (<103%) as a result of imperfect
construction of the bolus material in the planning system, but the dose
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distribution for the 8 × 8 cm2 field is almost restored to what would be
expected for a flat phantom.
Unfortunately, the dose distribution in the phantom is changed
significantly as a result of internal heterogeneities, as shown in Figure
17.17B, and it is obvious that a simple flat bolus may be inadequate if
internal heterogeneities are significant. The dose distribution in the
patient can be customized by changing the thickness of the bolus as a
function of position in the field. Because of complex interplay between
surface irregularities and internal heterogeneities, doing this by trial and
error would be difficult at best. That was the motivation for Low et al.’s
bolus design investigations (24), to provide a framework to
systematically design an electron bolus to conformally treat the target
volume and/or spare distal normal tissues. This technology has been
further developed (25–27) and is now commercially available
(BolusECT, .decimal, Inc., Sanford, FL, http://dotdecimal.com/).
Clinically, the technology has been used in the treatment of paraspinal
muscles (28), post-mastectomy chest wall (29), and head-and-neck target
volumes (30). When using this technology, there is generally a tradeoff
between target conformality and dose homogeneity. One way to
decrease the impact of this tradeoff (improved dose homogeneity for the
same conformality, or improved conformality for the same homogeneity)
is to modulate the intensity of the electron beam within the field (31),
although technology for intensity modulation of electron beams is not
readily available.
Calibration and Monitor Units

In radiation therapy, calibration of the linear accelerator refers to the
establishment of a relationship between the measured dose under
reference conditions and the monitor units set on the treatment machine.
The calibration protocol currently used in the United States and Canada
is TG-51 (32), while the very similar TRS-398 (33) is used almost
everywhere else. While the calibration protocols are quite specific when
describing how the measurements are to be performed, the measured
dose at the reference depth (in the protocol) is usually transferred to the
R100 depth using the clinical percentage depth dose. A typical calibration
statement for an electron beam might be 1 cGy per MU at a depth of
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R100 for a 10 × 10 cm2 field size in a 10 × 10 cm2 applicator at an SSD
of 100 cm. The calibration and reference conditions are entered into the
TPS by the physicist as part of the commissioning process. Other data,
such as dose rates for other applicators, dose rates for different inserts,
percent depth doses, and virtual and/or effective SSDs for each energy
may also be needed. The physicist needs to consult the documentation
for the TPS to determine the required input data so that it can be
measured at the time of machine commissioning.
Because surface irregularities and internal heterogeneities have a very
significant effect on the dose distribution, the use of heterogeneity
corrections in the TPS is highly recommended. Ideally, the treatment
planner should be able to create the treatment plan to cover the target
volume and have the TPS provide the monitor units required to deliver
the treatment. If the planning system is capable of doing this, it is good
practice to have an independent second check of the monitor units using
either a hand calculation or another computer program (13,15). If the
planning system is not able to directly provide monitor units, the
physicist will need to create a process to convert the beam weight in the
TPS to monitor units that can be delivered on the treatment machine.
The physicist will also need to determine the range of treatment over
which the planning system provides adequate clinical accuracy (e.g.,
±3%) by comparing to measured commissioning data.
The ability of the TPS to adequately handle surface irregularities and
internal heterogeneities is determined more by the algorithm
implementation, although the quality of the input data may also affect
the results. Shiu et al. (34) made an attempt to provide a standard set of
measured data to test electron dose calculations, but there were some
small but significant inconsistencies in the data due to measurements
being carried out at different institutions on different machines. Boyd et
al. (35) repeated the measurements on a single linear accelerator and
validated the results using EGS4 Monte Carlo calculations (36), creating
a much more consistent and reliable dataset. The data is available from
the authors and has been used to validate the accuracy of the pencil-
beam redefinition algorithm (37) and the Varian Eclipse electron Monte
Carlo algorithm (10).
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BASIC TREATMENT PLANNING
Electron Dose Prescription
Recommendations for prescribing and reporting electron radiotherapy
can be found in ICRU Report 71 (38), and the recommendations of the
AAPM (5,6) are consistent with those recommendations. The basic
concepts of gross tumor volume (GTV), clinical target volume (CTV), and
planning target volume (PTV) that are used for x-ray therapy and
recommended by ICRU Reports 50 and 62 (39,40) can be used for
electron beam treatment planning. ICRU Report 71 recommends that
dose be reported for a reference condition of the same beam incident on
a homogeneous phantom. In general, this reference point should be in
the center of the target volume; if not, then the reference dose in the
center of the target volume should also be reported. In addition, the
maximum and minimum dose to the PTV should be reported, as well as
doses to organs at risk and/or dose–volume histograms.
Within the TPS, the treatment planner must enter a dose prescription
for the electron treatment plan. While the precise details of how this is
done in every TPS are beyond the scope of this work, there are a couple
of general methods for accomplishing this task. Before the use of TPS for
electron beams became ubiquitous, a common old-style prescription
would be something like a dose to 90% of the central-axis maximum
dose. It is assumed that the central-axis maximum dose is in a water
phantom at the same SSD as the patient’s plan. If the beam weight in the
TPS is directly related to the maximum dose in a water phantom for that
beam at the same SSD, then it is possible to calculate the beam weight
for the given prescription. However, it is more likely that the monitor
units need to be calculated first and entered into the planning system. In
other words, the second check is setting the beam weight, which is not
the most desirable situation.
A more modern approach is to adjust the beam weight (or monitor
units) until the prescription isodose line covers the target volume
appropriately with the maximum dose inside the target volume
approximately 10% higher than the prescription dose. In this case, the
secondary monitor unit calculation or hand calculation is a true
independent check. However, it is not entirely clear what dose should be
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entered into the second-check calculation. As described above, the dose
in the electron beam is greatly affected by the patient surface and
internal heterogeneities. There is no easy accurate heterogeneity correct
method available for electron beams, so a method to estimate the dose
for that same beam incident on a flat water phantom is needed. Similar
to what is commonly done for IMRT verification, the treatment plan can
be cast onto a water phantom to extract the desired dose. This removes
the patient surface and internal heterogeneity effects, allowing the
central-axis maximum dose to be obtained more reliably.
En-face Beams
The simplest situation to deal with is treatment planning for a single
field (e.g., scar boost for a breast treatment). We’re dealing with target
volumes that are small enough to be treated with a single field cutout in
a single applicator. All of the effects that were described above can come
into play, which is why so much effort was put into describing how
electron beams behave.
The first steps are to choose the energy, field size, and beam direction
to use. The energy is primarily determined by the maximum depth of the
target, with a good first approximation for the energy (in MeV) being 3.3
times the maximum depth of the target (in cm). The beam direction
should be chosen to be approximately perpendicular to the skin surface
that is nearest the target volume, because this maximizes the penetration
of the electrons relative to the skin surface.
One strategy for choosing the SSD is to make it as close as possible to
the skin surface to minimize the spreading of the electrons in the air gap
between the final collimation and the skin surface. This allows the
penumbra to be as sharp as possible, for sparing normal tissues lateral to
the target volume. However, there is a risk to aggressively choosing a
shorter SSD since potential collisions of the bulky applicator with the
patient are not easily visualized in most TPSs. Therefore, another
common strategy is to choose a safe SSD (e.g., 110 cm) that is very
unlikely to cause a collision problem. The former strategy (choosing a
shorter SSD) can give slightly better lateral penumbra at the expense of
having to occasionally replan the patient treatment if the shorter SSD
can’t be realized on the treatment machine. Proponents of the latter
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strategy would also argue that using the same SSD for all electron beams
could potentially reduce setup errors that could occur if the norm was to
use a different SSD for each patient. The author favors using a standard
SSD that is slightly shorter than the safe SSD. Evaluating the plan for
potential collision issues should be a standard part of the treatment-
planning process, and the SSD could be extended for potential problem
cases.
Once the beam direction, SSD, and energy are chosen, the beam
aperture needs to be created in the TPS. As described above, the
penumbra of the electron beam necessitates that there is a margin
between the PTV and the beam portal, and a margin of 1 cm is a good
starting point. This is very much like treatment planning for x-ray
beams. The exact details of how these steps are accomplished differs
from one system to another, so a step-by-step description of the process
will not be given and it will be assumed that the treatment planner is
familiar with the tools available for positioning beams, defining beam
properties, and creating beam apertures. After setting the beam
parameters, the dose can be calculated and the beam weight set to get
(or verify) the desired coverage.
The next task is for the treatment planner and/or physician to
evaluate the dose distribution to determine if the goals of the treatment
plan have been met. For example, the magnitude of hot and cold spots
due to the external patient contour and internal heterogeneities should
be compared to the planning objectives, and the conformality of the
prescription isodose line should be compared to the PTV. It may be
necessary to add a bolus to the patient surface, as described above, to
make the dose more homogeneous and/or make the dose coverage more
conformal. Field-size effects may have reduced the depth dose of the
electron beam and the electron beam energy may need to be increased.
An understanding of all of the effects described above will allow the
planner to determine if the dose calculation results make sense and what
can be done to improve the dose distribution to meet the treatment-
planning goals.
Skin Collimation
In Figure 17.3, it was shown that the therapeutic portion of the beam
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can be on the order of 1 cm smaller than the field aperture, and the
precise relationship between the therapeutic treatment volume and the
total irradiated volume depends on the energy of the beam and the SSD.
When the target is very small (e.g., 2 to 3 cm), the field size may need to
be double the size of the target or greater to be able to give a uniform
dose to the target. This means that the volume of significant dose
extends well beyond the target. If a critical structure is located close
(laterally) to the target volume, it is then very difficult to irradiate the
target volume while sparing the critical structure.
For a given energy, the width of the penumbra depends on the
distance between the final collimation and the patient surface, and the
amount of scattering inside the patient. There isn’t a lot that can be done
about patient scattering. However, the component of the penumbra due
to the collimator distance can be reduced if the patient can be moved
closer to the final collimation. Unfortunately, that is often not possible
and one still has to consider setup uncertainty and its contribution to
being able to spare the critical structure. Collimation can also be placed
on the skin surface, in the form of lead sheets. The required thickness of
lead was given by AAPM TG-25 (see Field Shaping section above) and
the adequacy of the lead shielding should be verified before the skin
collimation is used in the clinic. Lead shielding can be placed over a
portion of the treated area, to shield a critical structure, or around the
entire treated area to provide a more conformal treatment. The width of
the lead shielding needs to be greater than the width of the penumbra.
The projection of the aperture edge needs to be placed such that the
edge of the lead is at approximately the 90% point on the beam profile if
the lead were not there. The width of the lead needs to extend far
enough to block the entire penumbra, extending out to the 5% level on
the beam profile without the lead (for example).
Figure 17.18 illustrates some of the issues involved when using skin
collimation. In Figure 17.18A, a high-density material is placed on the
skin surface with a 4 × 4 cm2 opening. It is relatively easy to see that
using skin collimation in this way can give a nice sharp penumbra, and
because placing it on the skin can be very reproducible, skin collimation
can be used to shield structures that are quite close to the target region.
Figure 17.18B shows the dose distribution for the 6 × 6 cm2 electron
field without the skin collimation. Note that the width of the 90% dose
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region is approximately the same size as the opening of the skin
collimation. This is required so that the dose can be relatively uniform in
the volume exposed by the skin collimation. The lateral extent of the
dose distribution without the skin collimation gives you an idea of how
far the shielding needs to be extended. The dashed horizontal line is at
the depth of R100, and it is readily apparent that the depth penetration of
the beam with skin collimation is less than the beam without skin
collimation. It is also apparent that electrons scatter from the skin
collimation and contribute to hot spots near the edge of the skin
collimation. Because lateral scatter is the dominant factor determining
the depth dose characteristics, the depth dose for the beam with skin
collimation is determined by the size of the opening. The dose output,
however, is determined by the size of the applicator insert. To illustrate
this point, the same monitor units were used with and without skin
collimation.
Figure 17.18 Calculated dose for a 9-MeV 6 × 6 cm2 field at 110-cm SSD incident on a water
phantom (A) with and (B) without skin collimation. The monitor units for each beam are the same
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and set to deliver 100% at the depth of maximum dose for the beam without skin collimation. The
skin collimation was approximated by a bolus of density 5 g cm−3, and has an opening of 4 × 4
cm2 on the skin surface. The lower panels show the calculated dose for a 9-MeV beam with (C) a
field size of 4 × 4 cm2 on the skin surface, and (D) a field size of 4.6 × 4.6 cm2 on the skin
surface. The monitor units for the beams in the lower panels were set to deliver 100% at the depth
of maximum dose for the blocked beam.
For comparison, Figure 17.18C shows the dose distribution if we used

just an applicator insert that projected to 4 × 4 cm2 on the skin surface
(without skin collimation). The first observation about this dose
distribution is that the size of the therapeutic region is significantly
smaller than the dose distribution with skin collimation. In Figure
17.18D, the insert size was increased to 4.6 × 4.6 cm2 to increase the
size of the therapeutic region. In both of these cases, the therapeutic
dose coverage is arguably inferior to the case with skin collimation, and
the total volume of irradiated tissue is larger.
Currently, there are no commercially available TPSs that support skin
collimation, which means that planning these treatments is not easy.
Assuming that you have a way to fabricate the skin collimation in the
first place, the planner will have to figure out a way to enter the skin
collimation into the TPS, and then design the electron cutout to place
the 90% point (or greater) of the beam profile at the edge of the lead
collimation, keeping in mind that the outer edge of the lead collimation
needs to block the rest of the penumbra. All of these margins depend on
the beam energy and SSD, so if it is desired to do this on a regular basis,
it might be worthwhile to tabulate some of these values in advance to
assist in planning. Obviously, some tools available in the TPS could be
potentially very useful, but we’ll just have to keep our hopes up.
Electron–Electron Field Junctions

Electron field sizes using standard applicators are generally limited to 25
× 25 cm2 by the size of the largest applicator. Rotating the collimator
by 45° will allow for a slightly longer field that can be useful for treating
the craniospinal axis (41). Even then, it may be necessary to join
multiple electron fields together to treat the entire spinal axis. There
may also be scenarios where it may be desirable to treat different
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portions of the field with different energies because of the target depth
differences. The scattering of the electrons complicates the dosimetry of
the field junction.
Figure 17.19A shows the resulting dose distribution for two adjacent
12-MeV 10 × 10 cm2 fields where the field junction is at the phantom
surface, and it is obvious that this beam arrangement would not be
desirable for a real patient case. The hot spot due to the field overlap at
depth is greater than 25% of the delivered dose for each beam. This
problem is not unique to electron beams however, and a similar hot spot
(different magnitude) would be seen if x-ray beams were used instead.
Figure 17.19B shows the same fields, but with a slightly larger
separation between the beams to create a smooth junction at the R100
depth. Unfortunately, it is pretty obvious that the dose near the surface
is significantly colder than each electron beam, and if there were target
tissue at that location, the dose would be inadequate.
A better geometry for field junctions (photon or electron) is to
maintain a common source position for the fields and match the field
edges at the junction. The simplest case is shown in Figure 17.20A, with
two electron beams with half-beam blocks. Since the block is the only
thing that is changed and the energy is the same, the dose in the
junction is quite smooth. Another way to junction the fields is to angle
the fields away from each other, as shown in Figure 17.20B, where the
beams have been rotated by 2.9° such that the edges of the beams, as
drawn by the TPS, are aligned with each other. Unfortunately, the field
junction hot spot is almost 109%, so it is obvious that aligning the TPS
field edge is not the correct way to do this. In this case, the TPS draws
the field edge as if the source of the electrons was at the same position
as the photon (or light-field) source. However, the actual source of the
electron beam for this particular linear accelerator is approximately 90
cm from isocenter. Allowing for this difference in source position, the
angle of the beam away from vertical and the separation of the beams
both need to be increased slightly (3.2°) to create a smoother junction,
as shown in Figure 17.20C. In this case, the magnitude of the hot spot is
less than 103%, so this is quite close to aligning the actual edges of the
electron beams. While not shown here, the virtual source position used
by the dose calculation is approximately 82 cm from isocenter, so the
ideal beam angulation is a little more than shown in Figure 17.20C.
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Figure 17.19 Calculated dose for two adjacent 12-MeV 10 × 10 cm2 fields at 100-cm SSD
incident on a water phantom. The monitor units for each field were set to deliver 100% dose at
R100 for each field, and the central axes of the fields are separated by (A) 10 cm to junction the
fields on the phantom surface, and (B) 10.4 cm to junction the fields at the depth of R100. Note
that the dose scale for the colorwash is not the same in each panel.
To further complicate matters, it is not uncommon for the energies of

the electron beams to be different. Figure 17.20D shows the dose
distribution for a junction between a 12-MeV and 16-MeV electron
beam, using the same beam parameters as Figure 17.20C. Because
penumbra of the two beams is no longer matched, even though the beam
edges are matched, there is a hot spot on the higher-energy side that is
probably larger than we would like for a patient treatment.
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Figure 17.20 Calculated dose distributions for electron beam field junctions incident on a water
phantom at 100-cm SSD. (A) Two adjacent 12-MeV 10 × 5 cm2 fields, with monitor set to deliver
100% dose at R100 for a 10 × 10 cm2 field. (B) Two adjacent 12-MeV 10 × 10 cm2 fields, with
monitor set to deliver 100% dose at R100. The beam angles are 2.9° from vertical and the central
axes of the fields on the phantom surface are separated by 9.99 cm to align the field edges (as
drawn by the TPS) with each other. (C) Two adjacent 12-MeV 10 × 10 cm2 fields, with monitor set
to deliver 100% dose at R100. The beam angles are 3.2° from vertical and the central axes of the
fields are separated by 10.04 cm. (D) Adjacent 12-MeV and 16-MeV 10 × 10 cm2 fields, with
monitor set to deliver 100% dose at R100. The beam angles are 3.2° from vertical and the central
axes of the fields are separated by 10.04 cm.
A fairly standard solution for this problem is to feather the junction, as

shown in Figure 17.21A. In this case, we started by aligning the beams
vertically as shown in Figure 17.19B (matching field edges at R100), and
moving the junction edge by ±1 cm. The monitor units for each original
field are equally divided into the sub-fields, and the resulting junction is
quite smooth at all depths. There are still three fairly small low-dose
regions near the skin surface. This could be improved further by starting
with the beam arrangement with the virtual source at the same position
(see Fig. 17.20C), but depending on the dosimetric requirements, the
simpler method shown in Figure 17.21A is probably adequate. In many
cases, using an extended SSD (e.g., 110 cm) is fairly common, and Figure
17.21B shows that this relatively simple approach works quite well even
if the energies of the adjacent beams are not the same.
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At this point it would be useful to review why this method works as
well as it does. Figure 17.22 shows a dose profile at a depth of 3 cm for
the junction as shown in Figure 17.21B. For each beam, the penumbra of
the feathered edge is much wider than the nonfeathered edge and the
width of the feathered penumbra is more dependent on the amount of
feathering (±1 cm) than the penumbra width of the electron beam. With
a wide penumbra, the summed dose profile does not change significantly
for small changes in the junction position, which also explains why the
junction is relatively smooth at all depths. A more practical problem is
the number of cutouts and the sequence of treatment. One choice is to
treat each sub-field every day, dividing the monitor units equally as
shown in the figure. However, this involves several trips into the
treatment room to change the field cutout, which is inconvenient. It is
also possible to change the cutouts once per week (for example), which
reduces trips into the treatment room. However, there will be a cold spot
near the patient surface on a daily basis. If the cold spot was a concern,
the adjacent field could be matched on the patient surface before
feathering the junction, or perhaps be matched at an intermediate depth.
It would obviously be nice to have a device and algorithm to automate
the edge feathering such as that proposed by Eley et al. (42).
Photon–Electron Field Junctions

It is also possible to have a junction between an electron field and a
photon field, an example of which would be the junction between the
whole-brain photon fields and the spinal electron field for the
craniospinal technique described by Maor et al. (41). A more common
example is the internal mammary chain (IMC) electron field commonly
used with tangent photon fields for treating chest wall or whole breast.
The traditional wisdom about the IMC electron field is that it should be
angled a few degrees away from the anterior tangent field because of the
bowing of the electron isodose lines. However, it should be angled away
from the tangent because, even if the penumbra of the electron field was
the same as the photon field, the angle is needed to match the
divergence of the electron beam to the posterior edge of the tangent
beams.
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Figure 17.21 Calculated dose for two adjacent feathered 10 × 10 cm2 fields (15 × 15 cm2
applicator) incident on a water phantom. Each field has two additional sub-fields with the junction
edge moved by 1 cm. The monitor units for each field are equally divided between the sub-fields,
and the total number of monitor units for each field-set was set to deliver 100% dose at R100 for a
single field. (A) Feathered field junction for 12-MeV fields at 100-cm SSD, where the central axes
of the fields are separated by 10.4 cm to junction the fields at the depth of R100. (B) Feathered
field junction for 12-MeV and 16-MeV fields at 110-cm SSD, where the central axes of the fields
are separated by 11.4 cm to junction the fields at the depth of 3 cm.
The difference in penumbra between the photon and electron beams

makes a good junction very difficult to achieve. Figure 17.23 shows the
result of blindly applying the feathering technique that worked for
electron–electron beam junctions. The resulting dose across the junction
is not very homogeneous, and clearly another approach is needed. Figure
17.24 shows a lateral dose profile at a depth of 2.8 cm for this junction,
and it is a little clearer why this naive approach doesn’t work as well as
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it did for the electron–electron junction. Feathering the junction for the
electron beams produces a penumbra that is broad and fairly linear,
while feathering the junction of the photon beam produces a stepped
profile. While the hot and cold spots are reduced compared to a
nonfeathered junction, it is clear that this is not an optimal solution.
Figure 17.22 Calculated lateral dose profile for two adjacent feathered 10 × 10 cm2 fields at 110-
cm SSD incident on a water phantom (16-MeV on patient right, 12-MeV on patient left) at a depth
of 3 cm (see Figure 17.21B).
The basic field junction problem boils down to matching the field
edges and the penumbral profile. Because the photon beam has a very
sharp penumbra relative to the electron beam, the amount of feathering
(smoothing) required to match the penumbral shape is greater for the
photon beam. Figure 17.25 shows one possible approach where the
penumbra of the photon beam is feathered to try to match the penumbra
of the single electron beam (without feathering). While not as smooth as
the electron–electron junction, hot and cold spots in the junction are less
than 10%. Further improvements could be made by feathering the
electron field edge, and more feathering of the photon field edge to
match that. In principle, IMRT optimization could be used to optimize
the photon fluence to more accurately match the electron field edge with
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much less trial and error in planning.
Figure 17.23 Calculated dose for two adjacent 10 × 10 cm2 fields at 110-cm SSD incident on a
water phantom (12-MeV electrons on patient right, 6 MV photons on patient left). Each field has
two additional sub-fields with the junction edge moved by 1 cm. The monitor units for each field
were set to deliver 100% dose at a depth of 2.8 cm, and the monitor units for each field were
equally divided between the sub-fields.
Figure 17.24 Calculated lateral dose profile for two adjacent feathered 10 × 10 cm2 fields at 110-
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cm SSD incident on a water phantom (12-MeV electrons on patient right, 6 MV photons on patient
left) at a depth of 2.8 cm (see Fig. 17.23).
Figure 17.25 Calculated dose for two adjacent 10 × 10 cm2 fields at 110-cm SSD incident on a
water phantom (12-MeV electrons on patient right, 6 MV photons on patient left). The photon field
has four additional sub-fields with the junction edge moved by 0.4 cm and 0.9 cm. The monitor
units for each field were set to deliver 100% dose at a depth of 2.8 cm, and the monitor units for
each field were equally divided between the sub-fields.
Energy Mixing
There are usually five to six choices for electron beam energy on a
modern medical linear accelerator, and the typical energy range is 6 to
20 MeV. This gives a maximum therapeutic depth of approximately 6 cm
and the spacing between beams is approximately 1 cm in therapeutic
depth, as shown in Figure 17.1. There are a couple of ways to deal with
target depths that are between the available therapeutic depths. The first
method is to add bolus to the patient, either a constant thickness bolus
such as superflab, or a commercially available customized electron bolus
(BolusECT, .decimal, Inc., Sanford, FL, http://dotdecimal.com/). A
second method is to use a weighted mixture of two energies to get the
desired depth coverage. Advantages of this technique are slightly lower
surface dose (if that is desired) and not having to deal with a treatment
accessory.
Mixing with Photon Beams
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Given a situation where an electron beam provides adequate depth
penetration but too much skin dose, combining an x-ray beam with an
electron beam from the same direction provides a depth dose
distribution that is similar to an electron beam with lower surface dose,
transitioning to an x-ray depth dose after the electrons range out. Where
this transition occurs depends on the electron and x-ray energies, and
the beam weights. Modern TPSs should give a reasonable representation
of the dose distribution for this situation, except for perhaps the
immediate surface, which tends to be problematic for most TPSs. For a
more accurate surface dose, measured surface doses are probably
required.
MONITOR UNIT VERIFICATION

As mentioned above, it is recommended that the monitor units from the
TPS be verified using an independent system, and most commonly this is
done using a separate computer program. The current AAPM
recommendations are contained in the TG-71 report (13) and the
formalism used by the monitor unit verification system should be
compatible with current recommendations. There are several different
ways to accomplish this and it is beyond the scope of this chapter to
provide an overview.
SPECIAL TECHNIQUES
Total Skin Electron Irradiation
Total skin electron irradiation (TSEI) was developed to treat the entire
skin surface to a homogeneous dose (generally within ±10%) to treat
mycosis fungoides, or cutaneous T-cell lymphoma. Once the treatment
technique has been designed, there is generally very little treatment
planning to be done. AAPM Report 23 (43) describes the technique and
dosimetry for this technique. Antolak and Hogstrom (44) provided more
details on how TSEI beams can be designed for standard techniques, and
the dosimetry that can be expected for such a technique was described
by Antolak et al. (45). For patients that are unable to stand, a lying-on-
the-floor technique, such as that described by Deufel and Antolak, can be
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considered.
Electron Arc Therapy

As pointed out in the AAPM TG-70 report (6), commercial TPSs do not
implement the tools necessary to be able to do electron arc therapy. In
particular, while some treatment machines are capable of delivering the
treatment fields, there are no commercial TPSs that can calculate the
dose distribution for those beams, or deal appropriately with the skin
collimation that is necessary for this technique. As such, the reader is
referred to the AAPM report if they are interested in this historic
technique.
Total Limb Irradiation

Wooden et al. (46) described a technique for treating the entire
circumference of a limb. In their case, the patient had Kaposi sarcoma,
although other indications for such a technique might include melanoma
or lymphoma. In some ways, the treatment goal is similar to electron arc
therapy in that the target volume is 2 cm or less around the
circumference of an extremity. However, the technique that they
described uses standard electron fields with a virtual isocenter in the
center of the limb, and six to eight fields around the limb. Similar to
TSEI, the fields should be larger than the limb so that the electron beams
can wrap around the limb and each point around the limb is irradiated
by multiple beams. Wooden et al. described a methodology where the
monitor units could be determined from the prescribed dose and output
factor of the open field using a body factor, in their case 2.55, although
the exact value will depend on the electron energy and the delivery
equipment. Using a modern TPS, with the capability to accurately
determine monitor units to deliver the required dose, planning becomes
more straightforward, although it might be useful to do some sort of in
vivo dosimetry to verify that the dose delivery is accurate. Using the
TPS, it would also be possible to perhaps use different energies from
different beam angles to vary the depth of the therapeutic dose region.
The most significant problem when delivering this type of treatment is
the setup and immobilization of the patient. The extremity needs to be
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extended away from the body so that beams can be placed around the
extremity. The immobilization can make it difficult or impossible to get
the patient into the bore of the CT scanner to get images for treatment
planning, so it might be necessary to resort to alternative methods of
obtaining or estimating the patient contour for treatment planning,
which will not be discussed here. To see how the immobilization might
work for such a technique, the reader is referred to the original
publication or to the AAPM TG-70 report (6).
THE FUTURE
After intensity-modulated techniques became available for high-energy
x-ray beams, a natural progression for electron beams was the
development of modulated electron radiation therapy (MERT) by several
investigators (47–50). Intensity modulation can be done with the x-ray
MLC (51–53) or an add-on electron MLC (42,54,55). The former device
is available on virtually every conventional linear accelerator in use
today, while the latter device is only available as a research tool.
Seuntjens et al. are developing a few leaf electron collimator (FLEC) as a
simpler device that is capable of some degree of intensity modulation
(56–58). This device is less flexible than a dedicated electron MLC, but
has the advantage of being lighter and simpler, which could make it
easier to integrate with the treatment machine. Unfortunately, there are
no commercial TPSs that are currently able to deal with such devices, so
while promising, it will require many more years before we start seeing
MERT in the clinic.
Despite the fact that electron beam radiotherapy has been around for
many decades, its use in the clinic has been declining over the past
several years. Competing technologies include conventional IMRT
(including VMAT), helical tomotherapy, proton therapy, and HDR
brachytherapy, and many of these technologies have seen major
improvements in the last couple of decades. Delivery technology for
electron beams is much the same as it was decades ago and has not seen
the same kind of development. In order to be able to more fully utilize
the unique advantages that electron beam radiotherapy offers, we need
to convince commercial partners to make improvements to both electron
delivery and planning systems.
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KEY POINTS
• Megavoltage electron beams are useful for treating target volumes
within a few centimeters of the patient surface.
• Understanding scatter effects, in-air and in-patient, is key to
understanding the properties of electron beam dose distributions.
• Surface irregularities and heterogeneities scatter and redistribute
electrons, giving rise to hot and cold spots in the dose distribution.
• Improved treatment-planning tools are needed to increase the
clinical utility of electron beam radiotherapy, and treatment-planning
vendors need to be made aware of this need.
• Improved electron delivery tools (e.g., electron MLC, bolus ECT)
are needed to allow electron beam radiotherapy to contribute to
more effective delivery of conformal radiation therapy, and
treatment machine vendors need to be made aware of this need.
QUESTIONS
1. For an electron beam incident on a chest wall with rib
heterogeneities, what is the approximate magnitude of the hot
spots caused by the ribs?
A. 3%
B. 10%
C. 15%
D. 20%
2. A 9-MeV electron beam (Rp = 4.5 cm) is incident on a chest wall
of thickness 2 cm. Assuming a lung density of 0.33, what is the
total range of the electron beam (from the skin surface)?
A. 2.5 cm
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B. 5.0 cm
C. 7.5 cm
D. 10.0 cm
3. What is the thickness of lead required for skin collimation in a
16-MeV electron beam?
A. 3 mm
B. 5 mm
C. 7 mm
D. 9 mm
E. 11 mm
4. An electron beam is incident on the patient surface at an angle of
30° relative to perpendicular incidence. Compared to the same
beam delivered at perpendicular incidence, the therapeutic depth
of the electron beam is
A. larger
B. smaller
C. the same
D. not enough information
5. As the air gap between the final collimation and the patient
increases, the output of an electron beam (dose per MU)
decreases
A. and follows the inverse square law
B. more slowly than the inverse square law
C. more rapidly than the inverse square law
ANSWERS
1. A
2. C
3. D
4. B
5. C
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REFERENCES
1. Hogstrom KR, Almond PR. Review of electron beam therapy physics.
Phys Med Biol. 2006;51(13):R455–R489.
2. Slater JM. From x-rays to ion beams: a short history of radiation
therapy. In: Linz U, ed. Ion Beam Therapy. Springer-Verlag Berlin
Heidelberg; 2012:3–16.
3. Tapley ND, ed. Clinical Applications of the Electron Beam. New York,
NY: John Wiley & Sons, Inc.; 1976.
4. Tapley Nd. Radiation therapy with the electron beam. Semin Oncol.
1981;8(1):49–58.
5. Khan FM, Doppke KP, Hogstrom KR, et al. Clinical electron-beam
dosimetry: report of AAPM Radiation Therapy Committee Task
Group No. 25. Med Phys. 1991;18(1):73–109.
6. Gerbi BJ, Antolak JA, Deibel FC, et al. Recommendations for clinical
electron beam dosimetry: supplement to the recommendations of
Task Group 25. Med Phys. 2009;36(7):3239–3279.
7. Gerbi BJ, Antolak JA, Deibel FC, Followill DS, Herman MG, Higgins
PD, et al. Erratum: “Recommendations for clinical electron beam
dosimetry: Supplement to the recommendations of Task Group 25”
[Med. Phys. 36, 3239–3279 (2009)]. Med Phys. 2011;38(1):548.
8. Freeman T. Electrons: are they underused in radiotherapy? IOP;
2013 Available from:
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9. Klevenhagen SC, Lambert GD, Arbabi A. Backscattering in electron
beam therapy for energies between 3 and 35 MeV. Phys Med Biol.
1982;27(3):363–373.
10. Popple RA, Weinberg R, Antolak JA, et al. Comprehensive
evaluation of a commercial macro Monte Carlo electron dose
calculation implementation using a standard verification data set.
Med Phys. 2006;33(6):1540–1551.
11. Khan FM, Higgins PD, Gerbi BJ, et al. Calculation of depth dose and
dose per monitor unit for irregularly shaped electron fields. Phys
Med Biol. 1998;43(10):2741–2754.
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12. Shiu AS, Tung SS, Nyerick CE, et al. Comprehensive analysis of
electron beam central axis dose for a radiotherapy linear
accelerator. Med Phys. 1994;21(4):559–566.
13. Gibbons JP, Antolak JA, Followill DS, et al. Monitor unit
calculations for external photon and electron beams: Report of the
AAPM Therapy Physics Committee Task Group No. 71. Med Phys.
2014;41(3):031501.
14. Fraass B, Doppke K, Hunt M, et al. American Association of
Physicists in Medicine Radiation Therapy Committee Task Group
53: quality assurance for clinical radiotherapy treatment planning.
Med Phys. 1998;25(10):1773–1829.
15. Kutcher GJ, Coia L, Gillin M, et al. Comprehensive QA for radiation
oncology: report of AAPM Radiation Therapy Committee Task
Group 40. Med Phys. 1994;21(4):581–618.
calculations. Phys Med Biol. 1981;26(3):445–459.
17. Khan FZ. The Physics of Radiation Therapy. Baltimore, MD: Williams
& Wilkins; 1984:456.
18. Hogstrom KR, Steadham RE, Wong PF, et al. Monitor unit
calculations for electron beams. In: Gibbons JP, ed. Monitor Unit
Calculations for External Photon and Electron Beams. Middleton, WI:
Advanced Medical Publishing, Inc.; 2000:113–125.
19. Hogstrom KR, Steadham RE. Electron beam dose computation. In:
Palta J, Mackie TR, eds. Teletherapy: Present and Future. Madison,
WI: Advanced Medical Publishing; 1996:137–174.
20. Mills MD, Hogstrom KR, Fields RS. Determination of electron beam
output factors for a 20-MeV linear accelerator. Med Phys.
1985;12(4):473–476.
21. Khan FM, Higgins PD. Calculation of depth dose and dose per
monitor unit for irregularly shaped electron fields: an addendum.
Phys Med Biol. 1999;44(6):N77–80.
22. Khan FM, Higgins PD. Field equivalence for clinical electron beams.
Phys Med Biol. 2001;46(1):N9–N14.
23. Higgins PD, Gerbi BJ, Khan FM. Application of measured pencil
beam parameters for electron beam model evaluation. Med Phys.
2003;30(4):514–520.
24. Low DA, Starkschall G, Bujnowski SW, et al. Electron bolus design
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for radiotherapy treatment planning: bolus design algorithms. Med
Phys. 1992;19(1):115–124.
25. Antolak JA, Starkschall G, Bawiec ER Jr., et al. Clinical
implementation of customized electron bolus. Med Phys.
1994;21(6):901.
26. Boyd R, Hogstrom KR, Antolak JA, et al. Custom electron bolus
treatment planning with skin collimation using the pencil-beam
redefinition algorithm. Int J Radiat Oncol Biol Phys. 2003;57(2
Suppl):S425.
27. Starkschall G, Antolak JA, Hogstrom KR, eds. Electron-beam bolus
for 3-D conformal radiation therapy. 3D Radiation Treatment
Planning and Conformal Therapy Symposium. St. Louis, MO: Medical
Physics Publishing, Madison, WI; 1993, 1995.
28. Low DA, Starkschall G, Sherman NE, et al. Computer-aided design
and fabrication of an electron bolus for treatment of the paraspinal
muscles. Int J Radiat Oncol Biol Phys. 1995;33(5):1127–1138.
29. Perkins GH, McNeese MD, Antolak JA, et al. A custom three-
dimensional electron bolus technique for optimization of
postmastectomy irradiation. Int J Radiat Oncol Biol Phys.
2001;51(4):1142–1151.
30. Kudchadker R, Antolak JA, Morrison WH, et al. Conformal head and
neck radiotherapy using custom electron bolus. Med Phys.
2002;29(6):1337.
31. Kudchadker R, Hogstrom KR, Antolak JA. Electron conformal
therapy combining bolus and intensity modulation. Med Phys.
2001;28(6):1227–1228.
32. Almond PR, Biggs PJ, Coursey BM, et al. AAPM’s TG-51 protocol for
clinical reference dosimetry of high-energy photon and electron
beams. Med Phys. 1999;26(9):1847–1870.
33. IAEA. Absorbed Dose Determination in External Beam Radiotherapy.
Vienna, Austria: IAEA; December, 2000. Report No.: TRS-398
Contract No.: 398.
34. Shiu AS, Tung S, Hogstrom KR, et al. Verification data for electron
beam dose algorithms. Med Phys. 1992;19(3):623–636.
35. Boyd RA, Hogstrom KR, Antolak JA, et al. A measured data set for
evaluating electron-beam dose algorithms. Med Phys.
2001;28(6):950–958.
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36. Rogers DWO, Faddegon BA, Ding GX, et al. BEAM: a Monte Carlo
code to simulate radiotherapy treatment units. Med Phys.
1995;22(5):503–524.
37. Boyd RA, Hogstrom KR, Starkschall G. Electron pencil-beam
redefinition algorithm dose calculations in the presence of
heterogeneities. Med Phys. 2001;28(10):2096–2104.
38. ICRU. Prescribing, recording and reporting electron beam therapy.
Oxford University Press; June, 2004. Report No.: 71.
39. ICRU. Prescribing, recording, and reporting photon beam therapy.
Bethesda, MD: International Commission on Radiation Units and
Measurements; September 1, 1993. Report No.: 50.
40. ICRU. Prescribing, Recording and Reporting Photon Beam Therapy
(Supplement to ICRU Report 50). Bethesda, MD: International
Commission on Radiation Units and Measurements; 1999. Report
No.: 62.
41. Maor MH, Fields RS, Hogstrom KR, et al. Improving the therapeutic
ratio of craniospinal irradiation in medulloblastoma. Int J Radiat
Oncol Biol Phys. 1985;11(4):687–697.
42. Eley JG, Hogstrom KR, Matthews KL, et al. Potential of discrete
Gaussian edge feathering method for improving abutment dosimetry
in eMLC-delivered segmented-field electron conformal therapy. Med
Phys. 2011;38(12):6610–6622.
43. AAPM. AAPM Report No. 23, Total skin electron therapy: technique
and dosimetry. New York, NY: American Institute of Physics, Inc.;
December, 1988. Report No.: 23.
44. Antolak JA, Hogstrom KR. Multiple scattering theory for total skin
electron beam design. Med Phys. 1998;25(6):851–859.
45. Antolak JA, Cundiff JH, Ha CS. Utilization of thermoluminescent
dosimetry in total skin electron beam radiotherapy of mycosis
fungoides. Int J Radiat Oncol Biol Phys. 1998;40(1):101–108.
46. Wooden KK, Hogstrom KR, Blum P, et al. Whole-limb irradiation of
the lower calf using a six-field electron technique. Med Dosim.
1996;21(4):211–218.
47. Lee MC, Jiang SB, Ma CM. Monte Carlo and experimental
investigations of multileaf collimated electron beams for modulated
electron radiation therapy. Med Phys. 2000;27(12):2708–2718.
48. Ma CM, Pawlicki T, Lee MC, et al. Energy- and intensity-modulated
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electron beams for radiotherapy. Phys Med Biol. 2000;45(8):2293–
2311.
49. Ma CM, Ding M, Li JS, et al. A comparative dosimetric study on
tangential photon beams, IMRT and MERT for breast cancer
treatment. Phys Med Biol. 2003;48(7):909–924.
50. Das SK, Bell M, Marks LB, et al. A preliminary study of the role of
modulated electron beams in intensity modulated radiotherapy,
using automated beam orientation and modality selection. Int J
51. Klein EE, Li Z, Low DA. Feasibility study of multileaf collimated
electrons with a scattering foil based accelerator. Radiother Oncol.
1996;41(2):189–196.
52. Klein EE. Modulated electron beams using multi-segmented
multileaf collimation. Radiother Oncol. 1998;48(3):307–311.
53. Weinberg R, Antolak JA, Hogstrom KR, et al. Electron intensity
modulation with multileaf collimation for mixed-beam partial breast
irradiation. Int J Radiat Oncol Biol Phys. 2008;72(1):S527–S528.
54. Hogstrom KR, Boyd RA, Antolak JA, et al. Dosimetry of a prototype
retractable eMLC for fixed-beam electron therapy. Med Phys.
2004;31(3):443–462.
55. Gauer T, Sokoll J, Cremers F, et al. Characterization of an add-on
multileaf collimator for electron beam therapy. Phys Med Biol.
2008;53(4):1071–1085.
56. Al-Yahya K, Schwartz M, Shenouda G, et al. Energy modulated
electron therapy using a few leaf electron collimator in combination
with IMRT and 3D-CRT: Monte Carlo-based planning and dosimetric
evaluation. Med Phys. 2005;32(9):2976–2986.
57. Al-Yahya K, Verhaegen F, Seuntjens J. Design and dosimetry of a
few leaf electron collimator for energy modulated electron therapy.
Med Phys. 2007;34(12):4782–4791.
58. Connell T, Alexander A, Evans M, et al. An experimental feasibility
study on the use of scattering foil free beams for modulated electron
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18 Proton Beam Therapy
Hanne M. Kooy and Judy A. Adams
INTRODUCTION
Proton beam radiotherapy further advances a central aim of radiation
therapy: significant reduction in healthy tissue dose and, as a corollary,
significant safe increase in malignant tissue dose. Proton beam
radiotherapy is not new and was used as a definitive modality as early as
50 years ago. Its recent emergence as a viable, and even necessary,
technology is a consequence of its historical success in treating otherwise
incurable disease, the present desire for increased conformal radiation
therapy, and the commercial availability of proton beam equipment.
The evolution of proton and photon radiotherapy is diametrically
opposite. Proton radiotherapy was, ab initio, a conformal modality but
only sparsely available; radiotherapy was a therapeutic analog to planar
x-ray imaging and broadly available. Of course, brachytherapy also was,
and is, a local conformal modality but has its own application and is in
equal competition to proton and photon radiotherapy.
Proton radiotherapy from its inception required careful attention to
detail as a consequence of the intrinsic precision afforded by the proton
beam itself even while the supporting technologies were minimal. As a
result, the early adopters of proton beam radiotherapy were
neurosurgeons: Lars Leksell in Stockholm, Sweden and Raymond
Kjellberg in Boston, USA. Neurosurgeons, by training, have an exquisite
understanding of the cranial anatomy as visualized on x-rays, as CT was
not yet available. The early use was in abnormalities visible on those x-
rays such as pituitary and arteriovenous abnormalities. The x-ray
information allowed effective use of the advantageous properties of the
proton beam. Easy access to a proton beam, at the Harvard Cyclotron
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Laboratory at Harvard University, allowed Kjellberg to establish a proton
radiosurgery program that continues to date. Leksell did not have this
convenience and out of necessity looked for alternative conformal
methods, which culminated in the gamma knife.
Treatment of ocular melanomas was another early adopter of proton
beam therapy. Again, the orbital anatomy and the use of x-ray opaque
markers at the target margin provided sufficient information to apply
proton beams.
These early adopters used existing, postnuclear research cyclotrons.
Many of these, at Clatterbridge, UK, for example, were of low energy
and could only be used for ocular targets. A few cyclotrons, those at
Harvard University (USA) and later in Orsay (France), for example, had
sufficiently high energy to treat internal targets. The treatment of those
targets, however, did not commence until the late 1970s when
volumetric imaging with CT was available and the treatment planning
tools for using those images had been developed (1). It is the treatment
of those targets that introduced proton radiotherapy to the general
practice of radiotherapy. Proton radiotherapy, as an intrinsically
conformal modality, introduced many elements of “modern” conformal
radiotherapy: attention to the details of imaging, setup, treatment
planning, and delivery.
CLINICALLY EFFECTIVE PROPERTIES OF THE PROTON

BEAM
The clinical potential of a proton beam was recognized by Robert R.
Wilson, then at the Harvard Cyclotron Laboratory, in his article of 1947
(2), in which the geometric and dosimetric localization properties of a
monoenergetic proton beam were proposed for treating targets inside the
body. The practicalities were in doubt, as available proton beams had
insufficient penetrating energy: the first Harvard Cyclotron, built in
1937, had an energy of 12 MeV equal to 17 mm range! This cyclotron
was moved, by Wilson, to Los Alamos for the Manhattan project in 1943,
which allowed the construction of the second Harvard Cyclotron in 1947
with an initial energy of 90 MeV (6.4-cm range in water) and later
upgraded to 160 MeV (17.7-cm range in water) in 1955. It was another
12 years before Wilson’s vision became a reality (3).
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A proton beam, as any charged particle, loses energy along its track as
a function of the local stopping power. The stopping power, the energy
loss per unit length, increases rapidly as the proton in water slows down
and equals 5.2 MeV/cm at 160 MeV, 12.4 MeV/cm at 50 MeV, and 26.1
MeV/cm at 20 MeV. This rapid increase in energy loss per unit length
results in a very large dose enhancement at the end of the particle track
and results in the characteristic Bragg peak beyond which no dose is
deposited (see Fig. 10.2). The large mass of the proton (938.3 MeV/c2)
results in tracks that deviate little from the initial proton direction, and
thus all protons along the same direction yield Bragg peaks at the same
depth and the overall dose distribution is, in essence, a simple addition
of the dose distribution along a single track. This is in contrast to a beam
of electrons where the small mass of the electron (0.511 MeV/c2) results
in tracks that lose any correlation with the initial direction and as a
consequence the electron Bragg peak is “smeared” throughout the
effective treatment volume and only a distinct distal fall-off remains (see
Fig. 18.1). The intact or pristine Bragg peak characteristic of heavy
charged particles and its large peak to entrance dose ratio offers the
opportunity for localizing dose at a point in a target volume. Thus, a
proton beam has intrinsic three-dimensional (3D) shaping features, in
depth and laterally, compared to the two-dimensional (2D) lateral
controls in a photon beam.
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Figure 18.1 The use of range-compensators requires two steps, smearing and tapering, to
achieve satisfactory target coverage. Smearing considers each point on the range-compensator
and replaces the thickness of that point with the minimum thickness found at other points within a
smearing radius of the point under consideration. This has the effect to “throw” the dose deeper
into the patient (see bottom right compared to bottom left). The middle inset illustrates the
example where the CT represents the unsmeared compensator, while (B) is the compensator if a
shift was to occur. The composite compensator considers positions (CT) and (B). Smearing,
originally, was introduced to compensate for geometric uncertainties by considering the “worst”-
case penetration range within a region. Tapering considers range-compensator gradients along
the aperture edge and applies a smoothing to those gradients to remove scattering artifacts. In
general, support for smearing and tapering is poor within existing treatment planning systems and
requires considerable knowledge on the treatment planner to achieve a satisfactory result.
The depth of the Bragg peak is a function of the initial proton beam
energy and there is a direct correspondence between energy E (in MeV)
and penetration depth or range R (in g/cm2). The terms “energy” and
“range” are interchangeable although the range is more effective in
clinical communication. A consequence of the energy–range relationship
is that the energy loss can be equated to material thickness. Thus,
inserting a material of certain thickness in a proton beam results in a
proportional energy reduction and a known shift downward of the
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range. The proton beam intensity, however, does not change: all
entering protons exit. This is in contrast to a clinical photon beam where
the mean energy is minimally affected while the intensity reduces
exponentially as a function of thickness.
The near-straight tracks of the protons produce a beam whose
penumbral edge is intrinsically sharp. The individual protons undergo
(primarily) many multiple Coulomb scattering events, which result in a
Gaussian-shaped broadening of an initially parallel proton beam. The
Gaussian spread increases with depth and results in a depth-dependent
penumbra (80/20%) (see Fig. 18.2 where the penumbra profile increases
per depth).
The proton beam penumbra is intrinsically sharper compared to a
single photon beam penumbra at depths below ~18 cm (in water). This
single beam penumbra is relevant when one wishes to achieve the
sharpest lateral fall-off of dose between the target and a critical
structure. Thus, proton beam treatments in the head and neck achieve a
sharper lateral fall-off, for example, in a target around the brainstem
compared to a photon (intensity-modulated radiotherapy [IMRT]) beam
treatment. On the other hand, a prostate or other deep-seated target does
not show a penumbral advantage for a proton beam. Of course, other
benefits may still favor the proton beam dosimetry.
In practice, however, it is the composite penumbra of multiple fields
that is of relevance as it determines not only the sharpest achievable
penumbra but also the integral dose “bath” throughout the patient.
Photon beams have no localization ability along depth and “pass”
through the target. Proton beams, in contrast, deposit no dose beyond
the distal edge of the Bragg peak. This simple difference means that a
composite of multiple proton beams will have approximately half the
integral dose of a similarly arranged set of photon beams (see Fig. 18.3).
A single proton field, as the composite of multiple individual dose-
weighted Bragg peaks, can deliver an arbitrary dose distribution to a
target volume. Scattered proton fields, in clinical practice, are shaped to
deliver homogeneous dose to all or part of the target volume. In the case
of partial target coverage, a second field is used to fill-in or “patch” (see
below) the remainder. Thus, a single proton field can achieve the desired
dose description. Such a single proton field can achieve superior dose
shaping by virtue of the lateral penumbra and the distal fall-off that
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spares distal tissues. A single-scattered proton field cannot control the
entrance dose, given the fixed modulation width of a spread-out Bragg
peak (SOBP). An example of such a field is shown in Figure 18.3 in
comparison to an IMRT treatment.
Figure 18.2 The effect of increasing the air gap in a scattered field results in an increase in
penumbra because the projection of the effective source size, on the order of 7 cm in scattered
proton fields, in the patient increases. The penumbra also increases, but much less so, as a
consequence of the scatter in patient as a function of depth (depths of 0, 5.3, and 10.5 cm are
shown for a field of 14-cm range and 8-cm modulation). The initial penumbra at a depth of 0
equals the projected source size only as the proton beam has not yet scattered in the patient. The
inset (top left) shows the penumbra for this field as a function of depth for an air gap of 5 cm.
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Figure 18.3 Treatment plans, intensity-modulated radiotherapy (IMRT) and scattered fields (DS)
for endometrial nodal disease are compared. The IMRT plan uses seven fields and has an
unavoidable dose bath (yellow between 50% and 80% isodose lines). The DS plan, in contrast,
achieves superior coverage with a single posterior aperture and range-compensator field
(examples of these devices, not those used for this treatment, are shown on the right). The
aperture, as for a photon beam, achieves lateral beam’s-eye-view conformance. The range-
compensator shifts the proton penetration range in proportion to the local thickness to conform the
dose to the distal surface of the target volume. Note that for a scattered field, the entrance dose
cannot be controlled and results for this case in near, full skin dose.
The distal fall-off of the Bragg peak has the sharpest dose gradient
(about half of the lateral penumbra) and should offer the best
opportunity to achieve a dose differential between target and healthy
tissues. In practice, however, the range in patient has an uncertainty
estimated on the order of 3.5%. This uncertainty arises from the
uncertainty in (relative) stopping power in the patient as derived in
practice from CT. CT data measures, per voxel, the electron density in
Hounsfield units. For proton radiotherapy treatment planning, the
Hounsfield unit in each voxel is converted to stopping power using a
tissue-dependent conversion curve (Fig. 18.4). This conversion is
empirical and global, and ignorant of patient-specific variations. Proton
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radiotherapy planning assumes the worst-case scenarios concerning the
possible position of the distal edge of the Bragg peak. In practice, the
distal edge is extended beyond the target volume by 3.5% of the distal
range. The modulation, that is, the difference between distal and
proximal (90% to 98%, in our practice), is extended by 7%. Most
significantly, it means that the distal edge cannot be used to achieve a
dose gradient between the target and a critical structure—doing so could
imply a direct overshoot into the critical structure!
Figure 18.4 The radiosurgery beamline uses a single-scattered proton beam. A stack of lead and
lexan absorbers shift and scatter the proton beam (of R = 20.7 cm) to the desired energy and
fixed scattering angle. The reference ionization chamber (IC) counts the appropriate number of
MU to create spread-out Bragg peaks (SOBPs) of the desired modulation. The patient is
positioned on the patient positioner (PPS) at 450 cm from isocenter (the dot in the lamination
pattern on bottom left). The position is verified with x-ray and the snout (SN) allows imaging of
the full cranial anatomy and with the aperture. The beam energy is verified by a multilayered
Faraday cup (FC). A thick neutron absorber (white) between the FC and IC reduces the neutron
dose well below the required levels at the patient.
Proton dose distributions are biologically equivalent to photon dose

distributions except for a constant relative biologic effect (RBE) factor of
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1.1. That is, a photon dose of 54 Gy (Co-60 equivalent) equals a physical
—as measured in an ionization chamber (IC)—proton dose of 54/1.1, or
49.1 Gy. Proton dose distributions are, therefore, stated as 54 Gy (RBE)
(4) to indicate that the physical dose has been corrected by the RBE
factor and can be compared directly to an equivalent photon dose
distribution of 54 Gy. Dose effect knowledge from photon radiotherapy
can thus be transferred to proton radiotherapy. This is a major
advantage in the clinical application of proton radiotherapy. In contrast,
the RBE of heavier charged particles, that is, for lithium and beyond,
introduces significant complexities and unknowns in dose reporting.
GENERATION OF CLINICAL PROTON FIELDS

The proton pristine Bragg peak is too narrow, on the order of 6 mm, to
be clinically useful. Thus, many Bragg peaks must be added and
distributed through the target volume to achieve a clinical dose
distribution.
Accelerators
The generation of a clinical proton beam requires an accelerator to
achieve a desirable clinical energy range of up to about 250 MeV. The
latter corresponds to about 38 cm in water and is considered good
maximum choice, given the deepest seated targets. The lowest minimum
range is about 3 to 4 cm (60 MeV) and is needed for orbital and other
shallow targets.
Current accelerating technologies are cyclotrons and synchrotrons. A
cyclotron accelerates a proton beam when it crosses repeatedly over a
gap over which a strong cyclical (of a period equal to the proton
traversal time between gap crossings) electrical field is applied. The
proton beam is in a constant magnetic field B = BT and the accelerating
proton beam assumes an ever-increasing radial orbit R, that is, R =
R(E). At the highest design energy, that is, at the maximum radius T =
R(Emax) of the cyclotron cavity, the proton beam is extracted from the
cyclotron. Thus, a cyclotron produces a single energy beam Emax and the
proton beam must pass through a carbon or beryllium (i.e., a low scatter
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material) variable thickness degrader to achieve the desired clinical
energy. A synchrotron accelerates the proton beam by passing it through
an accelerating cavity and keeps the beam in a constant-radius orbit T by
synchronizing (and increasing) the magnetic field with the proton
energy, that is, B = B(E) such that the proton bending radius equals T. A
synchrotron can produce any energy E, proportional to the number of
passes through the cavity and limited by the maximum magnetic field B,
without the need for postextraction degradation.
The primary difference between a synchrotron and cyclotron is the
need for energy degradation of the latter. The degrading material,
however, scatters the beam, which results in a large emittance, that is,
the position and momentum phase space, for a cyclotron. This, in turn,
affects the beam transport design and the ability to achieve a narrow
beam at the patient. The choice of cyclotron was preferred due to their
simpler operation and higher beam current. The latter is to compensate
for proton loss in scattered fields where a large portion of protons
(between 50% and 90%) is lost to scatter and field collimation within
the scattered-field radius. The emerging preference for scanned beam
technology, however, places different requirements on the beam
parameters compared to scattered beams, and the choice between
synchrotron and cyclotron may shift in favor of the synchrotron.
The generated beam is transported to the treatment delivery device
using a magnetic beamline. A distributed beamline allows a single
accelerating device to supply multiple treatment rooms which reduce the
overall facility cost.
Scattered Proton Fields

An initially narrow proton beam of a given energy is shifted to lower
energies and spread in depth by different thickness absorbers, broadened
and flattened laterally by carefully designed scatterers, and “stacked”
with appropriate weights by synchronizing absorber insertion with
monitor units (MU) or another integrated beam-current measure (see
Fig. 18.4). Such composite and scattered proton fields are labeled SOBP
fields and, in general, produce homogeneous dose per field over a
desired modulation width up to a maximum range.
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Single Scattering
A proton beam scattered by a series of flat absorbers is labeled a single-
scattered beam. The scattered beam profile is Gaussian and, with a large
SAD and sufficiently large scattering angle, a near-uniform collimated
field can be created over a radius at the top of this profile. An example
of such a system is the radiosurgery beamline at the F. H. Burr Proton
Therapy Center (see Fig. 18.4). An incoming proton beam of 185 MeV
(22-cm range in water) is centered on a binary stack of lexan and lead
absorbers. Lexan is a low-Z material and is an efficient energy absorber
with low relative scatter (1 g/cm2 has a mean angle of 0.0072 radian at
130 MeV) while lead is a high-Z material with high scatter (1 g/cm2 has
a mean angle 0.021 rad) and low relative absorption. The stack has
10 lexan absorbers with thicknesses from 0.022 to 11.5 g/cm2, where
each subsequent thickness is twice the previous, and five lead absorbers
from 0.088 to 1.403 g/cm2, again with doubling of thickness.
Combinations of lexan and lead produce pristine Bragg peaks between
4 and 22 cm, where each emerging beam is scattered into a Gaussian
profile within which a 10-cm diameter field has a minimum intensity of
95% relative to the center. By switching combinations of lexan and lead
absorbers for appropriate beam-on times, as measured in an IC, for
example, SOBP fields of arbitrary modulation widths can be created.
Double Scattering
A common mechanical method for creating SOBP fields uses a rotating
wheel where the thickness of a particular angular interval encodes the
pullback of the pristine peak in an SOBP and the width of the angular
interval encodes the weight of the pristine peak (see Fig. 18.5). Such a
wheel can be constructed of a lexan and lead combination to create a
constant-scatter angle as a function of rotation and combined with a
second scatterer to increase the efficiency of the proton beam and to
broaden and flatten the field. The second scatterer, again, is constructed
of two, low-Z/high-Z, materials and is contoured along its radius to
uniformly absorb the proton energy. The scatterer is shaped
differentially to scatter the protons to create a uniform field. A photon
scatterer, in contrast, is shaped differentially to absorb photons.
Dual-scattering systems have been the primary technology, up to now,
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for proton-radiotherapy field delivery. Here we summarize, briefly, the
operation of the IBA* dual-scattering nozzle at the F. H. Burr Proton
Therapy Center as an example (see Fig. 18.5 top). In such a system, one
wishes to minimize the number of scatterers and modulators to reduce
complexity. The system is fully automated, efficient to operate, but not
necessarily optimal in terms of proton efficiency or field parameters due
to pragmatic operational considerations. The IBA nozzle offers SOBP
ranges between 3 and 30 cm in water with a field diameter of up to 24
cm for ranges <25 cm and up to 12 cm for ranges >25 cm.
The nozzle has three rotating modulator wheels, each of which has
three tracks. The nozzle defines eight combinations of modulator wheel
track and scatterer where each combination, called an option, covers a
particular clinical-range interval of about 3 to 4 cm. A total of eight
options thus cover the desired clinical minimum and maximum ranges.
In theory, a pair of modulator wheel track and scatterer only produces a
flat field, laterally and in depth, for the design energy. Below that
energy, the field is “over” scattered, and above it “under” scattered. The
nozzle has a set of thin-foiled lead insertable scatterers upstream from
the modulator track that increases the mean scatter angle and flattens
the field, as the energy increases in the option interval.
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Figure 18.5 Patching of fields is a necessary technique in scattered fields to wrap the dose
distributions around a target. In the above example, the through-field (top left where the circle is a
12-cm aperture) covers the anterior part of the GTV and the patch field covers the posterior
“horns.” The top right three figures show the dose distributions for the scattered (DS) fields. The
bottom right three figures show the result using the DS-field approaches and using the pencil-
beam scanning (PBS) optimization to achieve a total dose distribution without the benefit of either
apertures or range-compensators. In the PBS optimization, all fields are optimized as an
ensemble. The desired prescription dose is 14.4 Gy (RBE). The construction of patching fields in
DS is tedious as the field parameters—range, modulation, and aperture size—must be carefully
tweaked to achieve a dose distribution that covers the partial volumes to yield coverage of the
total volume. For example, the through-field for the DS plan shows a distinct softening at its distal
edge, which makes it harder for the patch field to cover that volume. The PBS patching, by virtue
of its simultaneous optimization of all fields and its ability to vary local intensity, achieves a much
more satisfactory result. In addition, the posterior lateral gradient of the PBS through-field is not
as sharp compared to the DS through-field. The PBS gradient is defined by the varying pencil-
beam intensities while the DS gradient is defined by the field edge. Thus, the PBS patch is
probably less sensitive to errors. The PBS fields used a total of 1,600 pencil-beams with an initial
spread of σ = 5 mm and with ranges between 4.5 and 14.5 cm (in water). The bottom right figure
shows the 1,103 spots for each of 24 energy layers for the through PBS beam. The color
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indicates the number of gigaprotons (Gp) in each spot.
The SOBP depth dose plateau flatness (better than ±1% in our
practice) can be controlled by modulating the cyclotron beam current
during the rotation (at 10 Hz) of the modulator track. This is a
convenient property of a cyclotron which acts as a continuous and
variable current source. The SOBP flatness is determined by the set of
weights for each of the pristine Bragg peaks in the SOBP. These weights
of each peak’s contribution to the SOBP are hard-coded in the modulator
track but are not “exact” for a particular SOBP range. The modulation of
the beam current adjusts the weight by varying the number of protons
that pass through an angular segment. The use of current modulation
reduces the complexity of modulator track design, which now can be
“corrected,” and allows a particular track to be applied well outside its
initial design interval (see Fig. 18.6).
The beam-current control also controls the width of the SOBP field.
The modulator track, over its full rotation, achieves a maximum constant
pullback SOBP width. The current can be turned off at an angle within
the full rotation to allow for arbitrary modulation up to the maximum
pullback to deliver the desired modulation width for a particular patient
field.
Figure 18.6 The ability to control the current (relative to the current I0 set for a specific dose rate)
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as a function of the rotation time (100 ms) of the modulator wheel allows a track to be “tuned” to
produce a perfectly flat spread-out Bragg peak (SOBP) (blue) compared to that produced with a
constant current (red).
Field-Shaping Devices
Scattered fields are shaped laterally by apertures, as photon fields, and
in depth by range-compensators (Fig. 18.3). Apertures are collimated to
the beam’s-eye-view projection of the target volume and require a
distance of 7 to 10 mm between the target and aperture edges to account
for the depth-dependent penumbra. The apertures must have sufficient
thickness to absorb the incident range as a proton field does not change
in intensity as it passes through an absorber. Thus, insufficient thickness
will result in full dose to the patient! The range-compensator is unique
to proton and heavy charged particles. The range-compensator adjusts
the range across the lateral field profile such that the resultant distal
dose surface closely matches the distal target volume surface. A range-
compensator thus spares tissues distal to the target.
The thickness of the target volume, measured as the difference
between the deepest and shallowest radiologic path-lengths in the target
volume, determines the desired maximum range of the SOBP field and
the modulation width. The combination of an aperture and range-
compensator can thus achieve, for a single SOBP field, lateral and distal
conformation and homogeneous dose in the target volume (see Fig.
18.3).
The aperture is placed as close as possible to the patient to reduce the
effect of the large effective proton source, whose size is on the order of 5
to 10 cm, due to scattering material in the beam, compared to 1 to 2 mm
for a photon beam! The penumbra of this source can only be mitigated
by, first, placing it as far as possible from the patient, typically at an SAD
∼300 cm, and demagnify it by the aperture–patient distance over the
aperture–source distance. Thus, in clinical practice, the effective source
size is demagnified 40-fold and its contribution to the penumbra for
double-scattered fields is on the order of 5% (see Fig. 18.2).
The design of the range-compensator considers individual radiologic
path-lengths from the source to the distal surface and sets the range-
compensator thickness such that the distal fall-off of the SOBP is just
beyond the target distal surface. Consider an “open” field of range Rd
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that reaches, as measured from the source to that point, just beyond the
deepest point Pd on the target distal surface. We wish to insert material
for every other point Pi on the target distal surface equal to Ti = Rd −
Ri, where Ri is radiologic path-length to point Pi. The range-compensator
is constructed with the thicknesses Ti. The result is that the range Rd as it
passes through the range-compensator is shifted along each ray from the
source such that the distal edge of the proton composite dose
distribution lies just beyond the target distal surface (see Fig. 18.3).
Known uncertainties in the patient or target position, caused by setup
errors or otherwise, create variations in path-lengths that could lead to
an underdose of the target or an overshoot into the healthy tissues. The
range-compensator profile is, therefore, “smeared” where each point is
assigned the largest range (or least thickness) from among the points in
its neighborhood within a radius corresponding to the total expected
variation (see Fig. 18.1). This ensures worst-case coverage of the distal
target surface in the presence of these variations. It does, however, push
the distal fall-off dose further into the healthy tissues. This, and the
inherent uncertainty in range stated above, means that the distal fall-off
of the SOBP cannot be used to shape a gradient between the target
volume and a critical structure.
Absolute Dosimetry
The relationship between dose in patient and number of protons
produced by the cyclotron is not trivial for scattered fields. The number
of protons, as usual, is monitored by a reference IC placed upstream of
the collimated field, which produces a signal proportional to the proton
flux. In general, we can refer to proton beam flux in terms of absolute
number of protons, that is, gigaprotons or Gp; or in terms of the IC
response in MU as the two are related by the stopping power Sair, that is,
MU ∝ Sair × G for G protons passing through the collection volume of
the IC. For scanning beams, discussed below, the use of Gp is
recommended. For scattered fields in a continuous system such as a
dual-scattered system with a rotating modulator wheel, the target
volume receives the fractional prescription dose at every wheel rotation
interval (i.e., 0.1 seconds). Thus, MU is proportional to the fraction of
prescription dose in patient. A delivery interruption (within 0.1 seconds)
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results in the whole volume receiving partial prescription dose. For the
single-scattered system described above, however, an IC count interval
corresponds to the delivery of an individual pristine peak in the set of
peaks of the SOBP. In such a system, a delivery interruption results in
some parts of the target volume receiving full dose, while other parts
receive incomplete dose. Resumption of such fields must be accurately
handled in the delivery system.
The relationship between physical dose (in Gy) in the SOBP plateau
and MU is complicated. In principle, one could calibrate each pristine
Bragg peak in units of Gy per number of protons (or MU). This
relationship for scattered fields is impractical except for the simplest
beamlines. In general, the complex secondary interactions in a dual-
scattering system and the variability of mechanical device settings
preclude such a calibration or derivation.
One can establish a semitheoretical relationship for the output factor
Ψ (in Gy/MU) between MU and physical dose in water. The SOBP
output factor is the ratio between dose DP in the plateau and dose (i.e.,
MU) measured in the IC. The latter, in turn, is proportional to the
entrance dose D0 of the SOBP. Thus Ψ is proportional to the ratio of
DP/D0, which can be derived from a mathematical description of the
Bragg peak and equals
where D0R is the SOBP entrance dose of the reference SOBP which has
an output factor ΨR, and the entrance dose of the SOBP of interest, with
range R and modulation M, is D0(R, M) and described by the two-
parameter function characterized by a form factor r = (R, M)/M. The
function parameters, a and b, have the theoretical values of 0.44 and
0.6, respectively. In practice, these differ due to the secondary effects in
the nozzle.
In clinical practice, the applicability of Equation 18.1 depends very
much on the construction details of the delivery system. In our practice,
the formula is successfully applied to both the single-scattering beamline
and our dual-scattering gantry nozzle. The parameters a and b are
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obtained from calibration and are constant for each option. In general,
Equation 18.1 will apply to a constant configuration of a nozzle where
the SOBP-shaping devices do not change, which is the case in the IBA
nozzle for each option.
Scanned Proton Fields

The clinical practice of proton radiotherapy, about 50,000 patients to
date, has been based almost exclusively on scattered-field technology.
The use of scattered fields to achieve complex dose distributions requires
considerable manual planning and time. Scanned proton beam
technology is clinically viable, as by the PSI team, and should become
the future of proton radiotherapy. Only scanned proton fields can match
the level of automation and complexity integration that now is expected
in photon radiotherapy considering technologies enabled by IMRT and
treatment planning optimization.
Scanned proton fields use a narrow beam of protons of variable
energy, to control depth penetration, and which is moved in the lateral
dimensions by magnetic fields (Fig. 10.8 bottom). Thus, an almost
arbitrary 3D dose distribution can be created inside the patient without
the aid of mechanical beam modifiers or field-shaping devices such as
apertures and range-compensators. The latter, however, may continue to
have clinical use or benefit and their use should not be considered void.
There are two clinical modes of using pencil-beam scanning (PBS)
technology. The first mode, labeled single-field uniform dose (SFUD) (5),
is analogous to the clinical use of SOBP fields. In this mode, each PBS
field is designed to deliver a homogeneous dose, like an SOBP field, to
the target volume. Unlike an SOBP field of constant modulation width,
the dose to the volume proximal to the target volume now conforms as
well. This offers further healthy tissue sparing compared to scattered
SOBP fields. The second mode uses two or more fields and optimizes the
dose as a composite for all fields. This mode is analogous to IMRT field
optimization, where each individual field delivers inhomogeneous dose,
and is labeled intensity-modulated proton therapy (IMPT).
The clinical application of PBS to date (at PSI) has been primarily with
SFUD fields and not with IMPT fields. The reason is twofold. First, IMPT
fields have uncertainties in the precise knowledge of the end-of-range of
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the pencil-beam and also require precise knowledge of the sources of
geometric errors. These uncertainties could cause the individual fields
not to “mesh” correctly to yield the desired composite dose. Second, the
optimization problem for IMPT is significantly more complex compared
to IMRT optimization. In IMPT optimization, the number of variables is
one or two orders of magnitude larger compared to IMRT and requires a
substantial increase in numerical computing power which only has
become available recently with the advent of 64-bit computing
architectures.
The optimization unit for IMPT, that is, the pencil-beam itself, also
complicates the convergence of conventional optimization algorithms as
it presents to the optimizer a sharp distal fall-off and a coarser (by a
factor of two) lateral fall-off. This causes conventional optimization
algorithms, that is, those based on squared dose differences, to prefer the
distal edge fall-off which exacerbates the problem of distal edge
uncertainty. SFUD field optimization only considers a single field at a
time and avoids these problems.
Thus, the successful clinical introduction of IMPT requires new
optimization technologies that consider the robustness of the final
treatment plan. The robustness of a treatment plan measures its
invariance against the known and specified sets of uncertainties that
have been included in the optimization methodology. For IMPT plans,
this set includes range and positional uncertainties, including those of
target motion (6). The positional uncertainties, especially, are significant
for SOBP fields in general and for IMPT in particular. For both, the local
motion of a target volume, such as may be present, in the lung, causes
significant changes in radiologic path-lengths and cannot be considered
by a simple expansion of the clinical target volume (CTV) into a
planning target volume (PTV). Such an expansion can be used for the
lateral extent, that is, in the Beam’s Eye View (BEV) plane. Along the
depth dimension, however, the final beam profile, managed with a
range-compensator for SOBP fields and by differential pencil-beam
intensities for IMPT, must ensure coverage of the target for all phases of
motion. The correct consideration of these effects requires a computation
over all phases instead of a geometric assumption such as the Imaging
Target Volume, the composite volume from all imaging sets, concept.
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Multicriteria Optimization
In current clinical practice, optimization algorithms use a quadratic cost-
function F of the form
which specifies, for each organ of interest, the prescription dose Dk and
weight factor ak as an indicator of the significance of meeting the
prescription dose. The function F is minimized for all dose point dj that
contribute dose to the organ k. This methodology, in practice, yields
treatment plans that approximate the desired solution, that is, the
“optimal” treatment plan, but often requires arbitrary recalculations that
“tweak” the parameters ak and Dk to achieve the physician’s intent. This
intent is typically not specifiable as it depends on a trade-off analysis by
the physician which can only be done given the actual possibilities.
Recent developments in optimization introduce the use of multicriteria
optimization (MCO) which considers multiple trade-offs simultaneously
(7). The MCO approach, at least in our practice, computes all “possible”
treatment plans, each of which is optimal within the choice of trade-offs.
In MCO, the physician specifies a set of absolute constraints, such as
minimum and maximum doses allowed to the target and/or structures,
and a set of objectives, such as “minimize the mean to the lung” or
“minimize the maximum to the GTV.” The MCO optimizer generates a
set of plans, each of which meets the constraints, of sufficient number to
sample all the possibilities of the stated objectives. These optimal
treatment plans lie on the Pareto trade-off surface, which is a
multidimensional surface (of dimension proportional to the number of
objectives) formed by those points whose values are the optimal trade-
offs. That is, changing one trade-off (such as increasing the target dose)
will decrease another trade-off (such as higher critical structure dose).
The user traverses this surface to select the desired set of trade-offs.
Consider the example in Figure 18.7 that shows the Pareto surface (a
curve in this case of two objectives) of a chest wall target volume with a
desired optimal dose of 70 Gy (RBE) but where a minimum of 40 Gy
(RBE) was set to allow sufficient “room” to assess lung dose. The two
objectives are “minimize the mean lung dose” and “maximize the
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minimum dose to the GTV.” An optimal plan that lies on the curve
means that improving lung dose will degrade target dose and vice versa.
Absolute Dosimetry
PBS dosimetry is, in essence, simple as one only considers the interaction
of a pure proton beam in medium. The proton pencil-beam control
parameters are its lateral deflection as defined in the reference plane and
measured in a positional IC, its energy as defined by the accelerator, and
its instantaneous or integrated current. All these parameters must be
specified by the treatment planning system as the final dose calculation
must consider, at a minimum, the exact relative dose contribution from
each pencil-beam. Figure 18.8 shows a set of pristine Bragg peaks as a
function of range which have been carefully calibrated for treatment
planning to match those delivered on the equipment. The peaks are
specified in units of Gy (RBE) mm2/Gp. These units allow the treatment
planning system to relate the dose in patient directly in terms of a
delivery system control parameter, that is, the number of protons (in
Gp). This relation between dose in patient and the beam charge
(assuming a pure Gaussian model, see Chapter 10, Proton Dose
Calculations) is
where σi(z) is the spread of pencil-beam i at depth at z (in the pencil-

beam coordinate system with z equals to pencil-beam axis), ri(x, y, z) is
the lateral displacement of the calculation point with respect to the
pencil-beam axis, Gi is the number of protons in the pencil-beam, and
Di∞(z) is the pristine Bragg-peak depth dose. The index i includes
summation over pencil-beams of different energies and positions. The
pencil-beam spread σi(z) includes both the inpatient scatter due to
(primarily) multiple Coulomb interactions and the initial spread of the
pencil-beam prior to entering the patient as produced in the delivery
equipment. The final dose thus has the correct units of Gy. It is the
responsibility of the treatment planning optimization system to compute
the set Gi to be delivered by the delivery equipment. The pencil-beam
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energies and deflections are typically precomputed, given the target
shape and location.
CLINICAL CASE ANALYSIS

Our example is a pediatric cervical chordoma. This site has as critical
structures: brainstem, cord, cochlea, and chiasm. The prescription dose is
50.4 Gy (RBE) to the CTV and 79.2 Gy (RBE) to the GTV, while keeping
the chiasm below 62 Gy (RBE), brainstem and cord center (surface)
below 55 (67) Gy (RBE), and the cochlea below 60 Gy (RBE). The
treatment approach reflects a long experience in sequencing the fields.
Figure 18.7 The challenge of selecting the “optimal” plan is illustrated by the above hypothetical,
proton pencil-beam scanning (PBS) irradiation of a chest wall. The PBS treatment uses three
beams: a posterior (gantry 170), anterior (gantry 350), and right posterior oblique (gantry 225).
The GTV (red) is constrained to a dose range of 40 to 70 Gy (RBE) and the competing objectives
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are to “maximize the minimum GTV dose” and to “minimize the mean to the right lung” (note that
there is no contralateral lung dose concern as the proton beams have no exit dose). The top right
figure shows the Pareto surface of optimal plans (a curve in this case given two objectives). The
Pareto optimizer computes a mathematical representation of all plans that lie on the curve. This
representation allows a rapid computation of any plan that corresponds to a point on the curve.
The “red” plan is a suboptimal plan because, given its mean RT lung dose, it should allow a GTV
dose of 68 Gy (RBE; arrow); a Pareto optimizer would not yield such a plan by definition. The
“cyan” and “green” plans (labeled 18,48 and 23,60 for the curve coordinates) are Pareto-optimal
plans. Note how the GTV dose can be significantly increased in the central curve region with only
a modest increase in lung dose. The analysis afforded by the multicriteria optimization (MCO) is
essential for PBS, given the higher level of variability in a treatment plan because of the large
number of PBS pencil-beams (on the order of 103 to 104). The corresponding dose distributions
and DVHs are shown on the left and bottom right, respectively.
The first set of five fields to the CTV have gantry angles of 70, 100,
230, and 260 at a couch angle of 0, and a gantry angle of 155 at a couch
angle of 90. The main objective of this field arrangement is to reduce the
dose to the parotid glands but little to the spinal cord. Each field, in the
scattered-field (DS) delivery, covers the CTV to homogeneous dose. The
DS fields are not all delivered at each treatment session. Instead, triplets
of rotating combinations are used. Figure 18.8 shows the normalized
dose distribution for a single field and the composite dose distributions
for all five fields.
The GTV fields, as a consequence of the full CTV dose inclusion, must
avoid the brainstem and spinal cord. For DS fields, this can only be
achieved by patch combinations. A patch combination is the proton
equivalent of field edge matching. Given the finite range of the proton,
one can now also patch the distal edge of one field to the penumbral
edge of another field. Each field delivers full dose within its subtarget
volume and the combination of patch fields achieves full dose to the
target volume. As noted before, however, the uncertainty in the distal
range can lead to a cold or a hot spot. As a consequence, patch
combinations are always “switched” around to feather this hot or cold
spot. The construction of patch-field combinations for scattered SOBP
fields is cumbersome in spite of some available support in treatment
planning systems. For illustration purposes (Fig. 18.5), we use one of the
three DS patch-field combination (in fact a “double” patch) and use the
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PBS optimization engine to “auto-patch” the field without the use of an
aperture and range-compensator. The result is (probably) more robust to
cold or hot spots as the individual field dose distributions present a more
gradual distal fall-off compared to the “true” pristine peak dose fall-off.
Thus, any over- or undershoot effect is minimized by the lower gradient.
We expect, in the clinical practice of PBS and subject to further
validation, to continue to use the DS-field approaches as these have
inherent robust properties such as target avoidance with the penumbral
edge and distal edges away from critical structures. Even with available
robust optimization techniques, these DS-field approaches retain their
use.
Figure 18.8 The figure shows a near-symmetric chordoma wrapping around the spinal cord in this
transverse image. The GTV is shown in red, the spinal cord in purple, and the parotid glands in
cyan and purple. Isodose values are shown in Gy (RBE). The desired prescription dose for the
GTV is 78 Gy (RBE). The left half of the picture shows an IMPT treatment plan, and the right half
shows a scattered-field (DS) treatment plan. Both plans used the identical beam angles, as
created for the DS plan. The choice of the DS beams inherently selects “robust” approaches (see
text). Distinctive features in favor of the intensity-modulated proton therapy (IMPT) plan are (1)
tighter and more complete coverage of the GTV especially into the posterior tails (see 78-Gy
[RBE] isodose), (2) better sparing of the parotid (see 30-Gy [RBE] isodose), (3) significantly less
spinal cord dose (see 55 Gy [RBE] isodose), and (4) lower integral dose as apparent from the 30-
and 40-Gy (RBE) isodose lines. Overall, however, the scattered-field approach achieves a very
comparable treatment plan.
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Figures 18.9 and 18.10 show the total, CTV + GTV, dose distributions
for both the IMPT and DS plans. The IMPT plan does significantly
improve on the parotid glands, which are primarily located in the
integral dose region, which—as stated before—can be reduced on an
average by 50% with protons and even more with IMPT compared to
photons. In general, however, the DS plan is competitive with the IMPT
plan and, in general, we do not expect as dramatic a change between
IMPT and DS compared to IMRT and 3D conformal. Instead, we expect
PBS to significantly reduce the treatment planning overhead required to
create the numerous fields (12 for this case) required to achieve superior
DS dose distributions in patient.
Figure 18.9 An example of a double-scattered field delivery to the clinical target volume (CTV)
(green). Each of the five fields achieves full target coverage (>98% isodose line—not shown).
Note how each field arrangement (one of which is shown on the left) spares the contralateral
parotid. The full complement of five fields reduces the parotid dose to about 20% of 50 Gy (RBE)
as only one field passes through each parotid. Note that the fixed modulation of the DS SOBP
cannot control the entrance dose (as visible in the left figure where the 95% isodose line crosses
the parotid). The composite dose distribution (in Gy [RBE]) is on the right. The maximum dose to
the CTV is 51 Gy (RBE) and indicates the high degree of homogeneity achievable with SOBP
fields.
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Figure 18.10 The dose–volume histograms for the parotid glands and brainstem show significant
reduction in dose. This is primarily a consequence of the fact that pencil-beam scanning (PBS)
fields reduce the proximal dose that cannot be controlled in a scattered field. The spinal cord does
not show an overall reduction for the PBS approach as the field approaches deliberately, per
convention and per need to avoid the parotids, pass through it.
KEY POINTS
• A monoenergetic pristine narrow proton beam is modified by a
double or single scattering system to produce a lateral flat field
(within a desired diameter) and is modified by a set of range-
shifters (either a set of individual shifters or mechanically
constructed as a single device) to produce a depth-modulated
spread-out Bragg peak (SOBP) such that the composite pristine
peaks in the SOBP produce a flat depth-dose profile over a depth
interval (labeled modulation width) up to the deepest pristine peak
penetration.
• The SOBP field, either produced in a scattering system or by
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uniform scanning, is characterized by an unbounded (within a
maximum diameter) flat field and by a constant radiologic depth
penetration set by the maximum energy of the SOBP pristine peak.
The flat field needs to be tailored to the BEV projection of the target
by an aperture. The constant depth penetration needs to be
modulated by a variable thickness range-shifter or range-
compensator such that the penetration depth can be adjusted
across the field to minimize penetration distal to the target volume.
• Apertures in SOBP fields are characterized by a sharp penumbra
due to the large SAD and close placement of the aperture to the
patient. This geometry affects a source size penumbra on the order
of 10. Pencil-beam scanning of narrow proton beams without an
aperture may still have a large penumbra in comparison to the
SOBP penumbra. Thus, the use of an aperture in a pencil-beam
scanning field will yield a 10-fold reduction in source penumbra.
• The PTV concept in photon radiotherapy is valid because
geometric perturbations in the patient have a negligible effect on
the physical dose distribution. Thus, geometric alignment
corresponds to dosimetric alignment. Proton fields, however, are
very sensitive to geometric perturbations and the dose distributions
can become a strong function of the geometric perturbation. Thus,
a simple geometric expansion of the CTV will not suffice to a priori
account for the dosimetric effect of these perturbations.
• The number of optimization variables, the individual pencil-beam
intensities, in pencil-beam scanning fields is very large and on the
order of 1,000 to 5,000. One can therefore expect that given
multiple clinical competing objectives, multiple plans should be
considered to evaluate the best trade-off. Multicriteria optimization
aims to provide a model where, instead of producing a single
“optimal” plan, many optimal plans can be considered, each of
which is optimal given an actual choice of objective values.
• Uncertainties in proton treatment plans include geometric setup
errors, anatomical changes, and physical uncertainties in the
stopping power determination in the patient and thus in the range
penetration into the patient. Such uncertainties affect the dose
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distribution directly and cannot be mitigated by geometric solutions
such as the PTV concept. Instead, uncertainties need to be
considered in the treatment planning dosimetry directly to establish
that, given the uncertainty extents, dose constraints remain
clinically acceptable.
QUESTIONS
1. A Pareto-optimal plan defines a set of objective and their values.
If an objective value improves,
A. all other objective values worsen
B. some improve, some worsen
C. some worsen, some remain the same
D. some worsen, some reach a limit
2. Compared to an SOBP treatment plan, a PBS plan will always
show (indicate all that are correct):
A. Improved proximal dose reduction
B. Better distal penumbra
C. Worse distal penumbra
D. Better lateral penumbra
3. Why do proton plans significantly reduce integral dose?
A. Proton treatments use less fields
B. Protons deposit no dose beyond the distal edge
C. The proton Bragg peak deposits much more dose in the target
compared to the rest of the tissues
ANSWERS
1. A Every Pareto-optimal plan is a “point” on the Pareto
surface whose dimensionality is determined from the plan
objectives and where each point is a set of optimal
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objective values. Any change that improves one objective
worsens all other objectives.
2. A An SOBP field has a fixed modulation and therefore
cannot control the dose proximal to the target (C), the
SOBP field has a range-compensator that ensures that
every proton “stops” at the distal surface and thus the
distal penumbra is the distal penumbra from the pristine
peak (which is at least two times sharper than the lateral
penumbra). A PBS field whose spots are rather random
with respect to the distal surface does not expose the
pristine distal fall-off.
3. B Protons deposit no dose beyond the distal edge. This
(almost) reduces the integral dose by a factor of two.
REFERENCES
1. Goitein M, Abrams M, Rowell D, et al. Multi-dimensional treatment
planning: II. Beam’s eye-view, back projection, and projection
2. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–
491.
3. Richard W. A Brief History of the Harvard University Cyclotrons.
Cambridge: Harvard University Press; 2004. Available from
http://physics.harvard.edu/∼wilson/cyclotron/history.html.
4. Prescribing, recording, and reporting proton-beam therapy: contents.
J ICRU. 2007;7(2):NP.
5. Lomax A. Intensity modulation methods for proton radiotherapy.
Phys Med Biol. 1999;44:185–205.
treatment uncertainties 2: the potential effects of inter-fraction and
inter-field motions. Phys Med Biol. 2008;53:1043–1056.
7. Monz M, Küfer KH, Bortfeld TR, et al. Pareto navigation—
algorithmic foundation of interactive multi-criteria IMRT planning.
Phys Med Biol. 2008;53:985–998.
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19 Role of Protons Versus Photons
in Modern Radiotherapy: Clinical
Perspective
Darwin Yip, Yi Wang, and Thomas F. DeLaney
INTRODUCTION AND OVERVIEW

Radiation therapy remains a cornerstone for the curative treatment of a
broad range of malignancies. It can serve as a less toxic alternative to
surgery for local tumor control in a number of critical anatomic sites
where radical surgery is functionally or cosmetically debilitating (i.e.,
head and neck, spine), can be combined with surgery +/− systemic
therapy to allow more conservative surgery (i.e., breast, extremity), and
may have a more favorable toxicity profile for some patients than
surgery (prostate, early-stage lung cancer) (1). It is expected to continue
to be important for the treatment of cancer for some years to come, and
recent data suggest that it can be combined for therapeutic gain with
both targeted systemic therapies (2) and immunotherapy (3). Hence,
optimal radiation therapy will continue to be an important component of
a major cancer treatment program.
Protons are charged particles with mass that travel a fixed distance in
tissue that is related to the accelerating energy. They have a physical
advantage over x-rays (i.e., photons) because they deposit the bulk of
their energy in a narrow range at the depth related to the accelerating
energy; this nidus of energy deposition is referred to as the “Bragg
peak,” beyond which there is no energy delivered, hence sparing the
normal tissues distal to the Bragg peak of any radiation dose (Fig. 19.1).
Protons can deliver similar or higher radiation doses to the tumor target
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with up to 50% to 60% less integral or “total-body” radiation dose
compared to the highest technology photon (i.e., x-ray technique),
namely intensity-modulated radiation therapy (IMRT) (4). The current
generation of proton equipment can also perform intensity modulation,
which is referred to intensity-modulated proton therapy (IMPT) which
yields both highly conformal radiation doses around the tumor with
integral radiation doses that are 50% to 60% lower than photons.
Because of the substantially lower total-body radiation doses, protons
are already felt to be optimal for treatment of children with solid tumors
who require radiation therapy. Protons are FDA-approved for treatment
of patients in the United States. Medicare and commercial payers
provide coverage for proton treatment for selected indications, which are
not standardized and are evolving. Randomized phase II or III studies
comparing IMRT versus protons are currently in progress or planned for
brain tumors, head and neck, nonsmall cell lung, hepatocellular,
prostate, and breast cancers (clinicaltrials.gov; NRG Oncology;
Massachusetts General Hospital [MGH]/M. D. Anderson U19 Grant;
PCORI). There are 14 operating proton centers in the United States with
another dozen or so in various stages of construction and planning (5).
Proton facilities have traditionally entailed a particle accelerator
(cyclotron or synchrotron) and magnetic beam line(s) to steer protons
into three to five treatment rooms, using either fixed beams or more
versatile but expensive rotational gantries. The cost of these facilities is
generally in the range of $125 to $200 million depending on the size and
configuration of the facility. The cost for proton treatment has been
estimated to be ∼2.7 to 3.2 times more than IMRT, much of it related to
the upfront capital expenditure, which could be ameliorated by
charitable contributions toward the construction of the facility, since the
treatment costs otherwise (i.e., physician consultation, CT simulation,
treatment planning, treatment delivery) are comparable, although
ongoing maintenance is also higher with a proton facility (6,7). Single
room proton facilities have recently opened with lower cost, ∼$30
million per gantry-based room, which represents a significant cost
reduction and also allows a “modular” concept, namely starting with one
room but leaving space for the addition of additional beam lines and
rooms to the accelerator at a later date (8). Even with the more costly
traditional multi-room proton facilities, and certainly for the newer, less-
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costly single room facilities, protons have been estimated to be cost-
effective for some diseases/anatomic sites, primarily pediatric, because
of the reduction in medical costs associated with the treatment of late
effects related to the larger radiation treatment volumes associated with
radiation therapy with photons (9–11).
Because of ongoing concern about rising medical costs, it is
increasingly likely that a societal acceptable cost benefit for protons be
demonstrated if they are to be a viable technology. A legacy physics
research facility at University of Indiana, which was modified for
medical proton therapy and began patient treatments in 2004, was
closed in 2014, in part because of high staff-to-patient ratio and high
fixed operating costs. Although the other operating proton facilities in
the United States currently appear to be financially viable and new
lower cost single-room facilities have more favorable financial
projections than the larger centers, cost-effectiveness remains an issue
that will need to be addressed.
Figure 19.1 Proton Bragg peaks of increasing energy and range. (Courtesy of Hanne Kooy, PhD,
Massachusetts General Hospital, Boston, MA.)
Carbon ions are heavier charged particles, with 12 times the mass of a
proton. Physically, their greater mass and charge produce a denser track
of ionization and, biologically, more double-stranded DNA breaks. They
have a higher relative biologic effect (RBE) that is estimated to be ∼2.5
times greater than that of protons, which, however, changes over the
course of the carbon particle track and requires very sophisticated
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modeling for patient treatment (12). Carbon ions do have a sharper
lateral penumbra than protons, particularly at deeper ranges, although
they also produce some spallation products distal to the Bragg peak that
give some unwanted dose distal to the target. Interesting data from
Japan and Germany suggest some encouraging results for sacral
chordomas, pelvic recurrences of rectal cancer, peripheral nonsmall cell
lung cancer (NSCLC), and cancer of the pancreas (12). Because the
radiation dose schedules for carbon ions have tended to be
hypofractionated and not strictly comparable to those generally used
with protons, it is not clear in the absence of randomized comparative
studies whether the clinical results to date represent a clinical advantage
over protons, and, if so, is it related to simply higher doses, the
alternative fractionation schedules tested for carbon ions, or reflective of
the higher RBE for carbon ions. Higher RBE by itself is not an advantage,
proven by the use of neutrons which had a higher RBE but poor physical
dose distribution and resulted in much greater normal tissue side effects
than x-rays (13); that is, the higher RBE has to be confined to the tumor
volume because higher RBE particles releasing energy in normal tissue
may result in normal tissue injury.
There are randomized studies comparing carbon ions with protons
underway in Heidelberg, Germany, looking at skull base chordomas and
chondrosarcomas, as well as sacral chordomas, and glioblastomas
(clinical trial information available at clinicaltrials.gov). Skull base
chondrosarcomas have ∼95% local tumor control at 10 years with
protons (14); so from a clinical trial perspective carbon ions cannot
realistically be shown to be superior to that, although it is theoretically
possible that carbon ions cause less toxicity than protons related to the
sharper penumbra. The randomized studies of skull base chordoma and
sacral chordoma may yield the most enlightening data, although the
fractionation scheme chosen for sacral chordomas, 4 GyRBE × 16 = 64
GyRBE, has been used with carbon ions without much experience with
that schedule for protons; so if there is a difference between the arms of
the sacral chordoma study, it will not be clear whether the optimal
radiation fractionation scheme was used in the proton arm. In the
glioblastoma study, patients receive 50 Gy with x-rays in each arm to the
tumor with several centimeter margin followed by a boost of 10
GyRBE/5 fractions of 2 GyRBE with protons versus 18 GyRBE/6
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fractions of 3 GyRBE with carbon ions. In our opinion, the glioblastoma
study presents a design problem; if the carbon arm is superior, it will not
be clear if this is related to a difference in total dose or to the use of
carbon ions, although any improvement in the outcome for patients with
glioblastoma will of course always be welcome.
Some facility designs allow delivery of both protons and carbon ions,
but these are more costly than a proton facility (see below). There are
also other charged particles which are intermediate in weight and charge
between protons and carbon ions (i.e., helium, neon, lithium), which
may have some advantages over either protons or carbons. While these
have not been studied extensively to date, these have been discussed in
the charged particle literature as possible candidates for future
consideration for clinical trials (15). The design of some charged particle
facilities may allow the future use of variable charged particles, although
the additional cost would need to be weighed against what is currently
an uncertain future utility.
The cost of a combined carbon–proton facility was estimated in 2010
as €138 million compared to €94.9 million a proton-only facility and
€23.4 million for a photon (i.e., x-ray)-only facility (7). The estimated
cost ratio for the combined-particle facility compared to photons was 4.8
and for the proton-only facility compared to photons was 3.2. These cost
ratios depend upon how these facilities are configured, including
whether they have gantries. Gantries, which rotate around the tumor
and allow treatment from multiple angles to optimally deliver dose to
the tumor and avoid normal tissue, are standard for photons (x-rays) and
comprise the majority of treatment rooms in proton centers. Most carbon
ion facilities have only fixed beam lines, generally from superior, lateral,
and/or 45-degree directions, because of the weight of a carbon ion
gantry. The carbon ion gantry in Heidelberg is 670 tons, compared to
∼120 to 200 tons for a proton gantry. One other carbon facility in Japan
is currently developing a gantry, with a plan for a compact
superconducting design that is projected to weigh less than 300 tons.
Carbon ion therapy is not currently FDA-approved in the United
States, so it is currently considered an investigational therapy. The NCI
has awarded two recent carbon-ion facility planning grants with the
thought that it would be of scientific interest to have a carbon or other
heavy charged particle facility in the United States for comparative
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studies with protons, but there are currently no operating carbon or
other heavy charged ion facilities in the United States.
HISTORY OF PROTON BEAM THERAPY

Dr. Robert Wilson first proposed the clinical use of proton beam, as well
as heavier charged particle therapy for treatment of cancer (16). His
proposal was based on the characteristic Bragg peak of the proton and
heavier charged particles, whereby the majority of a particle’s energy is
deposited in the final few millimeters of the proton’s track in tissue at a
depth proportional to its energy. This would eliminate “exit” dose
beyond the tumor target, resulting in a marked reduction in integral
dose of up to ∼60% compared to photons. This reduction in normal
tissue dose could reduce the possible side effects of radiation and offered
the possibility of better concentrating the radiation dose in the tumor,
and hence the possibility of increasing the radiation dose to the tumor
and improving local tumor control. Dr. J. Lawrence and associates at
Lawrence Berkeley Laboratory launched a phase I trial in 1954 of proton
irradiation of the pituitary gland to suppress hormone productions in
breast cancer patients (17). Radiation doses of 140 to 300 Gy were
administered in three fractions over approximately 2 weeks using a
crossfire technique in which multiple small 340-MeV proton beams
intersected at the pituitary. Interestingly, because of the high proton
energy, the treatments in fact used the plateau region of the beam rather
than the Bragg peak and the beams exited the skull. Some of the treated
patients had good responses to treatment.
Proton beam therapy (PBT) began in Europe in 1957 in Uppsala (18).
The MGH Neurosurgical Department and the Harvard Cyclotron
Laboratory (HCL) developed a clinical program in 1961 using, primarily,
single fraction treatments to treat pituitary adenomas (19) and
arteriovenous malformations (20). The Bragg peaks of multiple narrow
beams were targeted at the tumor. Herman Suit and Michael Goitein
started a program of fractionated proton treatment of cancer patients in
1974 designed to test the hypothesis that protons would allow dose
escalation to improve local tumor control with acceptable clinical
toxicity in clinical sites where (1) local control (LC) was poor with
photons and (2) dose could be escalated with protons in a facility with
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that was limited by a fixed, horizontal beam of limited energy (160
MeV). They were successful for treatment of uveal melanomas in the eye
(21), skull base chondrosarcomas and chordomas (22), and prostate
cancer (23). From a technical perspective, the facility pioneered many of
the treatment techniques that serve as the foundation for passively
scattered proton therapy.
Their results were confirmed at other centers in Europe (Orsay in
France (24), PSI in Switzerland (25)). These encouraging clinical results
provided the impetus for the development of hospital-based facilities.
The first hospital-based proton therapy center was opened at Loma Linda
University Medical Center in 1990 (26). This facility utilized a
synchrotron from which protons were magnetically steered to three
gantry-based rooms and a single fixed beam room. Additional hospital-
based facilities opened in the United States at MGH (2001), Indiana
(2004), University of Florida (2006), and Houston (2006); as of April,
2015, there were 14 centers operating in the United States
(http://www.ptcog.ch/index.php/facilities-in-operation).
DEVELOPMENT OF PROTON THERAPY TECHNIQUES

The stepped rotating absorber to generate a spread-out Bragg peak
(SOBP) that was broad enough to treat a human tumor was first
proposed by Wilson (16). Koehler and Schneider from the HCL described
variable thickness rotating propellers that readily achieved the planned
distributions of proton energies that resulted in the desired SOBP (27).
They then developed a method for double scattering that achieved a
relatively flat lateral dose distribution (28), further refined by Gottschalk
and Wagner by the utilization of contoured bi-material filters (29).
Techniques for distal edge compensation (32) were also developed at the
MGH and the HCL (30–32). These latter beam modification systems and
techniques or variants thereof are still widely used in broad beam
energy-modulated proton beam therapy. Larsson at Uppsala developed a
technique of ridge filters to generate the required SOBPs (33). He was
the first to employ magnetic beam scanning for broad-beam SOBP on the
187-MeV proton beam (33). Kanai et al. developed beam scanning for
use in the proton beam line in Chiba, Japan (34).
Verhey et al. quite early developed methods of dosimetry (35) and
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accurate patient positioning (36) at the HCL. Goitein made a series of
major conceptual and practical contributions to proton therapy that are
equally applicable to photon therapy. These include the first 3D
treatment planning systems (37), DVHs (dose–volume histograms) (38),
DRRs (digitally reconstructed radiographs) (30), and the display of
uncertainty bands around isodose contours (30,39–41).
Even early in the history of PBT, it was recognized that the proton
charge would also enable magnetic scanning of narrow proton pencil
beams through the target. The first case of proton pencil beam scanning
was reported from Chiba in Japan (34). The scanning was achieved with
a 70-MeV proton beam, too low in energy to be attractive for clinical
application and the system was not used in patient treatments. Clinical
beam scanning, however, was employed in the pion program in
Switzerland between 1981 and 1992 (42) and led to its adoption for the
proton therapy program at the Paul Scherer Institute. Magnetic beam
scanning permitted the development of IMPT, which has emerged as the
preferred technique for PBT in many anatomic sites (43).
Protons versus 2D Photons

It must be recognized that protons developed initially in the 2D
radiation treatment planning era; in fact, 3D treatment planning was
developed by Michael Goitein to facilitate clinical proton radiation
therapy (39). Protons could successfully deliver higher radiation doses
with lower integral dose than was achievable with 2D or 3D photons,
explaining, in part why the majority of clinical studies that were initially
conducted were nonrandomized phase I and then phase II studies of
protons, because one could not deliver the same radiation dose(s) with
2D or 3D photons that were achievable with protons.
Indeed, in the phase III study of protons versus photons for prostate
cancer at the Harvard Cyclotron, patients received 50.4 Gy using
conventional 2D photons via a four-field box beam arrangement to a
CTV that included the prostate, seminal vesicles, and pelvic nodes, with
one half randomized to receive a boost to 67.2 Gy using conventional
photons through lateral portals and the other half to a total dose of 77.2
GyRBE using perineal protons (23). This study was really asking whether
the higher proton radiation dose of 77.2 GyRBE (established as safer in
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an earlier phase I dose escalation study) improved patient outcome; it
was judged not clinically feasible to deliver this radiation dose with
conventional photons. A similar dose question was asked in a second
randomized study conducted by MGH and Loma Linda investigators for
earlier stage prostate cancer diagnosed in the PSA era (44).
PROTON THERAPY IN THE AGE OF IMRT AND ADVANCED

TECHNOLOGY PHOTON THERAPY
It was only after the development of IMRT which permitted dose
escalation with photons that we were really able to frame the current
question about the role of protons versus photons in modern
radiotherapy. IMRT may achieve similar target doses as protons, and
may in fact be more conformal than 3D passively scattered protons in
the high-dose region but will almost always have higher integral doses
(45). IMPT should theoretically be as conformal as IMRT in the high-
dose region (46) but current studies are looking to ensure that IMPT is
“robust” so that the planned dose distribution is actually realized in the
patient (47). Hence, the relevant questions currently revolve around (1)
whether the lower integral dose which can be achieved in most patients
with protons compared to IMRT and other advanced technology photon
techniques (i.e., image-guided stereotactic radiation) results in
measurably lower acute or late toxicity, and if so, which patients derive
the most benefit and (2) whether the higher cost of protons (based on
the fact that protons are 1,800 times heavier than the electrons used for
photon generation, resulting in higher costs for acceleration and
steering) can be justified in terms of higher LC or survival or less toxicity
within a societally acceptable cost-effectiveness framework.
From first principles, it would follow that the largest benefit for
protons will be in the youngest patients (who will be at risk for the late
effects of radiation for the longest period of time) with potentially
curative (either localized or oligometastatic) tumors who require
treatment to large target volumes (where a larger volume of normal
tissue would be spared exit dose) or to a large proportion of a critical
organ (i.e., eye, liver) and need high doses of radiation. Some additional
clinical scenarios such as re-irradiation and large target volumes where
critical organs can be injured with irradiation such as lymphomas and
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breast cancers near the heart may also benefit from protons (48).
Patients with benign tumors, because of the greater likelihood of their
long-term survival, may also derive benefit from PBT. Winkfield et al.
evaluated eight different radiation techniques for treatment of pituitary
adenoma and found that PBT achieves the best therapeutic ratio when
evaluating treatment plans (49). Limiting the irradiated volume of
normal brain was desirable to minimize excess risk of radiation-
associated second tumors (49).
Systems for allocating patients for treatment with protons have been
developed based on ethical principles for allocation of scarce resources,
perceived benefit based on the best available evidence and expert
opinion, patient age, and eligibility for research protocols (50,51). In
spite of a PBT allocation system based on these principles, the practical
reality of proton treatment assignment was also related to whether a
patient’s insurance would cover the costs of proton treatment (51).
Because the lower integral dose associated with protons is judged to
offer the largest potential benefit in pediatric patients, a substantially
higher proportion of these patients currently receive protons than adult
patients. In 2012, it was estimated that ∼10% of pediatric cancer
patients in the United States were treated with proton radiation therapy
(52). This contrasts with the use of protons in the adult patient
population, where ∼0.85% of adult patients are treated with protons.
Between 2010 and 2012, there was a steady increase in the number of
pediatric patients receiving protons in the United States. In 2010, 465
pediatric patients were treated with proton radiation; 613 patients in
2011, and 694 patients in 2012. This represents an increase from ∼10%
of the total number of proton treatments in the United States in 2010 to
12% in 2011 and 13% in 2013. There are currently over 5,000 patients
per year in the United States receiving protons, although this remains
<1% of the patients undergoing radiation therapy each year in the
United States.
Acute Toxicity
There are data documenting a reduction in acute toxicity in patients
undergoing protons compared to photons. These include a study by
Brown et al. demonstrating less acute gastrointestinal and hematologic
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toxicity in adult patients undergoing craniospinal irradiation (CSI) with
protons compared to photons (53). Because CSI is such a large target
volume, it is a patient population where one would a priori expect an
advantage for protons; that is, the larger the target, the larger the
volume beyond the target that would be spared with protons (Fig. 19.2).
Proton CSI patients lost less weight than photon patients (1.2% vs. 5.8%;
p = 0.004), fewer proton patients had >5% weight loss compared with
photons (16% vs. 64%; p = 0.004). Proton patients experienced less
grade 2 nausea and vomiting (26% vs. 71%; p = 0.004) as well as a
smaller reduction in peripheral white blood cells, hemoglobin, and
platelets (white blood cells 46% vs. 55%, p = 0.04; hemoglobin 88% vs.
97%, p = 0.009; platelets 48% vs. 65%, p = 0.05). Patients treated with
photons were more likely to require medical management of esophagitis
(57% vs. 5%, p < 0.001).
Figure 19.2 Craniospinal irradiation with protons, illustrating sparing of tissues anterior to the
vertebral bodies including heart, mediastinum, thyroid, and lungs. (Courtesy of Judy Adams,
CMD, Massachusetts General Hospital, Boston, MA.)
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Potential Late Toxicity
The MGH and M. D. Anderson Cancer Center conducted a joint phase II
trial of passively scattered PBT for treatment of pediatric
rhabdomyosarcoma. Between 2005 and 2012, 54 patients were enrolled
and treated with proton therapy. As part of the study, IMRT plans for
comparison were also generated for each patient (54). The median
number of beams for IMRT plans were 7 versus 3 for proton therapy.
The mean integral dose was 1.8 times higher for IMRT (range 1.0 to 4.9)
in comparison to proton therapy. By site, the mean integral dose was 1.8
times higher for head/neck and genitourinary (p < 0.01), 2.0 times
higher for trunk/extremity (p < 0.01), and 3.5 times higher for orbit (p
< 0.01) in comparison to proton therapy. The authors argued the
reduction of dose in the low-to-medium dose region could result in a
clinically important difference in late effects. Specifically, they cited the
reduction of dose to hypothalamus in the patients treated for head and
neck rhabdomyosarcoma, since Merchant et al. (55) have reported that
growth hormone deficiency is seen in 50% of patients receiving 16 Gy
and 99% receiving 35 Gy to the hypothalamus. Ladra et al. observed
dose above 16 Gy to the hypothalamus in 15% of proton therapy plans
versus 30% of the IMRT plans (54).
Secondary Malignancy
Lower integral dose with protons could also reduce the risk of radiation-
associated secondary malignancies. Chung et al. compared 558 patients
treated with proton radiation from 1973 to 2001 at the Harvard
Cyclotron in Cambridge, MA, with 558 matched patients in the SEER
registry who were treated with photons (56). The median follow-up was
6.7 and 6.0 years, respectively, in the proton and photon cohorts.
Median age at treatment was 59 years for both cohorts. They observed
6.9 cancers per 1,000 person-years for the proton patients, and 10.3
cancers per 1,000 person-years for the photon patients. There was no
significant difference in proportion of second malignancies within the
primary field of radiation between the proton patients (10%) and photon
patients (16.7%). The authors suggest that the fewer observed cancers
with protons may be due to reduction of second cancers outside of
primary radiation field, possibly due to less integral dose from proton
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radiation.
Modeling studies suggest a significant reduction in the risk of second
malignancies with protons compared to photons (57–59). Proton beams
reduced the expected incidence of radiation-induced secondary cancers
for a pediatric patient with an orbital rhabdomyosarcoma by a factor of
≥2 and for a medulloblastoma patient undergoing CSI by a factor of 8 to
15 when compared with either intensity-modulated or conventional x-
ray plans (57). Notably, protons provided more risk reduction for larger
radiation target volumes than smaller ones.
Nevertheless, secondary malignancies are relatively uncommon with
modern radiotherapy. An analysis of SEER data by Berrington de
Gonzalez et al. estimated that five excess cancers per 1,000 patients
could be attributed to radiotherapy 15 years after diagnosis, that is,
0.5% risk at 15 years (60). Therefore, a very large number of patients
would be required to show a difference in the rate of secondary
malignancies after proton versus photon radiation therapy. Assuming an
80% power to detect a target of 60% reduction in radiation-associated
second malignancies with a significance level of 0.05, Dr. Beow Yeap
(Harvard Medical School, personal communication) estimated that
13,509, 6,759, or 4,510 patients would be needed in each arm if there
were 5, 10, or 15 years average follow-up available in the studied
patients using one-sided statistics (with the assumption that protons
could only lower the risk of radiation-associated malignancy); if a two-
sided test were used (with the assumption that protons could either
decrease or increase the risk), those numbers would increase to 17,280,
8,646, and 5,768 patients. These numbers are prohibitively large for any
randomized clinical trial looking to use protons to reduce the risk of
radiation-associated second malignancy, although this question might be
amenable to a registry or database assessment.
However, selected patient populations are known to carry a higher
risk of a second malignancy. Kuttesch et al. estimated the cumulative
risk of a second malignancy in young patients treated for Ewing sarcoma
as 9.2% at 20 years (61). In this patient population, Dr. Yeap (Harvard
Medical School, personal communication) estimated that only 1,264,
638, and 430 patients (with 5, 10, or 15 years average follow-up) would
be needed in the proton and in the photon cohort to have an 80% power
to detect a 60% reduction in second malignancy risk with a p-value of
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0.05. Dr. Torunn Yock is leading an ongoing multi-institutional Pediatric
Proton Consortium Registry (62). The goal of the registry is to determine
the acute and late effects in the children enrolled at the participating
proton facilities. It is hoped that the collected data, when compared to
photon-treated patients, will help clarify whether protons can contribute
to second malignancy reduction in a high-risk patient population.
Cost-Effectiveness
Mailhot Vega et al. performed a cost-effectiveness analysis from a
societal perspective using a Monte Carlo simulation model, based on a
population of 18-year-old patients treated at age 5 for a
medulloblastoma and who were at risk for developing 10 possible
adverse events including growth hormone deficiency, coronary artery
disease, ototoxicity, secondary cancers, and death (63). Costing data
included the cost of investment and the costs of diagnosis and
management of adverse health states from institutional and Medicare
data. Longitudinal outcomes data and recent modeling studies informed
risk parameters for the model. Incremental cost-effectiveness ratios were
used to measure outcomes. Results from the base case demonstrated that
proton therapy was associated with higher quality-adjusted life years
and lower costs; therefore, it dominated photon therapy. In one-way
sensitivity analyses, proton therapy remained the more attractive
strategy, either dominating photon therapy or having a very low cost per
quality-adjust life year gained. Probabilistic sensitivity analysis
illustrated the domination of proton therapy over photon therapy in
96.4% of simulations, demonstrating that proton therapy is a cost-
effective strategy for the management of pediatric patients with
medulloblastoma compared with standard of care photon therapy.
Cost-effectiveness seems reasonably assured in the pediatric
population. In the adult patient population, however, cost-effectiveness
determinations are still emerging, hampered in part by the lack of
comparative clinical outcome data. However, it is expected that the
results will depend on the particular cancer, the anatomic site, the size
of the target volume, and the available alternatives. In a systematic
review of the cost-effectiveness of radiation therapy for prostate cancer,
PBT was not judged to be cost-effective (64). On the other hand,
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Lundqvist et al. found that proton therapy for breast cancer could be
cost-effective if appropriate risk groups, such as those with left-sided
breast cancer at risk for cardiac disease, are chosen as candidates for the
therapy (9).
For countries without their own facilities for proton therapy, the cost
of referral abroad for their patients can be substantial. For example, the
Alberta Health Service estimated that Canada sent 96 patients abroad at
a mean cost of $200,000 per patient in 2013. In addition to the specific
diagnosis, the Alberta guideline also requires patients to be treated with
curative intent, to have good performance status, and life expectancy
>5 years (65). While the upfront cost of building a proton facility may
be relatively high, there may be long-term economic benefit by investing
in such facilities. Worldwide, there are 56 particle therapy centers in
operation as of the beginning of 2015, of which 48 are PBT centers, and
eight offer carbon ion therapy (5).
Proton radiation therapy, especially with more advanced techniques
such as IMPT and in vivo dosimetry, can offer superior dose distribution
versus photon radiation. However, the substantial difference in cost
between proton therapy and photon therapy, and the lack of direct
comparison of clinical outcome, prevent more widespread adaption of
proton therapy. With more clinical evidence, and continued reduction in
cost, proton therapy is likely to play an increasingly important role in
radiation therapy.
This discussion, of course, also raises the question of whether the cost
of proton therapy can be reduced, as this would improve its cost-
effectiveness. Indeed, Newhauser et al. were able to document cost
reduction for proton treatment of prostate cancer with passively
scattered protons by using a multi-leaf collimator instead of custom-
fabricated apertures as well as modest hypofractionation strategies (66).
Hong et al. were able to deliver a well-tolerated five-fraction
hypofractionated course of preoperative proton chemoradiation of 5
GyRBE/fraction concurrent with capecitabine in a week (67); the
radiation therapy charges for this regimen were lower than those for a
standard 28-fraction, 5.5-week course of 3D conformal or IMRT photon
course of radiation (T. Hong MD, personal communication). The initial,
hospital-based proton centers generally included a proton accelerator
and multiple treatment rooms, generally with multiple gantries (26).
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More recently, smaller single-room facilities have been developed with
markedly reduced initial capital costs and lower estimated cost per
patient (8). These efforts to reduce the costs of proton therapy will
improve its cost-effectiveness and make it cost-effective for a broader
group of adult patients.
Requirements for the Radiation Oncologist and Radiation

Physicist
The American College of Radiology (ACR) and ASTRO have published a
Practice Parameter for the Performance of Proton Beam Radiation
Therapy (68). The guideline calls for specific training in proton therapy
for the physician prior to performing any such treatments. Specifically,
the radiation oncologist must understand the spatial distribution of the
proton beam, with particular attention given to sharp dose fall-off at the
distal and lateral edges, which can lead to underdosing of target, or
overdosing of critical structures.
Details regarding the qualifications and responsibilities of the qualified
medical physicist for proton therapy are enumerated in the ACR–
American Association of Physicists in Medicine (AAPM) Technical
Standard for the Performance of Proton Beam Radiation Therapy (69).
Notably, the qualified medical physicist must have proton-specific
training before assuming responsibility for the technical aspects of
patient care for patients receiving proton therapy.
ASTRO Recommendations Regarding Proton Beam

Therapy
There is currently no uniform consensus on whom should be treated
with PBT. ASTRO considers protons reasonable in instances where
sparing the surrounding normal tissue cannot be adequately achieved
with photon-based radiotherapy and are of adequate clinical benefit to
the patient (70). Examples of such advantages might be (1) when the
target volume is in close proximity to one or more critical structures and
a steep dose gradient outside the target must be achieved to avoid
exceeding the tolerance dose to the critical structure(s); (2) a decrease in
the amount of dose inhomogeneity in a large treatment volume is
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required to avoid an excessive dose “hotspot” within the treated volume
to lessen the risk of excessive early or late normal tissue toxicity; (3) a
photon-based technique would increase the probability of clinically
meaningful normal tissue toxicity by exceeding an integral dose-based
metric associated with toxicity; or (4) the same or an immediately
adjacent area has been previously irradiated, and the dose distribution
within the patient must be sculpted to avoid exceeding the cumulative
tolerance dose of nearby normal tissue. ASTRO indicated that the final
determination of the appropriateness and medical necessity for PBT
resides with the treating radiation oncologist who should document the
justification for PBT for each patient.
Based on these considerations and published data, ASTRO noted that
disease sites that frequently support the use of PBT include for ocular
tumors including intraocular melanomas, skull base tumors including
chordoma and chondrosarcomas, primary or metastatic tumors in the
spine where spinal cord tolerance may be exceeded with photons or
where the spinal cord has previously been irradiated, hepatocellular
carcinoma treated in a hypofractionated regimen, primary or benign
solid tumors in children treated with curative intent as well as
occasional palliative treatment of childhood tumors where at least one of
the four considerations noted above apply. In addition, proton therapy
should be considered for patients with certain genetic syndromes.
For other disease sites and patients, ASTRO suggested that there was a
need for continued evidence development and comparative effectiveness
analyses for the appropriate use of PBT for various disease sites. Other
anatomic sites would be considered appropriate for insurance coverage
as long as the patient was enrolled in either an IRB-approved clinical
trial or a multi-institutional registry adhering to Medicare requirements
for Coverage with Evidence Development. These latter would include
but not be limited to head and neck, thoracic, abdominal, and pelvic
malignancies, including genitourinary, gynecologic, and gastrointestinal
tumors. ASTRO felt it was essential to develop additional evidence for
the use of PBT for prostate cancer, in particular, its effectiveness
compares with IMRT and brachytherapy, calling for the use of PBT for
prostate cancer only within the context of a prospective clinical trial or
registry, with a plan to revise its recommendations as evident from these
studies emerged.
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ASTRO also outlined clinical scenarios for which PBT is rarely
indicated, including (1) situations where PBT does not offer an
advantage over photon-based therapies that otherwise deliver good
clinical outcome and low toxicity; (2) spinal cord compression, superior
vena cava syndrome, malignant airway obstruction, poorly controlled
tumor hemorrhage, and other urgent scenarios; (3) inability to
accommodate tumor or organ motion; and (4) palliative treatment in a
clinical situation where normal tissue tolerance would not be exceeded
in previously irradiated areas.
Highlights of Clinical Results with Proton Beam Therapy

Some salient results achieved with PBT are discussed below. Given the
limitations of space, the reader is referred to a monograph dedicated to
this subject (71) or published reviews (72–80).
Pediatric Tumors
Retinoblastoma. A retrospective review was performed on
retinoblastoma patients, 55 of whom were treated with PBT at the MGH
and 31 were treated with photon therapy at Boston Children’s Hospital.
With median follow-up of 6.9 years in the proton cohort, and 13.1 years
in the photon cohort, the 10-year in-field secondary malignancy rate was
0% in the proton group versus 14% in the photon group (p = 0.015)
(81).
Ependymoma. Seventeen pediatric patients with ependymoma who
were treated with PBT at Francis H. Burr Proton Center and Harvard
Cyclotron had comparative IMRT plans generated. These demonstrated
substantial sparing of normal tissue with proton beam therapy (82). At a
median follow-up of 26 months from the start date of radiation therapy,
LC, progression-free survival, and overall survival rates were 86%, 80%,
and 89%, respectively.
Rhabdomyosarcoma. Yock et al. reported seven children who were
treated for orbital rhabdomyosarcoma with proton irradiation and
standard chemotherapy (83). Local and distant disease control compared
favorably to those in other published accounts. Conformal 3D photon
and proton radiotherapy plans with dose–volume histograms were
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generated for the patients and compared for important orbital and
central nervous system structures. Protons provided a dosimetric
advantage in limiting the dose to the brain, pituitary, hypothalamus,
temporal lobes, and ipsilateral and contralateral orbital structures.
Tumor size and location affected the degree of sparing of normal
structures.
Kozak et al. compared tumor and normal tissue dosimetry of PBT with
intensity-modulated radiation therapy (IMRT) for 10 patients with
pediatric parameningeal rhabdomyosarcomas. Proton and IMRT plans
provided acceptable and comparable target volume coverage but proton
therapy resulted in significant sparing of all examined normal tissues
except for ipsilateral cochlea and mastoid; ipsilateral parotid gland
sparing was of borderline statistical significance (p = 0.05) (84).
Ewing Sarcoma. Rhombi et al. reported 30 children with Ewing
sarcoma treated with chemotherapy and PBT to a median dose of 54
GyRBE. The 3-year actuarial rates of event-free survival, LC, and overall
survival were 60%, 86%, and 89%, respectively (85). PBT was acutely
well tolerated, with mostly mild-to-moderate skin reactions. At the time
of the report, the only serious late effects were four hematologic
malignancies, which are known risks of topoisomerase and anthracycline
exposure.
Medulloblastoma and Supratentorial Primitive Neuroectodermal
Tumors. Jimenez et al. reported on early outcomes for 15 children aged
<5 years treated with induction chemotherapy followed by 3D
conformal craniospinal PBT followed by involved-field PBT or involved-
field PBT alone for these tumors (86). At a median of 39 months from
completion of radiation, 2 of 15 had died, one after a local failure and
one from a non–disease-related cause, while the remaining 13 patients
were alive without evidence of disease recurrence. Ototoxicity and
endocrinopathies were the most common long-term toxicities, with two
children requiring hearing aids and three requiring exogenous hormones.
Central Nervous System Tumors

Benign. PBT may be especially beneficial for patients with benign CNS
tumors because of the potential for very long survival, and thus, greater
period at risk for developing secondary malignancy. Single fraction
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proton beam stereotactic radiosurgery for cerebral arteriovenous
malformations has shown 5- and 10-year cumulative incidences of total
obliteration of 70% and 91%, with median time to total obliteration of
31 months (87). Winkfield et al. evaluated eight different radiation
techniques for treatment of pituitary adenoma and found that PBT
achieves the best therapeutic ratio when evaluating treatment plans
(49).
Intracranial Meningioma. The Paul Scherrer Institute used scanning-
based proton therapy to treat 39 patients with meningioma, with median
GTV size of 21.5 cc. The 5-year actuarial LC was 84.8% for entire cohort,
and 100% for benign histology. With a mean follow-up of 62 months,
the cumulative 5-year grade 3 late toxicity-free survival was 84.5% (88).
Adult Medulloblastoma Craniospinal Irradiation. M. D. Anderson
conducted a retrospective review of 21 patients treated with photon CSI,
and 19 patients treated with proton CSI. As noted above, PBT patients
experienced significantly less acute weight loss, nausea and vomiting,
esophagitis, and cytopenias (53).
Ocular Tumors
Fifty-nine patients were treated with 54 GyRBE or 60 GyRBE in
Vancouver with PBT for ocular melanoma. The treatments were
delivered in four fractions on four consecutive days at TRIUMF cyclotron
facility, with the proton beam energy set at 74 MeV. The 5-year actuarial
LC rate was 91% (97% in patients treated with 60 GyRBE). The eye
conservation rate was 80%. At median follow-up of 63 months, there
was a 31% rate of neovascular glaucoma, and 74% rate of retinopathy
(89). Princess Margaret Hospital in Toronto, Canada, treated 64 patients
with ocular melanoma with stereotactic photon radiation, 70 Gy in five
fractions over 10 days. With a relatively shorter 37-month follow-up
period, there were higher rates of neovascular glaucoma (42%) and
retinopathy (81%) reported (90).
Bone and Soft Tissue Sarcomas

Skull base chordoma and chondrosarcoma can be a challenge to
manage with conventional photon radiotherapy, due to the inherent
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relative radioresistance of the tumors, as well as the proximity of the
tumors to neurologic structures. A retrospective review of 621 patients
with spinal and skull base chordomas or chondrosarcomas treated at the
HCL reported 5-year local relapse-free and overall survival rates of 73%
and 80%, respectively, for chordoma and 98% and 91% for
chondrosarcoma (91).
Chordomas have traditionally to be considered very radioresistant,
and surgical resection was considered the only curative treatment. A
retrospective review reported 24 patients with spinal chordomas treated
with definitive combined proton/photon radiation to a median total dose
of 77.4 GyRBE after biopsy and without surgical resection. At median
follow-up of 56 months, the 5-year overall survival rate was 78.1%,
chordoma specific survival rate was 81.5%, local progression-free
survival rate was 79.8%, and metastases-free survival rate was 76.3%
(92).
DeLaney et al. reported the long-term results of a prospective phase II
clinical trial incorporating high-dose proton-based RT for patients with
primary or locally recurrent thoracic, lumbar, and/or sacral
spine/paraspinal chordomas or sarcomas (93). Treatment included pre-
and/or postoperative photon/proton RT +/− radical resection. Fifty
patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross
total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13).
Radiation dose was ≤72.0 GyRBE in 25 patients and 76.6 to 77.4
GyRBE in 25 patients. With 7.3-year median follow-up, the 5- and 8-year
actuarial LC rates were 94% and 85% for primary tumors and 81% and
74% for the entire group. Local recurrence was less common for primary
tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, p = 0.002.
The 8-year actuarial risk of grade 3 to 4 late RT morbidity was 13%. No
myelopathies were seen. No late neurologic toxicities were noted with
radiation doses ≤72.0 GyRBE while three sacral neuropathies appeared
after doses of 76.6 to 77.4 GyRBE. The authors concluded that LC with
this treatment was high in patients with primary tumors with acceptable
late morbidity (93).
Ciernik et al. reported the results of PBT for unresectable or
incompletely resected osteosarcoma (94). Fifty-five patients were
treated to a mean dose of 68.4 GyRBE. LC rates after 3 and 5 years were
82% and 72%, respectively. The 5-year DFS was 65%, and the 5-year OS
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was 67%. Risk factors for local failure were ≥2 grade disease (p <
0.0001) and prolonged treatment time (p = .008). Grade 3 to 4 late
toxicity was seen in 30.1% of patients. One patient died from treatment-
associated acute lymphocytic leukemia, and another from secondary
carcinoma of the maxilla. The authors concluded that PBT allows locally
curative treatment for some patients with unresectable or incompletely
resected osteosarcoma.
HEAD AND NECK TUMORS

An M. D. Anderson dosimetric study of IMRT versus spot-scanned PBT
for five patients with head and neck cancer showed lower mean dose to
oral cavity, brainstem, spinal cord, and contralateral parotid and
submandibular glands using protons. The maximum doses to the spinal
cord and brainstem were also lower with scanned PBT than with IMRT
(95). The University of Pennsylvania reported a dosimetric study
comparing IMRT versus pencil beam-scanned PBT in a series of eight
patients receiving postoperative radiation therapy for parotid gland
carcinoma. The prescription target dose was 60 Gy(RBE). Scanning
beam PBT had a lower mean dose to the ipsilateral cochlea and temporal
lobe, as well as the contralateral parotid gland. The maximum brainstem
dose was 22.9 Gy with IMRT versus 1.6 GyRBE with scanning beam PBT
(96).
A phase II trial of chemoradiation using PBT for nasopharyngeal
carcinoma enrolled 23 patients, stages IIB to IVB (61% T3–4, 75% EBV
positive) from 2006 to 2012. With a median follow-up of 4 years, the
investigators reported 92% 4-year locoregional control, 91% overall
survival, and 87% distant-metastasis-free (97). A randomized phase II
study of IMRT versus IMPT for chemoradiation of nasopharyngeal cancer
has been proposed (http://grantome.com/grant/NIH/U19-CA021239–
35). Figure 19.3 illustrates oral cavity sparing that can be achieved with
IMPT versus IMRT.
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Figure 19.3 Comparative plans illustrate oral cavity sparing that can be achieved with IMPT (A)
versus IMRT (B).
A randomized phase II study of IMRT versus IMPT of oropharyngeal

cancer (NCT01893307) is now underway at M. D. Anderson and
collaborating centers
(https://clinicaltrials.gov/ct2/show/NCT01893307?
term=oropharynx+and+proton&rank=2).
Lung Cancer
Chang et al. enrolled 44 patients in a phase II study of concurrent
weekly carboplatin and paclitaxel with 74 GyRBE in 37 fractions of
passively scattered PBT for treatment of stage III NSCLC (98). Median
overall survival time was 29.4 months and no patient experienced grade
4 or 5 proton-related adverse events. Nine (20.5%) patients experienced
local disease recurrence, but only 4 (9.1%) had isolated local failure. The
overall survival and progression-free survival rates were 86% and 63%
at 1 year. This led to a phase II study comparing photons versus photon
chemoradiation for locally advanced NSCLC (NCT00915005,
https://clinicaltrials.gov/ct2/show/NCT00915005?
term=lung+cancer+and+proton&rank=13), the results of which are
pending, and an ongoing NRG Oncology phase III study (NCT01993810)
comparing photons versus protons in these patients
(https://clinicaltrials.gov/ct2/show/NCT01993810?term =
lung+cancer+and+proton&rank=4).
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Esophageal Cancer
Investigators at Tsukuba University evaluated 40 consecutive patients
with esophageal cancer treated with chemotherapy and concurrent
passively scattered PBT to a total dose of 60 GyRBE/30 fractions, with
additional 4 to 10 GyRBE boost when residual tumors were suspected.
No cardiopulmonary toxicities of grade 3 or higher were observed.
Recurrences were observed in 16 patients, and the 2-year rates of
disease-specific survival and locoregional control were 77% and 66%,
respectively (99). A randomized Phase III study of protons versus IMRT
for esophageal cancer is currently underway (NCT01512589,
https://clinicaltrials.gov/ct2/show/NCT01512589?
term=proton+radiation+esophageal+ cancer&rank=2).
Hepatocellular Carcinoma
High rates of local tumor control with low rates of toxicity have been
reported for hepatocellular carcinoma with PBT by several groups
(100–102). The group at Tsukuba University reported LC rates after 1, 3,
and 5 years of 98%, 87%, and 81%, respectively (100). An ongoing
study is currently comparing transarterial chemoembolization versus
proton beam radiotherapy for the treatment of hepatocellular carcinoma
(NCT00857805, https://clinicaltrials.gov/ct2/show/NCT00857805?
term=proton+radiation+hepatocellular&rank=6).
Breast Cancer
The use of hypofractionated regiments in proton therapy may be a
potential option to balance the relatively high cost of proton therapy.
Loma Linda University treated 50 patients with 40 GyRBE in 10 fractions
over 2 weeks after lumpectomy for early-stage breast cancer. Actuarial
5-year overall survival and disease-free survival were 96% and 92%,
respectively. There was near complete elimination of dose to
contralateral breast, lung and heart, thus, allowing hypofractionation to
be done safely. There were no reported cases of fat necrosis, rib
fractures, radiation pneumonitis, or cardiac events (103).
Long-term risk of cardiovascular events such as congestive heart
failure, coronary artery disease, and myocardial infarction can be
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increased following postmastectomy radiation therapy, especially for
left-sided breast cancer. The relatively risk of these events have been
estimated to be 1.2 to 3.5 (104). The MGH conducted a phase I trial on
postmastectomy radiation therapy with PBT for 12 patients. Eleven of
the patients had left-sided breast cancer, and one patient had right-sided
breast cancer with bilateral implants. All patients were treated to 50.4
GyRBE to chest wall and regional lymphatics. Proton therapy allowed
excellent coverage of target volume, with D95 of 46.3 GyRBE to
combined CTV, while limiting average V20 (GyRBE) of heart to 0.01%,
and mean V20 of lung to 12.7% (105).
The Patient-Centered Outcomes Research Institute has recently funded
a study in which The Radiotherapy Comparative Effectiveness
(RADCOMP) Consortium will conduct a pragmatic randomized clinical
trial in which 1,716 patients with stage II and III breast cancer
involving axillary or supraclavicular lymph nodes will be randomized
after surgery to either proton therapy or photon therapy
(http://www.pcori.org/research-results/2015/pragmatic-randomized-
trial-proton-vs-photon-therapy-patients-stage-ii-or-iii).
Glioblastoma
The RTOG-NRG is currently conducting a trial of dose escalated IMRT or
proton therapy versus conventional photon radiation with concurrent
temozolamide in patients with newly diagnosed glioblastoma. The
higher dose arm will receive 75 Gy CTV2/50Gy CTV1 via simultaneous
integrated, dose-painted technique in 30 fractions by proton or IMRT,
and the conventional arm will receive 60 Gy CTV2/50Gy CTV1. This
phase II study will permit indirect comparison of photon IMRT to proton
therapy for overall survival, neurocognitive function and patient-
reported quality of life (106).
Prostate
A study utilizing Medicare data argued that there was no significant
difference in toxicity for treatment of prostate cancer utilizing IMRT
versus proton therapy in 2008 and/or 2009, with proton therapy being
significantly more costly than IMRT (107). However, one may argue that
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there are limitations when extrapolating from retrospective Medicare
data, and that the proton therapy techniques have evolved since that
time. The MGH and the University of Pennsylvania are leading a multi-
center phase III randomized trial, Prostate Advanced Radiation
Technologies Investigating Quality of Life (PARTIQoL), comparing IMRT
versus proton therapy for treatment of prostate cancer (108). The trial
plans to enroll 400 patients.
KEY POINTS
• Proton radiation allows a reduction in integral dose compared to
photons of up to 60%.
• In the era of 2D and 3D photons, protons were able to deliver
higher radiation dose to the target in clinical studies that included
prostate, ocular melanoma, and skull base sarcomas.
• Image-guided IMRT can often deliver comparable target doses to
protons, although integral dose with protons may be up to 60%
lower.
• Protons are increasingly the preferred radiation dose for children,
where the lower integral dose is acknowledged to have the highest
potential benefit.
• The clinical significance of the lower integral dose of protons
compared to IMRT is currently being tested in adults in multiple
randomized controlled clinical trials.
• The original mode of proton delivery, passively scattered protons, is
being replaced by spot-scanned proton treatment, which also
allows IMPT. Some new proton facilities only have spot scanning
technology available.
• The clinical use of protons may require the use of adaptive re-
planning as well as “robust” treatment planning to ensure that the
planned dose distribution is actually realized in the patient.
• Carbon ions are charged particles with a mass 12 times heavier
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than protons with a higher RBE. They are being compared in
randomized clinical trials to see if they offer any clinical advantage
over protons.
QUESTIONS
1. What is a potential disadvantage of passively scattered protons
compared to spot-scanned protons?
A. Higher RBE.
B. Lower RBE.
C. Higher scattered neutron dose.
D. Lower scattered neutron dose.
2. The potential clinical advantage for protons compared to photons
is:
A. Biologic, related to higher oxygen enhancement ratio with
protons
B. Biologic, related to higher LET than carbon ions
C. Physical, related to the photoelectric effect
D. Physical, related to lower integral dose than photons
3. Magnetically spot-scanned proton beams
A. Are being replaced by passively scattered protons in new
proton facilities
B. Allow for intensity modulated proton therapy
C. Are available in only one energy
D. Require range modulators to spread out the Bragg peak.
4. The higher RBE of the carbon ion
A. Has been shown to improve clinical outcome
B. May provide a clinical advantage for tumors not well treated
by protons
C. Fortunately does not change over the course of the range of
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the ion
D. Prevents the use of spot scanning with carbon ions.
5. The greatest potential normal tissue sparing with protons
compared to photons
A. Is with the largest target volumes
B. Is with the smallest target volumes
C. Is at the highest energies
D. Is at the lowest energies
ANSWERS
1. C
2. D
3. B
4. B
5. A
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and Adjuvant Temozolamide in Patients with Newly Diagnosed
Glioblastoma. Philadelphia, PA: NRG Oncology;. Available at:
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107. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated
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20 Fractionation: Radiobiologic
Principles and Clinical Practice
Colin G. Orton
INTRODUCTION
Radiotherapy for the treatment of cancer was first started in 1896 but it
was not realized that fractionation was essential if cancerocidal doses
were to be delivered without exceeding normal tissue tolerance until
1932. It was then that Henri Coutard published the excellent results he
had obtained using fractionated radiotherapy (1) and fractionation was
thereafter established as the standard of practice. However, it took many
decades before the radiobiologic rationales for fractionated radiotherapy
were fully understood.
RADIOBIOLOGIC PRINCIPLES OF FRACTIONATION

The basic principle of radiotherapy is the destruction of all cancer cells
without killing so many normal cells as to exceed tolerance. Thus, cell
survival and the shape of cell-survival curves is of utmost importance in
radiotherapy.
Cell-Survival Curves
A plot of the fraction of surviving cells as a function of dose for acutely
irradiated cells is shown in Figure 20.1. Note that surviving fraction is
plotted on a log scale. This is partly because, as we will see later, the
shape of the log-linear survival curve for specific cell types tells us
something about the important radiobiologic properties of these cells,
and partly because much of the important information about cell
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survival is contained within the low- and high-dose extremes of the
survival curve (regions A and B in Fig. 20.1). Plotting cell survival on a
log scale helps us visualize and study the shape of the survival curve in
these regions. It is low doses per fraction (in region A) that are
commonly used for fractionated radiotherapy (1 to 3 Gy/fraction) and,
to cure a tumor with typically 108 to 1010 cells, cell-surviving fractions
as low as 10−8 to 10−12 are required (region B).
Since the shapes of cell-survival curves are so important, it is
necessary to have a mathematical model that can predict these shapes.
Currently, the model of choice is the linear quadratic (LQ) theory of cell
survival.
Linear Quadratic Theory

The basis of the LQ theory is that a cell is inactivated only when both
strands of a deoxyribonucleic acid (DNA) molecule are damaged in close
proximity. Actually, this is a gross oversimplification of the highly
complex chemical and biologic responses triggered by irradiation of
cells, but this was the basic assumption made when the LQ model was
first devised (2) so, for simplicity, we will adopt this approach here.
Readers interested in a more thorough (and accurate) discussion of the
complex events that occur when cells are irradiated are referred to an
excellent review by Wouters and Begg (3).
On this simple model, double-strand breaks in close proximity can be
produced either during the passage across the cell of a single ionizing
particle or by independent interactions by two separate ionizing
particles. Such events are random and, because there are large numbers
of cells, the probability that any specific DNA molecule will be damaged
will be extremely low. Under such conditions, the statistics of rare events
(Poisson statistics) prevails. According to Poisson statistics, the
probability, P0, of there being no such events, is given by the expression
(4):
where p is the mean number of hits per target molecule. For single-
particle events, p is a linear function of dose, D, so the mean number of
lethal events per DNA molecule can be expressed as αD and P0 represents
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the probability of there being no single-particle–induced lethal events,
that is, it is the surviving fraction of cells, S. Then, Equation 20.1 can be
written as:
where α is the average probability per unit dose that such a single-
particle event will occur. In order for a single particle to damage both
arms of the DNA in its passage across the molecule, it has to be fairly
densely ionizing, that is, high linear energy transfer (LET). With photon
and electron irradiation, it is only the slow electrons that are responsible
for most of these interactions. Conversely, when cells are irradiated with
high-LET radiations, such as α-particles and heavy ions, almost all the
events will be by single particles, so cell survival will be governed by
Equation 20.2 and cell survival will be an exponential function of dose
so that survival curves plotted on log-linear scales will be practically
linear.
For the two separate ionizing particle events of the LQ theory, the
mean probability of one particle causing damage in one arm of a DNA
molecule in any specific cell is linearly proportional to dose, as also is
the mean probability that a second particle will have such an interaction
in the adjacent arm of this same DNA molecule. Therefore, unless the
damage to the first arm of the DNA is repaired before the damage to the
second arm occurs (see section on Repair later), the mean probability of
both arms being damaged at any one time is βD 2, so the probability that
no such two-particle events will occur, that is, the surviving fraction S, is
given by:
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Figure 20.1 Graph showing the surviving fraction of cells (log scale) as a function of dose. The
two shaded areas represent the regions of most interest in fractionated radiotherapy for which
doses per fraction normally range from 1 to 3 Gy (region A) and the cell-surviving fraction required
to control a typical tumor containing 108 to 1010 cells must be on the order of 10−8 to 10−12
(region B). This hypothetical graph has been constructed according to the linear quadratic (LQ)
model with parameters α = 0.4 Gy−1, α/β = 10 Gy.
where β is the mean probability per unit square of the dose that such
complementary events will occur.
The overall LQ equation for cell survival is therefore:
This is illustrated in Figure 20.2, which shows how the two

components of cell killing, α-damage and β-damage, combine to form the
cell-survival curve. It will be shown later that α-damage and β-damage
relate to irreparable and repairable damage, respectively. For two-
particle events (β-type), if the damage from the second particle occurs
before the lesion from the first particle has been repaired, the cell will be
inactivated (“killed”). Since cellular repair half-times are of the order of
1 hour, this gives rise to the dose-rate effect: the higher the dose rate,
the greater the effect.
Figure 20.2 Linear-quadratic cell-survival curve, with α = 0.22 Gy−1 and α/β = 2.5 Gy, and d is the
dose/fraction. Note that the log cell kill for α-type damage equals that for β-damage at a dose
equal to α/β.
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Figure 20.3 Typical survival curves for cancer and late-reacting normal tissue cells, superimposed
for comparison. Compared with the cancer curve, the normal tissue cell-survival curve has a
shallower initial slope (lower α) and is “curvier” (lower α/β). Note that there is a “Window of
Opportunity” below ∼4 Gy (with the parameters used here) where normal tissue cells exhibit a
higher survival than cancer cells. Parameters used to draw these hypothetical curves are as
follows: tumor, α = 0.4 Gy−1, α/β = 10 Gy; late-reacting normal tissues, α = 0.22 Gy−1, α/β = 2.5
Gy.
Of special interest is the dose at which the log-surviving fraction for α-

damage (e−ad) equals that for β-damage ( ), that is, αd = βd2, or d =
α/β. This is also illustrated in Figure 20.2. This parameter, α/β,
represents the curviness of the cell-survival curve. Specifically, the
higher the α/β, the straighter the survival curve. A high α/β is
characteristic of a type of cell that exhibits considerable irreparable
damage and/or little repair (high α and/or low β). In contrast, a low α/β
(low α and/or high β) indicates little irreparable damage and/or a high
capability of repair. Here lies the major difference between the cells of
tumors and those of late-responding normal tissues: α/β values tend to
be high for cancers and low for late-reacting normal tissues. For
example, typical α/β values determined for cancer cells range from 5 to
20 Gy (mean ∼10 Gy), but for late-responding normal tissues the range
is 1 to 4 Gy (mean ∼2.5 Gy). There appear to be some exceptions,
however. For example, the α/β values for prostate and breast cancer cells
have been reported to be about 1.5 and 4 Gy, respectively (5,6).
Figure 20.3 shows typical survival curves for tumor and late-reacting
normal cells, superimposed for comparison. The difference in the shapes
of cell-survival curves of cancer and normal cells provides the major
rationale for fractionated radiotherapy.
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Rationale for Fractionation
Radiotherapy, in general, is governed by the four Rs: repair,
reoxygenation, repopulation, and redistribution, and so also is
fractionation. Following is a discussion of how each of the four Rs affects
the practice of fractionation.
Repair
Of the four Rs, repair is the most important in terms of the rationale for
fractionation. As discussed in the preceding section, late-reacting normal
tissue cells tend to exhibit a greater propensity for repair than do tumor
cells. This is exhibited by their low α/β values and hence their curvier
survival curves, as shown in Figure 20.3. In this illustration, the normal
tissue and tumor cell curves cross at doses of the order of 4 Gy. At doses
below the crossover point, cell survival for late-reacting tissues is greater
than that for tumors, and the reverse is true above the crossover. This
means that delivery of doses greater than ∼4 Gy will be more
destructive to normal tissues than to cancer cells. There is essentially a
“Window of Opportunity” centered at ∼2 Gy within which normal cells
have a greater survival than cancer cells. However, doses far in excess of
4 Gy are needed to control tumors. There are two ways to safely deliver
such high doses. One is to deliver much higher doses to the tumor than
to the normal tissues, such as with stereotactic radiosurgery (SRS),
intensity-modulated radiation therapy (IMRT), and various other forms
of conformal therapy. This will be discussed in detail later. The second
option is to fractionate with doses/fraction within the “Window of
Opportunity.”
If a course of fractionated radiotherapy is delivered with time between
fractions sufficient for complete repair (which clinical evidence has
shown to be about 6 hours or more), all the cells that have been
sublethally (but not lethally) damaged during the first fraction (i.e., only
one DNA strand has been damaged or both arms are damaged but the
lesions are far apart), will have repaired before the second fraction is
delivered, and so on. This relates to the β-type damage in the LQ model.
Then, at least to a first approximation, cell-surviving fractions for each
successive treatment will be identical and the shape of the survival curve
will simply repeat for each fraction. Then the cell-surviving fraction
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equation becomes:
where N is the number of fractions and d is the dose/fraction. Then, if

the dose per fraction is below the crossover point shown in Figure 20.3,
the resultant cell-survival curves gradually separate, with tumor cells
suffering more damage than normal cells, as illustrated in Figure 20.4,
which has been derived using Equation 20.5.
At least as far as repair is concerned, the optimal dose per fraction is
that which will produce the maximum separation of the two fractionated
radiotherapy curves in Figure 20.4. However, the LQ model predicts that
this maximum separation occurs with an infinite number of infinitely
small dose fractions, each separated by sufficient time for complete
repair. Clearly, this is not a realistic fractionation scheme, and in any
event it ignores the influence of the other three Rs of radiotherapy,
especially repopulation (see later discussion). With this in mind, a better
definition of the optimal (or at least the most efficient) dose per fraction
might be where the rate of increase in separation of the two fractionated
radiotherapy curves in Figure 20.4 per unit number of fractions is a
maximum. It can be shown that this occurs at the point of maximum
separation between the cancer and normal tissue curves shown in Figure
20.3, which turns out to be at exactly 50% of the dose at the crossover
point. For the parameters used to plot the survival curves in Figure 20.3,
this dose is ∼2 Gy. Hence, the optimal dose per fraction is about 2 Gy. If
the α and β values for normal tissues and tumor were known for each
patient, it would be possible to design patient-specific fractionation
regimens but, unfortunately, the technology to do this is not refined
enough at present. The alternative is to determine the optimal dose per
fraction for specific types of disease for the average patient, and this has
been the objective of numerous clinical trials of altered fractionation
(2,6–17).
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Figure 20.4 How fractionation with dose per fraction below the crossover point of the late-
responding normal tissue and tumor cell-survival curves in Figure 20.3 results in higher cell
survival for the normal tissue cells as the total dose increases.
The situation is somewhat different for SRS and other types of highly
conformal radiotherapy because the effective dose to normal tissues is
usually kept well below that to the tumor, where the “effective dose”
may be defined as the dose that, if delivered uniformly to the tissue in
question, would result in the same probability of local control or
complication as the actual inhomogeneous dose distribution in that
tissue. Several methods to determine such effective doses from dose–
volume data have been published (18–24) and these are reviewed in
Chapter 23. For example, if f (the geometrical sparing factor) is the ratio
of the effective dose in normal tissues to effective dose in tumor, even a
modest sparing represented by f = 0.8 moves the crossover point to
considerably higher doses and significantly widens the “Window of
Opportunity,” as shown in Figure 20.5. In this example, the crossover
point moves from 4 Gy all the way out to about 14 Gy, so the optimal
tumor dose per fraction becomes ∼7 Gy.
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Figure 20.5 How the crossover point for single (acute) irradiations shown in Figure 20.3 moves to
considerably higher tumor doses if there is even a modest amount of “geometrical sparing” of the
normal tissues (the normal tissue curve moves 20% to the right). In this example, a 20% sparing (f
= 0.8) causes the crossover point to move from ∼4 Gy out to 14 Gy. The same linear quadratic
(LQ) model parameters as for Figure 20.3 are used here.
For SRS, single doses of the order of 20 Gy are used. It is readily

shown that with the parameters used to plot Figures 20.3 to 20.5, this
will be optimal if f equals ∼0.6, not too unlikely, especially for small
tumors. For large tumors, f may exceed 0.6, so fractionated radiotherapy
might be required.
One concern with SRS and other types of radiotherapy such as IMRT,
CyberKnife, and so on, for which the time it takes to deliver a treatment
session can be of the same order of magnitude as the half-time for
cellular repair, is that repair during irradiation might reduce the
effectiveness of the treatment. Studies have shown that this effect might
cause reductions in effective dose by as much as 12% if the time to
deliver the treatment is as high as 0.5 hours, with concomitant
reductions in tumor control as much as 30% (25). Fortunately, it is
possible that protraction of irradiation time during a treatment might
reduce the effect on normal tissues more than on cancers (26). Hence, it
might be possible to increase the total dose sufficiently to offset the
effect of this intrafraction repair without increasing the damage to
normal tissues.
All the foregoing discussions, and especially the dose per fraction
estimates are, of course, highly dependent on the α and β values
assumed. They also totally ignore the effect of the other three Rs of
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radiotherapy.
Reoxygenation and the Oxygen Effect

Oxygen is the most powerful of all radiation sensitizers, so cells deprived
of oxygen are relatively resistant to radiation and require approximately
three times as much dose as well-oxygenated cells to destroy them. Such
doses in a course of radiotherapy will likely exceed normal tissue
tolerance unless highly conformal therapy is used. Furthermore, there is
evidence that a significant proportion of human cancers contain hypoxic
cells (27–32). For such tumors it would be expected that, immediately
after exposure, the fraction of the surviving cells that are hypoxic should
increase because the sensitive, well-oxygenated cells will be killed
preferentially. Indeed, this is exactly what has been observed in many
animal in vivo experiments. However, in some of these experiments, the
hypoxic-cell fraction rapidly returned to the much lower pre-irradiation
levels, and this has been interpreted as reoxygenation (33). In that case,
if enough time is allowed for reoxygenation between exposures in a
course of fractionated radiotherapy (typically 24 hours is sufficient), the
number of hypoxic cells in a tumor gradually decreases. Hence,
fractionation takes on added importance when treating tumors with a
significant hypoxic-cell fraction. However, because cell kill is reduced
during each fraction due to the presence of some resistant hypoxic cells,
it is possible that, even with reoxygenation, delivery of a high enough
dose to kill all the cancer cells without exceeding normal tissue tolerance
might not be possible. For example, several clinical trials have
demonstrated that pre-irradiation hypoxia significantly reduces local
control even after an extended course of fractionated radiotherapy long
enough to ensure reoxygenation (27–32).
Another aspect of the effect of oxygen on fractionated radiotherapy
relates to the effect of LET. When cells are exposed to high-LET
radiation, the protective effect of hypoxia is greatly reduced (33). Hence,
in the part of the cell-survival curve where α (i.e., high-LET) damage
predominates, at low dose or low dose/fraction (see Fig. 20.2), the effect
of hypoxia should be less than where β-damage predominates, which is
at high dose or high dose/fraction. This effect of dose or dose/fraction
has been demonstrated by cell-survival experiments (34,35) and has
been shown to be consistent with clinical data (30).
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The effect of O2 is represented by the oxygen enhancement ratio
(OER), where:
to produce the same biologic effect, for example, the cell-surviving

fraction. Low OER means that the protective effect of hypoxia on cell
survival is little, and high OER means that the effect is great. The
potential magnitude of the effect of dose/fraction on the OER can be
illustrated using the LQ model in Equation 20.5 and taking the natural
logs of both sides giving:
Then, if subscripts a and h represent aerobic and hypoxic irradiation

conditions, respectively, and equating values of −ln S for N fractions of
dose d/fraction for equal biologic effect:
Then,
Figure 20.6 Illustration of the increase in oxygen enhancement ratio (OER) with increase in
dose/fraction. Parameters used (see text) are those derived to fit clinical data for the treatment of
prostate cancers by Nahum et al. (30).
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Figure 20.6 shows how OER varies with dose/fraction for prostate
cancer using values of α and β that have been shown to fit clinical data
(36,37): αa = 0.26 Gy−1, βa = 0.0312 Gy−2, αh = 0.149 Gy−1, and βh
= 0.00293 Gy−2. This figure shows the trend of increasing OER as
dose/fraction increases but it should be realized that the actual numbers
depicted here represent just a single study for a single type of cancer.
Data from other analyses of clinical results for prostate and other cancers
will yield different OER versus dose/fraction curves, but the trend
should be as shown in Figure 20.6.
Similar observations of increasing OER with dose/fraction above 1
Gy/fraction have been made using modified versions of the LQ model
and different parameters (38,39). This would indicate that, for the
treatment of cancers that might contain significant numbers of hypoxic
cells, low dose/fraction techniques, with the order of 1 Gy/fraction,
might have an advantage over conventional (about 2 Gy/fraction) and
high dose/fraction (>2 Gy/fraction) regimes. The inappropriateness of
high dose/fraction radiotherapy for hypoxic cancers was demonstrated
by Carlson et al. (40) who modified the LQ model to take into account
the effect of oxygen partial pressure, the change in OER as a function of
dose/fraction, and reoxygenation. As illustrated for head-and-neck
cancers in Figure 20.7, they showed that cancer cell survival should
increase with increase in dose/fraction, especially above 5 Gy/fraction.
In summary, fractionation is essential for reoxygenation but, even with
fractionated radiotherapy, it may not be possible to deliver doses high
enough to control cancers without exceeding normal tissue tolerance.
Also, with high doses/fraction above about 5 Gy, the OER is high and
reoxygenation between fractions is reduced because of the fewer number
of fractions, so survival of cells in hypoxic cancers is increased. It would
appear that the use of high doses/fraction for hypoxic cancers is
contraindicated, but this ignores the effect of the third R of radiotherapy,
repopulation.
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Figure 20.7 Surviving fraction of tumor cells as a function of the number of fractions and the
dose/fraction to yield equivalent tumor control under normoxic conditions for hypoxic fractions 0.1
(red), 0.2 (blue), and 0.3 (green), assuming daily fractionation, full reoxygenation, and no
repopulation. Modified from Carlson DJ, Keall PJ, Loo BW, et al. Hypofractionation results in
reduced cell kill compared to conventional fractionation for tumors with regions of hypoxia. Int J
Repopulation
By their very nature, all cancers contain dividing cells, with viable
cancer cells usually dividing much faster than those of late-reacting
normal tissues. Hence, during a course of radiotherapy, there is
considerably more repopulation of cancer cells than cells of the late-
responding normal tissues, so the longer a course of radiotherapy, the
more difficult it becomes to control the tumor without exceeding normal
tissue tolerance. Furthermore, some studies show that repopulation of
cancer cells might accelerate during a course of fractionated
radiotherapy (accelerated repopulation), with the faster rate of division
kicking in after the first 2 to 4 weeks of treatment (the so-called kick-in
time Tk) (41). On these grounds, therefore, repopulation appears to
dictate that courses of radiotherapy should not be overly protracted and
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that accelerated repopulation, if it exists—there is some controversy
about this (42)—even indicates that optimal schedules of treatment
might be as short as 2 to 4 weeks, or even less. However, repopulation is
not entirely detrimental. Acutely responding normal tissues need to
repopulate during a course of radiotherapy to avoid exceeding acute
tolerance. Hence, the length of a course of radiotherapy, and therefore
the fractionation, must be controlled so as to not allow too much time
for excessive repopulation of tumor cells, at the same time not treating
so rapidly that acute tolerance is exceeded.
One problem with shortening the course of therapy is that this
probably means increasing the dose/fraction unless multiple fractions
are to be delivered each day, which is very inconvenient (see later). But,
as shown in the previous section, increasing the dose/fraction will
reduce the effectiveness of the treatments if hypoxic cells are present in
the tumor (Fig. 20.7). A delicate balance has to be struck between too
few fractions (less opportunity for reoxygenation) and too many
fractions (increased repopulation of cancer cells). Carlson et al.
demonstrated this for the head-and-neck cancers shown in Fig. 20.7, and
showed that there ought to be an optimal number of fractions and
dose/fraction (40), as shown in Figure 20.8. With the parameters used in
this study, this occurs at about 15 fractions of 3.7 Gy, but the actual
optimal fractionation is highly dependent upon the parameters used and
the accuracy of the model. For example, in this study a kick-in time Tk of
21 days was assumed for five fraction/week treatments. Hence,
accelerated repopulation kicked in after 15 fractions. But, as shown in
Figure 20.7, after 15 fractions the decrease in surviving fraction of the
cancer cells due to OER and reoxygenation effects has practically
saturated. Hence the effect of accelerated repopulation kicking in causes
the cell-survival curve to increase suddenly, thus making 15 fractions the
apparent optimal fractionation. The optimal fractionation is, therefore,
highly dependent upon the value of Tk assumed. For Tk less than 15
days, the optimal number of fractions should be less than 15, and high
dose/fraction regimes will not, after all, be contraindicated for hypoxic
cancers.
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Figure 20.8 Surviving fraction of tumor cells as a function of the number of fractions and the
dose/fraction at five fractions/week to yield equivalent tumor control under normoxic conditions for
hypoxic fraction 0.2, including repopulation with a kick-in time Tk of 21 days. Modified from
Carlson DJ, Keall PJ, Loo BW, et al. Hypofractionation results in reduced cell kill compared to
conventional fractionation for tumors with regions of hypoxia. Int J Radiat Oncol Biol Phys.
2011;79:1188–1195.
Redistribution
According to the cell cycle effect, cells irradiated during the mitotic (M)
phase of the cell cycle are most sensitive, and during late synthesis (late
S) they are most resistant, with a second peak of resistance in G1 in
some cells (43). For cells irradiated in the M phase, the survival curve is
practically linear, indicating minimal repair. In contrast, for cells
irradiated in late S, survival curves exhibit the greatest curvature,
representing considerable repair. Consequently, when tumors are treated
with fractionated radiotherapy, cells surviving the first fraction tend to
be partially synchronized, with an overabundance of surviving cells in
late S moving into early G2 immediately after exposure. If a second
exposure is delivered sometime after the first, the number of cells
inactivated depends on how far this surviving bolus of cells has traveled
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around the cell cycle. For example, if they have reached the M phase at
the time of the second fraction, they will be most sensitive. It is this
radiation-induced partial synchronization of cells that is known as
redistribution (or reassortment).
TABLE 20.1 Fractionation Schemes with Typical Parameters
Redistribution can be a benefit in a course of fractionated

radiotherapy if the cancer cells can be caught in mitosis after each
fraction, or detrimental if they have reached a resistant phase of the cell
cycle. In theory, it ought to be possible to adjust the interval between
fractions so as to gain maximum benefit from redistribution, but to date
there has been no evidence that such an advantage can be obtained in
practice. Consequently, potential effects of redistribution are generally
ignored when designing fractionation strategies.
Fractionation Strategies
The radiobiologic principles discussed in the foregoing sections have
been used extensively to guide in the design of numerous clinical trials
of altered-fractionation regimens. In this section, the rationale for
various fractionation schemes will be presented. Table 20.1 lists a
variety of fractionation schemes, their typical parameters, and some
brief comments. Following is a detailed description of each of these
fractionation schemes.
Conventional Fractionation
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The most common fractionation for curative radiotherapy is about 1.8 to
2.2 Gy/fraction delivered at five fractions a week. This has evolved as
the conventional fractionation regimen because it is convenient (no
weekend treatments), efficient (treatment every weekday), and effective
(high doses can be delivered without exceeding either acute or chronic
normal tissue tolerance). The principal rationale for the prescription of
conventional fractionation for a particular patient or disease is that most
experience is with this type of fractionation, for which both tumoricidal
and tolerance doses are well documented. Unless there is a good reason
to change, radiation oncologists are reluctant to deviate from this tried-
and-true method of treatment.
Hyperfractionation
A hyperfractionated course of radiotherapy is one in which more than
one fraction is delivered each day but the overall treatment time remains
similar to that for conventional fractionation. Typically, this means 1.2
to 1.3 Gy/fraction, two fractions a day, with an increase in total dose of
the order of 20% to account for increased repair at the lower dose per
fraction.
The major rationale for hyperfractionation is to take full advantage of
the difference in repair capacity of late-reacting normal tissues compared
with tumors. This was illustrated by the curvier cell-survival curves for
these normal tissues (Fig. 20.3) and the concomitantly lower α/β values.
If conventional radiotherapy is not producing particularly good clinical
results and no obvious reasons for this are evident, maybe the reason is
that the dose per fraction that adequately separates the two fractionated
radiotherapy curves in Figure 20.4 is below that used in conventional
fractionation. With such a low dose per fraction, more than one fraction
per day is necessary to keep the course of therapy short enough to avoid
the risk of excessive tumor cell repopulation. Such hyperfractionation
regimes will have to be delivered at about 1.2 to 1.3 Gy/fraction, two
fractions a day. To treat with higher than 1.3 Gy/fraction at more than
one fraction per day may exceed acute tolerance, and to use <1.2
Gy/fraction will require three fractions per day in order to not overly
increase overall treatment time, with at least 6 hours between fractions
required for complete repair, a treatment schedule that would be highly
inconvenient.
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Another potential advantage of hyperfractionation might be the
reduced OER at low dose/fraction compared with that with conventional
fractionation (see Fig. 20.6). This could be important for cancers that
might be expected to contain significant numbers of hypoxic cells.
Accelerated Fractionation
For rapidly growing tumors with short potential doubling times of the
viable cycling cancer cells (Tpot), accelerated treatment is desirable.
There are several ways to achieve reduced overall treatment time. The
simplest is to treat 6 or 7 days a week instead of the normal 5, keeping
the dose per fraction the same as with conventional fractionation. This
produces a modest acceleration that may be enough to influence clinical
outcome. A more drastic acceleration can be achieved by treating twice
a day at 1.4 to 1.6 Gy/fraction, but only at the risk of exceeding acute
normal tissue tolerance. Such accelerated fractionation regimens have
been tried but have usually been unsuccessful because many patients
had to be given a rest of 1 to 2 weeks during the course of therapy to
allow acute reactions to subside, negating the intent to accelerate the
treatments.
Another possibility is to increase the dose per fraction to about 2.5 Gy
(often called rapid fractionation), but this risks losing the repair
advantage of late-responding normal tissues. Increased late reactions
usually occur unless the dose to the normal tissues can be reduced, such
as with conformal therapy. Alternatively, for rapidly growing cancers it
is possible to exploit the difference in repair between late-reacting
normal tissues and tumors by hyperfractionating while accelerating the
course of therapy by treating with three fractions per day. Such
treatment is known as accelerated hyperfractionation.
Accelerated Hyperfractionation
A major problem with accelerated fractionation is that cancerocidal
doses delivered in such short overall times are likely to exceed acute
tolerance unless a rest period is included part way through treatment to
allow early reactions to subside. One way around this is to complete the
treatments in such a short time that the acute reactions reach their peak
only after the radiotherapy has been completed. This was the rationale
for the development of the continuous hyperfractionated accelerated
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radiotherapy (CHART) regimen at Mount Vernon Hospital in London
(10). With CHART, treatments 6 hours apart are delivered three times a
day, 7 days a week. With a dose/fraction of 1.5 Gy, a total dose of 54 Gy
can be delivered in 36 fractions over 12 successive treatment days
including weekends. With this schedule, patients can complete treatment
without a break because peak acute reactions occur approximately 2
weeks after the start of therapy. Although clinical results for the
treatment of lung and head-and-neck cancers have been promising with
CHART, they have been achieved with considerable trauma to the
patients: many of these patients developed grade 3 or worse acute
complications (44). CHART is also difficult for the staff, since delivery of
three fractions per day 6 hours apart for 12 successive days, including
weekends, is very inconvenient. Some of this inconvenience is reduced
with an alternative form of CHART called CHARTWEL (CHART weekend
less), wherein the 54 Gy at 1.5 Gy/fraction at three fractions per day is
delivered over a total of 16 days without the weekend treatments (13).
Clinical trials have shown that CHARTWEL is a viable alternative to
CHART (45).
Hypofractionation
All the fractionation regimes presented above require the delivery of
many fractions over many days. They are costly in terms of resources
and are inconvenient for patients. These fractionation schemes were
necessitated by the desire to “cure” cancers without exceeding normal
tissue tolerance. However, not all radiotherapy is aimed at “cure.” For
many patients, the aim is to simply palliate, so there is no need to
employ the very high doses required for “cure” and hence no need to
approach tolerance of normal tissues. For these patients it is, therefore,
possible to design much more convenient and cost-effective treatments,
which use far fewer fractions, that is, to employ hypofractionation.
Typical hypofractionation schemes used for palliation range from as
many as 10 fractions of 3 Gy to as few as a single fraction of about 10
Gy, with anything from 1 to 5 fractions per week.
With conformal radiotherapy, because there is considerable
geometrical sparing of normal tissues, the “Window of Opportunity”
(Fig. 20.5) is widened such that the high doses/fraction needed for
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hypofractionated treatments can be used for curative radiotherapy. This
has led to the development of many clinical trials of hypofractionation,
especially for prostate and breast cancers for which the α/β ratio is lower
than the 10 Gy typically assumed for most cancers (9,14,16,46).
As discussed earlier, potential disadvantages of hypofractionation
relate to the increased OER and decreased reoxygenation that might be
expected with high dose/fraction schedules (Fig. 20.6). But this
disadvantage might be mitigated for rapidly dividing cancers if the
hypofractionation allows the course of treatment to be shortened. All
this depends significantly on radiobiologic properties of the cancer cells
that are difficult to predict. Hence, it seems prudent to not apply
hypofractionation for the treatment of cancers thought to contain
significant fractions of hypoxic cells without extensive clinical trials.
One possible advantage of hypofractionation for cancers with a high
α/β that might be exploited is the increase in intrafraction repair that
takes place with long treatment times, which should benefit late-reacting
normal tissues because of their lower α/β (prostate cancer might be an
exception). This would require increasing the total dose to account for
this increased repair just enough so as to not increase the risk of late
complications. This could be determined by, for example, a carefully
controlled dose-escalation clinical trial or, maybe, calculation of the
appropriate dose using a bioeffect dose model. This exemplifies a major
challenge with most modified fractionation regimens for which there is
no previous experience: the determination of the appropriate total dose
to use. Rather than just guessing, it has been a common practice to use
mathematical bioeffect dose models to calculate these doses. The most
popular of these is the biologically effective dose (BED) model.
The Biologically Effective Dose Model

The BED model for fractionated radiotherapy can be derived directly
from the LQ equation for cell survival for fractionated irradiations
presented earlier (Equation 20.7): .
This equation could be used to calculate treatment regimes that are
equally effective biologically (constant − ln S) but, to do so, we would
need to know the values of the two parameters α and β for each tissue
involved. Unfortunately, it is difficult enough to determine a single
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biologic parameter from clinical data, let alone two. However, it is
possible to reduce the number of unknown parameters to one by
dividing both sides of Equation 20.7 by α to derive the BED, originally
called the extrapolated response dose (ERD) (47,48):
Fractionation schemes for which BEDs are equal will be equally

effective biologically. Here, we have just one biologic parameter, α/β, to
determine from clinical data for each type of tissue involved where, as
we saw earlier, α/β is the dose at which α-type and β-type damages are
equal (Fig. 20.2).
Equation 20.10 was derived assuming acute radiation conditions (i.e.,
no time for repair during each fraction) and complete repair between
fractions. This does not always prevail, however, since there may be
occasions when the time between fractions is not sufficient for full
repair, or the time to deliver each fraction is long enough for some
repair to occur during irradiation. The former has been observed
clinically with some of the early three fractions per day patients, for
example, when less than 6 hours between fractions was used (49), and
the latter probably occurs for some of the highly conformal therapy
techniques such as with SRS, IMRT, SBRT, and CyberKnife treatments
(25,26,50). For these situations, a more complex form of the BED
equation is needed that takes into account both the rate at which cells
repair, the rate at which each part of the tissue is irradiated, and the
time between fractions. The full BED equation for such fractionated
therapy has been published (25,51,52) but it is extremely complicated
and outside the scope of this chapter.
Equation 20.10 accounts for repair only, but cells, especially cancer
cells, are known to repopulate during a course of therapy. If tumor cell
repopulation is assumed to be an exponential function of time, with
doubling time for repopulation of the cycling cells Tpot, then ln S will be
increased by (0.693/Tpot)T, so (53):
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and hence the BED equation becomes:
However, since the two additional biologic parameters Tpot and α are
very difficult to determine from analysis of clinical data, it is useful to
replace 0.693/αTpot by a single repopulation rate parameter, k,
estimated from loss of local control when radiotherapy is prolonged
(54). For example, if retrospective analysis of data shows that a patient
has a rapidly repopulating type of tumor, a value of k = 0.6 BED
units/day might be used. At the other extreme, for a slowly proliferating
disease like prostate cancer, k = 0.1 BED units/day might be more
appropriate. Note that it is usual to assume that k = 0 for late-
responding normal tissues, since little or no repopulation of these cells
would be expected to occur during a course of therapy. For acutely
responding normal tissues, the value of k is probably in the range of 0.2
to 0.4 BED units/day (54).
One further refinement of the BED equation is required if cells are
believed to exhibit accelerated repopulation after a kick-in time Tk. If it
is assumed that repopulation is negligible before Tk and after that
proceeds at a rate represented by k BED units/day (54):
where k = 0 for T < Tk.

A further useful application of the LQ model for comparison of
different fractionation regimes is to calculate the equivalent dose at 2
Gy/fraction, because much of the clinical data used to represent tumor
control and normal tissue complication probabilities has been published
for 2 Gy/fraction treatment schedules (55–57). This is achieved by
equating BEDs. For example, if we ignore repopulation effects, the 2
Gy/fraction total dose, D2, equivalent to a regime of Dd Gy delivered at d
Gy/fraction, is given by:
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Then
Another useful application of the LQ model is to correct for errors in

dose/fraction. For example, if the wrong dose/fraction is delivered for
the first several fractions, Joiner showed that it is possible (with some
obvious exceptions) to use the LQ model to calculate a treatment
schedule to complete the course of treatment and achieve the same
biologic effects that were originally planned for both tumor and normal
tissues, provided repopulation effects can be ignored (58). He showed
that, if the planned total dose was Dp Gy at dp Gy/fraction but, due to an
error, the first De Gy was delivered at dose/fraction de Gy, the course
could be completed with dose Dc delivered at dc Gy/fraction, where Dc
= Dp − De and
Note that the total dose is unchanged (Dp = De + Dc) and that the
solution is independent of the α/β of the tissues involved, which is why
the effects on both tumor and normal tissues are the same as originally
planned. Also, although not stated in Joiner’s paper (58), it can be
shown that the solution is independent of any geometrical sparing of
normal tissues, that is, it is independent of geometrical sparing factor, f.
The LQ Model in Clinical Practice

It is important to realize that the LQ model is an approximation. How
could such a simple mathematical model account for all the complex
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changes that occur in tissues and cells when they are irradiated? But,
like all models, it can be useful and has been shown to provide an
adequate fit to clinical data in many studies. Problems with the model,
apart from the over-simplicity of the model itself, include lack of
accurate values for the biologic parameters α, α/β, k, Tpot, and Tk, and a
concern that there may be an upper limit to the dose/fraction above
which the model no longer applies.
As far as the biologic parameters are concerned, studies of tumor and
normal tissue effects in clinical trials are gradually providing better and
better estimates of their values. Of special interest as far as normal
tissues are concerned are the studies being analyzed as part of the
Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)
program (59). Hopefully, this will provide reliable estimates of the
parameters for a whole variety of normal tissues.
The problem of a possible upper limit in dose/fraction for the LQ
model is a concern for uses of the model for extreme hypofractionation
with doses/fraction above about 7 Gy. One concern relates to the shape
of cell-survival curves at high doses. Many have claimed that these
straighten out at doses above about 7 Gy, whereas the LQ model predicts
that they continue to curve downward (60). This would mean that the
LQ model would predict more cell kill than really occurs at high doses,
that is, it overestimates radiation effects. On the other hand, many claim
that the LQ model underestimates the effect at high doses above about 10
Gy because it ignores indirect cell death due to vascular damage (61,62).
This is discussed in depth in Chapter 21. Maybe because the LQ model
overestimates the direct effect on cells but underestimates it in tissues,
these two “errors” at least partially cancel and the LQ model can be used
at doses well above 10 Gy. Only carefully designed clinical trials are
likely to give us a clear answer to this conundrum. Regardless, the LQ
model is always an approximation. It should be applied with caution
when designing or modifying fractionation schemes and, if used for
patients, it is important to watch out for signs of unexpected tissue
reactions or poor tumor control.
The following examples illustrate how these models can be applied to
the solution of practical radiotherapy problems.
Examples
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Problem 1: Gap in treatment: A patient with a rapidly growing cancer is
planned to receive a course of 70 Gy in 35 fractions in 7 weeks. After 25
fractions the patient develops a severe acute reaction that necessitates a
2-week rest period. To complete the treatment in 10 more fractions in 2
weeks, what dose per fraction should be delivered?
SOLUTION
Application of the LQ model to problems such as this is complicated
since different solutions are possible for different tissues considered and
several tissue-specific parameters have to be assumed. For this problem,
assume the following parameters for this patient:
For tumor:
For late-responding normal tissues:
Tumor solution. Before the break the BED is (using Equation 20.13):
After the break this reduces to:
The planned BED was:
Therefore, the residual BED that needs to be delivered is:
If d is the dose per fraction required to complete the treatment in 10

fractions over 2 weeks:
Therefore:
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Solving this for d gives:
Late-responding normal tissue solution. Since no repopulation is assumed

for late-responding normal tissues (k = 0), the break should have no
effect, so the dose to complete the course of therapy should be
unchanged. Therefore:
If it is assumed that the original course represented the maximum dose

that could be delivered safely to this patient then, in order not to
increase the risk of late normal tissue injuries, the treatment should be
completed in 10 fractions of 2 Gy. However, since the dose per fraction
required for the tumor (2.58 Gy) is much higher than this, it might be
necessary to compromise in order to not reduce tumor control too much.
It might be decided to treat with more than 10 fractions of 2 Gy, but less
than the number that would be required for the full tumor effect. This
illustrates the undesirability of allowing rest periods during the
treatment of rapidly proliferating cancers.
Problem 2: Hyperfractionation: A hyperfractionation regimen consisting

of 2 fractions per day, 6 hours apart, for a total of 60 fractions in 6
weeks is designed to be equivalent to 60 Gy in 30 fractions in 6 weeks.
What dose per fraction is required?
SOLUTION
Assume all the same parameters as in the first problem. However, since
the overall time is unchanged, no account need be taken of repopulation.
Tumor solution. Equating the conventional to the hyperfractionated

regimens, the dose/fraction d is determined using Equation 20.10:
or
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Solving for d gives:
Late-responding normal tissue solution. Equating the two regimens gives

(using Equation 20.10):
or
The solution to this is:
Note that the late-reacting tissues can tolerate doses much higher than
that required for the tumor. This is a consequence of the low dose per
fraction and is the major rationale for hyperfractionation. However, even
though a course of 60 fractions at 1.21 Gy/fraction in 6 weeks is
tolerable as far as late reactions are concerned, the risk of acute
reactions might be higher than that for the conventional course of
treatment because a total of 2.42 Gy will be delivered each day. But this
might not be a problem if the risk of acute injuries is negligible for the
conventional course. If these calculations are to be used as the basis for
the design of a hyperfractionation regime for real patients, it might be
prudent for the radiation oncologist to develop some experience by
treating the first few patients with slightly fewer fractions and, if the
acute reactions appear tolerable, to escalate the number of fractions to
the required 60. Several national clinical trials of hyperfractionation
have been designed using dose escalation in this way.
Problem 3: Accelerated fractionation: An accelerated fractionation

scheme consisting of 40 treatments, twice a day for 4 weeks is to be
equivalent to 60 Gy in 30 fractions in 6 weeks. What dose per fraction is
required? Assume the same parameters as in Problem 1.
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Tumor solution. The accelerated regimen is completed before the kick-in
time for repopulation (28 days), and equating BEDs using Equation
20.13 to determine the dose/fraction d:
or
Late-responding normal tissue solution. No repopulation correction is

needed, so (using Equation 20.10):
or
The solution is:
According to these calculations, it would be safe to deliver the

treatment at 1.63 Gy/fraction, which means that the effect on the tumor
should be greater than that for the conventional fractionation scheme.
This is the rationale for accelerated fractionation for such rapidly
proliferating cancers. Note that the daily dose for the accelerated regime
is 3.26 Gy, which might not be tolerated acutely. As in the previous
problem, it might prudent to start out using less than the desired 40
fractions of 1.63 Gy/fraction and to dose-escalate with this accelerated
radiotherapy schedule, carefully watching out for excessive acute
reactions.
Problem 4: Hypofractionation: What is the appropriate dose/fraction

required for hypofractionated total breast radiotherapy in 13 fractions
over 5 weeks in order for this to be equivalent in terms of tumor control
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to standard radiotherapy with 25 fractions of 2 Gy delivered over 5
weeks assuming α/β for breast cancer is 4 Gy?
SOLUTION
Since the overall time is unchanged, there is no need to take
repopulation into account, so Equation 20.10 can be used.
For the standard treatment the BED is 50(1 + 2/4) = 75. Then, if d
Gy is the dose/fraction needed for the hypofractionated treatments:
Therefore:
Note that hypofractionation regimes consisting of 13 fractions of about

3.2 Gy delivered over 5 weeks have been studied in clinical trials and
found to be acceptable in terms of both tumor control and complications
(7).
Problem 5: Correction of treatment error: A patient is planned to

receive 30 daily fractions of 1.8 Gy but, due to an error, the first 5
fractions are delivered at 2 Gy/fraction. How can the treatment continue
so as to result in the same effects on tumor and normal tissues as
originally planned?
SOLUTION
According to Equation 20.16, the remainder of the treatments should be
delivered at a dose/fraction dc given by:
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The total dose remains as planned at 54 Gy, so the remaining 44 Gy
has to be delivered in 44/1.75 = 25.1 fractions. Since we cannot deliver
0.1 of a fraction, 25 fractions of 44/25 = 1.76 Gy should be used.
Problem 6: Accelerated hyperfractionation: A CHART scheme consisting

of 36 treatments, 3 times a day for 12 successive days with at least 6
hours between fractions is to be equivalent to 70 Gy in 35 fractions in 49
days as far as tumor control is concerned. What dose per fraction is
required? With this treatment regime, will the effect on late-responding
normal tissues exceed that expected from a conventional course of 30
fractions of 2 Gy in 42 days?
SOLUTION
Assume the same parameters as before, except for the repopulation kick-
in time for the tumor, which is assumed to be 0 (assume CHART is being
tried for these patients because their cancers are rapidly proliferating
right from the start of treatment).
For tumor: equating BEDs, the CHART dose/fraction d is given by (using
Equation 20.13):
or
For late-reacting normal tissues: the BED for the conventional regime is
(using Equation 21.10):
and for the CHART treatments it is:
Hence, the CHART treatments should be far more tolerable as far as
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late reactions are concerned. One would expect that, compared to
conventional therapy with 60 Gy at 2 Gy/fraction, CHART should
provide equivalent tumor control without the added risk of severe late
reactions. However, because the daily dose is about 4.5 Gy, one would
expect acute reactions to be very severe, as clinical results have
demonstrated (13).
SUMMARY
Treatments have been fractionated from the very inception of
radiotherapy a century ago, although it was not until the early 1930s
that it was generally accepted that curative therapy required
fractionation. Recent studies of the radiobiologic principles of cell
survival demonstrate that the major reason fractionation is so important
is the difference in the capacity of tumor and late-responding normal
tissue cells to repair damage at low doses per fraction. Specifically,
normal tissue cells are more capable of repair than are tumor cells. This
causes their cell-survival curves to be curvier than those for tumors
which, according to the LQ model, correspond to a lower value of the α/
β ratio.
A second difference between tumor and late-reacting normal cells is
repopulation. These normal cells repopulate little, if at all, during a
course of fractionated radiotherapy, whereas tumor cells, especially
those with a short potential doubling time, exhibit significant
repopulation.
These repair and repopulation differences between normal and tumor
cells provide the major rationale for clinical trials of several types of
modified fractionation schemes, such as hyperfractionation, accelerated
fractionation, and accelerated hyperfractionation.
One problem encountered whenever fractionation regimens are
modified is how to decide on an appropriate total dose when little prior
clinical experience is available. The most common way this has been
done is by the use of the BED model. However, it must be realized that
this model provides only approximate solutions to clinical problems. It
represents a grossly oversimplified view of the extremely complex
biologic changes that occur during a course of fractionated radiotherapy.
It is useful for demonstration of the effects of fractionation but, if
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applied to actual patient treatment calculations, it should be used with
caution, preferably only when previous clinical experience is not
available.
KEY POINTS
• The clinical need to fractionate treatments first became accepted in
the 1930s.
• Late-reacting normal tissue cells are better able to repair damage
than are cancer cells.
• There is a “Window of Opportunity” at low dose and low
doses/fraction within which cancers can be controlled without
exceeding normal tissue tolerance.
• The “Window of Opportunity” widens with geometrical sparing of
normal tissues, thus allowing much higher doses/fraction to be
used for curative therapy.
• Radiobiologic effects are regulated by the four Rs of radiotherapy:
repair, reoxygenation, repopulation, and redistribution.
• Different fractionation strategies have been investigated to try to
find the best treatment for specific types of cancers.
• The linear quadratic model can be used to compare different
fractionation schemes but, because it is an approximation, it has to
be used with caution.
QUESTIONS
1. The principle radiobiologic rationale for fractionating
radiotherapy at low doses/fraction is that
A. this improves utilization of treatment machines
B. cells of late-reacting normal tissues are better able to repair
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than those of most cancers
C. this gives the staff time to rest between treatments
D. survival curves for cancer cells are typically “curvier” than for
normal cells
E. cancer cells repair faster than normal cells so session times
have to be kept short
2. One reason why the CHART technique might be better for
reducing the overall time of a course of treatment than
conventional accelerated fractionation is that, with CHART
A. there will be increased probability of reoxygenation of
hypoxic cancer cells
B. treatments are more convenient to deliver
C. there is a comparable risk of severe acute complications with
increased tumor control
D. there is a reduced risk of severe acute complications
E. severe acute reactions peak after the course of radiotherapy
has been completed
3. Hypofractionation might better than other forms of fractionation
because
A. with fewer fractions, reduced reoxygenation will protect late-
reacting normal tissues
B. longer treatment times will allow some cancer cells to repair
C. fewer fractions will be more cost-effective
D. shorter courses of radiotherapy will reduce the risk of acute
reactions
E. shorter courses of radiotherapy will reduce the risk of late
complications
4. The major radiobiologic rationale for hyperfractionation is to take
A. full advantage of the difference in repair capacity of late-
reacting normal tissues compared with tumors
B. full advantage of the difference in repair capacity of acutely
reacting normal tissues compared with tumors
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C. advantage of the higher OER for tumors at low dose/fraction
D. advantage of the short time between fractions to “catch” the
cancer cells in a sensitive phase of the cell cycle
E. advantage of the short time between fractions to “catch” the
normal tissue cells in a resistant phase of the cell cycle
5. In the 1930s it was realized that treatments needed to be
fractionated because
A. repair at low doses/fraction was known to be better for
normal tissue cells than for tumor cells
B. repair at low doses/fraction was known to be better for tumor
cells than for normal tissue cells
C. it was known that reoxygenation improved as fractionation
was increased
D. it was known that the OER of tumor cells was lower for
fractionated as opposed to single dose treatments
E. clinical experience had demonstrated that, only by
fractionating, could cancerocidal doses be delivered without
exceeding normal tissue tolerance
ANSWERS
1. B. At low doses and doses/fraction, cell survival is greater for
late-reacting normal tissue cells than for cancer cells due to
their better ability to repair, thus giving rise to the “Window of
Opportunity.”
2. E. With accelerated radiotherapy regimens, acute reactions tend
to reach a peak after about 2 weeks of treatment, and this often
makes it impossible to complete the course of therapy without
giving the patient a rest period, thus negating the benefit of
accelerated treatment desired. With CHART, this peak in acute
reactions occurs after the completion of treatment.
3. C. “Fewer fractions” is clearly more cost-effective and the other
potential answers either have no significant effect or make the
treatments worse.
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4. A. At low doses/fraction, the surviving fraction of both late-
reacting normal tissue and tumor cells will both be increased
but, because the normal tissue cells are better able to repair,
the differential advantage will increase. The other potential
answers either have no significant effect or make the
treatments worse.
5. E. It was the excellent clinical results Coutard published in 1932
that demonstrated that fractionation was needed if
cancerocidal doses were to be delivered without exceeding
normal tissue tolerance. Answer B is wrong and the rationales
given in the A, C, and D are now known to be good reasons to
fractionate but they were not understood for several decades
after Coutard’s results were published.
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using CHARTWEL (continuous hyperfractionated accelerated
radiotherapy weekend less) in non-small cell lung cancer. Br J
Cancer. 1998;78:1323–1328.
46. Fowler JF, Ritter MA, Chappell RJ, et al. What hypofractionated
protocols should be tested for prostate cancer? Int J Radiat Oncol
Biol Phys. 2003;56:1093–1104.
47. Barendsen GW. Dose fractionation, dose-rate and isoeffect
relationships for normal tissue responses. Int J Radiat Oncol Biol
Phys. 1982;8:1981–1997.
48. Dale RG. The application of the linear-quadratic dose-effect
equation to fractionated and protracted radiotherapy. Br J Radiol.
1985;58:515–528.
49. Bentzen SM, Ruifrok ACC, Thames HD. Repair capacity and kinetics
for human mucosa and epithelial tumors in the head and neck:
clinical data on the effect of changing the time interval between
multiple fractions per day in radiotherapy. Radiother Oncol.
1996;38:89–101.
50. Murphy MJ, Peck-Sun L. Intra-fraction dose delivery timing during
stereotactic radiotherapy can influence the radiobiological effect.
Med Phys. 2007;34:481–484.
51. Narayana V, Orton C. Pulsed brachytherapy: a formalism to account
for the variation in dose rate of the stepping source. Med Phys.
1999;26:161–165.
52. Manning MA, Zwicker RD, Arthur DW, et al. Biologic treatment
planning for high-dose-rate brachytherapy. Int J Radiat Oncol Biol
Phys. 2001;49:839–845.
53. Fowler JF. Brief summary of radiobiological principles in
fractionated radiotherapy. Semin Radiat Oncol. 1992;2:16–21.
54. Orton CG. Recent developments in time–dose modeling. Austral Phys
Eng Sci Med. 1991;14:57–64.
55. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to
therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–
122.
56. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
complication models in the clinic. Int J Radiat Oncol Biol Phys.
2010;76:S10–S19.
57. Kirkpatrick JP, Van Der Kogel AJ, Schultheiss TE. Radiation dose–
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volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010;
76:S42–S49.
58. Joiner MC. A simple α/β-independent method to derive fully
isoeffective schedules following changes in dose per fraction. Int J
59. Marks LB, TenHaken RK, Martel MK. Guest Editor’s introduction to
QUANTEC: A users guide. Int J Radiat Oncol Biol Phys. 2010;76:S1–
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60. Astrahan M. Some implications of linear-quadratic-linear radiation
dose-response with regard to hypofractionation. Med Phys.
2008;35:4161–4172.
61. Song CW, Mi-Sook K, Cho C, et al. Radiobiological basis of SBRT
and SRS. Int J Clin Oncol. 2014;19:570–578.
62. Kirkpatrick J, Meyer J, Marks L. The linear-quadratic model is
inappropriate to model high-dose per fraction effects. Semin Radiat
Oncol. 2008;18:240–243.
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21 Radiobiology of Stereotactic
Radiosurgery and Stereotactic
Ablative Radiotherapy
Paul W. Sperduto and Chang W. Song
INTRODUCTION
The previous chapter focused on treatment planning for stereotactic
radiosurgery (SRS) and stereotactic ablative radiotherapy (SAbR), which
is also known as stereotactic body radiation therapy (SBRT). This
chapter complements that work with a concise primer on the evolving
radiobiologic principles and current understanding of the mechanism of
action of SRS/SAbR. While direct tumor cell death remains important,
recent research shows indirect cell death from the vascular and
immunologic effects of SRS/SAbR may be equally or more important.
This chapter will also briefly summarize how hypoxia-inducible factor 1-
alpha (HIF-1α) and vascular endothelial growth factor (VEGF) impact
tumor progression and how inhibition of these factors may enhance
indirect cell death, thereby further improving the efficacy of SRS/SAbR.
Finally, this chapter will revisit the enduring debate regarding whether
the linear quadratic (LQ) model, or any modified version thereof, is
applicable to SRS/SAbR.
A major paradigm shift in cancer biology came with the realization
that cancer is not merely a normal cell gone awry but the result of a
complex process by which the cell responds to intercellular signals, the
surrounding microenvironment and the therapies directed against it. The
importance of the tumor microenvironment and specifically hypoxia was
highlighted by Gray, who suggested in 1953 that hypoxic cancer cells
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are resistant to radiation therapy (1). Hypoxia, hypoxic cell
radiosensitizers, hypoxic cytotoxins, and reoxygenation have since been
the focus of extensive research in radiation oncology (2). A key advance
was the discovery that angiogenesis is a critical factor in cancer
progression (3,4). It was later shown by multiple investigators that not
only are hypoxic cells resistant to radiation but that hypoxia is the
principal physiologic stimulus for angiogenesis (5,6). The subsequent
discovery that HIF-1α regulates hypoxia-induced angiogenesis through
activation of multiple angiogenic growth factors, including VEGF,
suggests that to the extent that radiation causes endothelial cell death
resulting in indirect tumor cell death, it may also activate HIF-1α, which
may contribute to radiation resistance (7,8). Thus, more recent work has
focused on the effects of radiation on tumor vasculature and potential
methods for inhibiting HIF-1α and VEGF which, in turn, should enhance
cell death (9,10). Figure 21.1 shows a schematic representation of the
current understanding of the radiobiologic mechanisms of action of
SRS/SBRT, which are different than the traditional radiobiology
principles that have been used to describe the effects of conventionally
fractionated radiation therapy.
Evidence of Indirect Cell Death from Vascular Damage by

SRS/SAbR
Recent clinical experience has demonstrated high local control rates in
patients treated with SRS/SAbR (11–17) and other work (18–20) has
suggested that the mechanism of SRS/SAbR is different than
conventional radiobiology. Park et al. recently published a
comprehensive review of the literature on the effects of radiation on
tumor vasculature and concluded that extensive vascular damage may
lead to indirect cell death (21). Both recent and remote data clearly
indicate that secondary or indirect cell death resulting from vascular
damage plays an important role in the response to tumors to high dose
per fraction SRS or SAbR. Song et al. published a series of investigations
in the 1970s showing irradiation of experimental tumors with 10 Gy or
higher doses in a single dose induced severe vascular destruction and
such vascular damage caused considerable indirect tumor cell death in
Walker tumors of rats or SCK tumors of mice (22). Other investigators
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have reported similar observations that radiation-induced endothelial
cell death and vascular dysfunction by high-dose irradiation induced
secondary cell death in various types of tumors (23,24).
The number of viable tumor cells in 1 g human tumor is known to be
as many as 108 to 109 implying that 8 to 9 logs cancer cells have to be
killed for complete control of a 1 g tumor (25). Traditional radiobiologic
principles would indicate that the radiation doses used for SRS and SAbR
are supposed to sterilize only 3 to 4 logs of tumor cells, assuming 10% to
20% of tumor cells are hypoxic. Leith et al. reported that a single dose of
irradiation with as high as 80 to 90 Gy in a single treatment is needed to
control 3-cm diameter brain tumors, assuming 20% of the tumor cells
are hypoxic (26). However, SRS with only 18 to 25 Gy in a single
fraction has been shown to be highly effective to control primary or
metastatic brain tumors by a number of investigators (11,12). Likewise,
SAbR with doses less than 60 Gy in three to five fractions has also been
shown to be highly effective to achieve local control of various types of
large tumors (13–18). For example, SAbR of 5- to 7-cm diameter liver
tumors with only 54 Gy in three equal fractions resulted in more than
90% local control for 2 years (15). Taken together, it is highly likely that
mechanisms other than direct killing of cancer cells through DNA
double-strand breaks are involved in the response of tumors to high dose
per fraction SRS and SAbR.
Figure 21.1 A schematic representation of the current understanding of the mechanism of action
for SRS/SBRT.
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Figure 21.2 The effect of dose on indirect cell death in fibrosarcoma. Effect of 10-, 15-, 20-, and
30-Gy irradiation in a single dose on the surviving cell fraction in FSaII fibrosarcoma tumors grown
in the hind limb of C3H mice. The cell survival was determined immediately after irradiation or
after leaving the irradiated tumors in situ for 1 to 5 days. The cell survival in individual irradiated
tumors was normalized to the mean cell survival of unirradiated control tumors (15 tumors).
Recent in vivo experiments using animal tumor models by Song et al.

confirm that indirect cell death is induced when tumors are irradiated
with high-dose irradiation (27). Figure 21.2 shows the effect of 10-, 15-,
20-, and 30-Gy irradiation in a single dose on the surviving cell fraction
in FSaII fibrosarcoma grown in the hind limb of C3H mice. The cell
survival was determined immediately after irradiation or after leaving
the irradiated tumors in situ for 1 to 5 days. The cell survival in
individual irradiated tumors was normalized to the mean cell survival of
unirradiated control tumors (15 tumors). Figure 21.3 shows radiation
survival curves of FSaII fibrosarcoma cells in vivo obtained immediately
(Day 0) and 5 days (Day 5) after irradiation with various doses, based on
the data from Figure 21.2. These data show that the surviving cell
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fractions on day 5 were significantly smaller than those immediately
after irradiation with 15 to 30 Gy due to the secondary cell death within
5 days after high-dose irradiation. The radiation doses at which the
indirect death is triggered may vary depending on various factors
including tumor type. For example, 10-Gy irradiation induced
considerable indirect cell death in Walker mammary tumors of rats
whereas few cells died of indirect effect after 10-Gy irradiation in FSaII
mouse fibrosarcoma (Figure 21.2) (22).
When all the aforementioned literature and the representative data
presented here, it is evident that irradiation with high dose per fraction
(>10 Gy) causes indirect death in tumor cells by causing vascular
damage. It may be further concluded that such additional cell death
through indirect mechanisms play an important role in the response of
tumor to high-dose SRS/SAbR and that fraction size is important to
exploit the radiation-induced vascular damage.
Hypoxia-Inducible Factor 1-alpha and Vascular Endothelial Growth

Factor
The role of HIF-1α and VEGF in the response of tumors to radiotherapy
has become the focus of much research (7–10). Colbert et al. (9) studied
98 patients with adenocarcinoma of the pancreas and found HIF-1α
expression correlated directly with recurrence. Those patients with high
HIF-1α expression were more likely to develop distant metastases
whereas those with relatively low HIF-1α expression were more likely to
have local recurrence (9). Lee et al. showed trimodality therapy
(radiation and inhibition of both HIF-1α and VEGF-A) was highly
effective in blocking sarcoma growth in a murine model by maximizing
DNA damage and apoptosis in tumor endothelial cells, leading to loss of
tumor vasculature (10).
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Figure 21.3 Cell survival curves by dose and time. Radiation survival curves of FSaII
fibrosarcoma tumor cells in vivo obtained immediately (Day 0) and 5 days (Day 5) after irradiation
with various doses. The data points are from Figure 21.2. These data suggest indirect cell death
is dose dependent.
As discussed above (27), the secondary cell death in FSaII tumors

progressed for about 3 days after 15- or 20-Gy irradiation and then the
surviving cell population began to increase in some tumors whereas no
such recovery of cell survival was evident after 30-Gy irradiation. These
results suggested that indirect cell death in FSaII tumors is limited after
irradiation with doses lower than 10 Gy. In these experiments,
irradiation of FSaII tumors with 20 Gy significantly increased the
expression of both HIF-1α and VEGF (Figs. 21.4 and 21.5). Such
increases in HIF-1α and VEGF may account for the recovery of surviving
cell population following the initial indirect cell death in the tumors
irradiated with 15 or 20 Gy (Fig. 21.2). As shown in Figure 21.1,
eradication of the surviving hypoxia cells with hypoxic cytotoxins, and
suppression of HIF-1α with small molecule inhibitors may prevent
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relapse and metastases caused by the cells which escaped the direct and
indirect insults of SRS/SAbR.
Evidence of Radiation-Induced Immune Enhancement with

SRS/SAbR
Immunotherapy is an attractive therapeutic approach that harnesses the
power of the immune system to eliminate malignant disease. Many
tumors express tumor-associated antigens that can be recognized by T
cells and have the potential to mount an immune response that would
cause tumor destruction (28). However, ionizing radiation is often
immunosuppressive because lymphoid tissues, including lymphocytes,
are radiosensitive. When patients are treated with conventional
fractionated radiotherapy, the multiple radiation exposure for a
prolonged period may cause suppression instead of augmentation of
antitumor immunity. On the other hand, accumulating evidence suggests
radiation-induced immune enhancement in that high-dose local
irradiation of tumors elicits antitumor immune reactions (29–35).
Indications are that extensive injury and death of tumor cells caused by
high-dose irradiation induces a massive release of tumor-specific
antigens as well as various pro-inflammatory and pro-oxidant cytokines,
leading to improvement of priming of tumor-specific T cells. In addition,
irradiation promoted the antigen presentation by increasing the
activation and maturation of dendritic cells (DCs), and also increased the
traffic of effector T cells to tumors. Finkelstein et al. showed SAbR can
induce cellular expression of major histocompatibility complex (MHC),
adhesion molecules, costimulatory molecules, heat shock proteins,
inflammatory mediators, immunomodulatory cytokines, and death
receptors to enhance antitumor immune responses (33).
Although large field radiation has been historically associated with
immunosuppression, targeted radiation in SRS/SAbR doses has been
shown to induce changes in the tumor microenvironment beyond
cellular cytotoxicity that evoke immune enhancement, including changes
in proinflammatory cytokines, chemokines, effector, and
immunosuppressive T-cell subsets as well as in immune receptors on
tumor cells. These changes have been linked to expansion of tumor-
reactive T cells, improved clinical responses, and increased overall
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survival in both preclinical and clinical models (34). Thus, combination
of SRS and/or SAbR with immunotherapy may be synergistic by
promoting the release and processing of antigens that can be presented
by DCs. This may then augment the response to treatments that expand
or activate antitumor T cells (35).
Postow et al. reported the abscopal effect, a phenomenon in which
local radiotherapy is associated with the regression of metastatic cancer
in unirradiated locations, in a patient with metastatic melanoma treated
with SBRT (9.5 Gy × 3) and an immune checkpoint inhibitor (ICI),
ipilimumab, an inhibitor of cytotoxic T-lymphocyte–associated antigen
(CTLA-4), an immunologic checkpoint on T cells. The abscopal effect,
rare with conventionally fractionated radiation therapy, may be more
common and predictably induced with SRS/SAbR, which can cause
massive antigen release from the irradiated tumor, which then promotes
the immunologic attack on other tumors (the abscopal effect) (36). Just
as the aforementioned vascular damage may vary by tumor cell type, we
hypothesize the extent of antigen release may vary by both dose and
volume of tumor irradiated. In summary, as shown in Figure 21.1, the
ability of SRS or SAbR to elicit antitumor immunity may be potentiated
with the use of immune agents targeting various steps of antigen
processing, generation of effector cells, and trafficking the effector cells
into tumors.
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Figure 21.4 Immunohistochemical study for CA9, HIF-1α, VEGF, and CD3. FSall tumors grown in
the hind limb of C3H mice were irradiated with 20 Gy in a single exposure and tumors were
dissected 1, 3, and 5 days later. Tissues were sectioned and processed for immunohistochemical
staining for CA9, HIF-1α, VEGF, and CD31. Representative samples from control tumors and
those 3 days after irradiation are shown. Results show increased expression of HIF-1α and VEGF
suggesting tumor response to radiation-induced hypoxia. A: Brown: CA9 (Carbonic anhydrase 9).
B: Dark brown: HIF-1α. C: Reddish brown: VEGF. D: Dark brown: CD31-labeled micro vessels. E:
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Immunofluoresence assessment: Green: CD31-positive endothelial cells. Red: HIF-1α. Blue:
Nucleus stained with DAP1. D: Brown: VEGF.
The Debate Regarding the Applicability of the Linear

Quadratic Model to SRS/SAbR
Given the aforementioned evidence of the vascular and immunologic
changes associated with SRS/SAbR, it is not surprising that many, if not
most, investigators now believe the traditional radiobiologic principles
do not apply to SRS and SAbR (19,37,38,41). Nonetheless, the debate
endures (37–41). First, the LQ model and the modified LQ models are
based on the assumption that radiation-induced cell death in tumors is
due solely to DNA double-strand breaks. The many seminal and recent
articles cited herein, however, strongly suggest that high dose/fraction
(>10 Gy) radiation causes devascularization in tumors, which then
induces delayed indirect tumor cell death. The massive cell death
directly and indirectly caused by SRS/SAbR then would release large
amounts of tumor antigens leading to tumor-specific immune
stimulation, thereby inducing further indirect cell death. Thus it is
reasonable to hypothesize that the doses routinely delivered in
SRS/SAbR would induce indirect cell death via both vascular and
immunologic effects. The cellular alpha/beta ratio in the LQ model is
directly quantified by an in vitro survival curve, which simply does not
account for vascular or immune responses. Therefore, we assert that
applying the LQ model, which has been very useful and extensively used
for conventionally fractionated radiotherapy, to high dose/fraction SRS
and SAbR is conceptually flawed.
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Figure 21.5 Hypothetical model of cell survival by dose. 0 to 5 Gy correlates with death well-
oxygenated tumor (curve a); 6 to 10 Gy correlates with death of hypoxic tumor (curve b); doses of
>10 Gy correlate with indirect delayed death of hypoxic cells by devascularization and possibly
radiation-induced immune enhancement (curves c and d).
Figure 21.5 illustrates hypothetical radiation cell survival curves of

tumors irradiated in vivo, which account for both high-dose radiation-
induced vascular damage and immune enhancement resulting in
increased indirect cell death and improved tumor control. If it is
assumed that about 10% of tumor cells are hypoxic and that the
radiation-induced cell death occurs only by the classical radiobiologic
principle, the survival curve of tumor cells will be biphasic denoted by
“a” and “b”: the initial rapid decrease in cell survival “a” represents the
death of oxic cells and the subsequent gradual decline in cell survival
with the increase in radiation dose indicated by “b” corresponds to the
death of hypoxic cells. However, it is likely that irradiation of tumors
with doses above 10 to 12 Gy causes vascular damage, thereby
triggering indirect death of hypoxic cells, as shown by the downward
curve “c” or d (41).
CONCLUSION
Stereotactic radiation (both SRS and SAbR) is now more frequently used
in the treatment of intracranial and extracranial tumors. The rapid
adoption of these techniques is due largely to the technologic advances
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in positioning and targeting that have made the precise delivery of such
high doses both safe and effective. Multiple clinical trials have confirmed
dramatic improvement in tumor control for many different types of
tumors with SRS and SAbR. Even though SRS and SAbR are now widely
accepted as established treatment modalities in modern radiation
oncology, the radiobiologic rationale for SRS and SAbR has been unclear
until recent laboratory studies indicated that vascular damage and
immune reaction may be responsible for the high response rate of
tumors to SRS and SAbR. It is well known that newly formed tumor
blood vessels are exquisitely sensitive to ionizing radiation. Various lines
of experimental evidence indicate that the high-dose radiation, that is,
>10 Gy, per fraction, causes marked vascular damage leading to
deterioration of the intratumor environment, which then causes
secondary or indirect tumor cell death. In tumors treated with SRS and
SAbR, extensive initial cell death through direct effect and vascular
damage leads to release of antigens, which may be dose and volume
dependent. Conventional radiobiology principles cannot account for the
high rates of tumor control produced with high dose per fraction SAbR
and SRS. The LQ model is for cell death caused by DNA breaks, and thus
the usefulness of this model for SAbR and SRS is limited. Recent and
future research will focus on methods to enhance indirect cell death.
This work will include the discovery and delivery of hypoxic cell
cytotoxins, inhibitors of HIF-1α, VEGF, and immune checkpoint
inhibitors.
ACKNOWLEDGMENT
This work was supported by research funds from Elekta and the University of
Minnesota Foundation.
KEY POINTS
• While direct cell death remains important, recent research shows
indirect cell death from vascular and immunologic effects of high
dose/fraction radiation (SRS/SAbR) play a key role in the overall
effect of these modalities.
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• Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial
growth factor (VEGF), and various immune checkpoint inhibitors
(ICI) may enhance indirect cell death associated with SRS/SAbR.
• Radiation-induced immune enhancement (abscopal effect) is
mediated by antigen release from irradiated tumors, which then
causes indirect cell death in un-irradiated tumors.
• Early results suggest the combination of SRS/SAbR and
immunotherapy may be synergistic by promoting the release and
processing of antigens that can be presented by dendritic cells,
which may activate antitumor T cells and result in radiation-induced
immune enhancement.
• The linear-quadratic model, although very useful for predicting the
effects of conventionally fractionated radiation therapy, does not
take into account the indirect effects of SRS/SAbR, and thus
application of the LQ model to SRS/SAbR is conceptually flawed.
QUESTIONS
1. Which of the following are possible mechanisms for indirect cell
death in SRS/SAbR?
A. DNA strand breaks
B. Tumor hypoxia from vascular effects of radiation
C. Radiation-induced immune effects
D. All of the above
2. Which of the following does not occur when fibrosarcoma in mice
is irradiated with 20 Gy?
A. Reduced blood perfusion of tumor.
B. HIF-1α is upregulated.
C. CA9 expression is increased.
D. VEGF expression is decreased.
3. True/False: Cell survival studies of fibrosarcoma treated with 30
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Gy in a single dose show that relative to day 1, no further cell
death occurs by day 5.
4. True/False: Radiation-induced immune enhancement (abscopal
effect) is a phenomenon in which local radiotherapy is associated
with regression of other unirradiated tumors. This effect is rare
with conventionally fractionated radiotherapy. This effect has not
been demonstrated in both preclinical and clinical case reports in
response to SAbR?
5. Although large field radiation therapy with conventional
fractionation has historically been associated with
immunosuppression, targeted radiation in high doses has been
shown to induce immune enhancement, including changes in
proinflammatory cytokines, chemokines, effector, and
immunosuppressive T cell subsets as well as immune receptors on
tumor cells. These changes have been linked to which of the
following?
A. Expansion of tumor-reactive T cells
B. Improved clinical responses
C. Increased survival in both preclinical and clinical models
D. All of the above
ANSWERS
1. D
2. D VEGF is increased. All of the above effects indicate
increasing tumor hypoxia.
3. False. Cell survival continues to decrease over that time
period suggesting both direct and subsequent indirect cell
death.
4. False. The abscopal effect has been shown in response to
SAbR in both preclinical research and clinical case reports.
5. D
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35. Okwan-Duodu D, Pollack BP, Lawson D, et al. Role of radiation
therapy as immune activator in the era of modern immunotherapy
for metastatic malignant melanoma. Am J Clin Oncol. 2015;
38(1):119–125.
36. Postow M, Callahan MK, Barker CA, et al. Immunologic correlates of
the abscopal effect in a patient with melanoma. N Engl J Med.
2012;366:925–931.
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37. Fowler JF, Wolfgang AT, Fenwick JD, et al. A challenge to
traditional radiation oncology. Int J Radiat Oncol Biol Phys.
2004;60:1241–1256.
38. Song CW, Cho LC, Yuan J, et al. Radiobiology of stereotactic body
radiation therapy/stereotactic radiosurgery and the linear-quadratic
model. Int J Radiat Oncol Biol Phys. 2013;87:18–19.
39. Brown JM, Brenner DJ, Carlson DJ. Dose escalation, not “new
biology”, can account for the efficacy of stereotactic body radiation
therapy with non-small cell lung cancer. Int J Radiat Oncol Biol Phys.
2013;85:1159–1160.
40. Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS
and SBRT: Are more than the 5Rs involved? Int J Radiat Oncol Biol
Phys. 2014;88:254–262.
41. Sperduto PW, Song CW, Kirkpatrick J, et al. A hypothesis on
indirect cell death in radiosurgery era. Int J Radiat Oncol Biol Phys.
2015;91:11–13.
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22 Tolerance of Normal Tissue to
Therapeutic Radiation
Bahman Emami and Fiori Alite
INTRODUCTION
Radiation therapy is an integral part of the treatment of patients
inflicted with cancer. It is estimated that over 60% of patients with
cancer will have radiotherapy as part of their total course of treatment
(1). Radiation therapy affects both tumor cells and uninvolved normal
cells; the former to the benefit and the latter to the detriment of patients.
With the goal of achieving uncomplicated local regional control of
cancer, balancing between the two is both the art and science of
radiation oncology. Unfortunately, after over 100 years of practicing
radiation oncology and in spite of much recent progress, knowledge of
either of the two is far from complete.
From a historical point of view, the first formal attempt to address at
least one of the goals, namely normal tissue tolerance to radiation, was
carried out by Rubin and Cassarett (2). Even though this publication was
a collection of anecdotal reports, it has served radiation oncologists as a
raw reference to build on their own experience. The decade of the 1980s
represents a quantum leap of progress in the field of radiation oncology.
With the work of researchers on four National Cancer Institute multi-
institutional contracts, the science and practice of radiation oncology
changed from a two-dimensional to a three-dimensional/volumetric
process (3). During the work on these contracts it became apparent to
the clinicians that information on the tumoricidal doses of radiation as
well as normal tissue complication doses, especially on partial volumes,
is mostly empirical and totally inadequate. A committee was formed to
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address a part of this dilemma by comprehensively reviewing the
available published data. In the process of this review by the committee,
it became clear that much of the data was nonexistent and they would
have to rely on the collective experience of eight clinicians from major
institutions in the United States. Moreover, in order to shed some light
on the volumetric aspect of these issues, it was decided that organs be
divided into one-third, two-thirds, and whole-organ volumes. In spite of
the clear indication in the manuscript on the paucity of solid
experimental/prospectively driven data, this publication by Emami et al.
gained much popularity. Obvious limitations of the publication include:
(1) It was literature review up to 1991. (2) It completely pre-dated the
3DCRT-IMRT-IGRT era. Even at that time dose–volume histograms were
not in routine clinical use. (3) It was a tabulation of the estimates for
three of the aforementioned arbitrary volumes. (4) It was only for
external beam radiation with conventional fractionation. (5) Only one
severe complication was chosen as an endpoint.
During the last two decades, the practice of radiation oncology has
been completely revolutionized. Multidisciplinary management of cancer
has become the standard of care. The choice of an endpoint for
complication analysis and modeling has significantly changed. There has
been a major change in technology with the routine use of CT simulation
and the incorporation of other modalities such as MRI, PET, 4D-CT, etc.
In addition, 3D-CRT/IMRT/IGRT has become standard with an array of
evaluation tools. There has also been a vast amount of published
information that has become available to address the relationship
between dosimetric parameters and the clinical outcomes of normal
tissues. Due to different analytic methodologies, calculation methods,
endpoints, grading schemes, etc., the data is noisy and sifting through
these data for practicing radiation oncologists represents a nearly
impossible task. Realizing this difficulty and the obvious need for a
simplistic format, a group of physicians and researchers were formed
with the name “The Quantitative Analysis of Normal Tissue Effects in
the Clinic” (QUANTEC). The first goal was to review the available
literature of the last 18 years on volumetric/dosimetric information of
normal tissue complication and provide a simple set of data to be used
by the busy community practitioners of radiation oncology, physicists,
and dosimetrists. The second goal of the QUANTEC group was to provide
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reliable predictive models on relationships between dose–volume
parameters and the normal tissue complications to be utilized during the
planning of radiation oncology. The results of several years of data
collection since the original work by Emami et al. culminated in the
publication of the so-called QUANTEC “white papers” in 2010 (4–6,27).
Although these publications contain a comprehensive review of
published information and can serve as a guide for future research on
this issue, they still have many shortcomings mainly due to the basic
complexity of the subject (26–27). This shortcoming has been clearly
indicated in the QUANTEC publication and the need for much more data
in the future has been emphasized. However, the presented data in the
publication is still cumbersome and lacks the “user-friendliness” required
for it to be used in the day-to-day practice of a busy community
clinician. As shown in Table 22.1, there are numerous factors that affect
the radiation-induced complications of normal tissues on any given
clinical situation (23–25). Thus, the experience and judgment of the
clinician still plays the most important role in treating patients.
After reviewing the publication by the QUANTEC group, we attempt
to provide the clinicians and the practitioners of radiation oncology a
comprehensive but simpler, more user-friendly set of data (Tables 22.2
and 22.3). Several additional organs/tissues are also reviewed that were
not discussed in the QUANTEC publication, as well as our constraints for
hypofractionated regimens. It should be noted that the data is not
intended to be extrapolated to pediatric patients. The data should be
used only as a guide and does not substitute for a physician’s clinical
judgment. We believe, as indicated in the QUANTEC publication, there is
an urgent need for systematic research on this issue which we hope will
be forthcoming.
TABLE 22.1 Variables That Can Impact Normal Tissue Tolerance
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TABLE 22.2 Normal Tissue Tolerance for Standard Fractionation
TABLE 22.3 Normal Tissue Dose Tolerances for Hypofractionated
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Regimens Synthesized from Available Literature
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Word of Caution About BED
Recently it has become popular (as in many sections of QUANTEC
publication) to convert the dose–fractionation to a biologically effective
dose (BED) in order to compare various dosimetric parameters. A
practical version of isoeffect formula based on the linear-quadratic (LQ)
model is:
The index of α/β is calculated based on information from cell survival

curves and has been extrapolated and extended to human tumor and
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normal tissues by some computer scientists. Unverified assignment of an
α/β ratio and using it to calculate a normal tissue tolerance dose can be
misleading, or at least should be experimentally validated before being
recommended for routine clinical use (7,9,10). The following are some
basic facts based on current knowledge:
The following example depicts the basic fallacies of using BED,

calculated from the above formula, in clinics.
If we arbitrarily choose 1 Gy/fraction/day of brain tissue, then the

conversion of BED to dose/fractionation of 1 Gy/day:
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In the authors’ limited informal survey, no radiation oncologists would
use 90 Gy at 1 Gy/day or 45 Gy at 3 Gy/day (despite being the same
BED as 60 Gy in 30 fractions using an α/β of 1), thus limiting the
applicability of BED for routine clinical use.
The following descriptive paragraphs of Tables 22.2 and 22.3 are
presented as general guidelines.
Note: Evolution of Dose Calculation and Treatment Planning System
As treatment planning systems continue to evolve in their ability to
calculate planned dose with higher precision, significant dose
discrepancies between calculation algorithms have been reported in the
literature that will require a reevaluation of organ at risk tolerance
doses. For example, we have demonstrated that utilizing Monte Carlo–
based treatment optimization to achieve constraints previously
developed in an era of pencil-beam algorithms without heterogeneity
corrections results in significant differences from normal tissue RTOG
constraints (80). As an era of higher accuracy Monte Carlo treatment
planning is ushered in, it is important that normal tissue constraints be
reevaluated to reflect this change.
Standard Fractionation
Central Nervous System
Brain. Radiation necrosis of the brain typically occurs 3 months to
several years after radiotherapy (median 1 to 2 years) (3,7). The original
Emami publication estimated a 5% risk of radionecrosis at 5 years with a
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dose of 60 Gy to 1/3 of the brain with standard fractionation (3). More
recently, QUANTEC conducted an extensive review of the modern
literature and published new dose constraints for the brain (6,7). The
review was based on a heterogeneous group of studies with varied dose
and fractionation schemes. Studies were compared using the biologically
effective dose (BED) with an α/β ratio of 3. A dose–response relationship
was found to exist. For standard fractionation, the incidence of
radionecrosis appears to be <3% for a dose of <60 Gy. The incidence
increases to 5% with a dose of 72 Gy and 10% with a dose of 90 Gy.
However, these doses were based on studies with widely varying
parameters (target volumes, sample size, brain region, etc.). It should be
noted that an α/β ratio of 3 is greater than the values frequently used in
the literature and caution should be used when converting to BEDs (see
above discussion). In our practice, we strive to achieve very
homogeneous dose distributions with a Dmax (point dose) ≤65 Gy with
only rare occurrences of symptomatic radiation necrosis (personal data,
unpublished).
Brainstem. RT-induced brainstem toxicity can be incapacitating and

potentially lethal. The initial estimates by Emami et al. (3) were of a TD
5/5 of 50 Gy to the entire brainstem and 60 Gy to 1/3 of the brainstem.
These estimates were based on the scant amount of data in the literature
at that time and on clinical experience. The QUANTEC review identified
additional modern series focusing on brainstem dose and dose–volume
measures (6,9). The review included series that treated patients with
either photons, protons, or both. The QUANTEC review concluded the
original Emami constraint of 50 Gy was overly conservative. The entire
brainstem can tolerate up to 54 Gy with a <5% risk of brainstem
necrosis or neurologic toxicity. Small volumes (1 to 10 cc) can tolerate
up to 59 Gy while a point (<<1 cc) may receive up to 64 Gy.
Spinal Cord. Spinal cord injury due to irradiation, though rare, can be
extremely debilitating resulting is paralysis, sensory, deficits, pain, and
bowel/bladder incontinence (10,30). Schultheiss (30) published an
extensive review of the literature regarding de novo irradiation of the
spinal cord. Among the reviewed studies, a wide range of fractionation
regimens were used (2 to 9 Gy/fraction). An α/β ratio of 0.87 was
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estimated for the spinal cord and corresponding 2-Gy equivalent doses
were calculated. The review estimated the risk of myelopathy to be 0.2%
at 50 Gy and 5% at 59.3 Gy. Similar conclusions regarding α/β ratio and
dose–volume limits were published by QUANTEC (6,10). It should be
noted that an α/β ratio of 0.87 is less than the values frequently used in
the literature and caution should be used when converting to BEDs (see
above discussion).
Chiasm and Optic Nerves. Radiation-induced optic neuropathy (RION)

is infrequent but usually results in rapid painless visual loss (8). The
initial Emami review listed a TD 5/5 of 50 Gy to the whole organ
without partial volume tolerance data (3). Again, this was based
primarily on clinical experience and sparse published data. Many more
studies are now published and were reviewed by QUANTEC (6,8). Based
on the QUANTEC review, a Dmax of 50 Gy is associated with a “near-
zero” risk of blindness. In fact, blindness was quite rare (<3%) until a
Dmax of ≥55 Gy. Between 55 and 60 Gy, the risk of blindness is
approximately 3% to 7%, although it must be noted that except for
patients being treated for pituitary tumors where there is optic nerve
compression, in standard fractionated patients none experienced RION at
doses less than 59 Gy (see Figure 1 in Mayo et al. (8)). At doses >60 Gy,
the risk of RION greatly increases.
Head and Neck

Retina. Radiation retinopathy, resulting in loss of vision or visual
acuity, presents similarly to diabetic retinopathy often within 5 years of
radiotherapy. Parsons (31,32) reported only one instance of retinopathy
with a dose <50 Gy to at least half the posterior pole of the eye with a
steep dose–response curve at doses >50 Gy. Subsequently, Parsons et al.
(33) demonstrated no cases of retinopathy at doses below 45 Gy but a
steep dose curve at doses >45 Gy. More recently, Monroe et al. reported
a 4% rate of retinopathy after <50 Gy was received by at least 25% of
the globe with conventional fractionation and modern conformal
techniques (34). Using hyperfractionation, the rate of retinopathy
decreased from 37% to 13% with doses ≥50 Gy. Takeda et al. reported
no cases of retinal complications when the Dmax was <50 Gy (35).
Clearly, the dose tolerance of the retina is dependent upon multiple
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factors including predisposing comorbidities, the fractionation schema
employed, and the volume that is irradiated. Multiple publications have
demonstrated a steep dose–response curve for doses >50 Gy (33–35).
Using modern treatment planning techniques and standard fractionation,
we recommend limiting the retina to a Dmax <50 Gy consistent with
current RTOG protocol guidelines (76–78).
Lacrimal Gland. Severe dry eye leading to visual compromise can

develop in patients receiving head-and-neck radiation. In a review of 78
patients, Bhandare et al. noted 40 cases of severe dry eye syndrome,
with incidence increasing from 6% at mean total doses of 35 to 40 Gy to
50% at 45 to 50 Gy and 90% at 60 to 65 Gy. Higher total doses and dose
per fraction to the lacrimal gland also correspond to faster time to the
onset of severe dry eye symptoms (81,82).
Cochlea. Damage to the cochlea may result in sensorineural hearing loss

(SNHL). As summarized by QUANTEC, high-frequency hearing loss is
much more common than low-frequency hearing loss (11). Cisplatin-
based chemotherapy can have an additional adverse effect on SNHL. The
definition of clinically significant SNHL varies throughout the literature
but is generally considered to be an increase in bone conduction
threshold of 10 to 30 dB. The QUANTEC review examined several series
and suggested a mean dose constraint of ≤45 Gy (6,11). Chan et al.
conducted a longitudinal study of 87 consecutive patients treated for
nasopharyngeal carcinoma, mostly treated with cisplatin-based
chemoradiotherapy (36). A mean dose of ≤47 Gy to the cochlea resulted
in <15% rate of SNHL. Therefore, based on a review of the literature
with modern treatment planning techniques and concurrent cisplatin
chemoradiotherapy, we believe a cochlear mean dose constraint of ≤45
Gy will result in a <15% rate of SNHL.
Parotid. Late salivary dysfunction is a common toxicity from

radiotherapy for head-and-neck cancer that can take up to 2 years to
recover (37,38). Xerostomia has been widely defined in the literature
from patient-reported outcomes to objective salivary flow. Quantifiably,
xerostomia is defined by the LENT-SOMA scale. Grade 4 xerostomia
consists of an objective reduction of ≥75% of baseline salivary function.
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The QUANTEC review (6,12) summarized the literature including the
Washington University experience (37). Blanco demonstrated that
sparing (mean dose <20 Gy) of at least one parotid gland minimized the
incidence of grade 4 xerostomia. Likewise, limiting both parotids to a
mean dose <25 Gy resulted in minimal of grade 4 xerostomia. Dose to
the parotids should be reduced as much as clinically allowable as lower
mean doses generally result in better salivary function (12).
Mandible. The rates of osteoradionecrosis (ORN) of the mandible have

decreased over the past few decades (39). The risk of ORN is dependent
on several factors including radiation dose, use of chemotherapy, dental
hygiene, tumor location, mandibular surgery, and radiation technique
(39–44). Ben-David et al. (40) demonstrated a steep dose fall-off across
the mandible when IMRT is employed. In their study, 50% of the
patients in their study received ≥70 Gy to ≥1% of the mandibular
volume with no cases of grade ≥2 ORN. Additional studies, including
IMRT for oral cavity cancers, demonstrate a rate of ORN near 5%
(41–43). Therefore, we recommend limiting the mandible to a Dmax
(point dose) ≤70 Gy when using IMRT. However, there may be clinical
scenarios where, based on the judgment of the clinician, it may be
necessary for larger volumes of the mandible to receive higher doses of
radiation in order to achieve adequate tumoricidal dose and target
coverage.
Pharyngeal Constrictors. Treatment intensification for head-and-neck

cancer has resulted in an increased rate of late sequela including
dysphagia and aspiration. Modern treatment planning has allowed the
study of various components of the swallowing apparatus. The results in
the literature in this burgeoning area of research are variable as
summarized in the QUANTEC review (6,13). Several groups have found
the dose to the superior and/or middle pharyngeal constrictor muscles to
be of paramount importance. Others have demonstrated the dose to the
inferior pharyngeal constrictors or larynx to be of importance. Feng et al.
(45) found no patients to have aspiration when the pharyngeal
constrictors were limited to a mean dose <60 Gy. We base our practice
primarily on the findings from the University of Michigan and limit the
superior pharyngeal constrictors to a mean dose <60 Gy whenever
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clinically possible after maintaining appropriate tumoricidal dose and
target coverage.
Larynx. Toxicity from radiotherapy to the larynx can include vocal

dysfunction and laryngeal edema. The original Emami publication (3)
addressed the risk of cartilage necrosis; however, this is rarely seen in
modern radiotherapy and is not as relevant of an endpoint as vocal
function and laryngeal edema. The QUANTEC publication reviewed
several studies involving vocal dysfunction, concluding doses to multiple
structures (larynx, pharynx, oral cavity) play an important role in voice
function (6,13). Radiotherapy is commonly used for the treatment of
early-stage glottic cancer, employing doses >60 Gy, with a good voice
outcome. A single publication (46) on laryngeal edema was reviewed,
which found <20% incidence of ≥grade 2 edema when the mean
laryngeal dose was <43.5 Gy and the V50 <27%.
Thyroid. Radiation-induced clinical hypothyroidism is a documented

late effect after tumor-directed radiation therapy to the region of the
neck. Reports of incidence have varied based on clinical definition and
extent of cancer-directed therapies employed. A recently published
normal tissue complication probability (NTCP) model for radiation-
induced biochemical hypothyroidism (TSH >4) has related mean
thyroid dose to irradiated thyroid volume. Dose constraints for a 25%
risk of hypothyroidism were 26, 38, 4,8 and 61 Gy for thyroid volumes
of 10, 15, 20, and 25 cc, respectively (83).
Thorax
Brachial Plexus. Brachial plexopathy can manifest as pain, paresthesias,
or motor deficits of the upper extremity (47). Muscular atrophy and
edema may develop. Emami et al. (3) suggested the TD 5/5 to the entire
brachial plexus was 60 Gy. More recently, several studies with over 20
years of follow-up have suggested that the incidence of brachial
plexopathy continues to rise after 5 years and may not be apparent for
up to 20 years after radiotherapy (47,48). The brachial plexus appears to
be especially sensitive to fractionation schedules, with the risk of injury
much higher for larger fractions despite equivalent BED (49). With
standard fractionation the risk of clinically apparent nerve damage
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seems to be <5%, after 5 years of completing radiotherapy, when the
brachial plexus is limited to 60 Gy.
Lung. Symptomatic radiation pneumonitis (RP) is one of the most

common toxicities in patients treated with radiation for cancers of the
lung, breast, and mediastinal lymphatics. The risk of RP often limits the
dose delivered for the treatment of these malignancies. Since the initial
Emami publication (3) there has been an extensive amount of research
attempting to relate many different dose–volume parameters to RP. The
QUANTEC publication reviewed >70 published articles looking at both
mean lung doses and Vx parameters (6,14). This comprehensive review
demonstrated no clear threshold dose for symptomatic RP. The compiled
data showed a mean dose–response curve with a 20% risk of RP for a
mean lung dose of 20 Gy. In addition, multiple Vx values have been
investigated for predicting RP but the data are not as consistent as the
data for mean lung doses. Using 3D techniques, Graham found the V20
to be the most useful parameter for predicting the risk of RP (50). When
Vx values are used, the V20 is the most commonly incorporated
parameter.
Esophagus. Acute esophagitis commonly occurs during radiotherapy for

thoracic malignancies and can lead to hospitalizations, procedures, and
treatment breaks (16). Most series in the literature report rates of RTOG
grade ≥2 esophagitis. The QUANTEC review summarized 11 studies
that used three-dimensional treatment planning (6,16). A single best
parameter was not identified due to the diverse range of dose–volume
metrics that correlated with acute esophagitis (51–53). As demonstrated
in the QUANTEC publication, there appears to be a trend demonstrating
increased rates of acute esophagitis for volumes receiving >40 to 50 Gy.
Currently, the ongoing RTOG 0617 is collecting V60 data on all patients
and recommends keeping the mean dose <34 Gy (54).
Heart. Clinical pericarditis and long-term cardiac mortality are the two
most relevant cardiac toxicities. Since the original Emami publication
(3), there remains a paucity of data reporting rates of pericarditis with
dose–volume parameters. Indeed, several current RTOG protocols
continue to use constraints similar to the original Emami TD 5/5 dose–
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volume estimates for the heart (54–56). As reviewed by QUANTEC
(6,15), two esophageal cancer studies (57,58) assessed 3D-derived data
with both studies demonstrating a rate of pericarditis <15% when the
mean pericardial dose was <26 Gy. In addition, Wei found the
pericardial V30 <46% to be significant on multivariate analysis. Long-
term cardiac mortality has been demonstrated in multiple studies, most
commonly in the treatment of breast cancer and Hodgkin lymphoma
(15). A joint analysis of the Hodgkin and breast cancer data (59,60),
summarized by QUANTEC, produced a dose–response curve for cardiac
mortality. QUANTEC proposed a conservative approach, predicting a
V25 <10% of the heart will be associated with a <1% probability of
cardiac mortality at 15 years after radiotherapy.
A recently published population-based case-control study analyzing
over 2,000 women treated for breast cancer in Sweden and Denmark
from 1958 to 2001 demonstrated a dose–response relationship for mean
heart dose and major coronary events including myocardial infarction,
coronary revascularization, and death from ischemic heart disease (84).
The study noted an increase of 7.4% risk for major coronary events for
each additional Gray to mean heart dose, and no threshold for initiation
of increased risk was found. Current RTOG protocols have placed an
unacceptable deviation for mean heart dose of greater than 500 cGy, and
per protocol goal of V20 less than 5% for left-sided treatments (85,86).
Abdomen
Liver. Radiation-induced liver disease (RILD) typically occurs between 2
weeks and 3 months after radiotherapy. Pre-existing liver disease may
render patients more susceptible to RILD (17). The findings by
QUANTEC (6,17) are very similar to the original estimates by Emami et
al. (3), suggesting a <5% rate of RILD when the mean liver dose is ≤30
Gy in patients without pre-existing liver disease or primary liver cancer.
The mean liver dose should be ≤28 Gy in those patients with pre-
existing liver disease.
Kidney. Radiation-induced renal dysfunction can be expressed in

various ways including symptomatic expression, biochemical changes, or
radiologic findings. As summarized by QUANTEC, a wide array of
endpoints has been used in the literature from a decrease in creatinine
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clearance to renal failure (6,19). For bilateral whole kidney irradiation, a
pooled analysis by Cassady (61) concluded a mean dose of 18 Gy
corresponded to a 5% risk of injury at 5 years. For bilateral partial
kidney irradiation, the data is less clear with a multitude of dose–volume
metrics studied by several investigators (19). Small volumes of the
kidney can tolerate relatively high doses of radiation. QUANTEC
estimated a <5% risk of injury for the combined kidney when V20
<32%. A recent RTOG protocol limited the combined kidney D50 <18
Gy and the mean dose <18 Gy (79). In addition, the current common
practice of limiting the equivalent of one kidney to <20 Gy seems to be
reasonable and is frequently used in our practice.
Stomach. Late radiation-induced toxicity to the stomach can include

dyspepsia and ulceration. Since the original Emami publication (3), few
studies have reported severe RT-related gastric toxicity. The QUANTEC
publication reviewed these studies, primarily pancreatic cancer trials,
and concluded a whole-organ dose of 50 Gy has been associated with a
2% to 6% risk of severe late toxicity (6,18) (similar to Emami et al.).
Small Bowel. Small bowel toxicity can be greatly affected by the use of
concurrent chemotherapy and prior abdominal surgery. In particular,
concurrent chemotherapy can impact the rates of acute small bowel
toxicity. Modern series employing 3D-conformal RT or IMRT have
demonstrated that the volume of small bowel receiving relatively low
doses of radiation plays a significant role in the rate of acute toxicity
(18). When contouring individual bowel loops, the most robust dose–
volume metric is the V15. The rate of grade ≥3 acute toxicity is <10%
when the V15 <120 cc (62,63). When the entire potential space within
the peritoneal cavity is contoured, a V45 <195 cc results in <10%
acute toxicity (64). Late small bowel toxicity, consisting of obstruction
or perforation, can be influenced by prior abdominal surgery. Modern
series reviewed by QUANTEC generally confirm the Emami et al. (3)
TD5/5 estimate for partial organ irradiation (6,18). In practice, we limit
the volume of the small bowel receiving 50 Gy to much less than 1/3.
We generally limit the V50 <5% based on the clinical scenario.
Pelvis
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Rectum. The treatment of prostate cancer has evolved such that the
great majority of patients will be alive for many years after
radiotherapy. Late rectal toxicities from radiotherapy can significantly
impact quality of life. Since Emami et al. (3), numerous studies have
employed dose escalation using 3D-CRT or IMRT for the treatment of
prostate cancer. These trials have resulted in the publication of many
dose–volume analyses as summarized by the QUANTEC review (6,21).
The dose–volume results are surprisingly consistent suggesting that high
doses are most important in determining risk of toxicity.
Bladder. The bladder frequently receives radiation during the treatment

of commonly encountered pelvic malignancies such as prostate, cervical,
and bladder cancer. Due to the distensibility of the bladder it is difficult
to conduct robust dose–volume analyses. The QUANTEC publication was
unable to find any reliable data for partial bladder volume constraints in
the treatment of prostate cancer and recommended using RTOG 0415
dose limits (6,20,65). In the treatment of bladder cancer, where the
entire organ is targeted, rates of severe late bladder toxicity are varied
(20). Shipley et al. (66) reported the pooled results of multiple RTOG
trials demonstrating a grade ≥3 toxicity rate of ≤6% when treating the
bladder to a dose of 64 to 65 Gy.
Penile Bulb. Erectile dysfunction can have a significant detrimental

effect on quality of life after treatment for prostate cancer. QUANTEC
summarized the published studies correlating the dose and volume of the
penile bulb that is irradiated with rates of erectile dysfunction (22). The
results for various dose–volume parameters are conflicting. There is
some data to support limiting the D70 <70 Gy and D90 <50 Gy.
However, the strongest data support the recommendation of limiting the
penile bulb to a mean dose <52 Gy without compromising target
coverage (67).
Femoral Head. Toxicity of radiation treatment to the pelvis includes

femoral head necrosis, femoral neck fracture, or long-term sequela
resulting in hip replacement surgery. Besides radiation dose and volume,
additional risk factors may include pre-existing osteoporosis/osteopenia
and androgen deprivation therapy (68–70). Emami et al. (3) suggested a
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TD 5/5 of 52 Gy to the whole femoral head. Grigsby et al. published the
Washington University experience and documented a 4.8% incidence of
femoral neck fracture following groin irradiation (68). Of note, there
was only one case of femoral neck fracture when the whole femoral neck
received ≤50 Gy. There is little data describing femoral toxicity when
higher doses are delivered to small volumes of the femoral head or neck
(71–74). We generally limit the entire femoral head to <50 Gy in an
attempt to limit femoral head/neck toxicity to <<5%.
Hypofractionation
Some of the earliest radiotherapy treatments were delivered using
hypofractionated dose regimens. As technology and radiobiology
advanced, protracted fractionation schemes became the norm.
Eventually, hypofractionation was again pursued and used to treat
intracranial lesions. Stereotactic radiosurgery (SRS) has been used for
decades and its success led to the use of hypofractionated treatment
outside of the brain. Over the past 15 years, the use of stereotactic body
radiotherapy (SBRT) has become widespread and utilized to treat a
number of cancers. Its role continues to expand, especially in the setting
of early-stage NSCLC, prostate adenocarcinoma, and treatment of
oligometastases. The QUANTEC group reviewed the literature pertaining
to SRS and published tolerance doses for some CNS organs at risk
(6–11). The most comprehensive review to date has been published by
Timmerman, and reviewed by Grimm et al. (75,87). In Table 22.3 we
provide a synthesized data of this table, and in Table 22.4 we provide an
example of standardized dose constraints used in our clinic for lung
SBRT. Both intracranial and extracranial organ tolerances were reviewed
and adjusted for either single-fraction, three-fraction, or five-fraction
treatments. Because the data in this burgeoning modality is relatively
limited, the dose constraints are largely not validated. Rather, they are
based on a combination of published data, clinical observations,
modeling, and educated guessing. Despite these caveats, the dose
constraints adapted from the Timmerman and Grimm reviews provide an
excellent starting point for adaptation in the clinic (see Table 22.3). The
QUANTEC steering committee has expressed interest in developing a
similar set of guidelines in setting of SBRT and hypofractionation as data
in these fields evolves.
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TABLE 22.4 Guidelines Employed by Loyola University Medical
Center for 50 Gy in Five-Fraction Thoracic Stereotactic Body
Irradiation
Conclusion
From the pioneering work of Rubin and Cassarett, to the historic work
by Emami et al. and now the exhaustive review by QUANTEC, great
progress has been made in the field of normal tissue tolerance to
therapeutic radiation. Despite these efforts, many questions still remain.
Normal tissue tolerance is an extremely complex issue and multifactorial
in nature. There continues to be an urgent need for comprehensive and
collaborative research. The preceding dose–volume parameters should
only be used as a guide. For instance, there are clinical scenarios where
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a 5% rate of a particular toxicity is unacceptable. In contrast, there may
be cases where one is willing to accept the risk a 20% rate of a particular
side effect in order to obtain a desired clinical outcome. Therefore, it is
imperative that the clinical judgment of the treating physician prevails
in the treatment decision-making process.
KEY POINTS
• Multiple clinicopathologic, treatment, and reporting variables can
impact normal tissue tolerance.
• The history and evolution of normal tissue tolerance to radiation

therapy culminated with the publication of the Emami estimates of
normal tissue constraints (3).
• The normal tissue compatibility models of the quantitative analysis

of normal tissue effects in the clinic (QUANTEC) was developed to
integrate additional studies providing dose/volume/outcome data.
• Radiobiologic dose and fractionation principles that guide tumor

control probability can affect normal tissue tolerances, but there are
limitations to applying these principles in the clinic.
• Table 22.3 provides normal tissue constraints for each organ at risk
site, integrates the most up-to-date literature, and provides dose
constraints for several hypofractionated regimens.
QUESTIONS
1. According to Darby et al., the increase per Gray (Gy) of Mean
Heart Dose (MHD) resulted in an increase of what percentage of
risk for major coronary event?
A. 1%
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B. 7%
C. 15%
D. 35%
E. 50%
2. Which of the following variables can affect the rate of risk of
development of clinically relevant radiation pneumonitis in a
patient undergoing chemoradiation for stage IIIA lung cancer?
A. Age
B. Smoking status
C. V20
D. Previous contralateral lobectomy
E. All of the above
3. According to QUANTEC, what is the maximum brainstem dose
that results in <5% risk of neuropathy for patients undergoing
single-fraction stereotactic radiosurgery?
A. 5 Gy
B. 12.5 Gy
C. 27 Gy
D. 25 Gy
E. 50.4 Gy
4. How many cubic centimeters of normal liver must be spared at
least 17 Gy in order to maintain normal liver function in three-
fraction stereotactic body radiation therapy?
A. 100 cc
B. 300 cc
C. 700 cc
D. 1,000 cc
E. 1,300 cc
5. The alpha/beta ratio for most tumors and normal tissues is
empirically derived from which of the following?
A. Large retrospective datasets comparing dose per fraction and
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local control and tissue toxicity.
B. Large prospective datasets comparing dose per fraction and
overall survival and tissue toxicity.
C. Large case-control datasets comparing dose delivered and risk
of normal tissue complication.
D. For a particular cell line, plotting the log of the surviving
fraction versus dose, and calculating the dose at which the
linear and quadratic contributions to cell killing are equal.
ANSWERS
1. B 7%. According to recently published case cohort review by
Darby et al. (84), with each Gy increased of MHD, there
was a 7.4% increase in risk of major coronary event, which
included myocardial infarction, coronary
revascularization, and death from ischemic heart disease.
2. E All of the above. Several clinicopathologic as well as
treatment characteristics can affect the rates of risk of
developing normal tissue toxicity. See Table 22.1.
3. B 12.5 Gy. According to Mayo et al. (9) maximum brainstem
dose of 12.5 Gy is associated with low (<5%) risk of
brainstem toxicity.
4. C 700 cc is an important partially spared volume of liver
that has been shown to correlate with radiation-induced
liver disease. See Table 22.3.
5. D For a particular cell line, plotting the log of the surviving
fraction versus dose, and calculating the dose at which the
linear and quadratic contributions to cell killing are equal.
It is important to note that BED calculations are dependent
on alpha/beta ratios, which are derived from colony assays
performed on individual cell lines. Unverified assignments
of an alpha/beta ratio and using it to calculate a normal
tissue tolerance dose can be misleading, or at least should
be experimentally validated before being recommended for
routine clinical use (7,9,10).
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23 Treatment Plan Evaluation
Ellen D. Yorke, Andrew Jackson, and Gerald J. Kutcher
Since the previous edition of this book, the basic tools of plan evaluation
—dose–volume histograms (DVHs) and high-quality graphic dose
displays—have not changed except for increase in calculation speed.
These tools are available on all modern treatment planning systems and
are almost universally used. A variety of dose–volume metrics that have
been shown to correlate with outcomes are applied in daily clinical
practice. “Biologic models” which condense the entire dose distribution
into a single number that represents the probability of a specified
outcome are not widely used in clinical practice but are still of interest,
and increasingly sophisticated statistical techniques are being used to
extract model parameters and significant dose–volume points from
clinical data.
The report of AAPM’s Task Group 166, “The Use and QA of
Biologically Related Models for Treatment Planning,” (1) includes a
thorough review of current models and their implementations in
commercial treatment planning systems for planning and plan
evaluation.
INTRODUCTION: WHAT IS NEW?

Since the late 1990s, three-dimensional conformal radiation therapy
(3DCRT) has gone from novel to passé, use of intensity-modulated
radiation therapy (IMRT) has burgeoned and other delivery techniques—
volumetric-modulated arc therapy (VMAT), tomotherapy,
“CyberKnife”—are now routinely used. Greatly increased computer
speed and graphic capabilities make it possible to routinely plan these
treatments in busy clinics—indeed, many planners find it easier to
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generate an IMRT or VMAT plan than a 3DCRT plan. Registered positron
emission tomography (PET) and magnetic resonance imaging (MRI)
studies are routinely used to supplement the planning computerized
tomography (CT) scan. Treatment accuracy has been greatly increased
by readily available tools for online image guidance. Partly thanks to
this image-guided radiation therapy (IGRT), it is now possible to safely
and effectively deliver highly hypofractionated treatment schedules to
tumors anywhere in the body using stereotactic body radiotherapy
(SBRT) (also called stereotactic ablative body radiotherapy [SABR]).
SBRT consists of a small number (1 to 10) of daily fractions, each
delivering a high dose per fraction (5 to 30 Gy). SBRT is perhaps the
greatest change in radiation therapy since the advent of IMRT and its use
has grown explosively (Fig. 23.1). It provides superior tumor control
with a remarkably low rate of serious complications, although some new
and unexpected complications have been observed (2,3). There is
incomplete mechanistic understanding of the excellent tumor control but
the rarity of serious complication is at least partly due to very accurate
setup with online image guidance (IGRT) and the fact that many
applications of SBRT are to small tumors (<100 cc). Thanks to the
combination of 3D IGRT and increasing planning computer speed,
clinicians are more seriously considering both online and off-line
“adaptive radiotherapy,” where plans are changed during a treatment
course to accommodate anatomical changes such as tumor shrinkage or
growth.
Knowledge of relationships between dose distributions, medical
variables, and normal tissue complications continues to grow as
researchers take advantage of electronic medical records to more readily
analyze outcomes from single and multi-institutional patient cohorts.
The systematic reviews of publications on normal tissue complications
by the “QUANTEC” (Quantitative Analysis of Normal Tissue Effects in
the Clinic) group have provided updated treatment planning dose–
volume guidelines and impetus for new studies to address areas where
information is lacking (4). Members of the American Association of
Physicists in Medicine (AAPM) can access the QUANTEC reports through
the AAPM website.
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INTRODUCTION: NOT NEW BUT NECESSARY
Inspecting isodose distributions superimposed on a patient’s planning CT
scan (or on a registered PET or MRI scan) remains an important plan
evaluation tool that can rapidly inform the planner of deficiencies in the
dose distribution. The rapid volumetric dose calculations of modern
planning systems allow users to rapidly scroll through the treated
volume for a complete picture of the dose distribution in relation to
anatomy and locate hot and cold spots with a single mouse click. For
complex plans, this is a great improvement over the traditional “three
principal planes through isocenter” displays. Clinicians often prefer
uniform target dose distributions unless there is a deliberate effort at
nonuniform target coverage—called simultaneous integrated boost (SIB)
or “dose painting” (5). The planner can deal with unintended high-dose
regions by changing beam number or directions, using higher-energy
beams and using dose-controlling “dummy structures” in optimization to
arrive at a final plan. Graphic displays also provide useful geometric
information such as whether a beam enters through a support device
where attenuation must be considered or unnecessarily through an organ
at risk (OAR), or whether the planning scan was acquired with an
inadequate field of view such that a beam appears to traverse a shorter
path length than it does in reality. However, for most people, graphic
displays are hard to interpret in a comprehensive manner. For optimum
plan evaluation, they should be used in parallel with the two general sets
of tools described below: DVHs, based on either physical or biologically
equivalent doses, and metrics derived from biologic models of tumor
control probability (TCP) and normal tissue complication probability
(NTCP).
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Figure 23.1 Growth in the number of Radiation Oncology articles dealing with SBRT and in
PubMed. There were approximately 1,500 articles in 2014. Data from Dr. Jimm Grimm.
The questions posed in the previous edition of this book still plague
clinicians:
Conventional evaluation of treatment plans, which judges a “best
treatment plan” using tradition, inspection of graphic isodoses and
practical knowledge alone, is no longer adequate to answer the issues
that continually arise in modern practice. For example, should we
escalate the dose to the prostate to the highest nonuniform dose or to a
lower, more uniform, target dose? Can the rectum and bladder tolerate a
high localized dose to a small volume? And if so, how small a volume
and how high a dose? And finally, how should we balance tumor control
and the risk of normal tissue complications?
Recent developments lead to new, unsolved questions in plan
evaluation. Under what conditions might nonuniform target doses be
more effective? When applying TCP models, should one look at the gross
target volume (GTV), the clinical target volume (CTV) of suspected
disease or the planning target volume (PTV) within which the CTV
might be found under conditions of setup error? What normal tissue
evaluation metrics should be used for hypofractionated treatment?
Below, we describe briefly the basic structure and some applications of
DVHs and modeling. We also describe some of the QUANTEC normal
tissue guidelines and compare them with previous consensus
recommendations.
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Dose–Volume Histograms
DVHs may be represented in either differential or integral form. The
former represents the volume of the organ receiving a dose within a
specified dose interval, whereas the latter is defined as the volume
receiving at least dose D as a function of D. The volume is either
represented as the percent (or fraction) of the total volume of the organ
or as the volume in cubic centimeters. The differential form lends itself
well to rapid visual inspection of the range and uniformity of dose. This
works well in finding cold spots in the target volume or hot spots in
normal organs. The integral form facilitates the assessment of the total
volume of tissue in such hot or cold spots and is the preferred format. A
major deficiency of DVHs is that they give no information as to the
anatomical location of hot or cold spots. In clinical plan evaluation, this
is partly resolved by parallel inspection of the graphic dose distribution.
In traditional radiation therapy, the ideal target integral DVH is a step
function—uniform dose to the entire target (Fig. 23.2). Since that is not
physically achievable, a “good” target DVH is considered to be one
where the bulk of the target receives prescription (e.g., D95 =
prescription dose to 95% of the target receives prescription dose or
higher) while restricting the minimum and maximum point doses (often
to approximately 90% and 110% of prescription, respectively). For dose-
painting treatments, the deliberate nonuniformity is reflected in the
target DVH (Fig. 23.2B). The ideal DVH for a normal tissue is a delta-
function at zero dose, which is also unachievable. OAR DVHs are
analyzed in two ways. Most often, key dose–volume points on the
integral DVH which are correlated with treatment outcome are
evaluated (Fig. 23.3). For example, in conventionally fractionated
therapy (1.5 to 2.5 Gy/treatment), the maximum spinal cord dose
(Dmax) is usually restricted to below 50 Gy in order to avoid the very
serious complication of radiation myelitis. The limit is based on clinical
experience and numerous publications: a 0.2% rate myelitis is estimated
at Dmax = 50 Gy in 2-Gy fractions (6). The maximum organ dose is also
significantly related to complication for the brainstem and optic nerves.
The fraction of lung volume receiving over 20 Gy at standard
fractionation (V20) is often held below 35% to limit the incidence of
symptomatic radiation pneumonitis. Similarly, intermediate DVH points
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are correlated with complication for other organs such as esophagus and
rectum. Mean organ dose—the area under the integral DVH (with
percent volume)—is another commonly used evaluation criterion, as it is
strongly related to symptomatic complications for organs such as lung,
parotid, liver, and kidney (4).
Figure 23.2 A: An ideal target DVH (dashed) to treat target to 5,400 cGy with uniform dose and
(solid) an actual target DVH. B: DVHs for a dose-painting case—PTV 7,000 (dashed) is inside
PTV 5940 (solid).
The second approach is to use the entire DVH of the OAR as input to a
model which estimates NTCP. Several models are described in this
chapter, as well as in an AAPM task group report (1) and many primary
source papers. At present, despite their potential, use of models to
evaluate treatment plans in routine clinical practice is largely confined
to major academic centers where radiation oncologists and planners are
sufficiently confident in models—sometimes ones developed at their
center—to use them comfortably. An exception to this is the use of mean
dose which is directly evaluated in many planning systems and with
which there is known strong correlation with several complications (e.g.,
xerostomia or radiation pneumonitis). Models are sometimes used in
treatment planning studies to evaluate possible effects of changes in
treatment practice (7) or to compare proposed and existing techniques
(8). They also provide essential support for responsible extrapolation of
treatments to new regimes (e.g., dose escalation) under phase I protocols
(9,10). In that context it is not necessary for the model to be correct in
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all details, provided it gives a reasonable estimate of how far the current
treatment may be modified without excessive risk. Finally, models are
used in advanced methods for optimization of treatment plans, where
they enable quantification of tradeoffs (11,12).
Figure 23.3 Normal organ (parotid) DVH with different dose–volume points indicated. Dmax
∼7,500 cGy, V40 ∼33%, D20 ∼5,400 cGy.
A robust model might determine the optimal DVH between two

similar plans. For example, suppose an integral DVH for plan A lies to
the left of one for plan B. If the organ is a nontarget tissue, then plan A
is better; if the organ is the target, then plan B is better. A more complex
comparison is given in Figure 23.4 where integral DVHs for a normal
organ planned with a parallel-opposed (traditional) and multifield 3D
plan are shown. Although the volume irradiated to any dose level can be
used to quantitatively compare the treatment plans, the location of high-
dose (or other) regions cannot be determined from the DVHs. Moreover,
in the example shown, the DVHs cross one another so that it is not
obvious which DVH is better.
Because SBRT is now widely used, it is necessary to be able to
interpret both graphic distributions and DVHs of treatment plans for
hypofractionated treatments and to rationally compare hypofractionated
with conventionally fractionated plans. In order to do this, a detour to
classical radiobiology is needed. Hypofractionation has a strong effect on
biologic responses and using physical DVHs for SBRT may be misleading.
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Cell Survival Models
Decades of clinical and experimental experience show that the same
dose delivered over a small number of daily fractions (e.g., 20 Gy × 3
fractions) has a greater cell-killing effect than if delivered over a large
number of daily fractions (e.g., 2 Gy × 30 fractions). This is well known
to radiation oncologists and medical physicists, for whom a course in
radiobiology is a standard part of training (13,14). Many mathematical
models describe this behavior, but the Linear-Quadratic (LQ) model is by
far the most used because of its mathematical simplicity and because,
over decades, its parameters have been measured for many cell types
and under many conditions (7–10). According to the LQ model, if a
collection of identical cells receives a uniform dose D delivered in n
acute fractions spaced several hours apart, the surviving fraction (SF) of
cells is
Figure 23.4 Dose–volume histograms (DVHs) for the mandible. (Reprinted from Kutcher GJ.
Quantitative plan evaluation. In: Purdy JA, Simpson LR, eds. Advances in Radiation Oncology
Physics: Dosimetry, Treatment Planning, Brachytherapy. New York, NY: American Institute of
Physics; 1992:998–1021, with permission.)
α and β depend on the cell type and environment (e.g., oxic or hypoxic)
and the type of radiation (e.g., heavy ions vs. megavoltage photons) but
are independent of dose. Typical cell survival curves are found in many
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texts (13,14). Because the range of SF over an experimentally achievable
dose range covers 5 to 6 orders of magnitude, it is typical to use semilog
plots.
The solid curve in Figure 23.5 shows the SF predicted by the LQ model
for single acute doses to cells with α = 0.33 Gy−1 and α/β = 8.6 Gy
(chosen to agree with α/β in a competing model (29)).
A mechanistic interpretation of the LQ model is that α describes
irreparable DNA damage due to a single radiation “hit” while β describes
the effect of two lesions, neither of which is lethal on its own but which
can interact to produce lethal damage. Overall cell radiosensitivity is
dominated by α, which is measured at low doses (when the quadratic
term is negligible) or at low dose rates, when most double-hit lesions are
repaired. Typical in vitro values of α range between about 0.05 Gy−1
(radioresistant, SF due to single-hit alone at 2 Gy ∼90%) through 1.5 Gy
−1 (radiosensitive, single hit SF at 2 Gy = 5%) (15–17).
The parameter α/β is of particular clinical interest in clinical
radiotherapy (and it is much easier to find tabulations of it) because it
captures, with reasonable accuracy, changes in biologic response for
different dose fractionation schedules. Knowing α/β allows clinicians to
find treatment schedules with the same TCP or NTCP (isoeffective dose
schedule) by assuming that isoeffective schedules result in the same SF
of the relevant cells. From Equation 23.1, a total dose D given in n
fractions and total dose D′ given in n′ fractions to an identical tissue are
isoeffective if
The quantity D(1 + (D/n)/(α/β)) is called the biologically effective

dose (BED); it depends on the total dose, the number of fractions, the
type of radiation, and the tissue of interest (13,14). For clinical photon
beams, many—but not all—tumors and “acutely responding” normal
tissues, like skin, have high α/β of 10 Gy or more while “late responding
tissues,” where complications occur months to years after treatment,
have low α/β, typically 1 to 5 Gy, depending on the tissue and the
complication. Possible reasons for this difference are given by Thames
and Hendry (18).
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Figure 23.5 Semi-log plot of surviving fraction of cells predicted by the LQ model (solid) and the
Universal Survival Curve (USC dotted). At high doses the LQ curve is “curvier” due to the effect of
the β term. (Parameters were taken from Park C, Papiez L, Zhang S, et al. Universal survival
curve and single fraction equivalent dose: useful tools in understanding potency of ablative
radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70:847–852.)
For a tumor with α/β = 10 Gy, the BED of a typical fractionated

schedule of 60 Gy in 30 fractions is 72 Gy while for a hypofractionated
schedule of 60 Gy in 3 fractions, the tumor BED is 180 Gy. A nearby
normal tissue with α/β = 3 Gy receives a BED of 100 Gy for
conventional fractionation and 460 Gy for the hypofractionated
schedule. In order to express LQ corrected doses on a scale that is more
comparable to clinical experience, the LQ-corrected dose is often
presented as the equivalent dose in 2-Gy fractions (EQD2) (19,20) where
Regardless of α/β, EQD2 for dose delivered at 2 Gy/fraction must

equal the physical dose. For dose/fraction less than 2 Gy, EQD2 is less
than the physical dose and for dose/fraction above 2 Gy, EQD2 is
greater. In the hypofractionation example above, the tumor EQD2 is 150
Gy while the normal tissue EQD2 is 276 Gy. It is very clear that
hypofractionation calls for extreme protection of normal tissues.
In the interest of clarity, the International Commission on Radiation
Units and Measurements (ICRU) recently introduced the symbol and
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term “Equieffective dose” = EQDXα/β to describe the dose delivered at
an arbitrary dose per fraction X to a tissue with a specified α/β that is
equivalent to the dose D delivered to the same tissue in n fractions (21)
(at dose per fraction d = D/n). Thus
The first equality is as stated in Reference (21) while in the second,

numerator and denominator are in more typical LQ model form. Until
ICRU nomenclature is generally accepted, when reading publications, it
is important to know whether the authors are reporting physical dose,
BED, EQD2, or something else, and that for “biologically corrected”
doses, they have specified α/β.
An important recent result of the isoeffective concept is the realization
that α/β for prostate cancer is much lower than the generic α/β = 10 Gy
usually assumed for tumors. For prostate cancer, α/β is now considered
to be ∼1.5 Gy. This has important consequences for hypofractionated
treatment of prostate cancer, the most common male cancer in the
United States, with ∼221,000 new cases per year. The initial discovery
was prompted by work by Brenner and Hall and was motivated by the
observation that prostate cancer cells—like many late-responding normal
tissues—replicate slowly (22). They started from the common hypothesis
that the TCP of a uniformly irradiated tumor containing N clonogenic
cells is achieved if zero clonogenic cells survive the treatment, that the
SF, SF(D), is determined by the LQ model, and that cell killing is a
random process that is well described by a Poisson distribution (23).
Under these conditions,
They extracted the radiobiologic parameters from two large clinical

studies of “biochemical failure” after treatment for prostate cancer; one
after a course of external beam therapy and the other after low dose-rate
brachytherapy. Biochemical failure is a rise in the blood concentration of
prostate-specific antigen (PSA) following a drop to a nadir in the months
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after therapy. PSA rise can be detected by a blood test long before
clinical evidence of recurrence and freedom from biochemical failure
(FFBF) is clinically equated with TCP at a chosen time point. In the
external beam dataset (233 patients), the dose per fraction was 2 Gy and
the number of treatments was escalated from 30 to 40. For these
patients, the LQ model was directly applied. The second dataset
consisted of 134 patients who had received I-125 brachytherapy with
known peripheral dose D. Because of the extremely low dose rate of such
implants (∼6 cGy/hr), two-hit damage is completely repaired so the SF
was exp-(αD). Each patient’s initial PSA level and dosimetry
(approximated as uniform tumor dose) was known and the endpoint was
FFBF at 3 years in both studies. The pretreatment PSA was taken as
indicative of the initial number of cancer cells (N); N and α were
determined by fitting the FFBF of groups of brachytherapy patients with
the same initial PSA to their delivered doses. Knowing these parameters,
β was determined from external beam patients with similar initial PSA.
The study concluded that α/β was 1.5 Gy with 95% CI (0.8 to 2.2 Gy).
There have since been numerous papers comparing PSA outcomes for
prostate cancer patients treated under well-defined conditions with
different fractionation schedules. Fowler et al. (24) summarized three
large reviews (each involving thousands of patient records) which were
all statistically consistent with α/β ∼1.5 Gy and concluded that “high
fractionation sensitivity is an intrinsic property of prostate carcinomas.”
The clinical impact of this realization is that SBRT is feasible for a
large population of patients with prostate cancer because the tumor α/β
is lower than that of the closest critical normal tissue—the rectum—for
which α/β is believed to be ∼3 Gy (25). A major problem in prostate
cancer treatment planning is that the prostate and the anterior rectal
surface are in contact with each other and that rectal complications are
associated with the high-dose region of the dose distribution. Therefore,
tumor control and rectal sparing are strongly competing treatment goals.
The minimum biologic target dose cannot be too low, yet it must be
consistent with rectal sparing where the two organs are in contact. Given
the excellent results and clinical efficiency of SBRT at other disease sites
and the high prevalence of prostate cancer, it is desirable from medical
and economic perspectives to safely treat prostate cancer with SBRT.
Figure 23.6 shows the physical DVHs for the PTV and the rectal wall
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from the dose distribution of a hypofractionated external beam prostate
cancer treatment (8 Gy × 5 fractions). In Figure 23.6, the rectal
maximum dose is clearly less than the physical dose to most of the PTV
and, at conventional fractionation, would be well tolerated. However, at
conventional fractionation, 40 Gy is totally inadequate to control
prostate cancer; prescriptions for definitive conventionally fractionated
prostate cancer treatments, which have both good tumor control and
normal tissue sparing range from ∼80 to 86 Gy. DVHs can be converted
to EQD2α/β_VHs by transforming the dose at the midpoint of each dose
bin using Equation 23.3. The large dashes in Figure 23.6 show the PTV
EQD2α/β_VH assuming that the tumor α/β is 10 Gy and the smaller
dashes are the PTV EQD2α/β_VH for α/β = 1.5 Gy. The rectum EQD2α/
β_VH is calculated for α/β = 3 Gy (small, light dashes). If the tumor α/β
were 10 Gy, SBRT would not be feasible because target equivalent dose
(∼60 Gy) is still much lower than what is curative at conventional
fractionation while the high equivalent doses to the rectum far exceed
those to the target. Increasing the target dose would raise the rectal
maximum dose well beyond its tolerance level. But because it is well
confirmed that prostate cancer has a low α/β, the EQD2α/β-VHs for the
same dose distribution with the prostate α/β = 1.5 Gy show a
favorable therapeutic ratio because rectal complications are most
correlated with maximum dose. Hypofractionated external beam
treatment of prostate cancer is now widely and safely used (26) although
longer follow-up is needed to determine whether long-term TCP is
comparable to conventionally fractionated treatment. The fractionation
of Figure 23.6 is a realistic schedule, though some groups treat on
alternate days to improve OAR sparing. As a general rule,
hypofractionation is favored if the tumor has a smaller α/β than the
most important adjacent critical normal structures and the dominant
complications depend strongly on the structure maximum dose.
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Figure 23.6 DVHs and EQD2_VHs from a hypofractionated prostate plan of 8 Gy × 5 fractions.
Solid curves are the PTV and rectal wall DVHs using physical dose. The medium-dashed curve is
the rectal wall EQD2_VH taking α/β = 3 Gy, which is typical for a late-responding normal tissue.
The dark dashes are the EQD2_VH for the PTV assuming that α/β = 10 Gy, a value often used for
tumors. The small-dash curve is EQD2_VH for the PTV assuming that α/β = 1.5 Gy, as is currently
believed to hold for prostate cancer. The dose distribution is the same for all the curves but their
biologic effects are quite different.
There is considerable controversy as to the validity of the LQ model

for large fraction doses based on in vitro evidence that LQ overestimates
cell killing for fraction doses above ∼10Gy (27,28). The dotted curve in
Figure 23.5 compares the SF predicted by the LQ model with predictions
of one of the competing models, the Universal Survival Curve (29). But
to date, no model has replaced LQ, because of its mathematical
simplicity, the availability of model parameters acquired over many
decades and the lack of definitive evidence that it is wrong in cases of
clinical interest (16). Further investigations are needed for a definitive
answer.
Biologic Models
Biologic models are an alternative method of evaluating treatment plans
that use the complete DVH as well as other information to predict
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treatment outcomes. Although models are not currently in common use
for plan evaluation, they may ultimately prove to be more effective than
predictions based on single or a small number of dose–volume points. In
general, TCP and NTCP are thought to increase sigmoidally from 0% to
100% as a function of dose or a combination of dose and other factors
(e.g., smoking, age, chemotherapy, genetics (30)). The parameters that
determine the midpoint and slope in the middle region of the curve are
obtained from analyses of clinical outcomes. This section further
describes some approaches to modeling TCP and NTCP.
TUMOR CONTROL PROBABILITY

The central assumption of most TCP models is that a tumor is destroyed
if all viable clonogenic cells within it are killed (23).
From this assumption, Brahme (31) and Goitein (32) derive TCP from
the product of probabilities that individual clonogens (or tumorlets) are
killed. The simplest form of these models assumes that clonogens in a
tumor have identical radiosensitivities, respond independently to
radiation damage, are uniformly distributed, and that the tumorlets are
small enough so that the dose D in each tumorlet is homogeneous. Under
these conditions, the TCP for a tumorlet with partial volume v can be
inferred from the TCP for uniform irradiation of the whole tumor,
It then follows that the TCP of an inhomogeneously irradiated tumor

is given by the product of tumorlet TCPs,
where TCP(vi, Di) is the TCP for the ith tumorlet receiving dose Di and N
is the number of tumorlets.
Several features of the model emerge immediately. The probability of
controlling a tumor is dominated by any clonogens with low probability
of being killed, thus TCP is very sensitive to cold spots in the dose
distribution. Given the large numbers of clonogens in a tumor, when the
dose is uniform the probability of destroying any individual clonogen
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must be very close to one for TCP to be appreciable. Given reasonable
values for radiosensitivities of tumor cells, the model implies a very
sharp dose response not seen in clinical studies. This discrepancy is not
explainable by variations in tumor size (33,34). One way the observed
shallow dose response might occur is if only a small number of
clonogens can repopulate the tumor is small (approximately 200, which
is many orders of magnitude less than the overall cell density of
∼108/cc (35)). But definitive evidence for this hypothesis other than the
shallow dose response, for which there are other explanations, has not
been presented.
Goitein and others (36–40) propose that the radiosensitivity of tumors
differs from patient to patient and that the averaging over this difference
results in the relatively broad dose response seen in clinical studies of
TCP. which are always population averages. Site-, stage-, and grade-
specific parameters that describe the radiosensitivity of individual
tumors and their variation in the patient population have been collected
from clinical studies and summarized by Okunieff et al. (41). Webb (42)
adopted a similar approach, using it to fit four clinical tumor control
datasets while assuming large (∼107 cells/cc) clonogen density and
Webb and Nahum (43) included the possibility of variations in clonogen
density within a tumor. As a consequence of a distribution in
radiosensitivities among patients, Zagars et al. (40) and Thames et al.
(44) point out that an escalation in dose is most effective for patients
with intermediate sensitivity. Those whose tumors are most sensitive do
not require such a high prescribed dose, and those who are least
sensitive rarely require a dose in excess of normal tissue constraints. This
implies that assays predicting radiosensitivity would be useful in
identifying patients who would benefit from dose escalation. Such a
personalized approach is under investigation for HPV-positive H&N
cancers, which have superior survival at the high-dose levels (45)
possibly due to increased radiosensitivity.
As was shown by Brahme (31) for a tumor with identical clonogens,
the highest TCP for a given mean dose is achieved by a uniform tumor
dose distribution. Perhaps partly for this reason, a historical treatment
planning goal is uniform PTV coverage. But there is mounting evidence
for intratumoral heterogeneity due to both genetic (46) and
environmental factors such as hypoxia (17,47,48). Although this does
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not broaden the dose–response, it is increasingly important in treatment
planning, as it suggests that nonuniform target coverage which places
hot spots in regions that are known to be radioresistant or at high risk
for failure for other reasons should be advantageous. IMRT can quite
easily achieve such distributions and is instrumental to the now widely
used technique of dose-painting (simultaneous integrated boost or SIB).
Here the physician identifies tumor subvolumes at different degrees of
risk and specifies the dose to be delivered to each by a single treatment
plan. Usually the regions painted to higher or lower doses are
determined by characteristics such as natural history of disease spread,
surgical margins, and pretreatment (18) FDG imaging. In theory, high-
dose regions could also be identified by hypoxia imaging using the
positron-emitting tracer 18F-misonidazole though instability of hypoxic
regions, which tend to reoxygenate during treatment, may be
confounding (49–52).
It is likely that clinical TCP observations are due to a combination of
intratumoral and population distributions of tumor characteristics and
that both dose painting and methods of predicting radiosensitivity
within the patient population will be useful strategies.
The uncertainties in defining tumor boundaries, clonogenic tumor cell
densities, the distribution of heterogeneous clonogen radiosensitivity,
and the interaction between these uncertainties and the uncertainties in
delivered dose distributions—setup error, physiologic motion, and
anatomy changes over a treatment course—make it difficult to test
model predictions of the effects of dose inhomogeneity against clinical
TCP data. Nonetheless, a growing number of studies indicate effects of
inadvertent target dose inhomogeneity on TCP. Terahara et al. (53)
studied the effects of dose inhomogeneity on local control using DVH
and outcome data from 115 patients treated for skull base chordomas
with combined photons and protons. In these patients, with relatively
small positional uncertainties and relatively large dose inhomogeneities
in the target, a Cox multivariate analysis showed that models including
gender and the minimum target dose were significantly associated with
the outcome. A case report (54) described treatment failure near a
parotid gland in three patients treated with parotid-sparing IMRT and
suggested that future patients receive pretreatment PET imaging to
assure that the parotid region is free of suspicious nodules. A study that
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reviewed records of 23 consecutive orbital lymphoma patients treated
with 3DCRT, of whom 12 were treated to only the partial orbit, found
that 4 of these had an intraorbital recurrence in volumes that had not
been covered while no patient treated with whole orbit RT had such
recurrence (55). A study of the GTV dose distribution of 91 tumors (79
patients) treated with single-dose SBRT for paraspinal tumors reported 7
local failures. All were significantly correlated with the low dose regions
and no failures were observed if the minimum PTV dose exceeded 15 Gy
(56). The target dose distributions in paraspinal SBRT are deliberately
nonuniform in order to protect the spinal cord which abuts the GTV.
There were similar observations in a 332 paraspinal SBRT dataset where
1-year local control was 88%. The minimum GTV BED was the only
variable to remain correlated with local failure under multivariate Cox
analysis and the authors recommended maintaining the minimum GTV
dose above 14 Gy in 1 fraction and 21 Gy in 3 fractions (57). In contrast,
Levegrun et al. (58,59) found that the mean, but not the minimum, PTV
dose was significantly correlated with biopsy outcome in a series of 132
patients treated with 3DCRT for prostate cancer. PTV coverage in this
population was fairly homogeneous and the CTV was defined as the
prostate gland and seminal vesicles, although it is likely that the tumor
clonogens were confined to subvolumes of the prostate. Setup
uncertainty was greater for these patients than those in the other studies,
as they were treated before the era of image-guided RT. Random
positional uncertainty on the order of 1 cm can be expected in the CTV
location during treatment due to setup error and organ motion and the
location of resulting underdoses with respect to tumor clonogens was
unknown. The possible influence of setup uncertainty which may
introduce tumor underdoses, on TCP of prostate cancer is suggested by a
much later study from the same institution comparing outcomes for 186
patients treated with conventionally fractionated IMRT for prostate
cancer using IGRT with 190 patients who also received IMRT to the
same dose and the same planning and delivery technique but without
IGRT. The image guidance consisted of setting the patients up by
registering the images of radiopaque fiducials implanted in the prostate
with their location at simulation using kilovoltage orthogonal
radiographs. This assured that the planned high-dose region was
delivered to the prostate rather than partially missing on some days due
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to physiologic changes such as bladder or rectal filling. The high-risk
patients treated with IGRT had significantly better FFBF (PSA relapse-
free survival) than those without IGRT (97% vs. 77.7%) (60).
Normal Tissue Complication Probability

The goal of NTCP models is to predict the probability of a complication
as a function of the dose (or BED) distribution; more recently other
factors such as smoking, comorbidities, and chemotherapy may also be
included in the function. Intuitively, the modeled NTCP should increase
in a roughly sigmoidal fashion (Fig. 23.7) as a function of the organ dose
distribution, going from zero at no dose up to 100% with the model; the
model parameters determine the location and shape of the curve. A
given organ may have several different types of complications with
different dose–volume parameters. For example, most organs have acute
(during or within a few months of treatment) and late complications.
Rectal complications include rectal bleeding (most analyzed
complication), fecal incontinence, and stool frequency (61).
Figure 23.7 Sigmoidal dose responses that are expected for both TCP and NTCP. The “metric”
might be purely dosimetric (e.g., mean dose or Dmax) or might be a combination of dosimetric
and other factors (smoker or nonsmoker). The location and shape of the curve is obtained by
analysis of clinical data.
All NTCP models must deal with the volume effect. Some
complications are most sensitive to “hot spots” in the OAR, others to the
mean organ dose, and yet others depend on the entire DVH in a more
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complex way. The phenomenologic model of Lyman (62) augmented by
Kutcher and Burman (LKB model) (63,64) seeks to describe NTCP in
terms of four parameters. They introduced the idea of “partial organ
irradiation,” where a fraction of an organ, v, receives a uniform dose D
while the rest receives zero dose. This is not completely artificial—dose
distributions of parallel opposed fields are good approximations to
partial organ irradiation and such treatments were the clinical norm
prior to 3DCRT. In the Lyman model, partial volume tolerance doses are
related to each other through a power law in volume fraction.
Specifically, if a complication rate c% is produced by uniform dose D to
a whole organ, the same complication rate is produced by partial
irradiation to a dose D′ of a fraction v of the total organ or a chosen
reference volume to a dose if
where n ≥ 0. If n is very small, vn is approximately 1 and the

complication has little volume dependence. The larger n, the stronger
the volume dependence. A feature of the Lyman model is that there is
always a partial volume dose for which complication will occur at a
specific rate, no matter how small the irradiated partial volume is. The
Lyman model is widely used in outcomes analysis, but much less so in
clinical plan evaluation though it is implemented on some planning
systems (1).
In the 1990s, there were efforts to develop other models based on the
tissue architecture of organs. Withers (64) hypothesized that the work of
an organ is carried out by “functional subunits” (FSUs) and that the
volume effect of a complication is determined by how the FSUs combine
to carry out the organ function. Nephrons in the kidney and alveoli in
the lung are sometimes used as possible examples of FSUs. Architectural
models are thoroughly described in the previous edition of this book,
part of which is quoted here. Serial (critical element) models assume
that certain organs are organized like chains; when one link (a
functional subunit or FSU) is damaged the entire chain is broken (65). A
candidate for a serial organ is the spinal cord. Organs with this
architecture have a small volume effect. For the parallel model (also
called critical volume), a complication does not occur until a significant
fraction of independent functional subunits (functional reserve) have
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been incapacitated (66–68). The volume effect in these tissues is large,
because a complication does not occur if less than the functional reserve
is irradiated. This behavior is not reflected in the LKB models unless
augmented by an additional parameter such as a critical volume below
which there is no complication.
The serial and parallel models are conceptually attractive and it was
hoped that they might lead to mechanistic understanding of NTCP, but
this goal has not been achieved. The models are seldom used in clinical
plan evaluation although the names prevail. “Serial” is used for
complications that depend mostly on the highest doses to the organ
(small n in the Lyman model) and “parallel” for complications with a
strong volume dependence (large n). However, a variant (also
nonmechanistic), the “relative seriality” model (69), is almost as widely
used for NTCP calculation as the Lyman model, mostly in Europe. There
is currently no definitive evidence that would lead users to prefer one of
the three NTCP model types (Lyman, tissue architecture, relative
seriality) in the clinic. For further discussion, see the references cited
here and the earlier edition of this book.
Uniform Irradiation
Lyman (62) represents the NTCP for uniform partial volume irradiation
of an organ with an error function of dose and volume.
The model contains four parameters: TD50 (62), the tolerance dose for
whole organ irradiation; m, the steepness of the dose–response curve;
Vref, the reference volume, which in some cases may be the whole
volume of the organ; n, which relates the tolerance doses for uniform
whole and uniform partial organ irradiation. This latter parameter
represents the volume effect. When n is near unity, the volume effect is
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large1 and when it is near zero, the volume effect is small. A value of n
∼ 1 implies that NTCP correlates with the mean dose, whereas a small
volume effect implies a correlation with the peak organ dose. The NTCP
for partial organ irradiation in the Lyman model was originally based on
clinical estimates of partial organ tolerance doses. An early compilation
by Emami et al. (70) was fitted to the model by Burman et al. (71).
Although many of the parameter values he obtained are still in use,
values resulting from maximum likelihood fits of DVH and complication
data from 3D conformal dose escalation protocols are available for a
growing list of organs. This will be described in more detail in the
section “Current Supporting Data for NTCP”.
Nonuniform Irradiation—Histogram Reduction and Equivalent

Uniform Dose
The approach in the preceding text has been extended to inhomogeneous
irradiation by converting the organ’s DVH into an “equivalent” uniform
one using the effective volume method (63). The DVH is transformed
into one in which the partial volume, veff, which is equal to or less than
the whole organ volume, receives a dose equal to the peak organ dose.
This effective volume transformation is self-consistent with the power
law model for uniform irradiation in that it can be derived from just two
hypotheses: The organ is homogeneous in response and each element of
the organ obeys the same power law relationship as the whole organ.
Moreover, there is a family of equivalent uniform DVHs with effective
volume and dose related through the defining power law relationship.
This method was extended to calculate the effective whole volume dose
(deff) by Mohan et al. (72). More recently, use of the generalized
equivalent uniform dose (gEUD, sometimes simply called EUD) (1,5,73),
has become popular. This quantity is calculated in an identical fashion to
deff (in the EUD formalism, the LKB model parameter n is replaced by the
parameter a, they are related by n = 1/a).
While the LKB model was designed only for NTCP, gEUD is also used
as a surrogate for TCP. Given the DVH for an organ or tumor, gEUD is
calculated as
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where the sum runs over all the dose bins of the DVH, Di is the dose at
the center of the ith bin, and vi is the fraction of the organ volume in
that bin. To describe complications, a ≥ 0 while to describe TCP, a < 0.
Serial complications (small n or large a) depend strongly on the high-
dose part of the DVH while the entire DVH affects the gEUD for small a
(large n); for n = 1, gEUD is the mean dose. If a is large and negative,
gEUD accentuates the low-dose portion of the DVH—the cold spots
which are important for tumor control. gEUD is useful for relative
ranking of treatment plans in regard to a chosen organ or target without
the “judgmental” character of a full TCP or NTCP calculation.2
Although the original formulations of the Lyman model and gEUD
used physical dose, EQD2α/β (or a similar reduction to any desired
reference dose) can replace physical dose if the DVH is converted to
EQD2α/β-VH. Within the simplest form of the LQ model, this biologically
equivalent EUD has only two parameters (a and α/β) and can potentially
incorporate fractionation and volume dependence in a single number
that can rank dose distributions delivered at nonstandard fractionation
schedules in terms of their risk.
CURRENT SUPPORTING DATA FOR NTCP

Both models and dose–volume plan evaluation criteria are based on
clinical data, although for many complications, data is still quite sparse
and unreliable. This is due to several factors, including: treatments are
designed to be “safe” so many reported series have low numbers of
complications; publications use qualitatively different criteria for
reporting complication severity; for some organs, publications use
different definitions of the reference volume; doses are often not clearly
specified—for example, a publication might report the number of
complications and the prescription dose but give minimal details of an
organ dose distribution. Developments such as computerized planning,
accurate dose calculation algorithms, electronic record keeping, and
prospective collection of dose distribution and complication data allow
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more opportunities for data collection, but radiation oncology still has a
long way to go (75).
The 1991 compilation of normal tissue tolerance doses and volume
effects by Emami and eight co-authors (70) is one of the most cited
articles in radiation oncology and its guidelines are still in use. It was the
product of an NCI Collaborative Group charged with investigating the
then-new tools and potentials of 3D, CT-based treatment planning. Most
of the literature they reviewed was from the “2D” era when most
treatments were simple (often parallel opposed), simulation images (if
taken) were plane radiographs and, if patient-specific dose distributions
were generated, they were often superimposed on a manually acquired,
two-dimensional contour. In 2010, a group of physicists and physicians
performed a systematic review that included more recent publications on
dose and volume dependence of clinically reported normal tissue
complications for 16 organs. They reviewed many studies that were
published in the “3D” era, where patients were treated with the benefit
of 3DCRT (and occasionally IMRT) and modern delivery tools (though
most studies preceded IGRT). This group named itself QUANTEC
(Quantitative Analysis of Normal Tissue Effects in the Clinic). It received
funding from both AAPM and ASTRO, but was not a formal part of
either organization. Its reports are published in a supplement to the
International Journal of Radiation Oncology, Biology and Physics (4).
Surprisingly, QUANTEC found it difficult to extract dosimetric guidelines
even from modern published literature for reasons summarized in
Reference (75).
However, the QUANTEC groups were able to make recommendations
and, for some complications, develop NTCP models for several organs.
These are summarized in a large table in the QUANTEC issue (76). These
recommendations involve mean doses or one or a few DVH points and
do not include more complex models. However, many of the organ-
specific articles developed models based on the reviewed clinical data
and in some cases recommended their use to limit toxicity. QUANTEC
repeatedly urges caution in applying its guidelines to IMRT, since much
of the reviewed literature described outcomes of 3DCRT, but not IMRT,
treatment.
Here we briefly compare the QUANTEC and the 1991 guidance for
several complications. For some organs, guidelines are similar although
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the modern complication endpoints may be less severe (perhaps thanks
to guidance from the 1991 study as well as to improved dose
conformality with 3DCRT).
Spinal cord (6): The QUANTEC endpoint (grade 2 or greater
myelopathy) includes complications that are less severe than “transverse
myelitis,” used in the 1991 study. The QUANTEC spinal cord group
reviewed 16 publications covering 2,281 patients without prior
irradiation, 14 papers with prior spinal radiation, and 10 papers
reporting on patients who received SBRT. All reported complications
were, understandably, at the low end of the dose–response curve—
myelitis is the most feared radiation therapy complication and even
slightly risky treatments are usually avoided. Using a logistic function
model developed by Schultheiss (77) based on his earlier review of
publications extending back into the 1970s, the QUANTEC group
concluded that irradiation of the full cord cross-section to a maximum
dose of 50, 60, and 69 Gy was associated with 0.2%, 6%, and 50% rate
of myelopathy. The spinal cord is narrow and visualizing it requires a
myelogram or an MRI. Therefore, dosimetrists often contour the spinal
canal and the dose distribution within the cord itself (or even the canal)
is rarely closely examined in clinical plans. Also, many conventionally
fractionated treatments have setup uncertainty that can blur the
delivered dose distribution on the 0.5 to 1 cm scale of the cord diameter.
Therefore, the QUANTEC guidelines (76) are to keep the cord point
maximum dose ≤50 Gy, similar to the 1991 recommendation. For the
increasingly common situation of retreatment of a volume which
includes the spinal cord, QUANTEC found that when more than
6 months elapsed between two treatments, myelopathy was not seen for
cumulative doses less than 60 Gy. For SBRT, they recommended that the
point maximum be ≤13 Gy in a single fraction and 20 Gy in 3 fractions
to keep the complication rate below 1%.
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Figure 23.8 QUANTEC rate of symptomatic pneumonitis as a function of mean lung dose—
comparison of data from 10 institutions. The dashed line is a logistic fit to the form f/(1 + f) where f
= exp(b0+b1 × mean lung dose). The best fit values (95% CI) are b0 = −3.87 (−3.33, −4.49), b1 =
0.126 (0.100, 0.153) corresponding to TD50 = 30.75 (28.7, 33.9) Gy and γ50 = 0.969 (0.833,
1.122) where γ50 represents the increase in response (measured as percentage) per 1%
increase in dose near the 50% dose–response level. (Reprinted with permission from Marks, LB,
Bentzen, SM, Deasy, JO, et al., (2010). Radiation Dose-Volume Effects in the Lung. Int J Radiat
Oncol Biol Phys 2010;76(3):S70–S76.)
Lung (78): For lung, the QUANTEC and the 1991 recommendations
were again similar. Lung, regarding the complication of radiation
pneumonitis (RP), is considered a “parallel” organ with a large volume
effect. The 1991 paper (71) set the Lyman volume parameter n = 0.87
and TD50 = 24.5 Gy, m = 0.18. The QUANTEC group reviewed ∼70
publications (all conventional fractionation), most of which had more
statistically elegant analyses of institutional data than the “by eye” fits
used in 1991. Their best estimate of n was 1.03, indicating that the mean
lung dose is significantly correlated with RP. This correlation is robust
across institutions, as shown in Figure 23.8. The QUANTEC team
developed logistic and probit fits to the data in Figure 23.8, from which
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they recommended mean doses for keeping symptomatic RP between 5%
and 40%.
Rectum (25): Rectum is one of the organs which is defined differently
in different studies: rectal wall, rectum including the lumen, anatomical
rectum, and lengths determined by the high-dose region. The shape and
volume of the rectum change between, and sometimes during, treatment
fractions; thus the delivered rectal dose—which determines the outcome
—may differ in an unknown way from the planned dose. QUANTEC’s
preferred definition is the anatomical rectum on the planning scan,
including the lumen. Most of the papers the QUANTEC team reviewed
dealt with rectal complications following prostate external beam
treatment (other cancers which give substantial rectal dose have a large
brachytherapy component or are treating rectal disease). The QUANTEC
endpoints were ≥ grade 2 and ≥ grade 3 late rectal toxicity, mostly
bleeding and usually defined according to the RTOG grading scale (79).
These include milder complications than the 1991 study (“severe
proctitis/necrosis/fistula”) despite the higher doses used for modern
prostate treatments. This reflects improvement in rectal protection with
the use of 3DCRT. Both QUANTEC and the 1991 studies found that
rectal complications have a weak volume dependence. In the 1991
Lyman model parameters, “n” is 0.12 (71) while the QUANTEC n is 0.09
with 95% CI 0; 04–0.14. Both find rectum to be fairly radioresistant; the
1991 TD50 is 80 Gy, QUANTEC’s is 76.9 Gy or 78.5 Gy, depending on
the publications they included in analysis. However, rather than simply
specifying a maximum rectal point dose, QUANTEC recommends five
intermediate DVH points, thus defining the upper limit of the DVH
between 50 and 75 Gy.
Rectal complications other than bleeding may be better correlated
with the dose distribution in specific parts of the rectum (61). Because
rectal dose distributions for IMRT treatment of prostate cancer look
quite different from those from 3DCRT and the rectal complication rate
following IMRT prostate treatment is much lower than for 3DCRT (80),
QUANTEC made no recommendations for IMRT. However, a recent
publication confirmed the QUANTEC Lyman parameters (7) as a
secondary aspect of the research in that paper while another study on a
large, different dataset found a large discrepancy between Lyman
parameters for rectal toxicity in 3DCRT versus IMRT (81). Deciding
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whether or not the QUANTEC parameters describe rectal toxicity in
IMRT and modeling rectal complications for SBRT prostate treatment
remains to be done.
Optic structures (optic nerves and chiasm) (82): The endpoint for
the 1991 study was blindness while QUANTEC included less severe
complications as well (visual impairment or optic neuropathy). The optic
structures are very small and both contouring and dose delivery
accuracy confound efforts to find a volume effect. The 1991 guidelines
are a 5% probability of blindness for a whole organ dose of 50 Gy and a
50% probability of blindness for 65 Gy. In general, QUANTEC finds that
the optic structures are more radiation tolerant than suggested by the
1991 study, which may allow better target coverage in some brain and
head and neck (H&N) cases.
QUANTEC’s recommendations are for three point maximum values
with the caveat that the Dmax values are often very close to the dose to
the whole organ. The QUANTEC maximum dose points are Dmax < 55
Gy for NTCP < 3% (the 1991 model predicts 13.6%); Dmax 55 to 60 Gy,
NTCP 3% to 7% (the 1991 model predicts up to 29%). The third Dmax
point involves only upper limits above 60 Gy (NTCP > 7% to 20%)
which doesn’t allow comparisons.
1991 models more aggressive: For parotid, cochlea, kidneys, heart,
and stomach, using the 1991 constraints is likely to lead to a higher
complication rate than expected from subsequent literature; the
QUANTEC recommendations are more conservative. For example, the
parotids are key risk organs for H&N treatment: these cancers have a
high cure rate and the nonlethal complication of xerostomia, with great
impact on quality of life, is a concern. The parotids are “parallel” organs,
with the 1991 Lyman model assigning an n of 0.7 while QUANTEC (83),
based on more recent information, focuses on the mean parotid dose.
The 1991 Lyman model predicts <20% complication for mean parotid
dose below 39 Gy, while today most H&N treatment protocols advise
keeping the mean bilateral gland dose below 25 Gy if possible or, if high
dose must be given to one parotid to achieve tumor control, keeping the
spared parotid mean dose below 20 Gy.
Finally, for esophagitis and radiation-induced liver disease, the dose–
volume behavior extracted by QUANTEC from modern studies is simply
different than reported in the 1991 publication. And for the bladder, the
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quality of available data was inadequate to support guidelines. The 1991
report gives Lyman model parameters for several organs not included in
QUANTEC (brachial plexus, external ear, rib cage, femoral head, thyroid,
TM joint, and mandible) while QUANTEC makes recommendations on
the penile bulb.
For many organs, QUANTEC made no recommendations for
hypofractionated treatment because literature at that time was scarce.
Also, most of the literature reviewed by QUANTEC dealt with
complications in adult patients. There are now two efforts patterned
after QUANTEC—one to make literature-based recommendations for
pediatric radiation therapy (PENTEC), and one to make similar
recommendations for hypofractionated treatment (WGSBRT). These
groups hope to make recommendations in the near future.
Fitting Clinical Complications Data to a Model: An Example

Thanks to the knowledge gained from over a century of radiation
therapy and to advanced planning and delivery techniques, radiation-
induced normal tissue complications are infrequent. Differences between
patient populations, local preferences for certain treatment methods and
dosing schedules, and local variations in accompanying therapies
(surgery, chemotherapy) make the study of NTCP an exercise in
extracting a weak signal from a noisy background. Controlled
randomized clinical trials might provide high-quality data, but they are
often cost-limited to small patient numbers and are aimed at answering a
few specific questions that the funding organization deems important.
Increasingly, sophisticated statistical methods are being applied to the
problem of mining institutional databases or using peer-reviewed clinical
data to develop and validate NTCP models.
Statistical Model of a Parallel Organ

In parallel element tissues, which have been modeled using binomial
statistics (66–68), a complication occurs if the fraction of eradicated
FSUs exceeds a threshold fraction, the functional reserve of the organ.
The kidney, liver, and lung are conjectured to behave as parallel organs.
Because the number of FSUs is always large in these organs, the
functional reserve can be defined by the fraction rather than the number
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of eradicated FSUs. Furthermore, as with TCP, the large number of FSUs
leads to unrealistically large gradients of NTCP with dose in the region
of NTCP = 50%. To remedy this, population averaging is invoked,
which requires additional parameters. For example, if the functional
reserve and the FSU radiosensitivity (defined by the dose required for
50% FSU death) vary among a population of patients, then two
additional parameters are required to represent the widths of these
distributions. In addition, intraorgan variation in radiosensitivity may
also be considered. Fortunately, it can be demonstrated that intraorgan
variability has a negligible effect on the slope of the local dose–response
curve (84).
A further simplification is possible if the width of the distribution of
radiosensitivities is narrower than that of the functional reserve. In this
limit the NTCP is given by the integral of the functional reserve up to the
mean fraction of eradicated FSUs, that is, up to the fraction damaged
(84). This form is quite useful for fitting clinical complication data.
Fitting the Parallel Model to Clinical Complication Data

The method described here is now widely used in fitting biophysical
models to clinical data. Such an approach is a starting point to suggest
further developments in the collection and analysis of clinical data. We
describe here one example in which a parallel model (described in
preceding text) and the method of maximum likelihood is used to fit
DVHs and complication data for radiation hepatitis of 93 patients treated
for tumors of the liver (84–86).
The method of maximum likelihood can be applied as follows. The
DVH for each patient is used to calculate NTCP by first assigning a best
guess for the model parameters. The predicted probability of a
complication for each patient is then compared against the observed
grade of complication in that patient. The overall likelihood L of the
observations is then modeled according to:
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where
where L is the likelihood, O(tm) is the probability that a complication

will manifest itself after the follow-up time tm for the mth patient—
calculated from complication and follow-up time data with the Kaplan–
Meier method (87) and γ1, γ2, . . . indicates the model parameters. The
likelihood function is then maximized with respect to the model
parameters. Note that the likelihood is essentially the probability in the
model of the observed complication pattern.
Furthermore, it is convenient to assume, as described earlier, that the
organ has a functional reserve described with two parameters (whose
values are to be obtained from the maximum likelihood fit) and that
NTCP is given by the integral of the functional reserve up to the mean
fraction of eradicated FSUs, that is, up to the fraction damaged (84). For
each patient, the fraction damaged is calculated by summing up the
product of the fractional volume of each voxel of the organ and the
probability of damage. The latter can be calculated using each patient’s
DVH and an assumed local response function with two parameters
(whose values are to be obtained from the maximum likelihood fit).
The results of applying such an analysis to the hepatitis data is shown
in Figure 23.9 for observed complication rate as a function of the
calculated fraction of the liver that is damaged. The observed
complications for this dataset show a threshold effect with a steep
response, which is described well with the parallel model. In this
application, the best-fit functional reserve distribution and their
confidence intervals predict that irradiation of less than one-third of the
liver volume leads to negligible complications (84). That is, the
threshold volume is about one-third. A more detailed analysis of the fit
revealed that the uncertainties in the width of the functional reserve
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distribution and radiosensitivity of functional subunits were correlated.
This arose because complications were seen only in the cohort of
patients who received a whole liver irradiation as part of the treatment
course. The lack of complications among patients given only partial
volume irradiation suggested that an attempt to increase local control
through dose escalation was feasible. After follow-up of subsequently
treated patients, some of whom had received 90 Gy, Dawson et al.
analyzed data from 138 patients, including 19 with radiation-induced
liver disease (RILD). Observation of complications in patients with only
partial volume irradiation helped to resolve the correlated uncertainties
in the model parameters and the threshold limit was revised down from
one-third to one-fourth (88,89).
Figure 23.9 Observed complication rate for radiation hepatitis versus calculated fraction
damaged. (Reprinted from Jackson A, Ten Haken RK, Robertson JM, et al. Analysis of clinical
complication data for radiation hepatitis using a parallel architecture model. Int J Radiat Oncol Biol
Phys. 1995;31:883–892, with permission.)
Current and Future Clinical Use of Normal Tissue Dose–Volume

Criteria
Treatment plans are often designed to meet competing goals of target
coverage and protection for nearby normal organs. These goals have
been refined through experience so that they are relatively safe and
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effective (“acceptable” complication and control rates) and can be
satisfied by plans that can be done by skilled planners (dosimetrists)
within clinically reasonable times using acceptable beam arrangements
(no mechanical collisions, not too many beams, none passing through
strongly attenuating support structures). There are protection goals that
must be satisfied (e.g., spinal cord) even if target coverage is
compromised. For example, for conventionally fractionated treatments of
patients without prior radiation, the maximum permitted spinal cord
dose is below 50 Gy, which is often too low to achieve durable tumor
control. A compromise for mediastinal tumors (devised long before the
advent of 3DCRT, but still in use) is to treat to 40 to 45 Gy with AP/PA
beams that cover the entire PTV and then “cone down” to “off cord”
oblique beams which treat part of the PTV to 60 Gy but spare the spinal
cord from further direct dose. IMRT often allows a plan that treats the
tumor to 60 Gy in a single phase because intensity modulation decreases
target dose from some beams to protect the cord but fills in target dose
from other beam directions. In paraspinal SBRT, target coverage is
usually compromised to achieve sufficient cord protection; with minor
compromise, the treatments remain effective (56,57). In some situations,
it may be possible to make a clinical decision of priority between
protection and coverage goals. In these cases, it is valuable for the
planner to have guidance as to whether both can be satisfied before he
starts. As an early example, Hunt et al. (90) retrospectively analyzed the
treatment plans of 51 H&N cancer patients treated with dose-painting
IMRT (PTVs for dose levels 54, 59.4, and 70 Gy or 54 to 60 Gy and 66
Gy). One or both parotid glands overlapped PTVs. To maintain a <25%
risk of xerostomia, the mean parotid gland dose should be below 26 Gy
but for tumor control, the plan should give each PTV full dose according
to its level. The study derived the maximum fraction of parotid-PTV
overlap and the necessary mean dose to the non-overlap region to
achieve an overall mean parotid dose of 26 Gy without underdosing the
PTV. These doses could be used as optimization goals for parotid
portions outside the PTV. If a mean dose below 26 Gy cannot be
achieved for a gland, a clinical decision must be made.
A more elaborate version of this approach is now being applied to
“knowledge-based planning” (91,92). For a particular disease site and
perhaps beam arrangement, a database of previous “good” plans is used
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as a training set to parameterize a treatment plan model. The “best” (as
defined by the model) achievable OAR DVHs are then predicted for a
new patient based on his anatomy. Of course users must agree on an
appropriate training set. Knowledge-based planning is in its infancy, but
in the future, it may reduce planning time, improve plan quality, and
allow for more objective plan evaluation by comparison with high-
quality reference plans that meet established treatment standards. On
the down side, developing the plan model (commissioning the
knowledge-based system) will require much work and institutions with
different treatment goals would not be able to share models.
In a novel application of the knowledge-based approach (7), treatment
plans from an RTOG prostate IMRT treatment protocol were replanned
using a knowledge-based model. The training set was 20 high-quality
plans from one of the collaborating institutions. These plans satisfied all
the RTOG protocol constraints and were selected for best OAR (rectum
and bladder) sparing. The model was further tuned on the RTOG plans
with the smallest difference between the plan rectal NTCP and that
predicted by the knowledge-based program. Finally, for 30 RTOG plans
(10 with the smallest NTCP difference from predicted, 10 with the
largest difference, and 10 intermediate cases) model-predicted rectal
DVHs were obtained. Each case was then replanned to give
approximately the same PTV coverage as the original (in all cases
meeting protocol requirements), to maintain or improve the bladder
DVH and to use the rectal DVH predicted by the model as a guide for the
new plan. The QUANTEC Lyman model parameters were confirmed as a
separate part of the study and the improvement in plan quality was
evaluated as the reduction in Lyman NTCP achieved by the new plan.
Although all the original plans had met the protocol’s constraints, they
were not “optimal” in that the rectal NTCP was reduced in all the
replanned cases without sacrificing coverage or other planning
objectives. Should this or related methods become readily accessible and
efficient, one would expect treatment complication rates, as well as
planning time to decrease. Evaluation of individual plans would be
partly based on their similarity to the plans in the model knowledge
base. Models themselves might be evaluated by periodic institutional
plan intercomparisons, though there would undoubtedly be debates
about the gold standard. And of course with better quantitative
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understanding of plan outcome, plan quality metrics will change.
CONCLUSIONS
Dose–volume criteria are now widely used in planning and plan
evaluation; models are available and interesting, but in order to come
into general clinical use, proponents will have to demonstrate that they
add something to the clinical process—more efficient planning or more
efficient or objective plan evaluation. Especially the latter will require
stringent model validation and education of physicians, physicists, and
dosimetrists as to their appropriate use. Clinical data is being mined to
update evidence-based guidance, which is particularly needed to address
new treatment paradigms. Currently we are focused on
hypofractionation but future developments may include combined
modalities or molecular personalized medicine. Peer-reviewed clinical
data should be presented in a format that allows “data pooling” (93) so
that these efforts move forward more rapidly. Improved models and
dose–volume constraints combined with knowledge-based planning may
make it easier and more likely to arrive at superior plans to the benefit
of future patients.
KEY POINTS
• Both volumetric graphic dose distributions and dose-volume
histograms (DVHs) are required for evaluation of complex modern
treatment plans. The quality of treatment plan dosimetry must
achieve a balance between the probability of local tumor control
(tumor control probability or TCP) and the probability of normal
tissue complications (NTCP).
• The rapid growth of stereotactic body radiotherapy (SBRT) makes
it necessary to account for the greater biologic potency of
hypofractionated treatments in planning and plan evaluation. The
Linear Quadratic (LQ) cell survival model is most often used for this
purpose, although other models have been proposed.
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• Some dose–volume metrics that can be read directly off a DVH
(D_volume, V_dose) have been shown to correlate with outcomes
but predictive models have also been devised. Both TCP and
NTCP are approximately zero at low doses and rise to close to
100% at high doses but “low,” “high,” and the rate of increase with
dose depend on the tissue. Ideally the key parameters that
determine response are obtained and validated by analysis of
clinical outcomes.
• Most TCP models are based on the hypothesis that a tumor is
controlled only if the radiation course kills all clonogens (cells
capable of regrowing the tumor). This approach, combined with the
LQ cell survival model, led to recognition that SBRT can be safely
delivered to prostate cancer.
• For NTCP, it is noted that different complications have different
dependences on the radiation distribution in the organ. The two
extremes are called “serial” and “parallel” responses. Serial
responses depend on the highest dose in the organ while parallel
responses depend on the overall organ dose, often approximated
by the mean organ dose. NTCP models must account for these
effects. A classical collection of NTCP dose–response information
was published in 1991 (Emami et al., Burman et al.). Recently, the
QUANTEC group (Quantitative Analysis of Normal Tissue Effects in
the Clinic) reviewed modern papers and provided guidelines and
models for 16 organs. There is mixed agreement between
QUANTEC and the 1991 studies.
• Models may be effectively used in comparing rival plans and
delivery techniques, in dose–escalation trial design and in plan
optimization and they are used in this way at large academic
centers. However, for general use, they must be validated
sufficiently for many clinicians to have confidence in them.
QUESTIONS
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1. Tumor type A has radiobiologic parameter α/β = 10 Gy while
tumor type B has α/β = 1.5 Gy. Both tumors have 108 clonogens
and have radiobiologic parameter α = 0.1 Gy−1. Which tumor
type has the larger change in TCP when the treatment
fractionation is changed from 60 Gy in 30 fractions to 60 Gy in
3 fractions?
A. A
B. B
C. Equal response
D. Neither tumor responds to such low doses
2. The complication probability for a normal tissue is said to be of
“serial” type. What part of the dose distribution is most
important in determining its NTCP?
A. The mean organ dose
B. The low-dose part of the distribution
C. The high-dose part of the distribution
D. The % volume receiving 20 Gy
3. The complication probability for a normal tissue is said to be of
“serial” type. Which is most likely to be the Lyman model volume
effect parameter, n?
A. n = 0.05
B. n = 0.35
C. n = 0.75
D. n = 1.0
4. A recent analysis of published NTCP data up to approximately
2010 was conducted by
A. Emami_Burman
B. QUANTEC
C. NRC
D. NTQABS
5. One way to use biologic models in treatment planning is
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A. Comparing rival treatment plans
B. Reducing planning time
C. Reducing plan delivery time
D. All of the above
6. The gEUD is
A. The mean dose to an organ
B. The equivalent uniform dose that, when applied to the organ,
has the same biologic (TCP or NTCP) effect as the actual dose
distribution
C. The uniform radiation dose that has the same effect as a
specified chemotherapy dose
D. Applicable only to parallel normal tissues
ANSWERS
1. B Tumor B: For Tumor A, the BED changes from 72 Gy to 180 Gy
and TCP (Equation 23.4) changes from ~0 to 0.218
(approximately 21.8%). For Tumor B, the BED changes from
140 to 860 Gy and TCP changes from ~0 to 1 (or 100%).
2. C (the high-dose part) “Serial” is used for complications that
depend mostly on the highest doses to the organ (small n in the
Lyman model) and “parallel” for complications with a strong
volume dependence (large n).
3. A (n = 0.05)—see explanation above.
4. B (QUANTEC) “In 2010, a group of physicists and physicians
performed a systematic review that included more recent
publications on dose and volume dependence of clinically
reported normal tissue complications for 16 organs.”
5. A (comparing rival treatment plans). Biologic models have no
effect on plan delivery time and at present, there’s no definitive
evidence that they reduce planning time.
6. B (see section “Nonuniform Irradiation—Histogram Reduction
and Equivalent Uniform Dose”).
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REFERENCES
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28. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is
inappropriate to model high dose per fraction effects in
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31. Brahme A. Dosimetric precision requirements in radiation therapy.
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33. Goitein M. The probability of controlling an inhomogeneously
irradiated tumor. In Zink S ed. Evaluation of Treatment Planning for
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National Cancer Institute; 1987.
34. Bentzen SM, Thames HD. Tumor volume and local control
probability: clinical data and radiobiological interpretations. Int J
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35. Zaider M, Minerbo GN. Tumour control probability: a formulation
applicable to any temporal protocol of dose delivery. Phys Med Biol.
2000;45:279–293.
36. Niemierko A, Goitein M. Implementation of a model for estimating
tumor control probability for an inhomogeneously irradiated tumor.
37. Bentzen SM. Steepness of the clinical dose-control curve and
variation in the in vitro radiosensitivity of head and neck squamous
cell carcinoma. Int J Radiat Biol. 1992;62:417–423.
38. Suit H, Skates S, Taghian A, et al. Clinical implications of
heterogeneity of tumor response to radiation therapy. Radiother
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39. Dutreix J, Tubiana M, Dutreix A. An approach to the interpretation
of clinical data on the tumor control probability-dose relationship.
40. Zagars GK, Schultheiss T, Peters LJ. Inter-tumor heterogeneity and
radiation dose control curves. Radiother Oncol. 1987;8:353–361.
41. Okunieff P, Morgan D, Niemierko A, et al. Radiation dose-response
of human tumors. Int J Radiat Oncol Biol Phys. 1995;32:1227–1237.
42. Webb S. Optimum parameters in a model for tumour control
probability including interpatient heterogeneity. Phys Med Biol.
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43. Webb S, Nahum AE. A model for calculating tumour control
probability in radiotherapy including the effects of inhomogeneous
distribution of dose and clonogenic cell density. Phys Med Biol.
1933;38:653–666.
44. Thames HD, Schultheiss TE, Hendry JH, et al. Can modest
escalation of dose be detected as increased tumor control? Int J
45. Kimple RJ, Harari PM. Is radiation dose reduction the right answer
for HPV-positive head and neck cancer? Oral Oncol. 2014;50:560–
564.
46. Swanton C. Intratumor heterogeneity: evolution through space and
time. Cancer Res. 2012;72:4875–4882.
47. Horsman MR, Wouters BG, Joiner MC, et al. The Oxygen effect and
fractionated radiotherapy. In: Michael Joiner, Albert van derKogel,
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eds. Basic Clinical Radiobiology. 4th ed. London: Hodder Arnold;
2009:207–216.
48. Wouters BG, Koritzinsky M. The tumour microenvironment and
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49. Popple RA, Ove R, Shen S. Tumor control probability for selective
boosting of hypoxic subvolumes, including the effect of
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50. Kim Y, Tome WA. Dose-painting IMRT optimization using biological
parameters. Acta Oncol. 2010;49:1374–1384.
51. For an example, see RTOG protocol RTOG 0225, A phase II study of
intensity modulated radiation therapy (IMRT) +/- chemotherapy
for nasopharyngeal cancer;
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?
study=0225.
52. Lin Z, Mechalakos J, Nehmeh S, et al. The influence of changes in
tumor hypoxia on dose-painting treatment plans based on 18F-Miso
positron emission tomography. Int J Radiat Oncol Biol Phys.
2008;70:1219–1228.
53. Terahara A, Niemierko A, Goitein M, et al. Analysis of the
relationship between tumor dose inhomogeneity and local control in
patients with skull base chordoma. Int J Radiat Oncol Biol Phys.
1999;45:351–358.
54. Cannon DM, Lee NY. Recurrence in region of spared parotid gland
after definitive intensity-modulated radiotherapy for head and neck
cancer. .Int J Radiat Oncol Biol Phys. 2008:70:660–665.
55. Pfeffer MR, Rabin T, Tsvang L, et al. Orbital lymphoma: is it
necessary to treat the entire orbit? .Int J Radiat Oncol Biol Phys.
2004;60:527–530.
56. Lovelock DM, Zhang Z, Jackson A, et al. Correlation of local failure
with measures of dose insufficiency in the high-dose single fraction
treatment of bony metastases. Int J Radiat Oncol Biol Phys.
2010;77:1282–1287.
57. Bishop AJ, Tao R, Rebueno NC, et al. Outcomes for spine
stereotactic body radiation therapy and an analysis of predictors of
local recurrence .Int J Radiat Oncol Biol Phys. 2015;92:1016–1026.
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58. Levegrun S, Jackson A, Zelefsky MJ, et al. Analysis of biopsy
outcome after three-dimensional conformal radiation therapy of
prostate cancer using dose distribution variables and tumor control
probability models. Int J Radiat Oncol Biol Phys. 2000;47:1245–
1260.
59. Levegrun S, Jackson A, Zelefsky MJ, et al. Fitting tumor control
probability models to biopsy outcome after three-dimensional
conformal radiation therapy of prostate cancer: pitfalls in deducing
radiobiologic parameters for tumors from clinical data. Int J Radiat
Oncol Biol Phys. 2001;51:1064–1080.
60. Zelefsky MJ, Kollmeier M, Cox B, et al Improved clinical outcomes
with high-dose image guided radiotherapy compared with non-IGRT
for the treatment of clinically localized prostate cancer. Int J Radiat
Oncol Biol Phys. 2012;84:125–129.
61. Peeters ST, Lebesque JV, Heemsbergen WD. Localized volume
effects for late rectal and anal toxicity after radiotherapy for
prostate cancer. Int J Radiat Oncol Biol Phys. 2006;64:1151–1161.
62. Lyman JT. Complication probabilities as assessed from dose-volume
histograms. Radiat Res Suppl. 1985;104:S13–S19.
63. Kutcher GJ, Burman C, Brewster L, et al. Histogram reduction
method for calculating complication probabilities for three-
dimensional treatment planning evaluations. Int J Radiat Oncol Biol
Phys. 1991;21:137–146.
64. Withers HR, Taylor JM, Maciejewski B. Treatment volume and
tissue tolerance. Int J Radiat Oncol Biol Phys. 1988;15:751–759.
probability and dose-volume histogram reduction schemes for
tissues with a critical element architecture. Radiother Oncol.
1991;20:166–176.
66. Niemierko A, Goitein M. Modeling of normal tissue response to
radiation: the critical volume model. Int J Radiat Oncol Biol Phys.
1993;25:135–145.
67. Yorke ED, Kutcher GJ, Jackson A, et al. Probability of radiation-
induced complications in normal tissues with parallel architecture
under conditions of uniform whole or partial organ irradiation.
68. Jackson A, Kutcher GJ, Yorke ED. Probability of radiation-induced
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complications for normal tissues with parallel architecture subject to
non-uniform irradiation. Med Phys. 1993;20:613–625.
69. Källman P, Agren A, Brahme A. Tumor and normal tissue responses
to fractionated non uniform dose delivery. Int J Radiat Biol. 1992;
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tolerance data to an analytic function. Int Radiat Oncol Biol Phys.
1991;21:123–135.
72. Mohan R, Mageras GS, Baldwin B. Clinically relevant optimization
of 3D conformal treatments. Med Phys. 1992;19:933–944.
73. Niemierko A. A generalized concept of equivalent uniform dose
(EUD). Med Phys. 1999;26;1101.
74. Niemierko A. Reporting and analyzing dose distributions: a concept
of equivalent uniform dose. Med Phys. 1997;24;103–110.
75. Jackson A, Marks LB, Bentzen SM, et al. The lessons of Quantec:
recommendations for reporting and gathering data on dose-volume
dependencies of treatment outcome. Int J Radiat Oncol Biol Phys.
2010;76:S155–S160.
Phys. 2010;76:S10–S19.
1112.
78. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume
effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76:S70–S76.
79. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy
Oncology Group (RTOG) and the European Organization for
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Phys. 1995;31:1341–1346.
80. Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and
urinary toxicities after three-dimensional conformal radiotherapy
and intensity-modulated radiotherapy for localized prostate cancer.
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81. Troeller A, Yan D, Marina O, et al. Comparison and limitations of
DVH-based NTCP models derived from 3D-CRT and IMRT data for
prediction of gastrointestinal toxicities in prostate cancer patients by
using propensity score matched pair analysis. Int J Radiat Oncol Biol
Phys. 2015;91:435–443.
82. Mayo C, Martel MK, Marks LB, et al, Radiation dose-volume effects
of optic nerves and chiasm. Int J Radiat Oncol Biol Phys.
2010;76:S28–S35.
83. Deasy JO, Moiseenko V, Marks L, et al. Radiotherapy dose-volume
effects on salivary gland function. Int J Radiat Oncol Biol Phys.
2010;76:S58–S63.
84. Jackson A, Ten Haken RK, Robertson JM, et al. Analysis of clinical
complication data for radiation hepatitis using a parallel
architecture model. Int J Radiat Oncol Biol Phys. 1995;31:883–891.
85. Lawrence TS, Tesser RJ, ten Haken RK. An application of dose
volume histograms to the treatment of intrahepatic malignancies
with radiation therapy. Int J Radiat Oncol Biol Phys. 1990;19:1041–
1047.
86. Lawrence TS, Ten Haken RK, Kessler ML, et al. The use of 3D dose
volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol
Phys. 1992;23:781–788.
87. Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J Am Stat Assoc. 1958;53:457–816.
88. Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the
liver. Semin Radiat Oncol. 2001;11:240–246.
89. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to
radiation. Semin Radiat Oncol. 2005;15:279–283.
90. Hunt MA, Jackson A, Narayana A, et al. Geometric factors
influencing dosimetric sparing of the parotid glands using IMRT. Int
91. Wu B, Ricchetti F, Sanguineti G, et al. Patient geometry-driven
information retrieval for IMRT treatment plan quality control. Med
Phys. 2009;36:5497–5505.
92. Appenzoller LM, Michalski JM, Thorstad WL, et al. Predicting dose-
volume histograms for organs-at-risk in IMRT planning. Med Phys.
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complication probability models: the need to adopt a “data pooling”
culture. Int J Radiat Oncol Biol Phys. 2010;76:S151–S154.
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SECTION II
Treatment Planning for

Specific Cancers
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24 Cancers of the Gastrointestinal
Tract
Jordan A. Torok, Bradford A. Perez, Brian G. Czito,

Christopher G. Willett, Fang-Fang Yin, and Manisha Palta
INTRODUCTION
Radiotherapy in combination with chemotherapy has a significant role
in the treatment of cancers of the esophagus, stomach, pancreas, rectum,
and anus. The role of combined modality therapy in the treatment of
these diseases has been defined largely as a result of numerous
prospective clinical trials conducted over the past 20 years. This chapter
highlights the technical aspects of treatment of gastrointestinal cancer,
with particular emphasis on anatomic target definitions and modern
treatment planning techniques.
ESOPHAGEAL CANCER
In 2015, there will be an estimated 16,980 new cases of esophageal
cancer in the United States and 15,590 deaths (1). While esophageal and
gastric cancers are often described together, they are quite distinct
malignancies—anatomically, etiologically, and therapeutically.
Squamous cell carcinoma and adenocarcinoma are the predominant
histologies in esophageal cancer, each attributable to specific risk factors
(2). A dramatic increase in adenocarcinoma incidence has been seen in
the United States for the past several decades, which only recently
appears to have plateaued (3). Internationally, there is significant
geographic variation in the incidence of esophageal cancer (4) where the
predominant histology in endemic regions is squamous cell carcinoma
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(5,6). Radiation therapy (RT) plays an important role in the management
of esophageal cancer, particularly in the neoadjuvant setting for locally
advanced disease.
DIAGNOSTIC EVALUATION
A complete diagnostic workup is crucial in defining the maximal extent
of locoregional disease prior to treatment. Due to the limitations of
diagnostic imaging in staging this disease, no single study should be
relied on solely to define the extent of tumor during treatment planning.
Description of the mucosal extent of disease is best defined visually by
upper endoscopy and frequently this will define tumor beyond what is
appreciated by imaging modalities. Review of endoscopy reports and/or
discussion with the gastroenterologist is imperative. Measurements of
tumor extent in the esophagus are referenced by endoscopic distance
from the incisors and location of the tumor in reference to the
gastroesophageal junction (GEJ). These measurements may be
inconsistent and imprecise between examinations, but they should be
noted and compared to radiologic findings to ensure general consistency
between modalities. The distance from the incisors to the thoracic inlet
is generally 18 cm (beginning of upper thoracic esophagus), the carina is
located at ∼24 cm (demarcating the beginning of the mid-esophagus),
and the lower esophagus begins at 32 cm and ends at ∼40 cm (GEJ) (7).
Endoscopic ultrasound (EUS) is an established modality for local
staging in experienced hands. The accuracy of EUS for T stage is
generally reported to be between 80% and 90% for esophageal cancer,
with higher accuracy for tumors which penetrate the muscularis propria
(T3) (8). Regional staging by EUS, which characterizes both nodal size
and architecture, has been reported to have ∼75% accuracy. Fine-needle
aspiration may augment the accuracy of the procedure for determining
lymph node involvement by tumor.
Axial imaging of the chest and abdomen with computed tomography
(CT) or magnetic resonance imaging (MRI) can detect lymphadenopathy
beyond the range of EUS, but more importantly evaluates for distant
metastases. Positron emission tomography (PET) is more accurate than
CT or EUS in detecting distant metastases, and may increase diagnostic
specificity for regional and distant lymphadenopathy (9,10). Integrated
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PET/CT takes advantage of the improved spatial resolution of CT,
making this a complementary study to the local staging provided by
EUS.
Among patients with concerning respiratory symptoms at
presentation, or any patient with a cervical or upper esophageal tumor,
bronchoscopy should be considered to evaluate for fistula within the
tracheobronchial tree prior to treatment planning. Although the presence
of a fistula has traditionally been considered a contraindication to
radiotherapy, there are multiple reports of irradiating these patients
successfully (11–13). At times, the fistula may even close with treatment
and the survival of irradiated patients appears superior to patients
treated with chemotherapy or supportive care alone (13). Consideration
should be given to endoscopically stenting these patients (12).
TREATMENT OPTIONS
The optimal coordination of surgery, chemotherapy, and radiotherapy
continues to be studied by large multi-institutional studies in patients
with esophageal and GEJ cancers. Surgical resection has long been the
foundation of curative strategies for locoregionally confined esophageal
and GEJ cancers, but is inadequate as monotherapy for most cases (14).
Adjuvant treatment of GEJ tumors in the United States has largely been
informed by Intergroup 0116, which demonstrated an overall survival
benefit of chemoradiotherapy (CRT) compared to surgery alone (15). All
patients had adenocarcinomas, the majority of which were gastric
cancers, with GEJ tumors making up about 20% of the population.
Similarly, phase II data supports the adjuvant CRT approach, particularly
in patients with pT3+ and/or node positive disease (16). Retrospective
evidence suggests adjuvant CRT is also beneficial for esophageal
squamous cell carcinoma (17). Adjuvant RT alone is of uncertain benefit.
Dated trials using antiquated techniques and/or unusual fractionation
schemes showed either no improvement or even a possible detrimental
effect to RT alone (18,19).
More recently, neoadjuvant CRT has supplanted the traditional
adjuvant paradigm for potentially, resectable cancers of the esophagus,
largely as a result of the CROSS trial. In this trial, patients with T1N1 or
T2–3N0–1 esophageal or GEJ cancer were randomized to preoperative
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CRT or surgery alone. Trimodality therapy was associated with improved
complete resection rates, a pathologic complete response rate of ∼30%
as well as an overall survival benefit (median survival 49.4 vs. 24
months) (20). Early-stage esophageal cancer (particularly T1N0) may
not benefit from a trimodality approach (21), and are more
appropriately managed with upfront surgery or definitive CRT. The
accuracy of preoperative staging is therefore critical in determining the
appropriate management for these patients.
Surgical resection may not benefit all patients with potentially
resectable disease after CRT. Randomized trials of the addition of
surgical resection to initial CRT for locally advanced squamous cell
carcinomas of the esophagus have shown improved locoregional control
but no significant improvement in patient survival (22,23). Outside of
medically inoperable patients, it is currently unclear which patients may
be best suited for this approach. In patients with unresectable disease,
CRT represents the standard of care (24).
TREATMENT PLANNING
Simulation
Patients are generally simulated in the supine position with arms
extended over the head using a wing-board or similar device to ensure
reproducibility and to allow treatment with oblique or lateral fields.
Although prone positioning may be less reproducible, it may be
advantageous for some patients with middle or lower esophageal lesions.
Prone positioning is reported to move the esophageal lumen anteriorly,
an average of 1.7 cm away from the spinal cord, compared to supine
positioning (25). It should be noted that despite such maneuvers,
periesophageal tissue posterior to the esophagus still remains fixed to the
vertebral column. If treatment fields will encompass any stomach, the
patient should be both simulated and treated with an empty stomach
(minimum 3 h NPO) to reduce gastric distension and improve target
reproducibility. Although CT-based planning is essential, fluoroscopic
simulation may also be a useful step for identifying surgical staple lines,
clips, and respiratory motion. Administration of oral contrast, whether at
the time of simulation or flouroscopy, aides in localizing the mucosal
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extent of esophageal cancers. In addition, respiratory movement of the
left hemidiaphragm can be noted and incorporated into parameters of
the planning target volume (PTV) for GEJ tumors. Studies of 4DCT-
simulation (4DCT) of esophageal cancers have demonstrated significant
primary tumor as well as nodal (celiac) movement with respiration in all
directions (26,27). Given wide patient variation in such target motion,
individual assessment of target motion is preferred to standardized
internal target margins for all patients.
Radiotherapy Target
For patients treated neoadjuvantly or definitively with radiotherapy, the
gross tumor volume (GTV) includes the maximal extent of gross disease
as defined by the combination of all staging modalities. Dependence on
upper gastroesophageal radiography alone at the time of simulation will
likely underestimate both the radial tumor margin and regional nodal
disease. CT may be better at defining the radial and regional extent of
gross disease, but longitudinal tumor boundaries may not be distinct. In
addition, small tumors (T1 or T2) are often not discernable on CT. Oral
contrast may assist in defining an area of mucosal irregularity. Upper
endoscopy may provide the most accurate assessment of longitudinal
mucosal tumor boundaries, but is often not possible to precisely
correlate these measurements with a planning CT. EUS is probably the
best modality for defining both longitudinal and radial extent of the
primary tumor. By coordinating with the endoscopist, the superior and
inferior boundaries of tumor can be referenced to an intrathoracic
structure such as the top of the aortic arch or GEJ rather than just the
incisors (28).
PET imaging is also useful in defining the GTV. With clinical
judgment, the GTV may be expanded to include FDG-avid tissue not
appreciated as tumor with other imaging. At times, other imaging
modalities may define greater extent of tumor volumes than defined by
PET. For example, the longitudinal extent of tumor is often perceived
greater on CT than PET (29). However, given the risks of false-negative
imaging, target contours should not be reduced to include only abnormal
volumes defined by PET (30). While PET may improve target
delineation, its contribution to improving treatment efficacy seems
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limited (31).
The clinical target volume (CTV) includes areas of microscopic risk of
disease from either primary tumor extension or nodal metastases not
detected by clinical staging. The lymphatic drainage of the esophagus is
primarily longitudinal with channels extending some distance before
perforating the muscularis propria to communicate with adventitial
lymphatics (32). Autopsy studies in patients dying of esophageal cancer
have found lymphangitic carcinomatosis of the esophageal wall in up to
one-third of patients, with in situ or invasive skip lesions at a distance of
2 to 10 cm in 13% of patients (33). Thus, in the preoperative or
definitive setting, radiotherapy ports for esophageal cancer have
traditionally included a generous longitudinal margin of mucosa.
Although initial ports in RTOG 85–01 treated the entire esophagus for
30 Gy (34), subsequent trials have limited the longitudinal margin to 5
cm (35).
With 3D target definition, this 5-cm margin is comparable to a 3- to 4-
cm CTV of longitudinal margin of esophagus from the GTV (assuming 1-
cm PTV and 0.5 to 1 cm to block edge for dosimetric buildup). For
tumors of the lower esophagus and GEJ, a 3 to 4 cm inferior extension of
the CTV often includes proximal stomach. Pathologic study of resected
squamous cell carcinoma and adenocarcinoma has shown the risk of
microscopic extension to be limited to 3 and 5 cm, respectively (36). In
addition to longitudinal extension, the CTV includes radial expansion
from the GTV as well. Although this radial expansion of CTV around the
GTV should include 1 to 2 cm of adjacent soft tissue, generally this is
well within the CTV boundary required for regional nodal coverage. In
the CROSS trial, longitudinal margins were 4 cm with the distal margin
shortened to 3 cm when tumor extended to the stomach (20). A radial
margin of 1.5 cm around the GTV was used. It is important to note that
these expansions formed a PTV, and a CTV was not utilized. Recurrences
at the border of the treatment fields were rare (∼2%), suggesting these
margins are adequate at least when followed by esophagectomy (37).
The regional lymphatics included within the CTV depend on the
anatomic location of the primary tumor. Huang et al. examined the
pattern of lymph node metastases based on location of the primary
tumor in patients undergoing esophagectomy and lymphadnectomy (38).
To summarize, upper thoracic tumors more commonly involved cervical,
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upper and middle mediastinal lymph nodes while lower thoracic tumors
more commonly involved middle to lower mediastinal and abdominal
nodes. For primary tumors of the esophagus, the CTV should be
extended radially to include periesophageal lymph nodes around the
GTV and along the longitudinal extent of the normal esophagus included
within the CTV (see Fig. 24.1). The periesophageal lymph nodes lie in
the posterior mediastinum in the soft tissue immediately surrounding the
esophagus. Although conventional radiotherapy fields have
accommodated these nodes by a 2- to 2.5-cm margin on the esophagus,
such guidelines do not account for the often asymmetric and variable
distribution of this tissue surrounding the esophagus. Thus, the CTV
should be contoured based on individual patient anatomy. Given a
>40% rate of subclinical metastases to the supraclavicular lymph nodes
for upper esophageal cancers as defined by surgical dissections (39),
extension of the CTV to this region is indicated for tumors in this
location. Similarly, if the upper esophagus is within the CTV, adjacent
paratracheal lymphatics should be included in addition to
periesophageal tissue. In the mid-esophagus, the subcarinal lymph node
region should be included in the CTV if esophagus or tumor is included
to this axial level as a target volume. Treatment of the thoracic hilar or
anterior mediastinal lymph nodes is not indicated unless they are grossly
involved on pretreatment imaging.
Distal esophageal tumors that extend to or involve the GEJ pose a
threat to upper abdominal lymph nodes. Pericardial lymph nodes
(medial and lateral borders of gastric cardia) and celiac lymph nodes are
included in the CTV. While splenic hilar lymph nodes may be at risk for
T3 or T4 GEJ tumors (40), failure rates were low in the CROSS study
where ∼25% had GEJ tumors and these lymph nodes were not
electively treated (37). With extension of tumor inferiorly/laterally into
the gastric cardia, lymph nodes of the entire celiac axis and splenic hilar
nodes are at risk and should be covered as described in the gastric
cancer section.
Target identification is inherently more challenging in the
postoperative setting. Using preoperative staging studies and operative
findings, the original extent of the primary cancer (and gross nodal
disease) must be reconstructed on the planning CT and included within
the CTV. In addition, the gastroesophageal anastomosis must be
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identified and included. Although there may be temptation to exclude
the anastomosis among patients where it lies high in the thorax or even
lower neck, such an omission has been associated in one series with a
29% anastomotic recurrence rate (compared to 0% with treatment) (41).
Normal Tissue Tolerances

The percentage of total lung receiving >20 Gy should be kept to <30%,
and preferably <25%. Among patients treated neoadjuvantly,
postoperative pulmonary complications have been inversely associated
with the absolute volume of lung spared 5 Gy (42,43). The whole heart
should not receive beyond a mean dose of 30 Gy. One-half of the heart
should be restricted to 40 Gy or less. Doses of 50 Gy or slightly beyond
may be delivered to a maximum of 30% of heart volume, but an attempt
should be made to limit high doses to the left ventricle when possible.
The spinal cord should not receive >45 Gy.
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Figure 24.1 A 63-year-old woman with a cT2N0 adenocarcinoma of the distal esophagus treated
with neoadjuvant chemoradiotherapy utilizing a four-field technique. AP (A) and right lateral (B)
fields, GTV (red). Axial (C) and sagittal (D) dosimetry, with GTV (red) and 45 Gy (yellow), 42.75
Gy (orange), 40.5 Gy (dark blue), 36 Gy (dark green) and 18 Gy (pink) isodose lines.
Radiotherapy Dose
RTOG 95–05 (35) evaluated the radiotherapy dose for definitive
treatment of esophageal cancer in conjunction with concurrent
chemotherapy. No difference in locoregional control or overall survival
was detected between the 50.4 and 64.8 Gy arms of the trial, with a
trend toward inferior outcome with high-dose CRT. Thus, 50.4 Gy given
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at 1.8 Gy/fraction is the recommended dose for patients with esophageal
cancer treated definitively with radiation. In the neoadjuvant setting, the
CROSS trial utilized a lower total dose of 41.4 Gy in 1.8 Gy/fraction to a
single volume (20). It is important to note that this was in a well-
selected patient population fit for surgery, with 94% of patients
subsequently undergoing esophagectomy. In practice, many patients may
not ultimately go to surgery, where a total dose of 41.4 Gy may be
inadequate. An alternative approach is to deliver 45 Gy at
1.8 Gy/fraction to the initial CTV with consideration of a 5.4-Gy boost to
gross disease. In this manner, a definitive dose has been administered
even if the patient ultimately does not go for surgery. Whether this
additional dose results in enhanced perioperative complications
compared to that used in the CROSS regimen is unknown.
In the postoperative setting, 45 Gy at 1.8 Gy/fraction is considered
standard based on Intergroup 0116 (15). Boost treatment beyond 45 Gy
for such indications as close or involved surgical margins may be
considered cautiously in the setting of normal tissue and patient
tolerances.
RADIOTHERAPY FIELDS AND TECHNIQUES

Common field arrangements for the treatment of esophageal cancers are
influenced by the total dose limits of the spinal cord. AP–PA techniques
irradiate the least amount of normal lung, but care must be taken with
lower esophageal/GEJ tumors where such a field arrangement can
include a significant amount of heart. Supplementation with lateral or
oblique fields which avoid the spinal cord are required to deliver doses
beyond 45 Gy to the thorax, but will generally lead to increased doses to
the lung. A four-field technique (AP, PA, and laterals) usually enables a
satisfactory dose distribution when the weighting of lateral fields is
limited according to lung tolerance (see Fig. 24.1). Oblique ports include
less lung than lateral fields, but depending on orientation may include
more heart (25). Another option is to treat the patient with a three-field
technique (AP and posterior oblique fields), with at least one field not
contributing to spinal cord dose.
Traditional field borders for esophageal cancers have generally been
defined with 2-cm lateral (radial) margins beyond the esophagus and a
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5-cm longitudinal margin from tumor (superior–inferior) (35). 3D
treatment planning allows for further optimization of field shaping and
orientation based on individual patient anatomy compared to 2D
techniques. However, the transition from 2D to 3D field definitions of
target must be done with caution in order to avoid undertreatment of
tissues at risk, which were previously included in multi-institutional
trials. Target motion should be assessed, either with 4DCT or
fluoroscopy and upper gastrointestinal contrast. Internal motion can
then be added to the CTV to create an internal target volume (ITV). The
PTV should be expanded by a minimum of 5 mm to 1 cm, depending on
the frequency of image guidance, to account for setup uncertainty.
Conforming field borders should then be devised that allow dosimetric
coverage of the PTV (usually another 5 to 10 mm to the field edge).
Given the complex geometric targets associated with esophageal
cancers and the proximity of critical normal tissue, the increased
conformality of IMRT may provide dosimetric advantages compared to
standard radiotherapy techniques. However, this technology must be
employed with care, given the challenges of respiratory and cardiac
motion, the intolerance of large volumes of the lung to even modest
doses of radiation, and the undesirability of dose inhomogeneity within
the PTV. There is limited prospective clinical experience with the use of
IMRT in the treatment of esophageal cancer. Its careful implementation
has been associated with decreased exposure of the lungs and heart
compared to traditional techniques (44–47), with one retrospective
series suggesting improved clinical outcomes compared to 3D conformal
RT (48).
Chemotherapy
Based on Intergroup 0116, 5-fluorouracil (FU)–based CRT is typical for
adjuvant CRT (15). Patients initially received 5-FU (425 mg/m2) with
leucovorin (20 mg/m2) for 5 days. CRT began 28 days later with
reduced doses of 5-FU (400 mg/m2) and leucovorin on the first 4 days
and last 3 days of radiotherapy. Two more monthly cycles of
chemotherapy were given a month after completion of radiotherapy.
Grade 3 or higher hematologic and gastrointestinal toxicity associated
with this regimen was seen in 54% and 33% of patients, respectively.
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For patients treated with definitive CRT of the esophagus, both
cisplatin and 5-FU are used concurrently with radiation. RTOG 85–01
established the clear superiority of CRT over radiotherapy alone for
patients with squamous cell carcinoma of the esophagus (34). Cisplatin
(75 mg/m2) was administered on the first and fifth weeks of
radiotherapy with 5-FU (1,000 mg/m2) for 4 days. Two additional cycles
of cisplatin and 5-FU were administered after completion of
radiotherapy. Rates of grade 3 or higher hematologic and
gastrointestinal toxicity were comparable to those seen in the Intergroup
trial. Initial randomized trials of neoadjuvant CRT have similarly
included various schedules of concurrent cisplatin, generally with 5-FU
as well (49–52). The more recent CROSS regimen included carboplatin
at an area under the curve of 2 mg/mL/min and paclitaxel 50 mg/m2,
both given weekly (20) with preoperative radiotherapy. Acute toxicity
was considerably less compared to earlier trials containing 5-FU, with
grade 3+ hematologic, and all other nonhematologic toxicity reported
in 7% and 13% of patients, respectively. The optimal agent(s), dose and
schedule are currently unknown.
PROGNOSIS
The outcome of patients with esophageal cancer treated with curative
intent has been defined by randomized clinical trials. For locally
advanced, unresectable esophageal cancers, the 5-year overall survival
after definitive CRT was 26% in RTOG 85–01 (24). Five-year survival
among patients undergoing trimodality therapy has been reported as
high as 47% (20). Surgical or endoscopic treatment of T1 esophageal
cancer results in a 5-year survival of ∼80% (53).
GASTRIC CANCER
In 2015, there will be an estimated 24,590 new cases of gastric cancer in
the United States, with 10,720 deaths attributed to the disease (1). As
with esophageal cancer, there is marked variation in the incidence of
gastric cancer based on geographic region (54). Gastric cancers are
predominantly adenocarcinomas, with diffuse and intestinal subtypes.
Distal gastric cancers have been decreasing in incidence, while more
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proximal/cardia lesions have become more common (55). While often
used in the adjuvant setting in North America, the role of RT in the
management of gastric cancer in Europe is somewhat controversial and
remains to be defined by ongoing trials.
Similar to esophageal cancer, upper endoscopy is critical in delineating
the location and extent of mucosal disease involvement. The location of
the tumor “epicenter” and its extension to the GEJ/distal esophagus
should be determined based on endoscopy reports and/or discussion
with the gastroenterologist. The Siewert classification can be useful in
differentiating true gastric cancers from GEJ cancers (56). As with
esophageal cancer, EUS may play an important role in the local and
regional staging of gastric cancer. EUS accuracy in determining both
correct T and N stage is ∼80% (57–59).
A contrast-enhanced CT of the chest, abdomen, and pelvis is done to
evaluate for regional lymph node and distant metastases, but is limited
in the detection of peritoneal implants (60). The addition of PET to CT
can improve accuracy of staging, primarily as a result of increased
specificity in diagnosing lymph node metastases (61) and in the
detection of distant metastases (62). An important limitation of PET is
that diffuse type/signet-ring gastric cancers can be associated with false-
negative results (63–65). In addition, PET also has limited sensitivity in
the diagnosis of peritoneal metastases (66). As a result, the role of PET is
not as clearly defined in gastric cancer.
The use of routine staging laparoscopy for gastric cancer is evolving.
In a large series from the Memorial Sloan Kettering Cancer Center, 30%
of patients without CT-evidence of distant metastases were found to
have metastatic disease at laparoscopy (67). In patients without obvious
metastatic disease and EUS-staged T1–T2N0 disease, occult metastatic
disease is rarely found at laparoscopy (68), suggesting the procedure can
be safely omitted in these patients. Laparoscopy is therefore more likely
to change management in advanced cases and should be considered in
these patients (69).
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TREATMENT OPTIONS
The optimal treatment paradigm for gastric cancer remains an active
area of investigation. Upfront surgical resection is indicated for early-
stage gastric cancers (T1N0). For more advanced cases, local recurrence
and/or regional failure occurs in a significant number of patients
following a curative resection (70). As a result, two multimodality
approaches have evolved in parallel. Intergroup 0116 investigated the
use of adjuvant CRT in a heterogeneous patient population including
T1N+, T2–4N0–2 gastric cancers as well as a smaller proportion of GEJ
cancers (15). The addition of adjuvant CRT to surgical resection resulted
in a significant reduction in local regional failure and an improvement in
survival (median survival 35 vs. 27 months) (71). As a result, adjuvant
CRT became the standard treatment for patients with gastric cancer in
North America. Critics have suggested the survival benefit of CRT was a
result of inadequate lymphadenectomy, as the majority of patients
underwent a D0 resection (72). Retrospective evidence suggests adjuvant
CRT is still beneficial for patients following D2 resection compared to
surgery alone (73). The Korean ARTIST trial compared the use of
adjuvant chemotherapy to CRT in patients undergoing a D2 resection. A
recent update of this trial found a significant reduction in locoregional
relapse with CRT, but no difference in overall survival (74). Subset
analysis of the results suggested patients with node positive disease were
more likely to benefit from CRT, leading to an ongoing trial in this
population.
Perioperative chemotherapy has also been investigated for advanced
gastric cancer, primarily in European countries. The UK MAGIC trial
compared this approach to surgical resection alone in a heterogeneous
patient population of mostly gastric (∼75%) but also GEJ and distal
esophageal cancers. The perioperative chemotherapy regimen was
associated with tumor downstaging and a significant improvement in
overall survival (5-year 36% vs. 23%) (75). A meta-analysis of
perioperative chemotherapy compared to surgery alone (including the
MAGIC trial and several other similarly designed trials) demonstrated a
small, but significant, improvement in survival (76). Perioperative
chemotherapy has subsequently become the preferred approach in
Europe. Whether the addition of neoadjuvant RT to perioperative
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chemotherapy will improve outcome is currently under investigation.
The role of neoadjuvant CRT was evaluated in the RTOG 9904, a single-
arm phase II study. This study demonstrated the feasibility of this
approach with a pathologic complete response rate in greater than 20%
of patients (77).
For unresectable disease, some patients can be downstaged with
neoadjuvant therapy, but the optimal approach is unknown. Therapy for
the majority of these patients is typically palliative. The role of RT in
this setting is largely based on historical trials. The addition of
chemotherapy to RT improved survival (78), while the comparison of
CRT to chemotherapy alone appeared to result in more long-term
survivors (79). Most contemporary trials have focused on improving
combination chemotherapy efficacy for these patients.
TREATMENT PLANNING
Simulation
As with esophageal cancers, patients are generally simulated in the
supine position with arms extended over the head using a wing-board or
similar device. Patients should be both simulated and treated with an
empty stomach (minimum 3 h) to reduce gastric distension and improve
target reproducibility. Oral contrast can be given, which in the
preoperative or definitive setting can help identify mucosal extent of
disease. In the postoperative setting, oral contrast helps identify
anatomical structures, including the gastric remnant and anastomosis. IV
contrast is routinely given to assist in the detection of lymphadenopathy.
4DCT may be useful in terms of organ motion related to respiration
which can be incorporated into parameters of the treatment volumes
(80). Fluoroscopic imaging with contrast agent or fiducial markers may
also be an effective approach to estimate the extent of organ motion
(81).
Radiotherapy Target
In the neoadjuvant and definitive setting, the GTV includes the maximal
extent of gross disease as defined by upper endoscopy and imaging
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modalities, primarily CT and EUS. The CTV includes areas at risk for
microscopic disease from either primary tumor extension or nodal
metastases not detected by clinical staging. Areas at risk for local and
regional recurrence have been identified, most notably from a seminal
re-operation series (70). The CTV includes all the perigastric lymph
nodes along the lesser and greater curvatures of the stomach. Adequate
longitudinal normal mucosal margin within the CTV should be generated
(∼5 cm). For proximal gastric tumors, extension of CTV cranially may
include distal esophagus with associated periesophageal lymphatics. For
very distal gastric cancers, similar caudal extension including a portion
of the duodenum is appropriate. Tumors of the gastric cardia or fundus
(especially if T3) should include the medial left hemidiaphragm.
In addition to the perigastric lymph nodes, nodal stations to be
included in the CTV for gastric tumors include the celiac, porta hepatis
(including gastrohepatic and hepatoduodenal), suprapancreatic (along
the splenic artery), splenic hilar, supra- and infrapyloric (above and
below the pylorus), pancreaticoduodenal (tissue around and posterior to
the pancreatic head), and local paraaortic/retroperitoneal lymph nodes
(along the cranial-caudad extent of the stomach). Similar principles for
target identification exist in the postoperative setting. Using preoperative
staging studies and operative findings, the original extent of the primary
cancer (and gross nodal disease) must be reconstructed on the planning
CT and included within the CTV. A recently published contouring atlas
helps identify these regional nodes on CT in patients with both intact
and postoperative anatomy (82). Among gastric tumors that involve only
the upper one-third of the stomach and who have minimal lymphatic
tumor involvement pathologically, cautious consideration can be given
for exclusion of the infrapyloric and pancreaticoduodenal lymph nodes
(83). Similarly, lesions of the lower one-third of the stomach may have a
lower propensity for involvement of the splenic hilar lymph nodes (83).

The amount of small bowel receiving over 45 Gy should be minimized
without compromising target coverage. Any small bowel within a
possible boost volume of treatment should be limited and not receive
beyond 50 Gy. At least 75% of one kidney or the composite of one whole
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kidney should be kept below 18 to 20 Gy. If the large majority of one
kidney will receive doses beyond 20 Gy, consideration should be given
to a quantitative renal scan prior to treatment to ensure sufficient
function of the other kidney. Sixty (and preferably less) percent of the
liver should be kept below 30 Gy and the whole liver should not receive
>25 Gy. Heart and spinal cord constraints are similar to those described
for esophageal cancer.
RADIOTHERAPY DOSE
In the neoadjuvant setting, 45 Gy at 1.8 Gy/fraction was utilized in
RTOG 9904 and is the dose being used in the ongoing TOPGEAR trial. In
the postoperative setting, 45 Gy at 1.8 Gy/fraction is the standard dose
based on Intergroup 0116 (15). Boost treatment beyond 45 Gy for such
indications as close or involved surgical margins may be considered
cautiously, with regard given to normal tissue and patient tolerances.
Radiotherapy Fields and Techniques

The PTV is in part based on organ motion assessment and should be
individualized based on 4DCT. For 3D planning, a minimum 5-mm
margin is necessary for dosimetric coverage of the PTV. Postoperative
field design continues to be influenced by Intergroup 0116. Smalley et
al. (83) describe the traditional borders as follows: the superior field
border includes the left hemidiaphragm, though it may be significantly
higher for proximal gastric tumors whose anastomoses are in the thorax.
In order to include the infrapyloric and pancreaticoduodenal nodes, the
inferior field border is generally located at L3. The left lateral border
extends sufficiently to include the lateral border of the perigastric lymph
nodes of the greater curvature and the splenic hilum. The medial border
is placed to include the porta hepatis and the medial extent of the
preoperative tumor volume. Using this technique, the addition of lateral
or oblique fields to AP–PA ports may have some benefit. The gastric
fundus and adjacent perigastric lymph nodes often extend posteriorly
enough that straight lateral fields are unable to spare the entire spinal
cord or a significant amount of kidney. In addition, more liver is
irradiated with such fields, and so if used they must be weighted to
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ensure their contribution is <20 Gy. The anterior borders of lateral and
oblique fields must cover the preoperative extent of the ventral gastric
wall.
Modern 3D conformal treatment planning should incorporate CT-
defined volumes while taking into account volumes included in
traditional ports to avoid undertreatment. Customized field technique
may be advantageous for some patients depending on the anatomic
extent of target. Oblique fields optimized to avoid spinal cord or kidney
while covering the PTV may often prove superior to straight lateral
fields. 3D treatment planning with five or more fields has been studied
in comparison to the AP–PA technique used in Intergroup 0116 with
reported dosimetric gains in regard to normal structures (84) and
favorable clinical assessment of toxicity (85). The dosimetric benefit
achieved was from reduction in kidney and spinal cord doses, at the
expense of small increases in dose to the liver.
Dosimetric studies of IMRT in the postoperative treatment of gastric
cancer have reported a possible improvement target coverage and
sparing of critical structures (86), most notably in reducing kidney
exposure (87–89) compared to conventional techniques. However,
clinically apparent renal dysfunction has not been described as a
common problem after treatment with more conventional techniques,
such as among patients treated in Intergroup 0116 (15). Preoperative
IMRT is associated with excellent target coverage and normal tissue
sparing but appeared to have similar acute toxicity to patients treated
with 3D CRT (90).
Chemotherapy
Intergroup 0116 employed an adjuvant/concurrent regimen of 5-FU as
described in the esophageal section. This has subsequently served as the
backbone for most CRT regimens. The RTOG investigated combination
and alternate regimens in both the preoperative and postoperative
settings. RTOG 9904 utilized an induction regimen of 5-FU (200 mg/m2)
by continuous infusion on days 1 to 21 and cisplatin (20 mg/m2) on
days 1 to 5 for two cycles followed by concurrent 5-FU (300 mg/m2) 5
days a week and paclitaxel (45 mg/m2) weekly during radiotherapy
(77). RTOG 0114 conducted a randomized phase II study comparing an
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intensified regimen of paclitaxel, cisplatin, and 5-FU (PCF) induction
followed by PF CRT to a non–5-FU containing regimen of PC induction
followed by PC CRT (91). The PCF arm closed early due to excess
toxicity, while the PC arm did not improve outcomes compared to INT
0116. Intergroup trial CALGB 80101 compared the INT 0116 5-FU
regimen used before and after CRT to a regimen similar to that used in
the MAGIC trial containing epirubicin (50 mg/m2 d1), cisplatin (60
mg/m2 d1), and 5-FU (200 mg/m2/d1–21, ECF). The CRT component
was the same in both arms with 5-FU given via continuous infusion at a
dose of 200 mg/m2/d. Results presented at the 2011 ASCO meeting
revealed no significant difference in survival between the arms. A
possible alternative to intravenous 5-FU is daily oral capecitabine (825
mg/m2 BID) as used in the ARTIST trial (74), although there is no
prospective evidence comparing the two in gastric cancer. Additional
agents used in the adjuvant setting not previously mentioned include S-1
and oxaliplatin. While fluoropyrimidine-based CRT has been a consistent
theme across trials, the optimal perioperative and adjuvant regimen
remains an area of active investigation.
Prognosis
The outcome of patients with gastric cancer varies depending on the
geographic region treated. The 5-year overall survival from the ARTIST
trial based in South Korea was ∼75% (74), compared to a 5-year
survival of ∼40% in the combined modality arms from INT 0116 (71)
and the MAGIC trial (75). The 5-year survival rate was <30% in the
surgery alone arms from the latter two trials, while it was 60% to 70%
in the surgery alone arms from recent Japanese and Korean studies
(92,93). This may be explained in part by more advanced patients
included in the North American and European trials, but may also reflect
differences in the biology of the disease, surgical experience, and
screening practices resulting in stage migration between the countries.
PANCREATIC CANCER
In the year 2015, the American Cancer Society estimated 48,960 new
pancreatic cancers in the United States (1). They also predicted 40,560
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deaths from this disease, highlighting the unfavorable prognosis of this
cancer at any stage and the need for more effective therapies.
The pretreatment diagnostic evaluation is crucial for selection of patients
who are candidates for surgical resection, those with unresectable
disease, and patients with distant metastases. Abdominal CT or MRI
remains the most useful modality for defining local extent of disease and
to detect metastasis within the abdomen. Resectability criteria are based
on tumor involvement along nearby arteries and veins which can be
assessed with these imaging modalities (94). Refinements in abdominal
CT imaging, such as acquisition of thin sections, dual-phase contrast
imaging, 3D reconstruction, and use of multi-detector CT, have greatly
improved the accuracy in defining local tumor extension. With these
techniques, accurate prediction of resectability has been reported in up
to 87% of patients (95). In addition to CT or MRI, EUS in experienced
hands may add further information regarding tumor extent, vascular
involvement, and regional adenopathy, but probably is most useful in
obtaining cytologic diagnosis. Endoscopic retrograde
cholangiopancreatography (ERCP) is a useful technique as it can be
utilized as a diagnostic tool to collect brushings which can confirm
malignancy within the biliary and/or pancreatic ducts, and as a
therapeutic tool to place a biliary stent which can relieve extrinsic
compression from the pancreatic tumor. Imaging from ERCP should also
be reviewed as it may assist in defining tumor boundaries during
treatment planning based on abnormalities of the biliary and/or
pancreatic ducts.
Although PET imaging has been reported to have a high sensitivity in
detecting pancreatic carcinomas, its poor anatomic resolution limits its
usefulness for local staging (surgical resectability or nodal involvement)
(96). Some studies suggest PET/CT may be more sensitive than other
modalities in detecting distant metastases (97), although currently this
approach is not commonly utilized for pancreatic cancer staging.
TREATMENT OPTIONS
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When a patient is medically fit and their tumor is anatomically
resectable, surgical resection is clearly indicated as it is the only strategy
that contributes to long-term survival in this disease. After surgical
resection, patients not only have a high-risk distant metastasis
development, but local failure as well. A high rate of local recurrence
has been reported after surgery (98,99). A small randomized trial
conducted by the GITSG reported a doubling in median survival (10.9
vs. 21.0 months) among patients treated with adjuvant CRT compared to
patients undergoing surgical resection alone (100). Two subsequent
randomized trials from Europe (EORTC 40891 and ESPAC-1) failed to
detect a survival benefit for adjuvant chemoradiation (101,102). These
studies should be interpreted with caution given the split course
radiotherapy in all three trials, the small numbers of the GITSG trial, the
inclusion of favorable periampullary tumors in the EORTC study, and the
lack of radiotherapy quality assurance or standardized specimen review
in the ESPAC-1. Recent retrospective analysis of large cohorts of patients
from Mayo Clinic and Johns Hopkins Hospital strongly support the use
of postoperative CRT in the management of resected pancreas cancer
(103,104). Thus, postoperative CRT may be considered part of the
overall adjuvant treatment plan in medically fit patients.
Multiple series have reported the feasibility and outcome of patients
with resectable tumors treated with preoperative CRT (105–108).
Preoperative CRT, however, has not been established as a treatment
standard by prospective randomized trials. Some of the theoretic
advantages of this strategy include local tumor downstaging to facilitate
an R0 resection, better oxygenation of the target tissues during radiation
and chemotherapy, reduced risk of intraoperative seeding, and improved
treatment tolerance compared to adjuvant therapy in the postoperative
setting. Practically, neoadjuvant therapy may also allow for
identification of those patients not likely to benefit from curative intent
surgical resection, particularly pancreaticoduodenectomy, which carries
a high degree of associated morbidity (109). A course of neoadjuvant
therapy followed by restaging may select patients who benefit from
resection and conversely avoid surgery in those patients with adverse
biologic features leading to early development of metastatic disease.
Patients with unresectable cancers who have a favorable functional
status can be considered for noncurative approaches including CRT or
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chemotherapy alone. Two randomized studies including preliminary
results of a large, recently presented European study (LAP-07) have not
shown any benefit with the addition of RT to initial chemotherapy
among patients with unresectable disease (110,111). In contrast, other
studies reporting on use of combined modality therapy have been
associated with improved overall survival compared to radiotherapy
alone (112), chemotherapy alone (113,114), or supportive care (115). In
light of this conflicting data, one approach for patients without local
symptoms is to offer initial systemic therapy followed by combined
modality therapy in patients without disease progression. Among
symptomatic patients, local therapy with radiation is likely to be an
effective palliative tool, and therefore consideration should be given to
upfront combined modality therapy.
Patients who present with metastatic disease are generally best
managed with systemic chemotherapy, although short palliative courses
of radiotherapy for symptoms such as pain may be beneficial in some
instances.
TREATMENT PLANNING
Simulation
Patients should be simulated in the supine position with arms over the
head using a wing-board or similar device to ensure reproducibility and
to allow treatment with lateral fields. Use of oral contrast is helpful to
identify the duodenal C-loop as an important reference for field design.
Intravenous contrast during CT planning aids in detection of vascular
landmarks and target definition, but generally, planning CT images are
inferior to diagnostic scans optimized for pancreas imaging (acquisition
during arterial and portal-venous phases of contrast). Therefore,
diagnostic films should be reviewed in conjunction with planning CT
images. Respiratory motion can be significant within the radiation target
areas and such variation can be accounted for by use of 4DCT and/or
use of oral contrast during fluoroscopic simulation. These approaches
allow for quantification of duodenal C-loop motion and ensure
appropriate coverage of the target regions.
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Radiotherapy Target
Accurate target definition is important not only to impact locoregional
control with radiation, but also to reduce toxicity of treatment. For
unresectable tumors or those treated neoadjuvantly, the GTV includes
the primary tumor (including vessels involved by tumor) and any
radiographically enlarged lymph nodes. The CTV includes the primary
tumor and involved nodes plus margin for microscopic extension and
any at-risk abdominal lymph nodes. A 1- to 2-cm margin of soft tissue
around the primary tumor should be included in the CTV. This margin,
however, is usually within the volume required to include the
peripancreatic lymph nodes. Given the proximity of the pancreatic head
to duodenum, the adjacent medial wall is included. The entire
circumference of duodenum should be included for tumor with gross
duodenal invasion. For patients to be treated postoperatively, surgical
and pathologic information should be carefully reviewed at the time of
treatment planning to assist with target delineation. The postoperative
CTV includes the postoperative bed, anastomoses, and the abdominal
lymph nodes at risk. Often a postoperative boost volume (CTV2) is
delineated which attempts to reconstruct the preoperative tumor
volume. The RTOG has published a contouring atlas to assist with
postoperative target delineation which is also useful for identifying
nodal areas at risk when radiation is delivered neoadjuvantly (116).
Brunner et al. (117) have provided an excellent analysis of nodal
regions at risk based on pathologic specimens from 175 cancers of the
pancreatic head. Peripancreatic nodal regions at >5% risk of nodal
metastasis include (in order of decreasing frequency): posterior
pancreaticoduodenal area, superior/inferior border of the pancreatic
head, anterior pancreaticoduodenal area, hepatoduodenal ligament
(porta hepatis), superior margin of pancreatic body, and superior
mesenteric artery. Thus, a CTV that includes a small rim of
peripancreatic soft tissue in all directions of the pancreatic head and
neck will include all but the nodes along the porta hepatis, SMA, aorta,
and celiac artery, which should also be included within the CTV.
Attention to a biliary stent may assist in locating the porta hepatis
during target contouring. Although the location of the celiac artery and
SMA has traditionally been described in relationship to T12 and L1,
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respectively, data from angiography (118) suggests that there is enough
individual variability that identification should be based on CT imaging
rather than relying solely on boney landmarks. Although the paraaortic
lymph nodes are considered a distant site of disease for staging purposes,
given the over 20% risk of subclinical metastases (117), they should be
included in the CTV. With respect to the inferior vena cava and aorta, in
>90% of cases, retroperitoneal metastases are anterior to these vessels,
between them, or lateral to the aorta (<5% metastases are
retrocaval/retroaortic or lateral to the cava) (119). In the craniocaudad
dimension, the majority of paraaortic nodal involvement is between the
celiac artery superiorly and the level of the renal veins inferiorly (except
for tumors >3 cm, where the CTV volume should extend inferiorly to
the level of inferior mesenteric artery) (120). For tumors involving the
pancreatic tail, inclusion of the suprapancreatic lymph nodes (along
splenic vessels) and splenic hilum is recommended. In addition, elective
treatment of inferior pancreaticoduodenal lymph nodes may be excluded
in these patients, which allows for relative sparing of the right kidney.
Given the predominance of tumor recurrence within radiotherapy
ports even when small local fields are used (121), some have questioned
the value of treating the regional lymph nodes in patients with
unresectable pancreatic cancer. Initial reports have described treating
the primary tumor only with stereotactic body radiotherapy (SBRT)
(122–125). Local control rates using this approach are encouraging and
significant toxicity is rare with careful attention to duodenal wall dose
constraints. SBRT has also been used as a boost after initial standard
fractionation (126). Given that pathologic nodal involvement is reported
in up to 76% of patients undergoing surgical resection (117,120),
elective treatment of regional lymphatics seems justified, unless directed
otherwise on an investigational trial. SBRT techniques in the setting of
pancreatic cancer are still best performed in the context of a clinical
trial.

The amount of small bowel receiving 45 Gy should be minimized
without compromising target coverage. Any small bowel within the
boost volume of treatment should be limited and not receive beyond 50
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Gy, though up to 55 Gy may be cautiously delivered to small portions of
the duodenum wall if clinically indicated. At least 75% of one kidney or
the composite of one whole kidney should be kept below 18 to 20 Gy. If
the large majority of one kidney will receive doses beyond 20 Gy,
consideration should be given to a quantitative renal scan prior to
treatment to ensure sufficient function of the other kidney. Our bias is
keep 60% of the liver below 30 Gy and the whole liver should not
receive >25 Gy. The spinal cord should not receive >45 Gy.
Radiotherapy Dose
The only data from randomized trials regarding radiotherapy dose in
pancreatic cancer is the GITSG trial for unresectable tumors. No
difference in patient outcome was detected between 40 and 60 Gy (split
course schedule with concurrent 5-FU) (112). The radiotherapy and
imaging techniques of this trial would be considered outdated by current
standards, and so current radiotherapy dose guidelines are based on
normal organ tolerance to upper abdominal radiation rather than the
results of this trial. Elective nodal stations (CTV) are treated to 45 Gy at
1.8 Gy/fraction. A subsequent boost of 5.4 Gy is delivered to the GTV or
CTV2 (postoperatively). Higher boost doses may be considered for
unresectable patients or those with positive margins when dose can be
delivered within the constraints of normal organs (especially small
bowel).

The pancreas is commonly treated with a four-field technique with
disproportionate weighting of the anterior and posterior fields to reduce
dose to the liver from the lateral fields (see Fig. 24.2). While maintaining
a 2- to 3-cm margin on the primary tumor (or tumor bed), traditional
fields typically encompass T11 superiorly through L3 inferiorly. The left
field edge is at least 2 cm from the left vertebral body edge (or past the
splenic hilum for pancreatic tail lesions). The right field border is
extended to cover the duodenum and porta hepatis. With the lateral
fields, the posterior border generally splits the vertebral bodies, while
the anterior border is placed at least 2 cm anterior to the tumor,
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maintaining a 3- to 4-cm margin anterior to the vertebral bodies to
ensure coverage of paraaortic lymph nodes. These boundaries should be
customized based on patient differences in target volumes as well as
normal structure location. Boost fields generally encompass unresected
tumor or original tumor bed with 1.5- to 2-cm margins.
Figure 24.2 A 62-year-old woman with a cT2N1 borderline resectable adenocarcinoma of the
pancreas treated with neoadjuvant chemoradiotherapy utilizing a four-field technique. AP (A) and
right lateral (B) views showing primary (yellow) and boost (red) fields with MLC blocks targeting
GTV (red), PTV_45 Gy (dark blue) and PTV_50.4 Gy (light blue). Sagittal (C), axial (D) and
coronal (E) dosimetry, with GTV (red) and 50.4 Gy (yellow), 45 Gy (dark blue), 40 Gy (cyan) and
15 Gy (light green) isodose lines.
With a 3D reconstruction of carefully defined CT-based target

volumes, field borders can be refined, which reflect individual tumor
and patient anatomy. A four-field technique is often still appropriate
with optimization of field weighting with computer dosimetry. To
account for setup error and target movement, a PTV margin of 1 cm
beyond the CTV is advised. If respiratory motion and image-guided setup
techniques are utilized, PTV margins as small as 5 mm can be
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considered. Given the movement of upper abdominal organs due to
respiration, greater margin in the superior to inferior dimension may be
prudent (127). Field edges are devised at an additional 5 to 10 mm
beyond the PTV to provide dosimetric coverage. The use of highly
conformal radiotherapy techniques should be used cautiously due to
substantial inter- and intrafraction variations in the pancreas position.
Study of pancreas movement by cine MRI has shown that changes in
pancreas position are larger and more variable than often appreciated,
especially in the craniocaudad dimension, and do not necessarily
correlate well with the diaphragm location (128). Similarly, image
guidance based on boney landmarks has been found to correlate with
accurate pancreas target setup in only 20% of treatments when
compared to tumor fiducial markers even when using respiratory gating
(129).
Radiation treatment using a traditional four-field technique remains
standard in the treatment of pancreatic cancer. 3D treatment planning
with four to six noncoplanar beams has been objectively compared to
traditional four-field techniques and may provide some dosimetric
advantages, particularly in sparing the kidneys (130). Alternative field
orientations may be considered for patients with dosimetric challenges
due to atypical target volumes or normal organs (e.g., one kidney). The
use of IMRT for pancreatic cancers may also provide some dosimetric
advantages by sparing kidneys, bowel, and liver (131–133) as well as
enabling possible dose escalation to the GTV (134). A few institutions
have reported patient outcomes after treatment with IMRT with
favorable tolerance and expected survival (131,135). Care must be taken
when employing this modality to account for target motion, avoid
dosimetric hot spots, and be certain the devised plan is clinically
superior to that which could be achieved with less advanced techniques.
Although there is no high-level evidence to date supporting the use of
SBRT, there are multiple single-institution experiences describing SBRT
techniques for the treatment of pancreatic cancer (122,123,125) in
addition to one prospective, multi-institutional Phase II study (136). Due
to variability in target volume delineation and limited experience with
SBRT for pancreatic cancer, prescription doses using SBRT have varied
widely. A recent phase II retrospective multi-institution experience
prescribed 6.6 Gy in five fractions with concurrent gemcitabine (124).
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SBRT planning typically consists of 4DCT simulation and consideration
of advanced respiratory motion management techniques such as
inspiratory/expiratory breathhold or abdominal compression to
minimize the size of target volume while accounting for organ motion.
Fiducial markers can be placed and utilized as part of image guided
radiation therapy (IGRT) to assist with treatment setup. Treatment
delivery with linear accelerator–based RT typically utilizes volumetric-
modulated arc therapy or IMRT with multiple noncoplanar beams to
maximize dose gradients and minimize high dose to nontarget normal
tissues in close proximity to the target.
Chemotherapy
Given the high rates of distant metastatic disease, systemic treatment
with chemotherapy is a critical component to the management of all
patients with pancreatic cancer. Recent studies have shown improved
survival with the use of newer, multi-drug regimens. Conroy et al.
showed improved survival among patients with good performance status
and metastatic pancreatic adenocarcinoma treated with oxaliplatin,
irinotecan, FU, and leucovorin (FOLFIRINOX) compared to gemcitabine
alone (137). Van Hoff et al., recently published a phase III randomized
study demonstrating improved 1- and 2-year survival rates among
patients with metastatic pancreatic adenocarcinoma treated with nab-
paclitaxel and gemcitabine compared to gemcitabine alone (138). The
role of these multi-drug regimens has not been as well established in
nonmetastatic patients, although retrospective series suggest these
agents may also be more active among patients with locally advanced
pancreatic cancer (139,140) and among those patients with borderline
resectable disease (141).
Chemotherapy has a long history of utilization as a radiosensitizer for
patients with pancreatic cancer. Among unresectable patients, a
randomized trial conducted by the GITSG established the superiority of
bolus 5-FU concurrent with radiotherapy over radiotherapy alone (113).
In current practice, continuous venous infusion 5-FU or oral capecitabine
are now more commonly utilized with RT although the data to support
this is extrapolated largely from randomized studies of patients treated
with combined modality therapy for rectal cancer (142,143).
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Gemcitabine has been studied concurrently with radiation both among
unresectable patients and in the postoperative setting with conflicting
data from small randomized studies regarding its efficacy compared to 5-
FU–based regimens (144,145). Toxicity with combined modality therapy
using gemcitabine is dependent on an inverse relationship between
gemcitabine schedule/dose and radiation field size/dose (146). Without
standardized parameters or large trials showing benefit over 5-FU–based
therapy and radiation, gemcitabine delivered concurrently with
radiation should be approached with caution.
Prognosis
The overall prognosis for patients with pancreatic cancer is poor.
Approximately 40% of patients have distant metastatic disease at
presentation and an additional 30% to 40% have locally advanced,
unresectable tumors. Only about 15% to 20% of patients with pancreatic
cancer have potentially resectable disease at diagnosis. The median
survival for patients presenting with metastatic disease treated with
modern chemotherapy techniques remains less than 1 year (137,138).
Among locally advanced, unresectable patients who receive
chemotherapy alone or combined modality therapy, median survival is
about 15 to 16 months (110). Long-term survival is not anticipated in
patients with inoperable tumors. For patients with resectable pancreatic
cancer, the median survival is 20 months, with a 5-year overall survival
rate of 8% to 20% (101). Innovative approaches are necessary to change
the natural progression of this disease before significant improvements
in outcomes can be made.
COLORECTAL CANCER
In 2015, an estimated 93,090 cancers of the colon and 39,610 cancers of
the rectum will be diagnosed in the United States (1). Radiotherapy
plays an important neoadjuvant or adjuvant role in the management of
rectal cancers, but is uncommonly indicated in the treatment of colon
cancer.
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Careful diagnostic evaluation is essential not only for accurate staging
and selection of patients for neoadjuvant strategies, but also to assist
appropriate target definition during treatment planning. During the
patient history, careful attention should be given not only to bowel-
related symptoms, but also to indicators of local tumor extension into
other pelvic structures (bladder/prostate or pelvic wall). The radiation
oncologist’s digital rectal examination should assess the distance of the
tumor from the anal verge, size and location, degree of circumferential
involvement, and palpable morphology. The mobility of palpable lesions
is described as mobile, tethered, or fixed, the latter implying initial
unresectability. Proximal rectal cancers that are not palpable are
referenced to the anal verge by endoscopy. Measurements from flexible
endoscopies should be relied upon with caution as they are notoriously
imprecise and inconsistent between examinations. Measurements from
rigid proctoscopy tend to be more reliable.
Pretreatment imaging is not only important to rule out distant
metastases, but also to determine patients who are candidates for
neoadjuvant radiotherapy. EUS or MRI has been reported superior to CT
in both determination of tumor depth of penetration (T stage) and
detection of perirectal adenopathy (147). High-resolution MRI may be of
particular benefit in predicting involvement of circumferential resection
margin (148,149). Pelvic CT or MRI is indicated for the evaluation of
pelvic lymphatic stations beyond perirectal lymph nodes. Among
patients with locally advanced disease, PET has detected liver metastases
in up to 8% of patients, which were not identified by other modalities
(150). PET without CT registration generally does not have sufficient
spatial resolution to determine depth of tumor penetration nor
consistently distinguish perirectal adenopathy from adjacent tumor.
TREATMENT OPTIONS
The use of adjuvant or neoadjuvant RT is generally reserved for patients
whose tumors penetrate the bowel wall (≥T3) or are node positive.
Among such patients, randomized trials clearly support the benefit of
adjuvant combined modality therapy (pelvic radiotherapy and 5-FU–
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based chemotherapy) in regard to both local control and overall survival
(151–153). The presence of node positivity, penetration of tumor
through the bowel wall and involvement of adjacent structures needs to
be determined by EUS or MRI in order to justify a neoadjuvant
approach. Two paradigms have emerged in the neoadjuvant treatment of
rectal cancer: a short course of hypofractionated RT and a long course of
CRT. The German Rectal Cancer Study Group found a significant
downstaging effect and higher rate of sphincter preservation with long-
course preoperative CRT (154). A significant improvement in local
control was seen with preoperative CRT versus similar postoperative
treatment (10-year local relapse rate of 7% vs. 10%, p = 0.048) (155).
Alternatively, Dutch investigators found that a short course of
preoperative hypofractionated RT improved local control compared to
patients undergoing total mesorectal excision (TME) alone (10-year LR
5% vs. 11%, p < 0.0001) (156). Two trials have directly compared
short- and long-course neoadjuvant RT. In the Polish trial, the long-
course CRT group was given bolus 5-FU (157). The more recent
Australian trial utilized a more contemporary dosing of continuous
infusion 5-FU in the CRT arm (158). Neither trial showed a significant
difference in clinical outcomes between treatment arms. While either
approach is acceptable in resectable disease, long-course CRT should be
administered in unresectable cases due to the known downstaging effect
of the treatment (159).
Adjuvant radiotherapy for patients with colon cancer is not routinely
indicated. Although retrospective series have shown favorable local
control outcomes with the use of adjuvant radiotherapy among patients
with T4 tumors and selected T3 tumors with positive lymph nodes
(160,161), this has not be corroborated in clinical trials. Among such
patients, Martenson et al. (162) reported the results of a randomized
trial investigating the use of adjuvant CRT. This study did not detect a
benefit to CRT for patient survival, however, this study was
underpowered for the primary endpoint. Preoperative treatment may be
considered in patients whose tumors are considered unresectable at
presentation.
TREATMENT PLANNING FOR RECTAL CANCERS
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Simulation
Proper patient positioning can significantly reduce the amount of small
bowel within the pelvis and limit toxicity from treatment. In addition to
decreasing the volume of bowel receiving maximal organ tolerance (45
to 50 Gy), reduction of bowel receiving doses as low as 5 Gy has been
associated with improved patient tolerance to pelvic radiation
(163–165). Maximal displacement of small bowel out of the pelvis is
achieved with prone positioning and bladder distension. Without the use
of a belly-board or lower abdominal wall compression, however, ∼25%
of patients will have more small bowel in the pelvis with supine
positioning (166). Multiple studies have documented significant
reduction in pelvic small bowel volume with use of a belly-board device
(167–169) or lower abdominal wall compression (166). Bladder
distension may actually contribute more to bowel displacement than a
belly-board, but the effect of each method appears additive (170) and
concurrent use of both techniques should be considered. Efforts displace
bowel from the pelvis may be less reproducible and associated with
variation in patient setup, which should be accounted for when
employing highly conformal radiation techniques.
Simulation in the prone position enables verification of lower and
middle rectal lesion location in relationship to the anal verge based on
findings on digital examination. The anal verge should be marked with a
radiopaque marker and rectal contrast may be instilled into the rectum
to assist radiographic identification of the primary lesion. Taping the
buttocks laterally may reduce their self-bolusing effect on the perianal
skin during treatment. Patients who have undergone abdominoperineal
resection (APR) must have the perineal scar marked and included in the
initial pelvic fields, with appropriate bolus utilized posteriorly if
exposed. Perineal recurrence has been described in 8% to 30% of
patients in the absence of adjuvant RT (171–173), but as low as 2%
when the scar is adequately treated (174). CT-based planning has
replaced conventional fluoroscopic imaging as the preferred simulation
technique.
Radiotherapy Target
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For patients treated preoperatively, the GTV includes the primary tumor
and any radiographically enlarged lymph nodes. All clinical, endoscopic,
and imaging information must be used to define the maximal extent of
the rectal tumor. Relying solely on one modality risks underestimation of
the tumor extent and inaccurate field design (especially within boost
portals). Although not mandatory in treatment planning, the addition of
PET to CT in GTV contouring has been shown to increase the target size
by an average of 25% (175) and lead to a change in treatment fields in
17% of patients (176). Soft tissue extension or suspected infiltration of
rectal tumors into adjacent mesorectal fat should be included within the
GTV, particularly posteriorly.
The CTV encompasses all the perirectal tissue/mesorectum, presacral
space, and lymphatics of the internal iliac chain (which are not
commonly dissected at the time of surgery). A report of 269 cases of
rectal cancer that recurred in the pelvis after surgery alone emphasized
the predilection for rectal cancer recurrence in the posterior pelvis,
specifically the presacral space. Among patients undergoing anterior
resection, 93% recurred at or posterior to the colorectal anastomosis
(177). Other studies of rectal cancer failure patterns have shown
infrequent recurrence above the S1–S2 interspace, lateral pelvic nodes,
or in the anal sphincter (178,179).
Accurate contouring of the pelvic CTV involves more than simply
identifying the internal iliac vessels. A study comparing locations of
external and common pelvic lymphatics (by lymphangiography) to
vessel location revealed that lymph nodes are not directly
superimposable upon vasculature (180). Myerson and Drzymala (181)
and Roels et al. (182) provide a review of CT-based treatment planning
for rectal cancer. In the upper pelvis, the CTV should extend cephalad to
include the sacral promontory, posteriorly to include the anterior wall of
the sacrum, and laterally it should encompass vasculature and presacral
soft tissue to the border of the iliopsoas muscles. In the mid-pelvis, the
CTV includes similar tissues with care taken to include perirectal fat
anterior to the rectum. In addition, 1 to 2 cm of posterior bladder or
uterus may be included if at risk of subclinical extension of disease for
patients who have adjacent, locally advanced lesions. In the lower
pelvis, the CTV includes all the perirectal fat inferiorly and laterally
extending to the levator ani muscles. It should extend to the posterior
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wall of the prostate or vagina as well. A larger margin of anterior pelvic
organs is indicated for tumors with documented invasion (T4). The
inclusion of the external iliac lymph nodes is generally reserved for
patients with T4 tumors, which extend into anterior organs of the pelvis
(prostate, bladder, vagina, and cervix/uterus) for whom these nodes are
at risk. This modification is supported by failure patterns (177) from
patients treated with surgery alone. However, in a series of patients with
T4 rectal cancers where external iliac lymph nodes were not routinely
included within RT portals, regional recurrence of disease still occurred
almost exclusively within the radiotherapy field (183).
The CTV should also include a minimum of 2 cm of normal rectum
cephalad and caudad to the primary tumor. A subsequent PTV expansion
of at least 1 cm (without IGRT) around the CTV will provide a minimum
4-cm longitudinal margin from GTV to block edge (assuming an
additional 0.5- to 1-cm margin beyond PTV to block edge for dosimetric
buildup). With the use of daily image guidance, smaller CTV to PTV
margins may be utilized. Given the distensibility of the rectum, more
PTV margin may be indicated anteriorly, especially for anterior wall
tumors of the mid- and upper rectum. Bladder, small bowel, and femoral
heads should also be contoured for evaluation of normal tissue tolerance.
Tumors of the lower rectum, which extend to the dentate line of the
anal canal, have a theoretical risk of failure in the inguinal lymph nodes.
A report of 184 patients with such lesions revealed only six groin failures
(5-year actuarial rate of 4%) without elective radiotherapy to the
inguinal lymph nodes (184). Thus, for patients with low-lying rectal
cancers, careful attention should be given to the groins during initial
staging, but the added toxicity of treatment does not seem justified if the
inguinal nodes are clinically negative.
In the postoperative setting, treatment volumes are similar except that
with the removal of the primary lesion, the entire preoperative tumor
bed must be reconstructed and included within the CTV (often identified
separately as a boost volume—CTV2). Review of preoperative imaging,
operative reports, and surgical clip placement is imperative. As
mentioned above, the perineal scar must be included in the initial fields
for patients who have undergone APR.
To account for internal target motion and patient setup variability, a
PTV is delineated beyond the CTV. In the absence of IGRT, a PTV margin
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of at least 1 cm is appropriate. However, a retrospective study of
interfraction variability has shown that patient setup without IGRT can
easily approach these margins, especially among patients with a large
body mass index treated in the prone position (185). Intrafraction
movement of the mesorectum has also been evaluated and found on
average to move <4 mm in various dimensions, but significant
individual variability is observed (186).

The amount of small bowel receiving 45 Gy should be minimized
without compromising target coverage. Any small bowel within the
boost volume of treatment should be limited and not receive beyond 50
Gy. In addition to maximum dose, acute intestinal side effects from
pelvic radiotherapy have been found to correlate with volume of bowel
receiving all dose levels to as low as 5 Gy (164,165). Thus, bowel
exposure at any dose should be minimized. The femoral heads and necks
should receive <45 to 50 Gy (187), and preferably <40 Gy. Blocking in
the lateral fields excludes the anterior genitalia in addition to small
bowel and bladder.
Radiotherapy Dose
There is very little data in the literature regarding the optimal
radiotherapy dose in the treatment of rectal cancer. One retrospective
study supporting current dosing guidelines is from Brizel and
Teppererman (188) who observed superior local control with adjuvant
radiotherapy doses ≥45 Gy compared to patients who received lower
doses. Forty-five Gray, given in 1.8-Gy fractions, is the currently
accepted dose and fractionation for initial pelvic fields in the adjuvant
setting based on its repeated use in clinic trial designs (153,189). After
the initial 45 Gy, a boost of 5.4 to 9 Gy is generally given to the tumor
bed and adjacent lymphatics (CTV2). In the neoadjuvant setting, the
radiotherapy dose depends on the use of short- or long-course radiation
therapy. In the former approach, five daily 5-Gy fractions are
administered to a single volume for a total cumulative dose of 25 Gy
(190). Long-course CRT doses are similar to those used in the adjuvant
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setting, typically 45 Gy with a 5.4-Gy boost to the GTV (158,191) or
treatment of the entire volume to 50.4 Gy (154). In any case, careful
attention should be made to minimize small bowel within the field.
Treating beyond a cumulative dose of 50 Gy should only be considered
when small bowel can be completely excluded from the high-dose region
of treatment.
Figure 24.3 A 41-year-old woman with a cT3N+ adenocarcinoma of the distal rectum treated with
a three-field technique. Beam’s eye view of PA (A) and lateral (B) fields. Note the GTV (red) and
CTV (orange) including mesorectum and rectal contrast. Axial view (C) showing field arrangement
and dosimetry (red and light green lines denote the 98% and 95% isodose lines, respectively).
Prescription dose was 4,500 cGy in daily 180-cGy fractions.

Patients are commonly treated with a three-field technique consisting of
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a PA and laterals (see Fig. 24.3). When inclusion of the anterior pelvis is
indicated (e.g., treatment of the external iliac lymph nodes or larger
habitus patients), an additional AP field may be advantageous to
improve dose homogeneity. High-energy photons and appropriate beam
wedging and weighting are mandatory to ensure a homogeneous dose
distribution within the pelvis.
Traditional field design has been based on boney landmarks, the
location of contrast-enhanced bowel/rectum and the anal verge. The
superior border of the PA (and AP) fields generally covers the sacral
promontory while the inferior border is placed at least 3 to 4 cm distal
to the rectal cancer. For upper rectal cancers, the distal border need not
include the entire anal canal, but should extend to approximately the
level of the dentate line (about 2 to 3 cm from the anal verge) so that all
the mesorectum is encompassed. The lateral borders of the PA field
should include 1.5- to 2-cm margin beyond the pelvic brim, with
appropriate blocking of almost all of the femoral head. Lateral fields
should cover the anterior bony margin of sacrum with 1.5- to 2-cm
margin posteriorly to allow for setup error and dosimetric coverage.
Anteriorly, the field includes the internal iliac lymph nodes by placing
its border at approximately the posterior edge of pubic symphysis. Care
is taken, however, when devising this border to ensure at least 3-cm
coverage of the primary tumor anteriorly. In the superior–anterior
portion of the field, it is usually possible to block a portion of small
bowel. Similarly, the anterior genitalia in most patients should be
blocked in the lateral fields. Custom boost fields are devised that include
the GTV (or tumor bed) with a 2- to 3-cm margin. A three-field
technique or laterals alone will often suffice.
While traditional field orientations (PA and laterals) are usually
adequate for three-dimensional reconstructed targets, they do not fully
account for the variability inherent in individual patient anatomy. In
addition, more conformal techniques including IMRT require delineation
of a CTV in 3D. Consensus guidelines have been reported to assist in
contouring these volumes (192). The caudad extent of the CTV should be
a minimum of 2-cm caudad to gross disease, including the entire
mesorectum to the pelvic floor. The lateral CTV should include the
mesorectum and only a few millimeters of the levator muscles unless
radiographically involved. Involvement of adjacent organs and/or pelvic
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sidewall requires a more generous margin (1 to 2 cm). In the mid-pelvis,
the CTV extends to the pelvic sidewall and musculature posterolaterally.
Anteriorly, the posterior 1 cm of the bladder is included to account for
variation in bladder position (193). The superior extent of the rectal CTV
is a minimum of 2-cm cephalad to gross disease, including the
rectosigmoid junction. A minimum 7- to 8-mm margin around the
internal iliac vessels is included up to the common iliac bifurcation
including at least 1 cm anterior to the sacrum. CTV expansion to create a
PTV depends on treatment technique and the use of IGRT. The PTV
margin should be 0.7 to 1 cm when using IMRT with IGRT. Conventional
field borders are generally expanded another 5 to 10 mm in order to
achieve sufficient dosimetric target coverage.
Possible benefits of treatment of rectal cancer with IMRT include dose
escalation to the GTV and construction of a concave dose distribution
that reduces small bowel dose, in addition to bladder and bone marrow.
Dosimetric studies comparing IMRT to traditional techniques in rectal
cancer have shown clinically significant reductions in dose to bowel
(194–196) as well as bladder, pelvic bones, and femoral heads while also
achieving superior target coverage, homogeneity, and conformality
(197). The successful implementation of IMRT in the management of
rectal cancer has been reported from multiple institutions, generally
with dose escalation to the GTV with favorable outcomes (198–200). A
retrospective review of 92 patients treated at the Mayo Clinic in Arizona
demonstrated a 32% incidence of ≥grade 2 gastrointestinal toxicity
among patients treated with IMRT compared to 62% (p = 0.006) among
patients treated with conventional fields during the same era (201). In
view of the challenges of internal movement, distensibility of pelvic
organs (rectum, bowel, and bladder) as well as the dose inhomogeneity
produced by some treatment planning systems, caution should be used
before undertaking IMRT in rectal cancer.
Chemotherapy
Adjuvant or neoadjuvant radiotherapy has traditionally been delivered
with concurrent 5-FU. In the postoperative setting, protracted venous
infusion (PVI) of 5-FU (225 mg/m2/d) throughout the course of pelvic
radiotherapy has been shown to decrease tumor recurrence and improve
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overall survival compared to the administration of bolus 5-FU (189),
although not confirmed in a subsequent trial (202). Despite this,
continuous infusion 5-FU became the standard in subsequent
neoadjuvant trials (154). More contemporary studies have found the use
of capecitabine, an orally administered premetabolite of 5-FU, is at least
equivalent if not superior to PVI 5-FU in conjunction with pelvic
radiation for rectal cancer (203,204). Multiple studies have attempted to
integrate additional chemotherapeutics, namely oxaliplatin, into the
neoadjuvant and adjuvant fluoropyrimidine backbone. The majority of
these studies found no improvement in clinical outcome at the expense
of added toxicity (204–206).
Treatment Planning for Colon Cancer

Patients treated with radiotherapy for colon cancer are treated with the
same chemotherapeutic and radiation principles as rectal cancer.
Decubitus positioning at simulation and during treatment may reduce
the amount of small bowel in the treatment field. The initial CTV
generally includes the tumor bed and adjacent pelvic/retroperitoneal
lymphatics, with a subsequent boost to the tumor bed (or tumor
preoperatively). Review of preoperative imaging, operative reports, and
identification of surgical clips demarcating the tumor bed are essential in
order to define targets and design fields that may impact local control
and the prognosis of this disease.
Prognosis
The incidence and mortality of colorectal cancer in the United States has
been declining in recent years, most likely as a result of screening
practices (1). Based on the Dutch TME results, 10-year overall survival
for TNM stages I, II, and III patients are ∼70%, 55%, and 40%,
respectively (156). The inclusion criteria for the German rectal cancer
study more closely approximates those patients eligible for neoadjuvant
CRT (cT3–4 and/or N+; TNM stages II to III), where 10-year overall
survival was ∼60% (155).
ANAL CANCER
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In 2015, there will be an estimated 7,270 new cases and approximately
1,010 deaths from anal cancer in the United States (1). Historically, APR
was the standard of care in the management of anal cancer (207,208).
Although this procedure resulted in cure for many patients, there were
significant drawbacks including permanent colostomy and high rates of
morbidity and mortality. In 1974, Nigro et al. introduced chemotherapy
and radiation as a novel treatment approach in the management of anal
cancer (209). Since Nigro’s publications, phase III randomized trials have
examined different strategies of chemotherapy and radiation
administration (210–215). Given the favorable results of definitive
chemoradiation, a sphincter-preserving approach is the standard of care
for this disease.
Patients who are being considered for RT and chemotherapy should
undergo a complete history and physical examination. Risk factors for
HIV infection should be reviewed, with a low threshold for ordering
laboratory testing. Careful review of gastrointestinal and genitourinary
symptoms may indicate extension of tumor beyond what is clinically or
radiographically detected. It is necessary to perform a thorough clinical
evaluation of inguinal lymph nodes, digital rectal examination, and
proctoscopy to determine tumor extent. Thorough examination of the
perianal skin is imperative for accurate treatment planning as it often
reveals disease beyond what is visible on imaging studies alone. When
patients have severe anal discomfort that inhibits adequate examination,
such examinations should be scheduled under anesthesia. In females, a
pelvic examination to rule out vaginal extension is indicated as well as
identification of synchronous gynecologic cancers (HPV related).
Axial CT imaging of the chest, abdomen, and pelvis is critical for
appropriate staging. Anal cancer most commonly spreads by local and
lymphatic invasion, however, in about 13% of cases distant metastases
are present at initial presentation (216). Distant metastases are most
commonly seen in the liver and lungs (217). An alternative to CT or MRI
is PET/CT, which can be useful for assessing disease extent and often
assists in treatment planning. Multiple, small studies have shown that
PET/CT alters staging in about 20% of patients compared to
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conventional imaging due to improved sensitivity in detection of
primary tumor, involved regional lymph nodes, and distant metastases
(218–222). Winton et al. reported that initial diagnostic PET/CT altered
design of radiation treatment fields in 8 of 61 (13%) of patients with
anal cancer (218). Similarly, a series of 50 patients from Australia
reported 19% of cases underwent treatment planning revision based on
pelvic or nodal inguinal involvement on PET/CT (221). All patients
should have a biopsy to confirm invasive malignancy at the primary site.
In patients with suspicious inguinal adenopathy, biopsy may be
performed to clarify the diagnosis as it can alter radiation treatment
volumes and doses.
TREATMENT OPTIONS
Patients with anal carcinoma in situ (anal intraepithelial neoplasia or
AIN) and tumors of the perianal skin (which do not extend to the anal
verge), should initially be considered for local excision in selected cases.
When these lesions cannot be excised adequately without significantly
compromising anal function, definitive RT alone or chemoradiation is an
efficacious option. Patients with invasive carcinoma of the anal canal
should generally be treated with definitive CRT. The addition of
mitomycin-C and 5-FU to radiotherapy has been shown to improve local
control and colostomy-free and disease-free survival (210–212). Multiple
subsequent phase III randomized trials have examined different
strategies of chemotherapy administration including use of cisplatin in
place of mitomycin-C (213–215). Despite these efforts, mitomycin-C and
5-FU with concurrent radiotherapy remains the standard treatment for
patients with anal cancer. APR is usually reserved as salvage treatment
for patients with persistent or recurrent disease after radiotherapy. It
should be noted that there can be significant delays in tumor regression
after CRT and a recent randomized study of chemoradiation for anal
cancer indicates that tumor regression can occur up to at least 26 weeks
after completion of therapy (214). Therefore, in the absence of
progression, a decision to proceed with APR for persistent disease should
usually be delayed until at least 6 months and perhaps up to 1 year after
completion of therapy in selected circumstances.
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TREATMENT PLANNING
Simulation
After clinical and radiographic staging, CT-based simulation is
performed for radiation treatment planning. If available, PET/CT at the
time of simulation may be helpful to define local and regional target
structures. Patients can be simulated in the supine or prone position and
there are benefits to each approach in the appropriate clinical setting.
Prone setup with a false tabletop allows for improved small bowel
avoidance and may be useful in individuals with a large pannus and
pelvic node involvement. Supine setup is usually more reproducible,
potentially allowing for reduced PTV margins and smaller treatment
fields. Typically for IMRT patients should be simulated in the supine
position with legs slightly abducted (frog-legged) with semi-rigid
immobilization in vacuum-locked bag or alpha-cradle. Patients are
instructed to maintain a full bladder for simulation and treatment to
decrease the amount of small bowel within the pelvis. In males, the
external genitalia are typically positioned inferiorly such that setup is
reproducible. In females, a vaginal dilator can be placed to help
delineate the genitalia and displace the vulva, vagina, and urethra away
from the primary tumor. A radiopaque marker should be placed at the
anal verge. The clinical extent of any visible or palpable perianal tumor
should be demarcated with radiopaque catheters as it may not be
apparent on simulation imaging. It may be helpful to place a catheter
with rectal contrast in the anal canal at the time of simulation for tumor
delineation. In patients with adequate renal function, IV contrast
facilitates identification of the pelvic and groin vasculature (which
approximates at-risk nodal regions). Oral contrast identifies small bowel
as an avoidance structure during treatment planning. For tumors
involving the perianal skin or superficial inguinal nodes, bolus should be
placed as necessary for adequate dosing of gross disease in these areas.
Routine use of bolus may not be necessary as the tangential effect of
IMRT may minimize skin sparing. In situations where adequate dosing of
superficial targets is uncertain, in vivo diode dosimetry with the first
treatment fraction can ensure appropriate dose at the skin surface.
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Radiotherapy Target
Target volume definition should be performed per ICRU 50
recommendations (223). GTV should include all primary tumor and
involved lymph nodes, utilizing information from physical examination,
endoscopic findings, diagnostic imaging, and simulation planning study
for delineation. CTV should include the GTV plus areas at risk for
microscopic spread from the primary tumor and at-risk nodal areas. If
the primary tumor cannot be determined with available information
(such as after local excision), the anal canal may be used as a surrogate
target. Ortholan et al. (224) published a study of 181 patients with anal
cancer without inguinal nodal involvement at presentation. Seventy-five
patients received elective inguinal irradiation compared to 106 patients
who did not receive elective inguinal irradiation. With a median follow-
up of 61 months, rates of inguinal recurrence were 2% in patients
receiving inguinal irradiation compared to 16% in patients without
inguinal irradiation. Given these recurrence rates, pelvic and inguinal
nodes should be routinely treated in most patients. At-risk nodal regions
include the mesorectum, presacral, internal and external iliac, and
inguinal nodes (225). The presacral nodal volume is typically defined as
an approximately 1-cm strip over the anterior sacral prominence. To
contour the internal and external iliac nodes, our practice generally is to
contour the iliac arteries and veins with approximately 0.7-cm margin (1
to 1.5 cm anteriorly on external iliac vessels) to include adjacent lymph
nodes. In order to include the obturator lymph nodes, external and
internal iliac volume contours should be joined parallel to the pelvic
sidewall. The inguinal node volume extends beyond the external iliac
contour along the femoral artery from approximately the upper edge of
the superior pubic rami to approximately 2-cm caudad to
saphenous/femoral artery junction. The medial and lateral borders may
be defined by adductor longus and sartorius muscles, respectively.
Several recently published atlases are helpful to review when defining
elective nodal CTVs (226–228). The above descriptions are
generalizations and target volume should be individual based on the
anatomy of each patient and tumor distribution.
When using IMRT, a separate CTV volume for each planned treatment
dose tier is contoured. Our approach has been to define three tiers: a
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gross disease volume, a high-risk elective nodal volume (including gross
disease), and a low-risk elective nodal volume (including gross disease
and high-risk elective nodal volume) (229,230). Alternatively, a gross
disease volume with a single elective nodal volume can be used to
deliver the prescribed course (231–238).
In defining the gross disease CTV around the primary tumor,
approximately 2.5-cm of margin the around GTV should be used with
manual editing to avoid muscle or bone at low risk for tumor
infiltration. To define the gross disease CTV around involved nodes, a 1-
cm expansion should be made beyond the contoured involved lymph
node(s) with manual editing to exclude areas at low risk for tumor
infiltration. In addition, the entire mesorectum is included within the
volume defined as gross disease CTV for the purposes of treatment
planning. The mesorectal volume encompasses the rectum and
surrounding lymphatic tissue.
The high-risk elective nodal volume typically includes the gross
disease CTV including the entire mesorectum, presacral nodes, and
bilateral internal and external iliac lymph nodes inferior to the sacroiliac
joint as per conventional field definitions utilized in RTOG 98–11 (213).
In patients with gross inguinal nodal involvement, the bilateral or
unilateral inguinal nodes may be included in the high-risk elective nodal
volume.
The low-risk elective nodal volume should include the gross disease
CTV, high-risk elective nodal CTV as well as presacral, bilateral internal,
and external iliac nodes above the inferior border of the sacroiliac joint
to the bifurcation of the internal and external iliac vessels at
approximately L5/S1 vertebral body junction. If there is no obvious
involvement of the bilateral inguinal nodes, these are only included in
the low-risk elective nodal volume.
The PTVs should account for effects of organ and patient movement
and inaccuracies in beam and patient setup. PTV expansions should
typically be about 0.5 to 1.0 cm from CTV depending on use of image
guidance and physician practice with treatment setup for each defined
CTV. To account for differences in bladder and rectal filling, a more
generous CTV to PTV margin is applied in these regions. Future
development of real-time adaptive RT will potentially reduce this
margin. When using IMRT, especially with small PTV margins, use of
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daily image guidance with kV orthogonal imaging to ensure excellent
alignment of the bony anatomy is recommended. In addition, cone-beam
CT should be performed prior to the first treatment and periodically to
ensure target soft tissue volumes remain within the appropriate PTV and
ensure bladder filling is relatively stable.

It is important to accurately define organs at risk (OARs) so that dose to
these structures can be minimized during treatment. With IMRT, dose to
small bowel, bladder, pelvic/femoral bones, and external genitalia can
be sculpted and minimized despite close proximity of these organs to
target volumes. When contouring these structures, it is typically best to
demarcate normal tissues on axial CT at least 2 cm above and below the
PTV. Contouring atlases offer excellent guidance on defining OAR
(226,227). Once the OARs have been identified, the chief aim of IMRT
planning is to limit the dose to these structures without compromising
PTV coverage. The extent to which OARs can be avoided largely depends
on the location and extent of tumor involvement at presentation as well
as the extent to which the bowel extends into the lower pelvis and a
given individual’s anatomy.
While there is significant variability in how to contour the small
bowel, one approach entails contouring the entire volume of peritoneal
space in which the small bowel can move. Oral contrast is helpful to
delineate small bowel. The amount of small bowel treated to >45 Gy
should be minimized. Although this is generally achievable due to the
inferior location of the boost target volume, large volumes of bowel
receiving even moderate doses of radiation (as low as 15 to 30 Gy)
contribute to acute toxicity and should be minimized when possible.
Devisetty et al. published a multi-institution, dosimetric analysis which
found that limiting the volume of bowel receiving 30 Gy (V30 Gy) to less
than 450 cc significantly reduced acute GI toxicity (8% vs. 33%) (239).
DeFoe et al. have published retrospective data correlating lower rates of
acute GI toxicity with V30 Gy less than 310 cc and V40 Gy less than 70
cc (240). Emami et al. estimate a dose of 50 Gy to one-third of the small
bowel is associated with 5% likelihood of obstruction or perforation at 5
years (241). To minimize late small bowel toxicity, the Quantitative
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Analysis of Normal Tissue Effects in the Clinic (QUANTEC) analysis
reviewed available clinical data for small bowel dose and recommends
minimizing volume receiving greater than 45 Gy to less than 195 cc
when contouring the entire potential peritoneal space (242).
There are limited clinical data correlating bladder dose-volume
relationships with increased GU toxicity in anal cancer. Extrapolating
from other cancer treatment sites, normal tissue complication probability
models suggest that the risk of serious GU complications with bladder
doses below 65 Gy is low (243). The risk of clinical complications
appears to increase with larger volumes of bladder receiving high dose.
Marks et al. estimate that limiting 50% of the bladder to less than 40–50
Gy will limit complications to less than 5–10% (based on cervical cancer
clinical literature) (244). Despite limited available data for anal cancer,
many patients experience acute grade 1–2 GU toxicity during RT and
limiting dose to the bladder, without compromising PTV coverage, may
help minimize these symptoms further.
Reduction in radiation dose to the proximal femoral and pelvic bones
is also important. A retrospective cohort study using Surveillance,
Epidemiology, and End Results (SEER) cancer registry data linked to
Medicare claims reported that in women treated for anal cancer, the
cumulative 5-year pelvic fracture rate was 14.0% among women
receiving radiation treatment versus 7.5% among women who did not
receive RT (245). There is limited empirical data on dose–response
relationships for femoral neck complications. Emami et al. reported a
tolerance dose of 52 Gy to the entire femoral neck to limit the risk of
complication to less than 5% (241). Bedford et al. have recommended
limiting the volume of femoral neck receiving 52 Gy to less than 10%
(246). The femoral heads and necks should receive <45 to 50 Gy (187),
and preferably <40 Gy.
Studies indicate that sexual dysfunction is a late effect of RT for anal
cancer with significant impact on quality of life (247,248). Pelvic
radiotherapy has been associated with high rates of impotence, sterility
in young men, as well as dyspareunia, vaginal bleeding, and vaginal
dryness in women. Limited data on dose–response relationships between
late sexual toxicity and genitalia dose are available. As with other pelvic
OARs where data are limited, it is advisable to minimize genitalia dose
without compromising PTV coverage.
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The perianal skin develops significant moist desquamation as a result
of combined modality therapy. Dosimetric hot spots in this region should
generally be avoided. Prolongation of overall treatment due to treatment
breaks for skin toxicity time have been associated with a detriment in
local control (249,250). In the absence of infection, treatment breaks for
skin toxicity should be avoided by instituting early, aggressive
supportive measures.
Given patient variation with respect to OAR position and areas of
tumor involvement, practical dose constraint guidelines are challenging.
In tumors without gross nodal involvement it is often possible to limit
OAR doses even further. Alternatively, in tumors with gross nodal
involvement within the pelvis, compromise of PTV coverage may be
necessary to limit doses to the small bowel. Normal tissue dose
constraints from RTOG 05–29 are a reasonable guide to assist with IMRT
treatment planning (232).
Radiotherapy Dose
The appropriate dose for elective nodal sites has not been well defined.
In RTOG 87–04, 30.6 Gy in 1.8-Gy fractions was delivered to initial
pelvic fields with the superior border placed at the L4–L5 interspace
(212). Subsequently, the superior field borders were reduced to the
bottom of the sacroiliac joints, and the pelvis and inguinal nodes
continued treatment to 36 Gy. Finally, 10- × 10-cm fields which
included the primary tumor and lowermost pelvis were treated to
cumulative doses of 45 to 50.4 Gy. In RTOG 98–11, the initial pelvic
fields were treated to 30.6 Gy with the superior border placed at L5–S1
(213). Reducing the superior border to the bottom of the sacroiliac
joints, the lower pelvis was treated to 45 Gy. The inguinal lymph nodes
electively received 36 Gy. In the ACT II study, all patients received a
dose of 30.6 Gy in 1.8-Gy fractions to the pelvis and inguinal nodes with
the superior border placed at least 3 cm above the SI joints (214). A
second volume including the gross primary tumor plus 3-cm margin was
prescribed an additional 19.8 Gy for a total dose of 50.4 Gy. Among
patients with macroscopic nodal involvement on CT, all gross disease
plus margin was prescribed 50.4 Gy.
RTOG 05–29 is the first phase II prospective study utilizing IMRT for
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the treatment of anal cancer (232). The prescription parameters
designate a single elective nodal volume inclusive of mesorectum,
presacrum, bilateral internal and external iliac, and bilateral inguinal
regions as outlined in the RTOG atlas (228). A simultaneous integrated
boost (SIB) plan was utilized to treat the elective nodal volume plus
areas of gross tumor and nodal involvement with slightly different dose
prescriptions depending on tumor stage and nodal volume. T2N0 tumors
received 42 Gy elective nodal and 50.4 Gy to the anal tumor in 28
fractions. T3–4N0–3 tumors received 45 Gy elective nodal and 50.4 Gy
for involved nodes <3 cm, 54 Gy for involved nodes >3 cm and 54 Gy
to the anal tumor in 30 fractions.
Although successive pelvic field reductions probably address the
gradient of risk for micrometastatic disease within lymph nodes,
retrospective series suggest that doses as low as 30 Gy with concurrent
chemotherapy may be sufficient to achieve control of subclinical disease
within nodes or at the primary site after excisional biopsy of small
lesions (251–253). The SIB approach offers the convenience of
developing a single treatment plan with reduced planning complexity,
albeit with a lower biologic dose delivered to the elective nodal areas.
Utilization of SIB dose painting implements 1.5 Gy per fraction to the
elective nodal region, and such doses are not well studied. When
concurrently treating multiple targets at different doses per fraction (i.e.,
IMRT), higher total doses may be indicated for regions receiving <1.8
Gy/d (232). Only small primary tumors that have completely responded
to radiation should be treated to 45 to 50.4 Gy. Larger tumors (T3/T4)
and incompletely responding tumors should receive at least 50.4 to 54
Gy. Multiple retrospective series have reported superior local control
rates in this dose range compared to lower doses (251,254,255).

The treatment of patients with anal cancer can be technically
challenging given the complex geometric distribution of targets,
particularly the inguinal nodes, in relationship to normal pelvic
structures. By reducing radiation to normal structures, IMRT minimizes
toxicities and treatment interruptions. Institutional experiences
(229,230,233–238,256) and a single phase II, multi-institutional
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prospective study (232) have shown the feasibility of IMRT with
improvements in acute toxicity compared to historical studies. Although
no direct comparison of IMRT to conventional radiotherapy planning has
been performed, utilization of IMRT is recommended to minimize
treatment toxicity and associated treatment breaks. Due to the high
precision of IMRT, planning and delivery of RT require a thorough
understanding of the local and regional progression patterns to define
PTVs and surrounding normal organs. A knowledgeable treatment
planning team is required to optimally utilize IMRT planning algorithms,
ensuring homogeneous dose to target areas while reducing dose to
normal tissues (see Fig. 24.4).
If IMRT planning is not available, alternative approaches utilizing
treatment field design based on bony anatomy may be feasible. A wide
AP photon field, which includes the inguinal lymph nodes, is simulated
with a narrow PA field that excludes the femoral neck (may include a
small portion of the medial femoral head for margin on the obturator
nodes). Due to divergence, it is sometimes possible to match the lateral
exit of the narrow PA beam with the surface entrance of the wide AP
photon beam and provide sufficient dosimetric coverage of the groins
(257). More commonly, however, supplemental anterior electrons are
indicated. The lateral exit of the narrow PA field is marked anteriorly on
the patient’s groins (done at time of fluoroscopic simulation). This serves
as the medial border for each electron supplement. The lateral border of
each electron supplement is placed at or 1 cm lateral (due to beam
constriction) to the surface entrance of the wide anterior photon beam.
Particular attention must be made during treatment to any shifts made
with the PA field to ensure similar movement in the anterior electron
field junctions. Radiopaque wire placed on these junctions may assist
proper setup when porting the PA field. To reduce the complexities
associated with electron groin setups, photons have also been used to
supplement the lateral inguinal lymph nodes using the same AP photon
field and setup. This can be achieved with multileaf collimation
(258,259).
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Figure 24.4 A 60-year-old male patient with T2N2 squamous cell carcinoma of the anal canal.
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Diagnostic CT (A) and with PET (B) indicate abnormal FDG avidity in left inguinal lymph node and
anal canal. Sequential nine-field IMRT treatment plans were delivered. Axial (C, D, E), coronal (F,
G) and sagittal (H) dosimetry, with GTV (red) and 54 Gy (green), 45 Gy (magenta), 30.6 Gy (cyan)
isodose lines.
For patients treated with conventional radiotherapy techniques, gross

tumor should be boosted with reduced fields encompassing primary
tumor and involved nodes with a 2- to 3-cm margin to the field edge.
When possible, a composite representation of dose between the initial
and boost treatments should be created to ensure normal organ tolerance
is not exceeded during the boost phase of treatment. A variety of beam
arrangements may be used. Separate boost fields for involved inguinal
lymph nodes are usually necessary, but care should be taken not to
concurrently overlap any tissues irradiated by the boost treatment to the
anus.
Chemotherapy
Careful coordination of the timing of concurrent chemotherapy with the
delivery of radiation is important for successful treatment of anal cancer.
The addition of mitomycin-C (10 mg/m2 on days 1 and 29 of
radiotherapy) to 5-FU (1 g/m2/d for 96 hours on days 1 to 4 and 29 to
32 of radiotherapy) was established as the standard of care by the results
of RTOG 87–04 (212), which compared both drugs to concurrent 5-FU
alone. With this approach, treatment should generally begin on a
Monday or Tuesday so that radiotherapy may be given on each day of
chemotherapy delivery (4 days of 5-FU). As an alternative to mitomycin-
C, multiple institutions have reported excellent results with cisplatin and
5-FU concurrent with radiation (260,261). The recently reported ACT II
study reports similar outcomes in their randomized comparison of
cisplatin + 5-FU versus mitomycin-C + 5-FU with concurrent
radiotherapy (214). However, in RTOG 98–11, cisplatin and 5-FU, given
as induction therapy and concurrent with RT, has been shown to be
inferior to RT concurrent with mitomycin-C and 5-FU with a reported
overall survival detriment reported after 10 years of follow-up (262).
Prognosis
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The outcome of patients treated with combined modality therapy is well
described from the results of randomized trials. More recent series
utilizing combined modality therapy with mitomycin-C, 5-FU, and
radiotherapy indicate that outcome is somewhat dependent on the
clinical stage. ACT II, the largest recent randomized controlled trial of
940 patients, reports 5-year progression-free survival, colostomy-free,
and overall survival rates of 69%, 68%, and 79%, respectively among
patients receiving radiation therapy concurrent with mitomycin-C and 5-
FU (214). Among patients who experience local failure, approximately
50% may be salvaged with surgical resection (212).
KEY POINTS
• Esophageal cancers are most commonly treated with neoadjuvant
chemoradiation with carboplatin/paclitaxel followed by surgical
resection. The role of surgical resection in squamous cell
carcinoma is less clear with no associated improvement in overall
survival.
• Gastric cancers are most commonly treated with resection followed
by adjuvant chemotherapy or chemoradiation.
• Pancreatic cancers are practically classified into resectable,
unresectable, and metastatic. The data for adjuvant chemoradiation
is less robust and the subject of ongoing clinical investigation.
• Rectal malignancies are treated with neoadjuvant 5-FU–based
chemoradiation or hypofractionated short-course radiation alone
prior to surgical resection.
• For anal cancers, sphincter sparing is achieved with radiotherapy
combined with 5-FU and mitomycin.
QUESTIONS
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1. Which of the following nodal areas would not be routinely
included in a cT3N1 rectal adenocarcinoma?
A. Presacral
B. Internal iliac
C. External iliac
D. Mesorectum
2. For a T2N1 gastric cardia cancer, which of the following regions
may be excluded from the RT treatment fields?
A. Gastric remnant
B. Splenic hilum nodes
C. Celiac axis
D. Porta
E. Pancreaticoduodenal nodes
3. The following nodal areas are encompassed in both anal cancer
and rectal cancer treatment volumes with the exception of which
of the following?
A. Inguinal nodes
B. Mesorectum
C. External iliac
D. Presacral
4. Which of the following are appropriate adjuvant therapies for
resected pancreatic cancer? Select all that apply.
A. Adjuvant chemotherapy
B. Adjuvant chemoradiation
C. Clinical trial
D. All of the above
5. The appropriate concurrent chemoradiation regimen for
resectable esophageal cancer is which of the following?
A. CDDP/5-FU and RT
B. Carboplatin/paclitaxel and RT
C. CDDP/mitomycin and RT
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D. Capecitabine and RT
ANSWERS
1. C
2. B
3. A
4. D
5. B
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer
J Clin. 2015;65:5–29.
2. Engel LS, Chow WH, Vaughan TL, et al. Population attributable risks
of esophageal and gastric cancers. J Natl Cancer Inst. 2003;95:1404–
1413.
3. Pohl H, Sirovich B, Welch HG. Esophageal adenocarcinoma
incidence: are we reaching the peak? Cancer Epidemiol Biomarkers
Prev. 2010;19:1468–1470.
4. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA
Cancer J Clin. 2011;61:69–90.
5. Tran GD, Sun XD, Abnet CC, et al. Prospective study of risk factors
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radiotherapy for anal cancer using the ACTII schedule: a comparison
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outcome. Int J Radiat Oncol Biol Phys. 2005;63:354–361.
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radiation therapy for anal cancer: a multi-institutional report of
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therapy with concurrent chemotherapy for anal cancer: outcomes
and toxicity. Am J Clin Oncol. 2014;37(5):461–466.
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gastrointestinal toxicity analysis of anal cancer patients treated with
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effects of the urinary bladder. Int J Radiat Oncol Biol Phys.
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bladder, urethra, and ureter to radiation and chemotherapy. Int J
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25 Gynecologic Malignancies
Anthony Paravati, Daniel R. Simpson, Loren K. Mell,
Catheryn M. Yashar, and Arno J. Mundt
INTRODUCTION
Gynecologic cancers arise from organs throughout the female
reproductive tract, including the ovaries, uterus, cervix, vagina, and
vulva. Gynecologic cancers represent the fourth most common malignant
tumors diagnosed in women in the United States each year, with nearly
95,000 cases expected in 2014 (1). Worldwide, gynecologic cancers
represent approximately 20% of all cancers, with nearly 1 million cases
diagnosed per year (2).
Radiation therapy (RT) occupies an important role in the treatment of
nearly all gynecologic malignancies. Radiation is commonly used as
definitive treatment in many early-stage patients and in conjunction
with surgery and/or chemotherapy in women with locally advanced
disease. It is also frequently used to palliate patients when cure is not
possible.
This chapter provides an overview of the role of RT in the treatment of
gynecologic malignancies, with a focus on the planning of various
radiotherapeutic approaches used in these patients, including external-
beam RT and brachytherapy. Technologies to be discussed include
intensity-modulated RT (IMRT), image-guided RT (IGRT), and image-
guided brachytherapy.
RADIOTHERAPEUTIC MANAGEMENT
Cervical Cancer
Radiation is commonly used in the treatment of nearly all stages of
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cervical cancer. Selected early (microscopic) tumors (stage IA) are
treated primarily with surgery; however, when such patients are unable
to undergo surgery due to advanced age and/or significant
comorbidities, RT can be used and is associated with excellent results
(3). Early-stage patients with gross disease (stages IB to IIA) are
managed well with either radical surgery or definitive RT, with cure
rates exceeding 80% following either approach (4).
The choice of surgery versus radiation in early-stage cervical cancer
depends on a number of factors, including patient age, comorbidities and
various tumor characteristics. Older women, particularly those with
multiple comorbidities, are generally treated with RT whereas younger
women receive surgery. A common reason for favoring surgery in young
women is the ability to preserve ovarian function. However, it may be
possible to preserve ovarian function in premenopausal patients by
performing an ovarian transposition prior to RT (5). Another oft-stated
reason for favoring surgery in young women is the commonly held belief
that sexual function would be less adversely affected. However,
prospective quality of life analyses have found equivalent sexual
function following surgery compared to RT (6).
In general, RT is recommended over surgery in early-stage cervical
cancer patients as lesion size and vaginal involvement increase. As
tumor diameter exceeds 4 cm, there is increased likelihood of tumor
spread to surrounding organs and regional lymph nodes, necessitating
the need for adjuvant RT following surgery. Randomized trials
conducted by the Gynecologic Oncology Group (GOG) and other
cooperative groups have found that postoperative RT is beneficial in
many cervical cancer patients following surgery. GOG 92 noted an
improved 2-year recurrence-free survival rate (88% vs. 79%, p = 0.008)
comparing adjuvant RT versus no further therapy in node negative
patients with high-risk features (deep stromal invasion, bulky primary
disease, and/or lymphovascular invasion) (7). GOG 109 compared
adjuvant pelvic RT versus pelvic RT plus chemotherapy in women found
to have involved pelvic nodes, parametrial invasion and/or positive
margins and noted a superior 4-year overall survival (81% vs. 71%, p =
0.007) with the combined approach (8). Whether concomitant
chemoradiotherapy is superior to RT alone in node negative patients
with high-risk features is currently being evaluated by GOG 263,
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whereas the benefit of adjuvant chemotherapy following
chemoradiotherapy in high-risk node positive patients is the subject of
GOG 0724.
While a treatment option in early-stage patients, radiation has long
been the cornerstone of treatment in cervical cancer patients with locally
advanced (stages IIB to IVA) disease. In these women, radiation is
combined with concomitant chemotherapy in light of multiple
prospective randomized trials demonstrating a survival advantage to the
combined approach (9–11). Surgery is typically not utilized in patients
with locally advanced disease, albeit some investigators have advocated
pelvic exenteration in cases with bladder and/or rectal invasion (stage
IVA) (12). Metastatic (stage IVB) patients may also undergo RT,
particularly those with a good response to chemotherapy or those
requiring palliative treatment due to uncontrolled vaginal bleeding.
Definitive RT in cervical cancer is administered with a combination of
pelvic RT and brachytherapy, except in earliest-stage patients in whom
brachytherapy alone is sufficient (3). Early-stage patients (stage IB1) are
standardly treated with radiation as there are currently no randomized
trials demonstrating improved outcomes with the addition of
chemotherapy. Early-stage patients with bulky (>4 cm) tumors (stage
IB2) are treated with a combination of pelvic RT and chemotherapy
(13), with or without an adjuvant hysterectomy (14). Hysterectomy
increases local control but does not alter survival. When delivered
adjuvantly, most patients receive pelvic RT with or without
chemotherapy. In women with locally advanced disease, pelvic fields are
also used, except in those with documented paraaortic lymph node
involvement in whom extended field RT (EFRT) is administered. In the
past, there was considerable interest in prophylactic paraaortic RT in
locally advanced patients, following the superior survival rates reported
on the Radiation Therapy Oncology Group (RTOG) trial using this
approach (15). Today, however, EFRT is rarely used without evidence of
paraaortic involvement, except at some centers in woman with
involvement of common iliac lymph nodes. Pelvic fields are extended to
include the inguinal lymph nodes in patients with lower vaginal
involvement and additional external-beam RT is often delivered in
patients with significant parametrial involvement and/or gross nodal
disease.
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Brachytherapy is commonly delivered in conjunction with pelvic RT in
cervical cancer patients undergoing definitive treatment. In the adjuvant
setting, brachytherapy is less commonly performed, except when
patients are treated preoperatively. If brachytherapy is prescribed, most
patients receive intracavitary brachytherapy (ICB). However, at some
centers, interstitial brachytherapy is favored in women with unfavorable
anatomy and/or significant parametrial involvement. See “Radiotherapy
Techniques” below for a full discussion of the various RT techniques
used in cervical cancer patients.
Uterine Cancer
Although radiation has traditionally been delivered prior to surgery in
many uterine cancer patients (16), the majority of patients today
undergo upfront surgery, consisting of total abdominal hysterectomy and
bilateral salpingo-oophorectomy (TAH-BSO), with RT delivered
postoperatively to selected patients based on pathologic features in the
surgical specimen. In the United States, many uterine cancer patients
undergo extended surgical staging (ESS) at the time of surgery as well,
consisting of pelvic and paraaortic lymphadenectomies, despite the
results of two randomized trials questioning its benefits in terms of
survival (17,18).
The most common pathologic features used to determine the need for
adjuvant RT in early-stage (stages I to II) uterine cancer are tumor grade,
histology, depth of myometrial invasion (MI), lymphovascular invasion
(LVI), and cervical involvement. Some investigators also use tumor size
and lower uterine segment (LUS) involvement. However, the prognostic
significance of such features, particularly in the absence of other more
established adverse features, remains unclear (19). Multiple randomized
trials have been performed by the GOG and other groups demonstrating
that adjuvant RT in early-stage uterine cancer patients with adverse
pathologic features significantly reduces locoregional failure (20–23).
Whether it improves survival, however, remains a matter of intense
debate, despite the results of two large Surveillance Epidemiology and
End Results (SEER) studies suggesting a survival benefit in most patients
(24,25).
At many centers today, low-risk early-stage uterine cancer patients
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(stage I, grade 1, no or minimal MI) are treated with surgery alone,
while those with intermediate risk factors (grade 3 with superficial MI or
grade 1–2 with deep MI, especially combined with advanced age and
LVI) receive adjuvant RT. In the latter group, pelvic RT is currently
reserved for patients who do not undergo ESS and vaginal brachytherapy
is delivered in those who do (provided all nodes are negative), a trend
that appears to be increasing in the United States (26). It may be
possible, however, to treat selected intermediate risk patients with
adjuvant vaginal brachytherapy alone even when ESS is not performed
(27). In the adjuvant setting, either pelvic RT or vaginal brachytherapy
is delivered. While commonly delivered together in the past, the routine
use of both appears to only increase the risk of serious toxicity without
improving local control and thus should be avoided whenever possible
(28).
The optimal approach in high-risk early-stage uterine cancer patients
(deep MI and grade 3 disease, cervical stromal invasion, LVI) remains
controversial. In Europe, the Postoperative Radiotherapy for Endometrial
Carcinoma (PORTEC)-3 trial is comparing pelvic RT versus pelvic RT
plus concomitant and adjuvant chemotherapy in these patients. In the
United States, GOG 0249 is randomizing patients to pelvic RT versus
vaginal brachytherapy plus chemotherapy. Preliminary results of GOG
0249 which randomized 601 patients with stage I endometrial
carcinoma with high-risk features, stage II endometrial carcinoma, and
stages I to II serous or clear cell to either pelvic radiation or vaginal
brachytherapy followed by chemotherapy with paclitaxel and
carboplatin were published in abstract form in 2014. The vaginal
recurrence rate after pelvic radiation was 5% versus 2% with VCB/C.
Pelvic recurrence was 2% with pelvic radiation and 19% after VCB/C.
There was no difference in distant failure, recurrence free survival, or
overall survival. The preliminary conclusion from GOG 0249 is that
VCB/C was not demonstrated to be superior to pelvic radiation. In early-
stage uterine cancer patients unable to undergo surgery due to advanced
age and/or multiple comorbidities, radiation can be used with curative
intent and typically consists of a combination of brachytherapy with or
without pelvic RT in grade 3 patients and brachytherapy alone in those
with grade 1–2 disease (28). Pelvic magnetic resonance imaging (MRI)
may be helpful in these women to evaluate MI and extrauterine spread.
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In stage III and IV uterine cancers, the standard approach has been for
many years surgery followed by adjuvant RT, using a variety of
techniques including pelvic RT, EFRT, and whole abdominal RT
(WART). Historically, selected locally advanced patients with positive
peritoneal cytology received intraperitoneal radioactive phosphorus
(32P) (29). Outcomes varied considerably in stage III to IV patients
depending on the type and number of extrauterine sites involved, with
the best results seen in patients with isolated adnexal involvement (30)
and poorer outcomes in those with involvement of multiple extrauterine
sites, nodal involvement, and/or residual disease (31).
Today, WART is rarely used in the United States following the
publication of the GOG 122 trial randomizing stage III to IV patients to
either WART or chemotherapy, which noted a superior 5-year survival
(55% vs. 42%) with adjuvant chemotherapy but inferior pelvic control
(32).
A secondary analysis of GOG 122 conducted to determine whether the
number of positive pelvic nodes (PPNs), cervical stromal involvement
(CSI), and/or lymphovascular space involvement (LVSI) were prognostic
factors in terms of PFS and OS among women with advanced
endometrial carcinoma treated with adriamycin plus cisplatin (AP) or
whole abdominal irradiation (WAI). This analysis revealed the presence
of CSI and increasing number of PPN were associated with poor
prognosis. For patients with CSI improved PFS and OS was achieved
with AP compared to WAI (33). However, the question remains whether
adjuvant RT has a role in conjunction with chemotherapy. Patterns of
failure studies suggest that it does, given the high risk of locoregional
recurrence in women undergoing surgery and chemotherapy (34). At
many centers today, stage III and selected stage IV patients are treated
with chemotherapy combined with limited volume RT (pelvic RT, EFRT,
and/or vaginal brachytherapy based on pathologic features), an
approach known as “tumor volume–directed” RT which was used in the
GOG 184 trial (35). Of note, GOG 258 is currently randomizing locally
advanced patients to chemotherapy versus chemoradiotherapy. The
results of this important trial will help define the role of RT in these
patients.
The role of RT in the treatment of patients with unfavorable
histologies, notably papillary serous and clear cell tumors, is
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controversial. However, RT may help reduce the risk of locoregional
recurrence in such patients who receive adjuvant chemotherapy
following surgery (36). Patients with early-stage uterine sarcomas,
except those with low-grade endometrial stromal sarcoma, have
traditionally been treated with adjuvant pelvic RT. Locally advanced
sarcoma patients are treated at many centers with adjuvant
chemotherapy without RT, due to the superior outcomes in patients
undergoing chemotherapy compared to WART on the GOG 150 trial
(37). Nonetheless, adjuvant RT still remains a common treatment of
choice in these patients, particularly in elderly women and others who
are unable to undergo adjuvant chemotherapy. See the “Radiotherapy
Techniques” below for a full discussion of the various RT techniques
used in patients with uterine cancer.
Ovarian Cancer
For many years, RT occupied an important role in the treatment of
ovarian cancer. Following upfront surgery, consisting of an
omentectomy, TAH-BSO, peritoneal sampling, and cytoreduction of
extra-ovarian disease throughout the abdomen and pelvis, and often
pelvic and paraaortic lymph node dissection, adjuvant RT was routinely
delivered in the form of intraperitoneal 32P in high-risk early stage and
WART in locally advanced disease patients.
Several randomized GOG studies have compared adjuvant 32P versus
chemotherapy (melphalan or cisplatin-cytoxan) in early-stage high-risk
disease (stages IA to B grade 3, stages IC to II) and found no differences
in either relapse-free or overall survival rates (38,39). Moreover, in GOG
7602, chemotherapy was associated with higher toxicity rate compared
to RT, including a higher rate of second malignancies (38). Despite these
favorable results, few patients receive intraperitoneal 32P today, apart
from its use at some centers in selected elderly high-risk early-stage
patients unable to receive chemotherapy, partly due to the development
of peritoneal adhesions in some patients.
In locally advanced ovarian cancer patients who were optimally
cytoreduced (previously defined as <2 cm residuum remaining
following surgery), WART was long considered the standard adjuvant
approach at many centers throughout the world. Published long-term
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outcomes have been highly favorable in such patients treated with
WART, particularly in those with microscopic or no residual disease after
cytoreductive surgery (40,41). Investigators at Stanford University
reported a 15-year relapse-free survival rate of 50% in stage I to III
optimally cytoreduced patients undergoing adjuvant WART (40). Despite
these favorable results and even a prospective phase III M. D. Anderson
Hospital randomized trial demonstrating identical survival rates
following WART or chemotherapy (42), adjuvant WART has been largely
abandoned at most centers today, at least in the United States. The
standard adjuvant approach is currently combination chemotherapy.
Unfortunately, a randomized trial comparing WART and chemotherapy
regimens popular today will most likely never be performed.
Although no longer used alone following surgery, the question
remains whether adjuvant RT has a role in conjunction with
chemotherapy and surgery in ovarian cancer. Several prospective trials
have evaluated the role of “consolidative” RT in stage I to III patients
following upfront surgery and adjuvant chemotherapy (43,44). No
benefit was seen using intraperitoneal 32P compared to observation in a
GOG trial focused on stage I to III patients with microscopic residual
disease following surgery and chemotherapy (43). In contrast, the
Swedish-Norwegian Ovarian Cancer Study Group trial compared WART
versus cisplatin-doxorubicin-epirubicin versus observation in stage III
patients achieving a pathologic complete response and noted 5-year
progression-free survivals of 56%, 36%, and 35% in the WART,
chemotherapy, and observation groups, respectively (44). Although
favorable results have been reported combining adjuvant RT with
modern taxane-based adjuvant chemotherapy (45), whether adjuvant RT
is truly beneficial in this setting remains unclear.
RT is occasionally used in the management of patients with
nonepithelial ovarian cancers. Given its exquisite radiosensitivity,
ovarian dysgerminoma may be treated with RT; however, in these
patients as well, the standard practice today is adjuvant chemotherapy,
particularly in those desiring fertility-sparing treatment. As in other
gynecologic cancers, RT has an important role in the palliative treatment
of ovarian cancer patients (45). See “Radiotherapy Techniques” below
for a discussion of the various RT techniques used in ovarian cancer.
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Vulvar Cancer
The treatment of vulvar cancer at most centers today consists of upfront
surgery, typically radical vulvectomy or radical wide local excision in
selected patients with small well-lateralized tumors (46), with RT
delivered adjuvantly in patients with high-risk features including LVI,
tumor invasion >5 mm, surgical margins <8 mm, grade 3 disease, and
microscopic positive margins (47,48). Most patients also undergo
bilateral inguinofemoral dissections, particularly those found to have
tumor invasion >3 mm, LVI and/or high-grade disease, due to their
high risk of nodal involvement.
Although commonly used in many other gynecologic cancers,
prophylactic nodal irradiation is rarely used to treat clinically negative
regional lymph nodes in vulvar cancer. This practice is based on the
GOG 88 trial which compared prophylactic inguinofemoral RT versus
lymphadenectomy in clinically node negative patients and found a
significantly higher rate of recurrence (p = 0.03) and death (p = 0.04)
in the RT group (49). See “Radiotherapy Techniques” below for critique
of this influential study.
In women with locally advanced but resectable disease, surgery is
typically performed followed by adjuvant radiation or chemoradiation.
Over 20 years ago, the GOG completed a landmark trial (GOG 37)
comparing adjuvant RT versus pelvic node dissection in patients found
to have involved inguinal nodes at the time of surgery (50). A
significantly higher survival rate was noted in the RT group, with the
greatest benefit seen in women with clinically suspicious and/or ≥2
pathologically involved nodes. Moreover, adjuvant RT significantly
reduced the risk of recurrence in the inguinal nodes (5% vs. 24%, p =
0.02). This trial established adjuvant RT as the treatment of choice in
these patients.
In unresectable vulvar cancer patients, RT has been used
preoperatively with promising results (51,52). Considerable interest has
been focused on further augmenting these results by combining RT with
chemotherapy (48,53,54). GOG 101 evaluated preoperative
chemoradiotherapy in locally advanced unresectable patients and found
that nearly all patients (97%) became resectable, with only 16%
ultimately failing locally (55).
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Adjuvant RT in vulvar cancer is delivered using a variety of
techniques, ranging from small electron fields directed solely at the
primary site to generous fields encompassing the primary, pelvis plus
one or both groins. The most common approach, however, is pelvic-
inguinal irradiation, delivered with or without a midline block.
Brachytherapy has a limited role in vulvar cancer, apart from patients
with a positive vaginal margin or in medically inoperable patients in
whom high doses are required to control the primary tumor. However,
at most centers, high-dose central boosts are delivered in such patients
using external-beam techniques. A description of the various RT
techniques used in vulvar cancer is provided below (see “Radiotherapy
Techniques”).
Vaginal Cancer
The treatment of choice in all stages of vaginal cancer is definitive RT.
However, selected early-stage patients, such as those with small volume
disease limited to the upper vagina, can be treated with a variety of
surgical approaches, including partial or radical vaginectomy (56).
Early-stage vaginal cancer patients typically receive brachytherapy
alone or combined with external beam when tumors invade the
paravaginal tissues (57,58). Some investigators advocate the use of
combined external beam and brachytherapy even in patients without
paravaginal invasion (59). Overall, definitive RT is associated with
excellent outcomes in most early-stage vaginal cancer patients,
particularly in those with stage I disease in whom locoregional control
rates exceed 85% (58). Patients with locally advanced disease undergo
pelvic RT and brachytherapy (57–59). At some institutions,
chemotherapy is delivered concomitantly in these patients in an effort to
improve tumor control and potentially survival extrapolating from
cervical cancer studies. Given the low number of vaginal cancer patients
diagnosed each year, it is unlikely that randomized trials evaluating such
approaches will ever be successfully conducted.
Brachytherapy in early-stage vaginal cancer typically involves ICB, but
in women with >0.5 cm tumor invasion or thickness, interstitial
brachytherapy is recommended. Some investigators favor interstitial
brachytherapy combined with ICB even in patients with superficial
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tumors to reduce the total vaginal dose and, in distal vaginal tumors, the
rectal dose (59). If external beam is also delivered, vaginal cancer
patients receive either pelvic irradiation, or in cases involving the lower
one-third of the vagina, pelvic-inguinal RT. See “Radiotherapy
Techniques” below for a discussion of the various RT techniques used in
patients with ovarian cancer.
RADIOTHERAPY TECHNIQUES
External-Beam Therapy
Whole Pelvic Radiotherapy
Pelvic RT is used in many gynecologic cancers to irradiate multiple
target tissues within the pelvis, including the uterus/cervix (or the
postoperative bed), the upper vagina, paracervical/parametrial tissues,
and the pelvic (internal, external, and common iliac) lymph nodes.
Pelvic RT fields have traditionally been designed using fluoroscopic
simulation based on bony landmarks and are delivered with either two-
field (opposed anterior–posterior:posterior–anterior [APPA] fields) or
four-field (APPA plus opposed lateral fields) techniques (Fig. 25.1). In
recent years, however, most centers have moved away from APPA
treatment (60), since four-field approaches allow considerably more
normal tissue sparing, notably the anterior small bowel and posterior
rectum. Some investigators still favor opposed APPA fields, however, in
patients with locally advanced cervical cancer.
For many years, the superior border of the pelvic RT field was placed
at the L5–S1 interspace; however, most investigators currently favor the
L4–L5 interspace to include the common iliac lymph nodes. It is
important to note, however, that the common iliacs in some patients
may extend considerably higher, requiring an upper border as high as
L2–L3 to ensure their full coverage. The lower pelvic RT border is
typically placed at the inferior obturator foramen while the lateral
borders are set 1 to 1.5 cm beyond the pelvic brim. The anterior border
of the lateral field is at (or 1 cm anterior) to the pubic symphysis to
ensure coverage of the external iliac nodes; the posterior border is at the
S2–S3 interspace. Previously, the posterior border was commonly set at
the S1–S2 interspace; however, concerns were raised about adequate
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coverage of the attachment of the uterosacral ligament to the sacrum
with this approach, particularly in locally advanced cervical cancer
patients (61). Customized blocking is added to each field using either
cerrobend or multi-leaf collimation to reduce dose to the surrounding
normal tissues including the small bowel and rectum. Oral and rectal
contrast may be administered at simulation to aid in the design of these
blocks.
Figure 25.1 Anterior–posterior (AP) (A) and lateral fields (B) in a representative gynecologic
cancer patient undergoing whole pelvic radiation therapy.
Various modifications can be done to the traditional pelvic RT fields,

depending on the clinical scenario. In cervical or uterine cancer patients
with significant vaginal involvement, the lower border can be extended
to the introitus, ensuring irradiation of the entire vaginal canal. In such
cases, it is helpful to place a radiopaque marker in the vagina at the time
of simulation marking the inferior extent of disease. The superior border
may be extended superiorly to fully encompass the common iliac lymph
nodes, particularly in women with involvement of the external iliac
lymph nodes, or may be lowered to the L5–S1 interspace in patients
undergoing ESS and found to have negative pelvic nodes. The posterior
border of the lateral field can also be moved posterior to the sacrum in
cervical cancer patients with bulky disease, whereas the anterior border
may be moved anteriorly in women with an anteverted uterus and/or
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bulky external iliac nodes.
At many centers, patients undergoing pelvic RT are immobilized and
simulated in the supine position. Prone positioning with a “belly board”
is favored by some investigators to help reduce the volume of small
bowel irradiated. Similarly, at some centers, patients are simulated and
treated with a full bladder to displace small bowel. Whatever approach
is used, it is important to strive for consistent bladder and rectal filling
throughout treatment, given that the volume of these organs may impact
the position of the cervix/uterus (or vaginal cuff) (62,63).
Although pelvic RT fields have traditionally been designed based on
bony landmarks, multiple investigators have demonstrated that such an
approach may underdose the target tissues and/or inadequately shield
surrounding normal tissues in many patients (64,65). Finlay et al.
assessed the adequacy of nodal coverage of conventional pelvic RT fields
in 43 cervical cancer patients (64). Pelvic vessels were contoured
following computed tomography (CT) simulation and used as surrogates
for the pelvic lymph nodes. In 41 patients (95%), conventional fields
inadequately covered various lymph node groups. Of note, in 24 (56%),
conventional fields and blocks were found to be too generous. Others
have similarly used three-dimensional (3D) imaging and found that
conventional fields and blocking may result in inadequate target
coverage in up to 50% of patients, particularly with the placement of the
posterior field border of the lateral pelvic field at S2–S3 (65). These
results strongly support the design of pelvic RT field using CT
simulation, which is now the preferred approach throughout the United
States.
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Figure 25.2 Treatment plan with isodose lines in a representative gynecologic cancer patient
treated with whole pelvic radiation therapy.
Conventional pelvic RT fields are typically delivered using moderate–

high energy (≥10 MV) photon beams. However, lower energies can be
used in selected thin patients. Wedges may be added to the lateral fields
to reduce “hot spots” in the treatment plan. As example pelvic RT plan is
shown in Figure 25.2. Total doses prescribed typically range from 39.6
to 50.4 Gy delivered in 1.8 to 2 Gy/fractions, the higher doses used in
patients undergoing external beam alone and lower doses in those
treated with both external beam and brachytherapy.
In the past, there was considerable interest in the use of altered
fractionation schedules in gynecologic cancer patients, including
accelerated hyperfractionated RT as a means of escalating the pelvic
radiation dose. However, the RTOG 88–05 trial using this approach in
locally advanced cervical cancer patients failed to demonstrate a benefit
in terms of tumor control or complications (66). Others have also
reported high complication rates using a hyperfractionated approach
(67). Moreover, twice daily treatment in an effort to boost the cervical
tumor prior to brachytherapy has also been associated with increased
complications (68). In contrast, hypofractionated approaches, for
example, 2.5- to 3-Gy daily fractions (total doses 30 to 35 Gy), have
been used successfully in patients treated with palliative intent. Higher
dose per fraction (up to 10 Gy) palliative regimens have also been
explored (69,70).
Various blocks can be added to the conventional pelvic RT field. At
some centers, a midline block is utilized allowing a higher proportion of
the total dose to be delivered by brachytherapy in cervical cancer
patients, typically placed after approximately 20 Gy (71). A midline
block may also be placed following brachytherapy in cervical cancer
patients with significant parametrial involvement and/or involved pelvic
lymph nodes allowing an additional boost to be delivered, typically 10
to 12 Gy in five to six fractions.
At many centers, midline blocks are often standardized, but at others
the midline block may be customized based on the brachytherapy
isodose distributions (Fig. 25.3). In 1997, Wolfson et al. performed a
survey of GOG institutions and reported that the percentages of centers
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using standard and customized midline blocks were 76% and 21%,
respectively, at that time (72). Only 3% utilized step-wedge blocks as
popularized by Perez et al. (71). The width of the midline block should
fully encompass the ovoids (colpostats) on the anterior radiograph plus a
margin since narrow midline blocks inadequately shield the ureters and
are associated with increased complications 75(73). The inferior edge of
the block should be coincident with the lower border of the pelvic field.
However, various superior block edges can be used. In the GOG survey,
the upper border of the midline block was set at the top of the pelvic
field, the tip of the tandem plus a 1- to 2-cm margin, or the level of the
sacroiliac joint by 29%, 38%, and 33% of respondents, respectively (74).
IMRT is increasingly used in the treatment of gynecologic cancers.
Investigators at the University of Chicago were the first to compare
conventional and IMRT planning in gynecologic cancer patients
undergoing pelvic RT and found that IMRT reduced the volume of small
bowel irradiated by a factor of two and the volume of both the bladder
and rectum irradiated by 23% (75). Subsequently, others have confirmed
these results, with reductions up to 70% seen with IMRT planning in
terms of the volume of small bowel receiving the prescription dose
(73,76). More recently, IMRT planning has been shown to be an effective
means of reducing the volume of pelvic bone marrow irradiated in
patients undergoing pelvic RT, an appealing approach particularly in
patients receiving concomitant chemotherapy (77). The ongoing
International Evaluation Of Radiotherapy Technology Effectiveness In
Cervical Cancer (INTERTECC) is a phase II/III trial which randomizes
patients with biopsy-proven stage I to IVA invasive cervical carcinoma
either in the post-hysterectomy setting with high-risk features OR is
locally advanced, in the intact setting to either pelvic radiotherapy with
IMRT or with conventional 3D-conformal techniques with concurrent
cisplatin followed by brachytherapy to test whether IMRT will reduce
the rate of acute grade ≥3 hematologic or clinically significant grade
≥2 gastrointestinal toxicity. Patients undergoing pelvic IMRT are
typically immobilized in the supine position and undergo CT simulation
with thin (5 mm) slices, although at selected centers prone positioning is
favored (78). Contrast may be administered to aid in the delineation of
the target and normal tissues; intravenous contrast is particularly useful
since the pelvic vasculature is used as a surrogate for the lymph nodes in
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the planning process.
Figure 25.3 Example midline blocks used in patients with cervical cancer: (A) standard block and
(B) customized block based on brachytherapy isodose distribution. From Wolfson AH, Abdel-
Wahab M, Markoe AM, et al. A quantitative assessment of standard versus customized midline
shield construction for invasive cervical carcinoma. Int J Radiat Oncol Biol Phys. 1997;37:237–
242.
Following simulation, a gross tumor volume (GTV) and clinical target

volume (CTV) are contoured on the planning CT scan, based on ICRU 50
guidelines (79). The GTV should include all demonstrable disease,
including involved regional lymph nodes. A variety of imaging
modalities can be used to aid in target design, with growing attention on
positron emission tomography (PET) and MRI (80). Investigators at
Washington University in St. Louis base their target volume definition on
PET and contour a metabolically active tumor volume (MTV), specified
at the 40% threshold level (81).
The CTV in most patients undergoing pelvic IMRT consists of the
upper half of the vagina, uterus/cervix (if present), parametria, presacral
region, and pelvic lymph nodes (internal, external, and lower common
iliac nodes). The most superior extent of the CTV is typically placed 1 to
1.5 cm inferior to the L4–L5 interspace to account for planning target
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volume (PTV) expansions. In uterine cancer patients without cervical
involvement, the presacral region need not be included. At some centers,
a single CTV is drawn, whereas at others several CTVs are delineated. In
a postoperative patient, for example, two CTVs may be delineated: the
CTVnodes includes the common, external, and internal iliac nodes and
presacral space, whereas the CTVvagina includes the vaginal cuff and
paravaginal/parametrial tissues. At some centers, an integrated target
volume (ITV) is generated by fusing empty and full bladder planning CT
scans, encompassing contours of the cervix (or vaginal cuff in
postoperative patients) on both scans, with patients treated with a full
bladder or, at other centers, an empty bladder as maintaining a full
bladder has not been shown to be reproducible. Normal tissues are
contoured as well, including the small bowel, bladder, rectum, and, at
some centers, the sigmoid colon. The pelvic bones are used as a
surrogate for the pelvic bone marrow in patients undergoing
chemoradiotherapy. In the past, only the iliac crests were contoured;
however, recent data suggest that the pelvic bones are a better surrogate
for the bone marrow in the optimization process (78).
Figure 25.4 Mid-pelvic computed tomography (CT) image illustrating a clinical target volume
(CTV) delineated in a patient with cervical cancer treated postoperatively based on guidelines
developed for the Radiation Therapy Oncology Group (RTOG) 0418 trial. Upper external and
internal iliac (red) and presacral region (blue). From Small W Jr, Mell LK, Anderson P, et al.
Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic
radiotherapy in postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol
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Phys. 2008;71:428–434.
Consensus guidelines regarding CTV design in gynecologic cancer

patients undergoing postoperative pelvic IMRT were developed for the
RTOG 0418 phase II trial (Fig. 25.4) (82). These guidelines were based,
in part, on work of Taylor et al. who mapped pelvic lymph node regions
using iron oxide-enhanced MRI, a method to visualize benign lymph
nodes (83). In an analysis of 20 patients using this technique, a modified
margin of 7 mm around the major pelvic vessels was found to encompass
99% of the visualized lymph nodes. More recently, consensus guidelines
have been developed for cervical cancer patients treated with an intact
uterus based on MRI (Fig. 25.5) (83).
The next step in the IMRT planning process involves the expansion of
the CTV to generate a PTV, accounting for patient setup uncertainty and
organ motion. The optimal PTV expansion remains a matter of debate,
particularly in patients with intact cervical cancer in which there may be
considerable organ motion (62,63). A reasonable approach is to provide
generous expansions around the cervical tumor (definitive patients) and
the vaginal cuff (postoperative patients) on the order of 1.5 to 2 cm.
Tighter expansions can be placed around the CTV in the upper pelvis
(0.7 to 1 cm). Daily in-room IGRT techniques, notably cone-beam CT
(CBCT) imaging, may help ensure adequate coverage of the target tissues
on a daily basis (62).
No consensus exists regarding many IMRT planning parameters used
in gynecologic cancer patients. At many centers seven to nine equally
spaced 6 MV beams are used; however, others favor volumetric-
modulated arc or tomotherapy approaches. As in conventional RT, the
total dose prescribed is a function of the tumor site, stage, and treatment
volume. Most investigators deliver 45 Gy in 1.8-Gy daily fractions,
particularly in women subsequently undergoing brachytherapy. Higher
doses (50.4 Gy) can be used in patients treated with pelvic IMRT alone
(84). Some investigators are exploring the use of more sophisticated
simultaneous integrated boost (SIB) approaches, particularly in women
with grossly positive nodes (85).
Given the potential ability to safely deliver higher and potentially
more efficacious doses, some investigators have explored using IMRT as
a substitute for brachytherapy in cervical cancer (75,86). Investigators at
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the Princess Margaret Hospital presented a case study of a stage IIB
cervical cancer patient unsuitable for brachytherapy treated with an
IMRT boost (87). Using MRI guidance, a GTV was delineated consisting
of the cervix and LUS. The GTV was expanded by a 10-mm margin (7
mm posteriorly) generating the CTV which was subsequently expanded
by 5 mm (10 mm anteriorly) to generate the PTV. Six static 6 MV fields
were used to deliver 25.2 Gy in 1.8-Gy daily fractions to the PTV. The
resultant treatment plan was highly conformal; average doses delivered
to 50% of the rectum, bladder and small bowel were 21 Gy, 13 Gy, and
5 Gy, respectively. Treatment was tolerated well without significant
sequelae. Given the paucity of data using IMRT in lieu of brachytherapy,
this approach should be considered experimental at the present time and
only used in women unable to undergo brachytherapy.
Figure 25.5 Axial view of a T2-weighted magnetic resonance (MR) images illustrating contours of
the gross tumor volume (GTV) (red), cervix (pink), vagina (yellow), parametria (green), and uterus
(blue) in a patient with intact cervical cancer undergoing intensity-modulated radiation therapy
(IMRT) based on the Radiation Therapy Oncology Group (RTOG) consensus conference. From
Lim K, Small W, Portelance L, et al. Consensus guidelines for delineation of clinical target volume
for intensity-modulated pelvic radiotherapy for the definitive treatment of cervical cancer Int J
The optimal dose–volume constraints for the PTV and normal tissues
in gynecologic cancer patients undergoing pelvic IMRT remain unclear.
Investigators at Washington University reported the use of the following
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constraints: PTV (100% to receive 95% of the prescription dose), small
bowel (<40% to receive ≥30 Gy), rectum (<40% to receive ≥40 Gy),
and femoral heads (<40% to receive ≥30 Gy) (88). In the original
series from the University of Chicago, <40% of the small bowel, rectum
and bladder were constrained to receive ≥36 Gy, ≥40 Gy, and ≥40 Gy,
respectively. Moreover, >95% of the PTV needed to receive >95% of
the prescribed dose (89).
Preliminary clinical outcome studies in gynecologic cancer patients
undergoing pelvic IMRT have been extremely promising, with lower
rates of acute and chronic toxicities reported compared to conventional
techniques (9,89–93). Recent outcome studies have also reported
excellent tumor control rates in both cervical (88,90) and uterine (94)
cancers. Favorable outcomes have also been reported using adjuvant
pelvic IMRT on the RTOG 0418 prospective clinical trial (95). As
described earlier in this chapter, an international cooperative group trial
(INTERTECC) evaluating pelvic IMRT in cervical cancer is currently
enrolling patients (96).
In recent years, detailed normal tissue complication probability
(NTCP) studies have been performed in gynecologic cancer patients
undergoing pelvic IMRT which shed light on the optimal dose–volume
constraints for various normal tissues (Fig. 25.6) (97–99). In update of
the combined University of Chicago/University of California San Diego
experience, the small bowel volume receiving ≥45 Gy was constrained
to 250 cc and the volume of pelvic bone marrow (defined as entire
pelvic bones) receiving ≥10 Gy and ≥20 Gy were constrained to
receive ≤90% and ≤75%, respectively (90). The normal tissue dose
constraints used in the previously mentioned INTERTECC trial which is
ongoing are small bowel volume receiving >45 Gy (V45) ≤250 cc;
maximum dose <115%, rectum maximum dose <115% of the
prescription dose, and bone marrow volume receiving 10 Gy and 2 Gy
<90% and 75%, respectively. The Normal tissue planning goals are
small bowel volume receiving >45 Gy (V45) ≤200 cc; V40 <30%;
maximum dose <50 Gy, rectum V45 <50%; V30 <60%; maximum
dose <50 Gy, bone marrow V10 <80%; V20 <66%, bladder V45
<50%; maximum dose <50 Gy, femoral head V30 <15%; maximum
dose <50 Gy (96). There is also substantial interesting focused on the
use of more sophisticated image-guided approaches in an effort to
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further optimize IMRT planning (91).
Figure 25.6 Plot of white blood cell count log (WBC nadir) versus bone marrow volume receiving
20 Gy or more (V20) in a cohort of cervical cancer patients treated with combined
chemoradiotherapy, supporting the use of bone marrow V20 as a constraint in the optimization
process. Pelvic bones were used as a surrogate for pelvic bone marrow in this analysis.
Regression coefficient (b) = –0.021 k/mL/%, p = 0.002. From Rose BS, Aydogan B, Liang Y, et al.
Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer
patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2010; 78:912–919.
Extended Field Radiotherapy

EFRT is used to treat the pelvic and paraaortic regions. A variety of
techniques are currently utilized. At some centers, the entire volume is
treated with large opposed APPA fields, extending from pelvis to the
T12–L1 interspace. The paraaortic portion of these fields is typically 8 to
10 cm wide, depending on the patient’s anatomy and disease extent. CT
or PET/CT-based planning is helpful to ensure coverage of all enlarged
lymph nodes. To reduce the small bowel dose, some favor using four-
field approaches (APPA plus opposed laterals). However, when using
such approaches, care needs to be taken to minimize the dose to the
kidneys with variable weightings between the APPA and lateral fields
ensuring a maximum kidney dose of 18 Gy or less. At some centers, the
pelvis and paraaortic regions are treated separately with a place “gap”
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between fields. Selected patients may need to be treated at an extended
distance given the length of the fields treated.
Whichever field arrangement is used, moderate–high energy beams
(≥10 MV) are indicated except in selected thin women; all patients are
simulated and treated in the supine position. Prescribed doses range
from 39.6 to 45 Gy delivered in 1.8 to 2 Gy per fractions. In women with
involved paraaortic nodes, a 5- to 10-Gy boost may be delivered via
reduced fields. Selected involved sites may be treated to 60 Gy or higher;
however, care needs to be given to minimize the dose to the surrounding
bowel and other normal tissues including kidneys and spinal cord.
Multiple centers have explored the use of IMRT planning in
gynecologic cancer patients undergoing EFRT (100–102). Compared to
an APPA approach, investigators at Washington University noted that
intensity-modulated EFRT (IM-EFRT) reduced the volume of small
bowel, bladder, and rectum receiving the prescription dose by 61%,
96%, and 71%, respectively (100). Compared to a four-field approach,
corresponding reductions were 60%, 93%, and 56%, respectively. The
following normal tissue constraints were used in the IM-EFRT planning:
small bowel (<50% to receive ≥30 Gy), kidneys (<33% to receive
≥10 Gy), and spinal cord (<5% to receive ≥45 Gy). Lian et al.
compared 3D conformal EFRT plans in 10 endometrial cancer patients to
IMRT and helical tomotherapy (HT) plans (101). The following
constraints were used in the IMRT and HT optimization process: bladder
(<50% to receive ≥40 Gy), rectum (<40% to receive ≥40 Gy), bowel
(<35% to receive ≥35 Gy), kidneys (<35% to receive 16 Gy), and
spinal cord (maximum dose, 40 Gy). Overall, both IMRT and HT resulted
in superior target coverage and significantly reduced normal tissue doses
compared to 3D conformal planning; however, the HT achieved the best
normal tissue sparing (Fig. 25.7).
A potentially important role for IMRT in gynecologic cancer patients
undergoing EFRT is the ability to safely deliver higher than conventional
doses to involved paraaortic lymph nodes. Using conventional
techniques, doses above 60 Gy, except in patients with small volume
disease, are difficult to deliver. However, the likelihood of controlling
bulky paraaortic nodes with such doses is quite low. Multiple
investigators have demonstrated that higher doses may be possible using
SIB IMRT approaches in patients with involved paraaortic lymph nodes.
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Two different approaches have been proposed. Some investigators
recommend that the entire paraaortic region be treated with
conventional fraction sizes (1.8 Gy/day, 45 Gy total dose) and an SIB
technique used to irradiate the involved nodes with higher than
conventional fraction size (2.4 Gy/day, 60 Gy total dose) (103).
Alternatively, conventional fractions can be used for the SIB portion (1.8
Gy/day, 59.4 Gy total dose) and lower than conventional fractions used
to treat the paraaortic region (1.53 Gy/day, 50.4 Gy total dose) (85).
Figure 25.7 Comparison of planning target volume coverage by the 95% (green line) in three-
dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and
helical tomotherapy (HT) plans in a stage IIIC uterine cancer patient undergoing extended field
irradiation. Blue indicates the 50% isodose line; red line or red area indicates planning target
volume. From Lian J, Mackenzie M, Joseph K, et al. Assessment of extended-field radiotherapy
for stage IIIC endometrial cancer using three-dimensional conformal radiotherapy, intensity-
modulated radiotherapy, and helical tomotherapy. Int J Radiat Oncol Biol Phys. 2008;70:935–943.
Limited outcome data exist using IM-EFRT. Salama et al. treated 13

women to a total dose of 45 Gy in 1.8-Gy fractions (104). While 84% of
patients experienced acute grade 2 bowel toxicity, no grade 3 or higher
bowel or bladder sequelae were noted. Using the SIB approach with
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higher than conventional daily fractions (2.2 Gy/day, 55 Gy total dose)
to PET-defined paraaortic nodes, investigators at the University of
Pittsburgh noted acute grade 2 and 3 bowel sequelae in 10% and 0% of
patients, respectively (105). The University of Pittsburgh group also
published an expanded experience using IM-ERFT with the same SIB
technique in 61 consecutive women either with PET positive paraaortic
disease or with PET PPNs alone siting the false-negative rate of FDG-PET
for paraaortic metastases of approximately 20% to 25% (106). In this
series, at a mean follow-up time of 29 months, 8 patients experienced
recurrence. However, 10 patients (16.3%) had persistent or recurrent
local disease, 3 (4.9%) involving the regional nodes, and 14 patients
(23%) progressed distantly. The rate of paraaortic failure in patients
with pelvic-only PET positive nodes was 2.5%. Grade 3+ adverse events
developed in only two patients (4%). Du et al. randomized 60 cervical
cancer patients with involved paraaortic nodes to either IMRT or
conventional RT to the paraaortic region (107). While the IMRT patients
received a higher prescribed dose (58 to 68 Gy vs. 45 to 50 Gy) than the
conventional RT patients, they experienced less acute and chronic
toxicity. Moreover, IMRT patients had a superior 3-year survival (36.4%
vs. 15.6%, p = 0.016) compared to the conventional RT patients.
Pelvic-Inguinal Radiotherapy
In women with vulvar cancer and other gynecologic cancer patients
involving the lower vagina, pelvic-inguinal irradiation is used to
irradiate the pelvis, vagina, vulva, and bilateral inguinofemoral regions.
Such patients are immobilized and simulated supine in the “frog-leg”
position to minimize skin folds and thus the risk of acute perineal
toxicity. Moderate–high energy beams (≥10 MV) are used.
The upper border of the conventional pelvic-inguinal field differs
between institutions and is based on the disease extent. In vulvar cancer
patients, some advocate the treatment of reduced pelvic fields (“true
pelvis”) with the upper border placed inferiorly to the sacroiliac joints.
Others place the upper border at the L5–S1 or L4–L5 interspace. In a
survey of members of the Gynecologic Cancer Intergroup (GCIG), the
most common upper border was L5–S1 followed by L4–L5 (48). In
women with upper pelvic adenopathy, the upper border may need to be
even higher. The lower border is typically placed approximately 5 cm
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inferior to the vulva/perineum to ensure coverage of the inguinofemoral
lymph nodes.
A variety of treatment approaches have been used in patients
undergoing pelvic-inguinal RT. One common approach is to use opposed
APPA fields, with a “wide” AP field encompassing the pelvis and groin
regions and a “narrow” PA field treating only the pelvis. Supplemental
electron fields are used to treat the groins, reducing the dose received by
the femoral heads. Alternatively, APPA fields can be equally wide with
partial transmission blocks placed on the PA field minimizing dose to the
femoral heads. A third approach is to prescribe high-energy photons (10
to 24 MV) for the PA field and low-energy photons (4 to 6 MV) for the
AP field. A novel modified segmental boost technique has been
developed using a wide AP field, narrow PA field, and two angled
photon fields encompassing the bilateral groins (108). Whichever
technique is used, attention needs to be given to avoid underdosing the
vulvar region, particularly in patients treated preoperatively. Bolus is
typically used with doses confirmed via thermoluminescence dosimetry
(TLD). Total prescribed doses in patients undergoing pelvic-inguinal RT
range from 45 to 50.4 Gy in 1.8- to 2-Gy daily fractions. Additional
boosts may be delivered to the inguinal region in patients with involved
lymph nodes. In the GCIG survey, the mean pelvic and groin node doses
were 48.1 Gy and 49.9 Gy, respectively (47).
When treating the inguinal lymph nodes with electrons, care needs to
be taken to ensure the proper selection of beam energy. Routine use of
low-energy electron beams will likely underdose the groin nodes in a
significant number of patients, particularly obese women. The depth of
treatment should be tailored to the individual patient based on CT
imaging, since the depth of the inguinofemoral nodes is highly variable
with an average depth of 6.1 cm reported in one study (109). The high
rate of nodal failures observed in the RT patients treated on GOG 88
comparing prophylactic RT versus lymphadenectomy in clinically node
negative vulvar cancer patients was likely due, at least in part, to the
fact that the groins were treated via a single anterior field prescribed to
a depth of 3 cm (48). Such an approach would significantly underdose
the inguinal nodes in many patients. Prophylactic groin irradiation in
clinically node negative patients has been shown to be highly effective if
properly planned and delivered (110). Care must also be taken to also
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ensure an adequate volume is irradiated given inguinal nodal metastases
can occur throughout the groin region. Thus, small volume fields
designed to irradiate the vessels with a limited margin are not
recommended.
Considerable controversy exists regarding the use of a midline block in
vulvar cancer patients undergoing pelvic-inguinal RT. In one highly
quoted report, Dusenbery et al. noted a 48% central recurrence rate in
26 women treated with a midline block (111). However, all patients in
this study had pathologically positive lymph nodes and many did not
have wide negative margins. Of note, central recurrences were rare in
the GOG 37 trial despite the use of a midline block (50). Thus, in the
properly selected patient, a midline block may be reasonable,
particularly in elderly, frail patients who are at high risk of requiring
treatment breaks due to perineal toxicity if treated without a midline
block.
Limited experience is available evaluating IMRT in gynecologic cancer
patients undergoing pelvic-inguinal RT, with largest experience to date
from the University of Pittsburgh. Beriwal et al. compared IMRT and
conventional planning in terms of normal tissue sparing in 15 vulvar
cancer patients (112). Various IMRT techniques were used, with a
median number of seven beams (range 5 to 8). Normal tissue planning
constraints included: small bowel (<35% to receive ≥35 Gy), rectum
(<40% to receive ≥40 Gy), and bladder (<40% to receive ≥30 Gy).
The plans were considered acceptable if <5% of the PTV received
<100% of the prescribed dose and <10% received >110%. Mean
preoperative and postoperative prescribed doses were 46.4 and 50.4 Gy,
respectively. IMRT planning resulted in better sparing of the small
bowel, rectum, and bladder; however, unlike other reports (113), no
significant difference was seen in volume of the femoral heads
irradiated. Treatment was well tolerated, with only one patient
experiencing acute grade 3 toxicity and none developing a grade ≥3 late
toxicity. Two patients ultimately recurred locally, both were treated
postoperatively.
Investigators at the University of Pittsburgh also reported their
experience with preoperative chemotherapy and intensity modulated
pelvic-inguinal RT in 18 vulvar cancer patients (114). IMRT was
delivered twice daily during the first and last treatment weeks. Overall,
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treatment was well tolerated with no grade ≥3 late toxicities. Moreover,
no recurrences were seen in the nine patients achieving a pathologic
complete response, whereas three of five partial responders failed
locally.
Whole Abdominal Radiotherapy

WART involves the treatment of the entire peritoneal cavity. While in
the past, due to the limitations of machine field size, treatment was
delivered with a “moving strip” technique (115), WART is currently
delivered at most centers using large opposed APPA techniques. Care
needs to be taken at simulation to ensure that the upper border is placed
sufficiently high (1 to 1.5 cm superior to the dome of the diaphragm) to
cover the full excursion of the diaphragm during respiration. Laterally,
the field borders are set 3 to 4 cm beyond the peritoneal reflection.
Inferiorly, fields extend to the inferior obturator foramen. CT-based
planning is particularly helpful to ensure complete coverage of the entire
peritoneal cavity. Given the large volumes treated, selected patients may
need to be treated at an extended distance.
Patients undergoing WART are simulated in the supine position and
immobilized with their arms overhead. Prescribed doses range from 25
to 30 Gy in 1.5-Gy daily fractions, generally followed by a boost to the
pelvis (total pelvis dose, 45 to 50 Gy). Low–moderate beam energies are
recommended (6 MV) to avoid underdosing the anterior peritoneal
structures. At many centers, partial transmission blocks (2 to 5 half-
value layers) are placed on the posterior field over the kidneys (with a
0.5-cm margin) to limit the kidney dose to ≤18 Gy. Some centers elect
to limit the kidney dose to ≤15 Gy, particularly in women previously
treated with chemotherapy. If the total prescribed dose exceeds 25 Gy,
blocks are added at some centers to limit the liver dose to 25 Gy.
Various modifications to the conventional WART technique have been
introduced over the years to boost selected intra-abdominal and pelvic
sites. Martinez et al. at Stanford developed a technique incorporating
progressively shrinking fields delivering 30 Gy to the abdomen, 42 Gy to
the paraaortics and medial diaphragm surface, and 51 Gy to the pelvis
(40). Others have focused on hyperfractionated techniques, delivering
0.8 to 1 Gy twice daily to 30 to 30.4 Gy (116).
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Figure 25.8 Isodose distributions from an intensity-modulated whole abdominal radiotherapy (IM-
WART) plan with five gantry angles in a patient with locally advanced uterine cancer. Isodose
levels in %: (A) sagittal plane and (B) coronal plane. Also shown are isodose distributions from a
conventional WART plan delivered with opposed anterior–posterior:posterior–anterior (APPA)
fields in the patient: (C) sagittal plane and (D) coronal plane. From Hong L, Alektiar K, Chui C, et
al. IMRT of large fields: whole-abdomen irradiation. Int J Radiat Oncol Biol Phys. 2002;54:278–
289.
Limited data are available evaluating IMRT in gynecologic cancer

patients undergoing WART. Investigators at Memorial Sloan Kettering
Cancer Center compared IMRT using 5 equally spaced static fields and
conventional large field APPA techniques in 10 endometrial cancer
patients treated with WART (117). The target volume included a 1 cm
rim of liver but completely excluded the bilateral kidneys, which were
constrained to receive a maximum dose of 18 Gy. IMRT planning was
associated with significantly better coverage of the peritoneal cavity and
a 60% reduction in the volume of pelvic bones (a surrogate for pelvic
bone marrow) irradiated (Fig. 25.8). Others have reported equally
favorable early clinical results using volumetric arc IMRT techniques
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(118,119).
Stereotactic Body Radiotherapy

SBRT is a novel treatment approach used to deliver high, ablative doses
of radiation in a limited number of fractions (typically three to five) to
extracranial targets. Popularity is rapidly growing for this technique in
the treatment of primary and metastatic tumors, particularly in the liver,
lung, and spine tumors (120). Initially delivered on conventional linear
accelerators, SBRT today is currently delivered using specialized
machines such as the Cyberknife (Accuray Inc., Sunnyvale, CA), Novalis
(BrainLab AG, Feldkirchen, Germany), and the Trilogy or TrueBeam
(Varian Medical Systems, Palo Alto, CA). Moreover, while originally
developed using stereotactic localization methods, most SBRT
approaches today instead rely on image guidance, using either planar- or
volumetric-based imaging techniques (121).
Figure 25.9 Treatment plan of a gynecologic cancer patient with an isolated paraaortic recurrence
treated with stereotactic body radiation therapy (SBRT). The gross tumor volume (GTV) was
defined as the visible tumor in the paraaortic lymph node region on computed tomography (CT)
(innermost red line). The radiation dose was prescribed to the 81% isodose line of the maximum
dose to cover the GTV + 2-mm margin (sky-blue line indicated by the long arrow). The outermost
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line is the 30% isodose line (blue line indicated by the short arrow). From Choi CW, Cho CK, Yoo
SY, et al. Image-guided stereotactic body radiation therapy in patients with isolated paraaortic
lymph node metastases from uterine cervical and corpus cancer. Int J Radiat Oncol Biol Phys.
2009;74:147–153.
In recent years, several investigators have begun exploring the

potential of SBRT in gynecologic cancers. Choi et al. reported their
experience using SBRT to treat recurrent paraaortic lymph nodes with
the Cyberknife system (121). A total of 30 patients were treated with 33
to 45 Gy in three fractions, prescribed to the 73% to 87% isodose line.
Prior to treatment, fiducial markers were placed in adjacent vertebral
pedicles and used for online image guidance. In all patients, the GTV
consisted of the involved lymph node defined by either CT or PET/CT
imaging and was expanded by 2 mm to generate the PTV. Treatment was
well tolerated with few acute and chronic sequelae. Local control was
excellent, particularly in small volume (≤17 cc) disease. A treatment
plan in a representative patient from this series is shown in Figure 25.9.
The use of SBRT as a possible alternative to brachytherapy was
reported by Molla et al. (122,123). In their studies, the CTV was defined
as the vaginal vault, uterus/parametria, residual or recurrent tumor and
was expanded by 6 to 10 mm to generate the PTV. Following external-
beam RT, patients were immobilized and simulated in the supine
position with an endorectal probe in place to minimize internal organ
motion (which was also used during treatment). Using 5 to 15 static
IMRT fields, postoperative patients received 7 Gy × 2 while those with
intact disease underwent 4 Gy × 5 using the Novalis System. At a
median follow-up of 12.6 months, 15 of 16 patients remained locally
controlled. Only one patient developed a late grade 3 or higher toxicity.
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Figure 25.10 Tandem and ovoid applicator used for high dose rate (HDR) brachytherapy in
patients with intact cervical cancer.
Brachytherapy
Intracavitary Brachytherapy
ICB in gynecologic cancer patients was initially performed by placing
radioactive sources directly within the vagina and/or uterus. However,
by the 1960s, afterloading techniques were introduced whereby an
applicator was first positioned within the patient while the sources were
placed at a later time, typically after the patient had been transferred to
an isolated (and often shielded) hospital room. Using this approach,
radioactive sources were initially inserted manually but, more recently,
remote-afterloading techniques have been developed, significantly
reducing the exposure of the radiation oncologist and staff.
Various ICB applicators have been used in gynecologic cancer patients,
depending on the specific clinical scenario. In cervical cancer patients
treated with an intact uterus, the Fletcher–Suit–Delclos device based on
the original Manchester system (124) is typically used, consisting of a
curved tandem inserted into the uterus and two colpostats (ovoids)
placed in the vaginal fornice. Various tandem lengths and colpostat
diameters are available; most colpostats used today include shielding
along the medial aspects of the anterior and posterior colpostat faces,
reducing dose to the bladder and rectum (Fig. 25.10). A popular
variation of the traditional tandem and ovoid system consists of a
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tandem and ring, a system particularly useful in patients with
asymmetric fornices. Another ICB applicator used in the treatment of
cervical cancer is the Henschke device (125). Interstitial applicators
include the Vienna combined intracavitary and interstitial devices (126),
the Syed–Neblett template (127), and the Martinez Universal Perineal
Interstitial Template (MUPIT) (128).
While medically inoperable uterine cancer patients have historically
been treated with intrauterine Heyman–Simon capsules (129), newer
applicators have been developed, including the dual-tandem Rotte “Y”
device (130). In patients treated postoperatively, a variety of applicators
can be placed within the vagina, typically either a vaginal cylinder or
colpostats. The MIRALVA vaginal applicator consists of two ovoid
sources and a central tandem (131). The Capri vaginal applicator is a
multi-channel balloon applicator that consists of a single central channel
surrounded by two concentric arrays of channels (132).
Gynecologic cancer patients undergoing ICB can be treated using
either low dose rate (LDR) or high dose rate (HDR) techniques.
According to the ICRU Report 38, LDR is defined as dose rates ranging
from 0.4 to 2 Gy/h while HDR utilizes dose rates of >12 Gy/h, with
modern HDR systems capable of delivering dose rates exceeding 400
Gy/h (133). A variety of radioactive sources are used; however, the most
popular are Cesium-137 (137Cs) for LDR and high activity Iridium-192
(192Ir) for HDR. Unlike LDR, which is delivered in the hospital over
several days, HDR is performed in the outpatient setting over several
minutes obviating the need for anesthesia and prolonged bedrest,
making it an ideal approach in women with multiple medical
comorbidities. Other advantages of HDR include increased ability to
optimize treatment plans, reduced radiation exposure of personnel, and
better stability of the applicator during treatment. Disadvantages include
increased number of treatment sessions and greater equipment cost.
While some have argued that LDR is radiobiologically superior to HDR
in terms of normal tissue effects, particularly in patients with an intact
uterus (134), prospective randomized trials have demonstrated that the
two techniques are similar in terms of both tumor control and toxicity
(135,136). Some investigators favor the use of pulsed dose rate (PDR)
brachytherapy whereby intermittent “pulses” of radiation (10 to 30
minutes/h) are delivered using a machine similar to an afterloading HDR
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system. Proponents argue that PDR combines the logistic advantages of
HDR with the potential radiobiological advantages of LDR. However,
outcome data remain limited (137,138). Others have explored the use of
HDR electronic brachytherapy in gynecologic cancer patients (139).
Various doses and prescription points have been used for HDR and
LDR ICB. In patients with intact cervical cancer, dose is typically
prescribed to a reference point known as Point A. In the original
Manchester formulation (124), Point A was defined as 2 cm lateral to the
center of the intrauterine canal and 2 cm superior to the mucosal surface
of the lateral fornix, presumably at the medial edge of the broad
ligament where the uterine artery crosses the ureter. In the early 1950s,
however, the definition of Point A was modified to be 2 cm superior to
the external cervical os and 2 cm lateral to the intrauterine canal. A
second specified reference point in the Manchester system was Point B (3
cm lateral to Point A) which was felt to represent the location of the
obturator lymph nodes, although CT-based studies reveal that this is
rarely the case (140). Currently, the American Brachytherapy Society
(ABS) recommends using a sidewall dose point rather than Point B and,
in intact cervical cancer patients undergoing HDR ICB, Point H is the
recommended prescription dose point (Fig. 25.11) (141). At selected
centers, alternative prescription points are used including Point M (135)
and Point T (136). In postoperative cervical or uterine cancer patients or
patients with vaginal cancer, ICB is prescribed to either the vaginal
surface or at 0.5 cm depth. In uterine cancer patients treated with an
intact uterus (either preoperatively or definitively), ICB was traditionally
prescribed in terms of milligram-hours, but more recently most radiation
oncologists prescribe to 2 cm from the midpoint of the intrauterine
sources (142).
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Figure 25.11 Relevant geometry for intracavitary brachytherapy dosimetry for a tandem and ovoid
insertion. Finding Point H begins with drawing a line connecting the mid-dwell positions of the
ovoids. From the intersection of this line with tandem, move superiorly along the tandem 2 cm
plus the radius of the ovoids, and then 2 cm perpendicular to the tandem in the lateral direction.
The figure also shows variations in the position of the conventional Point A based on its evolving
definition. Ao located Point A in the original Manchester formulation. The positions of Af1 and Af2
follow the revised definition and Point M is based on the Madison System. Nag S, Erickson B,
Thomadsen B, et al. The American Brachytherapy Society recommendations for high-dose-rate
brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2009;48:201–211.
Additional points used in the planning of ICB of gynecologic cancer

patients include bladder and rectal reference points. The bladder point is
defined on planar orthogonal radiographs as the point on the surface of
the Foley balloon (pulled snugly into the bladder trigone) receiving the
highest dose, although volumetric studies have demonstrated that this
point consistently fails to capture the true maximum bladder dose (143).
A rectal reference point is defined 0.5 cm posterior to the posterior
vaginal wall.
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Intact cervical cancer patients undergoing LDR ICB are typically
treated with two separate insertions, although comparable tumor control
and complication rates have been reported with a single insertion,
particularly in early-stage patients (144). The first insertion should be
performed as soon as pelvic geometry allows, typically during the second
to fourth weeks of pelvic RT; the second 1 to 2 weeks later. Care should
be taken to complete the entire course of treatment within 8 weeks,
since more protracted courses have been associated with poorer
outcomes (145).
Intact cervical cancer patients undergoing HDR typically receive four
to six insertions. Given the increased number of fractions, HDR
necessitates interdigitating pelvic RT and the initial HDR insertions to
ensure that treatment is completed within 8 weeks, with the first
treatment delivered as soon as pelvic geometry allows. However, it is not
recommended that both ICB and external-beam RT or chemotherapy be
delivered on the same day. For postoperative cervical and uterine
cancers, vaginal cancer and medically inoperable uterine cancer, ICB is
delivered with one to two LDR or three to five HDR insertions.
Treatment planning for patients undergoing ICB has traditionally been
based on 2D radiographs. More recently, CT-based planning with
computerized dosimetry has come into wider use. In LDR patients, given
the limited overall number of source activities and positions, treatment
planning is typically performed manually by varying the various source
activities and positions, focusing on the doses to Point A as well as
normal tissues. Many radiation oncologists typically start with a
“standard” loading, for example, 15–10–10 milligram radium
equivalents (mg-Ra-eq) in the tandem and 10 to 15 mg-Ra-eq in both
colpostats in a patient with intact cervical cancer. The goal is to deliver
a total Point A dose (including the pelvic RT) of approximately 80 to 85
Gy for small tumors and 85 to 90 Gy for bulky tumors, while limiting the
rectal and bladder doses to <80% of the Point A dose. Different
investigators recommend different maximum acceptable rectal and
bladder doses, typically <75 to 80 Gy for the bladder and <70 to 75 Gy
for the rectum. Dose rates of 40 to 60 cGy/h to Point A are used at most
centers. Care must be taken not only to optimize the doses and dose
rates at the various reference and normal tissue points, but also to
review the isodose distributions themselves in an effort to obtain a
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classic “pear shape.” Patients treated postoperatively to the vaginal cuff
are typically treated with surface dose rates of 80 to 100 cGy/h or 50 to
80 cGy/h to 0.5 cm. Dose distributions in these patients should conform
to the shape of the cylinder.
Given the increased number of potential dwell positions and times,
HDR brachytherapy optimization lends itself to more sophisticated
optimization approaches. In fact, several inverse planning approaches
have been described in these patients (141). The ABS has provided
detailed guidelines on the optimization of HDR brachytherapy
treatments in patients with cervical cancer, using multiple optimization
points along the tandem and vaginal surface (141).
TABLE 25.1 American Brachytherapy Society Guidelines Definitive

Radiation Therapy for Cervical Cancer LDR Intracavitary
Brachytherapy
A large variety of dose–fractionation schemes have been used for

gynecologic cancer patients undergoing LDR and HDR brachytherapy.
The ABS has published guidelines for LDR and HDR ICB for both cervical
and uterine cancers (Tables 25.1 to 25.4) (141,142,146). No guidelines
are available for ICB dose–fractionation schemes for vaginal cancer.
Fortunately, a variety of LDR and HDR approaches have been published
using these techniques (56–59,147,148). The ABS has published
guidelines for interstitial brachytherapy for vaginal cancer and recurrent
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endometrial cancer, which will be discussed in a later section (149,150).
TABLE 25.2 American Brachytherapy Society Guidelines Definitive

Radiation Therapy for Cervical Cancer HDR Intracavitary
Brachytherapy
TABLE 25.3 American Brachytherapy Society Guidelines

Postoperative Radiation Therapy for Uterine Cancer HDR
Intracavitary Brachytherapy
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Considerable interest has recently focused on the use of volumetric
image-based treatment planning in intact cervical cancer patients.
European investigators have pioneered MRI-based approaches in these
patients. T2-weighted MRI using a pelvic coil provides excellent soft
tissue resolution and differentiation between tumor and normal tissues,
allowing more accurate assessment of parametrial and uterine tumor
extension (151,152) and improved sparing of the bladder and rectum
(153). Controversy exists, however, whether MRI is needed at every
insertion or whether CT imaging during subsequent insertions is
sufficient. Comparison studies have demonstrated that CT may
overestimate tumor width (154,155). However, if MRI with each implant
is infeasible, MRI may be used at the first insertion with CT-based
planning at subsequent implants for normal tissue delineation, relying on
the initial MRI for tumor delineation, especially in small tumors treated
with ICB (155,156).
TABLE 25.4 American Brachytherapy Society Guidelines Radiation
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Therapy for Inoperable Uterine Cancer HDR Intracavitary
Brachytherapy
Both the Group Européen de Curiethérapie-European Society for

Therapeutic Radiology and Oncology (GEC-ESTRO) and North American
IGRT Working Group have published recommendations for MRI-guided
brachytherapy in cervical cancer (157,158). The nomenclature that has
been adopted worldwide for treatment planning in these patients is
based on work primarily performed by GEC-ESTRO (Fig. 25.12). GEC-
ESTRO recommendations are to contour the GTV, high-risk CTV (HR-
CTV), intermediate-risk CTV, (IR-CTV), and normal tissues including the
bladder, rectum, sigmoid colon, and small bowel. The HR-CTV includes
the entire cervix as well as any macroscopic disease that persists in the
parametria, uterus, rectum, bladder, or vagina (but not to cross these
anatomic boundaries without clear rationale). The prescription goal is 80
to 95 Gy to the HR-CTV. The IR-CTV includes the HR-CTV, with the
intent to deliver 60 Gy to this volume. HR and IR-CTV contours in a
representative cervical cancer patient are shown in Figure 25.13.
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Figure 25.12 Group Européen de Curiethérapie–European Society for Therapeutic Radiology and
Oncology (GEC-ESTRO) working group concepts and terms used for image-guided
brachytherapy. Schematic diagram with coronal (A, C) and transverse (B, D) sections of an
optimized treatment plan for limited (A, B) and advanced (C, D) disease with partial remission
after external irradiation. GTV, gross tumor volume; HR CTV, high-risk clinical target volume; IR
CTV, intermediate-risk clinical target volume. From Haie-Meder C, Pötter R, Van Limbergen E, et
al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (1): concepts and
terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on
MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235–245.
Recommendations for reporting and quality assurance in patients

undergoing MRI-guided brachytherapy include calculation and reporting
of the minimum dose to 90% and 100% of the contoured target volume
(D90, D100). In addition, for evaluation within a single treatment scheme,
the volume encompassed by the 100% isodose line (IDL) (V100) should
also be determined. For the normal tissues, reporting of the ICRU
reference bladder and rectal points should continue for comparison with
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the dose–volume (DVH) data. The minimum dose received by the
maximally irradiated contiguous 0.1 cm3, 1 cm3, and 2 cm3 of the
bladder, rectum, sigmoid and small bowel, respectively, should also be
calculated and reported. Dose should be expressed as bioequivalent
doses given at 2 Gy per fraction, using the linear quadratic model, to
standardize for different dose rates. Provisional dose–volume constraints
for the normal tissues are to maintain the bladder below 85 to 90 Gy and
the rectum and sigmoid below 75 Gy. There has been validation for the
recommendation for rectum, but there is a weaker basis for
recommendations for bladder, sigmoid, and vagina (159,160).
Several promising outcome reports have been published in cervical
cancer patients undergoing MRI-guided HDR brachytherapy using the
GEC-ESTRO guidelines (160–164). In a series of the first 145 patients
(predominantly stages IIB to IIIB) treated at the University of Vienna, the
3-year actuarial local control was 85%. Local control was dependent on
tumor size with best results (>90%) seen in 2 to 5 cm tumors. However,
evaluating the most recent locally advanced patients with tumors >5
cm, the local control rate was 82%. Low rates of chronic treatment-
related toxicities were also seen.
MRI-guided brachytherapy in cervical cancer is the subject of the
multi-national observational EMBRACE study (165). The goal of the
study is to introduce MRI-guided brachytherapy to multiple centers in a
prospective setting and correlate DVH parameters for the tumor and
normal tissues with clinical outcomes. The results of the EMBRACE study
will then be used to design the interventional trial EMBRACE II.
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Figure 25.13 Target and organs at risk (OAR) delineation at the first magnetic resonance imaging
(MRI)-guided brachytherapy insertion. (A) Volume delineated on a coronal view, using clinical
drawings at the time of the first brachytherapy application. (B) Target and OAR delineation on the
MRI according to the GEC ESTRO guidelines, axial cut, and the corresponding sagittal level
identification (dotted line). From Sturdza A, Dimopoulos J, Potter R. MR-guided target delineation
in a patient with locally advanced cervical cancer undergoing brachytherapy (Case Study). In:
Mundt AJ, Roeske JC, eds. Image-Guided Radiation Therapy: A Clinical Perspective. Shelton, CT:
People’s Medical Publishing House—USA; 2011:430–435.
Investigators at Washington University have conducted several studies

on PET-guided brachytherapy planning for cervical cancer,
demonstrating the feasibility and dosimetric advantages of this approach
over conventional techniques (Fig. 25.14) (166–168). The procedure
involves scanning patients after both intravenous delivery of 18F-
fluorodeoxyglucose (18F-FDG) and insertion of tubes containing 18F-FDG
into the tandem and colpostats. To date, no outcome data are available
using this novel approach.
Interstitial Brachytherapy
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Interstitial brachytherapy involves implanting radioactive sources
directly within the target tissues. Unlike ICB, interstitial implants may be
temporary whereby sources are removed after the treatment, or
permanent with limited half-life sources left in place. In gynecologic
cancer patients undergoing interstitial brachytherapy, the great majority
are treated with temporary implants. Similar to patients undergoing ICB,
interstitial brachytherapy was previously performed using “live” sources
but is now performed primarily using afterloading techniques. As noted
in the ICB section above, afterloading approaches significantly reduce
the radiation exposure of the medical and ancillary staff, particularly
when performed using remote afterloading techniques.
While the great majority of gynecology patients undergoing
brachytherapy receive ICB (169), interstitial brachytherapy is
recommended in women in whom ICB would result in suboptimal dose
distributions (141). Interstitial brachytherapy should also be considered
in patients with extensive parametrial involvement, bulky primary
tumors, narrow or distal vaginal involvement, post-hysterectomy central
recurrence, or a history of prior RT. Other indications are distal or
extensive vaginal involvement (>0.5 cm thickness) or persistent disease
following external-beam RT and ICB. The ABS has published guidelines
describing potential candidates and proper techniques for interstitial
brachytherapy in various gynecologic malignancies including vaginal
cancer, vulvar cancer, and vaginal recurrence (149,150).
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Figure 25.14 Positron-emission tomography (PET)-guided brachytherapy planning in a patient
with cervical cancer. From Malyapa RS, Mutic S, Low DA, et al. Physiologic FDG-PET three-
dimensional brachytherapy treatment planning for cervical cancer. Int J Radiat Oncol Biol Phys.
2002;54:1140–1146.
Multiple afterloading commercial applicators are currently available

for interstitial brachytherapy, the most popular of which are the
Martinez Universal Perineal Interstitial Template (MUPIT) and the Syed–
Neblett template. The MUPIT consists of two acrylic cylinders, an acrylic
template with an array of equally spaced holes through which hollow
needles are inserted, and a cover plate (170). The Syed–Neblett template
is comprised of a vaginal cylinder, 2 lucite plates with 38 holes through
which hollow needles are introduced; 6 additional needles can be
inserted into groves along the vaginal cylinder (171). The Vienna ring
applicator allows placement of interstitial needles along with ICB
brachytherapy (Fig. 25.15) (164).
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Figure 25.15 The Vienna Ring applicator that allows placement of interstitial needs in patients
with residual parametrial involvement in conjunction with intracavitary brachytherapy. From
Sturdza A, Dimopoulos J, Potter R. MR-guided target delineation in a patient with locally
advanced cervical cancer undergoing brachytherapy (Case Study). In: Mundt AJ, Roeske JC, eds.
Image-Guided Radiation Therapy: A Clinical Perspective. Shelton, CT: People’s Medical
Publishing House—USA; 2011:430–435.
Pre-planning using CT and/or MRI can be used in patients undergoing

interstitial brachytherapy to help determine source number and
placement, particularly in patients treated with LDR techniques which
required ordering of radioactive seeds and/or wires. However, at the
time of implant with the patient under anesthesia, physical examination
should be performed to determine optimal applicator and needle
placement, based on the patient’s individual anatomy and tumor extent
(Fig. 25.16) (164,172). Care needs to be taken to avoid perforation of
adjacent organs including the small bowel, bladder, and rectum.
Intraoperative digital transrectal palpation is recommended not only to
assess tumor extent but also to help avoid implanting needles into the
rectum. Today, interstitial implants are performed at many centers under
image and/or laparoscopic guidance (173,174). Investigators at the
University of Vienna have also reported on the use of intraoperative
ultrasound guidance for transvaginal or transperineal needle placement
in advanced gynecologic malignancies (175). Care should be taken to
avoid excessive doses to the vaginal mucosa. If needles are inserted
along the periphery of the central cylinder of a Syed–Neblett template,
vaginal dose can be reduced with the placement of a sleeve over the
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cylinder (175).
Figure 25.16 Example customized implant plans for uterine cancer patients with (A) a vaginal
vault recurrence and (B) recurrence in the right lateral vaginal wall. Redrawn from Nag S, Yacoub
S, Copeland LJ, et al. Interstitial brachytherapy for salvage treatment of vaginal recurrences in
previously unirradiated endometrial cancer patients. Int J Radiat Oncol Biol Phys. 2002;54:1153–
1539.
As with ICB, interstitial brachytherapy can be delivered using LDR,

HDR, or PDR techniques (see earlier section on ICB for a discussion of
the advantages and disadvantages of each approach). 192Ir is the most
common isotope currently used, with high activity sources used for HDR.
Limited data are available using permanent 198Au or 103Pd interstitial
implants in gynecologic cancer patients (176,177).
Various doses and prescription points have been used for interstitial
brachytherapy in gynecologic cancer patients. The treatment volume is
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typically defined by the peripheral needles with or without an additional
5-mm margin, with the dose prescribed to an IDL encompassing this
volume. Growing interest is focused on MRI-based treatment planning
using the GEC-ESTRO guidelines in patients undergoing interstitial
brachytherapy (178).
Computerized dosimetry is useful to ensure dose homogeneity
throughout the implant. Maximum doses to the adjacent normal tissues
should be calculated and efforts made to spare the surrounding bladder
and rectum as much as possible. In a series of locally advanced cervical
cancer patients treated with interstitial brachytherapy, Demanes et al.
recommended bladder and rectal maximum doses <75% and <65% of
the prescribed dose, respectively (179). Nag et al. treated 13 locally
recurrent uterine cancer patients with salvage interstitial brachytherapy
and optimized the treatment plans to ensure maximum rectal and
bladder doses of 60% and 100% of the prescribed dose (146). Total
rectal doses of >76 Gy were noted in one study to be highly correlated
with the development of severe gastrointestinal toxicity including
rectovaginal fistulae (180). The ABS recommends equivalent cumulative
doses in 2-Gy fractions (EQD2) of ≤70 to 75 Gy to 2 cm3 of the rectum
and sigmoid colon and ≤90 Gy to 2 cm3 bladder for the entire course of
therapy (149).
Given the invasive nature of interstitial brachytherapy, an effort is
made to minimize the number of implants performed. Most patients
undergoing LDR interstitial brachytherapy are treated with a single
insertion, which requires several days of bedrest in the hospital. Patients
undergoing HDR interstitial brachytherapy undergo one to three
implants, often with multiple fractions delivered during each implant. If
multiple implants are performed in patients with intact cervical cancer,
it is recommended to initiate brachytherapy during external-beam RT to
avoid unnecessary treatment protractions (141). As with ICB, interstitial
brachytherapy should not be performed on the same day as either
external-beam RT or chemotherapy.
The ABS published guidelines on appropriate dose–fractionation
schedules to be used for gynecologic cancer patients receiving HDR
interstitial brachytherapy with cumulative EQD2 doses ranging from
71.5 to 81.5 Gy delivered with a combinations of EBRT and 3 to 10 HDR
fractions (Table 21.5) (150). In a series of 69 locally advanced/recurrent
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gynecologic cancer patients undergoing a single LDR interstitial implant,
Gupta et al. at William Beaumont Hospital prescribed median doses of
32 and 35 Gy in patients treated with and without external-beam RT,
respectively (181). Five-year actuarial local control rates were 54% and
44% in the entire group and the subset of primary cervical cancer
patients, respectively. Severe complications (grade 4) were noted in 14%
of patients. Demanes et al. at the California Endocurietherapy Cancer
Center (CET) presented the outcomes of 62 previously untreated locally
advanced cervical cancer patients undergoing HDR interstitial
brachytherapy (six fractions of 5.5 to 6 Gy) combined with external-
beam RT (179). Overall, the local control of the entire group was 94%,
with rates exceeding 90% even in stage IIB to IIIB patients. Severe
(grade 3 to 4) late sequelae were seen in 6.5% of patients.
TABLE 25.5 American Brachytherapy Society Guidelines Interstitial

HDR Brachytherapy for Gynecologic Cancer
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Other groups have published outcomes of patients treated with a
variety of interstitial dose–fractionation regimens, including in cervical
(178,182,183), vaginal (183–187), vulvar (183–189), and locally
recurrent uterine cancers (172,190), using predominantly HDR
techniques. More limited data exist regarding PDR dose–fractionation
regimens for interstitial brachytherapy (191).
FUTURE DIRECTIONS
Radiotherapeutic approaches and treatment planning in gynecologic
cancer patients are rapidly evolving. Long-held techniques and concepts
are rapidly giving way to ever newer ones. One area of current intense
research is the development of adaptive RT in gynecologic patients. It is
well known that in selected patients, particularly woman with bulky
cervical cancer, tumors rapidly regress throughout treatment and re-
planning may be beneficial (192). However, sophisticated high-speed
techniques are needed before adaptive RT can be introduced clinically
(193,194). Novel image-guided approaches are also currently being
explored which may further enhance IMRT treatment in these patients,
including bone marrow–sparing techniques which reduce dose to
functionally active bone marrow sites (195). It is also possible in the
future that novel approaches including SBRT (120,195,196) and even
proton therapy, (197) which are both growing in popularity throughout
the world, will be increasingly applied to gynecologic cancer patients.
KEY POINTS
• Radiation is commonly used as definitive treatment in early-stage
gynecologic cancer and in conjunction with surgery and/or
chemotherapy in women with locally advanced disease.
• Radiation therapy is recommended over surgery in early-stage
cervical cancer patients as lesion size and vaginal involvement
increase. As tumor diameter exceeds 4 cm, there is increased
likelihood of tumor spread to surrounding organs and regional
lymph nodes, which would necessitate adjuvant RT following
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surgery.
• In patients with locally advanced (stages IIB to IVA) cervix cancer,
radiation is combined with concomitant chemotherapy: multiple
prospective randomized trials have demonstrated a survival
advantage to the combined approach.
• Definitive RT in cervical cancer is administered with a combination
of pelvic RT and brachytherapy, except in earliest-stage patients for
whom brachytherapy or surgery alone is sufficient.
• The majority of patients with uterine cancer undergo upfront
surgery, consisting of total abdominal hysterectomy and bilateral
salpingo-oophorectomy (TAH-BSO), with RT delivered
postoperatively to selected patients based on pathologic features in
the surgical specimen: depth of invasion, tumor grade, and
lymphovascular invasion, cervical involvement.
• Following publication of GOG 122, stages III to IV endometrial
cancer is treated with adjuvant chemotherapy. GOG 258 is
currently randomizing locally advanced patients to chemotherapy
versus chemoradiotherapy. The results of this important trial will
help define the role of RT in these patients.
• Treatment of vulvar cancer consists of upfront surgery (radical
vulvectomy or radical wide local excision in selected patients with
small, well-lateralized tumors) with RT delivered adjuvantly in
patients with high-risk features including LVI, tumor invasion >5
mm, surgical margins <8 mm, grade 3 disease, and microscopic
positive margins.
• In a patient with intact cervical cancer: The goal is to deliver a total
Point A dose (including the pelvic RT) of approximately 80 to 85 Gy
for small tumors and 85 to 90 Gy for bulky tumors, while limiting the
rectal and bladder doses to <80% of the Point A dose.
• Both the Group Européen de Curiethérapie-European Society for
Therapeutic Radiology and Oncology (GEC-ESTRO) and North
American IGRT Working Group have published recommendations
for MRI-guided brachytherapy in cervical cancer. MRI-guided
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brachytherapy in cervical cancer is the subject of the multi-national
observational EMBRACE study. The goal of the study is to
introduce MRI-guided brachytherapy to multiple centers in a
prospective setting and correlate DVH parameters for the tumor
and normal tissues with clinical outcomes. The results of the
EMBRACE study will then be used to design the interventional trial
EMBRACE II.
• Interstitial brachytherapy should be considered in patients with
extensive parametrial involvement, bulky primary tumors, narrow or
distal vaginal involvement, post-hysterectomy central recurrence, or
a history of prior RT.
QUESTIONS
1. What structures comprise the CTV for stage IIIA cervical cancer
when using definitive IMRT?
A. GTV, cervix, uterus, and parametria, including the ovaries
B. GTV, cervix, uterus, and parametria, excluding the ovaries
C. GTV, cervix, uterus, parametria excluding the ovaries and
entire vagina
D. GTV, cervix, uterus, parametria including the ovaries and
entire vagina
2. Which examination best delineates the high-risk CTV when
performing image-based contouring with IV contrast for cervical
cancer brachytherapy?
A. CT scan before the implant only
B. CT scan before and at the time of the implant
C. MRI before the implant only
D. MRI before and at the time of the implant
3. What is considered to be a close surgical margin in fixed tissue
for carcinoma of the vulva?
A. 8 mm
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B. 10 mm
C. 15 mm
D. 18 mm
4. When treating cervical cancer with EBRT and HDR
brachytherapy, the EQD2 D2 cc for the bladder (the minimum
dose in the MOST irradiated 2 cm3 normal tissue volume) should
not exceed:
A. 60 Gy
B. 70 Gy
C. 80 Gy
D. 90 Gy
5. What was the HDR brachytherapy boost regimen (following 45
Gy in 25 fractions of EBRT) used in RTOG 0921?
A. 6 Gy × 3 to the vaginal mucosa
B. 6 Gy × 2 to the vaginal mucosa
C. 7 × 3 to 0.5 cm depth
D. 5.5 × 4 to 0.5 cm depth
ANSWERS
1. D The CTV includes the entire GTV as determined by the
intermediate/high signal seen in T2-weighted MR images;
the entire cervix if not included within the GTV contour;
the entire uterus; the entire parametrium including
ovaries. The entire mesorectum should be included if the
uterosacral ligament is involved; for the vagina: if there is
minimal or no vaginal extension of disease include the
upper half, if there is upper vaginal involvement include
the upper two-thirds, and if there is extensive vaginal
involvement then include the entire vagina.
Reference: Lim K, Small W, Portelance L, et al. Consensus
guidelines for delineation of clinical target volume for
intensity-modulated pelvic radiotherapy for the definitive
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treatment of cervix cancer. Int J Radiat Oncol Biol Phys.
2011;79(2):348–355.
2. D The advantage of MRI compared to CT with IV contrast is
that MRI allows for distinction between the corpus and the
cervix.
CT with IV contrast can delineate the cervicouterine
junction at the intersection of the uterine vessels and the
cervix which allows demarcation of the upper border of
the cervix. However, only MRI before and at the time of
brachytherapy can accurately delineate the superior
border of the HR-CTV for patients with tumor extending
beyond the cervix. If MRI is unavailable, the initial tumor
extension into the corpus, or the entire canal, must be
contoured to ensure that the CTV covers the entire extent
of the areas at risk. Delineation of the HR-CTV and IR-CTV
is also best informed by gynecological examination with
drawings at the initial evaluation and at the time of
brachytherapy.
Reference: Viswanathan AN, Dimopoulos J, Kirisits C, et
al. Computed tomography versus magnetic resonance
imaging based contouring in cervical cancer
brachytherapy: results of a prospective trial and
preliminary guidelines for standardized contours. Int J
Radiation Oncology Biol Phys. 2007;68(2):491–498.
3. A Surgical margin is the most powerful predictor of local
vulvar recurrence. Combining factors in a stepwise
logistical regression does not significantly improve this
predictive value. Accounting for specimen preparation and
fixation, a 1-cm tumor-free surgical margin on the vulva
results in a high rate of local control, whereas a margin
less than 8 mm is associated with a 50% chance of
recurrence.
These data come from a series of 135 patients with
vulvar squamous cell carcinoma treated at UCLA and City
of Hope Medical Centers between 1957 and 1985. Sixty-
two cases were stage I, 48 stage II, 18 stage III, and 7 stage
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IV. Twenty-one patients developed a local vulvar
recurrence after primary radical resection. Ninety-one
patients had a surgical tumor-free margin ≥8 mm on
tissue section and none had a local vulvar recurrence.
Forty-four patients had a margin less than 8 mm; 21 had a
local recurrence and 23 did not (p ≤ 0.0001).
Reference: Heaps JM, Fu YS, Montz FJ, et al. Surgical-
pathologic variables predictive of local recurrence in
squamous cell carcinoma of the vulva. Gynecol Oncol.
1990;38(3):309.
4. D The EQD2 D2 cc of bladder is = 90 Gy.
Reference: Viswanathan, Beriwal S, De Los Santos JF, et
al. American Brachytherapy Society consensus guidelines
for locally advanced carcinoma of the cervix. Part II: High-
dose-rate brachytherapy. Brachytherapy. 2012;11(1):47–52.
5. A Choices C and D are both dose/fractionation schemes for
HDR intracavitary brachytherapy when used adjuvantly
without EBRT.
Reference: RTOG 0921 Protocol.
REFERENCES
1. Cancer Factors and Figures 2014: American Cancer Society 2014
[cited 2014 10/24/14]. Available from:
http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/
2. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological
cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol.
2006;20(2):207–225.
3. Grigsby PW, Perez CA. Radiotherapy alone for medically inoperable
carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat
Oncol Biol Phys. 1991;21(2):375–378.
4. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical
surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet.
1997;350(9077):535–540.
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5. Bloemers MC, Portelance L, Legler C, et al. Preservation of ovarian
function by ovarian transposition prior to concurrent chemotherapy
and pelvic radiation for cervical cancer. A case report and review of
the literature. Eur J Gynaecol Oncol. 2010;31(2):194–197.
6. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Vaginal changes
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130. Coon D, Beriwal S, Heron DE, et al. High-dose-rate Rotte “Y”
applicator brachytherapy for definitive treatment of medically
inoperable endometrial cancer: 10-year results. Int J Radiat Oncol
Biol Phys. 2008;71(3):779–783.
131. Perez CA, Slessinger E, Grigsby PW. Design of an afterloading
vaginal applicator (MIRALVA). Int J Radiat Oncol Biol Phys.
1990;18(6):1503–1508.
132. Park SJ, Chung M, Demanes DJ, et al. Dosimetric comparison of 3-
dimensional planning techniques using an intravaginal multichannel
balloon applicator for high-dose-rate gynecologic brachytherapy. Int
133. ICRU Report 38. Dose and volume specifications for reporting
intracavitary therapy in gynecology. Bethesda, MD: ICRU; 1983:1–
16.
134. Eifel PJ. High-dose-rate brachytherapy for carcinoma of the cervix:
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high tech or high risk? Int J Radiat Oncol Biol Phys. 1992;24(2):383–
386; discussion 7–8.
135. Stitt JA, Fowler JF, Thomadsen BR, et al. High dose rate
intracavitary brachytherapy for carcinoma of the cervix: the
Madison system: I. Clinical and radiobiological considerations. Int J
136. Maruyama Y, Nagell JR Jr., Wrede DE, et al. Approaches to
optimization of dose in radiation therapy of cervix carcinoma.
Radiology. 1976;120(2):389–398.
137. Hareyama M, Sakata K, Oouchi A, et al. High-dose-rate versus low-
dose-rate intracavitary therapy for carcinoma of the uterine cervix:
a randomized trial. Cancer. 2002;94(1):117–124.
138. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.
Phase III randomized trial comparing LDR and HDR brachytherapy
in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys.
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139. Dooley WC, Thropay JP, Schreiber GJ, et al. Use of electronic
brachytherapy to deliver postsurgical adjuvant radiation therapy for
endometrial cancer: a retrospective multicenter study. Onco Targets
Ther. 2010;3:197–203.
140. Lee LJ, Sadow CA, Russell A, et al. Correlation of point B and
lymph node dose in 3D-planned high-dose-rate cervical cancer
brachytherapy. Int J Radiat Oncol Biol Phys. 2009;75(3):803–809.
141. Nag S, Erickson B, Thomadsen B, et al. The American
Brachytherapy Society recommendations for high-dose-rate
brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol
Phys. 2000;48(1):201–211.
142. Nag S, Erickson B, Parikh S, et al. The American Brachytherapy
Society recommendations for high-dose-rate brachytherapy for
carcinoma of the endometrium. Int J Radiat Oncol Biol Phys.
2000;48(3):779–790.
143. Patil VM, Patel FD, Chakraborty S, et al. Can point doses predict
volumetric dose to rectum and bladder: a CT-based planning study
in high dose rate intracavitary brachytherapy of cervical carcinoma.
Br J Radiol. 2011;84(1001):441–448.
144. Rotmensch J, Connell PP, Yamada D, et al. One versus two
intracavitary brachytherapy applications in early-stage cervical
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cancer patients undergoing definitive radiation therapy. Gynecol
Oncol. 2000;78(1):32–38.
145. Petereit DG, Sarkaria JN, Chappell R, et al. The adverse effect of
treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol
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146. Nag S, Chao C, Erickson B, et al. The American Brachytherapy
Society recommendations for low-dose-rate brachytherapy for
carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2002;52(1):33–
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147. Hegemann S, Schafer U, Lelle R, et al. Long-term results of
radiotherapy in primary carcinoma of the vagina. Strahlenther Onkol.
2009;185(3):184–189.
148. Mock U, Kucera H, Fellner C, et al. High-dose-rate (HDR)
brachytherapy with or without external beam radiotherapy in the
treatment of primary vaginal carcinoma: long-term results and side
effects. Int J Radiat Oncol Biol Phys. 2003;56(4):950–957.
149. Beriwal S, Demanes DJ, Erickson B, et al. American Brachytherapy
Society consensus guidelines for interstitial brachytherapy for
vaginal cancer. Brachytherapy. 2012;11(1):68–75.
150. Small W Jr, Beriwal S, Demanes DJ, et al. American Brachytherapy
Society consensus guidelines for adjuvant vaginal cuff
brachytherapy after hysterectomy. Brachytherapy. 2012;11(1):58–
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151. Dimopoulos JC, Schard G, Berger D, et al. Systematic evaluation of
MRI findings in different stages of treatment of cervical cancer:
potential of MRI on delineation of target, pathoanatomic structures,
and organs at risk. Int J Radiat Oncol Biol Phys. 2006;64(5):1380–
1388.
152. Mitchell DG, Snyder B, Coakley F, et al. Early invasive cervical
cancer: tumor delineation by magnetic resonance imaging,
computed tomography, and clinical examination, verified by
pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study. J
Clin Oncol. 2006;24(36):5687–5694.
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bladder reference point. Radiother Oncol. 2003;68(3):269–276.
154. Viswanathan AN, Dimopoulos J, Kirisits C, et al. Computed
tomography versus magnetic resonance imaging-based contouring in
cervical cancer brachytherapy: results of a prospective trial and
preliminary guidelines for standardized contours. Int J Radiat Oncol
Biol Phys. 2007;68(2):491–498.
155. Eskander RN, Scanderbeg D, Saenz CC, et al. Comparison of
computed tomography and magnetic resonance imaging in cervical
cancer brachytherapy target and normal tissue contouring. Int J
Gynecol Cancer. 2010;20(1):47–53.
156. Nesvacil N, Potter R, Sturdza A, et al. Adaptive image guided
brachytherapy for cervical cancer: a combined MRI-/CT-planning
technique with MRI only at first fraction. Radiother
Oncol.2013;107(1):75–81.
157. Haie-Meder C, Potter R, Van Limbergen E, et al. Recommendations
from Gynaecological (GYN) GEC-ESTRO Working Group (I):
concepts and terms in 3D image based 3D treatment planning in
cervix cancer brachytherapy with emphasis on MRI assessment of
GTV and CTV. Radiother Oncol. 2005;74(3):235–245.
158. Nag S, Cardenes H, Chang S, et al. Proposed guidelines for image-
based intracavitary brachytherapy for cervical carcinoma: report
from Image-Guided Brachytherapy Working Group. Int J Radiat
Oncol Biol Phys. 2004;60(4):1160–1172.
159. Koom WS, Sohn DK, Kim JY, et al. Computed tomography-based
high-dose-rate intracavitary brachytherapy for uterine cervical
cancer: preliminary demonstration of correlation between dose-
volume parameters and rectal mucosal changes observed by flexible
sigmoidoscopy. Int J Radiat Oncol Biol Phys. 2007;68(5):1446–1454.
160. Potter R, Dimopoulos J, Bachtiary B, et al. 3D conformal HDR-
brachy- and external beam therapy plus simultaneous cisplatin for
high-risk cervical cancer: clinical experience with 3 year follow-up.
161. Tanderup K, Georg D, Potter R, et al. Adaptive management of
cervical cancer radiotherapy. Semin Radiat Oncol. 2010;20(2):121–
129.
162. Dimopoulos JC, Potter R, Lang S, et al. Dose-effect relationship for
local control of cervical cancer by magnetic resonance image-guided
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brachytherapy. Radiother Oncology. 2009;93(2):311–315.
163. Potter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI
assisted dose volume adaptation and dose escalation in
brachytherapy of locally advanced cervix cancer. Radiother Oncol.
2007; 83(2):148–155.
164. Sturdza A DJ, Potter R. MR-guided target delineation in a patient with
locally advanced cervical cancer undergoing brachytherapy (Case
Study). In: Mundt AJ, ed. Shelton, CT: People’s Medical Publishing
House-USA; 2011: 430–435.
165. [cited 2014 7 October]. Available at:
https://www.embracestudy.dk/.
166. Grigsby PW. 18F-FDG PET-guided target delineation for external
beam radiotherapy and intracavitary brachytherapy planning in a
patient with stage IIB cervical cancer (Case Study). In: Mundt AJ,
Roeske JC, eds. Image-Guided Radiation Therapy: A Clinical
Perspective. Shelton, CT: People’s Medical Publishing House-USA;
2011:436–439.
167. Malyapa RS, Mutic S, Low DA, et al. Physiologic FDG-PET three-
dimensional brachytherapy treatment planning for cervical cancer.
168. Mutic S, Grigsby PW, Low DA, et al. PET-guided three-dimensional
treatment planning of intracavitary gynecologic implants. Int J
169. Erickson B, Eifel P, Moughan J, et al. Patterns of brachytherapy
practice for patients with carcinoma of the cervix (1996–1999): a
patterns of care study. Int J Radiat Oncol Biol Phys.
2005;63(4):1083–1092.
170. Martinez A, Edmundson GK, Cox RS, et al. Combination of external
beam irradiation and multiple-site perineal applicator (MUPIT) for
treatment of locally advanced or recurrent prostatic, anorectal, and
1985;11(2):391–398.
171. Ampuero F, Doss LL, Khan M, et al. The Syed-Neblett interstitial
template in locally advanced gynecological malignancies. Int J
172. Nag S, Yacoub S, Copeland LJ, et al. Interstitial brachytherapy for
salvage treatment of vaginal recurrences in previously unirradiated
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endometrial cancer patients. Int J Radiat Oncol Biol Phys. 2002;
54(4):1153–1159.
173. Erickson B, Albano K, Gillin M. CT-guided interstitial implantation
of gynecologic malignancies. Int J Radiat Oncol Biol Phys. 1996;
36(3):699–709.
174. Nag S, Martinez-Monge R, Ellis R, et al. The use of fluoroscopy to
guide needle placement in interstitial gynecological brachytherapy.
175. Weitmann HD, Knocke TH, Waldhausl C, et al. Ultrasound-guided
interstitial brachytherapy in the treatment of advanced vaginal
recurrences from cervical and endometrial carcinoma. Strahlenther
Onkol. 2006;182(2):86–95.
176. Randall ME, Evans L, Greven KM, et al. Interstitial reirradiation for
recurrent gynecologic malignancies: results and analysis of
prognostic factors. Gynecol Oncol. 1993;48(1):23–31.
177. Brabham JG, Cardenes HR. Permanent interstitial reirradiation with
198Au as salvage therapy for low volume recurrent gynecologic
malignancies: a single institution experience. Am J Clin Oncol.
2009;32(4):417–422.
178. Yoshida K, Yamazaki H, Takenaka T, et al. A dose-volume analysis
of magnetic resonance imaging-aided high-dose-rate image-based
interstitial brachytherapy for uterine cervical cancer. Int J Radiat
Oncol Biol Phys. 2010;77(3):765–772.
179. Demanes DJ, Rodriguez RR, Bendre DD, et al. High dose rate
transperineal interstitial brachytherapy for cervical cancer: high
pelvic control and low complication rates. Int J Radiat Oncol Biol
Phys. 1999;45(1):105–112.
180. Kasibhatla M, Clough RW, Montana GS, et al. Predictors of severe
gastrointestinal toxicity after external beam radiotherapy and
interstitial brachytherapy for advanced or recurrent gynecologic
malignancies. Int J Radiat Oncol Biol Phys. 2006;65(2):398–403.
181. Gupta AK, Vicini FA, Frazier AJ, et al. Iridium-192 transperineal
interstitial brachytherapy for locally advanced or recurrent
gynecological malignancies. Int J Radiat Oncol Biol Phys.
1999;43(5):1055–1060.
182. Mikami M, Yoshida K, Takenaka T, et al. Daily computed
tomography measurement of needle applicator displacement during
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high-dose-rate interstitial brachytherapy for previously untreated
uterine cervical cancer. Brachytherapy. 2011;10(4):318–324.
183. Beriwal S, Bhatnagar A, Heron DE, et al. High-dose-rate interstitial
brachytherapy for gynecologic malignancies. Brachytherapy.
2006;5(4):218–222.
184. Wei L, Shi M. Clinical outcomes of definitive intensity-modulated
radiation therapy with fluorodeoxyglucose-positron emission
tomography simulation in patients with locally advanced cervical
cancer. In regard to Kidd et al. (Int J Radiat Oncol Biol Phys
2010;77:1085–1091.). Int J Radiat Oncol Biol Phys. 2011;79(2):636–
637.
185. de Crevoisier R, Sanfilippo N, Gerbaulet A, et al. Exclusive
radiotherapy for primary squamous cell carcinoma of the vagina.
Radiother Oncol. 2007;85(3):362–370.
186. Beriwal S, Heron DE, Mogus R, et al. High-dose rate brachytherapy
(HDRB) for primary or recurrent cancer in the vagina. Radiat Oncol.
2008;3:7.
187. Tewari KS, Cappuccini F, Puthawala AA, et al. Primary invasive
carcinoma of the vagina: treatment with interstitial brachytherapy.
Cancer. 2001;91(4):758–770.
188. Pohar S, Hoffstetter S, Peiffert D, et al. Effectiveness of
brachytherapy in treating carcinoma of the vulva. Int J Radiat Oncol
Biol Phys. 1995;32(5):1455–1460.
189. Tewari K, Cappuccini F, Syed AM, et al. Interstitial brachytherapy
in the treatment of advanced and recurrent vulvar cancer. Am J
Obstet Gynecol. 1999;181(1):91–98.
190. Tewari K, Cappuccini F, Brewster WR, et al. Interstitial
brachytherapy for vaginal recurrences of endometrial carcinoma.
Gynecol Oncol. 1999;74(3):416–422.
191. Seeger AR, Windschall A, Lotter M, et al. The role of interstitial
brachytherapy in the treatment of vaginal and vulvar malignancies.
Strahlenther Onkol. 2006;182(3):142–148.
192. van de Bunt L, van der Heide UA, Ketelaars M, et al. Conventional,
conformal, and intensity-modulated radiation therapy treatment
planning of external beam radiotherapy for cervical cancer: the
impact of tumor regression. Int J Radiat Oncol Biol Phys.
2006;64(1):189–196.
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193. Men C, Jia X, Jiang SB. GPU-based ultra-fast direct aperture
optimization for online adaptive radiation therapy. Phys Med Biol.
2010;55(15):4309–4319.
194. Men C, Romeijn HE, Jia X, et al. Ultrafast treatment plan
optimization for volumetric modulated arc therapy (VMAT). Med
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195. Liang Y BM, Hoh C, et al. Correlation between increased bone
marrow glucose metabolism and acute changes in fat fraction during
pelvic radiation therapy. Int J Radiat Oncol Biol Phys.
2010;78(3):S118-S119.
196. Higginson DS, Morris DE, Jones EL, et al. Stereotactic body
radiotherapy (SBRT): technological innovation and application in
gynecologic oncology. Gynecol Oncol 2011;120(3):404–412.
197. Song WY, Huh SN, Liang Y, et al. Dosimetric comparison study
between intensity modulated radiation therapy and three-
dimensional conformal proton therapy for pelvic bone marrow
sparing in the treatment of cervical cancer. J Appl Clin Med Phys
2010;11(4):3255.
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26A Cancer of the Genitourinary
Tract: Prostate Cancer
Jason Chan and Albert Chang
INTRODUCTION
Epidemiology
Prostate cancer is the most common solid malignancy in men in the
United States with 233,000 new cases diagnosed and 29,480 dying of
prostate cancer in 2014 (1). Since PSA screening in the 1990s, prostate
cancer mortality rates have dropped dramatically (2). Because of earlier
diagnosis from screening with the majority of cases being localized, only
one in seven men will die from their disease (3). Even so, prostate cancer
is a heterogeneous disease with a highly variable natural history.
Advanced prostate cancer is not only a serious threat to life expectancy
but also to quality of life. It is therefore paramount to discern the
difference between aggressive and indolent disease to personalize
treatment for patients.
Clinical Anatomy
Anatomy
The prostate consists of four anatomic zones: peripheral, central,
transitional, and the anterior fibromuscular zone. The prostate gland lies
posterior to the pubic symphysis, anterior to the rectum, inferior to the
bladder neck, and superior to the urogenital diaphragm. A normal
prostate gland is 20 to 30 cc and the peripheral zone represents two-
thirds of this volume. Prostate cancer is often multifocal with the
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majority of tumors arising from the peripheral zone. The urethra
penetrates the prostate as it descends from the bladder neck to the
urogenital diaphragm. Nerve and vessel bundles course along the lateral
surfaces of the prostate in the superior–inferior direction and attach to
the base at the superior pedicles, and to the apex at the inferior pedicles.
Local Growth Patterns

The prostatic capsule has an inner layer of smooth muscle and an outer
layer of connective tissue though the capsule is ill-defined at the apex.
Tumor that extends beyond the capsule of the prostate may involve the
periprostatic fat, seminal vesicles, bladder neck, and neurovascular
bundles (superior and inferior pedicles). Tumor that invades superiorly
from the base of the prostate may cause bladder neck obstruction and
cause frequency, urgency, incomplete bladder emptying, and weak
urinary stream. Prostate cancer in the apex that extends to the
membranous urethra may cause similar obstructive urinary symptoms.
Seminal vesicle invasion may manifest as hematospermia. Extracapsular
extension is most common posterolaterally where the superior pedicles
course along the prostate base, which may result in erectile dysfunction.
While some patients present with symptoms of bulky tumors, many
patients are diagnosed with prostate cancer without ever developing
symptoms.
Regional and Distant Metastasis

Prostate cancer metastasizes through the blood and lymphatic systems.
The prostate gland is predominantly drained by the obturator and
internal iliac nodes (4). The external iliac, presacral, and presciatic
nodes are also involved with prostatic lymphatic drainage. Distant
metastasis most commonly results in osteoblastic bone lesions to the
axial skeleton.
Principles of Radiation Therapy in Prostate Cancer

Radiation therapy plays a critical role in the treatment of many of the
clinical stages of prostate cancer including (1) definitive treatment of
localized disease, (2) adjuvant treatment following radical prostatectomy
(RP), (3) salvage therapy following disease recurrence, and (4) palliation
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of locally advanced and metastatic disease.
Modern radiation therapy techniques for prostate cancer include
external photon and particle beam treatments, as well as low dose rate
(LDR) and high dose rate (HDR) brachytherapy radioisotope
implantation. External radiation now routinely consists of 3-dimensional
(3D) planning with CT and/or MRI, conformal treatment delivery with
inverse planning and IMRT, and image localization with various
techniques utilizing fiducial markers, ultrasound, and cone beam CT.
These improved treatment techniques have allowed for safe delivery of
higher radiation doses, which correlate with improved PSA control (5,6)
and overall survival (7) with only modest changes in toxicity (8) and
patient-reported quality of life (9). Brachytherapy, either performed
alone or in combination with EBRT, is another method of delivering
escalated doses of radiation therapy to the prostate.
The prostate is a moving target and delivery of higher radiation doses
not only require smaller treatment margins but accurate target tracking.
The unpredictable position and motion of the prostate gland puts
neighboring structures, most importantly the rectum and bladder, at risk
during radiation treatments. Inadequate target tracking can also lead to
underdosing of the tumor and inferior therapeutic outcomes and
increased toxicity (10). Therefore, target volume delineation, tumor
localization, patient immobilization and simulation, and treatment
delivery must be carefully considered.
CLINICAL ASSESSMENT
Diagnosis
A nodule palpated on digital rectal examination (DRE) warrants further
evaluation with a transrectal ultrasound (TRUS)-guided biopsy to rule
out cancer. With routine PSA screening, it is often an elevated absolute
PSA level or abnormal PSA kinetics that prompts a biopsy as a palpable
nodule is often not present at the time of diagnosis. An extended sextant
biopsy consisting of at least 12 biopsy cores is typically recommended
(11,12). A pathologist makes the definitive diagnosis and assigns a
Gleason primary and secondary grade to the biopsy specimen as an
indication of tumor aggressiveness. Unfortunately, TRUS-guided biopsies
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tend to underdiagnose and understage prostate cancers. Roughly one-
third of prostate cancers are not detected on first biopsy and roughly
half of detected cancers are less than the final Gleason scores assigned
on prostatectomy samples (13). Recent implementation of MRI-guided or
MRI-ultrasound fusion biopsies has been suggested to improve the
staging accuracy of biopsies (14). The extent of the primary tumor, PSA
level, and Gleason grade are used to determine the patient’s risk group,
which guides decision-making regarding treatment.
Risk Stratification
At least 130 different algorithms or nomograms have been developed to
predict clinically relevant outcomes for counseling patients on
appropriate treatment strategies (15). As previously mentioned, the
clinical T stage, Gleason grade, and pretreatment PSA level are the most
important prognostic indicators that determine a patient’s risk group.
The NCCN stratification system groups patients into five risk categories
(Table 26A.1): very low, low, intermediate, high, and very high
(although most typically only low, intermediate, and high risk groups
have been used). Similarly, the AJCC prognostic groups are based on T
stage, Gleason score, and pretreatment PSA. However, broad
heterogeneity can exist within a particular risk group and newer
classification systems incorporating factors such as age and percentage
of positive biopsies (16) and genetic testing (17) are increasingly used to
further risk stratify patients.
TABLE 26A.1 2010 American Joint Committee on Cancer (AJCC)

Clinical Primary Tumor (T) Staging for Prostate Cancer (7th Edition)
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Staging
The clinical T stage represents the size and extent of detectable tumor.
DRE has previously been the main tool in making this determination but
with routine PSA screening, prostate cancers are predominantly
diagnosed at earlier stages and T1c (nonpalpable disease) now represents
the most common clinical stage. As such, many imaging modalities are
used as adjuncts to provide more accurate staging information. The
American Joint Commission on Cancer (AJCC) clinical staging system for
primary tumor (T staging) is shown in Table 26A.2 (18).
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Ultrasound
TRUS most commonly identifies a tumor as a hypoechoic lesion in the
peripheral zone but is unreliable in evaluating the full extent of disease.
The hypoechoic lesion has a cancer detection sensitivity of 85.5% and
specificity of 28.4%. Nearly one-third of prostate cancers are not
identifiable on TRUS (19). Its most important role is to provide visual
guidance for prostate biopsy.
CT
Similar to TRUS, pelvic CT does not provide adequate soft tissue contrast
discrimination and may only accurately predict local tumor extent up to
65% of the time (20). Multiparametric MRI has improved accuracy for
delineating the primary tumor. In one study of low- to intermediate-risk
patients undergoing prostatectomy, endorectal coil MRI predicted local
extraprostatic extension and seminal vesicle invasion with sensitivity
and specificity of 65% and 100%, respectively (12). Nevertheless, CT
remains valuable in determining lymph node involvement and bone
metastases.
TABLE 26A.2 Prostate Cancer Recurrence Risk Group by NCCN

Criteria (2015 Version)
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MRI
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Multiparametric MR imaging with high-resolution T2-weighted imaging,
diffusion weighted imaging (DWI), and dynamic contrast enhanced MRI
(DCE-MRI), and MR spectroscopy (MRS) play an important role in the
assessment of prostate cancer. High-resolution T2-weighted imaging
provides exquisite definition of the prostate zonal anatomy. Endorectal
coil MRI may have a role in predicting extracapsular extension or
seminal vesicle invasion for imaging at 1.5T, although 3T MRI scanners
have superior signal-to-noise ratio (SNR) such that excellent image
quality can be achieved even without endorectal coils. DWI helps
differentiate benign from malignant tissue by inferring cellular density
by measuring Brownian motion of interstitial water molecules. DCE-MRI
adds information about prostatic vascularization through a series of high
temporal resolution T1-weighted images following the administration of
contrast. Finally, proton MRS is another useful functional imaging
technique to help localize prostate cancer by detecting levels of choline
and citrate, which accumulate in prostate cancer and benign prostate
tissues, respectively.
Bone Scan and PET

In patients with intermediate–high-risk disease, imaging evaluation is
indicated to identify and localize occult metastatic disease. Pelvic CT
and MRI are recommended in either of the following: (1) T3 or T4, (2)
T1–T2, and nomogram indicated probability of lymph node involvement
greater than 10%. Similarly a bone scan would need to be ordered only
in select scenarios: T1 and PSA >20 ng/mL, T2 and PSA >10 ng/mL,
Gleason score ≥8, T3 or T4, or symptomatic disease. However, bone
scans and pelvic CT or MRI scans are limited in their sensitivity for
detecting occult disease. Bone scans have limited sensitivity for detecting
osseous metastases and are not able to detect soft tissue metastases. The
sensitivity, specificity, PPV, and NPV of detecting metastatic lymph node
involvement by CT is 7%, 100%, 85%, and 100%, respectively (21). The
same limitations for detecting lymph node involvement in CT also hold
for standard pelvic MRI examinations. Newer imaging modalities
including Sodium Fluoride, 11C- and 18F-choline, 11C-acetate, and
PSMA PET imaging hold promise for improving the detection of occult
metastases and are being studied in the clinic.
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Gleason Grade
The Gleason system is based on the morphologic architecture of the
prostate cancer and is the most common method for histologic grading
(22). The Gleason grade applies to adenocarcinomas and squamous cell
carcinomas but not to sarcomas or transitional cell carcinomas of the
prostate. The scale ranges from 1 (most differentiated) to 5 (least
differentiated). The Gleason score is the sum of the two most prevalent
Gleason grades observed within a tissue sample and ranges from 2 to 10
with 2 being the most indolent and 10 being the most malignant. In
contemporary clinical practice, GS is broken down into three main
partitions: well-differentiated (GS 2 to 6), moderately differentiated (GS
7), and poorly differentiated (GS 8 to 10). A GS of <6 is rarely
encountered on needle biopsy due to a prevailing change in Gleason
grading by pathologists which has led to a shift in GS over time with
higher GSs being more prevalent in the PSA era even as other clinical
risk features have declined (23).
PSA
PSA screening should be discussed with men over the age of 40, whether
PSA is right for them based on health and family history risk factors. An
elevated PSA may prompt a biopsy. However, in addition to prostate
cancer, elevated PSAs may result from recent ejaculation, BPH, and
prostatitis and may lead to false positive results. There are other
supplementary tests and considerations that can help decide if a biopsy
is necessary including free PSA levels, PSA velocity, PSA density, family
history, and digital examination results. A PSA above 10 ng/mL
correlates with a 50% to 75% chance of diagnosis. A moderately
elevated PSA between 4 and 10 ng/mL correlates to only a 20% to 30%
risk of prostate cancer and can be difficult to interpret especially if BPH
is also present. In this range, a PSA density (serum total PSA level
divided by prostate volume) greater than 0.15, a free PSA below 10% of
total serum PSA level, and a PSA velocity above 0.75 ng/mL/yr should
further heighten suspicion for prostate cancer and prompt TRUS-guided
needle biopsies of the prostate to be performed by a urologist.
Prostate cancer antigen 3 (PCA3) is increasingly being utilized for
screening in addition to PSA testing. PCA3 is overexpressed in prostate
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cancer. PCA3 has a lower sensitivity but higher specificity and a better
positive and negative predictive value when compared to PSA. PCA3 is
measured in the urine after prostate massage with DRE. PCA3 testing has
been suggested to be clinically useful to predict the presence of prostate
cancer in patients with prior negative biopsies.
TREATMENT OPTIONS
Treatment Algorithms
Treatment recommendations are determined by the extent of disease:
localized, lymph node positive, and distantly metastatic. This section
will focus on the treatment paradigms for localized prostate cancer. The
treatment scheme used at UCSF is shown in Table 26A.3.
Watchful Waiting
Watchful waiting, or passive observation, is an appropriate strategy in
asymptomatic patients who do not to expect to derive a survival benefit
from treatment either due to advanced age or advanced co-morbid
illness. This approach forgoes upfront treatment with the expectation to
deliver palliative therapy for symptomatic disease. Two randomized
trials have compared RP with watchful waiting. The Scandinavian
Prostate Cancer Group Study Number 4 (SPCG-4), a trial that predated
routine PSA screening, found a disease-specific and overall survival
benefit for RP in patients younger than 65 years, but no survival benefit
in patients 65 years or older (24). The US-based Prostate Cancer
Intervention Versus Observation Trial (PIVOT) found no overall survival
benefit for RP in low-risk patients, but a benefit was observed in patients
with high-risk disease (25). In some clinical contexts, monitoring should
still include routine DRE and PSA as changes in examination or PSA
level may prompt patients to start therapy in anticipation of new
symptoms.
TABLE 26A.3 A Risk Stratification System for Clinically Localized

Prostate Cancer with 3D Conformal or Intensity Modulated External
Beam Radiation Therapy Treatment Guidelines Utilized at the
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Active Surveillance
In contrast to watchful waiting, active surveillance involves serial DRE,
PSA, and surveillance biopsies with the expectation to intervene with
definitive treatment at the time of disease progression. Active
surveillance is an alternative to definitive treatment for low-risk disease.
A prospective cohort from the University of Toronto is one of the most
mature and comprehensive data sets to date, which demonstrates the
safety and feasibility of active surveillance. In this series, patients were
offered definitive intervention with a PSA doubling time of <3 years,
Gleason upgrade (to 4+3 or greater), or unequivocal clinical
progression. The 10-year estimate of prostate-cancer specific death was
1.9% and the risk of death due to other causes in this cohort was 9.2
times greater (26). Comparison of active surveillance to RP and
definitive radiation therapy is the subject of the ongoing UK-based
Prostate testing for cancer and Treatment (ProtecT) (27).
Radical Prostatectomy
Approximately 40% to 50% of patients select to undergo an RP initially
(28). RP involves removal of the prostate, the surrounding capsule,
seminal vesicles, and the ampullae of the vas deferens. There are a
variety of approaches to the procedure: retropubic, perineal, and
laparoscopic, which may be robot-assisted. The advent of the nerve-
sparing RP in the early 1980s, increasing chances for retaining sexual
potency, as well as more recent refinements in surgical techniques such
as laparoscopic or robotic RP, have ensured that RP remains a popular
treatment option.
Prostatectomy results in a substantial risk of impotence, and at least
some degree of urinary incontinence is common (29,30). Nerve sparing
techniques may decrease these rates although most patients still report
significant sexual dysfunction even following nerve sparing RP (9,30,31).
Laparoscopic prostatectomy techniques have decreased acute surgical
morbidity, with decreased blood loss, shorter hospital stays, and more
rapid postoperative recovery (32). More recently, there has been an
increased use of surgery for locally advanced disease, which may
necessitate a higher rate of utilization of adjuvant RT for residual
disease, particularly among surgeons new to the technique (33). In
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addition, patients with clinical evidence of extracapsular (T3) disease or
high-risk features such as high GS or PSA may be at increased risk of
residual disease after nerve-sparing surgery. Although there are currently
no completed prospective, randomized trials comparing RP to radiation
therapy, it appears that cure rates are similar.
External Beam Radiation Therapy

External beam radiation therapy (EBRT) is commonly utilized to treat
men with clinically localized or locally advanced prostate cancer. EBRT
alone may be applied to any clinical stage—T1 to T4—but is also often
used with adjunctive antiandrogen therapy for selected higher-risk
patients. EBRT is also commonly utilized as either adjuvant or salvage
therapy in the postprostatectomy setting for patients with clinical high-
risk features or with a rising PSA following RP.
In the past, EBRT for prostate cancer consisted of a 4-field box or
bilateral 120-degree arcs that were delineated using bony landmarks or a
single CT slice to include the prostate, seminal vesicles, and pelvic
lymph nodes. Using these nonconformal techniques, prescription doses
to the prostate were limited from 64 to 70 Gy due to significant volumes
of normal tissues that were also irradiated, in particular rectum and
small bowel. Conformal radiation therapy simulation, planning, and
treatment became increasingly available in the late 1980s, and one
analysis estimated that a 10% increase in minimum tumor dose could be
achieved without increasing acute or chronic toxicity (34). Intensity-
modulated radiation therapy (IMRT) was introduced in the mid-1990s
and is now routinely utilized in the treatment of prostate cancer. IMRT
allows for the safe delivery of dose-escalated radiation therapy over 74
Gy, which has shown to improve biochemical free survival (7).
Androgen Deprivation Therapy

For high-risk prostate cancer patients, long-term ADT and RT is the
standard-of-care. The question of ADT added to RT was first evaluated in
a series of randomized trials, which revealed that for patients with
locally advanced (T3–T4) or high-grade prostate cancer (Gleason 8 to
10), the addition of ADT to conventional dose EBRT increased
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biochemical control and decreased risks of metastasis, death from
prostate cancer, and all cause mortality (35–38). For patients with the
highest risk disease, the use of 28 to 36 months of ADT along with
conventional dose EBRT appears better than either EBRT alone or EBRT
delivered with shorter duration ADT (4 to 6 months) (37,38). For
example, on RTOG 9202 the addition of 24 months adjuvant ADT in
addition to 4 months neoadjuvant ADT resulted in an absolute 16%
increase in biochemical control at 10 years (p < 0.0001) along with
improvements in local control (10% improvement, p < 0.0001),
metastasis (8% improvement, p < 0.0001), and disease-specific survival
(5% improvement, p = 0.004). Overall survival, however, was not
increased for all patients, but was significantly improved for those with
Gleason 8 to 10 disease (32% vs. 45%, p = 0.006). EORTC 22961 also
randomized patients with high-risk prostate cancer to 6 months versus 3
years of ADT. Patients receiving 3 years of ADT had a significant
improvement in overall survival and prostate cancer specific survival
(38). More recently it was also demonstrated that for node-negative men
with high-risk prostate cancer the addition of conventional dose RT
dramatically increased disease outcome when combined with long-term
ADT as compared to long-term ADT delivered alone (39). There was an
absolute risk reduction of 50% for biochemical failure at 10 years (75%
vs. 26%, p < 0.0001) with the addition of RT. More importantly, the
cumulative incidence at 10 years for prostate cancer-specific mortality
was 24% in the ADT alone group and 12% in the ADT plus RT group (p
< 0.0001), while the cumulative incidence for overall mortality was
39% in the endocrine alone group and 30% in the endocrine plus RT
group (p = 0.004).
For intermediate-risk prostate cancer, short-term ADT and RT is
recommended. The role of ADT in intermediate-risk disease has been
addressed in two randomized trials which would suggest a benefit to
shorter course antiandrogen therapy (4 to 6 months) when treated with
a conventional dose RT of ≤70 Gy (44,45). The role for ADT in patients
treated with higher dose RT (particularly if intermediate risk) is an area
of active evaluation at this time and is the subject of RTOG 0815.
Finally, there does not appear to be meaningful benefit with the addition
of short-term ADT in either cancer-specific or overall survival in men
with clinical low-risk disease by NCCN risk criteria even when treated
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with RT dose <70 Gy (40).
In addition, there is emerging data on the benefit of ADT in the
postoperative setting. RTOG 9601 compared salvage radiation therapy
(SRT) with SRT plus ADT with high dose bicalutamide in post-RP
patients and updated results were recently presented at the American
Society for Radiation Oncology (ASTRO)’s 57th annual meeting in San
Antonio. The study randomized post-RP patients with pT3N0 or pT2N0
with positive margins who had developed elevated PSA from 0.2 to 4.0
ng/mL to RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) versus RT
plus AAT (24 months of bicalutamide, 150 mg daily). Actuarial overall
survival at 10 years was 82% for RT plus AAT and 78% for RT +
placebo and a hazard ratio of 0.75 with a two-sided p-value of 0.036.
Brachytherapy
Interstitial brachytherapy is appropriate definitive treatment to the
intact prostate for low-risk patients and selected patients with
intermediate-risk cancers. Brachytherapy as monotherapy has several
advantages over EBRT, including the convenience of undergoing a 1-day
outpatient procedure, rapid dose fall-off outside the prostate, and less
problems presented by organ motion in planning and treatment delivery.
Prostate brachytherapy is also commonly used in combination with
EBRT to 45 to 50.4 Gy, particularly for patients with adverse risk
features. As risk of disease extending beyond the prostate capsule
increases, other modalities should be considered for definitive treatment.
LDR radioisotopic implants are performed using I-125, Pd-103, or more
recently Cs-131 seeds which are placed transperineally through a
template. HDR brachytherapy involve needle placement of catheters that
are used for afterloading of an Ir-192 source. Brachytherapy performs
comparably to surgery or EBRT for low-risk patients. There is also a
mounting body of literature supporting the use of brachytherapy for
locally recurrent prostate cancer after prior definitive radiation therapy.
Early results of the ASCENDE-RT study showed that the 7-year
biochemical control estimate was 82% for men who received LDR boost
compared to 39% for those who received dose-escalated EBRT (p =
0.0022).
Since the incidence of urethral stricture can be high after transurethral
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prostatic resection (TURP), implant is usually not recommended for
stage T1a and T1b tumors. Other relative contraindications to
brachytherapy include large prostate size, a prominent median lobe, or
significant preexisting obstructive urinary symptoms, as these may be
associated with technical difficulty in performing an adequate implant or
increased risks of complications. Patients with locally extensive tumors
—clinical stages T3 and T4—are generally not suitable candidates for
isotope therapy. Brachytherapy is also starting to have a role in salvage
treatment after localized recurrence for patients treated with definitive
RT although the results from this form of treatment at this time are still
limited (41–46).
Other Treatments
Cryotherapy and other local therapies lack long-term data comparing
these treatments to radiation or RP and are therefore not recommended
as routine primary therapy for localized prostate cancer. A Canadian
randomized trial did compare short-term ADT followed by either EBRT
or cryotherapy in men with localized prostate cancer where most (80%)
had NCCN high-risk disease (47). Sexual dysfunction was significantly
higher in those treated with cryotherapy. There were no significant
differences in clinical outcome between the two treatment arms although
a number of treatment features were suboptimal for the RT group
including low RT dose (most 70 Gy or less), no pelvic RT, and only a
short course of ADT. Each of these has been demonstrated alone to
increase the rate of biochemical control for men treated with EBRT for
prostate cancer. Furthermore, early repeat cryotherapy was not
considered a treatment failure, and a modest number of patients were
retreated after biopsy-proven residual disease in the cryotherapy arm.
Cryotherapy may be an option for patients with biopsy-proven
recurrence after previous RT.
TREATMENT PLANNING FOR DEFINITIVE EBRT

Target Volume Definition
Prostate
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The International Commission on Radiation Units and Measurements
(ICRU) has defined volumes for treatment planning that take into
account the extent of the known gross tumor, the areas of likely
microscopic extension, and daily variations in patient setup and tumor
position. Definitions of GTV, CTV, and PTV are shown in Table 26A.4.
The prostate is most commonly identified on a treatment planning CT.
The use of MRI is increasingly utilized to aid in delineation of the
prostate gland especially at the apical region (48). In addition, the penile
bulb is well delineated on MRI. The GTV and CTV is the extent of gross
tumor identified on DRE and imaging. Additional margin is added to the
CTV to account for variation in daily treatment setup and organ motion
to define the PTV.
TABLE 26A.4 International Commission on Radiation Units and

Measurements Designated Tumor Volumes and Definitions
The amount of margin added to the CTV to define the PTV has been
the subject of extensive study and discussion. While it is important to
make margins generous enough to consistently encompass gross and
microscopic tumor by the prescribed dose, there is also a compelling
reason to keep the margins as small as possible near organs of limited
tolerance, such as the rectum posteriorly, the bladder superiorly, and
(possibly) the penile bulb inferiorly. In general, 0.5 to 1 cm is added
around the prostate (and seminal vesicles) to ensure coverage of
extracapsular microscopic tumor extension and to account for setup
variability and organ motion. As an example, treatment guidelines from
RTOG 0924 suggest that the PTV be defined as the CTV plus a 0.5 to 1.0
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cm margin depending on institutional policy. These volumes are then
used for treatment planning using either 3D-CRT or IMRT techniques.
A CT simulation is obtained while the patient is supine with a
comfortably full bladder and an empty rectum. The prostate should be
contoured between the genitourinary diaphragm to the bladder neck
without the surrounding pelvic muscles. Gold seed fiducials or Calypso
beacon transponders are often utilized to improve the accuracy of daily
patient setup. At UCSF, three gold markers are placed into the prostate
transrectally, typically with one in the apex and two on both sides of the
base. Daily prostate position can then be confirmed and positional
adjustments made based on 2-dimensional (2D) alignments between
digitally reconstructed radiographs (DRRs) with EPID or 3D alignments
between CT and MV CBCT.
Rigid immobilization devices such as the Alpha Cradle or
thermoplastic body casts may increase setup accuracy. Rosenthal et al.
(49) found that with immobilization only 1 of 10 patients had >0.5 cm
variation in patient positioning for treatment, whereas 8 of 12 patients
had more variation than this without immobilization. Improved
positioning accuracy with rigid immobilization has been demonstrated
in prospective randomized comparisons as well (50,51). Intrarectal
balloons may be expanded within the rectum to stabilize the prostate
position, reducing the concerns over inter- and intra-fraction organ
motion (52) (Fig. 26A.1). However, use of these devices may be
inconvenient for daily treatment and somewhat uncomfortable for the
patient.
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FIGURE 26A.1 An intrarectal balloon device (top panel) can be used for stabilization of prostate
position during external beam radiation therapy (bottom panel). Courtesy Dr. Mark Ritter.
Daily imaging for prostate localization including daily CT (53),

ultrasound (54), radiographic imaging of implanted radiopaque fiducial
markers (55,56), or electromagnetic transponders (57,58) are also
utilized (Fig. 26A.2). Adjustments can then be made on a daily basis,
ensuring accurate localization and targeting of the PTV at the start of
treatment. These techniques fall under the category of a collection of
adaptive RT practices termed IGRT (59).
Prostate movement and the margin necessary to compensate for it
have been studied in detail. Ten Haken et al. (60) reported maximal
superior, inferior, anterior, and posterior prostate movement of 1, 1.25,
2, and 0.75 cm, respectively. The overall average movement was 0.5 cm,
most often in the anterior and superior direction, while the average left-
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to-right movement was <0.05 cm. Nevertheless, residual errors in
prostate position of over 7 mm after pretreatment localization and
adjustment of prostate position clearly demonstrate the influence of
intratreatment movement. In a limited trial using fluoroscopy, Dawson
et al. (61) demonstrated breathing-related movement of the prostate, the
magnitude of which increased with the amplitude of the breathing cycle
(deep breathing vs. shallow), which even varied in the same patients
based upon prone or supine positioning with greater movement in those
evaluated prone. Just as observed by others, the magnitude of movement
was greatest in the anterior–posterior and cranial–caudal directions
while minimal lateral movement was seen (62,63) using non-IGRT
techniques.
FIGURE 26A.2 Gold fiducial marker seeds (A), can be implanted into the prostate. The position of
the implanted markers, shown in a digitally reconstructed radiograph (DRR) (B), can be used for
daily localization of the prostate, shown with the proper alignment of a daily portal image (C).
Seminal Vesicles
While the prostate gland is always in the CTV, a decision must be made
as to whether the seminal vesicles and pelvic lymph nodes are included.
The seminal vesicles are superior and posterior to the prostate gland,
attaching at the base. The clinical risk factors of stage, GS, and PSA can
be related to risk of seminal vesicle involvement, similar to lymph node
risk (64). Ninety percent of seminal vesicle involvement is limited to the
proximal 2 cm and therefore some argue that only the proximal portion
of the seminal vesicles adjacent to the prostate needs to be included in
the target volume (65). Seminal vesicle involvement is associated with a
relatively high risk of lymph node disease and a worse clinical outcome
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(66). Some advocate for the CTV to include the base of the seminal
vesicles if the risk of seminal vesicle is less than 15% and for the CTV to
include the entire seminal vesicles if risk of SV involvement is above
15%. To date no study documents improved local control or survival if
seminal vesicles are electively irradiated for the risk of clinically
undetected microscopic disease; however, intuitively it seems important
to include these structures in higher-risk patients, so that likely potential
sites of local disease in its entirety is treated. Including the seminal
vesicles, lymph nodes, or both within the target volumes increases the
field size and may likewise increase the acute side effects and long-term
complications (67). The ongoing RTOG 0924 clinical trial, which
randomizes patients with unfavorable intermediate or favorable high-
risk disease to high dose radiotherapy with or without whole pelvic
radiation, requires the entire seminal vesicles to be treated at least to 45
Gy in both arms and for the proximal 1.0 cm of the seminal vesicle tissue
to be included in the boost target volumes.
Lymph Nodes
The benefit of pelvic lymph node irradiation has been a controversial
topic over many years (68). Lymph node irradiation is not standard for
low- or intermediate-risk prostate cancer and is controversial for high-
risk disease. Whole pelvis radiotherapy is generally recommended for T4
tumors, lymph node involvement, and seminal vesicle invasion. RTOG
9413 suggested that patients with a risk of lymph node involvement of
at least 15% may benefit from pelvic lymph node irradiation. Patients
were randomized to whole pelvic radiation versus prostate-only
radiation, as well as to short-term neoadjuvant and concurrent ADT
versus adjuvant ADT starting at the completion of RT. No statistically
significant differences were found in progression-free or overall survival
between the two study questions that patients were randomized to:
neoadjuvant ADT versus adjuvant ADT and pelvic RT compared with
prostate only RT. Nevertheless, a trend toward improved progression-
free survival was found in favor of the pelvic and neoadjuvant ADT arm
compared with the other three arms. In addition, when the size of the
pelvic field was separately evaluated, it appeared that there was a direct
benefit when using a whole pelvic field as compared to a mini-pelvic
field or prostate-only treatment with 7-year progression-free survival of
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40%, 35%, and 27%, respectively (p = 0.02) (80). The benefit of whole
pelvic irradiation is the subject of RTOG 0924, which randomizes
patients with unfavorable intermediate-risk disease and favorable high-
risk disease to ADT with prostate-only irradiation or ADT with whole
pelvis irradiation.
Current imaging technology, including CT, MRI, and
lymphangiograms, has limited accuracy for detecting pelvic lymph node
metastasis. Therefore, until improved methods for detecting pelvic
lymph node metastases are developed, clinicians will be limited to using
risk factor assessment and clinical judgment in deciding whether pelvic
lymph nodes should be encompassed in the target volumes.
Accurate targeting is critically important if 3D conformal or IMRT-
based treatment techniques are utilized to treat the pelvic lymph nodes,
yet there is significant heterogeneity in how pelvic lymph nodes are
contoured even amongst experienced genitourinary radiation oncologists
(69). A consensus definition was established to make pelvic nodal
volumes more uniform (70). Based upon this consensus, the pelvic
lymph node volumes to be irradiated include: distal common iliac,
presacral lymph nodes (S1–S3), external iliac lymph nodes, internal iliac
lymph nodes, and obturator lymph nodes. Lymph node CTVs include the
vessels (artery and vein) and a 7-mm radial margin without extending
into bowel, bladder, bone, and muscle. Volumes begin at the L5/S1
interspace and end at the superior aspect of the pubic bone (70). The
treatment of presacral lymphatics is somewhat controversial as these
nodes are infrequently problematic clinically and are rarely an isolated
site of recurrence if left untreated, and are not included in the standard
pelvic lymph node dissection. Their inclusion in the radiation field
necessitates that the posterior margin be expanded significantly,
encompassing additional rectum and large bowel, and unless using 3D
conformal or IMRT techniques may result in increased irradiation of the
rectum with increased risk of acute and long-term side effects. The role
of RT in patients with known pelvic lymph node positive disease is less
clear. However, as both RTOG 8531 and the EORTC studies of high-risk
prostate cancer allowed positive pelvic lymph nodes at diagnosis,
treatment of patients with positive lymph nodes with both irradiation
and ADT is a reasonable course of action.
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Field Setup
Localization, Immobilization, and Simulation
Day-to-day setup variations can result in significant treatment errors
(71). Volumetric planning with CT simulation is recommended and thin
axial slices of 3 mm or finer is preferred. There are many options for
image guidance, including CBCT, ultrasound localization system, or
implanted fiducials. Selection of image guidance methods depends on
patient factors and institutional experience. For instance, hip prosthesis
may limit CBCT due to artifact.
A comfortably full bladder and empty rectum minimizes dose to
critical structures. Patients lie supine, with arms folded on the chest.
They are immobilized with a body mold, such as a vacuum-lock bag or
Alpha Cradle. Intrarectal balloons may be expanded within the rectum to
stabilize the prostate position, reducing the concerns over inter- and
intrafraction organ motion (52) (Fig. 26A.1).
FIGURE 26A.3 A “dumbbell”-shaped clinical target volume (CTV) is outlined to encompass the
“prostate bed” between the bladder and rectum to facilitate treatment planning in the adjuvant or
salvage situation after radical prostatectomy. Surgical clips are visible and also aid in defining the
CTV.
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Instead of focusing on immobilization, many centers use daily imaging
for prostate localization (Fig. 26A.2). Adjustments can then be made on
a daily basis, ensuring adequate localization and targeting of the PTV at
the start of treatment.
Simulation involves a CT scan from the mid-abdomen to mid-femur.
Contrast agents, such as IV contrast, a retrograde urethrogram, and oral
contrast are optional. MRI fusion with T2-weighted scans also can be
done to provide better soft tissue resolution of the apex, EPE, SVI, and
penile bulb. Target volumes and OARs can then be defined (Fig. 26A.3).
Treatment Technique
In the past, a four-field technique was generally used to treat pelvic
lymph nodes (Fig. 26A.4): anterior, posterior, right, and left lateral
portals. Blocks can be drawn manually on simulation films or BEV DRRs
from CT planning software. Construction of these blocked fields can be
facilitated by reviewing the pelvic CT scan and entering lymph node
volumes that track along the course of the iliac vasculature (Fig. 26A.4).
Depending on the external contour, which can be done manually or
automatically by CT scan, small angle wedges on the lateral fields may
help to produce a more symmetrical dose distribution.
IMRT is currently the most common method of treatment planning for
prostate cancer. The prostate, seminal vesicles, pelvic lymph nodes, and
OAR must all be defined for appropriate treatment planning and
optimization. Examples of recommended OAR tolerances are provided
(Table 26A.5) (70).
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FIGURE 26A.4 Three axial treatment planning computed tomography (CT) images are shown at
the levels of the seminal vesicles (A), mid-prostate (B), and lower-prostate (C). The outlined
clinical target volume (CTV) encompassing the seminal vesicles and the prostate is shown along
with the planning target volume (PTV) expansion around the CTV. The normal bladder and rectum
are also contoured.
For CT-based planning, CT images are entered into a treatment

planning software package. The lymph node regions, prostate, and
seminal vesicles are outlined by the physician, and can be expanded by
adding appropriate margins to establish the CTVs and PTVs. As noted
previously, margins may vary between institutions and individual
physicians and by the use of IGRT. Normal structures are also outlined
including bladder, rectum, penile bulb, femoral heads, loops of small
bowel, or any other structures to which the physician may wish to limit
dose. Treatment planning software packages allow manipulation of
virtual 3D reconstructions of these volumes, providing a variety of views
for the planner, including “beam’s eye view” (BEV) perspectives. These
features are designed to allow the user to manipulate beam orientation
(gantry, table, and collimator angles) and shaping (blocking or multileaf
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collimation) to encompass targets and avoid normal structures.
For forward-planned 3D conformal treatment planning, high-energy
beams from 6 to 18 MV are routinely used for pelvic lymph node and
prostate irradiation. The software allows rapid calculation of the dose
that can be displayed on the overlying images in the form of isodose
lines or surfaces (Fig. 26A.5). Additional tools including dose–volume
histograms (DVHs) help the clinician to compare treatment plans to
determine the optimal plan for coverage of target volumes and
avoidance of normal tissue structures (Fig. 26A.6).
TABLE 26A.5 Dose Volume Histogram Constraints for Organs at

Risk (87)
Forward planned 3D CRT beam arrangements for prostate cancer

treatment may include the standard axial anterior, posterior, and lateral
beams common to 2D prostate plans, but can also easily make use of
oblique and nonaxial beam angles. Rotation of the collimator is
commonly used to place the orientation of the multileaf collimator
appropriately so as to maximize normal tissue blocking and target
coverage. Segmental fields, physical wedges, and dynamic wedge
techniques can be used to improve target coverage and dose
homogeneity. In addition to the classic four-field box technique, 3D CRT
beam configurations include a six-field conformal technique (72) as well
as a four-field variation using lateral and anterior obliques that eliminate
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the posterior-oblique beams. Marsh et al. (73) have found that the four-
field technique, using laterals and anterior–inferior obliques, often
improves the rectal DVH compared with axial plans (Fig. 26A.7). This
technique requires supine patient positioning to achieve table clearance
for the anterior–inferior beams.
FIGURE 26A.5 Digitally reconstructed radiograph (DRR) images are shown demonstrating typical
anterior (A) and lateral (B) treatment fields encompassing the prostate, seminal vesicles, and
regional pelvic nodes.
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FIGURE 26A.6 Axial (A), reconstructed sagittal (B), and coronal (C) computed tomography (CT)
images are shown with contoured normal tissue structures (bladder and rectum) and target
volumes (prostate and seminal vesicles). Isodose lines conforming to the planning target volume
(PTV) are overlaid, depicting the dose distribution of a three-dimensional (3D) conformal radiation
treatment plan.
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FIGURE 26A.7 A typical dose–volume histogram (DVH) plot is shown for bladder, rectum, and
planning target volume (PTV) from a three-dimensional (3D) conformal radiation treatment plan.
The application of IMRT technology to prostate cancer EBRT planning

has enabled further improvements in normal tissue DVHs, mainly due to
the ability of this technology to achieve convex dose distributions,
reducing rectal dose (Fig. 26A.8). The clinical significance of this
advance toward reducing rectal toxicity remains undetermined although
some groups have suggested that with the combination of IGRT and
IMRT high-dose EBRT can be delivered without increases in toxicity as
compared to that observed in historical control groups treated to lower
doses with less sophisticated techniques (8). For instance, Zelefsky et al.
noted an actuarial rate of grade 2 or greater rectal toxicity at 10 years of
13% in patients using 3D CRT and 5% using IMRT (p < 0.0001) (116).
Of note, IMRT patients received higher doses of RT than 3D conformal
patients, but IGRT was also used with much greater frequency in the
IMRT group. The inverse planning process starts with the contouring of
target and normal tissue volumes on an axial CT image set—just as for
3D CRT planning. However, instead of inputting a candidate beam
arrangement into the planning software and calculating a dose
distribution for that plan, the IMRT software package uses an
optimization algorithm to find a beam “solution” that maximizes a set of
“cost functions.” Typically, the process begins with a certain number of
axial beam angles for the algorithm to utilize. Each beam is subdivided
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into square “beamlets” that represent the incremental movement of
multileaf collimator leafs across the field in 1 cm or less increments. The
algorithm “modulates” the fluence through each of these beamlets in an
iterative process, evaluating and comparing each candidate plan to
identify a better one. Each plan is evaluated for dose coverage of target
volumes, as well as dose avoidance for normal tissue structures. Target
coverage and normal tissue structure sparing is prioritized based on
clinical judgment, and a cost for achieving or failing to achieve each
objective is assigned. The algorithm will iterate until it identifies a plan
that best achieves the stated objectives. Once the optimization algorithm
produces a plan, a formal dose calculation is performed, and a quality
assurance procedure is followed to ensure that the delivered dose will be
within a desired level of accuracy. For the prostate, where the target
shape and volume are relatively consistent from patient to patient, a
template can be established to make the treatment planning process
more efficient. Examples of typical dose constraints for rectum, bladder,
femoral heads, and both large and small bowel are given in Table 26A.5.
The sparing of the penile bulb is controversial as different authors have
come to differing conclusions about the utility of sparing the penile bulb
in preserving sexual function (74). However, it is clear that if a penile
bulb dose constraint is observed that it should not be at the cost of
decreasing dose to the PTV. An example of an IMRT plan as well as
DVHs for both an IMRT plan and a 3D-CRT plan are given in Figure
26A.9.
FIGURE 26A.8 An axial computed tomography (CT) image with isodose lines is shown from a
three-dimensional (3D) conformal radiation treatment plan utilizing a four-field technique with
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lateral and anterior inferior oblique beams.
In the past, the sharp dose gradients that can be created using highly
conformal techniques such as IMRT created a concern for missing the
target due to inter- and intrafraction setup uncertainty and organ
motion. However, careful delineation of treatment volumes, patient
setup and immobilization, and implementation of IGRT will ensure the
accuracy of treatment delivery to minimize marginal misses due to setup
error or changes in prostate position.
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FIGURE 26A.9 An axial computed tomography image is shown from a seven-field intensity
modulated radiation therapy (IMRT) plan (A). The dose distribution is demonstrated using a dose
“color-wash” and depicts the concave dose distribution achieved for the rectum. This results in the
improved normal tissue dose volume histogram (DVH) for the IMRT plan (B) as compared with a
four-field, three-dimensional (3D) conformal treatment plan DVH for the same patient (C).
Treatment planning software packages allow manipulation of virtual

3D reconstructions of these volumes, allowing a variety of views for the
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planner, including BEV perspectives. These features are designed to
allow the user to manipulate beam orientation (gantry, table, and
collimator angles) and shaping (blocking or multileaf collimation) to
encompass targets and avoid normal structures. High-energy beams from
6 MV to 18 MV are routinely used for pelvic lymph node and prostate
irradiation. The software allows rapid calculation of the dose that can be
displayed on the overlying images in the form of isodose lines or
surfaces (Fig. 26A.5). Additional tools including DVHs helps the clinician
to compare treatment plans to determine the optimal plan for coverage
of target volumes and avoidance of normal tissue structures (Fig. 26A.6).
Once the process of defining the patient positioning and localization
have been determined, the process of treatment planning can commence.
Most centers currently use inverse-planned IMRT. If the decision is made
to treat the pelvic nodes, the classical superior bony landmarks in the AP
view include the bottom of the L5 vertebral body to encompass the
common, internal, and external iliac nodes, midway through the
sacroiliac joints to encompass the distal common, internal, and external
iliac lymph nodes, or the bottom of the sacroiliac joints to encompass
the internal and external iliac lymph nodes. The inferior margin is often
set 1 cm below the ischial tuberosities inferiorly, and 1.5 to 2 cm to
either side of the lateral bony pelvis laterally. In the lateral projection
the anterior border is placed at the most anterior point of the pubis
symphysis. The posterior border generally falls along the posterior
ischium, although the field is usually shaped to bisect the rectum when
filled with 20 to 30 mL barium GI contrast, administered via rectal tube.
Retrograde urethrography may be performed using a small-gauge
catheter to administer 5 to 10 mL of 30% Hypaque into the urethra with
immediate penile clamping. The narrow point, or beak, in the contrast
column denotes the level where the urethra passes through the
urogenital diaphragm (75,76). The most inferior aspect of the prostate
gland is typically located 1 cm above the urethral apex, and the inferior
field margin is placed 1 cm below the apex or beak, allowing a 2-cm
inferior margin on the prostate.
In most practices, CT planning has now largely supplanted the setting
of fields using 2D fluoroscopic techniques. CT images facilitate the
identification and localization of both target and normal tissue structures
(70). Lymph node regions follow the path of the common iliac artery
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and its bifurcation into the internal and external iliac arteries, and can
usually be easily traced even without intravenous contrast
administration. Compared with the estimated general localization
provided by bony landmarks in 2D planning, the size, shape, and
location of the prostate and particularly the seminal vesicles can be
visualized and defined more precisely with CT planning. The seminal
vesicles drape around the rectum in some patients, and standard
blocking in 2D fields set using rectal contrast may not provide adequate
coverage of these structures. Identification of the prostate apex on axial
CT is sometime difficult and may be facilitated with MRI or with sagittal
and coronal reconstruction of CT data sets (77). Normal tissue structures
including the rectum, bladder, loops of small bowel, penile bulb, and
even important anatomic anomalies such as pelvic or horseshoe kidneys
can be readily identified and localized with CT planning.
Fluoroscopic or CT simulation for treatment planning may be
performed with the patient either supine or prone, with or without
customized immobilization as discussed above. External marks are
placed on the patient or immobilization device, often chosen to
designate a preliminary isocenter position. These locations may be
delineated with radiopaque markers taped to the patient in the x, y, and
z axes that can be referenced to the image set, facilitating the
transposition of the isocenter from the treatment plan to the patient at
the time of treatment. For CT-based planning, CT images are obtained at
1- to 5-mm intervals through the levels to be encompassed within the
treatment fields. Target and normal structures can then be defined and
expanded to create the relevant PTVs on axial CT images within
specialized treatment planning software (Fig. 26A.3).
The issues regarding immobilization technique, patient positioning,
and image guidance were discussed above. Common choices for
immobilization include the Alpha Cradle, thermoplastic cast material
similar to Aquaplast, and “vacuum lock” molds. The CT scan must be
done with the patient in the planned treatment position in the
immobilization device, with attention toward patient comfort and
maximization of daily reproducibility. Alternatively, for ease of position
adjustment, some practitioners utilize supine position without an
immobilization device if daily prostate localization techniques are
employed (see above). An advantage of the prone position is to shift the
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seminal vesicles forward, away from the rectum, potentially improving
rectal sparing (78). On the other hand, prone positioning may be
associated with more internal organ motion, including respiratory
motion particularly in men with any degree of obesity (61). Roach et al.
(34) advocated nonuniform expansions around the prostate because of
the variation in prostate movement depending on direction, the status of
rectum and bladder filling, as well as radiation tolerance of these two
structures. The recommendations included anterior and inferior margins
of 2 cm, lateral and superior margins of 1.5 cm, a posterior margin of
0.5 to 0.75 cm, and that CT planning be performed with the rectum
empty and the bladder full. If bladder fullness is inconsistent from
treatment to treatment, superior and inferior margins are more generous
and accommodating, and this also helps to keep small bowel out of the
field. If the rectum is empty when fields are planned, a rectum that is
fuller during treatment only pushes the prostate further into the field,
and 2-cm anterior margins should still provide adequate coverage of the
CTV. However, with the use of image-guided therapy smaller margins
may be appropriate (6).
TABLE 26A.6 Long-Term Follow-up of the MD Anderson Dose

Escalation Trial: Biochemical Freedom from Recurrence (Phoenix
Definition) at 8 Years (121)
Dose Fractionation
Prophylactic dose to the pelvic LN is 1.8 Gy/fx to 45 Gy. At UCSF,
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involved LN is typically treated to 54 to 60 Gy, with consideration of
normal organ dose tolerance. Comedown boosts cover the prostate to at
least 74 Gy. Dose escalation has shown to significantly improve
biochemical cure rates (Table 26A.6). The rationale for IMRT versus 3D-
CRT is to allow for smaller CTV–PTV margins as well as creating step
gradients between the PTV and adjacent structures, namely the bladder
and rectum. This is the motivation behind all forms of IMRT, such as
step and shoot, sliding window, helical fan beam, and volumetric
modulated arc therapy (VMAT).
As advances in treatment techniques have allowed more conformal
treatment of the target volumes with decreased dose to normal tissues,
improved outcomes have been documented with increased doses of >74
Gy to the prostate. However, the optimal treatment doses for various risk
categories of prostate cancer remain unknown. In the past, with 2D
treatment techniques, doses of 45 to 50 Gy to the pelvis, 55 to 65 Gy to
the seminal vesicles, and 65 to 72 Gy to the prostate were typical. With
the advent of 3D CRT, IMRT, and other highly conformal techniques,
doses have been escalated without significant increases in acute side
effects or late complications (79).
In a landmark trial, the MD Anderson Cancer Center compared 70 to
78 Gy using 3D CRT techniques and found that patients receiving the
higher dose had significant improved biochemical failure-free survival,
particularly those patients with a pretreatment PSA above 10 ng/mL or
with higher-risk clinical features (Table 26A.6) (80). Toxicity, however,
was increased as a function of the volume of rectum treated to higher
doses. Another significant randomized trial of dose escalation used a
combination of external beam photon radiotherapy with a proton beam
boost. Zeitman et al. have reported that mostly low–intermediate-risk
prostate cancer patients receiving 79.2 Gy had a 15% absolute reduction
in the risk of biochemical recurrence at 10 years as compared to those
receiving 70.2 Gy (32.4% vs. 16.7%) (2). Given the lack of biologic
difference between protons and photons, there is no reason to presume
that these results are unique to the use of a proton boost. Using this
technique, although there was a slight increase in mild acute rectal
toxicity, there was no significant difference in clinically substantial
toxicity rates or patient reported quality of life (9). These randomized
trials as well as others (81,82), combined with many retrospective
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studies, give strong evidence that dose escalation above 70 Gy may
significantly improve prostate cancer biochemical cure rates. However,
at present, dose escalated radiation has not resulted in clear differences
in rates of metastasis, prostate cancer-specific death, or overall survival.
When dose-escalation is performed using conformal techniques toxicity
rates seem to be acceptable (5,30,82).
Most treatments have used conventional fraction sizes of 1.8 to 2.0
Gy/day. The use of a smaller number of treatments delivered at a higher
daily dose (hypofractionation) has been suggested as a means to improve
prostate cancer control and decrease overall cost and treatment time,
while still achieving acceptable long-term rates of toxicity. Recent
reports have supported modest hypofractionation with daily fractions of
2.5 to 3.1 Gy (83–87) as being efficacious without increased risks of
toxicity. Nevertheless, the impact of hypofractionation on late toxicity
has not been clearly established at this time and most practitioners await
long-term results before adopting these shorter regimens. Evidence
supporting this more cautious approach comes from the RTOG 9408
dose escalation study, which was a sequential phase II trial that
evaluated increasing doses between 70 and 79.2 Gy in fractions of 1.8 or
2.0 Gy. Interestingly, the rate of late rectal toxicity was higher in those
treated with 78 Gy in daily fractions of 2 Gy than in any of the other
arms including those receiving 79.2 Gy in daily fractions of 1.8 Gy (88).
A number of reports have retrospectively analyzed biochemical control
of prostate cancer using EBRT, LDR, or HDR brachytherapy, or the
combination of these modalities (88–91). Based on α/b corrections that
take into account different radiation fraction sizes, it has been suggested
that the α/b for prostate cancer is not actually in the range of 10 Gy (as
commonly used for most tumor cells) but in the range of 1.2 to 3.0 Gy.
Therefore, treating prostate cancer with larger fraction sizes, but to an
appropriate total lower dose, would theoretically result in an increase in
the therapeutic ratio. Thus, by using larger radiation fraction sizes, one
might decrease overall treatment dose, time, and cost with a similar rate
of late toxicity and an increase in expected biologic efficacy for prostate
cancer. Extreme hypofractionation with doses in excess of 6 to 7 Gy
delivered in four to five fractions has been reported from a number of
limited single institutions’ experiences (92–94). At present, however,
follow-up on these studies is short, and the use of extreme
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hypofractionation or stereotactic radiotherapy for prostate cancer should
be considered experimental and is most appropriately utilized as part of
prospective clinical trials (95).
TREATMENT PLANNING FOR ADJUVANT OR SALVAGE

EBRT
Adjuvant versus Salvage EBRT Following Radical
Prostatectomy
Adjuvant radiation (ART) refers to immediate postoperative EBRT
following prostatectomy. No studies have directly compared ART
(delivered 10 to 12 weeks after surgery) due to the presence of high-risk
pathologic features even with undetectable PSA to salvage RT delivered
at the time of rising PSA. Three phase III randomized trials, ARO 96-02,
The South West Oncology Group (SWOG) 8794, and EORTC 22911,
support the use of ART (96–98). Furthermore, a number of retrospective
reviews have suggested an improved rate of biochemical control using
ART as compared to salvage RT (99,100). However, a blanket approach
of adjuvant treatment for all pT3 patients would needlessly irradiate
men who either have no disease or occult metastatic disease. The
balance between ART and early salvage RT remains to be determined.
For adjuvant therapy there is now level I evidence from randomized
trials supporting a decline in biochemical failure, metastasis, and
prostate cancer-specific death with an improvement in overall survival
with the use of ART (97,101). SWOG 8794 randomized men (stage
pT3N0M0 disease or positive surgical margins) to observation or ART
arms where the RT dose ranged from 60 to 64 Gy, with treatment portals
including the prostatic fossa and paraprostatic tissues. With >12 years
of follow-up the use of ART was associated with a 50% relative
reduction in the risk of PSA recurrence in the ART group (p < 0.001).
The use of ART yielded an absolute 10% improvement in metastasis-free
survival at 10 years (71% vs. 61%, p = 0.016) and an 8% improvement
in overall survival (66% vs. 74%, p = 0.023). Interestingly, the
magnitude of benefit was similar for those with or without detectable
PSA postoperatively although the utility of super-sensitive PSA remains
to be determined (102). Two additional randomized trials support
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similar benefit in biochemical control of prostate cancer using ART
although follow-up in these studies is insufficient to address more
clinically meaningful end-points (96,98).
The role of salvage RT for patients with a rising PSA after RP has not
been evaluated in randomized trials (although certainly a significant
portion of patients on both the SWOG and EORTC trials had detectable
PSA at the time of irradiation and as such would be consistent with
salvage therapy). In general, approximately 30% to 40% of patients
given salvage RT will have long-term disease control (103,104).
Preoperative, pathologic, and other clinical features have been utilized
to construct a nomogram predicting the likelihood of PSA control (104),
which was subsequently validated in a large multi-institutional data set
(103). In addition, others have presented data supporting an
improvement in prostate cancer-specific survival with the use of salvage
RT particularly in those with the most rapidly rising PSA (105). Den et
al. (106) reported a validation study for the use of a genetic test to
predict for the occurrence of clinical metastasis and which patients
might be spared from early postoperative RT. While promising, their
primary endpoint of clinical metastasis 5 years after RT may be
premature for basing management decisions considering that the median
actuarial time from a rising PSA after RP to metastasis is 8 years (107).

Postprostatectomy target volume delineation is subject to significant
variation, especially in the posterior and superior aspects. Several target
volume definition guidelines were created to improve interobserver
variability. The randomized trials of ART in general utilized large fields
and 2D treatment techniques; therefore, there was not a need to
precisely define target volume (96,98,101). Consensus guidelines have
been published defining recommended anatomic boundaries of the CTV
for RT delivered in the postoperative setting (108–111). The definition
of treatment volumes for ART or salvage RT for patients who have
undergone previous RP is difficult as there is usually no palpable or
visible disease on imaging to constitute a GTV. The vesicourethral
anastomosis (VUA), periurethral, and perivesicular tissues should all be
treated as these are the most common sites of recurrence following RP
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(112–114). Some practitioners also encompass lymph node regions (as
described above) but pelvic nodal irradiation in the postoperative setting
is controversial. Residual microscopic disease within the “prostate bed”
is targeted by delineating the CTV at the preoperative location of the
prostate and seminal vesicles. This can be accomplished using CT
planning, and contouring an elongated “dumbbell-shaped” volume
encompassing the plane between the posterior bladder and anterior
rectum (Fig. 26A.3). Surgical clips remaining from prostatectomy,
preoperative staging information, and postoperative pathology report
information that are valuable in delineating the CTV.
The VUA can frequently be identified in relationship to the urinary
diaphragm on a CT scan sagittal reconstruction; alternatively, either
ultrasound or MRI may aid in this process. Given the prior location of
the prostate at the level of the pubic symphysis, the region extending
anteriorly to posteriorly from the pubic symphysis to the rectum should
be included in the CTV. The most recent consensus guidelines are only to
include the seminal vesicles if they were pathologically involved at the
time of the surgical resection. If not including the seminal vesicles the
superior border should be either at or 5 mm above the cut of the vas
deferens, or alternatively, at the level of the most superior surgical clip.
In addition, ∼1.5 cm of posterior bladder and bladder wall are also
included to account for the shifting of the bladder into the space
previously occupied by the prostate. The inferior border should be ∼10
mm below the VUA; however, if there is concern that the initial prostate
tumor may have been apical, then the inferior border of the CTV should
end immediately superior to the penile bulb (109).
Dose Fractionation
Doses of 64.8 to 70.2 in 1.8 to 2.0 Gy/fraction are used postoperatively.
To date, there have been few studies investigating the role of dose
escalation in the adjuvant or salvage setting. Valicenti et al. (115)
suggested that doses of RT in excess of 64.8 Gy were associated with
improved outcomes. In addition, Ost et al. (116) reported on the clinical
outcome and safety of ART in 104 patients treated with IMRT and a
median dose of 74 Gy. The 3- and 5-year actuarial biochemical relapse-
free survival (bRFS) was 93%, a 20% gain as compared to the bRFS rate
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seen in the randomized trials with doses of 60 to 64 Gy. These results
are limited by the study’s retrospective nature, the short follow-up, and
the impact of stage migration as compared to the randomized ART trials
which enrolled patients from the late 1980s to early 1990s. Despite the
higher dose, acute and late toxicities were rare, with only 4% of patients
experiencing late grade 3 toxicities (all GU). These toxicity results are
similar to those reported from a multi-institutional analysis using more
conventional doses of radiation (117). It is possible that the use of IMRT
allowed dose distributions that partially spared the posterior and lateral
rectal walls, thus minimizing late rectal toxicity. King et al. (118)
recently evaluated a series of retrospective reviews to assess the impact
of RT dose on outcome in the adjuvant and salvage setting. The authors
found that the dose–response relationships were suggestive of a larger
burden of disease for salvage patients with a detectable PSA and
approximately one-tenth of this disease burden for adjuvant patients.
They estimated an increase in the bRFS rate of ∼3%/Gy over the range
of 60 to 70 Gy. Of note, this is similar to the 2% to 3% improvement in
bEFS observed per 1 Gy increase in radiation in the four randomized
trials of dose escalation for definitive radiation of the prostate. At
present, however, no prospective trials have directly compared different
doses of EBRT in the adjuvant or salvage setting. Therefore, at present
most practitioners will utilize RT doses of at least 64.8 Gy in the
adjuvant and salvage setting with some considering doses even up to 66
to 70.2 Gy.
Treatment Technique
Several IGRT methods have been developed to provide consistent
localization of the prostate bed and reduce daily setup error, including
Calypso beacon localization (119), daily portal imaging with implanted
gold seed fiducials (120), ultrasound (121), and daily cone-beam
imaging or kilovoltage imaging (122). The use of IGRT in the
postoperative setting is not as clearly established as that in the definitive
setting although the fundamental principles and rationale remain the
same. These techniques are useful in detecting the location of the VUA,
which in turn depends on variability in rectal and bladder distention.
Similarly, the use of IMRT in the postoperative setting has not been well
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studied at present. Given the somewhat poorly defined treatment volume
that includes a large portion of bladder and rectum as well as the
typically utilized RT doses of <70 Gy, the benefit of IMRT may be
limited. However, use of both IGRT and IMRT may allow dose escalation
in the postoperative setting, which some have suggested will correlate
with improvements in outcome just as it has in the definitive RT setting
(118).
TREATMENT PLANNING FOR RADIOISOTOPE IMPLANT

Indications
Advances in brachytherapy techniques have made it a popular, effective,
and safe treatment for localized prostate cancer. Brachytherapy is
categorized by dose rates defined in ICRU report 38. LDR brachytherapy
ranges between 0.4 and 2.0 Gy/h, medium dose rate (MDR) between 2.0
and 12.0 Gy/h, and HDR above 12.0 Gy/h. Radioactive seed implant
alone is effective in treating low-risk prostate cancer and indicated in
select patients with intermediate risk disease (123). Men with larger,
higher-grade tumors with higher PSA levels have a substantial risk of
having disease outside the prostate. These patients may be best treated
by a combination of external beam radiation and brachytherapy.
Compared to external beam radiotherapy, brachytherapy implants follow
the daily motion of the prostate and dosimetry primarily depends on
source arrangement within the prostate.

The prostate gland itself, with minimal margin, is the target for
radioisotopic implant. Candidates for implant are chosen carefully since
pelvic lymph nodes are not treated with implant techniques. Coverage of
seminal vesicles and extracapsular areas vary depending on the operator
and institution.
Localization and Treatment

The present era of low-energy permanent radioisotopic implantation for
prostate cancer traces its origins to Scardino and Carlton at Baylor
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College of Medicine in the 1960s and Whitemore and Harris at Memorial
Sloan-Kettering Cancer Center in the 1970s, where an open, retropubic
approach was used to perform implants using freehand placement of
needles containing gold or iodine radioisotopes (124). Unfortunately,
this technique was associated with inhomogeneous dose distribution,
inexact dosimetry, and disappointing local control and disease-free
survival, and by the mid-1980s, the retropubic technique was largely
abandoned in favor of a transperineal approach (125).
Soon thereafter ultrasonography and a transperineal implant approach
using a rigid template guidance system was developed (126). Two
ultrasound-based planning approaches are generally used, either a
preplan designed with the prostate in treatment position, or an
intraoperative plan approach. With the preplanned technique, transverse
TRUS images are recorded at 5-mm intervals from the base to the apex
of the prostate gland using a stepping device attached to the ultrasound
probe and the patient in the dorsal lithotomy position. The physician
may evaluate the pubic arch during this procedure to determine any
potential for bone interference with needle insertion. The ultrasound
software projects the template grid over each successive prostate image.
Typically, seven to nine images are displayed at 5-mm increments, and
the prostate volume is contoured by the physician on each image. The
prostate itself or the prostate with a margin of 2 to 5 mm around the
prostate may be defined as the PTV. Various software packages can be
used for planning of a 3D implant volume, determining the number of
needles, their placement according to template coordinates, and the
number of seeds inserted per needle, prior to the actual implant.
With intraoperative planning, all these steps are performed in one
setting in the operating suite, tailoring the plan to the individual.
Without a preplan, there may be a risk of ordering too few or too many
seeds; however, the intraoperative planning approach has the significant
advantage in that the planning images are of the patient under
anesthesia, minimizing discrepancies between the planning images and
the actual anatomy and geometry. Furthermore, some treatment
planning software packages now allow the users to register the location
of sources as they are implanted and recalculate dosimetry in “real-
time,” allowing further adjustments and refinements to be made in the
treatment plan to accommodate inaccuracies in needle placement and
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intraoperative prostate shift and swelling.
Seeds are usually spaced 0.5 to 1 cm apart in the transverse (right to
left), anterior–posterior, and the superior–inferior planes. Computer-
generated isodose curves predict the delivered dose, assuming the
implant is completed as planned (Fig. 26A.10). During the implant
process each needle is guided to its predetermined position with the
template placed against the perineum by the use of an on-screen
template grid system and direct ultrasound visualization (Fig. 26A.11).
The specified number of radioactive seeds is implanted from the base to
the apex of the gland as each needle is withdrawn, using either
individual seeds—seeds linked together with custom-assembled spacers
—or fixed-space seeds embedded within a polymer strand cut to the
desired length. After completion of the seed placement, cystoscopy or
fluoroscopy may be utilized to assess for inadvertent seed localization
within the bladder or urethra and a Foley catheter may be placed. After
anesthesia recovery and proper assessment of exposure rates outside the
patient, most patients are safely released home and instructed to return
for subsequent postimplant dosimetry studies.
FIGURE 26A.10 A typical preoperative or intraoperative prostate ultrasound is shown with the
central urethra, prostate (clinical target volume), and prostate + 2 mm (planning target volume)
contours. The loading positions and number of intended I-125 seeds to be implanted in each
position are indicated at specific template coordinates, and the 290 Gy, 217.5 Gy, and 145 Gy
isodose lines are shown. Courtesy of Dr. Vrinda Narayana.
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FIGURE 26A.11 Transperineal prostate brachytherapy with transrectal ultrasound visualization
and seed placement via needle insertion using template guidance.
FIGURE 26A.12 An axial computed tomography image is shown in a postimplant patient. Based
upon the positions of the seeds and the contour of the prostate clinical and planning target
volumes, one can assess the adequacy of the dose distribution, as shown by the overlaid 290,
217.5, and 145 Gy isodose lines. Courtesy of Dr. Vrinda Narayana.
A postimplant CT scan and dosimetry should be done on each patient

to evaluate implant quality, thereby detecting any consistent
underdosing or inhomogeneities. The positions of all seeds are identified,
the target and normal tissues are contoured (prostate, urethra, bladder,
rectum, bowel, penile bulb), and dose distributions are calculated (Fig.
26A.12). This allows calculation of various dose–volume metrics, such as
the D90 and D100, the doses that cover 90% and 100% of the prostate
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volume, respectively, as well as the V100, the volume of the prostate
receiving at least 100% of the prescribed dose. The reporting of these
metrics is important in the medical literature to enable comparisons
between treatment results and also for individual prostate seed
brachytherapy programs to enable ongoing assessment of implant
quality and correlation with disease and toxicity outcomes. This enables
any necessary adjustments to treatment techniques and procedures.
Postimplant bleeding and edema can have significant effects on prostate
volume. Given that this is a dynamic process, it can have significant
implications for postimplant CT dosimetry. Practitioners may have
varying preferences for the time interval between the implant procedure
and when to perform postimplant dosimetry imaging, but it is important
that implant programs remain consistent in their planning and dosimetry
procedures to apply their dosimetry lessons toward quality
improvement.
Isotopes and Dose

Several isotopes have been used for prostate LDR—permanent interstitial
prostate brachytherapy (Table 26A.7). The most extensive experience
with permanent interstitial, LDR implants has been with iodine-125 (I-
125), which has been used for >40 years. Some radiobiologic evidence
raised concerns that the dose-rate of ∼8 cGy/h from I-125 was too low
for prostate cancer doubling times, so palladium-103 (Pd-103), with a
higher dose rate near 20 cGy/h, has been advocated (155).. Since the
energy of Pd-103 is still low and similar to that of I-125, 21 versus 28
keV, this isotope retains the advantage of delivering a relatively low
dose to surrounding organs and minimal exposure to medical personnel.
Clinical comparisons between the two isotopes have revealed no
significant difference in biochemical control (127). More recently,
Cesium-131 has been FDA-approved for permanent prostate
brachytherapy. Cs-131 has an energy (29 keV) similar to I-125, but a
shorter half-life (9.7 days). Although early experience with this isotope
has been positive, the follow-up is short, and there is no data to suggest
superiority over I-125 or Pd-103 (128). Although given the shorter half-
life of Pd-103 and Cs-131, these two isotopes may be associated with
greater short-term urinary toxicity with the potential to also have earlier
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resolution of urinary irritative and obstructive symptoms.
The American Association of Physics and Medicine (AAPM) Task
Group 43 (TG-43), published in 1995, altered the dose calculation
algorithm used for I-125, and its recommendations have been broadly
implemented (129). As a result, prescription doses previously described
as being 160 Gy have been lowered to 145 Gy as calculated under TG-43
with no change in implant activity, distribution, or geometry. This has
consequently divided the prostate brachytherapy dosimetry literature
into “pre-TG-43” and “TG-43” eras, an important consideration for
clinicians’ interpretation of older I-125 publications. Similarly, the dose
for Pd-103 implant was 115 Gy before the National Institute of
Standards and Technology 1999 Guidelines (NISTG-99) and 125 Gy
afterward (130).
Analysis of matched peripheral dose calculations within the Memorial
Sloan-Kettering Cancer Center I-125 implant experience found that the
5-, 10-, and 15-year local relapse-free survival was 78%, 56%, and 30%
among patients receiving doses of at least 140 Gy (126 Gy by TG-43),
compared with 64%, 38%, and 21% among those receiving <140 Gy
(126 Gy by TG-43) (125). Using modern transperineal prostate
brachytherapy techniques with CT-based postimplant dosimetry, Stock et
al. reported that patients receiving a D90 140 Gy (using TG-43 criteria)
had a 92% rate of 4-year biochemical control compared with only 68%
for patients receiving a D90 < 140 Gy (131). Wallner demonstrated that
both dose and volume of normal urethral and rectal tissue are related to
toxicity from prostate implants (132). Based on these experiences and
others, the American Brachytherapy Society has published guidelines for
transperineal permanent brachytherapy for prostate cancer,
recommending prescription doses of 145 Gy (TG-43) for I-125 and 125
Gy for Pd-103 (after NISTG-99) as monotherapy (156). For combination
therapy, an EBRT dose of 40 to 50 Gy should be combined with 100 to
110 Gy (TG-43) I-125 or 90 to 100 Gy (NISTG-99) Pd-103 implantation.
For Cs-131, an experienced group of users has developed consensus
recommendations for prostate implantation, which includes a
monotherapy prescription dose of 115 Gy and a boost prescription dose
of 85 Gy, with special attention to urethral and rectal dosing (128).
TABLE 26A.7 Isotopes Used for Interstitial Prostate Implant
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Use of HDR iridium-192 (Ir-192) brachytherapy has become
increasingly popular at many centers either as monotherapy or as a
boost in combination with EBRT. As with LDR brachytherapy, the HDR
technique employs TRUS-guided transperineal placement of needles and
catheters either via a template or by freehand, which is fixed to the
perineum. Real-time, ultrasound-based dose planning software may be
utilized. Planning may be accomplished using CT, ultrasound, or MRI
images taken with the catheters in place. Targets and normal structures
are contoured, and dwell times for source positions can be calculated to
optimize delivery of the desired dose to the PTV while minimizing
normal tissue dose. The hollow catheters can then be loaded by remote
afterloading Ir-192 HDR unit either in single or in multiple insertions.
Treatment is hypofractionated, generally using two or more large
fractions delivered at dose rates of ∼100 Gy/h. This HDR, which
approximates that delivered with a linear accelerator during EBRT, is the
main theoretical advantage of HDR brachytherapy and may result in a
superior radiobiologic effect compared with LDR brachytherapy,
particularly for disease with adverse risk features (133).
Although several centers (134) and multi-institutional experience
(135) have been published on HDR brachytherapy, no randomized trials
have compared outcomes of HDR monotherapy with other primary
treatment modalities. The follow-up is still insufficient to establish the
role of HDR monotherapy for treatment of men with localized disease.
HDR brachytherapy is more commonly utilized as a boost in
combination with EBRT. A variety of dose and fractionation schedules
have been reported. As one example, the most recent RTOG study for
intermediate risk patients prescribed 45 Gy of conventional EBRT
followed by an HDR prostate boost dose of 19 Gy given in two 9.5 Gy
fractions with a minimum 6-hour interfraction time interval (135).
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PROGNOSIS
The likelihood of biochemical, local, and distant failure as well as
disease-specific survival after RT for prostate cancer is related to tumor
stage, grade, and pretreatment PSA level (136–141). As discussed above,
additional factors also contribute to long-term prognosis including
radiation dose, the use of adjunctive androgen ablative therapy, PSA
kinetics, and tumor volume. Posttreatment factors such as PSA nadir also
have predictive value in estimating biochemical and distant failure
(142). Provider experience and treatment volume have also been
demonstrated to influence the likelihood of recurrence and the need for
salvage hormonal therapy for both brachytherapy (143) and external
beam radiation.
At a RTOG symposium in Phoenix, numerous candidate definitions of
biochemical failure were evaluated, and a definition was endorsed of the
posttreatment nadir PSA plus 2 ng/mL as being the threshold for
defining clinically meaningful biochemical failure after primary EBRT
for prostate cancer (144). The Phoenix definition was initially only
defined for those receiving EBRT or brachytherapy with at most short-
term androgen therapy (145). However, others have suggested that it is
applicable to those treated with EBRT along with long-term ADT (146).
Biochemical failure by the Phoenix definition has been demonstrated to
correlate with patient survival although the risk of death from prostate
cancer following biochemical failure is dependent upon both the clinical
features of the cancer as well as patient age (146,147), and as a result it
is not a reasonable surrogate for patient survival in most patients.
Following biochemical failure patient risk group, the time to PSA failure
(148,149) and the PSA kinetics during failure may help further elucidate
those patients at high risk of distant metastasis and prostate cancer-
specific mortality (149,150).
Long-term follow-up of the MD Anderson randomized trial of 70
versus 78 Gy (without ADT) revealed 8-year freedom from biochemical
failure using the Phoenix definition of 88%, 86%, and 63% for low,
intermediate, and high-risk prostate cancer, respectively (Table 26A.7)
(80). Radiation dose did appear to predict for improved outcome as well
with freedom from biochemical or clinical failure at 8 years greater in
the 78 Gy arm as compared to the 70 Gy arm (78% vs. 59%, p = 0.004).
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Distant metastasis had only been observed in a small number of patients;
however, freedom from distant metastasis after 70 Gy versus 78 Gy was
95% versus 99% with a trend toward statistical significance (p < 0.06).
The difference in metastasis as a function of radiation dose was greater
in those in the high-risk group (83% vs. 96%, p < 0.04). With a median
of 8 years of follow-up there were few deaths due to prostate cancer, as
a result to date there was no difference in either prostate cancer-specific
or overall survival (80).
Brachytherapy outcomes have also improved significantly with
enhanced techniques, and multi-institutional and randomized trial data
are now becoming available in the literature which should provide more
generalizable experiences as opposed to single-institutional case series
which are more prone to selection, individual practitioner
experience/technique, and other biases. RTOG 9805 examined LDR
monotherapy for patients with low-risk prostate cancer treated at 27
different institutions with I-125 LDR monotherapy to 145 Gy (151). At 5
years, the biochemical failure-free survival rates exceeded 90%, which
was comparable with other published brachytherapy series and with
surgical or EBRT outcomes. Recently, a small Italian randomized trial
comparing RP with LDR brachytherapy for low-risk patients showed no
differences in 5-year bRFS rates between these two treatment modalities
(152). Brachytherapy patients were noted to have persistent increased
genitourinary irritative side effects, but superior urinary continence and
erectile function compared with RP patients. RTOG study 0019
examined combined EBRT with LDR brachytherapy boost for patients
with intermediate risk features treated at over 20 different institutions
(153). Treatment was delivered with combined conventionally
fractionated 3D conformal EBRT to 45 Gy with LDR brachytherapy boost
2 to 6 weeks later to 108 Gy. At 4 years, biochemical recurrence rates
were 14% to 19%, comparable with results achieved with dose-escalated
EBRT. However, incidence of grade 3 or higher genitourinary or
gastrointestinal toxicity was 15%, higher than that observed in
contemporary studies of patients treated with brachytherapy or EBRT
alone. RTOG study 0321 examined combined EBRT with HDR
brachytherapy boost for patients with a slightly higher intermediate risk
group of patients (135). Treatment was delivered with EBRT to 45 Gy
and two 9.5 Gy HDR boost fractions (total 19 Gy boost) within an
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overall treatment time of <8 weeks. At 29 months, the estimated rate of
grade 3 through 5 genitourinary and gastrointestinal adverse events was
2.4%, demonstrating the feasibility of EBRT/HDR treatment in the multi-
institutional setting and an acceptable level of adverse events. Finally, a
prospective (but not randomized) study for intermediate to high-risk
patients utilized ∼9 months ADT with either 76 Gy EBRT as compared
to 45 Gy EBRT with 18 Gy HDR boost given in two fractions and
demonstrated a small but not statistically significant difference in 5-year
bRFS between treatment arms, but lower rates of late grade 2 rectal
toxicity in the HDR-treated patients (13% vs. 3%, p < 0.005) (154).
CONCLUSION
Significant advances have been made in the treatment of prostate cancer
with RT over the last 10 years that have resulted in improvements in
disease control with decreased risks of toxicity and series adverse
impacts upon long-term patient quality of life. However, these advances
have depended upon closer detail to the process of planning and delivery
of RT to the prostate. The optimal selection of radiation modalities
either alone or in combination and the timing and duration of ADT in
this setting remain to be established. Nevertheless, the results to data
suggest that RT is an attractive and viable treatment option for men with
prostate cancer.
KEY POINTS
• Prostate cancer is the most common noncutaneous malignancy in
men in the United States and is the second most common cause of
cancer-related deaths in men.
• Clinical T stage, Gleason grade, and pretreatment PSA are the
most important factors used for risk stratification.
• Definitive treatment involves treatment of the entire prostate gland.
• While the prostate gland is always in the target volume, a decision
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must be made as to whether the seminal vesicles and pelvic lymph
nodes are included.
• There are many options for image guidance, including CBCT,
ultrasound localization system, or implanted fiducials.
• Postprostatectomy target volume delineation is subject to
significant variation but the vesicourethral anastomosis (VUA),
periurethral, and perivesicular tissues should all be treated as these
are the most common sites of recurrence following RP.
• The use of IGRT in the postoperative setting is not as clearly
established as that in the definitive setting.
• The prostate gland itself, with minimal margin, is the target for
radioisotopic implant.
QUESTIONS
1. NCCN guidelines recommend pelvic imaging with CT or MRI in
clinically localized prostate cancer when the probability of lymph
node involvement is greater than:
A. 5%
B. 10%
C. 15%
D. 20%
2. A bone scan is recommended in which of the following scenarios?
A. T1c and PSA 15
B. Gleason 4+3
C. T2b
D. PSA 25
3. What are the usual prescription doses for prostate brachytherapy
using I-125 and Pd-103, respectively?
A. 125 Gy and 145 Gy
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B. 110 Gy and 90 Gy
C. 145 Gy and 125 Gy
D. 125 Gy and 110 Gy
4. Which radioisotope is used in HDR brachytherapy?
A. I-125
B. Pd-103
C. Cs-131
D. Ir-192
5. RTOG pelvic nodal consensus CTV contours for high-risk prostate
cancer include which lymph nodes?
A. Presacral, distal common iliac, internal and external iliac,
obturator
B. Para-aortic, presacral, distal common iliac, internal iliac,
obturator
C. Presacral, distal common iliac, internal iliac
D. Para-aortic, presacral, distal common iliac, internal and
external iliac
ANSWERS
1. B
2. D
3. C
4. D
5. A
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Committee. Int J Radiat Oncol Biol Phys. 2010;76(5):1297–1304.
96. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy
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after radical prostatectomy: a randomised controlled trial (EORTC
trial 22911). Lancet. 2005;366(9485):572–578.
97. Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant
radiotherapy for pathologically advanced prostate cancer: a
randomized clinical trial. JAMA. 2006;296(19):2329–2335.
98. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant
radiotherapy after radical prostatectomy compared with radical
prostatectomy alone in pT3 prostate cancer with postoperative
undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95.
J Clin Oncol. 2009;27(18):2924–2930.
99. Trabulsi EJ, Valicenti RK, Hanlon AL, et al. A multi-institutional
matched-control analysis of adjuvant and salvage postoperative
radiation therapy for pt3–4n0 prostate cancer. Urology. 2008;
72(6):1298–1302.
100. Cozzarini C, Bolognesi A, Ceresoli GL, et al. Role of postoperative
radiotherapy after pelvic lymphadenectomy and radical retropubic
prostatectomy: a single institute experience of 415 patients. Int J
101. Thompson IM, Tangen CM, Paradelo J, et al Adjuvant radiotherapy
for pathological T3N0M0 prostate cancer significantly reduces risk
of metastases and improves survival: long-term followup of a
randomized clinical trial. J. Urol.2009;181(3):956–962.
102. Eisenberg ML, Davies BJ, Cooperberg MR, et al. Prognostic
implications of an undetectable ultrasensitive prostate-specific
antigen level after radical prostatectomy. Eur Urol. 2010;57(4):622–
630.
103. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the
outcome of salvage radiation therapy for recurrent prostate cancer
after radical prostatectomy. J Clin Oncol. 2007;25(15):2035–2041.
104. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy
for recurrent prostate cancer after radical prostatectomy. JAMA.
2004;291(11):1325–1332.
105. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific
survival following salvage radiotherapy vs. observation in men with
biochemical recurrence after radical prostatectomy. JAMA.
2008;299(23):2760–2769.
106. Den RB, Yousefi K, Trabulsi EJ, et al. Genomic classifier identifies
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men with adverse pathology after radical prostatectomy who benefit
from adjuvant radiation therapy. J Clin Oncol. 2015;33(8):944–951.
107. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of
progression after PSA elevation following radical prostatectomy.
JAMA. 1999;281(17):1591–1597.
108. Poortmans P, Bossi A, Vandeputte K, et al. Guidelines for target
volume definition in post-operative radiotherapy for prostate
cancer, on behalf of the EORTC Radiation Oncology Group.
Radiother Oncol. 2007;84(2):121–127.
109. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG
consensus guidelines for the definition of the clinical target volume
for postoperative conformal radiation therapy for prostate cancer.
110. Wiltshire KL, Brock KK, Haider MA, et al. Anatomic boundaries of
the clinical target volume (Prostate Bed) after radical prostatectomy.
111. Sidhom MA, Kneebone AB, Lehman M, et al. Post-prostatectomy
radiation therapy: consensus guidelines of the Australian and New
Zealand Radiation Oncology Genito-Urinary Group. Radiother Oncol.
2008;88(1):10–19.
112. Miralbell R, Vees H, Lozano J, et al. Endorectal MRI assessment of
local relapse after surgery for prostate cancer: A model to define
treatment field guidelines for adjuvant radiotherapy in patients at
high risk for local failure. Int J Radiat Oncol Biol Phys.
2007;67(2):356–361.
113. Silverman JM, Krebs TL. MR imaging evaluation with a transrectal
surface coil of local recurrence of prostatic cancer in men who have
undergone radical prostatectomy. AJR Am J Roentgenol.
1997;168(2):379–385.
114. Sella T, Schwartz LH, Swindle PW, et al. Suspected local recurrence
after radical prostatectomy: endorectal coil MR imaging. Radiology.
2004;231(2):379–385.
115. Valicenti RK, Gomella LG, Ismail M, et al. Durable efficacy of early
postoperative radiation therapy for high-risk pT3N0 prostate cancer:
the importance of radiation dose. Urology. 1998;52(6):1034–1040.
116. Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and
urinary toxicities after three-dimensional conformal radiotherapy
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and intensity-modulated radiotherapy for localized prostate cancer.
117. Feng M, Hanlon AL, Pisansky TM, et al. Predictive factors for late
genitourinary and gastrointestinal toxicity in patients with prostate
cancer treated with adjuvant or salvage radiotherapy. Int J Radiat
Oncol Biol Phys. 2007;68(5):1417–1423.
118. King CR, Kapp DS. Radiotherapy after prostatectomy: is the
evidence for dose escalation out there? Int J Radiat Oncol Biol Phys.
2008;71(2):346–350.
119. Wang K, Wu X, Bossart E, et al. The uncertainties in target
localization for prostate and prostate-bed radiotherapy with Calypso
4D. Int J Radiat Oncol. 2009;75(3):S594.
120. Schiffner DC, Gottschalk AR, Lometti M, et al. Daily electronic
portal imaging of implanted gold seed fiducials in patients
undergoing radiotherapy after radical prostatectomy. Int J Radiat
Oncol Biol Phys. 2007;67(2):610–619.
121. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D.
Anderson randomized dose-escalation trial for prostate cancer. Int J
122. Nath SK, Sandhu AP, Rose BS, et al. Toxicity analysis of
postoperative image-guided intensity-modulated radiotherapy for
prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(2):435–441.
123. Papagikos MA, Rossi PJ, Urbanic JJ, et al. A simple model predicts
freedom from biochemical recurrence after low-dose rate prostate
brachytherapy alone. Am J Clin Oncol. 2007;30(2):199–204.
124. Carlton CE Jr, Scardino PT. Combined interstitial and external
irradiation for prostatic cancer. Prog Clin Biol Res. 1987;243B:141–
169.
125. Zelefsky MJ, Whitmore WF Jr. Long-term results of retropubic
permanent 125iodine implantation of the prostate for clinically
localized prostatic cancer. J Urol. 1997;158(1):23–29.
126. Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ
preservation in the management of carcinoma of the prostate. Semin
Radiat Oncol. 1993;3(4):240–249.
127. Wallner K, Merrick G, True L, et al. 125I versus 103Pd for low-risk
prostate cancer: preliminary PSA outcomes from a prospective
randomized multicenter trial. Int J Radiat Oncol. 2003;57(5):1297–
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1303.
128. Bice WS, Prestidge BR, Kurtzman SM, et al. Recommendations for
permanent prostate brachytherapy with 131Cs: a consensus report
from the Cesium Advisory Group. Brachytherapy. 2008; 7(4):290–
296.
Therapy Committee Task Group 43. American Association of
Physicists in Medicine. Med Phys. 1995;22(2):209–234.
130. Williamson JF, Coursey BM, DeWerd LA, et al. Recommendations of
the American Association of Physicists in Medicine on 103Pd
interstitial source calibration and dosimetry: implications for dose
specification and prescription. Med Phys. 2000;27(4):634–642.
131. Stock RG, Stone NN, Tabert A, et al. A dose-response study for
{I}-125 prostate implants. Int J Radiat Oncol Biol Phys. 1998;
41(1):101–108.
132. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize
urethral and rectal morbidity following transperineal I-125 prostate
brachytherapy. Int J Radiat Oncol Biol Phys. 1995;32(2):465–471.
133. Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using
conformal high-dose-rate brachytherapy improves outcome in
unfavorable prostate cancer. Int J Radiat Oncol Biol Phys.
2002;53(2):316–327.
134. Pisansky TM, Gold DG, Furutani KM, et al. High-dose-rate
brachytherapy in the curative treatment of patients with localized
prostate cancer. Mayo Clin Proc. 2008;83(12):1364–1372.
135. Hsu IC, Bae K, Shinohara K, et al. Phase II trial of combined high-
dose-rate brachytherapy and external beam radiotherapy for
adenocarcinoma of the prostate: Preliminary results of RTOG 0321.
Int J Radiat Oncol Biol Phys. 78(3):751–758.
136. D’Amico AV, Whittington R, Malkowicz SB, et al Pretreatment
nomogram for prostate-specific antigen recurrence after radical
prostatectomy or external-beam radiation therapy for clinically
localized prostate cancer. J Clin Oncol. 1999;17(1):168–172.
137. Kattan MW, Zelefsky MJ, Kupelian PA, et al., Pretreatment
nomogram for predicting the outcome of three-dimensional
conformal radiotherapy in prostate cancer. J Clin Oncol.
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2000;18(19):3352–3359.
138. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for
clinically localized prostate cancer: a multi-institutional pooled
analysis. JAMA. 1999;281(17):1598–1604.
139. Kuban DA, Thames HD, Levy LB, et al. Long-term multi-
institutional analysis of stage T1-T2 prostate cancer treated with
radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys. 2003;
57(4):915–928.
140. Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment
nomogram that predicts 5-year probability of metastasis following
three-dimensional conformal radiation therapy for localized prostate
141. Kattan MW, Potters L, Blasko JC, et al. Pretreatment nomogram for
predicting freedom from recurrence after permanent prostate
brachytherapy in prostate cancer. Urology. 2001;58(3):393–399.
142. Ray ME, Levy LB, Horwitz EM, et al. Nadir prostate-specific antigen
within 12 months after radiotherapy predicts biochemical and
distant failure. Urology. 2006;68(6):1257–1262.
143. Chen AB, D’Amico AV, Neville BA, et al. Provider case volume and
outcomes following prostate brachytherapy. J Urol. 2009;
181(1):113–118.
144. Roach M Jr, Hanks G, Thames H Jr, et al. Defining biochemical
failure following radiotherapy with or without hormonal therapy in
men with clinically localized prostate cancer: Recommendations of
the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol
Biol Phys. 2006;65(4):965–974.
145. Kuban DA, Levy LB, Potters L, et al. Comparison of biochemical
failure definitions for permanent prostate brachytherapy. Int J
RadiatOncol Biol Phys. 2006;65(5):1487–1493.
146. Pickles T, Kim-Sing C, Morris WJ, et al. Evaluation of the Houston
biochemical relapse definition in men treated with prolonged
neoadjuvant and adjuvant androgen ablation and assessment of
follow-up lead-time bias. Int J Radiat Oncol Biol Phys.
2003;57(1):11–18.
147. Abramowitz MC, Li T, Buyyounouski MK, et al. The phoenix
definition of biochemical failure predicts for overall survival in
patients with prostate cancer. Cancer. 2008;112(1):55–60.
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148. Buyyounouski MK, Hanlon AL, Horwitz EM, et al. Interval to
biochemical failure highly prognostic for distant metastasis and
prostate cancer-specific mortality after radiotherapy. Int J Radiat
Oncol Biol Phys. 2008;70(1):59–66.
149. Denham JW, Steigler A, Wilcox C, et al. Time to biochemical failure
and prostate-specific antigen doubling time as surrogates for
prostate cancer-specific mortality: evidence from the TROG 96.01
randomised controlled trial. Lancet Oncol. 2008;9(11):1058–1068.
150. D’Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for
prostate cancer-specific mortality after radical prostatectomy or
radiation therapy. J Natl Cancer Inst. 2003;95(18):1376–1383.
151. Lawton CA, Hunt D, Lee WR, et al. Long-term results of a phase II
trial of ultrasound-guided radioactive implantation of the prostate
for definitive management of localized adenocarcinoma of the
prostate (RTOG 98–05). Int J Radiat Oncol Biol Phys. 2011;81(1):1–
7.
152. Giberti C, Chiono L, Gallo F, et al. Radical retropubic prostatectomy
versus brachytherapy for low-risk prostatic cancer: a prospective
study. World J Urol. 2009;27(5):607–612.
153. Lee WR, DeSilvio M, Lawton C, et al. A phase II study of external
beam radiotherapy combined with permanent source brachytherapy
for intermediate-risk, clinically localized adenocarcinoma of the
prostate: preliminary results of RTOG P-0019. Int J Radiat.Oncol Biol
Phys. 2006;64(3):804–809.
154. Guix B, Bartrina JM, Tello JI, et al. Dose escalation with high-dose
3D-conformal radiotherapy (HD-3D-CRT) or low-dose 3D-conformal
radiotherapy plus HDR brachytherapy (LD-3D-CRT+HDR-B) for
intermediate- or high-risk prostate cancer: Early results of a
prospective comparative trial. Brachytherapy. 2009;8(2):105–106.
155. Ling CC. Permanent implants using Au-198, Pd-103 and I-125:
radiobiological considerations based on the linear quadratic model.
156. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society
(ABS) recommendations for transperineal permanent brachytherapy
of prostate cancer. Int J Radiat Oncol Biol Phys. 1999;44:789–799.
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26B Genitourinary Cancers:
Bladder Cancer
INTRODUCTION
Bladder cancers are fairly common cancers of the urinary tract, affecting
70,000 adults in the United States each year. It is the fourth most
common tumor in men and the ninth most common cancer in women
(1). The majority of bladder cancers in the United States are transitional
cell carcinomas (TCCs) while the majority in the developing world are
squamous cell carcinomas. Curable bladder cancer can be conceptualized
in several categories: those that require superficial therapy, those with
more advanced disease who require more aggressive definitive therapy,
and finally those who are ineligible for bladder conservation but are
curable. Radiotherapy plays a pivotal role in bladder preservation and is
commonly utilized in the postoperative setting. Radiotherapy is not used
for superficial bladder cancers. This chapter will focus on how to
identify which patients fall into which subgroup, how to deliver
radiotherapy in the group of patients who are eligible for bladder
preservation, and finally postoperative radiotherapy.
Risk Stratification
The most important assessment in the risk stratification of patients with
bladder cancer is the depth of invasion of the primary tumor. Once
bladder cancer reaches the muscularis propria the risk of locoregional
spread is much higher and more aggressive definitive therapy is
required. The risk of lymph node spread for superficial tumors is 5% or
less compared to 20% for tumors that have reached the muscularis
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propria and 20% to 40% for tumors that have invaded beyond the
muscularis propria (2). Thankfully, the majority of bladder cancers are
limited to the mucosal surface (3). These superficial tumors can be
managed with transurethral resection of bladder tumor followed by
superficial therapy with intravesicular mitomycin C or bacilli Calmette–
Guerin (BCG). BCG is the preferred therapy for most superficial disease
(Tis), papillary tumors (Ta), and tumors confined to the mucosa (T1) of
all grades (low and high). Mitomycin C can be used for low grade, Ta
tumors. Superficial tumors have a high recurrence rate at 5 years; 50%
or greater. Many of these recurrences will progress to muscle invasion.
Unfortunately, half of all patients with muscle invasive disease will die
of bladder cancer in 5 years, regardless of therapy. But muscle invasive
TCC of the bladder can be curable. Identifying which therapies are
options for these patients requires an understanding of the diagnostic
studies that yield proper staging and risk stratification.
Diagnostic Studies and Staging

The classic presentation of bladder cancer is painless gross or
microscopic hematuria, which occurs in up to 80% of cases. Urinary
urgency, frequency, and dysuria without hematuria may occur in up to
30% of patients. Initial urologic evaluation must include urine cytology
and cystoscopy with possible transurethral biopsy/TURBT during
cystoscopy. TURBT specimens should generally contain some muscle to
properly evaluate for muscle invasion. If muscle invasion is discovered at
the time of TURBT, the patient should have a computed tomography
scan of the abdomen and pelvis to evaluate for suspicious lymph nodes.
Patients should also have the upper urinary tract evaluated (NCCN
guidelines version I.2016).
The standard staging system utilized is the tumor, nodal, and
metastasis (TNM) staging system of the American Joint Committee on
Cancer (AJCC) (Table 26B.1) (4). The system is based on sub-dividing
patients into groups by the extent of local tumor invasion and the
presence or absence of nodal or distant metastases. In this system, T-
staging, based upon the depth of invasion of the primary tumor (T),
conveys important prognostic information. The most useful assessment is
whether the tumor is organ-confined (≤T2) or non–organ-confined
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(≥T3). However, the utility of available methods for determining the
degree of muscle invasiveness preoperatively is modest with accuracy at
most 70% even with the combination of cystoscopic evaluation and
TURBT when compared to pathologic examination following cystectomy.
Determination of the extent of muscle invasion at biopsy also requires
adequate sampling of the bladder wall muscle. In addition to depth of
invasion, other factors to be determined at the time of staging include
the size and location of the lesion, the presence of CIS, the histologic
type, and the degree of differentiation. The majority (90%) of bladder
cancers in the United States are transitional cell malignancies, and for
these by consensus definition, the degree of differentiation is limited to
low-grade and high-grade. With rare exception, muscle-invasive (T2 or
greater) urothelial cancer is high-grade. Given the high incidence of
multicentric disease examination of specimens taken from clinically
uninvolved areas of the bladder is also recommended. (See Table 26B.1
for current AJCC staging system.)
TABLE 26B.1 2010 American Joint Committee on Cancer (AJCC)

TNM Staging System for Bladder Cancer
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Treatment Options
As mentioned above, bladder cancer is divided into superficial, muscle
invasive, and more advanced disease. Superficial cancers do not require
surgery, systemic chemotherapy, or radiotherapy. Bladder conserving
surgery using TURBT alone may be appropriate treatment for selected
early stage patients (5), particularly for patients who are poor candidates
for aggressive interventions. TURBT is also a critical component of
multimodality treatment strategies for more advanced disease, and the
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completeness of resection is an important predictor of local control and
survival (6). Even for noninvasive disease, recurrence after TURBT alone
is common, particularly for high-grade lesions (7). Recurrence rates can
be decreased by the use of intravesical BCG, resulting in 70% to 80% 5-
year survival for T1 tumors (8,9). With progression from T1 to muscle-
invasive disease, radical cystectomy has been the standard
recommendation; however, some would argue that at this point, organ-
preserving therapy with radiation and chemotherapy may also be an
option (10,11).
Muscle invasive cancer can be treated with cystectomy with or
without chemotherapy/radiotherapy or with bladder preservation with
TURBT followed by chemoradiation. No clinical trial has directly
compared cystectomy to bladder preservation, but the data seems to
indicate that overall survival rates are comparable (2,12–16). Generally
patients may proceed with bladder preservation based on patient or
clinician choice if they are eligible. Patients who have diffuse disease,
invasion of adjacent structures (T4 disease), hydronephrosis, diffuse
carcinoma in situ, inadequate TURBT, poor bladder function, or inability
to tolerate chemotherapy are ineligible for bladder preservation with
TURBT and chemoradiation.
Nonbladder Sparing Treatment Approaches for Muscle Invasive

Disease
Five-year overall survival estimates in modern radical cystectomy series
are approximately 50%. Radical cystectomy includes removal of the
bladder, prostate, seminal vesicles, and proximal urethra in males. In
females the bladder, urethra, uterus, fallopian tubes, ovaries, and
anterior vaginal wall are removed. Radical cystectomy may be followed
by various reconstruction options, which is beyond the scope of this
chapter.
Local control rates with radical cystectomy are high (17). However,
the risk of pelvic relapse may approach 30% in patients who are found
to have extravesicular extension (T3b) or positive nodes and may
approach 70% in patients with positive margins (18,19). These high
locoregional recurrence rates generated interest in chemotherapy and
radiotherapy in the adjuvant or neoadjuvant setting.
An approximately 5% overall survival benefit has been observed when
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neoadjuvant chemotherapy is utilized prior to radical cystectomy for
patients with muscle invasive bladder cancer (13,20,21). Initially MVAC
was the chemotherapy of choice in the neoadjuvant setting. However,
gemcitabine and cisplatin has been shown to be equally effective and
less toxic (22). It is worth noting that more than half of patients will
have notable downstaging when neoadjuvant chemotherapy is utilized.
More than one quarter may have a complete response. Responders to
chemotherapy enjoy a higher overall survival, but they still require
definitive therapy (cystectomy or chemoradiation). Adjuvant
chemotherapy has also demonstrated disease free and overall survival
benefits in several studies (23), but neoadjuvant chemotherapy is
favored because responders may be eligible for bladder-sparing
approaches.
An intergroup randomized trial showed that patients who had
preoperative radiotherapy had a 5-year overall survival of 53% and the
surgery alone group had an overall survival of 43%. This difference was
not statistically significant (24). A subsequent meta-analysis of five
randomized trials did not show a benefit to preoperative radiotherapy
compared to cystectomy alone (25). Overall, preoperative radiotherapy
is not commonly utilized because irradiated bowel is less suitable for
ileal conduit reconstructions and the data behind neoadjuvant
chemotherapy is stronger.
Interest in postoperative radiotherapy stems from the high rates of
local recurrence in the setting of T3b, T4, or positive margins. The local
recurrence rates in these situations are at least 30% (19,26).
Postoperative radiotherapy is generally not indicated for node positive
disease because at that point the primary concern is distant, not local
recurrence. It is worth noting that postoperative radiotherapy to the
pelvis after cystectomy is likely to cause more bowel toxicity since the
organs of the pelvis are no longer displacing the small bowel from the
true pelvis.
Bladder-Sparing Approaches for Muscle Invasive Disease

This section will focus on selective bladder-sparing techniques. There are
two subcategories of this approach: (1) patients who are medically
inoperable and (2) patients who are medically operable but would like
to preserve their bladder rather than have radical en bloc removal of the
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bladder and prostate or uterus and ovaries. Overall functional outcomes
after selective bladder preservation are excellent. A recent analysis of
late toxicity for 157 patients treated on 4 RTOG protocols revealed that
there were no grade 4 toxicities or treatment-related deaths. Further,
only 7% of patients experienced late grade 3 or greater pelvic toxicity
(6% GU and 2% GI), and the toxicities resolved in all but one patient.
Overall quality of life after combined modality therapy is excellent for
the majority of patients with only ∼30% requiring a cystectomy (27). In
addition, for those with a retained bladder, >75% are able to retain
normal urinary function by urodynamic studies, and >85% with no
bothersome urinary side effects (28).
The history of bladder preservation strategies began as early as the
1980s, investigators attempted to preserve the bladder. Definitive
radiotherapy series demonstrated that half of patients may be
recurrence-free at 5 years, but overall survival was notably lower than
cystectomy series; only 20% to 40% (29–34). When investigators at the
University of Paris noted a very high complete pathologic response rate
following combined maximal TURBT and neoadjuvant
chemoradiotherapy (5FU/cisplatin), they attempted to elucidate what
factors would allow patients to avoid cystectomy altogether (35).
Investigators at the University of Paris, University of Erlangen
(Germany), and Massachusetts General Hospital each developed bladder
preservation strategies that involved TURBT, chemoradiation, and
restaging cystoscopy at some point mid-way to two-thirds of the way
through chemoradiation to assess response. Nonresponders were sent for
cystectomy. Since then, there have been multiple RTOG trials published
on selective bladder preservation (Table 26B.3). The current treatment
paradigm involves an initial maximal TURBT, concurrent cisplatin-based
chemoradiotherapy to the entire pelvis up to 40 to 45 Gy with a
cystoscopy 3 to 4 weeks later with biopsy. If the tumor has decreased to
≤T1, there are two options. The first of which is to boost the entire
bladder with an additional 8 Gy followed by boosting the tumor only
with an additional 12 Gy. The second option is to boost the entire
bladder with an additional 12 Gy. Target volumes and fields will be
described in a subsequent section.
TABLE 26B.2 Approximate 5-Year Relapse-Free and Overall Survival
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After Radical Cystectomy for Bladder Cancer by Stage (5)
Overall, contemporary series show equivalent 5-year overall survival

when cystectomy is compared to selective bladder preservation (TURBT
+ chemoradiation); approximately 50% (Tables 26B.2 and 26B.3).
Again, selective bladder preservation and radical cystectomy have never
been directly compared in a randomized trial.
Palliative Radiotherapy
Patients with advanced bladder tumors who are not eligible for
cystectomy will often have metastatic disease. These patients may be
managed with chemotherapy and reassessed for the appropriateness of
concurrent chemoradiation. A randomized trial conducted in the United
Kingdom randomized patients with advanced symptomatic bladder
primaries to 35 Gy in 10 fractions or 21 Gy in 3 fractions. Sixty-eight
percent of patients had symptomatic improvement and there was no
difference between the two arms (36).
TABLE 26B.3 Radiation Therapy Oncology Group (RTOG) Protocols

for Invasive Bladder Cancer (1985–2009) (28) (42)
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Treatment Planning Technique
The traditional means of treating bladder cancer with external beam
radiotherapy is a four-field box. There are four separate fields: (1) the
whole pelvic field, (2) the bladder field, and (3) the final tumor boost. If
selective bladder preservation is the goal, the treatment break will take
place after the whole pelvic treatment. If the patient is medically
inoperable, the patient will not have a treatment break.
SIMULATION
Whole Pelvic Field
The whole pelvic field is typically treated with high-energy photons (6 to
15 MV) and a 3-dimensional (3D) conformal planning technique. The
whole pelvic field in bladder cancer radiotherapy targets the external
and internal iliac lymph nodes, the bladder, and the obturator lymph
nodes, and provides a margin around the bladder and prostate. The
common iliacs are not targeted because irradiation of bowel must be
limited and because the highest risk of nodal disease is in the external
and internal iliac lymph node chains. Therefore, the superior border of
all fields in the four-field box is at the mid-sacroiliac joint
(approximately S2–S3 vertebral bodies). The inferior border of all four
fields should adequately cover the prostate or in women the proximal 2
cm of urethra. In women, the inferior border should not be so low that
the vulva is irradiated to a high dose. Therefore, the inferior border is at
the bottom of the obturator foramen or 2 cm below the tumor,
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whichever is lower. The posterior border of the lateral fields is 2 cm
posterior to the bladder and internal iliac lymph nodes. Up to half of the
rectum should be blocked. The anterior border is 2 cm anterior to the
external iliac lymph nodes and bladder. The lateral border of the
anterior and posterior fields should extend 1.5 to 2 cm beyond the pelvic
inlet. The femoral heads should be blocked to keep the total dose below
40 to 50 Gy. During the treatment of the pelvic field, patients can be
treated with a full bladder to displace small bowel from the field. Point
doses to the bowel should remain below 50 Gy. The volume of bowel
receiving 45 Gy should be limited to less than 200 cc (Fig. 26B.1A,B).
FIGURE 26B.1 Whole pelvic fields for bladder cancer. A: Small/mini-pelvis field (45 Gy): superior
border is S2/S3; inferior border is bottom of the obturator foramen. The border is 1/5 to 2.0 cm
lateral to the medial aspect of the pelvic bone. Blocks can be used for the femoral heads. The
lateral beams have the same superior and inferior borders as the AP/PA beams. The anterior field
border is 1 cm anterior to the bladder or 1 cm anterior to the pubic symphysis, whichever is more
anterior. The posterior border is 2.5 cm posterior to the bladder or any visible tumor. The whole
bladder field (54 Gy) is the bladder with a 2-cm block margin. The tumor boost field (64 Gy) is a 2-
cm expansion on the primary tumor. B: Bladder.
Subsequent Boost Fields: Bladder Only or Bladder

Followed by Tumor Only
Patients undergoing selective bladder preservation will have a treatment
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break after initial treatment to the pelvic fields. The patient can be
simulated with an empty bladder during treatment of the bladder and/or
tumor fields. Patients may have significant irritative voiding symptoms
and urinary frequency after initial treatment to the pelvis, which may
make treatment with a full bladder difficult. If a third, tumor-only field
is treated, it should be tumor only with a 2-cm margin around the
tumor. Coning down from the bladder to the tumor is advantageous
because it may allow in minimizing radiation dose to normal bladder,
which may impact subsequent bladder function. However, it should only
be done if there is sufficient confidence that the original tumor will not
be missed. Keep in mind that the dose of the final treatment will be 60
to 65 Gy, which is the approximate tolerance for the whole bladder.
Some radiation oncologists advocate attempting to treat tumor-only
boost fields with a full bladder to further minimize the amount of
normal bladder mucosa irradiated. An example is rectal constraint V55
Gy <50%.
Postoperative Radiotherapy
Postoperative radiotherapy may be indicated for pathologic stage T3 or
for positive margins. Consider irradiating the cystectomy bed, external
iliac, internal iliac, common iliac, obturator, and presacral lymph node
chains for patients with positive margins. For patients with negative
margins, consider omitting the cystectomy bed and presacral lymph
nodes as the risk of failure there is low with negative margins (26).
Follow-up
Patients treated for muscle-invasive disease (stage T2 or greater) should
be followed with urine cytology and cystoscopy every 3 to 6 months for
2 years, with imaging of the chest, upper tract, abdomen, and pelvis. If
the patient has undergone cystectomy, urine cytology is still warranted
to assess for abnormal cells from the upper tract or ureters.
Prognosis
Survival from bladder cancer is largely determined by distant metastasis;
therefore, ongoing prospective trials are focusing on incorporating novel
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combinations of cytotoxic chemotherapy and targeted agents. Radical
cystectomy remains the standard treatment for muscle-invasive bladder
cancer. It provides excellent rates of local control, and a 5-year survival
that ranges from 30% to 90% depending on the extent of disease and
risk for distant metastasis (Table 26B.2). Multimodality treatment using
TURBT, chemotherapy, and radiotherapy provides high rates of complete
disease response, and survival that is comparable to radical cystectomy
(Table 26B.3). Furthermore, 60% to 70% of patients treated with
multimodality, bladder-preserving treatment strategies are able to retain
their native bladder, offering the potential of superior long-term bladder
function and patient quality of life.
KEY POINTS
• Bladder cancer is one of the most common cancers in adults in the
United States: it is the fourth most common in men and the ninth
most common in women.
• Most bladder cancers are superficial (Tis, Ta, T1) and require
superficial therapy only with maximal TURBT and intravesicular
therapy (MMC or BCG).
• One of the most important distinctions from a radiation oncologist’s
perspective is whether a patient has muscle invasive (≥T2) disease
or not. Such patients should be treated with chemoradiation or
cystectomy (unless metastatic).
• The factors that exclude medically operable patients from
attempted bladder preservation include diffuse disease, inability to
perform maximal TURBT, T4 disease, hydronephrosis, inability to
tolerate chemotherapy, and metastatic disease.
• Selective bladder preservation refers to a strategy in which patients
with a good or complete response noted on cystoscopy after 40 to
50 Gy of chemoradiation to the whole pelvis continue radiotherapy
for an additional 10 to 25 Gy to the bladder only. Nonresponders
are referred for radical cystectomy. Medically inoperable patients
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do not require a treatment break since there is no cystectomy
salvage option.
• Complete response rates after TURBT and chemoradiation are
70% to 80%.
• There are no trials that directly compare cystectomy to
chemoradiation. A 5-year overall survival for patients that are
eligible for bladder preservation is approximately 50%, which is
comparable to patients who undergo cystectomy.
• Eighty percent of the patients who survive 5 years will have an
intact bladder. Most patients report satisfactory bladder function.
• Example dose constraints: rectum V55 Gy <50%, bowel V45 <200
cc, Femoral head Dmax <50 Gy.
QUESTIONS
1. What is the next most appropriate management for a patient who
has had a cystoscopy with biopsies revealing an incompletely
resected muscle invasive bladder carcinoma in the background of
diffuse carcinoma in situ?
A. Repeat TURBT
B. Radical cystectomy
C. Taxane-based chemotherapy and radiation
D. Induction chemotherapy followed by concurrent
chemotherapy and radiation
2. What percentage of patients who survive selective bladder
preservation strategies with TURBT and chemoradiation will
have an intact bladder? What is the 5-year overall survival?
A. 15%
B. 25%
C. 60%
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D. 80%
3. The initial pelvic radiotherapy field for a bladder cancer being
treated with bladder-sparing chemoradiation is designed to
include which of the following?
A. Inguinal lymph nodes, obturator lymph nodes, and prostate in
men.
B. Obturator lymph nodes, proximal 2 cm of the female urethra,
and common iliac lymph nodes.
C. Prostate, internal iliac lymph nodes, and external iliac lymph
nodes.
D. External iliac lymph nodes, internal iliac lymph nodes, and
common iliac lymph nodes.
4. What clinical stage is a patient with a large tumor with extension
into the perivesicular tissues without invasion of adjacent organs
who also has three positive lymph nodes in the obturator and
internal iliac lymph nodes?
A. T2bN2
B. T3aN2
C. T3bN3
D. T4aN1a
5. Which of the following is the most appropriate next step in
management for a patient who has had a TURBT revealing a
high-grade papillary urothelial carcinoma without muscle
invasion?
A. Observation
B. CT of the abdomen to look for nodal disease
C. Intravesicular mitomycin C
D. Intravesicular BCG
REFERENCES
1. Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA Cancer J
Clin. 2010;60(5):277–300.
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2. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the
treatment of invasive bladder cancer: long-term results in 1,054
patients. J Clin Oncol. 2001;19(3):666–675.
3. Montie JE. Weekly paclitaxel and gemcitabine in advanced
transitional-cell carcinoma of the urothelium: a Phase II Hoosier
Oncology Group Study. J Urol. 2005;174(5):1784.
4. Edge S, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual.
Springer; 2010.
5. Herr HW. Conservative management of muscle-infiltrating bladder
cancer: prospective experience. J Urol. 1987;138(5):1162–1163.
6. Dunst J, Sauer R, Schrott KM, et al. Organ-sparing treatment of
advanced bladder cancer: a 10-year experience. Int J Radiat Oncol
Biol Phys. 1994;30(2):261–266.
7. Herr HW, Jakse G, Sheinfeld J. The T1 bladder tumor. Semin Urol.
1990;8(4):254–261.
8. Herr HW. Tumour progression and survival in patients with T1G3
bladder tumours: 15-year outcome. Br J Urol. 1997;80(5):762–765.
9. Brake M, Loertzer H, Horsch R, et al. Long-term results of
intravesical bacillus Calmette-Guérin therapy for stage T1 superficial
bladder cancer. Urology. 2000;55(5):673–678.
10. Wo JY, Shipley WU, Dahl DM, et al. The results of concurrent
chemo-radiotherapy for recurrence after treatment with bacillus
Calmette-Guérin for non-muscle-invasive bladder cancer: is
immediate cystectomy always necessary? Br J Urol.
2009;104(2):179–183.
11. Weiss C, Wolze C, Engehausen DG, et al. Radiochemotherapy after
transurethral resection for high-risk T1 bladder cancer: an
alternative to intravesical therapy or early cystectomy? J Clin Oncol.
2006; 24(15):2318–2324.
12. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder
cancer: a contemporary series. J Urol. 2001;165(4):1111–1116.
13. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant
chemotherapy plus cystectomy compared with cystectomy alone for
locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–
866.
14. Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality
treatment and selective organ preservation in invasive bladder
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cancer: long-term results. J Clin Oncol. 2002;20(14):3061–3071.
15. Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after
bladder-sparing therapy in patients with invasive bladder cancer:
RTOG 89–03, 95–06, 97–06, 99–06. J Clin Oncol.
2009;27(25):4055–4061.
16. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of
neoadjuvant chemotherapy in patients with invasive bladder cancer
treated with selective bladder preservation by combined radiation
therapy and chemotherapy: initial results of Radiation Therapy
Oncology Group 89–03. J Clin Oncol. 1998;16(11):3576–3583.
17. Greene FL. AJCC Cancer Staging Manual. 2002.
18. Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors
influence bladder cancer outcomes: a cooperative group report. J
Clin Oncol. 2004;22(14):2781–2789. doi:10.1200/JCO.2004.11.024.
19. Pollack A, Zagars GK, Cole CJ, et al. The relationship of local
control to distant metastasis in muscle invasive bladder cancer. J
Urol. 1995;154(6):2059–2063; discussion 2063–2064.
20. Sherif A, Holmberg L, Rintala E, et al. Neoadjuvant cisplatinum
based combination chemotherapy in patients with invasive bladder
cancer: a combined analysis of two Nordic studies. Eur Urol.
2004;45(3):297–303. doi:10.1016/j.eururo.2003.09.019.
21. Winquist E, Kirchner TS, Segal R, et al.; Genitourinary Cancer
Disease Site Group, Cancer Care Ontario Program in Evidence-based
Care Practice Guidelines Initiative. Neoadjuvant chemotherapy for
transitional cell carcinoma of the bladder: a systematic review and
meta-analysis. J Urol. 2004;171(2 Pt 1):561–569.
22. Roberts JT, Maase von der H, Sengeløv L, et al. Long-term survival
results of a randomized trial comparing gemcitabine/cisplatin and
methotrexate/vinblastine/doxorubicin/cisplatin in patients with
locally advanced and metastatic bladder cancer. Ann Oncol. 2006;
17 (Suppl 5):v118–v122. doi:10.1093/annonc/mdj965.
23. Ruggeri EM, Giannarelli D, Bria E, et al. Adjuvant chemotherapy in
muscle-invasive bladder carcinoma: a pooled analysis from phase III
studies. Cancer. 2006;106(4):783–788.
24. Smith JA, Crawford ED, Paradelo JC, et al. Treatment of advanced
bladder cancer with combined preoperative irradiation and radical
cystectomy versus radical cystectomy alone: a phase III intergroup
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study. J Urol. 1997;157(3):805–807; discussion 807–808.
25. Huncharek M, Muscat J, Geschwind JF. Planned preoperative
radiation therapy in muscle invasive bladder cancer; results of a
meta-analysis. Anticancer Res. 1998;18(3B):1931–1934.
26. Baumann BC, Guzzo TJ, He J, et al. Bladder cancer patterns of
pelvic failure: implications for adjuvant radiation therapy. Int J
27. Lagrange JL, Bascoul-Mollevi C, Geoffrois L, et al. Quality of life
assessment after concurrent chemoradiation for invasive bladder
cancer: results of a multicenter prospective study (GETUG 97–015).
28. Zietman AL, Sacco D, Skowronski U, et al. Organ conservation in
invasive bladder cancer by transurethral resection, chemotherapy
and radiation: results of a urodynamic and quality of life study on
long-term survivors. J Urol. 2003;170(5):1772–1776.
29. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al. Radical
radiotherapy for muscle invasive transitional cell carcinoma of the
bladder: failure analysis. J Urol. 1989;142(6):1448–1453; discussion
1453–1454.
30. Duncan W, Quilty PM. The results of a series of 963 patients with
transitional cell carcinoma of the urinary bladder primarily treated
by radical megavoltage X-ray therapy. Radiother Oncol.
1986;7(4):299–310.
31. Pollack A, Zagars GZ. Radiotherapy for stage T3b transitional cell
carcinoma of the bladder. Semin Urol Oncol. 1996;14(2):86–95.
32. De Neve W, Lybeert ML, Goor C, et al. Radiotherapy for T2 and T3
carcinoma of the bladder: the influence of overall treatment time.
Radiother Oncol. 1995;36(3):183–188.
33. Mameghan H, Fisher R, Mameghan J, et al. Analysis of failure
following definitive radiotherapy for invasive transitional cell
carcinoma of the bladder. Int J Radiat Oncol Biol Phys.
1995;31(2):247–254.
34. Gospodarowicz MK, Quilty PM, Scalliet P, et al. The place of
radiation therapy as definitive treatment of bladder cancer. Int J
Urol. 1995;2(Suppl 2):41–48.
35. Housset M, Maulard C, Chretien Y, et al. Combined radiation and
chemotherapy for invasive transitional-cell carcinoma of the
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bladder: a prospective study. J Clin Oncol. 1993;11(11):2150–2157.
36. Duchesne GM, Bolger JJ, Griffiths GO, et al. A randomized trial of
hypofractionated schedules of palliative radiotherapy in the
management of bladder carcinoma: results of medical research
council trial BA09. Int J Radiat Oncol Biol Phys. 2000;47(2):379–388.
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26C Cancers of the Genitourinary
Tract: Testis
INTRODUCTION
Testicular cancer is the most common malignancy in men between the
ages of 15 and 35 years (1,2). Testicular cancer only accounts for
approximately 1% of all malignancies in adults and <0.2% of all deaths.
Disturbingly, between 1973 and 2003 the incidence of germ cell tumors
increased 61% in the United States.
The most established risk factor for testicular cancer is a history of
cryptorchidism, which increases the risk of testicular cancer five times
(3,4). Only 10% of patients with testicular cancer will have a history of
cryptorchidism. Orchiopexy lowers the risk. Interestingly,
cryptorchidism increases the risk of testicular cancer in the contralateral
normally descended testis. Patients with a first-degree relative are also at
higher risk for testicular cancer (5). Testicular cancer is 5.4 times more
common in white men compared to black men.
Testicular cancers are divided into seminomatous and
nonseminomatous germ cell tumors (NSGCT). The purpose of this
chapter is to describe the approach to stage I and stage II seminomas.
NSGCT and later stage seminomas are treated with chemotherapy alone.
NSGCT are considered more dangerous than seminomas and at one time
were responsible for more than 10% of all cancer deaths in men aged 25
to 34 years (1). Today, NSGCTs are highly curable with platinum-based
multiagent chemotherapy alone; therefore, radiotherapy plays a minor
role (6). Radiotherapy is much more important in the treatment of
seminoma. Some early stage seminomas have a prognosis so favorable
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that they may be treated with transinguinal orchiectomy alone. Even
patients who require treatment can enjoy a long life after treatment,
increasing the focus on minimizing long-term sequelae of treatment (7).
DIAGNOSIS
The most common presentation is a painless testicular mass (3). Up to
half of patients will actually have pain in the testicle at diagnosis. A
detailed history and physical examination should be obtained, querying
for history of cryptorchidism, and prior inguinal or scrotal surgery. A
physical examination including testicular and abdominal examination
should be undertaken. The normal pattern of nodal drainage leads
directly from the testis to the para-aortic lymph nodes. In patients with a
history of inguinal or scrotal surgery, the risk of aberrant drainage to the
inguinal nodes may be increased, so this area should be examined.
Transillumination of the testicle may distinguish between solid and
cystic swelling of the scrotum. All patients should be referred for a
testicular ultrasound. The characteristic appearance of a testicular cancer
is a hypoechoic mass.
Patients with a suspected testicular cancer should undergo computed
tomography scan of the abdomen to identify liver or infradiaphragmatic
lymph node metastases. Chest imaging should be obtained to exclude
pulmonary metastases.
Laboratory studies should include completed blood count, serum
chemistry, and liver function studies. Serum lactate dehydrogenase, α-
fetoprotein (AFP), and serum β-human chorionic gonadotropin (β-HCG)
titers are prognostic and should be obtained. These serum markers also
aid the clinician in distinguishing between pure seminoma and other
germ cell tumors and are very useful in monitoring treatment response.
AFP or β-HCG levels may be elevated in up to 90% of nonseminomatous
germ cell tumors. A modest elevation of β-HCG may be found in 15% to
20% of patients with pure seminoma, whereas an elevated AFP raises the
suspicion of mixed tumor. The latter should be treated as
nonseminomatous disease even if histologic evaluation does not support
this finding. Elevation of these markers after treatment raises concern for
residual or recurrent disease.
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Treatment Options
Since more than half of all solid swellings of the testis are malignant, all
patients with suspicious solid testicular masses should undergo radical
inguinal orchiectomy to establish diagnosis. There should be no violation
of the scrotum nor should the mass simply be biopsied. Patients can
subsequently be managed based on their stage of disease. The American
Joint Commission on Cancer staging system incorporates primary tumor,
size of regional lymph nodes, presence or absence of distant metastases,
and tiered levels of serum LDH, α-fetoprotein, and β-HCG (Table 26C.1)
(8). Alternative staging systems exist, including the Royal Marsden
Staging, which divides patients into stage I (confined to testis), IIA (<2-
cm lymph nodes), IIB (2- to 5-cm lymph nodes), IIC (>5- to 10-cm
lymph nodes), IID (>10-cm lymph nodes), stage II (nodes above and/or
below the diaphragm), and stage IV (extralymphatic metastases). There
is also an International Germ Cell Cancer Collaborative Group (IGCCG)
classification, which divides tumors into good prognosis (no
nonpulmonary visceral metastases), intermediate prognosis
(nonpulmonary visceral metastases), and poor prognosis (9).
TABLE 26C.1 2010 American Joint Committee on Cancer (AJCC)

TNM Staging System for Testicular Cancer
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Stage I Seminoma
Patients with stage I seminoma enjoy a variety of options including
active surveillance, radiotherapy, and single-agent chemotherapy.
Observation/Active Surveillance
Overall, several studies have shown that early-stage patients who are
observed after inguinal orchiectomy have a 15% to 25% risk of relapse
at 5 years (10–15). Withholding radiotherapy from these patients is
advantageous because most of these patients would not relapse and
relapses are salvaged relatively easily (16). Observation protocols
involve computed tomography scans of the abdomen and pelvis with
chest radiographs every 4 months for 2 years, then every 6 months up to
10 years after diagnosis. Serum markers should be collected every 4
months for 2 years. The effect of multiple computed tomography scans
in this population has not been studied, and the theoretical increase in
the risk of secondary malignancy should be discussed.
A study published by Kaiser retrospectively evaluated 502 patients
with stage I seminoma who were treated with active surveillance,
chemotherapy, or radiotherapy after orchiectomy. Recurrence-free
survival at 5 years was 97.2% to 98.3% in the radiotherapy and
chemotherapy groups compared with 89.2% in the group of patients
who were observed. The salvage treatment of relapsed seminoma is quite
effective, resulting in no difference in overall survival or cause-specific
survival between groups (17). A study on a much larger group of
patients (n = 6,764) in the Surveillance, Epidemiology, and End Results
database demonstrated that radiotherapy was associated with an
improved cause-specific survival at 20 years with a hazard ratio of 0.37
(18). At 20 years, the difference in cause-specific survival was
statistically significant, but quite small (cause-specific survival was
98.7% vs. 99.2%). The avoidance of medical expenses, time off from
work, decreased sperm count, radiotherapy-associated fatigue, and
increased risk of second malignancy is attractive to patients and
oncologists. In fact, between 1998 and 2011, the rates of observation
after orchiectomy increased from approximately 24% to 54% (19).
Interestingly, this same US study found that observation was less
common at community hospitals and more commonly offered to ethnic
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minorities. A subset of patients with stage I seminoma may be at higher
risk of relapse, including those with larger tumors (>4 cm) and rete
testis invasion (20). A large group of researchers from Spain has
published a nomogram that incorporates tumor size as a continuous
variable and presence or absence of rete testis invasion (21).
Radiotherapy
When patients are unsuitable for observation due to tumor factors (large
tumors or tumors with rete testis invasion) or patient factors (patient
choice, or inability to follow up with surveillance protocol), patients
should be offered adjuvant treatment with chemotherapy or
radiotherapy.
Chemotherapy
The rates of chemotherapy administration increased from 1.5% to 16%
while the utilization of adjuvant radiotherapy decreased from 71% to
29% (19). A randomized trial in the United Kingdom compared
radiotherapy to single-agent carboplatin in 1,447 patients with stage I
seminoma. At 5 years, carboplatin was not inferior to adjuvant
radiotherapy for stage I seminomas treated with orchiectomy with
recurrence free survival rates ∼95%. The number of contralateral germ
cell tumors were also lower in the patients who received carboplatin
compared to radiotherapy (2 vs. 15) (22). The most common sites of
relapse after radiotherapy were outside of the radiation field
(supradiaphragmatic or inguinal), whereas patients treated with
carboplatin most commonly relapsed in the para-aortic nodes.
In summary, stage I seminoma has a very good prognosis. Some
patients are at such low risk of relapse that observation is the optimal
strategy. Relapses have good salvage rates, which makes observation an
even more attractive option. For those patients who require adjuvant
treatment to prevent relapse, either single-agent chemotherapy or
adjuvant para-aortic radiotherapy are options. With either treatment,
relapse rates are approximately 5% at 5 years. Cause-specific survival for
stage I seminoma remains >90% for all patients.
Of note, chemotherapy is preferred in patients with congenital
horseshoe kidney. Horseshoe kidney is associated with aberrant
lymphatic drainage, which makes traditional para-aortic and dog-leg
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fields possibly less efficacious. Furthermore, the presence of midline
renal tissue would predispose the patient to high rates of radiation-
induced nephritis.
Stage II Seminoma
Stage II seminoma is characterized by the presence of regional
infradiaphragmatic lymph node positivity. Biopsy confirmation of lymph
node positivity is generally not considered necessary. Seminoma is very
sensitive to chemotherapy and radiation, so lymph node dissection is
generally not part of the treatment for these patients. All patients with
positive lymph nodes require inguinal orchiectomy followed by adjuvant
treatment with chemotherapy or radiotherapy.
Patients referred for radiotherapy should be treated with 30 Gy to the
para-aortic and ipsilateral iliac lymph nodes (dog-leg field) followed by a
boost to enlarged lymph nodes. Nodes less than 2 cm should be boosted
to 34 Gy and nodes of 2 to 5 cm should be boosted to 36 Gy or more.
Stage II with Bulky (>5 cm) Lymph Nodes

Patients with lymph nodes greater than 5 cm should not be managed
with radiotherapy. Bulky lymph nodes portend a high risk of distant
relapse (23); therefore, the standard of care for these patients is
platinum-based, multiagent systemic chemotherapy. Even in the
presence of bulky lymph nodes, cure rates are nearly 90% (24). The
management of relapsed disease is similar to the management of bulky
disease in that platinum-based multiagent chemotherapy is the preferred
strategy.
Following chemotherapy for bulky node positive disease, patients
should have follow-up imaging until retroperitoneal masses resolve. The
data indicates that consolidative radiotherapy to residual masses does
not decrease rates of relapse (25,26). A surgical series from Memorial
Sloan-Kettering Cancer Center indicates that, in 55 patients with residual
masses after chemotherapy who underwent retroperitoneal lymph node
dissection, no patient with a residual mass less than 3 cm had viable
tumor. Therefore, patients with residual masses less than 3 cm are
typically observed.
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Treatment Planning
Planning radiotherapy for seminoma requires knowledge of the typical
patterns of disease spread. The right and left testicles differ slightly in
their lymphatic drainage. The right testicular lymphatic trunks terminate
in the sentinel nodes along the inferior vena cava and common iliac
vein. The left testicular lymphatic trunks travel along the spermatic vein
to drain into the lateral aortic nodes at the left renal vein pedicle. Right
testicular lymphatics may cross over directly to the left PA nodes, but
left testicular lymphatics generally cross to the right only after extensive
involvement of the first station nodes. Tumor may spread in a retrograde
fashion to nodes surrounding the vena cava and aorta. Further extension
may occur via the thoracic duct to the left supraclavicular region or by
the transdiaphragmatic lymphatics to the mediastinum. Although the
primary drainage is to the retroperitoneal area, some lymphatic channels
may also drain to the iliac lymph nodes. Normal lymphatic drainage may
be altered if the patient has had an orchiopexy, herniorrhaphy, or other
surgical procedures in the pelvis or inguinal region. Early tumor
involvement of the epididymis increases the risk of external iliac nodal
involvement.
Most published data on radiotherapy for testicular cancer utilizes
opposed anteroposterior fields with megavoltage photons.
The most common site of lymph node metastasis is the para-aortic
lymph nodes (14,27). Therefore, traditional radiotherapy fields have
encompassed the PA nodes and ipsilateral pelvic nodes (28,29). The
superior border is traditionally at the T11/T12 vertebral bodies, while
the inferior border was the inguinal ligament (the traditional “dog-leg”
or “hockey-stick” field). Under usual circumstances, pelvic nodal
involvement occurs in only 2% to 3% of patients. A British trial
published a comparison of the para-aortic field to the traditional dog-leg
field in 478 men with stage I seminoma. The total dose was 30 Gy in 15
fractions. Acute toxicity was less common and less severe in the patients
treated with para-aortic radiation only. Sperm counts were also
significantly higher in men on the para-aortic radiotherapy arm. There
was no difference in relapse rates between patients treated with para-
aortic compared to combined para-aortic and dog-leg fields (30). As a
result, patients with stage I seminoma who are treated with adjuvant
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radiotherapy are often treated with para-aortic fields only (30). In stage
II patients, the PA and ipsilateral pelvic nodes should be treated, and if
the PA disease is bulky, consideration may be given to including the
contralateral pelvic nodes. Although in the past inguinal nodes and the
orchiectomy incision have been treated, more recent information
indicates that this may be unnecessary, even if the inguinal area has
been violated by surgery. Surveillance studies have shown an extremely
low risk of relapse at these sites (31); therefore, adding the hemiscrotum
and inguinal nodal region to the treatment portal is normally not
required and should be avoided if possible because of the resulting
significant dose to the remaining testicle. Patients with a history of
inguinal or pelvic surgery were also thought to be at risk for altered
lymphatic drainage, and it has been recommended that the treatment
fields be altered to include the pelvic nodes (32). However, several
authors challenge this practice since recurrence rates in surveillance
studies are extremely low (29,33). The contralateral, remaining testis
should be placed in a scrotal shield to minimize radiation and prevent
azoospermia.
Intensity-modulated radiotherapy can be used to irradiate the at-risk
areas, but the combination of multiple beams vastly increases the
amount of tissue that receives low doses of radiation. The effect of such
a large volume irradiated to a low dose is very important to consider in
this group of young patients. Generally anteroposterior opposed fields
are the preferred means to irradiate the lymph nodes.
RADIATION TREATMENT FIELDS

Para-aortic Fields for Stage I
In patients with no history of pelvic or scrotal surgery and stage I
disease, the para-aortic lymph node region may be treated with equally
weighted AP/PA fields. The fields should target the retroperitoneal
lymph nodes but not necessarily the ipsilateral renal hilar nodes.
Preferably, one should contour the aorta and inferior vena cava from the
bottom of the T11 vertebrae to the bottom of L5.
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FIGURE 26C.1 A,B: Example of filed arrangement based on bony landmarks. Left: AP Para-
aortic field. The superior border is T11, the inferior border is L5. The spinous processes of the
vertebral bodies are covered. Right: AP Dog-leg field used for stage II seminoma. The common
and external iliac vessels are treated down to the upper border of the acetabulum. If gross nodes
are present, nodes should be identified on CT based planning and treated with a 0.8-cm GTV to
TV expansion.
The superior border should be placed at the bottom of the T11

vertebral body. The inferior border will be placed at the bottom of the
L5 vertebral body. The lateral borders should encompass the tips of the
transverse processes of the vertebrae and are approximately 10 cm wide.
The para-aortic field is depicted in the left panel of Figure 26C.1.
Dog-leg Fields for Stage IIA–IIB and patients who have undergone
ipsilateral pelvic surgery (i.e., inguinal herniorrhaphy or
orchiopexy).
In patients with a history of ipsilateral pelvic surgery or stage II
disease, the dog-leg field should encompass the retroperitoneal lymph
nodes, and the ipsilateral common, external, and proximal iliac lymph
nodes down to the top of the acetabulum. For patients with ipsilateral
pelvic surgery, the ipsilateral inguinal nodes and the inguinal scar
should also be targeted. Preferably, the aorta and the inferior vena cava
should be contoured from the bottom of T11 and further inferiorly to the
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ipsilateral iliac arteries and veins up to the top of the acetabulum.
The superior border should be placed at the bottom of the T11
vertebral body. The inferior border should be placed at the top of the
acetabulum. The medial border for the lower aspect of the modified dog-
leg field extends from the contralateral transverse process of the fifth
vertebrae to the medial border of the ipsilateral obturator foramen. The
lateral border of the lower aspect of the modified dog-leg field is
delineated by a line from the top of the ipsilateral transverse process of
the fifth vertebrae to the superolateral border of the ipsilateral
acetabulum. The dog-leg field is depicted in the right panel of Figure
26C.1.
Dosage and Fractionation

Dosage for Stage I
In addition to field size reduction, randomized data supports reducing
the dose of radiotherapy from 30 to 20 Gy. The MRC TE 18 trial
randomized 625 patients to 20 Gy in 10 fractions or 30 Gy in 15
fractions. At 2 years, the relapse rate in both arms was 3% to 4%. There
was no difference in relapse rates at longer follow-up (34). There was
only one death from seminoma in the study. There was significantly less
acute fatigue in the 20 Gy arm, but this difference disappeared by the
twelfth week (35). At Princess Margaret Hospital, 25 Gy in 1.25 Gy daily
fractions has been used for more than two decades without an in-field
recurrence (10).
Dosage for Stage II

Stage II seminomas treated with radiotherapy should receive 20 to 30 Gy
to the entire para-aortic and dog-leg field with a 4 to 10 Gy boost to
enlarged lymph nodes, which can be delivered concurrently or
sequentially. For example, frequent fractionation schemes would involve
20 Gy in 1.25 Gy daily fractions while the enlarged lymph nodes receive
30 Gy in 1.875 Gy daily fractions. Alternatively, the entire field can
receive 30 Gy in 2 Gy fractions followed by a 4 to 6 Gy boost to the
enlarged lymph nodes.
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Prognosis
Successful treatment of germ cell tumors offers the potential for many
years of productive life following treatment. Treatment results vary
significantly with tumor histology and disease stage (Table 26C.2). Pure
seminoma, even when metastatic to retroperitoneal nodes, can be cured
in the majority of patients. Stage I seminoma is associated with a 15% to
20% risk of relapse when treated with orchiectomy alone; however,
virtually all recurrences can be successfully salvaged, and disease-
specific survival approaches 100% (14,27,36). For stage I disease treated
with inguinal orchiectomy and infradiaphragmatic radiation approaches,
relapse rates are approximately 3% to 4% (28–30,33,35,37–45).
Virtually all recurrences will be outside the irradiated area, and again,
nearly all recurrences are successfully salvaged, most by systemic
chemotherapy.
TABLE 26C.2 Outcome Following Primary Radiation Therapy for

Early Stage Seminoma and Chemotherapy for Bulky or Advanced
Stage Seminoma
Relapse rates for stage II patients depend on the bulk of disease and
are higher than for stage I disease but are still only in the range of 5% to
15%. Nonetheless, due to excellent salvage options, postorchiectomy
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radiotherapy results in disease-specific survival rates above 90%
(46–48). Patients with bulky disease treated with cisplatin-based
chemotherapy still have excellent survival rates, with long-term survival
possible even in advanced metastatic disease (49,50).
Because of the success in treating testicular cancer, increased attention
is paid to the long-term sequelae resulting from treatment, particularly
impaired fertility, secondary malignancies, and cardiac disease. Men
with seminoma commonly have impaired spermatogenesis at baseline;
however, use of proper radiotherapy techniques is critical to minimize
dose to the remaining testicle and preserve fertility. Second malignancies
are increasingly recognized as a significant problem after radiotherapy
and/or chemotherapy for testicular cancer, perhaps occurring in close to
20% of patients treated for testicular cancer (51). Current trends toward
increased use of surveillance in selected patients and avoidance of
mediastinal irradiation should decrease the rates of these serious late
effects. In addition, the adoption of smaller volumes and lower doses of
RT is predicted to significantly reduce the risk of second malignancy
following RT without compromising long-term survival (52).
The relatively indolent course, predictable patterns of early
progression, and marked sensitivity to both radiation and chemotherapy
make seminoma one of the most curable malignancies. Testicular germ
cell tumors have become a model for curable cancer, with cure being the
goal of treatment while optimizing the risks of late effects even in
advanced disease. Clinical outcome and survival for nonseminomatous
disease is slightly less than that expected for seminoma, but with
cisplatin-based treatment, it is still quite good.
KEY POINTS
• Testicular cancer is the most common cancer in males of age 15 to
35 years. It is more common in caucasian males.
• Testicular cancer is divided into nonseminomatous germ cell
tumors (NSGCTs) and seminomas. Seminomas almost never have
a positive alpha-fetoprotein (α-FP or AFP).
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• Radiotherapy is most important as adjuvant treatment for early
stage I and II seminomas.
• Stage I seminomas require radical inguinal orchiectomy followed by
observation, para-aortic radiotherapy, or single-agent
chemotherapy.
• Primary tumors >4 cm and tumors with rete testis invasion may not
be appropriate for observation. Stage II seminomas with regional
lymph nodes ≤5 cm require adjuvant para-aortic and pelvic
radiotherapy or chemotherapy and are not eligible for observation.
• Lymph nodes larger than 5 cm are associated with a high risk of
distant metastases. These patients should be treated with inguinal
orchiectomy and adjuvant multiagent systemic chemotherapy
without radiotherapy.
• Following multiagent chemotherapy, residual disease measuring
less than 3 cm in size may be observed.
• At 5 years, overall survival for stage I, stage II, and stage III
seminoma is 100%, 97%, and 85%, respectively.
• For stage I seminoma, treat with 20 Gy in 2 Gy fractions. For stage
II seminomas, treat the entire field to 20 to 30 Gy, followed by a
boost to a higher dose for positive nodes of 4 to 6 Gy. Alternative
fractionation schemes can also be used.
QUESTIONS
1. A 20-year-old man presents with a painless unilateral swelling.
Inguinal orchiectomy reveals a 1-cm seminoma without rete
testis invasion. CT of the abdomen demonstrates several 2-cm
lymph nodes in the para-aortic chain. There are no visceral
metastases noted and no lymph nodes above the diaphragm.
Which of the following is the best course of management? The
patient wishes to conceive with his fiancée in the near future, so
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he is concerned about fertility.
A. Observation with CT scans of the chest, abdomen, and pelvis
every 4 months.
B. Single-agent carboplatin with follow-up imaging to monitor
for resolution of positive nodes.
C. Retroperitoneal lymph node dissection to prevent radiation
toxicity and chemotoxicity to the remaining testis.
D. Radiotherapy to the para-aortic and pelvic lymph nodes.
2. A 40-year-old man who has a 4-cm pure seminoma with rete
testis invasion and several enlarged para-aortic lymph nodes
undergoes a computed tomography scan (a priori, his computed
tomography scan reveals 1.5-cm residual disease 2 months after
chemotherapy). Which of the following is the most appropriate
management option?
A. Retroperitoneal lymph node dissection if the disease is PET
positive
B. Observation
C. Consolidative radiotherapy to the residual disease with a 1 cm
margin
D. Two additional cycles of chemotherapy followed by
3. What is the risk of nodal relapse for patients with stage I
seminoma who opt for observation after a radical inguinal
orchiectomy?
A. <5%
B. 15%
C. 40%
D. 80%
4. Which of the following is true regarding studies comparing 20
versus 30 Gy adjuvant radiotherapy for patients treated with
inguinal orchiectomy?
A. Patients who underwent radiotherapy with 30 Gy had a higher
risk of late side effects, including fatigue.
B. Patients who underwent radiotherapy with 30 Gy had a lower
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risk of pelvic relapse compared to patients treated with 20 Gy.
C. Patients were treated with para-aortic radiotherapy only in
both arms.
D. The relapse rate at 2 years exceeded 5% in the 20 Gy arm.
5. What is the Royal Marsden staging classification for a 3 cm
seminoma with rete testis invasion and a beta-HCG level of
6000?
A. Stage I
B. Stage IB
C. Stage III
D. Stage IS
ANSWERS
1. D
2. B
3. B
4. B
5. A
REFERENCES
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cancer. APMIS. 2003;111(1):76–83; discussion 83–85.
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17. Soper MS, Hastings JR, Cosmatos HA, et al. Observation versus
adjuvant radiation or chemotherapy in the management of stage I
seminoma: clinical outcomes and prognostic factors for relapse in a
large us cohort. Am J Clin Oncol. 2014;37(4):356–359.
18. Jones G, Arthurs B, Kaya H, et al. Overall survival analysis of
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adjuvant radiation versus observation in stage I testicular
seminoma: a Surveillance, Epidemiology, and End Results (SEER)
Analysis. Am J Clin Oncol. 2013;36(5):500–504.
19. Gray PJ, Lin CC, Sineshaw H, et al. Management trends in stage I
testicular seminoma: Impact of race, insurance status, and treatment
facility. Cancer. 2014;121(5):681–687.
20. Warde P, Specht L, Horwich A, et al. Prognostic factors for Relapse
in Stage I Seminoma Managed by Surveillance: a Pooled Analysis.
JCO. 2002;20(22):4448–4452.
21. Aparicio J, Maroto P, del Muro XG, et al. Prognostic factors for
relapse in stage I seminoma: a new nomogram derived from three
consecutive, risk-adapted studies from the Spanish Germ Cell Cancer
Group (SGCCG). Ann Oncol. 2014;25(11):2173–2178.
22. Oliver RTD, Mead GM, Rustin GJS, et al. Randomized trial of
carboplatin versus radiotherapy for stage I seminoma: mature
results on relapse and contralateral testis cancer rates in MRC
TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol.
2011;29(8):957–962.
23. Warde P, Gospodarowicz M, Panzarella T, et al. Management of
stage II seminoma. J Clin Oncol. 1998;16(1):290–294.
24. Gospodarwicz MK, Sturgeon JF, Jewett MA. Early stage and
advanced seminoma: role of radiation therapy, surgery, and
chemotherapy. Semin Oncol. 1998;25:160–173.
25. Duchesne GM, Stenning SP, Aass N, et al. Radiotherapy after
chemotherapy for metastatic seminoma—a diminishing role. Eur J
Cancer. 1997;33(6):829–835.
26. Horwich A, Paluchowska B, Norman A, et al. Residual mass
following chemotherapy of seminoma. Ann Oncol. 1997;8(1):37–40.
27. Warde PR, Gospodarowicz MK, Goodman PJ, et al. Results of a
policy of surveillance in stage I testicular seminoma. Int J Radiat
Oncol Biol Physics. 1993;27(1):11–15.
28. Dosoretz DE, Shipley WU, Blitzer PH, et al. Megavoltage irradiation
for pure testicular seminoma: results and patterns of failure. Cancer.
1981;48(10):2184–2190.
29. FossÅ SD, Aass N, Kaalhus O. Radiotherapy for testicular seminoma
stage I: Treatment results and long-term post-irradiation morbidity
in 365 patients. Int J Radiat Oncol Biol Phys. 1989;16(2):383–388.
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30. Fosså SD, Horwich A, Russell JM, et al. Optimal planning target
volume for Stage I testicular seminoma: a medical research council
randomized trial. J Clin Oncol. 1999;17(4):1146–1146.
31. Capelouto CC, Clark PE, Ransil BJ, et al. A review of scrotal
violation in testicular cancer: is adjuvant local therapy necessary? J
Urol. 1995;153(3 Pt 2):981–985.
32. Marks LB, Anscher MS, Shipley WU. Radiation therapy for testicular
seminoma: controversies in the management of early-stage disease.
Oncology (Williston Park). 1992;6:43–48.
33. Warde P, Gospodarowicz MK, Panzarella T, et al. Stage I testicular
seminoma: results of adjuvant irradiation and surveillance. J Clin
Oncol. 1995;13(9):2255–2262.
34. Mead GM, Fossa SD, Oliver RT, et al. Randomized trials in 2466
patients with stage I seminoma: patterns of relapse and follow-up. J
Natl Cancer Inst.2011;103(3):241–249.
35. Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus
20 Gy in the adjuvant treatment of stage I testicular seminoma: a
report on medical research council trial te18, European organisation
for the research and treatment of cancer trial 30942
(ISRCTN18525328). J Clin Oncol. 2005;23(6):1200–1208.
36. Warde P, Jewett MA. Surveillance for stage I testicular seminoma. Is
it a good option? Urol Clin North Am. 1998;25(3):425–433.
37. Oliver R, Mason MD, Mead GM, et al. Radiotherapy versus single-
dose carboplatin in adjuvant treatment of stage I seminoma: a
randomised trial. The Lancet. 2005;366(9482):293–300.
38. Dosmann MA, Zagars GK. Postorchiectomy radiotherapy for stages I
and II testicular seminoma. Int J Radiat Oncol Biol Phys.
1993;26(3):381–390.
39. Lai PP, Bernstein MJ, Kim H, et al. Radiation therapy for stage I and
IIa testicular seminoma. Int J Radiat Oncol Biol Phys. 1994;
28(2):373–379.
40. Giacchetti S, Raoul Y, Wibault P, et al. Treatment of stage I testis
seminoma by radiotherapy: long-term results—a 30-year experience.
41. Coleman J, Coleman RE, Turner AR, et al. The management and
clinical course of testicular seminoma: 15 years’ experience at a
single institution. Clin Oncol(R Coll Radiol). 1998;10(4):237–241.
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42. Bauman GS, Venkatesan VM, Ago CT, et al. Postoperative
radiotherapy for stage I/II seminoma: results for 212 patients. Int J
43. Bamberg M, Schmidberger H, Meisner C, et al. Radiotherapy for
stages I and IIA/B testicular seminoma. Int J Cancer.
1999;83(6):823–827.
44. Van Rooy EM, Sagerman RH. Long-term evaluation of
postorchiectomy irradiation for stage I seminoma. Radiology.
1994;191(3):857–861.
45. Bayens YC, Helle PA, Van Putten WLJ, et al. Orchidectomy followed
by radiotherapy in 176 stage I and II testicular seminoma patients:
benefits of a 10-year follow-up study. Radiother Oncol.
1992;25(2):97–102.
46. Vallis KA, Howard GC, Duncan W, et al. Radiotherapy for stages I
and II testicular seminoma: results and morbidity in 238 patients. Br
J Radiol. 2014;68(808):400–405.
47. Whipple GL, Sagerman RH, van Rooy EM. Long-term evaluation of
postorchiectomy radiotherapy for stage II seminoma. Am J Clin
Oncol. 1997;20(2):196–201.
48. Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages
IIa/b testicular seminoma: final report of a prospective multicenter
clinical trial. J Clin Oncol. 2003;21(6):1101–1106.
49. Mencel PJ, Motzer RJ, Mazumdar M, et al. Advanced seminoma:
treatment results, survival, and prognostic factors in 142 patients. J
Clin Oncol. 1994;12(1):120–126.
50. Schmoll HJ, Souchon R, Krege S, et al. European consensus on
diagnosis and treatment of germ cell cancer: a report of the
European Germ Cell Cancer Consensus Group (EGCCCG). In: Vol 15.
Oxford University Press; 2004:1377–1399.
51. Travis LB, Curtis RE, Joseph F, et al. Risk of second malignant
neoplasms among long-term survivors of testicular cancer. J Natl
Cancer Inst. 1997;89(19):1429–1439.
52. Zwahlen DR, Martin JM, Millar JL, et al. Effect of radiotherapy
volume and dose on secondary cancer risk in stage I testicular
seminoma. Int J Radiat Oncol Biol Phys. 2008;70(3):853–858.
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27 The Lymphomas
John P. Plastaras, Stefan Both, Amit Maity, and Eli
Glatstein
INTRODUCTION
The role of radiotherapy in the treatment of lymphomas has evolved
significantly in recent decades. Once a mainstay of curative treatment
for lymphoma, the role of radiation had become complementary to
multiagent chemotherapy for the majority of patients diagnosed with
lymphoma. Many of the studies have been aimed at reducing radiation
doses and volumes treated. In addition, many studies have also
investigated how to eliminate radiation altogether by appropriate use of
risk stratification and/or response to treatment. Modern radiotherapy for
lymphoma is thus aimed at maintaining efficacy while limiting toxicity
as much as possible.
The lymphomas are broadly divided between Hodgkin lymphomas
(HLs) and non-Hodgkin lymphomas (NHLs). The WHO has classified 83
subtypes of lymphoma, largely based on the implementation of
immunotyping, with recognition of borderline categories and entities
associated with certain age groups (1). HLs are broadly divided based on
histologic subtype into (1) classic HL (nodular sclerosing, mixed
cellularity, lymphocyte rich, and lymphocyte depleted); and (2)
nonclassic HL (nodular lymphocyte predominant).
NHLs are divided into B-cell and T-cell/NK-cell categories. Treatment
approaches depend not only on histologic subtype, but also on the stage,
patient factors, and predicted clinical behavior. In practice, clinicians
often categorize lymphomas as indolent, aggressive, or highly aggressive,
but true aggressiveness may not always track precisely with pathologic
subclassification. This behavior can range broadly from indolent
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lymphomas that can take decades to become clinically significant to
highly aggressive lymphomas that can progress within weeks. For diffuse
large B-cell lymphoma (DLBCL), the most commonly diagnosed NHL,
subclassification using genetic profiling is frequently used to divide
lymphomas into germinal center B-cell-like and activated B-cell-like (2).
In addition, alterations in c-MYC paired with Bcl-2 or Bcl-6, resulting in
so-called “double-hit lymphomas,” are associated with particularly poor
responses to standard therapy (3). Regardless, observation of the actual
clinical course is a still key factor in making treatment decisions.
Although radiation alone is sometimes used, such as for limited-stage,
low-grade follicular lymphomas and extranodal marginal zone
lymphomas, most lymphomas will be treated with chemotherapy first.
Radiotherapy timing, volume treated, and dose are highly dependent on
the type, effectiveness, and response to chemotherapy. When patients
are treated with radiation alone, relapses tend to occur outside of the
radiotherapy fields. When patients are treated with chemotherapy alone,
relapses tend to occur at sites of prior disease. Combining radiation and
chemotherapy allows for an opportunity to truncate both modalities,
which minimizes toxicities that are primarily dose dependent—without
sacrificing cure. Therefore, initial multidisciplinary integration is a key
for effectively and safely treating patients with lymphoma.
STAGING AND PROGNOSIS

The staging system most commonly used for HL and NHL has been the
Ann Arbor Staging System; however, the Lugano Classification, based on
an international working group that met in 2011, has refined the
approach to staging, especially with respect to the use of 18F-FDG
PET/CT (4). For nodal lymphomas, patients are grouped into three
general categories based on general treatment approaches: (1) limited
stage, (2) stage II bulky, or (3) advanced stage (Table 27.1). The
definition of “bulky” has been modified based on histology with a
recommendation to designate the longest measurement by CT scan,
omitting the term “X.” For HL, a single nodal mass of 10 cm or greater
than a third of the transthoracic diameter by CT is considered bulky, but
an upright chest x-ray is no longer required to determine bulk. For NHL,
6 cm may be used for follicular lymphoma and 6 to 10 cm for DLBCL.
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The designation of A or B is based on the presence of “B” symptoms,
which are unexplained fevers, night sweats, and unexplained weight loss
of >10% over a 6-month period. In the revised Lugano Classification, B
symptoms are now only assigned to HL patients since B symptoms do not
appear to affect prognosis in NHL. The wisdom of that decision remains
to be seen.
For limited stage HL, prognosis and intensity of treatment is based on
factors that divide patients into favorable or unfavorable risk categories.
If a patient has any one of the risk factors, they are considered
unfavorable. The factors that have been used have varied slightly
according to each cooperative group that have run important clinical
trials in HL (Table 27.2). For advanced stage patients, the International
Prognostic Score (IPS) can be used to predict prognosis, with higher
scores portending worse progression-free survival (5). One point is
assigned for each of the seven factors: male sex, age ≥45 years, stage IV,
hemoglobin <105 g/L, WBC count ≥15 × 109/L, lymphocyte count
<0.6 × 109/L or <8% of differential albumin <40 g/L. Although the
IPS can predict the chance of relapse and has been used to define high-
risk patients in clinical trials, it has not been frequently used to justify
the use of consolidative radiation.
TABLE 27.1 Revised Staging System for Primary Nodal Lymphomas

from the Lugano Classification (4)
For NHL, there are scoring systems based on clinical factors that can
predict outcomes. For DLBCL, the International Prognostic Index (IPI)
uses a point system similar to the IPS with a point assigned for each
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negative prognostic factor (elevated LDH, age >60 years, ECOG
performance status >1, Stage III/IV, >1 extranodal sites) (6). The
original IPI was developed before the introduction of rituximab, but the
same factors in the rituximab era, the “R-IPI,” identifies prognostic
groups with 4-year progression-free survival ranges of 53%, 80%, and
94% for the three risk groups (7). Separate IPI scoring systems have been
developed for follicular lymphoma and mantle cell lymphoma to account
for the different prognoses of these NHL subtypes.
TABLE 27.2 Factors for Limited-Stage, Unfavorable-Risk Disease
In HL, one of the most powerful and consistent predictors of outcome

is interim PET scans performed part-way through chemotherapy (8–10).
However, the value of interim PET scanning in DLBCL appears less
consistent, showing a correlation in some studies (11–14), but not in
others (15–17). When radiotherapy was consistently added to
chemotherapy, a positive interim PET scan did not predict for relapse
(18). In a separate study, an interim positive PET scan was associated
with relapse only in patients treated with chemotherapy alone, but not
in those treated with combined modality therapy (19).
INDICATIONS FOR TREATMENT

In the treatment of lymphomas, the radiation technique depends on the
clinical context and indications for treatment. It is important to
determine first and foremost whether the intent of treatment is curative
or palliative. Unlike most solid cancers where “Stage IV” is nearly
synonymous with incurable, advanced stage lymphomas, it can
frequently be cured by chemotherapy with or without radiation.
“Consolidative” radiation is the term used for radiation given after a
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complete response following chemotherapy as a strategy to sterilize
potential sites of relapse. This can be part of initial therapy or for
relapsed or refractory lymphoma. Although the chances of cure are
certainly less in the relapsed/refractory circumstance, more aggressive
treatments including high-dose chemotherapy with autologous stem cell
rescue can often still result in cure. When radiation alone is used for
cure, this is termed “definitive” radiation. Finally, when radiation is used
purely to relieve symptoms without an attempt to alter survival, this is
termed “palliative.” In the palliative setting, there is not an expectation
to permanently prevent sites of lymphoma growing again, and therefore
the volumes and doses are more limited. Due to the radiosensitivity of
most lymphomas, even extraordinarily low doses of radiation can often
accomplish goals of symptom control.
Combined Modality for Hodgkin Lymphoma

Combined modality therapy is a standard for limited stage HL in both
favorable and unfavorable risk patients. There are many who prefer a
chemotherapy-only approach for limited stage patients. NCCN
Guidelines and ACR Appropriateness Criteria for HL are frequently
updated and reflect the ongoing debate between these approaches with a
focus on matching the right intensity of treatment for each patient. One
approach to determining the intensity of treatment is based on
prognostic factors at the time of diagnosis (Table 27.2). The German
Hodgkin Study Group trials HD10 and HD11 trials both studied
combined modality approaches with an aim to find the correct intensity
of treatment using a 2 by 2 randomization. In the HD10 trial of
favorable risk patients, chemotherapy intensity was studied, ABVD × 2
versus ABVD × 4, along with involved field radiotherapy (IFRT) to 20
Gy versus 30 Gy (20). Reduced intensity therapy with ABVD × 2 and 20
Gy had equivalent freedom from failure compared to the other arms, and
has thus emerged as a standard of care for favorable risk patients. The
HD11 trial studied unfavorable risk patients, who were randomized
between ABVD × 4 versus BEACOPP (standard) and 20 Gy versus 30 Gy
(21). In this study, ABVD × 4 was much less toxic than BEACOPP
(standard), but had similar efficacy. Although there was no difference
between 20 and 30 Gy when combined with BEACOPP (standard), there
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were more relapses when 20 Gy was used with the less intense ABVD
regimen compared to 30 Gy. Thus, ABVD × 4 and 30 Gy remained a
standard for unfavorable risk patients following the results of that trial.
An alternate approach to using only prognostic factors is to use response-
adapted treatments, which we prefer. Although there has been a lot of
enthusiasm for using PET/CT during or after all chemotherapy to drive
radiotherapy decisions, there are data to question this approach. The
EORTC/LYSA/FIL H10 trial found that omitting radiation based on
interim PET scans lead to an increased risk of relapse (22). In fact, the
PET-response adapted arms had to be closed early in both the favorable
and unfavorable risk portions of this trial. The RAPID UK trial reported
results from a trial in which patients with early stage HL without bulky
mediastinal disease who had a negative PET scan after three cycles of
ABVD were randomized to observation or consolidative radiation (23).
Although these results have been interpreted in different ways, based on
their predetermined statistical goals, the authors were unable to show a
noninferiority of the no radiation arm versus the radiation arm.
The role of radiotherapy in advanced stage HL is very selective. It is
usually reserved for large volume residual disease after chemotherapy
(24). The decision to use radiation in advanced stage patients also
depends on the intensity of the chemotherapy. For example, the HD15
trial, which studied different schedules of the relatively intense
BEACOPP regimen, only gave radiation to PET-positive residual mass
that were 2.5 cm or larger (25). The use of radiotherapy in advanced
stage HL remains controversial, but ongoing clinical trials may help
clarify the role more precisely.
Combined Modality for Non-Hodgkin Lymphoma

Probably the most common role for combined modality therapy is for
limited stage DLBCL. Two randomized trials performed prior to the
introduction of rituximab have demonstrated value for the addition of
radiation to multiagent chemotherapy. The ECOG 1484 study evaluated
the role of adding radiation to complete responders after eight cycles of
CHOP chemotherapy (26). In this setting, radiation improved disease-
free survival but not overall survival. The SWOG 8736 study showed
that radiation combined with limited chemotherapy (CHOP × 3) had
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improved progression-free and overall survival to eight cycles of CHOP
(27). Although a subsequent report with longer follow-up showed that
significant differences diminished over time, limited chemotherapy with
radiation is still considered a standard of care for carefully selected
patients. However, there have been several other studies that have not
shown a benefit for radiation in the prerituximab era (28,29).
Retrospective data and results from a nonrandomized prospective study
(RICOVER-60) have suggested that patients who get radiation, especially
for initially bulky DLBCL, have superior outcomes (30–32).
Radiation Alone
Although radiation alone has been used in the past with curative intent
for both HL and NHL, the use of combination chemotherapy has been
shown to be more effective for classic HL and aggressive NHL
histologies. However, radiation alone is still used to cure limited stage
nonclassic HL (nodular lymphocyte predominant) and limited stage low-
grade NHL. Radiation alone for low-grade, limited stage follicular
lymphoma results in a sizable minority of patients with long-term
disease control (33). Limited stage extranodal marginal zone (MALT)
lymphomas of the stomach, thyroid, lung, salivary glands, and orbit, can
all be effectively controlled with doses ranging from 24 to 30 Gy
(34,35). Primary cutaneous B cell lymphomas of the skin can be
frequently controlled with low doses under 12 Gy (36). Radiation alone
is also commonly used in the palliative setting. Very low dose (2 Gy ×
2) is effective in low-grade histologies (37), but can result in meaningful
palliative responses, even in some aggressive histologies (38). Although
such low doses are effective for palliation, especially in patients with
multiple sites of involvement, higher doses are still recommended for the
curative setting (39).
Relapsed/Refractory Setting
With the trend of chemotherapy alone being used for initial therapy,
there has been an increased fraction of patients referred only after
chemotherapy has failed. There is still hope for cure in patients who
have persistent disease after initial standard therapy or when lymphoma
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relapses after first remission. For both HL and NHL, high-dose
chemotherapy with stem cell rescue can result in cure. There remains
uncertainty just exactly how good this strategy is because most analyses
fail to look at the intention to treat with transplant as opposed to those
who actually receive the autologous transplant. When radiotherapy can
be incorporated with salvage therapy, there appear to be improved
outcomes (40,41). For patients who relapse after high-dose
chemotherapy with stem cell rescue, radiation can help lead to long-
term survival in some patients, particularly if all sites of relapse are
radiated (42). The optimal sequence of when radiation should be used in
salvage regimens is not known, but there does appear to be value of
adding radiation when possible.
RADIATION THERAPY TECHNIQUES

History of Field Design
The history of the treatment of lymphoma paralleled the early history of
radiotherapy itself. While curative treatment for HL was being
developed, we also saw the introduction of the linear accelerator by
Henry Kaplan, the concept of treating microscopic disease in the hopes
of cures, and the use of customized blocks to shape fields to minimize
toxicity. Originally, radiation fields were designed using 2-dimensional
(2D) planning, based on anatomical landmarks visible on plain x-ray film
or fluoroscopy. When radiation was used as the primary modality for
cure, very large treatment volumes were employed, with the attempt to
treat all nodal tissue. As effective multiagent chemotherapy was
developed, trials demonstrated that fields could be reduced from total
nodal radiation, subtotal nodal irradiation, extended field, mantle,
inverted-Y, and then IFRT (Figs. 27.1 and 27.2). The 2D definitions for
IFRT were canonized in a 2002 review by Drs. Yahalom and Mauch (43).
For some time, IFRT was incorporated in a standard manner into
combined modality lymphoma trials (20,21,27). Most of these 2D fields
used anterior–posterior/posterior–anterior (AP/PA) field arrangements.
As 3-dimensional (3D) planned conformal radiation therapy and
intensity modulated radiation therapy (IMRT) became standard in other
disease sites, their application in lymphoma appeared (44,45). The
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application and comparison of volumetric treatment-planning techniques
obviously required delineation of treatment volumes, which was more
conceivable in the IFRT era (46,47). Different groups varied on exactly
how to contour the target volumes based on the IFRT concept, but
having specific targets enabled technique development to keep dose to
organs-at-risk (OAR) below predefined limits (48). Concurrently, with
the advent of volumetric planning for lymphoma, some centers adopted
even more limited radiation volumes, using an “involved node
radiotherapy” (INRT) concept. The INRT concept involves treating only
the areas of previously abnormal disease with margin, but not
attempting to treat any elective nodal volumes. Single-institution and
pooled results have shown that the risk of failure in regions that would
have been treated using IFRT was rare (49). The EORTC–GELA group
adopted INRT for their next study and described how to define these
volumes (50,51). Central to the precise definition of these limited
radiation volumes was the use of PET/CT in the treatment planning
position to ensure accuracy; however, this is difficult to achieve in
practice outside of a clinical trial. Smaller target volumes inevitably
result in lower dose to OARs, in particular heart, lung, breast, and
thyroid (52). In addition, compared to IFRT, INRT is predicted to have a
lower risk of secondary cancers (53). In practice, it is rare to have the
opportunity to simulate the patient prior to starting chemotherapy. Most
routine diagnostic PET/CT scans are not performed in optimal
radiotherapy positions, so rigid fusions with prechemotherapy scans are
flawed. However, the impact of positioning may be helped with the
advent of deformable image fusion.
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Figure 27.1 Historic very large radiation fields used in the treatment of lymphoma based on 2D
landmarks. A: Total nodal irradiation (TNI). B: Subtotal nodal lymph node irradiation (STLNI).
(Reproduced from Hill-Kayser CE, Plastaras JP, Tochner Z, et al. (95))
Figure 27.2 Historic limited radiation fields for mediastinal lymphoma based on 2D landmarks. A:
The classic mantle field consisted of treatment to the bilateral neck, supraclavicular regions,
axillae, hilae, mediastinum, and pericardial nodes. B: The “Modified mantle” that blocks the
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axillary regions reduces breast cancer risk (96) and pulmonary toxicity. C: IFRT for mediastinal
lymphoma based on Yahalom and Mauch (43) blocks the high neck and reduces dose to the
carotid arteries, salivary glands, and dentition. (Reproduced from Hill-Kayser CE, Plastaras JP,
Tochner Z, et al. (95))
Involved Site Radiotherapy

In order to take into account the reality of poor fusions, the concept of
“involved site radiotherapy” (ISRT) has been advocated by the
International Lymphoma Radiation Oncology Group for HL and NHL
(ILROG) (54,55). Essentially, the concept entails using volume-based
radiotherapy techniques according to the International Commission on
Radiation Units and Measurements (ICRU) without any elective nodal
radiation. Volumes are expanded liberally to account for inaccuracies in
fusion and uncertainty when trying to surmise how lymphomas shrink
during chemotherapy. When lymphomas shrink during chemotherapy,
the postchemotherapy volume is used to define the clinical target
volume radially, but the prechemotherapy volume is used superior-
inferiorly. Omission of elective nodal groups is only advocated in the
setting of effective chemotherapy.
Extranodal Lymphomas
Extranodal lymphomas pose a particular challenge when determining
the radiation volumes. The ILROG has published guidelines for a variety
of extranodal sites (56). According to ILROG guidelines, if an orbital
lymphoma only involves the conjunctiva or eyelid, the entire
conjunctival reflection to the fornices is usually treated, but not the
entire orbit. However, if the lymphoma involves the retrobulbar region,
lacrimal gland, or is a deep conjunctival lesion, the entire orbit is usually
treated. A small but poignant series demonstrated that partial orbital
radiation leads to a high ipsilateral relapse rate (57). Thus, lower doses
of radiation are advocated to decrease toxicity rather than geometric
attempts to avoid periorbital OARs. Other challenging locations are the
nasal/paranasal sinuses. Extranodal NK/T cell lymphomas, nasal type
are a particular subtype of NHL that requires special attention. For
limited stage extranodal NK/T cell lymphomas, primary radiotherapy,
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with or without concurrent chemotherapy to high doses (> or = 50
Gy), can result in cure. For aggressive NHL of the sinuses, the large
majority of which turn out to be DLBCL, induction chemotherapy with
R-CHOP is commonly employed. The consolidative radiation volume
should include the entirety of the affected sinus and any sinuses that are
breached, but uninvolved sinuses need not be included in the CTV in the
era of modern imaging and combined modality therapy (56).
Cutaneous lymphomas also pose challenges in determining the
appropriate radiation volume, technique, and dose. First and foremost,
an understanding of the dermatopathology is key to determining the
appropriate treatment. The ILROG has published general guidelines for
treatment of cutaneous lymphomas (58). When limited to a localized
distribution, certain lymphomas such as primary cutaneous follicle
center lymphoma, primary cutaneous marginal zone lymphoma, and
primary cutaneous anaplastic large-cell lymphoma can be cured with
radiotherapy alone using a margin of 1 to 1.5 cm for CTV. Primary
cutaneous diffuse large B-cell lymphoma, leg-type has a somewhat worse
prognosis and is generally treated with combined modality therapy (R-
CHOP) followed by radiation with 1- to 2-cm expansion to CTV.
Cutaneous T-cell lymphoma (mycosis fungoides) can be treated with
radiation depending on the situation. If diffuse control is required when
topicals and other systemic therapies fail, total skin electron therapy
may be a durable palliative treatment, particularly when intractable
pruritus is present. Implementation of total skin electron therapy
requires special commissioning, treatment stands to allow the patient to
adopt various positions, and close attention from physicists to ensure
homogenous and tolerable treatment (59). For focal palliation of CTCL,
limited en face electron fields can be used, but somewhat higher doses
than the 4 Gy used for low-grade B cell lymphomas are required for a
reliable response. Compared to a 30% response rate for 4 Gy (2 Gy × 2),
8 Gy (4 Gy × 2) results in a response rate of over 90% (60).
Simulation Techniques
In planning lymphoma cases, patient positioning and immobilization
depend on the site of treatment. For head and neck and mediastinal
lymphomas, thermoplastic masks can allow for limited PTV expansions
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by reducing interfraction setup errors. In certain situations, five-point
thermoplastic masks can be used to restrict rigidly the relationship
between the neck, clavicles, and mediastinal structures (Fig. 27.3). The
position of the arms depends on the treatment volume as well as the
technique. While arms up may better reproduce the prechemotherapy
PET/CT allowing better image fusion, it limits the potential use of lateral
beam angles to approach the neck and/or Waldeyer ring. Arms down
may limit certain lateral beam angles for thoracic volumes. The position
of the arms does alter the position of axillary nodes, which should be
considered if they need to be treated. Ultimately, the decision to treat
arms up, down, or akimbo is patient- and technique-specific. Putting
female patients on an incline board can move the breasts and heart away
from the upper mediastinum, potentially decreasing dose to the
structures (61). For inguinal lymphomas, “frog-leg” positions can
alleviate skin folds as a measure to reduce skin toxicity. In addition,
these positions allow for more freedom to move the penis/scrotum away
from intended fields or to use a “clamshell” to reduce dose to the
testicles. Ideally, CT-compatible mock clamshells can be used to position
optimally the patient when testicular shielding is desired (Fig. 27.4).
Figure 27.3 Thermoplastic immobilization mask. For optimal stabilization of the cervical and
thoracic spine with respect to clavicle position, a five-point mask that encompasses the shoulders
can be used. If breath-hold devices are used, holes need to be made to accommodate these
devices.
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In addition to fusion with PET/CT scans, intravenous contrast-
enhanced CT scans can be very helpful in delineating nodes. Small PET-
negative nodes that are present on prechemotherapy scans that
disappear are highly suspicious for involvement by lymphoma, but are
difficult to discern without contrast (50). When using the ISRT
paradigm, exclusion of normal structures is greatly aided by intravenous
contrast, especially around the heart and great vessels (54,55). If cardiac
substructures are to be preferentially avoided using ultra-conformal
techniques, then contrast is also a must (62). Oral contrast is appropriate
for certain abdominal lymphomas, particularly those in the mesentery.
Barium can be used, but it can cause some small errors in photon dose-
distributions if the Hounsfield units are not overridden to water-
equivalent prior to planning. If proton therapy is used, any structures
with contrast must be overridden due to profound effects on the dose
distribution, or noncontrast and contrast scans should be acquired at the
time of simulation. Alternative low attenuation oral contrast agents, such
as VoLumen or milk (63), with low Hounsfield units, can reduce this
issue, but delineating bowel using “negative contrast agents” can be
challenging when bowel is intimately involved with tumor (Figs. 27.5A
and 27.5B). The addition of intravenous contrast to negative contrast
agents improves the ability to distinguish bowel as the bowel wall is
enhanced (Figs. 27.5C and 27.5D).
Figure 27.4 CT-compatible testicular shield. The high-density “clamshell” used during treatment
creates artifact that compromises CT-based radiation contouring and planning. A mock testicular
shield made from CT-compatible material is shown in axial cross-section that allows for accurate
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body positioning.
Figure 27.5 High-density and low-density oral contrast agents with or without intravenous contrast
in CT simulation of abdomen and pelvis. A: High-density barium oral contrast with intravenous
contrast in the pelvis. Contrast shows clear delineation of small bowel and blood vessels, which
may need to be overridden during radiotherapy planning. B: Low-density oral contrast, VoLumen
without intravenous contrast in the pelvis. Delineation of bowel and vessel is more difficult. C:
VoLumen without intravenous contrast in the abdomen. D: VoLumen with intravenous contrast in
the abdomen shows small bowel more clearly with enhancement of the bowel wall.
Motion Management
With the advent of highly conformal radiation for lymphoma, close
attention to motion becomes increasingly relevant. In the mediastinum,
where respiratory motion predominates, gated 4-dimensinal (4D) CT
scans can be acquired to ascertain actual target movement. The ISRT
guidelines call for use of volumes as described by the International
Commission on Radiation Units and Measurements (ICRU) Report 83
(GTV, CTV, PTV) and Report 62, which delineate the internal target
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volume (ITV) (54,55). Large anterior mediastinal masses, even those
remaining after chemotherapy, tend to “pancake out” laterally when
patients are supine compared to when upright. These large masses can
move significantly during the breathing cycles, as shown in Figure 27.6.
During the exhale phase, mediastinal masses can extend laterally, which
can lead to increased dose to the lungs and breast tissues, especially
when AP/PA field arrangements are used. During the inhale phase,
masses elongate cranio-caudally, but show a more narrow profile
laterally. This narrowing of the mediastinum can be accentuated with
deep (maximum or near maximum) inspiratory breath hold (Fig. 27.7).
Figure 27.6 Effect of respiration on lateral dimensions of mediastinal lymphomas. Fused CT

images of axial slices in maximal inspiration (more narrow) and maximal expiration (wider) from a
planning 4D CT scan of a patient with a residual mass after chemotherapy for Hodgkin lymphoma.
Breath-hold techniques have been explored in treatment planning for

lymphoma (64–68). A Phase II study of deep inspiration breath hold
(DIBH) was conducted where free-breathing and DIBH PET/CT scans
were acquired in the treatment position prior to initiation of
chemotherapy as well as postchemotherapy scans. Of the 22 eligible
patients, 19 were preferentially treated with DIBH based on more
favorable lung, heart, and breast dosimetry (66). In this study, which
used the RPM system with video/goggle guidance, they found that the
DIBH on average could decrease the mean dose and V20 of the heart and
lung without an effect on female breast dose. An alternate approach,
using moderate DIBH with active breathing control, also decreased mean
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lung and heart doses, but actually showed increased dose to the breasts
(67). DIBH can reduce heart and lung doses beyond what can be
achieved by IMRT alone (64,65). In practice, the use of DIBH is more
practical for lymphoma patients than lung cancer patients as they are
usually healthy enough to participate in the rigorous demands of this
technique (66).
Figure 27.7 Effect of deep inspiratory breath hold on mediastinal width. Axial CT slices of a
patient with residual anterior mediastinal lymphoma imaged at the level of the carina using either
free-breathing (A) or at deep inspiratory breath-hold (B).
On-Board Imaging
The use of daily IGRT for lymphoma patients can help minimize PTV
expansions required. Alignment to bony anatomy with orthogonal
kilovoltage on-board imaging may be satisfactory for the majority of
cases, especially when optimized immobilization devices are employed.
Volumetric daily imaging, such as cone beam CT (CBCT) or CT-on-rails,
can be employed for confirmation of DIBH position and when using
highly conformal techniques, such as IMRT or volumetric modulated arc
therapy (VMAT) (69). Spatial resolution of soft tissue in the abdomen is
challenging with CBCT, with only moderate interobserver correlation for
gastric MALT lymphomas (70). When using proton therapy, variations in
patient positioning can result in alterations in the dose distribution, so
particular care is required for highly accurate and reproducible setup.
Close attention is paid to the position of the clavicles, which are
notoriously prone to motion that is independent of the thoracic spine.
Until volumetric on-board imaging is routinely available on proton
therapy equipment, verification of off-line 4D CT scans can help assess
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whether radiotherapy is robustly delivered.
Radiotherapy Planning Techniques

When ICRU standardized target volumes are used for lymphoma
radiation, comparative radiation planning can help determine the best
method for OAR-sparing with good coverage. Three-dimensional CRT
plans using customized beam arrangements other than AP/PA can
selectively spare OARs. For example, anterior mediastinal masses that
drape anteriorly over the upper portion of the heart can be approached
with inferior oblique fields to minimize dose to the heart (Fig. 27.8).
IMRT can be used to spare particular OARs, but this is usually at the
expense of larger volumes of lung and/or breast receiving low doses,
obviously an issue for some patients. Using involved field concept
volumes, early work with IMRT in mediastinal lymphomas demonstrated
the ability to lower mean lung (44) or heart (47) doses with IMRT
compared to 3D CRT. Dose-painted IMRT can be used to boost particular
regions of elevated risk (44). As in other thoracic sites, beam angles can
substantially drive the quality of IMRT plans for mediastinal lymphomas.
Equally spaced coaxial IMRT beam angles are likely to result in high
volumes of lung and breast tissue treated with low–moderate doses
compared to limited beams, such as the “butterfly” technique (69).
VMAT plans for mediastinal lymphomas that concentrically treat
patients (68,71) will deliver excessive dose to lung and breast compared
to optimized limited arcs (72). When concentric beam angles/arcs are
employed in the chest, dosimetric studies have suggested that
IMRT/VMAT will increase the risk of second cancers, especially in
female patients (53). Beam angle selection can limit, but not eliminate
this risk (69). Unlike the chest, concentrically delivered VMAT has an
appealing dose-distribution for mesenteric lymphomas. Although whole
abdomen radiation for mesenteric sites has fallen out of favor, VMAT
plans deliver a modest dose bath to the mesenteric tissues surrounding
residual abdominal lymphomas.
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Figure 27.8 Use of noncoaxial 3D conformal beam arrangements to limit dose to the heart. For
this patient with an anterior mediastinal mass that lay anterior to the heart, delineation of the ITV
(orange) and PTV (green) allows targeting with an off-axis field (anterior-inferior oblique) that
decreases dose to the heart compared to a traditional AP/PA beam arrangement.
Critical to successful implementation of IMRT/VMAT inverse planning

is the formulation of the target coverage goals and OAR dose constraints
that reflect a balance relative to important OARs. Typically for
mediastinal lymphomas, the balance between lung, heart, and breast
dose depends on the patient and their personal and family medical
history. The spinal cord becomes increasingly important in the case of
reirradiation. Pulmonary toxicity can manifest either as subacute
radiation pneumonitis or late pulmonary fibrosis. Radiation pneumonitis
is relatively uncommon, with rates ranging from 3% to 10% undergoing
initial treatment (73–76). Pneumonitis is more common (25% to 35%)
when radiation is combined with autologous stem cell transplant in the
relapsed/refractory setting (73,75). Lung dosimetric parameters are
strong predictors of risk, with MLD over 13.5 to 14 Gy and V20 of over
30% to 36% predicting for higher rates (73,75,76). Pinnix et al. (73)
specifically studied patients treated with IMRT, and found that V5 over
55% was the strongest dosimetric predictor with this technique. The
heart dose/volume constraints are particularly important because of the
high incidence of cardiac disease noted in survivors of HL. In a large
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study from the Netherlands Cancer Institute examining cardiovascular
risk in over 2,500 patients treated for HL with a median follow-up of 20
years, patients treated before the age of 25 were found to have
cumulative incidences at age 60 or older of 20%, 31%, and 11%,
respectively, for coronary heart disease (CHD), valvular heart disease
(VHD), and heart failure (HF) as first events. The hazard ratios for CHD,
VHD, and HF were 2.7, 6.6, and 2.7, respectively for those who received
mediastinal RT compared to those who did not. Likewise, the Harvard
group reported a 20-year risk of cardiac events of 16% with a median
follow-up of 14.7 years in patients who received mediastinal RT for HL
(77).
Of course, given their long follow-up, these studies examining 20-year
risk of cardiac disease included many patients treated with relatively
high doses of radiation with large outdated mantle fields in which much
of the heart would have been irradiated. With a trend in radiotherapy
practice over the last 2 decades toward lower doses and smaller fields,
one would expect that the incidence of future cardiac events for patients
receiving current state-of-the-art radiation will be much lower. Using a
dosimetric risk-modeling approach, Maraldo et al. (78) predicted a
substantially lower risk in cardiac disease risk in patients INRT
compared to mantle fields. One large study of pediatric patients treated
on German-Austrian DAL-HD trials between the years 1978 and 1995
showed that lower doses were less cardiotoxic, with the cumulative
incidence of cardiac disease after 25 years highest in those who received
36 Gy (21%), decreasing to 10%, 6%, 5%, and 3% in groups that
received 30, 25, 20, or 0 Gy respectively (79).
Dose constraints vary by institution, but Cella et al. (80) have
proposed the constraints listed in Table 27.3 based on published
literature. In practice, delineation of cardiac substructures may be
tedious, but may help preferentially spare regions when highly
conformal radiation is used. A methodologically controversial study in
breast cancer patients and phantoms claimed that each increase of the
mean heart dose of 100 cGy increased the rates of major coronary events
by 7.4% (81). Based on this, some use aggressive limitations on the
mean heart dose, such as 4 or 5 Gy, in the hopes of reducing coronary
events.
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TABLE 27.3 Organs-at-Risk Target Planning Parameters for
Mediastinal Lymphomas as Suggested by Cella et al. (80)
Similarly, there is not a consensus on a dose parameter for breast

tissue in order to reduce the risk of breast cancer. Travis et al. (82)
found an increased risk of breast cancer in all radiation dose categories
of 4 Gy or more in young patients. This study found that risk increased
with increasing dose to the location in the breast in which the
subsequent tumor developed, with up to an 8-fold increased risk for
doses >40 Gy. A similar conclusion regarding a dose response for breast
cancer was reached by Van Leewen et al. (83). The model that appears
to best fit these clinically observed rates of breast cancer was developed
by Sachs and Brenner and takes into account cellular repopulation by
proliferation that takes place during fractionated radiotherapy (84).
Using this model, Hodgson et al. (85) estimated the risk of breast cancer
in patients treated with radiation and predicted that 35 Gy IFRT would
reduce the 20-year excess relative risk of breast by 63% compared with
35 Gy mantle RT and that low-dose (20 Gy) IFRT would reduce the risk
by 77%. There are actual patient data supporting these theoretical
predictions with one study from the Netherlands showing that women
with HL treated with mediastinal irradiation (without axillae) had a
substantially lower risk of developing breast cancer than those treated
with mantle field irradiation that would have included the bilateral
axillae (86). Based on these data and given that even very low doses of
radiation may result in second cancers, the ALARA (as low as reasonably
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achievable) principle is generally followed along with using the smallest
volume of breast tissue that is feasible when doing treatment planning in
females receiving mediastinal irradiation.
Figure 27.9 Comparison of pencil beam scanned PBT plan with IMRT in mediastinal lymphoma
and bilateral hilar involvement. Axial CT-slice with dose color wash at the level of the hilae with
the ITV contoured (orange). A: IMRT; B: Pencil beam scanned proton therapy using posterior-
oblique fields, painted twice.
Proton beam therapy (PBT) for lymphomas is a modality, which

delivers a low integral dose and has the potential to lower dose to
specific OARs. For example, even a single posterior proton field can treat
female mediastinal HL patients with the beam stopping at the chest wall
with virtually no breast exposure (Fig. 27.9). This beam-stopping depth-
dose characteristic of PBT is governed by the Bragg peak. Although
having virtually no exit dose can result in dosimetrically superior plans
as shown in a treatment planning system, the depth of penetration
depends entirely on what tissue has been traversed by the beam. The
sensitivity of proton deposition to uncertainties, and in particular to the
range and setup, increases the potential for error in actual delivery and
needs to be accounted for carefully. Several dosimetric studies
comparing PBT to conventional 3D conformal photon therapy in patients
with mediastinal lymphomas have demonstrated significantly reduced
radiation dose to breast, lung, heart, and total body (87–90). One study
evaluating young women with HL demonstrated a reduction in
unnecessary breast dose by as much as 80% with PBT (88). A
comparative dosimetric study evaluated dose to the heart, lungs, and
breasts, and modeled risks of cardiovascular disease, lung cancer, breast
cancer, and the corresponding life years lost between 3D CRT, VMAT,
and PBT (71). They found that pencil-beam scanned (PBS) proton
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therapy was estimated to have the lowest life years lost due to predicted
treatment-related mortality. In addition, the National Comprehensive
Cancer Network (NCCN) guidelines for HL version 2.2015 stated that
therapy with either photons or protons is acceptable as significant dose
reduction to organs at risk (e.g., lung, heart, and breasts) can be
achieved with proton beam radiotherapy which can reduce the risk of
late effects (91). Because ISRT volumes are based on the unique
distributions of lymphomas, PBT beam arrangements need to be
customized to the individual patient. A young woman with axillary
disease and upper mediastinal disease may be best treated with posterior
beams, whereas a young man with an anterior mediastinal mass that
drapes over the heart may be best treated with anterior beams. In
general, AP/PA proton beam arrangements are avoided since they do not
exploit the beam stopping advantage of protons. One small study that
used AP/PA proton beams did not detect much of an advantage over
photons, which emphasizes the importance of careful beam selection
(92). Both double-scatter (DS) and PBS proton therapy may be used for
lymphoma, and each has its advantages and disadvantages. DS PBT is
less conformal than PBS, especially in the proximal edge of the target
volume. However, due to the necessity of using physical compensators
with DS, conformality distal to the target degrades with DS when the
depth of the target changes drastically over a short distance. This
transition typically occurs from the upper mediastinum to the lower
mediastinum when there is disease anterior to the heart. This issue can
be mitigated by splitting fields into upper and lower fields that use
different compensators and half-beam blocking, but this can be
cumbersome. PBS PBT offers high 3D dose conformality and can handle
sharply changing target volumes even using a single large field. The
conformality of PBS PBT depends in part by the size of the spot, which is
defined as “sigma.” PBS PBT has been shown to be dosimetrically
superior to DS PBT, IMRT, and 3D CRT with respect to mean heart and
lung dose (93). However, PBS is not a continuous beam and delivers the
dose to the target spot-by-spot, layer-by-layer with technical
specifications that vary. Therefore, the dose distribution is more
sensitive to the interplay effect generated by the beam delivery in
conjunction with respiratory-induced target motion. Plan robustness of
PBS plans has been confirmed through exhaustive modeling studies on
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4D CT scans taken through a course of radiation (94). Robustness of
target coverage relative to respiratory motion can be improved by
techniques such as dose “repainting,” use of larger spot sizes, active
respiratory motion management, or tracking of the target volume. Lastly,
fractionation itself can help smear out interplay problems. A rule of
thumb to maintain robust ITV coverage is to use a spot with sigma about
twice as large as the degree of motion perpendicular to the beam
direction and a single repainting of PBS PBT (94). Although active
motion management techniques (e.g., breath hold) are compatible with
PBS PBT, the longer time for delivery can make it less practical than for
DS PBT. Compared to IMRT, both DS and PBS PBT tend to be less
conformal in the high-dose region around the target volume. The
relationship between the target and a sensitive OAR, such as the left
anterior descending coronary artery, will affect which modality
dosimetrically is best for an individual patient.
Individualized Patient Care

For lymphomas, there are multiple ways to achieve cure, which can
involve all chemotherapy, all radiation therapy, or combined modality
approaches. Patient preference, proximity to facilities, co-morbidities,
family history, tolerance of chemotherapy, and PET-based responses can
all inform treatment decisions. Multidisciplinary clinics can help select
which patients will benefit from radiotherapy, which is still a powerful
tool in the treatment of lymphoma.
ACKNOWLEDGMENTS
The authors would like to thank Angela Natale for help in figure preparation.
KEY POINTS
• Radiation therapy for lymphomas has evolved significantly with
lower doses and smaller fields when effective chemotherapy has
been delivered.
• Radiation therapy planning requires target volume definition based
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on careful review of prechemotherapy PET/CT scans and
postchemotherapy scans to allow volumetric radiation planning.
• When treatment planning volumes are specifically defined, highly
conformal radiation techniques such as IMRT, VMAT, and proton
therapy can be employed to optimize target coverage and OAR
avoidance.
• Although PET/CT responses can help define lymphoma patients
with good prognosis, combined modality therapy results in the
highest disease-free survival which should be balanced with the
predicted risk of significant treatment-related toxicity.
QUESTIONS
1. What are the average dosimetric differences between deep breath
hold and free breathing techniques for mediastinal lymphomas?
A. Deep breath hold decreases dose to spinal cord
B. Deep breath hold decreases dose to lungs and heart
C. Deep breath hold decreases dose to female breasts
D. Deep breath hold decreases the PTV margin required for setup
error
2. When treating lymphoma patients with an involved site
radiotherapy (ISRT) paradigm, how are previously non-involved
lymph node regions incorporated into target volumes?
A. Previously non-involved regions are omitted when
chemotherapy was effective
B. Previously non-involved regions are omitted even when
chemotherapy was ineffective
C. Previously non-involved regions are treated to a lower dose
when chemotherapy was effective
D. Previously non-involved regions are treated to the full dose
unless there is overlap with OARs
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3. What are the average dosimetric differences between AP–PA
beam arrangements and IMRT when treating mediastinal
lymphomas?
A. IMRT lowers mean heart dose and lung V5
B. IMRT increases mean heart dose and lung V5
C. IMRT lowers mean heart dose and increases lung V5
D. IMRT increases mean heart dose and lowers lung V5
4. The risk of radiation pneumonitis in lymphoma patients is most
dependent on which factor?
A. Cumulative dose of bleomycin
B. History of smoking
C. History of allergic reaction to antibody therapy
D. Mean lung dose over 13.5 Gy
E. Radiotherapy given in newly diagnosed setting
5. Radiotherapy treatment planning using INRT or ISRT focuses on
what parameters for field design and daily alignment?
A. Customized radiation plans based on pre- and
postchemotherapy volumes and daily positioning based on
structures with a fixed relationship to the target volumes
B. Templated blocks with borders based on patient size
positioned daily based on surface anatomy
C. Customized blocks with borders based on easy-to-identify
bony anatomy and positioned daily based on surface anatomy
D. Customized blocks with borders based on easy-to-identify
bony anatomy and positioned daily based on bony anatomy
ANSWERS
1. B
2. A
3. C
4. D
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5. A
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delineating the radiation field in Hodgkin’s disease. Ann Oncol.
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44. Goodman KA, Toner S, Hunt M, et al. Intensity-modulated
radiotherapy for lymphoma involving the mediastinum. Int J Radiat
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45. MacDonald S, Bernard S, Balogh A, et al. Electronic compensation
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orientation optimization and dose constraints assigned to virtual
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50. Girinsky T, Specht L, Ghalibafian M, et al. The conundrum of
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51. Girinsky T, van der Maazen R, Specht L, et al. Involved-node
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52. Weber DC, Peguret N, Dipasquale G, et al. Involved-node and
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diaphragmatic Hodgkin lymphoma: a comparative planning study.
53. Weber DC, Johanson S, Peguret N, et al. Predicted risk of radiation-
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2011;81(2):490–497.
54. Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for
nodal non-Hodgkin lymphoma-target definition and dose guidelines
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55. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for
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56. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for
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58. Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for
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61. Dabaja BS, Rebueno NC, Mazloom A, et al. Radiation for Hodgkin’s
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breasts and decrease the dose to the heart. Int J Radiat Oncol Biol
Phys. 2011;79(2):503–507.
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cardiac structures using protons compared with 3DCRT and IMRT in
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63. Koo CW, Shah-Patel LR, Baer JW, et al. Cost-effectiveness and
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modulated radiotherapy, and three-dimensional proton
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93. Zeng C, Plastaras JP, James P, et al. Proton Beam Scanning for
Mediastinal Lymphoma: Dosimetric Evaluation and 4D Robustness
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2012;30(22):2745–2752.
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28 Cancers of the Head and Neck
Yolanda I. Garces, Charles Mayo, Christopher Beltran, and
Robert L. Foote
INTRODUCTION
Head and neck (H&N) cancer is a complex disease site to master because
there are many factors that one has to consider. First, this group of
malignancies encompasses more than just one disease site. H&N cancers
include a wide variety of primary sites from the orbit, ear, and scalp
cranially to the thyroid gland caudally. Further, H&N cancer physicians
need to be proficient in the treatment of a wide variety of histologic
subtypes, from the common squamous cell carcinomas to the rare
sarcomas. This review will focus on the more common adult squamous
cell carcinomas of the H&N as well as thyroid cancers given their
increasing incidence; it will not include rare diseases. In addition, a solid
understanding of H&N anatomy as well as the patterns of cancer spread,
both local as well as nodal, are critical to the development of optimal
treatment plans and strong decision making. Finally, a well-integrated
multidisciplinary team is also critical for treatment success.
INCIDENCE AND EPIDEMIOLOGY

An estimated 60,000 US citizens will be afflicted with H&N cancer in
2015. Another 62,500 will be diagnosed with thyroid cancer. The
incidence of cancer overall is declining; which is predominantly due to
increased cancer screening and smoking cessation in recent decades.
However, the incidence is increasing for human papilloma virus (HPV)-
related oropharyngeal cancer and thyroid cancer (1). Alarmingly, the 5-
year relative survival rates for larynx cancer have declined from 66% to
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63% when comparing the 1975–1977 to the 2004–2010 cohorts making
larynx cancer one of the two cancers where there has been a statistically
significant decline in 5-year survival; the other being cancer of the
uterine corpus. Conversely, the vast majority of other cancers are now
associated with a higher likelihood of 5-year survival (1).
The main risk factor for H&N cancer remains current or past tobacco
use. Concurrent alcohol use significantly augments the risk (2). H&N
cancer patients have often decreased or already quit smoking by the
time they are seen by their healthcare team (3). However, relapse back
to smoking remains high. Strong recommendations for quitting and
remaining quit are essential to help improve treatment outcomes, and
most healthcare providers are good at asking and providing this advice.
However, beyond asking and advising (4), it is essential that cancer
centers develop mechanisms to assist with behavioral counseling,
providing appropriate cessation medications as well as tobacco cessation
follow-up with patients to optimize outcomes (5). It is well known that
smoking cessation can reduce the risk of second primary cancers (6). The
epidemic of HPV-related oropharynx cancers among younger, relatively
healthy individuals who never smoked is changing the perception of
H&N cancer patients and survivors.
The causal relationship between HPV and oropharynx cancers was
first described in 2000 (7). The incidence of HPV-related cancers is
increasing in the United States and worldwide. HPV-related oropharynx
cancers are occurring predominantly in never smoking younger men
who are less than 60 years old (8). These cancers are predominantly
located in the tonsil, tongue base, or pharyngeal wall. It is felt that
changes in sex behaviors in developed countries have led to this
increase. Men also have higher rates of HPV prevalence than do women
(9). Interestingly, patients who have HPV-related tumors and are either
never smokers or smoked less than 10 pack-years in their lifetime have a
better prognosis (10). Clinical trials are being conducted to exploit this
benefit and to reduce morbidity of treatment.
TREATMENT
General Principles
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The treatment of H&N cancer with radiotherapy is typically complex and
utilizes intensity-modulated radiation therapy (IMRT) for the majority of
patients. IMRT is typically delivered with volumetric-modulated arc
therapy (VMAT) as discussed in the treatment section below. The only
general exception is for patients with early-stage larynx cancer, where
we generally still utilize 3D-conformal fields in which the outcomes are
excellent and the risk of long-term complications is low due to the small
field size (see Fig. 28.1A) (11). The field arrangement for an early-stage
larynx patient typically is opposed laterals that enter “above” or “cranial
to” the shoulders. One centimeter of bolus material is placed over the
skin overlying the anterior commissure region for patients who have
anterior commissure involvement and a “thin” neck with less than 1 cm
of subcutaneous tissue between the skin and the anterior thyroid
cartilage. Wedges with the heels placed anteriorly are utilized to keep
the dose uniform throughout the target volume (see Fig. 28.1B).
However, it is fairly common for centers to utilize field-in-field
techniques or dynamic wedges rather than physical wedges. The dose of
radiation for invasive cancers typically ranges from 225 to 200 cGy per
day to a total dose of 6,300 to 7,000 cGy, respectively. For some T2
larynx cancers utilizing a BID fractionation of 120 cGy with at least a 6-
hour interval between fractions to a total dose of 7,920 cGy provides
increased local control (12). There are dosimetric studies as well as early
retrospective clinical data that are evaluating carotid artery sparing
techniques to minimize possible long-term complications from definitive
treatments including carotid stenosis and stroke (13,14).
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Figure 28.1 A: Early larynx (cT1N0) cancer treatment field. B: Early larynx (cT1N0) cancer
isodoses.
The vast majority of H&N patients are being treated with IMRT in the
last decade with comparative effectiveness research showing that the
primary reason for this being an improvement in xerostomia for patients
who receive IMRT and are able to undergo parotid sparing techniques
(15). These patients require a multidisciplinary team to best identify the
most appropriate treatment options. Therefore, this section will focus on
general treatment principles for optimal H&N treatment and then review
unique issues as they relate to H&N cancers including the following:
target volumes and normal organ contouring, planning challenges for
dosimetrists and physicists, image-guided and adaptive radiation
therapy, and finally novel radiation therapy techniques like intensity-
modulated particle therapy.
General Treatment Recommendations

It is beyond the scope of this chapter to discuss which primary treatment
option (surgery vs. radiation therapy) is best for patients, and it will
focus primarily on definitive treatments for the majority of patients and
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discuss postoperative challenges for H&N cancer (squamous cell
carcinomas and well-differentiated thyroid carcinoma) patients as well.
Treatment volumes for both the primary (16,17) and nodes (18) are
summarized by disease site for the uninvolved neck to the N3 neck in
Tables 28.1 and 28.2. The primary and nodal tumor volume (gross
tumor volume: GTVp, GTVn) is determined by radiologic imaging which
could include CT simulation with or without IV contrast, contrast-
enhanced CT, PET/CT, or MRI as well as a good clinical examination
including nasopharyngolaryngoscopy. It is also beyond the scope of this
chapter to discuss the various dose options for each disease site and/or
clinical scenario. The typical doses of 7,000 cGy, 6,300 cGy, and 5,600
cGy in 35 fractions for high-, intermediate-, and low-risk target volumes
for definitive cases are displayed in Table 28.2. Similarly, postoperative
radiation doses are 6,000 cGy and 5,400 cGy in 30 fractions for the high-
and low-risk target volumes.
For postoperative patients, chemotherapy is added to radiation
therapy primarily for fit patients with high-risk features of extracapsular
extension and/or positive margins (19). Chemotherapy is typically
cisplatin-based, but there are ongoing clinical trials investigating various
chemotherapy regimens for high-risk patients including docetaxol and
cetuximab (Radiation Therapy Oncology Group (RTOG) 1216,
ClinicalTrial.gov Identifier NCT01810913). Of note, this trial includes
patients with high-risk non–HPV-related oropharynx cancers. There is an
intermediate-risk group of patients who should consider radiation
therapy alone or participation in a clinical trial that is looking at the
addition of cetuximab (RTOG 0920, ClinicalTrial.gov Identifier
NCT00956007). The patients eligible for this clinical trial have the
following risk factors: perineural or lymphovascular invasion, a single
lymph node greater than 3 cm or ≥2 lymph nodes (all less than 6 cm)
with no extracapsular extension, close margins (within 5 mm), a T3 or
T4 primary tumor of the oral cavity, oropharynx, or larynx, or a T2 oral
cavity cancer with >5-mm depth of invasion. It is essential that all
patients are seen promptly after surgery as the complexity of treatment
planning and the social factors associated with H&N cancer patients can
make a long and possibly toxic treatment challenging for patients.
Ideally, the entire “package” of treatment from surgery to the
completion of radiation therapy is delivered within 11 weeks from the
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date of surgery (20).
TABLE 28.1 Primary Tumor Site and Gross Tumor Volume (GTVp)
Delineations
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TABLE 28.2 Target Volumes by Dose and Disease Site for the N0
through N3 Neck
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Treatment volumes in the postoperative setting do differ slightly from
definitive cases as one needs to consider the surgery performed and
invasion of the tumor into adjacent sites for the primary and nodal
disease clinical target volume (CTV). Typically, no GTV is identified on
the planning study since the primary tumor and involved nodes have
been completely resected with negative margins. A pre-op GTV can be
added as a guide, but this volume is not used for CTV or planning target
volume (PTV) expansions. The nodal levels and volumes tend to be as
described by the International Multi-Cooperative Group Consensus 2013
Neck Node Guideline (18). A simultaneous integrated boost (SIB) to 66
Gy in 30 fractions to the site of a positive margin is included in the
treatment plan and is designed with the aid of surgical clips and/or a
thorough review of the operative note, pathology report, preoperative
imaging, and communication with the surgeon.
No data exist to support different volumes or expansions for patients
with HPV-related disease with or without extracapsular extension;
however, there is great interest in decreasing the dose or intensity of the
radiation treatments for patients with favorable prognosis who have
undergone resection. There are several studies looking at dose de-
escalation in the setting or primary radiation therapy including the
following ClinicalTrials.gov Identifiers—NCT02254278, NCT01706939,
NCT01088802, NCT01302834, NCT02258659, NCT01663259, and
NCT02159703. Three additional studies in the postoperative setting will
be highlighted as follows: First, the Eastern Cooperative Oncology Group
(ECOG) is conducting a randomized phase II trial of transoral surgery
followed by low-dose or standard-dose radiation therapy in HPV-related
stage III to IVA patients who are intermediate risk (ECOG E3311 trial,
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ClinicalTrials.gov Identifier NCT01898494). Second, Washington
University is conducting a three-institution trial called ADEPT which is
looking at adjuvant dose de-escalation for extracapsular spread among
p16 positive patients who have undergone transoral resection (ADEPT
trial, ClinicalTrials.gov Identifier NCT01687413). Finally, Mayo Clinic is
conducting a single institution trial which is offering patients twice-daily
adjuvant hyperfractionated radiation therapy to 3,000 or 3,600 cGy in
150 cGy fractions over 2 weeks in combination with docetaxol for
patients with or without extracapsular nodal extension, respectively
(MC1273, ClinicalTrials.gov Identifier NCT01932697). All these trials
are ongoing and will likely inform future treatment options for this
growing and favorable subgroup of patients.
Thyroid cancer patients can also be treated in the adjuvant setting.
However, the role of adjuvant radiation therapy remains somewhat
controversial for the well-differentiated thyroid cancers, given the lack
of randomized trials. There are several retrospective series that support
its use (21–23). Because of this lack of evidence, the national guidelines,
including those of the American Thyroid Association and the National
Comprehensive Cancer Network, recommend that radiation therapy be
discussed in those who have gross residual disease that is unresectable,
not radioiodine avid, and is threatening vital structures among those
patients with papillary, follicular, and Hurthle cell cancers (24,25). They
also recommend adjuvant radiation for those patients with medullary
cancers who have gross extrathyroidal extension and a positive margin
or have medium- to high-volume extranodal extension (26). Radiation
therapy can help decrease the risk of local recurrence and may improve
survival; studies support the use of IMRT (27). Because of the associated
acute side effects, many providers are reluctant to refer their patients for
radiation therapy and few centers have expertise in this setting.
Anaplastic thyroid cancer (ATC) represents a rare form of thyroid
cancer that does require intensive treatments if found when still locally
and regionally confined. Success with aggressive surgery, radiation
therapy, and chemotherapy (28–30) has led to the ongoing RTOG trial
evaluating paclitaxel and pazopanib with radiation therapy (RTOG 0912,
ClinicalTrials.gov Identifier NCT 01236547). The American Thyroid
Association published their guideline for the management of ATC in
2012 and advocates for an aggressive approach for patients with stage
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IVA or IVB resectable and select stage IVB unresectable patients (26).
Again, IMRT is an important component of treatment for these patients
and clinical experience is valuable. See Figure 28.2 for a case example.
Figure 28.2 Anaplastic thyroid case example. A 60-year-old female presented with localized stage
IVA (pT4 a N1 a M0) anaplastic thyroid carcinoma in 2012. At the time of her total thyroidectomy
and central compartment node dissection, she was found to have anaplastic thyroid carcinoma
arising from an encapsulated follicular variant of papillary thyroid carcinoma within the right lobe of
her thyroid gland (3.4 × 2.8 × 2.5 cm mass). She had extrathyroidal extension as well as a focally
positive margin. She had one out of two lymph nodes in the central compartment involved with
anaplastic thyroid carcinoma. She had four right central neck compartment lymph nodes and one
Delphian lymph node that were negative for carcinoma. She had no evidence of distant disease.
She was then treated on RTOG 0912 with definitive radiation (6,600 cGy and 5,940 cGy in 33
fractions delivered to her high- and low-risk regions, respectively). See the color wash figures in
the axial, coronal, and sagittal planes. The DVH curves shown in the upper-right panel show the
spinal cord (yellow curve) and right and left parotid glands (blue and brown curves, respectively).
The patient has done well with no evidence of local-regional disease recurrence, but did develop
biopsy-proven metastatic disease in her lungs and left lower extremity (adductor muscles, lymph
nodes, and skin) in May 2014 which has been treated with stereotactic body radiation therapy,
cryoablation, and surgery. She remains PS 0 and has not received systemic chemotherapy as of
July 2015.
Organs at Risk Contouring and Dose Constraints
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Contouring the organs at risk (OARs) for H&N cancer patients can be
very involved and time consuming. Oftentimes, contouring 20 to 30
OARs as well as 3 to 9 target volumes (GTV, CTV and/or PTVs) is
required. These GTVs and CTVs can be in close proximity to
radiosensitive structures (e.g., spinal cord, brachial plexus, optic
structures, and salivary glands) great care must be taken in contouring
and planning as these structures are likely adjacent to steep dose
gradients. Often a specified margin is placed on these OARs to develop a
planning organ at risk volume (PRV). CTV expansions do not include
bone, air, or adjacent organs unless they are involved. Further, PTV
expansions of 5 mm are utilized for patients undergoing cone beam CT
scan (CBCT) for patient setup based on studies of our immobilization
system (31), and 2 to 3 mm for Brainlab ExacTrac. There are excellent
atlases as well as anatomy books that can help with contouring of the
organs (32–36) as well as targets (16,18). The current dose constraints
that are utilized for H&N cancer planning at Mayo Clinic are outlined in
Table 28.3.
TABLE 28.3 Mayo Clinic H&N Cancer Normal Tissue Dose

Constraints for Standard Fractionation Adjuvant or Definitive
Radiation Therapy
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Dosimetric Considerations
Clearly defined nomenclature is critical to understanding dose
constraints and goals of treatment planning. Dosimetrists understand
that good plans are often a trade-off between target coverage and
protection of normal structures. Figure 28.3 illustrates the nomenclature
used in Tables 28.3 and 28.4 for defining dose volume histogram (DVH)
metrics. Planning priorities are requested where the physician requests a
priority of 1, 2, 3, or “report” after careful contouring and discussion
with the patient in terms of goals of therapy and the risks from the
treatment. These priorities are designed to balance the doses to the
targets and to the critical normal structures like the salivary glands,
spinal cord, and optic structures. Finally, a treatment plan is a
combination of evaluation of the isodose curves and DVH metrics while
taking into account target coverage and what was achievable on OARs.
One can also “report” doses to structures that might not have strict or
well-understood dose constraints like the thyroid gland, mastoids, or the
semicircular canals. The normal tissue constraints utilized come from a
combination of clinical experience, the Quantitative Analyses of Normal
Tissue Effect in the Clinic (QUANTEC) supplement, and prior and
ongoing RTOG studies (37). See Table 28.3.
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Figure 28.3 Dose versus volume nomenclature.
Table 28.4 describes the end point dictionary utilized for this clear
nomenclature. Both absolute and relative values for dose and volume are
used according to the issue addressed by the constraint. The
nomenclature defines both input and output units. Output units are
enclosed in square brackets. Limits on high doses are typically given a
higher priority for the minimum dose to the hottest 0.03 cc subvolume
of structure (D0.03 cc[Gy]) than for the maximum dose to any single
pixel in the structure (Max[Gy]). Similarly, keeping a subvolume of a
structure less than 0.1 cc receiving 54 Gy or more, for example in the
optic nerve (V54 Gy <0.1 cc), is also more valuable than the Max[Gy]
dose. In addition to monitoring volumes receiving a specified dose or
more (e.g., PTV:V95%[%], percentage of PTV volume receiving 95% of
the prescribed dose or more), we track the volume of target that is
underdosed. For example CTV:CV95%[cc] is the absolute volume of CTV
that received 95% of the prescribed dose or less.
TABLE 28.4 End Point Dictionary
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Physics Challenges
Treatment planning is a negotiation with what is possible. It is typically
not possible to meet all constraints for target coverage and for normal
tissue sparing, since these structures are often adjacent or overlapping.
Planning optimization can be made more efficient, quickly achieving
treatment plans that reflect overall planning objectives, through use of
dose sculpting structures in addition to constraints on normal and target
tissues alone.
For targets, a planning volume or “IMRT_PTV” is created for each PTV
dose level (e.g., IMRT_PTV5400, IMRT_PTV6300, IMRT_PTV7000) to
reflect physician preferences for dose compromises to coverage of the
PTV to spare OARs. Each volume is cropped away from the body surface
by 3 mm to reduce skin dose. High dose volumes are subtracted out of
lower dose volumes with a 1-mm margin. If these structures overlap
normal structures that are to be spared with a higher priority than the
target (e.g. brainstem, optic nerve, or brachial plexus), they are cropped
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out of the planning volume with a 1- to 3-mm margin. A dose limiting
annulus (DLA) is created for each IMRT_PTV to use in the optimizer to
drive the prescribed isodoses to conform to the PTV. Figure 28.4
illustrates creation of the DLAs, as 1- to 2-cm thick shells around their
respective IMRT_PTV with 1-mm gap.
Figure 28.4 High- and low-dose limiting annulus (DLA).
Buffer structures are created around critical normal structures control

dose gradients. Figure 28.5 illustrates a buffer around the spinal cord
and brainstem. The beam arrangement includes three VMAT arc beams.
Collimator angles are ±30 degrees and 90 degrees, with X jaws
≤22 cm. During optimization:
• Max and Min doses are set on IMRT PTVs; PTVs are used for plan
evaluation only
• Max dose are set on DLAs corresponding to IMRT_PTV min doses, to
drive conformality
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• Set max dose to cord ∼4,000 cGy as needed. During optimization, push
down volume at matching dose (e.g., V40 Gy[%] in buffer to soften the
dose gradient near the cord and push the 4,000 cGy line away from the
cord/brainstem)
• Push low- and intermediate-dose levels to lower parotid mean doses
• Push high/intermediate dose out of brain
• Push low- and intermediate-dose level on larynx, esophagus, and
constrictors as needed.
• Monitor DVH prescription constraints and add other constraints as
needed.
Figure 28.6 illustrates a dose distribution resulting from the use of this
approach. The dose distribution shows the 7,000 cGy (yellow isodose
line) covering the PTV_7000 while the 5,940 cGy (blue isodose line)
covers the PTV_5940. Treatment plans are typically produced within 1 to
2 hours by skilled planners. Prior to treatment, the plans are delivered to
a phantom (or other devices) to ensure accurate delivery of plan to a
patient.
Figure 28.5 Cord/brainstem buffer.
IMRT quality assurance (QA) measurements are carried out for each
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plan prior to treatment, to demonstrate the system produces the
expected absolute dose and dose distribution within acceptable limits.
There is a broad range of devices used in clinical practice to carry out
IMRT QA. Typically the dose distribution is measured in one or more flat
planes or in a curved plane embedded in a phantom. Typically,
measurements are carried out with the beams irradiating the array at the
treatment angles or a single angle. Measured doses are compared to
doses predicted by the treatment planning system for the measurement
plane, examining dose profiles, the fraction of measurement points
passing a gamma test, or both. Measurement devices typically use diode
or ionization chamber arrays, and radiochromic or radiographic film.
Some devices additionally use a single point ionization chamber for
assessment of absolute dose. For planar devices, the user may select a
measurement plane that specifically checks dose gradients near to
critical structures, for example, a sagittal plane to check regions near the
cord, brainstem, and larynx.
Figure 28.6 Dose distribution.
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IMRT and VMAT utilize dynamic modification of several parameters
(multileaf collimator, collimator, dose rate, gantry angle, etc.) during
irradiation. Disagreement of measured and predicted doses may result
from improper behavior of these components. In addition, other factors
contribute to disagreement. Positioning errors (1 to 2 mm) are common.
In addition, steep dose gradients perpendicular to the measurement
planes can result in substantial differences in measured dose as a result
of small (≤1 mm) errors in positioning of the device with respect to the
gradient.
Response of measurement devices may vary with angle of irradiation.
If the couch is not included in the verification plan then attenuation may
result in systematic errors. Calibration of the devices may vary over
time. Random, spatially varying errors in the dose response of the
detector range from 0.5% to 5%, depending on the type of detector used.
Treatment Delivery Including IGRT and ART

The delivery of radiation therapy is a key component to successful
treatment. A plan has to do more than “look good on paper”; it must be
deliverable. If a patient is unable to lay still due to a difficult setup or an
uncomfortable immobilization device, the treatment might not be
successful. Great care is taken in simulation for this reason. Our
institutional practice for H&N cancer is to perform two simulations. At
the first simulation, the 3- or 5-point thermoplastic mask (ORFIT
Industries, Jericho, NY) with either a bite block (Precise Bite, CIVCO
Medical Solutions, Coralville, IA), mandibular fluoride carrier or
maxillary and mandibular fluoride carriers, oral sponges and/or
customized oral stents, as appropriate, is fabricated. A standard H&N
rest is customized using a Klarity mold (Klarity Medical Products,
Newark, OH). The arms are at the patient sides with the hands holding a
ring over the abdomen. The chin is extended for all cases with the
exception of nasal cavity and paranasal sinus cancers. The patient then
returns after a minimum of 2 hours for the CT simulation, which may be
done with IV contrast. This allows the mask to cure and more closely
replicates setting the patient up for treatment each day. This has
minimized our need for re-simulation due to patient factors like the
mask feeling too tight or the interfraction flexion of the head, neck, and
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shoulders changing from simulation to treatment. To avoid dose errors
and enhanced skin dose resulting from scatter, immobilization devices
should be minimally attenuating, and not introduce significant dose
errors if the immobilization system is mistakenly omitted from the
treatment plan. The delivery of radiation therapy is image guided as
discussed below. We do not routinely utilize ART, but do consider it on a
case-by-case basis as discussed below.
IGRT is an evolving area due to improved computing capabilities and
advances in technology. For example, CBCTs can be obtained in
treatment position on the linear accelerator and a match with 6 degrees
of freedom (6-DOF) can be obtained in just 1 to 2 minutes. Our
institutional experience has shown this to be more accurate than 3-DOF
and has been rapidly adopted as our standard (31). We continue to use
Brainlab ExacTrac (BrainLab, Feldkirchen, Germany) for small-field
nasal cavity and paranasal sinus cases. On board daily imaging (OBI) is
also a quite reasonable approach for aligning the bony anatomy; but
very little soft tissue anatomy can be visualized and/or utilized. For
large fields, we perform OBI to align the patient prior to CBCTs. If tumor
size or shape changes or other systematic changes occur (weight loss or
change in size, shape and/or location of OARs) then no IGRT technique
can account for this and one might need to adapt or change the original
treatment plan.
ART is evolving into its own field as well. We counsel patients not to
swallow during simulation and radiation therapy. If the patient has had
significant tumor shrinkage or weight loss, the original plan may no
longer be covering the intended treatment volume (38). Alternatively,
the OARs might be receiving more dose than intended. For example, it
has been described that the parotid can shift medially into the high dose
volumes and receive more dose than intended, which would abolish the
primary reason for IMRT (39). Knowing when and how to replan a
patient is still an area of active research and no standard has been
developed. How to accumulate the doses across the targets and OARs is
a challenge. We often do not know when the volume change occurred.
We do not precisely know how much dose the target or OARs have
received. We do not know if it will make a clinically meaningful
difference in outcomes to replan (40,41). How this time- and labor-
intensive replanning can be incorporated into a safe, efficient, and cost-
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effective workflow is yet to be determined. Many questions remain to be
answered. The radiation oncology community is poised to answer these
questions to improve outcomes of radiation therapy.
NOVEL RADIATION THERAPY AND THE FUTURE OF H&N

CANCER TREATMENTS
In the last few years, charged particle radiation therapy has become an
accepted and, some would argue, the preferred treatment for
appropriately selected H&N cancers. This has been made possible by the
advent of spot scanning proton and carbon ion radiation therapy, and
thereby intensity-modulated charged particle therapy (IMCPT). Intensity-
modulated proton therapy (IMPT), in particular multi-field optimized
(MFO) IMPT, allows the sculpting of the radiation dose around critical
structures near the target area and good conformality to the target (42).
Figure 28.7 compares an IMRT plan to an MFO-IMPT plan for a H&N
cancer treated primarily with radiation therapy including bilateral
cervical lymph nodes. The conformality of the 7,000 cGy(RBE) dose
level to the target is very similar, but there is a distinct difference in the
doses below 5,000 cGy(RBE), with a clear advantage to the proton plan.
The advantage of proton therapy, and in particular MFO-IMPT, does
not come without a cost. There are three key points that are of particular
importance in H&N IMPT.
First is the robustness of the plan to positional and range errors. In
conventional IMRT planning, a PTV structure is created by adding an
appropriate margin to the CTV. The dose to the PTV is, in general, an
adequate surrogate of the CTV when positional uncertainties are
considered. In proton therapy, the PTV concept no longer holds and this
is especially true for H&N cancer treatments due to the large anatomical
heterogeneities, that is many bone-air-tissue interfaces. Some institutions
have therefore dropped the PTV nomenclature and instead use
optimization target volumes (OTVs) and directly evaluate the CTV (and
critical structures) under positional and range errors. It is possible that
two IMPT plans give very similar dose distributions, but under
robustness conditions one plan is severely degraded while the other only
has minor perturbations. When evaluating robustness, it is important
that the CTV does not encompass an air cavity as it is difficult to
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robustly cover air.
They second key point is anatomical changes during the course of
therapy. It is important for a new center treating H&N cancer patients
with IMPT to obtain a weekly CT scan in the treatment position and
recast the plan on the new CT. Not only would target coverage be
compromised if the volumes change, but a critical structure that was
previously being spared may now be receiving very high doses. These
changes may have been insignificant in an IMRT plan, but have the
potential to be devastating in the proton setting.
The last key point is to understand the limitation of the
immobilization system that is being used and properly work around
those limitations. For example, how does the neck flexion change on a
daily basis; are the shoulders in a reproducible position; or does the
chin/mandible position change throughout the course of treatment.
Minimizing these issues is the first step, but also field arrangements can
be chosen that would reduce the impact of these uncertainties.
Figure 28.7 Comparison of IMRT (left) and IMPT (right) 7,000 cGy(RBE) plan for a definitive
bilateral H&N cancer patient. Note the distinct difference in the doses below 5,000 cGy (RBE).
Finally, in this era of targeted agents and immunotherapies, the future

of H&N cancer treatments is bright. Cetuximab added to radiation
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therapy was a success (43). HPV-related malignancies likely have a
better prognosis in never smokers and the different molecular
mechanisms that underlie this difference could be further exploited.
Similarly, the non–HPV-related malignancies might also have different
molecular signatures that could be targeted (44,45). Various
immunotherapies are being explored for H&N cancers including the
following: monoclonal antibody therapies, cytokine therapies, cancer
vaccines, adoptive T-cell immunotherapies, and immunologic targeting
of stem cells (46). Continued understanding and exploration of these
molecular mechanisms and immune responses will play a crucial role in
the future of H&N cancer radiation therapy.
ACKNOWLEDGMENTS
We would like to acknowledge Marlene Huston for assistance with manuscript
preparation.
KEY POINTS
• H&N cancer represents a diverse collection of tumor sites and
histologies. In addition to a highly functional multidisciplinary team,
mastery of anatomy, patterns of spread, and tumor recurrence are
needed to optimize patient outcomes.
• Careful treatment simulation, planning, and delivery are essential
for treatment success.
• Proton beam therapy, in particular IMPT, and carbon ion therapy
are emerging technologies which can further reduce dose to normal
tissues and increase dose to target volumes.
QUESTIONS
1. According to SEER data, the incidence of which type of H&N
cancer is increasing when comparing a 1970 cohort to a 2000
cohort of patients?
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A. Larynx cancer
B. HPV-related oropharyngeal cancer
C. Oral cavity cancer
D. Hypopharynx cancer
2. Which of the following is the most appropriate adjustment of CTV
expansion in a 46-year-old never smoking male with an HPV-
related base of tongue cancer, given the favorable prognosis?
A. Decrease
B. None
C. Increase
3. Which of the following volumes is not used in proton beam
therapy treatment planning?
A. GTV
B. CTV
C. PTV
D. OTV
ANSWERS
1. B The incidence is increasing for HPV-related oropharyngeal
cancers.
2. B There are ongoing studies looking at various aspects of
dose de-escalation to reduce toxicity, but none are
decreasing the margins.
3. C PTV is not used in proton beam therapy treatment
planning due to range uncertainties and beam path tissue
inhomogeneity.
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10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and
survival of patients with oropharyngeal cancer. N Engl J Med.
2010;363(1):24–35.
11. Chera BS, Amdur RJ, Morris CG, et al. T1N0 to T2N0 squamous cell
carcinoma of the glottic larynx treated with definitive radiotherapy.
12. Trotti A, 3rd, Zhang Q, Bentzen SM, et al. Randomized trial of
hyperfractionation versus conventional fractionation in T2
squamous cell carcinoma of the vocal cord (RTOG 9512). Int J
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13. Gomez D, Cahlon O, Mechalakos J, et al. An investigation of
intensity-modulated radiation therapy versus conventional two-
dimensional and 3D-conformal radiation therapy for early stage
larynx cancer. Radiat Oncol. 2010;5:74.
14. Zumsteg ZS, Riaz N, Jaffery S, et al. Carotid sparing intensity-
modulated radiation therapy achieves comparable locoregional
control to conventional radiotherapy in T1–2N0 laryngeal
carcinoma. Oral Oncol. 2015;51(7):716–723.
15. Ratko TA, Douglas GW, de Souza JA, et al. Radiotherapy Treatments
for Head and Neck Cancer Update. Comparative Effectiveness Review
No. 144. (Prepared by Blue Cross and Blue Shield Association Evidence-
based Practice Center under Contract No. 290–2007–10058.) AHRQ
Publication No. 15-EHC001-EF. Rockville, MD: Agency for Healthcare
Research and Quality; 2014.
http://www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Accessed July, 2015.
16. Eisbruch A, Foote RL, O’Sullivan B, et al. Intensity-modulated
radiation therapy for head and neck cancer: emphasis on the
selection and delineation of the targets. Semin Radiat Oncol.
2002;12(3):238–249.
17. Clifford Chao KS, Tony W, Tim M. Practical Essentials of Intensity
Modulated Radiation Therapy. 3rd ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2013.
18. Gregoire V, Ang K, Budach W, et al. Delineation of the neck node
levels for head and neck tumors: a 2013 update. DAHANCA,
EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus
guidelines. Radiother Oncol. 2014;110(1):172–181.
19. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally
advanced head and neck cancers: a comparative analysis of
concurrent postoperative radiation plus chemotherapy trials of the
EORTC (#22931) and RTOG (# 9501). Head Neck.
2005;27(10):843–850.
20. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk
features and time factors of surgery plus radiotherapy in advanced
head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001; 51(3):571–
578.
21. Meadows KM, Amdur RJ, Morris CG, et al. External beam
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radiotherapy for differentiated thyroid cancer. Am J Otolaryngol.
2006; 27(1):24–28.
22. Schwartz DL, Lobo MJ, Ang KK, et al. Postoperative external beam
radiotherapy for differentiated thyroid cancer: outcomes and
morbidity with conformal treatment. Int J Radiat Oncol Biol Phys.
2009; 74(4):1083–1091.
23. Terezakis SA, Lee KS, Ghossein RA, et al. Role of external beam
radiotherapy in patients with advanced or recurrent nonanaplastic
thyroid cancer: Memorial Sloan-kettering Cancer Center experience.
24. Smallridge RC, Ain KB, Asa SL, et al. American thyroid association
guidelines for management of patients with anaplastic thyroid
cancer. Thyroid. 2012;22(11):1104–1139.
25. NCCN. Clinical Practice Guidelines in Oncology: Thyroid Carcinoma,
Version 1.2015.
http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf.
2015.
26. Wells SA, Jr, Asa SL, Dralle H, et al. Revised American Thyroid
Association guidelines for the management of medullary thyroid
carcinoma. Thyroid. 2015;25(6):567–610.
27. Urbano TG, Clark CH, Hansen VN, et al. Intensity Modulated
Radiotherapy (IMRT) in locally advanced thyroid cancer: acute
toxicity results of a phase I study. Radiother Oncol. 2007;85(1):58–
63.
28. Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in
locoregionally confined anaplastic thyroid carcinoma: a single-
institution experience using aggressive multimodal therapy. Thyroid.
2011;21(1):25–30.
29. Chen J, Tward JD, Shrieve DC, et al. Surgery and radiotherapy
improves survival in patients with anaplastic thyroid carcinoma:
analysis of the surveillance, epidemiology, and end results 1983–
2002. Am J Clin Oncol. 2008;31(5):460–464.
30. Isham CR, Bossou AR, Negron V, et al. Pazopanib enhances
paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer.
Sci Transl Med. 2013;5(166):166ra163.
31. Courneyea L, Mullins J, Howard M, et al. Positioning
reproducibility with and without rotational corrections for 2 head
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and neck immobilization systems. Pract Radiat Oncol. 2015; pii:
S1879-8500(15)00170-8.
32. Christianen ME, Langendijk JA, Westerlaan HE, et al. Delineation of
organs at risk involved in swallowing for radiotherapy treatment
planning. Radiother Oncol. 2011;101(3):394–402.
33. Hall WH, Guiou M, Lee NY, et al. Development and validation of a
standardized method for contouring the brachial plexus: preliminary
dosimetric analysis among patients treated with IMRT for head-and-
neck cancer. Int J Radiat Oncol Biol Phys. 2008;72(5):1362–1367.
34. Yi SK, Hall WH, Mathai M, et al. Validating the RTOG-endorsed
brachial plexus contouring atlas: an evaluation of reproducibility
among patients treated by intensity-modulated radiotherapy for
head-and-neck cancer. Int J Radiat Oncol Biol Phys.
2012;82(3):1060–1064.
35. van de Water TA, Bijl HP, Westerlaan HE, et al. Delineation
guidelines for organs at risk involved in radiation-induced salivary
dysfunction and xerostomia. Radiother Oncol. 2009;93(3):545–552.
36. A.J. Macdonald ME. Diagnostic and Surgical Imaging Anatomy, Brain,
Head and Neck, and Spine. 2nd ed. Salt Lake City, UT: Amirsys;
2009.
37. Marks LB, Yorke ED, Jackson A, et al. The use of normal tissue
complication probability (NTCP) models in the clinic. Int J Radiat
Oncol Biol Phys. 2010;76(30):S10–S19.
38. Schwartz DL, Dong L. Adaptive radiation therapy for head and neck
cancer-can an old goal evolve into a new standard? J Oncol.
2011;2011. pii: 690595.
39. Jensen AD, Nill S, Huber PE, et al. A clinical concept for
interfractional adaptive radiation therapy in the treatment of head
and neck cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):590–596.
40. Chen AM, Daly ME, Cui J, et al. Clinical outcomes among patients
with head and neck cancer treated by intensity-modulated
radiotherapy with and without adaptive replanning. Head Neck.
2014; 36(11):1541–1546.
41. Capelle L, Mackenzie M, Field C, et al. Adaptive radiotherapy using
helical tomotherapy for head and neck cancer in definitive and
postoperative settings: initial results. Clin Oncol (R Coll Radiol).
2012;24(3):208–215.
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42. Frank SJ, Cox JD, Gillin M, et al. Multifield optimization intensity
modulated proton therapy for head and neck tumors: a translation
to practice. Int J Radiat Oncol Biol Phys. 2014;89(4):846–853.
43. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab
for locoregionally advanced head and neck cancer: 5-year survival
data from a phase 3 randomised trial, and relation between
cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–
28.
44. Sepiashvili L, Bruce JP, Huang SH, et al. Novel insights into head
and neck cancer using next-generation “omic” technologies. Cancer
Res. 2015;75(3):480–486.
45. Du Y, Peyser ND, Grandis JR. Integration of molecular targeted
therapy with radiation in head and neck cancer. Pharmacol Ther.
2014;142(1):88–98.
46. Li Q, Prince ME, Moyer JS. Immunotherapy for head and neck
squamous cell carcinoma. Oral Oncol. 2015;51(4):299–304.
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29 Cancers of the Skin, Including
Mycosis Fungoides
Aditya N. Halthore, Kenneth R. Stevens Jr., James C. L.

Chow, Zhe (Jay) Chen, Alexander Sun, and Jonathan P. S.
Knisely
INTRODUCTION
The superiority of and justification for radiotherapy for cancers of the
skin derives from its ability to cure while preserving normal tissues,
thereby achieving both aesthetic and functional outcomes. To achieve
such an outcome, radiation therapy planning and implementation must
be tailored to the anatomic site and specific tumor characteristics, any
previous treatment, along with some consideration of the patient’s age
and performance status.
Contemporary radiotherapy treatment for skin cancer can be delivered
with superficial or orthovoltage radiotherapy, electron beam therapy, or
with isotope or electronic brachytherapy. Not all centers will have every
radiation treatment modality that may be potentially useful for a given
clinical indication. Therefore, critical and careful use of the available
treatment modalities is mandatory to assure that optimal treatment
results will be achieved. Indeed, good judgment may indicate that
certain patients should be referred to alternate centers where specialized
equipment or techniques and the expertise to employ them deftly may
be available.
Treatment planning and implementation are usually straightforward,
because the cancer can be directly visualized, palpated, and observed
directly during each treatment setup. The treatment volume is frequently
little more than a superficial thin slab requiring a single direct beam
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collimated by a simple field-defining device placed on or near the skin.
However, anatomical complexities and the need for individualization of
treatment may make these cases among the most complex encountered
by many centers.
The steps in planning irradiation for skin cancer are as follows:
1. Define the extent and size of the cancer (staging).

2. Determine what radiotherapy treatment technique may best address
the disease that needs to be treated.
3. Prescribe the treatment, including beam type, energy, daily fraction
size, and total dose, including, when appropriate, specification of
patient immobilization devices, beam filters, bolus, attenuator, and
shielding devices.
4. Design and create any necessary field-defining device, accounting for
margins.
5. Design and create device for blocking exit beam when appropriate.
6. Supervise and approve initial irradiation setup.
7. Document setup with photographs of the gross lesion, lesion with
shields in place, and with both machine and shields in place.
GENERAL PRINCIPLES
Staging and Target Volume Determination
It is generally accepted that cancer staging assists in selection of
therapies and provides prognostic information. In addition, for skin
cancer, accurate staging can assist with radiotherapy treatment planning,
augmenting its importance. The Union for International Cancer Control
and the American Joint Commission on Cancer have published staging
systems for squamous and basal cell carcinomas, Merkel cell carcinoma,
melanoma, and cutaneous T-cell lymphoma (1).
There are anatomic and histopathologic high-risk features for staging
of basal and squamous cancers that can be of value in assessing patients
for possible radiotherapeutic treatment. For example, in differentiating
between T1 and T2 tumors, high-risk histopathologic features should be
assessed, including differentiation, thickness and depth of invasion, and
whether perineural infiltration is seen. Also important is anatomic
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location, with tumors arising on the ear or lip deemed to be high-risk
features.
There is also a designated TNM staging system for carcinomas of the
eyelid that reflects the unique anatomic features and importance of the
eyelid and ocular adnexae in protecting the eye. Knowledge of these
staging systems can assist with advocating for patients receiving
appropriate radiation therapy and in optimizing radiotherapy treatment
parameters for these patients.
Despite the fact that skin cancers can be visualized and palpated
before planning treatment and on each day at treatment setup,
geographic miss is the most common cause of failure. Most of these
cancers arise on the face or neck, are detected early, grow slowly, and
present with a small tumor volume. The gross dimensions are usually
readily determined by visual examination with adequate lighting to aid
inspection for edema and by palpation to determine the extent of
induration and fixation. Visual magnification is often useful to define the
peripheral-most margin of the gross tumor. Occult extension of cancer
beyond the gross margins is generally limited to a few millimeters, but
this varies.
In certain circumstances, special imaging may be extraordinarily
valuable in assuring the high-dose volume completely covers the skin
cancer. This may be useful for cancers with clinically indistinct margins
or high histologic grade, for sclerosing basal cell carcinomas, and for
those cancers classified as recurrences following surgery or irradiation.
Patients with signs or symptoms of perineural involvement or regional
nodal metastases, fixity to bone, as well as lesions greater than 5 cm in
diameter may also benefit from specialized imaging.
It should be remembered that basal cell carcinomas arising on skin
closely overlying bone may spread along the periosteum. Tumors in the
medial canthal region, overlying the cranial vault, the malar eminences,
and the upper half of the nose are examples of such sites. Tumors arising
at or near periauricular and nasomalar embryonic fusion planes may
have occult deep extension, also meriting careful radiologic workup to
accurately determine the target volume extent. These diagnostic
evaluations are fortunately not required for the majority of skin
carcinomas.
The deep margin of the tumor should be encompassed by at least the
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90% isodose surface. Field margins for <2 cm primary tumors should be
1 to 1.5 cm; for tumors >2 cm, field margins should be 1.5 to 2 cm (2).
Caution should be exercised in planning and treating skin cancers over
the calvarium to minimize, when feasible, dose to cortical brain. The use
of CT scan-based treatment planning for small skin lesions may
introduce more errors than if a simpler technique of using a
transparency to determine the field size and shape is used. However, for
larger, more complex lesions that are deeply invading and are in
contiguity to critical structures, CT simulation, with appropriate use of
multimodal image fusion has improved the ability to accurately plan
treatments that will achieve tumor control and normal-tissue sparing.
RADIATION DELIVERY MODALITIES

Commissioning and Calibration
For all radiotherapy equipment, careful commissioning, calibration, and
appropriately detailed and frequent quality assurance are mandatory to
avoid underdosing or overdosing patients. Measurement and review of
each treatment machine’s central axis percent depth dose and cross-
sectional isodose curves, based on the type of radiation, energy, and
field size should be routine. A lack of familiarity with routine,
manufacturer-specified usage guidelines, and therapeutic directives that
are developed for the safe use of the equipment is neither in the best
interest of the patient nor of the responsible physician, physicists, and
therapy staff.
Superficial and Orthovoltage Therapy

Superficial and orthovoltage therapy refer to using low-energy photon
beams in the range of 50 to 150 kVp for surface lesions and 150 to 500
kVp for lesions deep to the skin. Although Grenz ray (<20 kVp) and
contact therapy (40 to 50 kVp) are no longer used for invasive skin
cancer due to their low penetration depth, superficial and orthovoltage
therapy are still popular because of their simple and effective treatment
administration. Superficial and orthovoltage therapy employ kilovoltage
(kV) x-ray treatment units that are less complicated and easier to set up
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than electron therapy delivered from a linear accelerator. Since kV
photon beams are used to treat superficial skin carcinomas and keloids
at the skin surface, 3-dimensional (3D) treatment planning with image
modalities such as computed tomography or magnetic resonance is
required only when the extent of deep tumor infiltration and invasion
needs to be assessed and accounted for.
Skin irradiation with superficial or orthovoltage therapy therefore
commonly only needs a clinical markup followed by a beam-on time or
monitor unit calculation at the first treatment fraction. Regarding
dosimetric characteristics, though electron beams have a sharper falloff
of depth dose to spare critical tissue deeper than the lesion, small field,
low-energy photon beams have a sharper penumbra and superior
flatness, and are therefore more suitable to treat small lesions. However,
low-energy photon beams will deliver a higher dose to bone than to soft
tissues at the same depth (3).
Superficial and Orthovoltage Treatment Units

Nowadays, most kV x-ray treatment units can produce low-energy
photon beams in both the superficial and orthovoltage range. Superficial
therapy is commonly delivered with circular collimators between 2 and
10 cm in diameter at a source-to-surface distance (SSD) of 20 cm and
orthovoltage therapy at an SSD of 50 cm with square applicators ranging
from 4 × 4 cm2 to 10 × 10 cm2. Some square applicators are closed at
the bottom using a piece of flat polymethyl methacrylate plate. Such
closed applicators help to maintain a nonvaried treatment distance from
the patient’s skin.
A typical kV x-ray unit (Fig. 29.1) contains a standalone transformer,
control console, treatment couch, and a floor-mounted tube stand, and
comes with the aforementioned circular and square collimators. The
treatment head of the unit contains the x-ray tube, primary collimator,
filter, transmission ionization chamber, and the applicator (Fig. 29.2).
The filters, made of copper or aluminum, remove low-energy photons
and are designed and specified for different photon beam energies,
applicators, and specific (e.g., 20 and 50 cm) SSDs. More recent
treatment unit models have an internal transmission ionization chamber
linked to the control console. The application of monitor units instead of
beam-on time avoids error due to the shutter effect in dose delivery.
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Figure 29.1 An example of a modern orthovoltage x-ray unit.
Relative Exposure and Backscatter Factors

In superficial and orthovoltage therapy of skin cancer, the irradiated
area may be tailored by a lead cutout placed on the skin in conjunction
with an appropriately sized circular or square applicator. The collimator
selected should be approximately 1 cm larger (circumferentially) than
the maximal size of the cutout, and the lead should, of course, be large
enough that any inadvertent patient motion after a given day’s setup has
been achieved will not result in unwanted exposure of normal tissue.
In calculating the monitor units from the daily prescription dose,
relative exposure and backscatter factors (BSFs) are selected based on
variations in applicator and cutout size for the treatment. Relative
exposure factor is the dose ratio of an applicator to a reference
applicator measured using the same SSD. The reference circular
applicator has a diameter of 5 cm while the reference square applicator
has a dimension of 10 × 10 cm2. Since absolute dose calibrations are
carried out using the reference circular and square applicators, the
relative exposure factor reflects the change in dose dependent on
applicator selection. The relative exposure factor varies with the
applicator size and photon beam energy, and increases as applicator size
increases.
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Figure 29.2 Circular collimators and square applicators of varying sizes for the orthovoltage unit
shown in Figure 29.1 are shown.
BSF is a ratio of the dose at the depth of maximum dose in water to

that in air without water. A special case of the tissue–air ratio is when
the depth of the ratio is equal to the depth of maximum dose. When the
applicator type and size are selected for skin therapy with lesion depth
equaling zero, the BSF for the corresponding applicator reflects the
percentage change in dose between the surface of the skin compared to
the dose in air. BSF is normally larger than 1 due to the contribution of
electron backscatter in water, and the factor depends on the field size
and photon beam energy. For skin irradiation, since the lesion is
outlined by a cutout made of lead, the BSF is a function of the field size
(cutout) covering the lesion with a margin. In monitor unit calculations,
BSF varies with the field size and photon beam energy delivered through
the applicator.
Stand-In/Off and Attenuator Correction

For skin lesions close to the bridge or tip of the nose, the irradiated area
may be curved toward (in) or away (off) from the applicator. The SSD is
therefore decreased or increased and a correction is needed in the
monitor unit calculation based on the inverse square/cube law. From
dosimetric measurements, the output of a treatment unit is known to
vary as a function of the inverse square of the distance for the open
applicator, and inverse cube of the distance for the closed applicator.
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The radiotherapist measures the stand-in or -off distance in the clinical
markup. In the stand-in case (e.g., tip of nose), the lesion is curved in
from the bottom of the applicator. As the SSD is decreased, a correction
is needed to reduce the monitor units. Similarly, more monitor units are
needed when the lesion is curved off from the bottom of the applicator,
leading to a larger SSD in the stand-off case (e.g., bridge of nose).
When the lesion is at the bridge or tip of nose, an attenuator may be
used to correct the dose distribution due to the surface curvature. For
superficial or orthovoltage energies, the nose bridge or tip attenuator is
made of a stack of either aluminum or copper foils, with thickness of
each foil equaling 0.5 mm. Each attenuator contains five layers of
aluminum/copper foil, each cut to progressively smaller or larger areas
to compensate for the dose variation from the differences in SSD and
oblique beam entry as a result of the skin surface curvature (Fig. 29.3).
The attenuator for the tip of the nose is therefore shaped like a ziggurat,
while that for the bridge of nose is shaped similarly, like a terraced
mountain ridge.
Figure 29.3 Cross-sectional schematic of an attenuator (compensator) used for 100 kV therapy
for bridge of nose cancers. Attenuators are best suited for kV x-ray therapy and should be
avoided in electron therapy where unwanted scatter may enlarge the field.
Monitor Unit Calculation

The monitor units required for superficial or orthovoltage therapy are
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calculated by the following equation:
Absolute dose calibration to deliver 1 cGy per monitor unit is done

using the reference applicator with a specific SSD. The BSF depends on
the field size and photon beam energy while the relative output factor
depends on the size of applicator. An attenuation factor is used in the
calculation to reflect the beam attenuation when a compensator is used
in treatment. The attenuation factor used is smaller than one. Percentage
depth dose (PDD) is needed when the lesion is at a depth from the
patient’s surface. When the lesion depth is set to zero, the value of PDD
is equal to 100 in the above equation. The stand-off correction needs a
measurement of the stand-in or -off distance in the clinical markup and
then the application of the inverse square/cube law. For monitor unit
calculation, tables of BSF, relative output factor, attenuation factor and
PDD are all incorporated. The calculation is carried out by two
radiotherapists individually with the result further approved by a
medical physicist.
Electron Beam Therapy

Electron beam therapy, delivered with a linear accelerator, has become
increasingly commonly used to treat superficial skin cancers, in part
because of some of the dosimetric advantages of charged particle
therapy, and in part because many radiotherapy departments no longer
have access to superficial and orthovoltage therapy units, as older units
have broken down and have not been replaced.
Static electron beam fields are easily employed for lesions on
relatively smooth surfaces where the beam may enter orthogonal to the
skin surface. A single direct electron field is employed at a nominal SSD
of 100 cm, and provides control rates for appropriately selected lesions
that do not differ from those achieved with x-ray therapy. Electron beam
therapy can provide relatively uniform dose from the surface to a
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defined depth (up to ∼5 to 6 cm) and dose rapidly falls off to near zero
thereafter. This can be a major advantage in sparing tissues deep to the
cancer, particularly if large fields need to be irradiated.
The dose specification for treatment is commonly given at a depth that
lies at, or beyond, the distal margin of the disease; the energy chosen for
the treatment depends on the depth of the lesion to be treated. The
relative biologic effectiveness (RBE) of electrons in cancer treatment is
10% to 20% less than that of superficial or orthovoltage x-rays. This can
be simply addressed by prescribing electron beam therapy to the 90%
isodose surface (as opposed to Dmax). The therapeutic range is defined
as the depth of the 90% isodose curve, and is, in centimeters, roughly
calculated as one-fourth of the electron energy in MeV. The therapeutic
range of available electron beam energies must be considered (together
with the thickness of bolus required to bring the skin dose up to full
dose) when considering what energy (and bolus thickness) to specify in
prescribing treatment. The therapeutic range of the electron energy
chosen should reach the deep edge of the planning target volume.
Because the dose falls off so rapidly for electron beam therapy (Fig.
29.4), the guiding principle is to select the next-higher electron energy if
there is concern that the 90% isodose surface is not covering the deep
edge of the planning target volume. The approximate range of the depth
of the 90% isodose line for electron beam energies is shown in Table
29.1. The depth and shape of the isodose lines should be determined for
each treatment machine at various energies and field sizes.
Figure 29.4 Isodose curves for 6-, 9-, and 12-MeV electrons, 8 × 8-cm field, showing greater skin
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sparing for lower-energy electron beams.
TABLE 29.1 Range of Depth of 90% Isodose Lines of Electron

Beams
Electron beam depth doses have extremely important changes that are
dependent on both field size and on treatment energy. The loss of lateral
electronic equilibrium in smaller electron beam fields can significantly
affect central axis dose, and this will lead to the 90% isodose surface
shifting to a shallower depth and an increased level of dose deposition in
the skin (4). It is very important to check and double-check small
electron field output factors. Microchambers, thermoluminescent
dosimeters (TLDs), or film dosimetry should be used to confirm the
proper output factor. The output factor for radiation fields of 2 to 3 cm
in diameter are ∼0.90 cGy/MU at 100 cm (SSD). Significant dosage
errors can occur if the output factor is not correct. Output factors that
are significantly greater or less than 0.90 should be critically reviewed
and double-checked.
For oblique beam entry, the effects on dose deposition can be quite
complex. Increasing degrees of obliquity beyond ∼20 degrees are
associated with a shallower Dmax and significant changes to the depth–
dose curves (4). Equations to permit calculation of point doses for
oblique beam entry on irregular surfaces have been developed; Monte
Carlo techniques can also be used to better understand the effects of
beam obliquity and irregular surface contours (4–6). Misunderstanding
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and neglecting the effect of beam obliquity when calculating dose per
MU for an oblique electron beam with an irregular field would lead to a
significant dosimetric deviation.
Several additional particular characteristics of electron beam isodose
curves that should be remembered when considering electron beam
therapy include the lateral bulging of lower isodose curves that arises
from larger scattering angles of the electrons in tissue as they lose
energy, the lateral constriction of the higher isodose curves (greater than
80%) at energies >15 MeV, and the fact that electron beams <12 MeV
are associated with skin sparing, which requires the use of bolus
material to raise the skin dose to acceptably high levels (Table 29.1 and
Fig. 29.4). This added thickness must, of course, be included in beam
selection and in depth dose calculation.
Bolus is frequently applied directly to the skin in electron beam
therapy to increase the surface dose to near 100% and to limit the dose
delivered to deep tissues beyond the planning target volume. Superflab
(Mick Radio-Nuclear Instruments, Mt. Vernon, NY) is a well-regarded
bolus material, because it is nearly tissue equivalent, transparent, and
easy to shape. It is available in 3-, 5-, and 10-mm thickness. This bolus,
of course, blurs or masks the outline of the treatment field. For this
reason, it is helpful during the treatment setup to align the patient and
machine as for irradiation but with a gap to permit bolus placement. The
correctness of the position of the treatment field should be visually
confirmed. The bolus is then slipped into place. The minimum thickness
of bolus to achieve maximum dose at the surface varies with the energy
of the electron beam (Table 29.1). Although 5- and 10-mm thick boluses
are commonly used for 6 and 9 MeV electrons, based on the percent
depth-dose data, an 8-mm thick bolus (e.g., a combination of 5- and 3-
mm thickness) may be more appropriate. Bolus can also flatten out
irregular surfaces and reduce the effects of beam obliquity. CT treatment
planning may permit the construction of a customized 3D wax bolus that
achieves the goals of decreasing beam obliquity, decreasing dose to
tissues deep to the target, and bringing the surface dose to an adequately
high level.
Field Defining Devices, Field Shaping, and Protection from
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Exit Beam
For superficial and orthovoltage photon therapy, an applicator cone and
a lead shield of a few millimeter thickness are adequate to protect the
skin adjacent to the radiotherapy portal. Field shaping for electron beam
therapy is considerably different from photon therapy. Electron
applicators are always used to decrease the penumbra from electron
scattering in the linac head and in air, and additional customized lead or
Cerrobend field shaping devices may be placed on the applicator, as
close as possible to the patient. To decrease the dose to the patient to
below 5% beneath lead shielding, it needs to be approximately one-tenth
as thick as the practical range (Rp) of the electron beam being used
(Table 29.2). A rule of thumb for estimating the thickness of shielding of
lead in millimeter to decrease the dose to below 5% is the energy of the
beam in MeV/2.
When shielding is placed upon the patient surface, as opposed to being
mounted on the applicator, it must be constructed of multiple layers of
thin lead, thick lead cut with a saw, or molded from Cerrobend. With
such a surface shield, a zone of increased dose develops just deep to the
edge of the cutout. The magnitude of this dose increases with beam
energy. At lower energies this effect is commonly disregarded. Concern
for this effect, the need for bolus, and the ease of block construction
encourage the practice of fixing the field-defining device for the electron
beam on the end of an electron cone several centimeters from the skin.
TABLE 29.2 Minimum Cerrobend Thickness to Block 95% of

Electron Treatment Beam (10 × 10 cm Field Size)
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A sequence of steps for fabricating customized shielding for photon or
electron beam therapy of skin cancer may be adapted from these
recommendations:
1. Overlay the skin surface with a clear plastic sheet that readily
conforms to undulations of the surface.
2. Trace the field outline on the plastic.
3. Overlay the lead with the plastic. Then, with the point of a knife or
awl, punch the outline through the plastic onto the surface of the lead.
Another technique is to draw the field outline on the skin with a
ballpoint pen. Overlay clear adhesive tape on the skin. The tape will
pick up the ink outline. Place the clear adhesive tape with outline on
lead sheet and proceed with the next step.
Cut out the lead sheet target field outline with a knife and smooth the
edges of the cutout. Adhesive tape placed over the cutout’s edges will
prevent any sharp edges from causing problems when the lead is shaped
to the patient’s contour. Thin lead can be shaped with the fingers. For
thicker lead or for shaping sharply undulating surfaces, such as the
medial canthus, the lead can be pressed or hammered lightly to conform
to a facial or other plaster cast created specifically for this purpose. The
hammering must not appreciably thin the lead.
Wrapping the patient’s custom tailored shielding lead with low-density
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polyethylene cling film will prevent heavy metal exposure to the
patient’s skin. Disposable gloves used for protection from exposure to
pathogens in patient care may also be used to prevent lead exposure, but
because visibility of the shielding device is compromised, this protection
may be better used only for exit beam shielding.
The protection of normal tissues from exit beam irradiation is
important to consider. A thin layer of lead will protect tissues distal to
the target from further direct irradiation. Because of the potential for
electron backscattering from the high-Z material of the shielding, a 3-
mm layer of wax, which will absorb any backscattered electrons, is often
used to cover a 1-mm lead shield. This wax will also protect the patient
from exposure to the heavy metals used to fabricate the internal
shielding. Such a device will adequately protect for energies up to 12
MeV. The final thickness of the shielding may lead to difficulty with
internal shielding placement or decreased patient tolerance of the
shielding during therapy. Care should be taken when using internal eye
shields—those made for photon therapy are inadequate for electron
beam therapy—the transmitted and scattered dose will be high enough
to produce cataracts (7,8).
Electron Arc Therapy

For treating large superficial lesions on a curved surface such as the
chest wall, electron arc therapy is an option. Electron arc therapy uses
an electron field rotating around the isocenter to provide a homogeneous
dose distribution to the target. The prediction of dose distribution is
complex as it is related to the beam energy, field size, SSD, patient
curvature, and depth of the isocenter. Since the source-to-axis setup
technique is used, an electron applicator provided by the manufacturer
for the SSD setup is not needed. The electron field for electron arc
therapy is defined by using a custom-made applicator with a rectangular
cutout. Electron arc therapy has been found to be efficient to treat large
superficial lesions of the nasal cavity; postmastectomy chest wall; and
reconstructed breast, torso, and limbs, which are difficult to irradiate
with a static electron or kV x-ray field. In this section, the electron beam
setup, dosimetry, and monitor unit calculations are discussed.
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Electron Beam Geometry and Setup
Since source-to-axis distance setup is used in electron arc therapy, the
distance between the cutout and isocenter should be large enough to
include the patient’s body. Normally, a distance of 35 cm is used with
the applicator height equal to about 15 cm. The cutout is usually made
to produce a rectangular field, for example, with physical size equal to
2.6 × 21 cm2, and is inserted at the bottom of a custom-made
applicator. This applicator is attached to the block tray holder on the
treatment head of the linear accelerator. Dosimetry calibration and
measurement are carried out using cubic and cylindrical solid water
phantoms with the accelerator gantry rotating to produce an electron
arc.
Monitor Unit Calculation

The monitor unit for electron arc therapy is calculated by the equation:
The dwell factor is defined as (9):
This factor accounts for the dosimetric variation when the static
electron beam changes to rotating status in the arc therapy. The relative
output factor is defined as the dose ratio of the electron arc cutout to the
reference 10 × 10 cm2 cutout. Measurement of the relative output factor
is performed at SSD equal to 100 cm and at a depth of reference (e.g., 2
cm for the 9 MeV electron beam) in water. This factor corrects the
single-beam dose from the absolute calibration to electron arc. The
inverse square law factor is used to correct the monitor unit with a
variation of SSD that differs from 100 cm in the electron arc delivery.
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For monitor unit calculation in electron arc therapy, the dwell factor,
relative output factor, and inverse square law factor can be determined
by measurements or Monte Carlo simulations (9).
Electronic and Radioisotope Brachytherapy

There has been recent interest in using low-energy photons in new
electronic and radioisotope brachytherapy devices and techniques.
Remote afterloading high-dose rate (HDR) brachytherapy devices were
initially used in locally irradiating intracavitary locations such as
gynecologic malignancies and breast operative sites (10). Their use
subsequently expanded to include irradiation of small superficial
cancers, including skin cancer such as Kaposi sarcoma (11). The
specialized Leipzig and Valencia applicators were developed by
investigators in Germany and Spain to facilitate brachytherapy of
superficial (e.g., cutaneous) tumor sites with these radiation sources.
HDR surface brachytherapy places an iridium-192 source in close
proximity to the target lesion using a computer-controlled remote
afterloader that houses a radioactive source that may be precisely
delivered using specialized catheters or applicators. The choice of
applicator is commonly dependent on the size and depth of the target.
Small, superficial tumors (up to 2.5 cm in diameter and 0.5 cm in
thickness) may be readily treated using vendor-specific Leipzig or
Valencia skin applicators, and applicators of even greater diameter are
commercially available; the risk of a poor cosmetic outcome may be
unacceptably high for hypofractionated regimens delivered to larger
volumes (12). Prefabricated silicone rubber sheets with parallel catheter
channels that permit a known distance between the catheters and the
skin surface may be used for more extensive skin lesions on uncovered
body parts with infiltration depth less than 1 cm, and in addition,
special, customized applicators may be prepared for complex geometries
(13).
The dosimetry of some specialized applicators may be nonuniform
because of the nonisotropic radiation dose distribution of the HDR
source and because of special geometric considerations as the radiation
is delivered to curved surfaces. Care is warranted in assuring acceptable
dosimetry for nonstandard settings; dose delivered cannot be recovered.
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The development of kV radiation sources that mimic the functionality
of the remote afterloading HDR brachytherapy devices has been
followed by vendor adaptation of the Leipzig and Valencia applicators.
These devices may be useful in treating small superficial skin cancers
that will fit well within the applicator selected and have a thickness of
less than 3 or 4 mm. Circular treatment cones of a range of sizes up to
50 mm in diameter may be used. The Valencia applicator has a
flattening filter, so although the dose rate is lower than for the Leipzig
applicator, the flattening filter does achieve its goal of greater dose
uniformity through the target volume (14). The target/source to skin
distance is 2 to 3 cm, resulting in a rapid decrease in radiation dose with
increasing depth from the cone applicator and skin surface. The percent
depth doses for a 50 keV beam at these treatment distances are
approximately 58% to 66% at 4 mm depth, and 51% to 60% at 5 mm
depth. Some treatment cones use a step filter to provide a flatter isodose
curve.
Not unexpectedly, these relatively novel radiotherapy devices harbor
the potential for misadministration and misunderstanding of directives,
but the process is amenable to standardization (15). There is limited
clinical information regarding the efficacy of these devices for treatment
of skin cancers at this time, but a significant number of patients have
been reported from Leipzig, where a complete response rate of 91% for
over 500 patients with a variety of conditions was observed (16). The
Valencia group has reported a much smaller series of patients with
nonmelanoma skin cancer and report 98% local control at 4 years (17).
There is, as yet, too little reported experience with electronic
brachytherapy to merit more than a mention here (10,18). Several
vendors have begun to market these devices, not only to radiation
oncologists, but to dermatologists as well. It may be hoped that with
appropriate case selection and careful attention to treatment-related
parameters, successful treatments will be reported in an adequately
detailed fashion to permit determination of this approach’s suitability for
continued use in treating skin cancer. Figure 29.5 shows an electronic
brachytherapy applicator and a treatment setup.
Selected Aspects of Treatment Setup
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Because the lateral radiation margins are often narrow, the importance
of effective patient immobilization and precision in cutout positioning
cannot be overemphasized. Immobilization techniques used for
irradiating head and neck cancers are used for skin cancers of the face
and neck. The surface of the treatment field should be as nearly
perpendicular to the treatment beam axis as is practical. With an
orthovoltage photon beam, dose inhomogeneities because of irregular
surface contours can usually be diminished to acceptable levels by
increasing the SSD. Lead cutout positioning and fixation are facilitated if
the shield conforms closely to the contours of the region and the tape
fixes the cutout to the patient. When the cutout can be fixed to the skin,
the treatment beam breadth should exceed that of the cutout area by
about 1 cm, minimizing the effect of patient movement. Of course, the
width of the lead must exceed that of the treatment beam. Frequent
clinical physician visualization of the treatment setup is very important
to confirm that the treatment field is properly aligned relative to the
tumor.
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Figure 29.5 An example of electronic brachytherapy using an Esteya applicator. A template
(specific for each applicator size) is placed on the patient’s lesion and the external diameter of the
applicator is drawn on the patient using the template’s open areas. The arm of the device with the
specific applicator is then placed in contact with the patient’s skin surface. (Adapted from Pons-
Llanas O, Ballester-Sánchez R, Celada-Álvarez FJ, et al. Clinical implementation of a new
electronic brachytherapy system for skin brachytherapy. J. Contemp Brachytherapy. 2015;6:417–
423.)
Fractionation Schedules
The National Comprehensive Cancer Network (NCCN) has published
recommended dose-fractionation schedules for curative treatment of skin
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cancers with orthovoltage, and have included recommendations for
prescription modifications for electron beam treatment (2). The dose-
fractionation recommendations are the same for both squamous and
basal cell carcinomas. There are recommendations for treatment of nodal
metastatic disease included in the recommendations for squamous cell
skin carcinoma. Additional orthovoltage radiotherapy prescriptions with
dose-fractionation schedules are shown in Tables 29.3 and 29.4. As
stated above, because of a difference in the RBE between photons and
electrons, the prescription for electrons should be to the 90% isodose
surface to ensure an adequate dose to the tumor.
The NCCN has also published recommendations for postsurgical
radiation therapy management of Merkel cell carcinoma (19). For
melanoma, the NCCN has not published recommendations on dose
fractionation, though they have published recommendations on the use
of radiation as an adjunct to surgical management and for palliative
treatments (20).
Clinical judgment and experience are necessary to give the appropriate
radiation dose. The total radiation dose ultimately delivered may vary
from the planned prescribed dose. The lesion at the completion of
treatment should show evidence of significant regression, and a moist
reaction and surface crusting may be present. It is important for the
radiation oncologist to closely observe the reaction of the surface of the
tumor and the surface of the surrounding normal skin, particularly
toward the end of the planned time of completion of the irradiation. The
desired radiation response may require a break in the treatments, and an
up- or down-titration in the number of planned treatments and the
ultimate total radiation dose, to achieve the desired result of tumor
control without normal tissue necrosis.
Cutaneous Basal and Squamous Cell Carcinomas

Basal and squamous cell carcinomas of the skin are most commonly
diagnosed in patients over the age of 50, are related to earlier sun
exposure, and are often optimally treated with radiation therapy. Many
patients with small tumors are not referred for consultative opinions,
and patients referred for radiation are often those that have neglected
skin cancers that are too locally advanced to be considered for attempts
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at radical resection or are recurrent after multiple ineffective local
procedures by other caregivers.
Basal cell carcinomas appear to arise in embryonic fusion plate regions
with a higher frequency than elsewhere on the face (21). Both basal and
squamous skin cancers have a linkage to a sun exposure history. One
important difference between basal and squamous cancers is that basal
cell carcinomas, though locally invasive and destructive, metastasize
extremely rarely, so that looking for metastatic disease is not generally
appropriate, though imaging to assist with local radiotherapy portal
design is often valuable. For squamous cell carcinomas, appropriate
management with surgery, radiation, or both of the primary site and of
any regional nodal metastases is critical to a good outcome.
TABLE 29.3 Recommended Orthovoltage Dose and Fractionation

Schedule
For small basal and squamous cell carcinomas of the skin, good results
have been published for superficial and orthovoltage photon therapy and
electron beam therapy. Field margins for <2 cm primary tumors should
be 1 to 1.5 cm; for tumors >2 cm, field margins should be 1.5 to 2 cm
(2). In practice, 1-cm lateral margins for photon fields applied to lesions
≤2 cm in diameter produce control rates greater than 90%, and it is
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conceivable that higher local control rates can be achieved through
meticulous attention to planning and delivering treatment. A review of
isodose curves reveals that lateral margins for fields irradiated with
electron beams should be wider compared to orthovoltage beams for
similar-sized cancers, but these margins have been less well defined. If a
lesion is <2 cm in diameter and a 1-cm margin is to be given a
minimum of 90% of Dmax, the lateral margin for the electron beam field
needs to be almost 1.5 cm. This requirement for a larger electron beam
field size can be a major disadvantage in treating lesions of the eyelids
and canthi. Generous lateral margins of 2 cm or more should be strongly
considered for larger lesions (7 to 8 cm diameter), infiltrating lesions,
and lesions at high risk for occult extension.
TABLE 29.4 Recommended Orthovoltage Dose and Fractionation

Schedule
The deep margin of the cancer should always be well-included within

the planning target volume; this may preclude use of electronic
brachytherapy or isotope brachytherapy treatment of some tumors
because of the shallow depth-dose characteristics of these low-energy
sources and the limited applicator sizes.
Perineural invasion occurs in 2% to 6% of cutaneous basal and
squamous cell carcinomas of the head and neck and is associated with
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midface location, recurrent tumors, high histologic grade, and increasing
tumor size (22). The cranial nerves most commonly involved are named
branches of the trigeminal and facial nerves. Cranial nerve involvement
may portend a worse prognosis, with tumor extension and recurrence
along the cranial nerves and metastases to adjacent lymph nodes often
also seen. Surgical resection should be considered for the primary if the
tumor is considered to be resectable, but the risk of perineural spread
beyond the excision margin should lower the threshold for definitive
adjuvant irradiation. It can sometimes be difficult to know whether
treatment portals should include both the distribution of the trigeminal
and facial nerves, but careful consideration of the location of the
primary lesion and clinical symptomatology may help refine
radiotherapy portal design.
University of Florida investigators recommend elective regional
irradiation of first-echelon lymph nodes for patients with clinical
(symptomatic) perineural invasion and for those with squamous cell
carcinoma with microscopic perineural invasion. Patients with
involvement of named branches of cranial nerves should have radiation
volumes that include the involved cranial nerve to the base of the skull
(22,23). Planning for these volumes requires careful clinical
examination, detailed CT and MRI imaging, and conformal radiation
treatment planning and delivery, for which intensity-modulated
techniques may permit normal tissue sparing to a greater degree than 3D
conformal techniques.
University of Michigan investigators have detailed the pathways of
recurrent tumor for skin squamous cell carcinomas involving the
trigeminal and facial cranial nerves (24). They identified the
auriculotemporal nerve and the greater superficial petrosal nerves as the
pathways of tumor spreading between those nerves. They recommend
that for tumors involving cranial nerve VII, the auriculotemporal nerve
and V3 are at risk; and for tumors involving V2, the greater superficial
petrosal and cranial nerve VII are at risk. They advocate that these at-
risk volumes should be included in the planning target volume when
these nerves are involved.
Cutaneous Melanoma
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Radiotherapy Indications
Surgical resection is the most common treatment of cutaneous
melanoma; primary irradiation is rarely used in the treatment of primary
melanoma, but there are well-defined roles for radiation in the
locoregional management of melanoma (25,26).
Lentigo maligna, also known as melanoma in situ (Clark Level 1, Stage
0 melanoma) or Hutchinson melanotic freckle is very well treated by
primary irradiation (25,27). Margins of 5 mm are recommended for
surgical management, but an Australian report on in vivo confocal
microscopy described subclinical tumor extending beyond 5 mm from
the lesion in most patients (28). The ability of radiotherapy fields to be
extended to cover larger margins is an advantage for this condition,
where skin flaps or skin grafts may be required to obtain adequate
wound closures, and facial cosmesis may be compromised permanently.
For resected melanomas of the head and neck, where anatomical
constraints on radical resection exist and ideal surgical margins are
difficult to obtain, adjuvant irradiation decreases locoregional
recurrences. The NCCN recommends adjuvant treatment of the primary
tumor site with radiation for selected patients with factors including, but
not limited to, deep desmoplastic melanoma with narrow margins,
extensive neurotropism, or locally recurrent disease. A wide range of
radiation dose/fractionation schedules is effective, but hypofractionated
regimens may increase the risk for long-term complications.
Radiotherapy to regional nodal basins (48 Gy in 20 fractions) or
observation after therapeutic nodal dissection significantly decreases
locoregional recurrence, though survival is not affected (29). Adjuvant
radiotherapy’s benefits must be weighed against the increased
probability of long-term skin and regional toxicities and potential
reduced quality of life.
Radiation Therapy Technique

An adjuvant radiotherapy technique was developed at the University of
Texas, M.D. Anderson Cancer Center that covered the primary site, nodal
operative site, and regional lymph nodes using shaped electron beams of
9 to 16 MeV to deliver 30 Gy in five fractions (6 Gy per fraction) over
2.5 weeks, Monday and Thursday, or Tuesday and Friday. Dose is
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calculated at Dmax. The central nervous system (brain and spinal cord)
must be spared and should be treated to a maximum of 24 Gy in four
fractions (30,31). This radiotherapy technique has also been extended to
treat metastatic nodal disease of the axilla and inguinal regions. IMRT
may be used to cover some of these same volumes as effectively with the
use of bolus to assure adequate skin dose.
Merkel Cell Carcinoma

Merkel cell carcinoma is a rare cutaneous malignancy with a roughly
25% mortality rate and a high propensity of regional and distant tumor
spread. There is no class I data evaluating radiotherapy’s role in the
management of this disease. The published literature appears to show an
improvement in locoregional control when radiotherapy is added to
management of the primary site and nodal beds, particularly when
surgical margins are compromised (32–39).
Because of the high incidence of nodal metastases, the regional
lymphatics should be electively treated with surgery and/or radiation in
all patients with apparently localized disease, The addition of radiation
to surgically managed regional nodes, even if sentinel nodes are
negative, appears to be of value (40,41). If nodal disease is found at
surgery, postoperative irradiation should be given. The radiation doses
are similar for squamous cell carcinomas of the head and neck: primary
tumor—negative margins, 60 Gy in 30 fractions over 6 weeks;
microscopically positive margins, 66 Gy in 33 fractions over 6 1/2
weeks; gross disease, 70 Gy in 35 fractions over 7 weeks. Elective
irradiation of subclinical disease in a nonresected neck would be 50 Gy
in 25 fractions over 5 weeks. Radiation fields should be generous (3 cm
margins) around the primary site because of the propensity of cutaneous
in-transit tumor spread. The location of the primary site in relation to
regional nodal basins may preclude including these nodal stations in the
same radiotherapy portals. It has been stated, “For some patients, you
can’t treat a radiation field big enough.”
Mycosis Fungoides
Mycosis fungoides (MF) is a low-grade, non-Hodgkin T-cell lymphoma
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that develops primarily in the skin. It can also involve lymph nodes,
blood, and visceral organs in patients with advanced cutaneous disease
(42). MF primarily affects adults over the age of 40, with approximately
1,400 new cases per year in the United States (43). Approximately 50%
of all cutaneous T-cell lymphoma (CTCL) cases are MF.
MF may start as a scaly, red rash in areas that usually are not exposed
to the sun (premycotic phase) and progress to patch phase (with thin,
reddened, eczema-like rash), plaque phase (with small raised bumps or
hardened lesions on the skin), and tumor phase (with tumors formed on
the skin). Patients present with tumors or erythroderma (with patches
and/or plaques covering greater than 80% body surface area) are at high
risk for extracutaneous dissemination to lymph nodes, viscera, and
blood.
Early-stage MF consists of patches and/or plaques on the skin with no
(stage IA & IB) or limited (stage IIA) lymph node involvement and no
visceral involvement. Patients present with advanced skin lesions (e.g.,
tumors, generalized erythroderma) or extracutaneous disease are
classified as having advanced stage MF (stages IIB to IV) (1).
Radiation Therapy Indications

Early stage MF is typically managed with skin-directed therapies, which
include topical corticosteroids, topical chemotherapy (nitrogen mustard
or carmustine), phototherapy (psoralen plus ultraviolet A (PUVA),
ultraviolet B (UVB)), and radiation therapy, among others. To achieve
and maintain long-term disease control, serial administration of skin-
directed therapies may be necessary. For patients with disease limited to
the skin, skin-directed therapy alone can usually produce high rates of
remission and even cure (43). Systemic therapy may be used after skin-
directed therapies fail to control the disease. For patients with advanced
stage disease, systemic therapy is used either alone or in combination
with skin-directed therapies.
MF are extremely sensitive to ionizing radiation. As such, radiation
therapy in the form of localized or total-skin irradiation provides one of
the most effective treatments for MF (42). For patients with unilesional
or localized MF (involving less than 10% of body surface area), local
radiation is typically used with efficient disease clearance. For patients
with extended or advanced diseases, total-skin electron therapy (TSET) is
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used in either primary or adjuvant settings. TSET monotherapy provides
rapid and effective palliation, with complete response rates of 95% for
T1, 90% for T2, 60% for T3, and 75% for T4 disease (44). For stage IA
disease, TSET monotherapy produces a 10-year relapse-free survival of
approximately 50% (44). For patients with more advanced disease, TSET
monotherapy is rarely curative; it is often administered to induce
cutaneous remission followed by adjuvant systemic and/or topical
therapy to prolong remission. Some patients may be candidates for a
second course of total-skin electron irradiation for recurrent MF (42,44).
Radiation Treatment Techniques

Key factors to consider in radiation treatment planning for MF include
the spatial extent of the lesions (i.e., the depth into the skin and lateral
spread over the skin surface), the dose required to control the lesions,
and the radiation impact on normal tissue and critical structures. The
lesion depth into the skin dictates the type and the energy of radiation to
be used. Because the primary targets of MF are mostly superficial,
radiation modalities that can concentrate dose to only the desired skin
layers are ideal. For this reason, electron beams are preferred over
photons. Electron beams stop at a finite penetration depth in tissue. The
penetration depth can be controlled by tuning the electron energy,
enabling confinement of radiation dose to a desired skin layer with little
radiation damage to deeper normal tissues. The spread of the lesions
over the skin surface determines the size of radiation fields and,
potentially, the treatment technique. For example, when total-skin
irradiation is required, only electron beams can be used because the
whole-body dose from a photon-based technique would be totally
unacceptable. Treatment planning considerations for localized and total-
skin irradiation are discussed further below.
Local Radiation Therapy. Local irradiation is highly effective for MF

with individual lesions or with limited skin involvement. Orthovoltage x-
rays (e.g., 120 kVp) and electron beams have both been used in the
treatment of localized MF lesions. While low-energy x-rays deposit
maximum dose at the skin surface, it is inherently more penetrating
compared to electron beams. Unwanted irradiation of normal tissues
along the beam path is unavoidable. Nonetheless, because an
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orthovoltage unit is relatively simple to maneuver for complicated
setups, it is still being used in some institutions for localized MF tumors
with deep disease infiltrations and/or for boost irradiation of skin areas
that are underdosed from a total-skin electron treatment, such as the
perineum and soles of feet.
Treatment planning considerations for local radiation therapy using
electrons (or orthovoltage x-rays) are similar to those discussed in the
earlier sections of this chapter for other superficial lesions. Radiation
field aperture is typically designed with a peripheral margin up to 2 cm,
although the exact size/shape is often influenced by the location of the
lesions and their proximity to sensitive normal tissues. Beam energy is
dictated by the desired treatment depth. Because the energy of available
electron beams is limited, custom bolus may be used to ensure adequate
dose to skin surface and/or to control the treatment depth.
A total treatment dose of 15 to 25 Gy delivered over 1 to 3 weeks is
usually effective in long-term control of local diseases. Total dose
ranging from 8 to 30 Gy has been reported in trials (45,46). Complete
responses were observed in greater than 90% of cases for those lesions
receiving over 3 Gy and lesions typically disappeared by 2 to 3 weeks
(45). In a single center retrospective study, a single fraction dose of 4 to
9 Gy produced a complete response in 255 of 270 individual lesions
(94%) (47). While radiation treatment is highly effective in local control,
new lesions can develop outside of the treated field. Skin-directed
maintenance therapy such as topical nitrogen mustard or topical
corticosteroids may be used after local radiation therapy. If indicated, it
is also appropriate to administer local radiation therapy either before or
following a course of total-skin electron treatment. Treatment related
toxicity from local radiation therapy is dependent upon the dose of
radiation used and the location of the lesion. Typical side effects include
erythema and hair loss.
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Figure 29.6 Illustration of a dual-field beam TSET setup currently used at Yale University. Note
the beam axis for the dual-field coincides with the central axis of a horizontally directed beam.
(Adapted from Chen Z, Agostinelli AG, Wilson LD, et al. Matching the dosimetry characteristics of
a dual-field Stanford technique to a customized single-field Stanford technique for total skin
electron therapy. Int J Radiat Oncol Biol Phys. 2004; 59:872–885.)
Total-Skin Electron Therapy. For patients with extended or advanced

MF, TSET is the most effective single agent treatment (44). The
dosimetric goal of TSET is to deliver sufficient dose to the superficial
layers (up to about 5 mm below the skin surface) of the entire body with
minimum or no dose to the normal tissues inside (42,48). Technical
challenges in fulfilling this dosimetric goal arise primarily from the
unusual target volume which wraps around the body amid ever-
changing curvatures and unavoidable self-shielding among the body
structures. In addition, bremsstrahlung x-rays produced from the
interactions of the electron beam with the materials in its beam path
must be kept low to prevent serious radiation toxicity arising from
whole-body exposure to these contaminating x-rays (42,49).
Modern TSET techniques are all based on linear accelerator-based
electron beams. The basic geometry involves a horizontally directed
electron beam with the patient standing at a distance of 3 to 7 m away
from the radiation source. By positioning the patient at an extended
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distance, a large electron beam is created at the location of the patient.
At an SSD of 7 m, a 3-mm diameter electron pencil beam can broaden
into an electron beam of about 180 cm in diameter due to electron
scattering through the air (50). At shorter SSD (e.g., 3 to 4 m), a
composite dual-field beam is typically used, which consists of two
horizontally directed beams with one angled toward patient’s head and
the other toward patient’s feet (51), resulting in an effective uniform
beam covering patient from head to toe (Fig. 29.6). The use of dual-field
beam is due primarily to the limitations imposed by accelerator design
and the extended SSD available in the accelerator room.
The first linear accelerator-based method reported by Stanford
University used a dual-field beam with the patient irradiated in two
treatment positions: one facing the beam source and the other with the
back toward the source (51). This is equivalent to a two-field AP-PA
treatment. Following basic treatment planning principles, the lateral
dose uniformity can be improved by increasing the number of treatment
positions, that is, the number of equivalent fields spaced equally around
the patient (52). Stanford ultimately settled on a six-field technique in
which patients stand in six different orientations with respect to the
dual-field beam: anteroposterior, posteroanterior, right and left anterior
oblique, and right and left posterior oblique (52).
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Figure 29.7 Illustration of the six treatment positions used in the Stanford total-skin electron
therapy. (Reprinted from Smith BD, Wilson LD. Cutaneous lymphomas. Semin Radiat Oncol.
2007;17:158–168.)
The Stanford six-field technique has been adopted by most institutions

as the standard TSET technique. The technique can be implemented with
either a single-field or a composite dual-field beam (50). Figure 29.6
depicts a dual-field beam setup currently used in the Yale TSET program.
With a patient standing at 3.8 m from the radiation source and a 3.2 mm
Lexan attenuate/scatter screen placed in front of the patient, the dual-
field beam is made up of two fields with the accelerator head rotated
17.5 degrees above and below the horizontal direction toward the
patient. The Lexan screen is used to attenuate and scatter the 6 MeV
incident electrons produced from a Varian 21EX linear accelerator using
the high dose rate total skin electron (HDTSe) mode. The mean energy of
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the electrons reaching patient’s skin surface is approximately 3.9 MeV.
For total-skin treatment, the patient is irradiated in six specific treatment
positions to maximize skin unfolding and lateral dose uniformity (Fig.
29.7). Traditionally, the treatment of all six positions is delivered over
the course of a 2-day treatment cycle. On day 1, the anteroposterior,
right posterior oblique, and left posterior oblique positions are treated.
On day 2, the posteroanterior, right anterior oblique, and left anterior
oblique positions are treated. Figure 29.8 compares the depth-dose
curves of a complete treatment cycle (all six positions) to a single
position (e.g., anteroposterior) at the level of beam axis. Due to the
obliquity of incident electrons from the neighboring irradiation
positions, the depth dose curve of a complete treatment cycle is shifted
toward the skin surface, with the dose maximum at 1 mm, the 80%
isodose line at 6 mm, and the 20% isodose line at 12 mm (50). Figure
29.9 demonstrates a relatively uniform dose delivered by this setup to
the entire skin surface with minimum dose to the deeper tissues inside
the body. The total x-ray contamination was 1.2% of the skin dose, well
within the acceptable limit (53).
Figure 29.8 Comparison of percent depth dose curves for a single position irradiation and a six-
position treatment. (Adapted from Chen Z, Agostinelli AG, Wilson LD, et al. Matching the
dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford
technique for total skin electron therapy. Int J Radiat Oncol Biol Phys. 2004;59:872–885.)
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Figure 29.9 A representation of single position and six position treatment setups. The six position
treatment setup can deliver a relatively uniform dose to the surface while minimizing delivery of
dose to deep tissues.
TABLE 29.5 Standard TSET Treatment Protocol at Yale-New Haven

Hospital (50)
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For standard TSET treatment (Table 29.5), the effective dose delivered
over the 2-day treatment cycle is typically 2 Gy to the skin surface.
Patient receives treatment 4 days (2 cycles) per week, with a total dose
of 36 Gy delivered over 9 weeks. A 1-week break may be given after a
dose of 18 Gy has been delivered to provide relief from the generalized
skin erythema associated with treatment. Although the six treatment
positions are designed to maximize skin unfolding and minimize self-
shielding, overdose may occur to certain structures such as hands and
ankles due to high convexity and radiation exposure from more than
three positions. Under dose could also occur to areas such as the top of
the scalp, the perineum, the underside of the breasts, panniculus folds,
and the soles of the feet due to self-shielding. Customized shielding and
supplemental irradiation are used to bring the dose to these areas close
to the desired value. In addition, some critical structures (such as the
lens of the eyes) and radiosensitive structures (such as the nail beds and
lips) may need additional shielding to prevent unnecessary radiation
injury. Detailed dosimetric measurements are typically required to
determine the most appropriate shielding regimen or supplemental
treatment for a particular treatment arrangement and patient geometry.
Table 29.5 lists the nominal shielding and supplemental treatment
regimen used at Yale-New Haven Hospital (50). Individualized
adjustments are made by the radiation oncologist based on the
conditions of specific patients and clinical judgment. The eyes and lens
are shielded with a combination of internal and external eye shields.
Because of the increased backscatter dose from the internal shield to the
eyelid, using internal eye shield throughout the treatment course would
have overdosed the eyelid. External eye shields made of lead sheets or
Cerrobend block casted in swimming goggles are used to keep eyelids
from over exposure. It is appropriate to start treatment with internal eye
shields and switch to external eye shields during the later portion of the
treatment course, or use internal and external shields in alternating
treatment cycles. To prevent severe reaction to the fingers, hands, lips,
and feet, lead-lined mitts, lead-sheet based shields, and blocks to protect
the feet can be used to reduce the dose to these areas.
Both electron beam and orthovoltage x-rays can be used for
supplemental treatment to underdosed areas. One can use 120 kVp, HVL
4.2 mm Al, x-rays to deliver patch treatments to the soles of feet (14 Gy,
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14 fractions, treatment days 1 to 7 and 30 to 36) and perineum (18 Gy,
18 fractions, treatment days 1 to 9 and 28 to 36). The scalp dose can be
supplemented with either orthovoltage patches (6 to 20 Gy over 1 to 3
weeks) or with an electron reflector mounted above the patient’s head
(50). Other areas of potential underdosing include the ventral penis, the
upper medial thighs, inframammary folds, folds under any pannus, and
the lateral and flatter regions of the face and trunk. Supplemental patch
fields, as guided by in vivo dosimetry or clinical suspicion, are
appropriate for these regions to ensure that the surface dose is at least
50% of the prescribed TSET dose (44). When determining the total dose
given in patch treatments, doses to areas such as the feet and perineum
may be reduced as clinically indicated to enhance patient tolerance,
provided such areas are uninvolved (44). For tumors having a thickness
greater than 6 mm, for example, for patients with bleeding, weeping, or
painful tumors at presentation, an initial or concurrent boost of 10 Gy in
five fractions using either 6 to 16 MeV electrons or orthovoltage photons
has been effective (44). Asymptomatic plaques and tumors that persist at
the end of treatment may receive a similar boost to ensure adequate
dose delivery at depth.
TSET has been proven to be an effective treatment modality for MF
(42,44). The typical response to radiation is a gradual decrease in the
size and symptoms that can start within a few days of starting the
treatments. Even large tumors or deeply ulcerated tumors will eventually
resolve and be replaced with normal skin. Nonetheless, total-skin
electron irradiation is a very specialized radiation treatment technique,
which requires knowledge and use of proper positioning of the patient’s
trunk and extremities to optimally expose all skin surfaces to the
electron beam. Significant medical physics effort is required to set up
and maintain such a technique. A team of experienced radiation
oncology physicians, medical physicists, medical dosimetrists, and
radiation therapists must be in place to properly plan and deliver the
optimal TSET. For these reasons, TSET is not readily available in all
radiation therapy departments.
For those centers planning to establish such a treatment technique,
European Organization for Research and Treatment of Cancer (EORTC)
Cutaneous Lymphoma Project Group has developed guidelines for total-
skin electron radiation in the management of MF (53). These guidelines
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include recommendations on optimal treatment distance (between 3 and
8 m); ideal beam uniformity (within 10% across clinically useful vertical
and lateral dimensions); acceptable photon contamination at the level of
the bone marrow (must be <0.7 Gy for a full course of treatment to
avoid hematologic sequelae); desired therapeutic treatment depth (80%
isodose surface should be at least 4 mm below the skin surface); primary
treatment dose (at least 26 Gy to a depth of 4 mm in truncal skin, ∼31
to 36 Gy to the skin surface); and the utilization of supplemental patch
treatments to underdosed skin surfaces (perineum, soles of feet, scalp,
and behind pendulous tissue). The guidelines recommend a minimum
dose of 26 Gy at a depth of 4 mm for all skin surfaces. However, caution
should be exercised in giving >20 Gy to the soles of the feet because of
the limited tolerance of the skin of the sole. The references included in
the end of this chapter may serve as a starting point for those intended
to embark on this endeavor.
CLINICAL CONSIDERATIONS
Examples of Treated Patients
Case 1: Squamous cell carcinoma of lip (Figs. 29.10–29.14)
An 87-year-old woman had a destructive squamous cell carcinoma of
the right side of her upper lip. Because of her age and difficulty in
arranging transportation, she was treated with 300 cGy/day to the 90%
line in three fractions per week, with 6 MeV electrons, with 5 mm of gel
bolus over the lip and a lead shield between the upper lip and the upper
alveolar ridge. Following eight fractions, she was given a 13-day break
because of an intense radiation reaction on the surface of the tumor and
the surrounding skin, and then she returned for an additional eight
fractions. Her tumor was subsequently totally controlled with good
cosmetic result with a total dose of 4,800 cGy in 16 fractions over 42
elapsed days.
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Figure 29.10 An 87-year-old woman with squamous cell carcinoma of right side of upper lip. Prior
to irradiation.
Case 2: Squamous cell carcinoma of the left ala nasi (Figs. 29.15–29.18)
This 79-year-old man had a very large ulcerated 4 × 4 × 3.5-cm
squamous carcinoma that involved and distorted the left ala nasi
blocking the left nostril (Fig. 29.15). The treatment planning CT scan
and the radiation treatments were performed with the patient
immobilized in a thermoplastic mask (Fig. 29.16). The CT scan showed
the depth of the tumor involvement. He was initially treated with a
combination of 12-MeV electrons (70% weighting) and 16-MeV electrons
(30% weighting). The shaped left anterior oblique field (Cerrobend
cutout in electron cone) included a 1-cm peripheral margin. He received
a total of 5,100 cGy to the 90% line in 17 fractions over 30 days,
treating 4 days/week. The final 1,800 cGy was given with a reduced
field size and with 12-MeV electrons because the tumor depth had
decreased by that time. No bolus was used because the 90% isodose line
(green line) of the 12- and 16-MeV electron beams was at the tumor
surface (Fig. 29.17). Excellent tumor control and cosmesis was provided
(Fig. 29.18).
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Figure 29.11 At the time of fourth radiation treatment with 6-MeV electrons, 5-mm gel bolus on
the skin, black line is edge of radiation field as defined by Cerrobend cutout, treated at 300 cGy
per day to 90% line, three fractions per week. A lead shield enclosed in a folded glove is placed
between the upper lip and the upper alveolar ridge.
Figure 29.12 At 7th radiation fraction, 2,100 cGy to the 90% isodose surface. Following the 8th
treatment (2,400 cGy), a 13-day treatment break was needed because of the intense symptomatic
radiation reaction over the tumor surface.
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Figure 29.13 At completion of radiation treatments, 4,800 cGy in 16 fractions, 3 fractions per
week, over 42 elapsed days. Eight fractions followed by a 13-day break, followed by eight more
fractions.
Cancer of the ala nasi commonly invades and destroys the underlying
cartilage. Laterally, the lesion may extend to the embryonic fusion
planes of the nasolabial fold. This permits deep infiltration. Although not
used in this patient, exit beam shields of lead, coated with paraffin, and
then slipped into the left nostril or anterior to the upper gum may be
used. When the tumor is close to the orbits, extra eye shields are used.
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Figure 29.14 Six weeks following completion of irradiation. No evidence of tumor. There is slight
deformity of the right side of the upper lip because of prior destruction from the tumor. Considering
the original tumor appearance, this is a very good functional and cosmetic result.
Figure 29.15 4 × 4 × 3.5 cm ulcerated and bleeding squamous cell carcinoma of left ala nasi,
prior to treatment.
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Figure 29.16 Photo taken at 3,000 cGy, original field is marked in black ink and reduced field is
marked in red ink; treatment continued to total of 4,800 cGy.
Figure 29.17 Isodose lines of treatment with combination of left anterior oblique 12 and 16 MeV
electrons, treatment prescription calculated to green 90% isodose surface, which surrounded
tumor volume and also included tumor surface. No bolus was used. Colors and percent isodose
surfaces: red 105%, blue 100%, green 90%, yellow 80%, magenta 70%, light blue 60%, orange
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50%, purple 30%, light yellow 20%.
Figure 29.18 Two months following the completion of radiation treatment, no visible tumor, slight
skin distortion, excellent cosmetic result considering initial tumor appearance.
Case 3: Basal cell carcinoma of the left medial canthus and bridge of
nose with extension into the left lower eyelid (Figs. 29.19 and 29.20).
Cancers near the eye may invade the bone or soft tissues of the orbit.
When there is any question of deep invasion, imaging studies through
this level may provide useful information. Such invasion was not present
in this patient. Gross margins were otherwise readily determined. The
relatively small size of the treatment field, together with the problems of
dose distribution and use of a lead eye shield of appropriate thickness for
the electron beam, made the x-ray beam preferable (7,8,54,55). The
contour across the treatment field was irregular. (The bridge of the nose
was ∼1.5 to 2 cm anterior to the canthus.) The resulting variation in
surface dose was decreased by increasing SSD of the x-ray beam to 50
cm rather than the usual 20 to 30 cm.
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Figure 29.19 An internal (Gougelman) eye shield is in place in the anesthetized left eye. An
external eye shield covers the right eye.
Figure 29.20 A lead cutout and the eye shields are in place.
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Figure 29.21 This 93-year-old woman with nodular squamous cell carcinoma was treated with 45
Gy in 10 fractions over 2 weeks using 250 kV photons.
A 200 keV x-ray beam of half-value layer (HVL) 1 mm copper at 50

cm SSD is appropriate. The field diameter, allowing at least 1 cm of
lateral margin around the lesion, was 4.5 cm. A lead cutout of 1 mm
thickness was constructed and shaped. Figure 29.19 shows that before it
was taped in place, an eye shield of 2-mm-thick lead was inserted on the
surface of the anesthetized left eye and the closed right eye was covered
with an additional 1-mm-thick shield to block radiation that might be
transmitted to the right lens through the lead of the cutout. The lead
cutout was then taped in place (Fig. 29.20). After each treatment, an eye
patch is worn until sensation returns to the cornea.
Fractionation and total dose schedules, chosen to produce minimum
fibrosis, telangiectasia, and edema of eyelids and adjacent skin, were 54
Gy given in 27 fractions. Obviously, larger and more deeply infiltrating
lesions require consideration of electron beam techniques, some
requiring 12 to 22 MeV electron beams (8). In such patients, loss of
vision or even of the eye may be unavoidable if the cancer is to be cured.
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Case 4: Nodular squamous cell carcinoma (Figs. 29.21 and 29.22)
This 93-year-old woman with a nodular squamous cell carcinoma
overlying her malar eminence (Fig. 29.21) was treated with 45 Gy in 10
fractions over 2 weeks using 250 kV photons with an orthovoltage unit
and applicators akin to those shown in Figures 29.1 and 29.2. At age
100, at 7-year follow-up, the patient was alert and well and had
maintained a clinical complete remission with excellent cosmesis (Fig.
29.22).
Figure 29.22 At age 100, at 7-year follow-up, the patient was alert and well, with a sustained
complete response to treatment and an excellent cosmetic result.
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Figure 29.23 Basal cell carcinoma, wrapping over the bridge of the nose, prior to irradiation.
Figure 29.24 Clinical setup photograph showing the use of an aluminum foil attenuator and
customized lead cutout shielding to protect normal tissues. The attenuator is placed to provide
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compensation for the missing tissue on each side of the bridge of the nose.
Figure 29.25 Regression of the lesion with complete re-epithelialization is present at 3 months,
time. This treatment approach minimizes irradiation of tissues deep to the skin.
Figure 29.26 Gold eye shields for superficial or orthovoltage therapy can shield one or both
eyelids. The spade-shaped shields can be placed to have the ‘handle’ overlying either the upper
or lower eyelid to help shield it from the therapy beam, and the spherical shields can be placed
below both eyelids.
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Figure 29.27 This gentleman was treated with 50 Gy in 20 fractions over 4 weeks time using 100
kV x-rays for a basal cell carcinoma of the right lower eyelid. An internal gold eye shield was
placed below the lower eyelid to protect the globe and upper eyelid.
Figure 29.28 Treatment setup that includes additional lead cutout shielding to help protect the
patient from incidental scattered irradiation.
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Figure 29.29 An example of a multi-beam IMRT plan showing that reasonable whole scalp
coverage is achievable with acceptable sparing of intracranial contents. Multiple beams are
arranged to tangentially irradiate the scalp without unacceptable over- or under-lap. Dose-volume
histogram is shown with whole brain (pink line) receiving a low dose relative to scalp (red line).
Fatigue may be observed in the elderly thus treated.
Case 5: Squamous cell carcinoma of the bridge of the nose (Figs.

29.23–29.25)
Figure 29.23 shows a gentleman with a basal cell carcinoma of the
bridge of the nose (delineated by dotted black line) and shows the
difficulty that can be encountered with complex surface changes. An
aluminum foil attenuator (Figure 29.3) was used to provide dose
homogeneity at the surface and relevant superficial depths across the
curved contour of the nasal bridge (Figure 29.24). He was treated with
45 Gy in 10 fractions using 100 kV x-rays over 2 weeks’ time, and the
cosmetic result at 3 months is shown in Figure 29.25.
KEY POINTS
• Skin cancer is currently most often treated with surgery, but
radiotherapy remains an important therapeutic modality, especially
for locations where R0 resections with acceptable cosmetic
outcomes are unlikely to be achieved.
• Not every skin cancer should be treated with the same approach.
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The selective use of advanced imaging can help identify ostensibly
normal areas that are involved with a recurrent or deeply infiltrating
tumor that might have been undertreated with a simple approach.
• Normal tissue protection is as important for skin cancer

radiotherapy as it is for other tumor sites. The selection of
treatment techniques and the design and use of shielding,
attenuators, and bolus, as well as assuring that all are being
appropriately used is incumbent on the physician prescribing the
treatment.
QUESTIONS
1. Which of these skin cancers is least likely to spread to regional
nodes?
A. Lentigo maligna
B. Squamous cell carcinoma
C. Merkel cell carcinoma
D. Basal cell carcinoma
2. What is the appropriate radial margin to use when prescribing
orthovoltage irradiation for a 2.1-cm, moderately differentiated
squamous cell carcinoma of the skin of the shoulder that recurred
after a community dermatologist performed a shave excision?
A. 1.0 to 1.3 cm
B. <1.5 cm
C. >2.0 cm
D. 1.3 cm
E. 1.5 to 2.0 cm
3. What is the appropriate radial margin on the primary tumor site
when treating a surgically excised Merkel cell carcinoma, where
the surgeon informs you that to achieve closure, she could not
achieve recommended margins of 1 to 2 cm? The pathology
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report indicates that the primary tumor was 1.5 cm in diameter
and there was no evidence of nodal spread on the sentinel lymph
node biopsy by H&E staining.
A. 2 cm
B. 3 cm
C. 4 cm
D. 5 cm
4. How many millimeters of lead must be used to protect normal
tissues from an 8 MeV electron beam?
A. 2.5 mm
B. 3 mm
C. 4 mm
D. 5 mm
ANSWERS
1. A. Although metastatic spread to regional nodes is often
seen with melanoma, squamous cell carcinoma, and
Merkel cell carcinoma, it is also seen, albeit very rarely, in
patients with basal cell carcinoma. Lentigo maligna is a
noninvasive malignancy, and therefore has no risk of nodal
metastatic spread.
2. E. NCCN guidelines for radiotherapy margins for
nonmelanoma skin cancer indicate that for lesions <2 cm,
a radial margin of 1 to 1.5 cm is adequate. For lesions >2
cm, a margin of 1.5 to 2 cm is needed. If electron beam
therapy is being used, even larger margins are required
because of the wider penumbra, and the prescription
should be written to include bolus if the full dose would
not be delivered to the skin surface when an energy is
chosen that will cover the deepest component of the tumor
by the 90% isodose surface.
3. D. Merkel cell carcinoma has a high propensity for occult
involvement of tissues beyond any clinically apparent
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disease. Surgical margins of 1 to 2 cm are therefore
recommended in the NCCN guidelines, and the prompt
initiation of radiotherapy to the resection bed is well
recognized to decrease local recurrence rates. In fact, the
risk of occult involvement of draining lymphatics is
significant enough that irradiation of nodal basins is
recommended by many, with in-transit skin also included
in the radiotherapy portals, if feasible, to further improve
locoregional control. The addition of radiotherapy to the
primary site and regional nodal volumes has not been
shown with class I data to improve survival, but the
relative rarity of this disease may prevent such studies
from being performed.
4. C. The “rule of thumb” for calculating the thickness of lead-
equivalent shielding to protect normal tissues from
incident electron beam therapy is that the thickness in
millimeters of lead required is one-half the incident
electron energy. This does not apply well for electron
energies beyond approximately 9 MeV.
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30 Breast Cancer
Yvonne M. Mowery, Sua Yoo, and Rachel C. Blitzblau
INTRODUCTION
Radiotherapy plays an essential role in the definitive management of in
situ and invasive breast carcinoma. This chapter reviews factors relevant
to breast radiation treatment planning, including breast and regional
nodal anatomy, breast cancer biology, and indications for adjuvant
radiotherapy after breast-conserving surgery and mastectomy. Patient
positioning, treatment techniques, target volumes, and dose
fractionation are discussed for different clinical scenarios.
ANATOMY
The breast is positioned within the superficial fascia on the anterior
chest wall (Fig. 30.1). It extends from the second rib superiorly to the
inframammary fold, typically at the sixth rib. Horizontally, the breast
spans from the lateral sternal edge to the midaxillary line. Breast tissue
extending into the axilla is referred to as the axillary tail of Spence. The
pectoral fascia, serratus anterior, external oblique muscles, and upper
rectus sheath form the posterior border of the breast. The retromammary
bursa consists of loose areolar tissue located between the glandular
breast elements and deep fascia of the pectoralis major. This space
allows for breast mobility along the chest wall. Anteriorly, the breast is
attached to the skin by fibrous connective tissue septa called suspensory
or Cooper ligaments. These ligaments insert perpendicularly to the
superficial fascia below the dermis and attach posteriorly to the deep
fascia, providing structural support without impairing mobility.
Infiltration of these ligaments by malignancy leads to skin retraction and
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dimpled appearance of the breast.
The breast consists of 15 to 20 lobes arranged radially around the
nipple. Each lobe contains 20 to 40 terminal ductal lobular units
(TDLU), which represent the functional unit of the breast. A TDLU
contains clusters of tubuloalevolar glands or lobules that drain into a
terminal duct. Terminal ducts coalesce to form interlobular ducts, and
ducts from each lobe join to empty into a larger lactiferous duct.
Typically 5 to 10 main lactiferous ducts converge to open at the nipple.
The glandular breast tissue with its branching duct system is embedded
in subcutaneous adipose tissue and surrounded by supportive connective
tissues, blood vessels, nerves, and lymphatics. The upper outer quadrant
contains the most glandular tissue and is the most common site of breast
carcinoma.
Blood Vessels
The internal mammary (IM) and lateral thoracic arteries provide the
majority of the breast blood supply (Fig. 30.2). The IM artery (internal
thoracic artery) is a branch of the subclavian artery and delivers blood
to greater than 50% of the breast. It descends vertically across
intercostal spaces lateral to the sternum and branches into perforating
arteries that supply the medial and central breast. The lateral thoracic
artery is a branch of the axillary artery and primarily supplies the upper
outer quadrant. The pectoral branch of the thoracoacromial artery runs
between the pectoralis major and minor to supply the posterior breast.
The subscapular artery and lateral branches of the third to fifth posterior
intercostal arteries provide minor contributions to the arterial blood
supply. Venous drainage is primarily through tributaries of the axillary
vein and perforating branches of the internal thoracic and posterior
intercostal veins.
Lymphatic Drainage
A dense network of lymphatic vessels exists within the breast, and
approximately 35% of breast cancer patients have positive lymph nodes
at presentation (1). The axilla is most commonly involved, followed by
the IM and supraclavicular regions, respectively. The probability of
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drainage to the infraclavicular or interpectoral regions is <2% (2).
Lymphatic drainage patterns vary based on breast “quadrant” (upper
outer, upper inner, lower outer, lower inner, and central) (2–4). The
dominant drainage site is the axilla regardless of location; however, IM
drainage is much more frequent for medial or central breast lesions (5).
Axillary nodes are categorized into three levels based on their position
relative to the pectoralis minor muscle (Fig. 30.3). Level I contains
axillary nodes situated lateral to the pectoralis minor. Level II nodes lie
posterior to the pectoralis minor and include the interpectoral (Rotter)
nodes situated between the pectoralis minor and major. Level III
(infraclavicular) nodes are located medial to the medial border of the
pectoralis minor and inferior to the clavicle. Supraclavicular lymph
nodes lie within the supraclavicular fossa, between the anterior scalene
and sternocleidomastoid muscles. Adjacent nodes above the cricoid
cartilage are considered lower cervical nodes and categorized as
metastatic disease. Nodal involvement typically exhibits progressive,
orderly spread from level I to adjacent axillary levels, then to the
supraclavicular region (6). Reported rates of “skip metastases” range
from 1.5% to 19.2% (7).
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Figure 30.1 Mammary gland (coronal and sagittal sections). Reprinted with permission from
Netter FH. Atlas of Human Anatomy. 5th ed. Philadelphia, PA: Elsevier; 2010.
A complete axillary lymph node dissection is usually limited to

surgical levels I and II, which differ from radiologically defined axillary
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levels. A level I and II axillary dissection removes all nodes below the
axillary vein, extending medially behind the pectoralis minor and
laterally to the point where the axillary vein crosses the latissimus dorsi
tendon. In an effort to reduce surgical morbidity, surgeons typically do
not skeletonize the axillary vessels. In contrast, the NRG oncology breast
contouring atlas defines axillary level II as beginning where the axillary
vessels cross the pectoralis muscle laterally and extending until the
vessels cross the medial border of the muscle. This volume is typically
superior to standard surgical fields.
IM nodes are situated in intercostal spaces within 3 cm of the sternal
edge. Most of these lymph nodes are located medial to the IM vessels
within the first and second intercostal spaces and lateral to the IM
vessels within the third intercostal space (8). Lymphatic drainage
infrequently occurs to IM nodes only (<2%), but drainage from ∼20%
of patients with early breast cancer flows to both axillary and IM nodes
(4). In the absence of grossly abnormal IM nodes, this nodal region is not
typically dissected.
Figure 30.2 Normal anatomy of the breast, chest wall muscles, and vasculature (A) 1. Perforating
branches from internal mammary artery and vein; 2. Pectoral branches from thoracoacromial
artery and vein; 3. External mammary branch from lateral thoracic artery and vein; 4. Branches
from subscapular and thoracodorsal arteries and veins; 5. Lateral branches of third, fourth, and
fifth intercostal arteries and veins; 6. Internal mammary artery and veins; 7. Sternocostal head of
pectoralis major muscle; 8. Clavicular head of pectoralis major muscle; 9. Axillary artery and vein;
10. Cephalic vein; 11. Axillary sheath; 12. Latissimus dorsi muscle; 13. Serratus anterior muscle;
14. External abdominal oblique muscle. (B) 1. External abdominal oblique muscle; 2. Rectus
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sheath; 3. Rectus abdominis muscle; 4. Internal intercostal muscle; 5. Transverse thoracic
muscle; 6. Pectoralis minor muscle; 7. Perforating branches from internal mammary artery and
vein; 8. Internal mammary artery and vein; 9. Cut edge of pectoralis major muscle; 10.
Sternoclavicular branch of thoracoacromial artery and vein; 11. Subclavius muscle and Halsted
ligament; 12. External intercostal muscle; 13. Axillary vein; 14. Axillary artery; 15. Lateral cord of
brachial plexus; 16. Lateral pectoral nerve (from the lateral cord); 17. Cephalic vein; 18.
Thoracoacromial vein; 19. Intercostobrachial nerve; 20. Lateral cutaneous nerves; 21. Lateral
thoracic artery and vein; 22. Scapular branches of lateral thoracic artery and vein; 23. Medial
pectoral nerve (from medial cord); 24. Ulnar nerve; 25. Pectoralis minor muscle; 26.
Coracoclavicular ligament; 27. Coracoacromial ligament; 28. Cut edge of deltoid muscle; 29.
Acromial and humeral branches of thoracoacromial artery and vein; 30. Musculocutaneous nerve;
31. Medial cutaneous nerve of arm; 32. Subscapularis muscle; 33. Lower subscapular nerve; 34.
Teres major muscle; 35. Long thoracic nerve; 36. Serratus anterior muscle; 37. Latissimus dorsi
muscle; 38. Latissimus dorsi muscle; 39. Thoracodorsal nerve; 40. Thoracodorsal artery and vein;
41. Scapular circumflex artery and vein; 42. Branching of intercostobrachial nerve; 43. Teres
major muscle; 44. Medial cutaneous nerve of forearm; 45. Subscapular artery and vein; 46.
Posterior humeral circumflex artery and vein; 47. Median nerve; 48. Coracobrachialis muscle; 49.
Pectoralis major muscle; 50. Biceps brachii muscle, long head; 51. Biceps brachii muscle, short
head; 52. Brachial artery; 53. Basilic vein; 54. Pectoral branch of thoracoacromial artery and vein.
(From Osborne MP, Boolbol SK. Breast anatomy and development. In: Harris JR, Lippmann ME,
Morrow M, et al., eds. Diseases of the Breast. 5th ed. Philadelphia, PA: Wolters Kluwer; 2014.)
Figure 30.3 Lymphatic drainage of the breast showing lymph node groups and levels. 2.
Substernal cross-drainage to contralateral internal mammary lymphatic chain; 3. Subclavius
muscle and Halsted ligament; 10. Pectoralis minor muscle; 11, Axillary artery and vein. Internal
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mammary lymph nodes (A); apical lymph nodes (B); interpectoral (Rotter) lymph nodes (C);
axillary vein lymph nodes (D); central lymph nodes (E); scapular lymph nodes (F); external
mammary lymph nodes (G). Level I lymph nodes: lateral to lateral border of pectoralis minor
muscle; level II lymph nodes: behind pectoralis minor muscle; level III lymph nodes: medial to
medial border of pectoralis minor muscle. (From Burstein HJ, Harris JR, Morrow M. Malignant
tumors of the breast. In: DeVita VT, Lawrence, TS, Rosenberg SA, eds. DeVita, Hellman, and
Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2011.)
EPIDEMIOLOGY
Breast cancer is the most common malignancy among women, with an
estimated cumulative lifetime risk of approximately 12% in the United
States. The American Cancer Society estimates that 231,840 new cases of
invasive breast cancer and 60,290 new cases of carcinoma in situ will be
diagnosed among US women in 2015. An additional 2,350 new cases are
anticipated among US men. Breast cancer is the second leading cause of
cancer death among women. Female breast cancer deaths in the US are
expected to be approximately 40,290 in 2015 (9). While breast cancer
incidence has been relatively stable for the past decade, death rates have
decreased by approximately 1.9% per year between 2002 and 2011 (10).
Greater than 90% of breast cancer cases are sporadic; however several
risk factors are associated with breast cancer development. Increasing
age is a major risk factor, with incidence rising sharply above age 40 and
peaking at ages 75 to 79. This pattern is reflected in recommendations to
initiate screening mammography at age 40 or 50 for women at normal
risk for breast cancer (11–13). Longer duration of endogenous estrogen
exposure also appears to play a role. This hormonal effect likely
accounts for the association between breast cancer and nulliparity, early
menarche, older age at first pregnancy, and delayed menopause (14–16).
Exogenous hormone exposure from postmenopausal hormone
replacement therapy has also been associated with increased breast
cancer risk (17,18). A small increase in relative risk has been
demonstrated among women currently or recently using oral
contraceptives (19).
Ionizing radiation is a well-established environmental risk factor for
breast cancer development. A dose-dependent relationship exists
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between radiation exposure and breast cancer, with greater risk with
exposure at a younger age (20,21). Cumulative breast cancer incidence
ranges from 13% to 20% by age 40 to 45 among women who received
chest radiotherapy during childhood, adolescence, or young adulthood
(22). Increased breast cancer risk is noted as early as 8 years after
therapeutic chest irradiation, and the risk does not plateau with longer
follow-up. Consequently, National Comprehensive Cancer Network
(NCCN) guidelines recommend early initiation of breast cancer screening
for women who have undergone thoracic irradiation between the ages of
10 and 30. For women aged <25 years at the time of treatment,
screening is recommended starting 8 to 10 years after radiation. For
women treated at age 25 to 30, screening should begin 8 to 10 years
after thoracic radiotherapy or at age 40, whichever comes first (13).
Approximately 5% to 10% of breast cancers are hereditary (23). Most
cases have been linked to mutations in BRCA1 or BRCA2, which are two
tumor suppressor genes involved in maintaining chromosomal stability.
Lifetime breast cancer risk is 28% to 84% among BRCA mutation
carriers, with diagnosis often occurring at a younger age compared to
sporadic cases (24). BRCA mutation carriers also have an increased risk
of bilateral breast cancer and ovarian cancer, which can influence
further workup and treatment decisions (25). Genetic testing should be
considered for breast cancer patients meeting any of the following
criteria: diagnosis at age ≤50, triple-negative breast cancer, ≥2 breast
cancer primaries, male, personal history of ovarian cancer, known BRCA
mutation within the family, or family history of breast and/or ovarian
cancer (26).
CLINICAL PRESENTATION AND HISTOLOGIC SUBTYPES

Breast cancer typically presents as an abnormality on screening
mammogram or a palpable breast mass. Less common presentations
include bloody nipple discharge, axillary adenopathy, and breast skin
changes such as erythema, thickening, or peau d’orange. The upper
outer quadrant is the region most commonly involved by both in situ
and invasive carcinoma. Primary tumor location is not correlated with
prognosis (27). Axillary lymph node status is the most important
predictor of disease-free and overall survival in nonmetastatic breast
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cancer (28). Approximately 5% of patients in the United States have
distant disease upon presentation (29,30).
Noninvasive breast cancer, or carcinoma in situ (Tis), represents a
proliferation of abnormal cells that do not extend beyond ducts or
lobules into surrounding stroma. Rates of ductal in situ carcinoma
(DCIS) diagnosis have increased dramatically with rising use of
screening mammography, and DCIS now represents approximately 20%
of breast cancers diagnosed by screening (31). DCIS most often presents
as microcalcifications on mammogram, and it is estimated that
approximately 15% to 60% of DCIS cases progress to invasive ductal
carcinoma (IDC) without treatment (32). By contrast, lobular carcinoma
in situ (LCIS) is typically an incidental pathologic finding. LCIS is
associated with increased breast cancer risk in the ipsilateral and
contralateral breast, however there is controversy regarding whether it
represents a precursor lesion for breast cancer (33).
IDC is the most common invasive histologic subtype, followed by
invasive lobular carcinoma (ILC). Invasive carcinomas extend through
the basement membrane to directly infiltrate surrounding breast tissue,
often resulting in a stellate or spiculated appearance. This infiltration
provides access to lymphatic and blood vessels, facilitating spread to
adjacent lymph nodes and distant hematogenous sites. Compared to IDC,
lobular carcinomas are more likely to be multifocal and diffusely
infiltrative, resulting in poorly defined margins on examination and
imaging (34). Hormone receptor and HER2 status have been increasingly
recognized as prognostic factors in breast cancer regardless of histologic
subtype.
Inflammatory breast cancer (IBC) is an aggressive breast cancer
subtype with a higher propensity for lymphatic and distant spread
compared to other invasive carcinomas. IBC typically presents with rapid
development of breast tenderness, warmth, erythema, skin thickening,
and/or peau d’orange appearance. Skin changes are secondary to tumor
emboli within dermal lymphatics. Due to this dermal lymphatic
involvement, most women with IBC have positive nodes and
approximately one-third have metastatic disease upon presentation.
Neglected primary tumors may have a similar appearance to IBC,
however there is a longer interval between initial symptoms and
development of skin changes.
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PATIENT SELECTION
Breast Conservation
Large randomized trials have established that breast conservation,
consisting of partial mastectomy followed by adjuvant radiotherapy,
provides equivalent outcomes to mastectomy in the treatment of early-
stage invasive and in situ breast carcinoma (35,36). The whole breast
with or without regional lymph nodes is irradiated to eradicate
microscopic residual disease and minimize the risk of local recurrence. A
large meta-analysis has demonstrated improved breast cancer survival
with adjuvant radiotherapy after breast-conserving surgery (37).
Breast conservation candidates must be motivated to preserve their
breasts and should not have any contraindication to adjuvant
radiotherapy. Contraindications to breast conservation include
widespread disease that cannot be incorporated in a local excision,
extensive suspicious microcalcifications, persistently positive margins,
and pregnancy at the time of radiotherapy. Collagen vascular disease
(38), prior ipsilateral breast irradiation, tumor size relative to breast size
or location resulting in subobtimal cosmetic results, and genetic
predisposition to breast cancer may be relative contraindications as well.
Young patient age, in and of itself, is not a contraindication to breast
conservation, as excellent outcomes have been reported for these
patients with breast conservation as well (39). Large pendulous breasts
are not a contraindication to breast conservation, but may affect patient
positioning considerations.
Postmastectomy
Locoregional postmastectomy radiotherapy is associated with
significantly improved outcomes for women with node-positive breast
cancer. A recent meta-analysis of randomized controlled trials by the
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed
relative risk reductions of 32% for locoregional recurrence and 20% for
breast cancer mortality among all node-positive women receiving
radiotherapy after mastectomy and axillary dissection (40). These results
are driven largely by the large British Columbia and Danish Breast
Cancer Cooperative Group trials, which showed improved overall
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survival with postmastectomy locoregional radiotherapy for node-
positive women (41–43). While guidelines universally endorse
postmastectomy radiotherapy for patients with four or more positive
axillary nodes, recommendations have been mixed for patients with one
to three positive axillary nodes (44–48).
The EBCTCG meta-analysis did not show any improvement in
locoregional control or breast cancer mortality with postmastectomy
radiotherapy for node-negative women (40). However, several guidelines
recommend at least consideration of postmastectomy radiotherapy for
patients with T3–T4 tumors or positive margins (44,46,47). Additional
factors such as lymphovascular invasion, high-grade histology,
multicentric disease, skin or nipple involvement, and young age or
premenopausal status have also been associated with postmastectomy
recurrence and therefore may influence decisions regarding adjuvant
radiotherapy (49,50). Currently, NCCN guidelines recommend use of the
highest pre- or post-treatment stage to make decisions regarding PMRT
in the setting of neoadjuvant chemotherapy.
Omission of Radiotherapy
Consideration of omission of radiotherapy after breast-conserving
surgery may be appropriate for a highly selected patient group. One such
population is women over the age of 70 with small (<2 cm), estrogen
receptor–positive, node-negative tumors. Ten-year results of the CALGB
9343 trial showed that patients who received tamoxifen alone, without
adjuvant radiotherapy, had slightly higher rates of local recurrence (9%
vs. 2%), but with no difference in overall survival (51). Breast-
conserving surgery without adjuvant radiotherapy may also be
appropriate for women with completely resected, small DCIS that is low-
or intermediate-grade (52). Similarly, the randomized RTOG 9804 trial
shows a statistically significant reduction in local recurrence risk for
small, completely resected DCIS, but with very low recurrence rates in
both arms (53).
SIMULATION
Historically, simulation for breast radiation was performed on a
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conventional simulator with asymmetric collimators and a breast tilt
board (54). Currently, most treatment centers in the United States utilize
computed tomography- (CT) based treatment planning.
Supine Intact Breast

The patient is placed in the supine position with arms up on a breast
board, Vac-Lok, or other immobilization device. A tilt should be applied
to the immobilization device in order to isolate breast tissue below the
clavicle. The head is turned slightly to the contralateral side if regional
nodal irradiation is planned. The clinical boundaries of breast are
marked with radiopaque fiducial wire. The medial border is placed at
midline over the sternum, and the lateral border is placed at the
midaxillary line. The superior border is placed at the inferior aspect of
the clavicular head, and the inferior border is placed approximately 2
cm below the inframammary fold. For an intact breast, adjustment of
wires may be required to allow approximately 2-cm margin around
palpable breast tissue, particularly for large-breasted women. A fiducial
wire is also placed over the lumpectomy scar and any drain sites. If
nodal volumes are to be included, a catheter can be placed 3-cm lateral
to the midline sternal catheter toward the contralateral side to facilitate
field design encompassing the IM nodes. Although these catheters are
placed as guides, target delineation is largely based on CT volumes as
discussed below.
A scout CT scan is obtained to verify patient positioning and setup.
Axial 3-mm CT slices are then acquired. The superior border of the CT
scan should be at least 4 cm above the superior border for breast-only
treatment or above the angle of the mandible if treating supraclavicular
nodes. The inferior border should be at least 4 cm below the inferior
catheter. For breathhold technique (further discussion below), the
inferior border is lowered to encompass the tracking device on the
patient’s abdomen. Axial CT images are reviewed at the time of
simulation to identify any needed positioning changes.
A stable reference point is set at the middle of the breast in the
longitudinal direction, at the center of the patient in the lateral
direction, and at the mid-chest level in the vertical direction. This
reference point is projected on the skin with the room lasers, and
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alignment marks are made on the patient with marker and protected
with clear stickers. These can be subsequently used during positioning
on the treatment table as a stable point from which to shift to treatment
isocenter. At some institutions, tattoos are used to delineate alignment
marks. An isocenter may also be selected at the time of simulation.
Prone
Prone positioning can be considered for patients who will not receive
nodal irradiation (55). Improved dose homogeneity and decreased lung
dose have been observed with this technique (56,57). Effect on cardiac
dose varies depending on patient anatomy (57,58). Prone setup may be
particularly beneficial for women with large breasts by facilitating
reduced separation (59).
The patient is initially placed in the supine position with arms up, and
catheters are placed to demarcate the clinical limits of breast tissue as
described for supine simulation. The patient is then positioned in the
prone position on a prone breast board with the ipsilateral breast
suspended in the open area of the breast board with both arms up. The
contralateral breast is pulled away beneath the patient with the support
of the contralateral breast board plate. The head can be turned toward
the treated side, away from the treated side, or in a neutral position
depending on prone breast board style and patient comfort.
A scout CT scan is obtained to verify patient positioning and setup.
Axial 3-mm CT images are then obtained with similar superior and
inferior borders as discussed for supine positioning. Breathhold
technique is not utilized in the prone position. A stable reference point is
set at the middle of the breast in the longitudinal direction, at the center
of the board in the lateral direction, and at the level of the contralateral
breast board plate. This reference point is marked on the patient skin.
Indexing and leveling marks are also made on the patient, primarily on
the back and arms, to maximize reproducibility on the treatment table.
This is particularly important for prone position due to greater
interfraction setup variability compared to supine position (60).
Repeat simulation in the supine position is typically performed for
tumor bed boost planning. For certain tumor locations and/or large
breasts, a lateral decubitus position is preferable to supine positioning
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for en face treatment. In other cases, boost may be best performed in the
prone position, most commonly with minitangent fields. If needed,
repeat simulation should be performed near the end of whole breast
irradiation (WBI) to allow for any changes in tumor bed or seroma.
Postmastectomy
The patient is immobilized in the supine position with both arms above
the head. The mastectomy scar, drain sites, and clinical boundaries of
breast tissue are marked with a radiopaque wire as described for intact
breast simulation. If intact, the contralateral breast can be used to
determine the appropriate location of the inferior, lateral, and superior
borders. The CT scan is then performed as described for breast
conservation. A stable reference point is set on the patient, and
alignment marks are made as discussed above.
Breathhold
The patient is simulated in the supine position as discussed above.
Respiratory gating or active breathing control can be used to monitor
respiration. Respiratory gating utilizes a reflective marker placed on the
patient during simulation and treatment. Marker motion with respiration
is tracked by an infrared camera, and the respiratory pattern is displayed
as a waveform. The patient practices deep inspiration and breathhold a
few times. Gating thresholds are set at the amplitude level where the
patient is able to perform stable deep inspiration breathhold over 15 to
20 seconds. Axial CT images are obtained during breathhold within this
optimal breathhold threshold, as well as during free breathing.
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Figure 30.4 Cardiac sparing with (A) free breathing versus (B) breathhold for treatment of left-
sided breast cancer. Isodose curves are shown at the same level within the breast for a patient
simulated in (A) free breathing and (B) deep inspiratory breathhold.
Active breathing control is an alternative technique in which the

patient breathes through a mouthpiece that is connected to a breathing
control device. This apparatus has respiratory flow monitors and valves
to control inspiration and expiration. The valves are closed to
immobilize breathing motion temporarily when the patient reaches the
optimal inspiratory phase of the respiratory cycle. A nose clip prevents
air leakage and facilitates accurate inspiratory volume measurement.
Axial CT images are obtained during this preselected respiratory phase,
as well as during free breathing.
Deep inspiration breathhold facilitates reduced cardiac dose compared
to free breathing during treatment of left-sided breast cancer for many
patients (61,62). Breathhold and free breathing images are compared at
the time of simulation to determine which position provides better
cardiac sparing (Fig. 30.4).
TREATMENT PLANNING: TARGET DELINEATION

Breast cancer was historically treated using clinical body landmarks. In
the current era of CT-based three-dimensional treatment planning,
targets can be more precisely delineated. CT images from simulation are
exported from the CT acquisition software and imported to the treatment
planning software. Contours of normal structures, including lungs, heart,
and potentially other structures such as the spinal cord, brachial plexus,
and contralateral breast, are drawn on the acquired CT images. Target
structures, including the breast or chest wall are contoured. Regional
lymph nodes consisting of axillary levels I, II, and III, supraclavicular,
and IM nodes are also contoured in the setting of nodal treatment. In the
intact breast setting, the lumpectomy cavity is contoured including
seroma, architectural distortion of the tissue, and any surgical clips
present in the breast.
Contouring is generally performed manually by the treating physician
and planning dosimetrist. However, automated contouring is
increasingly possible with newer treatment planning software (63).
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Studies show that even amongst experts, there is significant
interobserver variability in contouring of breast, chest wall, and regional
nodal targets (64). Published guidelines are available from NRG
Oncology regarding delineation of the breast, chest wall, and regional
draining nodal basins (65). While individual patient anatomy may not
strictly conform to the example images in this atlas, it provides a starting
point for practitioners, and continues to be utilized in current
cooperative group protocols.
Breast Conservation
The desired target in the breast conservation setting is the entire
ipsilateral breast. Care must be taken to ensure adequate coverage of the
tumor bed, particularly if this is located to one edge of the breast tissue.
Treatment of regional nodes may be appropriate after breast
conservation as well. Nodal irradiation has been universally considered
to be indicated in the setting of four or more involved axillary lymph
nodes. Comprehensive nodal irradiation is more controversial in the
setting of one to three positive lymph nodes. However, data recently
reported from the MA20 and EORTC 22922 trials, in which patients with
one to three positive nodes were randomized to WBI with or without
radiotherapy to lymph node targets, indicate at least a trend toward
survival benefit with the addition of nodal irradiation (66,67).
Additionally after publication of the ACOSOG Z0011 study showing
noninferior outcomes for patients who do not receive axillary dissection
in the setting of one or two positive sentinel lymph nodes, an increasing
number of patients are not undergoing axillary dissection after
identification of a positive sentinel node (68,69). An analysis of the
radiotherapy treatment patterns on the ACOSOG Z0011 study showed
that approximately 15% of patients did receive a third field to the
supraclavicular region. Approximately 50% of patients received coverage
of the lower axilla interpreted as high tangents, regardless of treatment
arm (70).
The EORTC 10981–22023 AMAROS trial showed equivalence of
radiotherapy to axillary dissection in controlling the axilla in the setting
of positive sentinel lymph node biopsy after breast conservation (67)
with a significantly lower rate of lymphedema. Therefore, it may be
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increasingly common to consider regional nodal radiotherapy rather
than axillary dissection in the setting of a small number of positive
sentinel nodes. In this context, it may be particularly important for the
radiation oncologist to consider inclusion of at least lower axillary levels
in high tangent fields versus full nodal irradiation with a third field
depending on individual patient risk. Of note, if axillary nodes were not
dissected, the full axilla and supraclavicular nodes (rather than a
supraclavicular field alone without attention to the lower axilla) should
be covered if nodal treatment is desired.
Postmastectomy
The desired target volumes in the setting of postmastectomy
radiotherapy include the chest wall, axillary, supraclavicular, and IM
lymph nodes. Though IM nodes were included in the large randomized
trials evaluating postmastectomy radiotherapy, inclusion of IM nodes in
the setting of PMRT remains controversial. Ten-year results from one
trial comparing outcomes for stage I and II breast cancer patients treated
with mastectomy and postoperative radiotherapy with or without
treatment of the IM nodes demonstrated no difference in overall survival
(71). The recently reported MA20 and EORTC 22922 trials evaluating
inclusion of nodal treatment (or not), also included IM coverage in
addition to axillary and supraclavicular treatment. For many
practitioners, the decision regarding inclusion of IM nodes may be
performed on an individual patient basis to achieve a balance between
local recurrence risk and morbidity of treatment. In particular,
consideration may be given to exclusion of IM nodes when treating left-
sided breast cancer, given concern for cardiotoxicity.
TREATMENT PLANNING: FIELD DESIGN

Tangent Fields for Intact Breast
Tangential fields are designed to encompass the entire breast as defined
by the treating physician (Fig. 30.5A–D). It is important to allow
adequate clearance of breast tissue. The entire contoured tumor bed
should be included within the tangential fields with adequate margin.
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The authors of this chapter recommend a margin of at least 2 cm around
the tumor bed within the tangential field to allow for variation in setup.
The isocenter is generally set along the chest wall, midway between the
superior and inferior aspects of the field. If treatment of only lower
axillary levels is desired, without inclusion of upper axillary or
supraclavicular nodes, high tangents can be considered. In this situation
the upper level of the tangents is raised to ensure coverage of the desired
axillary levels, generally at least level I, possibly also level II depending
on individual patient risk. It is important to note that inclusion of levels
I and II may be best achieved by contouring these axillary levels to
ensure appropriate coverage within tangents.
Tangent Fields for Chest Wall

The entire ipsilateral chest wall target, as defined by the treating
clinician, should be included within the tangential fields (Fig. 30.5E–G).
Fields may require modification to ensure inclusion of the entire
mastectomy scar and drain sites. When drain sites fall significantly
outside the tangents, an abutting electron field can be utilized to
supplement superficial dose in these areas.
Inclusion of Nodal Targets

Breast/chest wall and regional nodal treatment traditionally entails
matching opposed tangents to an anterior oblique supraclavicular field
that is half-beam blocked inferiorly (Fig. 30.5E–G). This can be
accomplished with single isocenter or dual isocenter methods. Couch
rotation and collimator angulation can be used to match diverging field
edges and minimize normal tissue toxicity from overlap (46–49). The use
of half-blocked or over-rotated tangents minimizes tangent beam
divergence into the lung.
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Figure 30.5 Tangent, supraclavicular, and internal mammary field design. (A) Medial and lateral
tangent fields with field entry shapes displayed on skin rendering with patient in the supine
position. (B) Isodose curves for the same supine patient. The isocenter (yellow circle) is located
within the patient at a point that is approximately midway along the central axis. (C) Medial and
lateral tangent fields are shown with field entry shapes displayed on skin rendering with patient in
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the prone position. (D) Isodose curves for the same prone patient. The isocenter (yellow circle) is
located medial to the breast, outside the body. The tumor bed is in red. (E) Single isocenter three-
field beam arrangement. The shared isocenter is marked by a blue sphere. The internal mammary
nodes are included within partially wide tangents. (F) Dual isocenter three-field beam
arrangement. The oblique nodal field isocenter is marked by a blue sphere. The isocenter for the
tangents is within the patient at the location of the red dot. The internal mammary nodes are
included within partially wide tangents. (G) Matched electron beam arrangement. An electron field
is matched medially to opposed tangents and superiorly to the anterior oblique field to encompass
the internal mammary nodes and lower inner chest wall.
Three-Field Single Isocenter

In this technique the single isocenter is set along the match line at the
bottom of the clavicular head (Fig. 30.5E). For the tangential fields, the
superior jaw is set to zero at the level of the isocenter and the inferior
jaw is opened to the inferior marking wire to encompass the entire chest
wall target. The supraclavicular field is designed with an inferior jaw set
to zero at the level of the isocenter and the superior jaw is set to the
level of the bottom of the cricoid cartilage. The supraclavicular field is
obliqued slightly an anterior oblique field to avoid the spinal cord. The
medial jaw edge is set to the lateral vertebral bodies, and custom multi-
leaf collimators (MLCs) can be used to shape this field medially and
laterally. The lateral field edge is set to cover desired axillary levels and
supraclavicular nodes, depending on the clinical situation and desired
axillary targets. While this technique has the advantage of simpler setup
and imaging on the treatment machine, one drawback is that the tangent
field length is limited to 20 cm, and tools for modulating dose are often
restricted further. The superior border of the tangent, that is the match
line, can be adjusted up or down to compensate for this. However,
lowering the match line can result in inadequate dose coverage for the
superior breast tissue area and increases in the ipsilateral lung dose.
Three-Field Dual Isocenter

With this technique, the supraclavicular field isocenter and borders are
placed as described for the single isocenter method. However, for
tangential field design, an isocenter is set along the chest wall
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approximately equal depth from medial and lateral tangential fields and
midway between the superior and inferior borders of the field (Fig.
30.5F). In order to create a nonoverlapping matching plane between the
superior border of the tangents and the inferior border of the half-beam
blocked supraclavicular field, table kick and collimation are utilized for
the medial and lateral tangential fields. Modern treatment planning
software can often perform this automatically and it can then be visually
double-checked within the computer planning software. While this
technique requires more complicated setup and imaging on the
treatment machine, it allows the tangential fields to be greater than 20
cm. This may be required for patients with larger habitus or breast size.
Internal Mammary Nodal Coverage

If the IM nodes are to be treated, multiple methods have been described
to ensure coverage. These include partially wide tangent fields (Fig.
30.5E–F), extended tangent fields, and matching electron/photon fields
(Fig. 30.5G). Dosimetric comparison studies have determined that the
partially wide tangent technique provides the optimal blend of target
coverage and normal tissue sparing (72–74). For patients requiring a
matched electron field, split electron fields using a lower energy below
the third intercostal space can help lower cardiac dose (75).
Supraclavicular/Axillary Field
The supraclavicular and desired axillary nodal levels are generally
included in a single anterior oblique photon field angled off the spinal
cord. The starting angle is often 15 degrees, but this can be adjusted as
needed based on patient anatomy. Historically dose was prescribed to a
depth of 3 cm. However, dose should be prescribed to adequately
encompass the contoured nodal volumes within the desired prescription
dose using modern CT-based treatment planning (Fig. 30.6A–B). Field
borders are set based on contoured nodal volumes, and custom MLCs can
be utilized to avoid spinal cord medially and the shoulder joint as
appropriate laterally. Avoidance of skin flash superiorly in the
supraclavicular region can decrease acute skin reaction and may
preserve a strip of lymphatics within the skin to help minimize risk of
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upper extremity lymphedema.
Posterior Axillary Field

If deeper axillary nodal volumes cannot be adequately encompassed
within a minimum dose of 4,500 cGy through a single anterior oblique
supraclavicular/axillary field without excessive hot spots, the dose to
deeper axillary structures can be supplemented with a posterior axillary
field. This field is designed to oppose the supraclavicular/axillary field.
Conventional field borders are the clavicle superiorly and the tangential
match line inferiorly. The lateral and medial borders are based on
patient anatomy and contoured axillary nodal targets (Fig. 30.6C–E).
The prescribed dose to this field is low, typically in the range of 25 to 50
cGy per day to supplement the dose from the anterior oblique
supraclavicular field.
Alternatively, a full posterior oblique opposed field can be used to
provide supplemental coverage of the entire supraclavicular/axillary
field (Fig. 30.6F–H). This field is designed with a nondivergent medial
border to avoid spinal cord dose. In this setting, the dose is generally
prescribed to a midpoint, and the anterior posterior field weighting can
be adjusted as desired based on patient anatomy, target coverage, and
placement of dose hot spots. In the setting of either type of posterior
field utilization, mixed beam energy, forward planned electronic
compensation, or field-in-field techniques may also be utilized to
improve dose homogeneity.
Dose Modulation
The large variability in tissue thickness within the breast poses a
challenge in achieving a homogeneous dose distribution. Lack of scatter
from lung tissue contributes to insufficient coverage near the central
chest wall region, leading to higher dose elsewhere when a plan is
normalized to provide adequate coverage near the chest wall. Hot spots
are typically greater in women with large breasts due to greater
separation. Traditionally, wedges have been utilized to improve dose
homogeneity (76–79). Physical wedges (typically 15, 30, 45, or 60
degrees) are placed along the desired plane with the heel compensating
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for the thinnest area of breast tissue. Field size is limited within the
wedge plane, with maximum dimension depending on wedge angle.
Alternatively, dynamic wedges use collimator jaw movement while the
beam is on to modulate dose. This allows additional wedge angles,
avoids manual wedge placement by the therapists, and permits larger
field size. Patient-customized physical compensators can also be used,
although construction of these devices is impractical due to the required
labor and time involved (80,81). Mixed beam energies represent another
simple method of improving dose homogeneity with standard tangential
fields (82,83).
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Figure 30.6 Supraclavicular and axillary nodal fields. (A) Digital reconstructed radiograph (DRR)
of a nodal field for a patient who has undergone a complete axillary dissection. The anterior
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oblique field has been shaped to include only the undissected axilla and supraclavicular region.
(B) DRR of a nodal field for a patient who has not undergone an axillary dissection or for whom
full axillary coverage is indicated. The field extends farther laterally than is seen in panel A to
encompass the entire axilla and supraclavicular region. (C–E) DRRs for a right anterior oblique
field (C) and partial posterior axillary boost beam (D) with an axial image (E) showing both fields.
(F–H) DRRs for a right anterior oblique field (F) and full opposed left posterior oblique field (G)
with an axial image (H) showing both fields. Axillary level I is yellow, II is green, III is brown, and
supraclavicular nodal region is red.
Several studies have shown reduced short-term toxicity and improved

cosmesis with intensity modulated radiation therapy (IMRT) compared
to wedge-based tangential whole breast radiotherapy (84–89). Improved
cardiac dose sparing has been proposed as an additional benefit (90–96).
Breast IMRT studies have utilized various techniques including “field-in-
field” or multi-segmented 3D conformal radiotherapy, inverse and
forward planned techniques, and dynamic or segmental multileaf
collimator modes. Helical tomotherapy and volume modulated arc
therapy (VMAT) have been introduced as additional methods of dose
modulation.
The American Society for Radiation Oncology (ASTRO) recently
recommended against routine usage of IMRT to deliver whole breast
radiotherapy. This was one of five recommendations released in 2013 for
the Choosing Wisely campaign, identifying treatment options that should
be carefully considered to avoid overuse (97). Inverse planned IMRT
should be limited to specific breast cancer cases such as patients with
unusual anatomy, where this technique will more likely provide
significant clinical benefit (98–101).
Electronic tissue compensation (ECOMP) represents an alternative
method of modulating dose to achieve homogeneous dose distribution.
ECOMP involves forward planning to modify the fluence distribution
manually within each tangential field to improve dose homogeneity.
Treatment planning software subsequently converts the fluence maps to
dynamic multileaf collimation sequences for treatment delivery. ECOMP
requires less planning time and utilizes fewer monitor units to deliver
compared to inverse planning IMRT, while providing similar target
coverage and normal tissue sparing (102,103).
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Normal Tissue Dose Constraints
The primary organs at risk during breast and chest wall irradiation are
the lungs and heart. Dose to the opposite breast should also be
minimized to reduce risk of radiation-induced contralateral breast
cancer. Lung dose has been correlated with radiation pneumonitis, and
V20 Gy ≤20% has been associated with significantly lower incidence of
radiation pneumonitis (104). However, achieving an ipsilateral lung V20
Gy ≤20% can be difficult when IM nodes are targeted. Symptomatic
radiation pneumonitis is rare with ipsilateral lung V20 Gy <30%
(105,106). Ipsilateral lung dose-volume constraints of V20 Gy ≤20% and
V20 Gy ≤30% are commonly accepted in breast treatment planning
(107).
Breast radiotherapy has been associated with cardiac mortality in
numerous trials predating the era of CT-based radiation treatment
planning (108–110). More recent studies indicate that radiotherapy-
associated cardiac toxicity has decreased with the advent of modern
treatment planning techniques (111–113). Normal Tissue Complication
Probability models in the Quantitative Analyses of Normal Tissue Effects
in the Clinic (QUANTEC) guidelines estimate a <1% risk of cardiac
mortality at 15 years with a cardiac V25 Gy <10% (114). A large
population-based case-control study of patients with prior radiotherapy
for breast cancer showed a linear increase in major coronary events of
7.4% per Gray mean radiation dose to the heart with no apparent
threshold (115). Shielding blocks or multileaf collimators should be used
to minimize radiation dose to the heart. Prone positioning, deep
inspiratory breathhold, and dose modulation techniques discussed above
may also facilitate lower cardiac doses.
Treatment Imaging
The CT dataset is used to create digitally reconstructed radiographs
(DRR) for orthogonal setup films (AP and lateral) and beam’s eye view
for each tangential treatment field. Port films and kV on-board imaging
are performed before delivering the first treatment to confirm isocenter
location and patient positioning. Imaging frequency during the
treatment course depends on numerous factors, including daily setup
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variability, patient positioning, and utilization of respiratory gating.
Free-breathing treatment in supine position typically requires less
frequent imaging than breathhold or prone breast treatment. Supine
treatment with respiratory gating requires port images for the first few
days to confirm patient breathhold level. Prone position typically
requires daily orthogonal setup imaging since the treatment area is
difficult to visualize.
DOSE AND FRACTIONATION

Breast Conservation
WBI has historically delivered 45 to 50 Gy in 25 to 28 fractions at 1.8 to
2 Gy per fraction. However, 10-year data from multiple large
randomized trials have demonstrated the noninferiority of
hypofractionated whole breast radiotherapy (42.5 Gy in 16 fractions
(116) or 40.05 Gy in 15 fractions (117)). The Canadian trial included
only node-negative patients and placed restrictions on breast size and
treatment hot spots (116). The UK START trials had broader inclusion
criteria, including approximately 25% node-positive patients (117).
Hypofractionated WBI should be strongly considered for appropriate
patients, given the high-quality evidence supporting its safety and
efficacy. This was highlighted in one of the ASTRO 2013 Choosing
Wisely recommendations, stating not to initiate radiotherapy in women
aged 50 years or older with early-stage invasive breast cancer without
considering a hypofractionated treatment schedule (97). ASTRO has also
released guidelines on dose and fractionation schedules in patients
appropriate for hypofractionated radiotherapy (118). Prone positioning
and advanced dose modulation strategies may help improve dose
homogeneity and increase the number of patients appropriate for
hypofractionation. More hypofractionated regimens are currently under
investigation, such as 28.5 or 30 Gy in five once-weekly fractions of 5.7
or 6 Gy (119).
If nodal targets are included in the treatment of the intact breast
setting, treatment planning and dose coverage are as described in the
postmastectomy setting. The authors are not currently using
hypofractionated radiotherapy in the treatment of lymph nodes on a
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routine basis, though it should be noted that this is more commonly used
in other countries (120,121). Patients with N1 disease were included on
the UK START trials, and a subset of patients received hypofractionated
nodal irradiation. Additionally, the original British Columbia
postmastectomy radiotherapy trial utilized a hypofractionated course
(37.5 Gy in 16 fractions). This regimen was well-tolerated; however, no
fractionation randomization was included in this trial (43).
Postmastectomy
Standard prescribed dose to the chest wall and IM nodes is 45 to 50.4 Gy
in 25 to 28 fractions. In most cases, chest wall bolus is utilized to ensure
adequate dose to the skin and superficial subcutaneous tissue. Significant
heterogeneity exists in the accepted bolus thickness and schedule (107).
The authors’ preferred technique is 0.5–1 cm bolus applied every other
day. However, this is modified based on the clinical situation and
estimated patient risk. More frequent bolus schedules, including possibly
daily bolus, may be considered for the patients at highest risk,
particularly those with IBC.
Tumor Bed Boost

Randomized controlled trials have demonstrated improved local tumor
control with additional radiotherapy to the tumor bed for patients with
invasive breast cancer in the setting of breast conservation (122–124). A
greater absolute benefit was observed for younger patients. There are no
level one data evaluating boost for DCIS, but practitioners often
extrapolate from the invasive data and utilize a boost in these patients.
This is particularly true in the setting of close or positive margins and for
young patients, supported by one series that showed a benefit for boost
in women younger than 40 years of age (125). A tumor bed boost
usually consists of 10 Gy to 16 Gy at 2 to 2.5 Gy per fraction delivered
to the lumpectomy cavity, typically with 1.5- to 2.5-cm additional
margin. Boosting to a total tumor bed dose greater than 60 Gy should be
considered in patients with positive margins.
Tumor bed boost is typically administered by en face electrons, with
beam energy chosen based on tumor depth. A normalization point can
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be set at D-max for the chosen electron energy and dose prescribed to
the desired isodose level. Alternatively, dose can be prescribed to a
specific depth. Photons may be necessary to provide adequate coverage
for deep tumors depending on patient anatomy. In this case, generally a
4- to 5-beam bouquet is used, often in a noncoplanar arrangement to
minimize exit dose into the lungs, heart, or contralateral breast.
Brachytherapy can also be utilized to deliver the boost dose, although
this is rarely performed (123). Historically, the boost has been
administered sequentially after WBI; however, studies are ongoing to
investigate simultaneous integrated photon boost (126).
Mastectomy Scar Boost

A radiotherapy boost is commonly administered to the mastectomy scar
in the postmastectomy setting based on extrapolation of tumor bed boost
data. While most local recurrences after mastectomy occur at or near the
scar (127), no randomized controlled trials have examined whether
additional radiotherapy provides any benefit. One retrospective review
has shown reduced local recurrence and improved survival in patients
with stage II–III breast cancer receiving a chest wall boost above 50.4 Gy
(128,129). Mastectomy scar boost typically consists of 10 Gy at 2 to 2.5
Gy per fraction delivered by en face electrons to a margin of 2 to 3 cm
around the scar. Additional dose above 60 Gy may be considered in
particularly high-risk settings such as IBC or other skin involvement.
PARTIAL BREAST IRRADIATION

Accelerated partial breast irradiation (APBI) is an alternative to WBI for
a subset of patients with low-risk breast cancer. APBI targets the
lumpectomy cavity with a small margin of normal surrounding tissue.
This limited treatment volume is based on studies showing that most
local recurrences occur in or near the tumor bed after breast-conserving
therapy (130–134). Irradiation of a smaller normal tissue volume allows
delivery of a higher dose per fraction and shorter total treatment course.
This may offer improved patient convenience and treatment
accessibility, as well as decreased healthcare system costs.
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Patient Selection
Appropriate patient selection for use of partial breast irradiation is
essential, particularly given the absence of long-term results from
randomized trials comparing APBI with conventional WBI. Several
groups have released selection guidelines, highlighting a favorable-risk
patient population with small tumors, negative margins, and no lymph
node involvement. APBI is typically not recommended for younger
women or patients with invasive lobular histology.
Treatment Planning
Several techniques can be utilized to deliver APBI, including
brachytherapy, intraoperative radiotherapy (IORT), and external-beam
radiotherapy (EBRT). The longest follow-up is available for
brachytherapy, but the optimal APBI method has not been determined
(135). The NSABP B-39/RTOG 0413 trial randomizing patients to APBI
or WBI allowed use of multicatheter brachytherapy, MammoSite balloon
catheter, or three-dimensional conformal radiation therapy (3D-CRT) in
the APBI treatment arm.
Simulation for treatment planning entails CT in the prone or supine
position as described previously for WBI. The lumpectomy cavity,
including surgical clips and postoperative changes, is outlined. Typical
postoperative clinical target volume (CTV) for EBRT-based APBI consists
of the lumpectomy cavity expanded by 1 to 1.5 cm (136–143). An
additional 0.5 to 1 cm is generally added to generate the planning target
volume (PTV), accounting for setup variability and patient motion. The
seroma cavity with 1- to 2-cm margin is the recommended PTV for
brachytherapy-based APBI (144).
Promising cosmetic and local control outcomes have been
demonstrated with brachytherapy-based APBI. The Budapest randomized
controlled trial demonstrated excellent local control and superior
cosmesis with interstitial APBI compared to WBI at 10 years (145).
Similar results have been shown in in small single-institution series and
the RTOG 95–17 phase II trial using multicatheter interstitial
brachytherapy (146–148). Implantation for interstitial brachytherapy is
typically performed under general anesthesia. The tumor bed is localized
by CT or an Integrated Brachytherapy Unit to visualize surgical clips,
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and catheters are inserted into the tumor bed and surrounding tissue.
Repeat CT or orthogonal x-ray imaging is performed to reconstruct
catheter placement for dosimetric planning. The most common
interstitial catheter dose regimens are 45 to 50 Gy over 4 days, 32 to 34
Gy in twice daily 4 Gy fractions over 4 to 5 days, and 36.4 Gy in twice
daily 5.2 Gy fractions over 4 days (HDR) (145–147).
Intracavitary and hybrid brachytherapy techniques have recently
gained favor due to increased reproducibility and easier use compared to
interstitial catheter placement. Available devices, including MammoSite,
Contura, SAVI, Axxent, and ClearPath, are typically placed into the
lumpectomy cavity at the time of surgery or postoperatively under
image guidance. A CT scan is performed to evaluate the quality of the
implant, including assessment of conformity to the cavity and distance to
skin (ideally ≥7 mm). Several dosimetric optimization methods have
been described (149). Data from the American Society of Breast
Surgeons MammoSite registry show excellent cosmesis and local control
comparable to WBI in a highly selected patient population receiving 34
Gy in 3.4 Gy fractions twice daily over 5 days (150).
IORT involves delivery of a single dose to the lumpectomy bed at the
time of resection. Two randomized controlled trials have shown slightly
higher local recurrence rates with IORT compared to external-beam WBI,
though low in both arms (151,152). The TARGIT technique delivers
approximately 20 Gy to the tumor bed surface from a point source of 50
kV x-rays within a spherical applicator (1.5- to 5-cm diameter, selected
to fit tumor bed dimensions) (151). Electron intraoperative radiation
therapy (ELIOT) uses a linear accelerator to deliver 21 Gy to the tumor
bed intraoperatively with 3 to 12 MeV electrons (152).
Numerous EBRT techniques have been utilized to deliver APBI without
requiring specialized equipment or training. 3D-CRT entails using three
to five noncoplanar conformal fields with different wedge angles, while
IMRT utilizes four to five coplanar or noncoplanar fields with dynamic
MLC movement. Beam orientations should be selected to minimize dose
to the critical normal structures. VMAT utilizes one or two partial arcs
with varying speed of gantry rotation, MLC movement, and dose rate.
Prescription dose is typically 3.85 Gy twice daily to 38.5 Gy
administered within 1 week. Notably, several studies utilizing these
widely available external-beam techniques have demonstrated
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suboptimal cosmetic outcomes (136,141,143). Increased rates of
subcutaneous fibrosis and fair to poor cosmesis have been associated
with large volumes of breast tissue receiving relatively high dose
(141,143). An analysis of patients treated with 3D-CRT APBI showed
high rates of excellent to good cosmesis when the ipsilateral breast
volume receiving more than 50% of the prescribed dose remained below
40% (153).
KEY POINTS
• Nodal involvement is common in breast cancer, with axillary nodes
most frequently involved regardless of tumor location within the
breast.
• Adjuvant whole breast irradiation is standard after breast-

conserving surgery to reduce locoregional recurrence risk and to
improve survival. Postmastectomy radiotherapy is typically
recommended for patients with nodal involvement, particularly >3
positive lymph nodes.
• Prone positioning may facilitate improved dose homogeneity and

reduced normal tissue dose for certain patients, particularly in the
setting of large, pendulous breasts.
• Contouring target volumes, including tumor bed and nodal regions

(if indicated), facilitates field design with CT-based three-
dimensional treatment planning.
• Medial and lateral tangential fields are designed to encompass the

entire breast or chest wall with adequate margin to allow for setup
variation.
• An anterior oblique field is utilized to cover the supraclavicular

nodes and undissected axilla. This field is matched inferiorly with
opposed tangents using a single or dual isocenter technique. IM
nodal coverage may be achieved with partially wide tangents,
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extended tangents, or matched electron fields.
• Wedges may be used to improve dose homogeneity within the

breast. Newer dose modulation methods include electronic
compensation and “field-in-field” techniques.
• Cardiac dose should be minimized using multileaf collimators.

Deep inspiratory breathhold or prone position may also facilitate
reduced cardiac dose.
• Standard whole breast radiotherapy fractionation is 45 to 50 Gy in

25 to 28 fractions. Hypofractionated whole breast radiotherapy is
also appropriate for many patients. Commonly used dose regimens
are 40.05 Gy in 15 fractions or 42.5 Gy in 16 fractions.
• Tumor bed boost is generally performed with en face electrons to

treat the lumpectomy cavity plus 1.5- to 2.5-cm margin.
• Accelerated partial breast irradiation is typically limited to older

patients with small tumors and no nodal involvement. Treatment
modalities include brachytherapy, intraoperative radiotherapy, and
external-beam radiotherapy.
QUESTIONS
1. Which of the following is NOT a risk factor for development of
breast cancer?
A. BRCA1 mutation
B. Young age
C. Radiation exposure
D. Early menarche
2. Which of the following is a potential benefit from treatment in
breathhold?
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A. Decreased radiation dose to heart
B. Decreased radiation dose to ipsilateral lung
C. Easier patient setup and shorter treatment time
D. Better axillary nodal coverage
3. Which of the following is a disadvantage of three-field single
isocenter versus three-field dual isocenter technique?
A. Increased contralateral lung dose
B. Supraclavicular nodal coverage omitted
C. More complicated setup
D. Tangent field size limited to 20 × 20 cm
4. All of the following are techniques used to cover internal
mammary nodes EXCEPT
A. Partially wide tangents
B. Three-field dual isocenter
C. Extended tangents
D. Matching photon and electron fields
5. Which of the following is a typical expansion on the lumpectomy
cavity to generate a clinical treatment volume (CTV) for tumor
bed boost?
A. 0.5 cm
B. 1 cm
C. 2 cm
D. 3 cm
ANSWERS
1. B Breast cancer incidence rises with increasing age.
Therefore, older age rather than young age is a risk factor
for developing breast cancer. Additional risk factors
include BRCA1 and BRCA2 mutations, radiation exposure,
early menarche, nulliparity, and late menopause.
2. A Deep inspiration breathhold often facilitates decreased
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cardiac dose when treating left-sided breast cancer. Longer
treatment time and more difficult patient setup are
required for respiratory gating with the breathhold
technique. Ipsilateral lung dose and nodal coverage are not
significantly affected by breathhold.
3. D Tangent field size is limited to 20 × 20 cm for three-field
single isocenter technique. Patient setup and imaging is
simpler with a single isocenter compared to dual isocenter.
Both techniques include an anterior oblique field for
supraclavicular nodal coverage. Contralateral lung dose
does not differ between techniques.
4. B Three-field dual isocenter technique is utilized to cover
supraclavicular nodes and the undissected axilla. Partially
wide tangents, extended tangents, and matching
photon/electron fields can be used to cover internal
mammary nodes.
5. C The tumor bed boost CTV typically includes the
lumpectomy cavity with a 1.5- to 2.5-cm margin.
REFERENCES
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142. Chafe S, Moughan J, McCormick B, et al. Late toxicity and patient
self-assessment of breast appearance/satisfaction on RTOG 0319: a
phase 2 trial of 3-dimensional conformal radiation therapy-
accelerated partial breast irradiation following lumpectomy for
stages I and II breast cancer. Int J Radiat Oncol Biol Phys. 2013;
86(5):854–859.
143. Leonard KL, Hepel JT, Hiatt JR, et al. The effect of dose-volume
parameters and interfraction interval on cosmetic outcome and
toxicity after 3-dimensional conformal accelerated partial breast
irradiation. Int J Radiat Oncol Biol Phys. 2013;85(3):623–629.
144. Shah C, Vicini F, Wazer DE, et al. The American Brachytherapy
Society consensus statement for accelerated partial breast
irradiation. Brachytherapy. 2013;12(4):267–277.
145. Polgar C, Fodor J, Major T, et al. Breast-conserving therapy with
partial or whole breast irradiation: ten-year results of the Budapest
randomized trial. Radiother Oncol. 2013;108(2):197–202.
146. Vicini FA, Antonucci JV, Wallace M, et al. Long-term efficacy and
patterns of failure after accelerated partial breast irradiation: a
molecular assay-based clonality evaluation. Int J Radiat Oncol Biol
Phys. 2007;68(2):341–346.
147. King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field
brachytherapy as the sole method of radiation therapy after
segmental mastectomy for T(is,1,2) breast cancer. Am J Surg. 2000;
180(4):299–304.
148. Rabinovitch R, Winter K, Kuske R, et al. RTOG 95–17, a Phase II
trial to evaluate brachytherapy as the sole method of radiation
therapy for Stage I and II breast carcinoma–year-5 toxicity and
cosmesis. Brachytherapy. 2014;13(1):17–22.
149. Dickler A, Kirk MC, Chu J, et al. The MammoSite™ breast
brachytherapy applicator: a review of technique and outcomes.
Brachytherapy. 2005;4(2):130–136.
150. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with
accelerated partial breast irradiation (APBI): final analysis of the
American Society of Breast Surgeons MammoSite((R)) breast
brachytherapy registry trial. Ann Surg Oncol. 2013;20(10):3279–
3285.
151. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted
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intraoperative radiotherapy versus whole-breast radiotherapy for
breast cancer: 5-year results for local control and overall survival
from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603–
613.
152. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative
radiotherapy versus external radiotherapy for early breast cancer
(ELIOT): a randomised controlled equivalence trial. Lancet Oncol.
2013;14(13):1269–1277.
153. Mellon EA, Sreeraman R, Gebhardt BJ, et al. Impact of radiation
treatment parameters and adjuvant systemic therapy on cosmetic
outcomes after accelerated partial breast irradiation using 3-
dimensional conformal radiation therapy technique. Pract Radiat
Oncol. 2014;4(3):e159–e66.
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31 Cancers of the Central Nervous
System
Vinai Gondi, Wolfgang A. Tome, and Minesh P. Mehta
INTRODUCTION
The central nervous system (CNS) comprises the brain, the spinal cord,
and their coverings. Patients with benign lesions may live out their
natural lifespan, whereas the survival of those with malignant tumors is
frequently measured in months to years. The optimal radiation therapy
treatment technique should maximize the therapeutic benefit and
minimize the potential toxicities, especially for long-term survivors.
EPIDEMIOLOGY
Primary Central Nervous System Tumors
Annually, an estimated 86,000 new cases of primary nonmalignant and
malignant CNS tumors are diagnosed in the United States with an
estimated 13,000 deaths (1,2). The incidence of all primary
nonmalignant and malignant brain and CNS tumors is 21.42 cases per
100,000 person-years. In the United States, the rate is slightly higher in
females (23.26 per 100,000 person-years) than males (19.42 per 100,000
person-years) (2). The incidence rates are higher in more developed
countries than in less-developed countries (3). The incidence rate of
childhood primary nonmalignant and malignant brain and CNS tumors is
5.42 cases per 100,000 person-years (2).
Most of the primary CNS tumors are located within the frontal,
temporal, parietal, and occipital lobes of the brain. Sixty-one percent of
gliomas occur in the frontal, temporal, parietal, and occipital lobes.
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Tumors in other locations in the cerebrum account for another 5%. Of
all tumors, 1%, 3%, and 4% are found in the ventricles, cerebellum, and
brainstem, respectively. The pituitary and craniopharyngeal duct
account for 16% of tumors. Tumors of the meninges represent 36% of all
tumors (2).
The overall incidence of primary spinal cord and cauda equina tumors
is approximately 3% of all primary CNS tumors (4). Schwannomas and
meningiomas account for 61% of primary spinal tumors, with
meningiomas being more frequent; both types occur primarily in adults.
The frequency of individual spinal cord tumors is quite different from
that of their histopathologic counterparts in the brain. Gliomas
constitute 46% of primary intracranial tumors but only 23% of spinal
tumors. The incidence ratios of intracranial to intraspinal astrocytomas,
ependymomas, and meningiomas are approximately 10:1, 3:1, and 18:1,
respectively (5). Finally, the incidence ratio of intracranial to intraspinal
tumors is higher up to four times in pediatric patients than in adults.
Table 31.1 shows the current WHO pathologic classification system of
common primary CNS tumors (6). The most frequently reported
histology is meningioma, which accounts for over 36% of all tumors,
followed closely by glioblastoma and astrocytoma (2). The
predominately benign nerve sheath tumors account for 8% of all tumors,
of which 54% are acoustic neuromas. Gliomas account for 28% of all
primary brain and CNS tumors and 80% of malignant tumors (2). The
most common spinal cord intramedullary tumors are those that are
derived from glial precursors (astrocytes, ependymocytes, and
oligodendrocytes) (7).
Tumors Metastatic to the Central Nervous System

Metastatic brain tumors are the most common intracranial neoplasms in
adults and are about 10 times more common than primary intracranial
tumors. In two cohorts of patients diagnosed with colorectal, lung,
breast, or kidney carcinoma or melanoma, brain metastases were
diagnosed in 8.5% to 9.6% (8,9). The cumulative incidence was
estimated between 16% and 20% in patients with lung carcinoma, 7% in
patients with renal carcinoma, 7% in patients with melanoma, 5% in
patients with breast carcinoma, and 1% to 2% in patients with colorectal
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carcinoma.
With the exception of a primary paraspinal or neuraxis tumor, spinal
cord tumors occur most often in the setting of disseminated disease from
a distant primary tumor site. The spine is overall the most common site
of bony metastases, with a reported incidence of 40% in patients with
cancer (10). Of those patients with spine metastases, 10% to 20%
develop malignant spinal cord compression (MSCC), accounting for
14,100 to 28,200 cases annually (11–13). MSCC from epidural
metastases occurs in 5% to 10% of all patients with cancer and in up to
40% of patients with preexisting nonspinal bone metastases (10,14–16).
MSCC may involve the spinal cord at any level, and symptoms depend
on the location of the compression. The incidence of MSCC by vertebral
levels is 10% to 16% cervical, 35% to 40% in T1 to 6, 44% to 55% in T7
to 12, and 20% in the lumbar spine (17–19). In 10% to 38% of cases,
metastatic lesions present initially at multiple, noncontiguous levels
(17,20,21).
TABLE 31.1 WHO Grades of CNS Tumors
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The histology of MSCC follows the incidence patterns of primary
malignancies, with the most common histologic diagnoses (i.e., breast,
lung, and prostate) accounting for approximately half of all cases (1,10).
Approximately 25% of all patients with MSCC have breast cancer, 15%
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have lung cancer, and 10% have prostate carcinomas. Overall, 5.5% of
patients with breast cancer, 2.6% of patients with lung cancer, 7.2% of
patients with prostate cancer, and 0.8% of patients with colorectal
cancer experience an MSCC (12). Other commonly reported histologic
diagnoses in adults include, in the order of cumulative incidence,
multiple myeloma, nasopharynx, renal cell, melanoma, small cell lung,
lymphoma, and cervix (10,12,22).
WORKUP AND STAGING

For both benign and malignant CNS tumors, magnetic resonance
imaging (MRI) is the gold standard for imaging (23). The preferred slice
thickness of MRI is ≤5 mm with ≤2.5 mm slice sampling, although
1.25 mm slice thickness on newer MRI volumetric sequences permits
more detailed visualization. T1-weighted images with contrast provide
excellent visualization of contrast-enhancing tumors, such as
meningiomas, glioblastoma multiforme, and brain metastases. T2-
weighted images generally demonstrate areas of edema, and T1-
weighted fluid-attenuated inversion recovery (FLAIR) images better
delineate infiltration by low- or high-grade gliomas. MRI registration
with the treatment-planning computed tomography (CT) scan is
therefore essential for target delineation. Additional imaging studies can
reflect the biologic characteristics of CNS tumors, such as tumor
metabolism, proliferation, oxygenation, blood flow, and the function of
surrounding normal brain; these include MRI spectroscopy, fMRI, PET
scans, and single photon emission tomography (SPECT) scans (24–26).
After radiation therapy, PET scans and MRI spectroscopy assist in
differentiating active tumor versus radionecrosis.
MRI of the entire neural axis along with cerebrospinal fluid (CSF)
cytology is required for staging of tumors with a high propensity for
spread within the CNS by involvement of the CSF, leptomeninges, or
spinal cord. These tumors include medulloblastomas, primitive
neuroectodermal tumors (PNETs), anaplastic ependymomas, choroid
plexus carcinomas, pineoblastomas, germ cell tumors, and lymphomas.
In patients who present for urgent symptom management, CT scan can
be obtained rapidly, providing information on ventricular obstruction,
hemorrhage, or edema. Owing to the risk of herniation and death,
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lumbar puncture should be avoided, if at all possible, until the
intracranial pressure has normalized. The most important modality in
the workup of suspected MSCC is gadolinium-enhanced MRI of the entire
spinal axis. In the initial evaluation of a patient with suspected
metastatic spinal cord compression, it is critical to image the entire
spine, as 25% of these patients have spinal cord compression verified at
multiple levels by MRI, and approximately two-thirds of these have
involvement of different regions of the spine (27). In addition, a sensory
level present on patient evaluation may be two or more levels different
from the actual lesion on MRI in 28% of patients, and four or more
levels distant in 21% of patients (27).
GENERAL MANAGEMENT
Multimodality therapy for CNS tumors may consist of medical therapy,
surgical resection, radiation therapy, or some combination of the above.
Medical Therapy
Medical treatment generally consists of steroids with or without
mannitol (28). Patients who present with emergent symptoms are
typically treated with dexamethasone. Response to therapy is usually
noted within 12 to 18 hours of administration with over 80% of patients
showing dramatic improvement by 3 to 4 days after initiation of therapy
(29,30). A common regimen in patients receiving radiation therapy is
high dose dexamethasone (10 to 25 mg IV or po) followed by
maintenance on oral steroids (4 to 6 mg three or four times a day), with
tapering initiated upon stabilization of symptoms and initiation of
therapy, usually over 1 to 2 months (28,31,32). In the setting of MSCC
from solid tumors, dexamethasone has been shown to improve rates of
surviving with intact gait function (33,34). Side effects of intermediate
to long-term steroid use may include hyperglycemia, insomnia,
emotional lability, thrush, gastric irritation, ulceration and possibly
perforation, proximal muscle wasting, weight gain and adiposity (moon
facies, buffalo hump, and centripetal obesity), osteoporotic compression
fractures, arthralgias with withdrawal, and aseptic necrosis of the hip
joints (35). Some of these side effects persist even after steroid
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withdrawal. Owing to the incidence of steroid-induced complications
with dosing longer than 21 days in duration, higher doses and longer
tapering schedules should be based on the physician’s assessment of
symptom severity and response (34,36,37). Patients should be instructed
during tapering to note signs of worsening headaches and/or existing
neurologic deficits. They should be instructed to resume a higher steroid
dose should such symptoms occur and consult their physician.
Asymptomatic patients generally do not require corticosteroids and
routine use of corticosteroids during radiation therapy in asymptomatic
patients should be avoided. Select patients with MSCC may not receive
steroids during treatment if they are at high risk of complications due to
underlying medical comorbidities, such as peptic ulcer disease,
uncontrolled diabetes, or other medical problems that may cause severe
or life-threatening problems if exacerbated by steroids (38).
Dexamethasone and mannitol decrease peritumoral brain edema by
different mechanisms of action and mannitol is therefore often used in
steroid-refractory patients (39). A common regimen of mannitol is a 20%
to 25% solution given intravenously over 30 minutes dosed at 0.5 to 2.0
g/kg (40).
Stabilization of the patient in status epilepticus is critical (41). After
securing the airway and stabilizing the patient, seizure activity must be
terminated as rapidly as possible, especially as failure to control seizures
can potentially lead to physical injuries, airway compromise, secondary
brain hypoxia/injury, or coma (40,41). Rapid onset/short-acting
benzodiazepines and phenytoin are commonly used. Recommended
initial regimens include 0.1 mg/kg at 2 mg/min of lorazepam or
diazepam at 0.2 mg/kg at 5 mg/min. Phenytoin infusion of 15 to
20 mg/kg at <50 mg/min in adults is indicated for seizure activity
refractory to benzodiazepines or after truncation of seizures with
diazepam (41). There is no clear evidence to support the prophylactic
use of anticonvulsants in patients diagnosed with a brain tumor in the
absence of documented seizures (42,43).
Surgical Therapy
Surgical resection and/or placement of a shunt are often required for
emergent management of brain tumors causing life-threatening
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hydrocephalus, mass effect, or profound neurologic impairment. This
may relieve symptoms enough for other treatment modalities to be
initiated. Symptoms are usually related to mass effect, so resection or
debulking are often the only logical choices if medical therapy fails to
provide improvement in neurologic symptoms. Rapid surgical
decompression is the treatment of choice for such problems when
surgery can be safely performed based on patient performance status or
tumor location.
Two randomized trials comparing radiotherapy with or without
surgical resection in the management of a solitary brain metastasis have
documented a survival advantage with the addition of surgery over
radiation alone (44,45). However, a third randomized trial was negative
(46). There is no level I evidence demonstrating any survival benefit
from operating on patients with multiple metastases. However, patients
with severe neurologic symptoms from one or more dominant metastases
who are unresponsive to medical therapy may benefit from a
craniotomy. An improvement in the patient’s performance status can
then be followed by external-beam radiation therapy.
Many patients with spinal cord compression are not candidates for
laminectomy and are treated with steroids and radiation therapy. Most
series in the literature show no difference in outcomes when comparing
laminectomy-treated patients to those managed with radiation therapy
alone (10,19,47,48). However, a randomized trial evaluating the benefit
of adding surgical decompression to the radiotherapeutic management of
symptomatic metastatic spinal cord compression showed that patients
who underwent decompressive surgery had a significantly improved
median time of gait retention and ability to regain gait function albeit
without affecting overall survival (49). Therefore, all patients presenting
with MSCC of short duration should be evaluated by an experienced
spine surgeon for emergent decompression before initiating radiation
therapy.
GENERAL CONCEPTS OF RADIATION THERAPY

Multimodality Imaging for Simulation, Treatment Planning,
and Dose Delivery
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The success of modern radiation therapy, besides the introduction of
new irradiation technologies, can also partially be attributed to the
development and availability of various novel imaging techniques that
help to (i) better delineate targets and regions of avoidance, (ii) better
understand the dosimetrically relevant composition of the tissue in the
path of the radiation, (iii) lower the setup uncertainty of the patient, (iv)
verify the location of the target during dose delivery, and (v) assess the
location of the deposited dose.
A high-resolution CT scan acquired at the time of treatment planning
simulation provides a 3-dimensional (3D) voxel grid of the patient. In
each voxel, the CT software calculates the linear attenuation coefficient
of the matter contained in it. Based on this, each voxel gets assigned a
shade of gray (for visualization purposes of the tissue) and a CT number,
the Hounsfield Unit, which later is translated into physical density in the
treatment planning software (for dose calculation purposes). Since the
CT modality has poor soft tissue contrast, iodine-based contrast agents
are often injected into the blood to better visualize vessels or tumors.
Images with sub-millimeter voxel dimensions can be acquired with only
a minute or two scanning time.
MRI is a complementary imaging modality to CT. Since it does not
involve ionizing radiation and has very good soft tissue contrast, it is one
of the most widely used imaging modalities in the management of CNS
tumors. Its signal is based on relaxation properties of proton spins in a
strong external magnetic field. Based on the signal strength of each voxel
received during imaging, a shade of gray is assigned and the image is
reconstructed. Numerous sequences have been researched and developed
to (i) disturb the spin lattice of patients’ protons in the applied external
magnetic field and (ii) detect their relaxation properties.
The two most commonly known techniques are the T1- and T2-
weighted sequences, where T1 and T2 are the longitudinal and
transverse relaxation times of proton spins, respectively. Generally
speaking, the shorter the voxel’s T1, the more signal it produces, and it
appears brighter on the scan. On the other hand, the longer the T2, the
longer the signal is acquired, making the signal-producing tissue
brighter. Water in the bulk phase (e.g., CSF) has long T1 and T2
relaxation times; therefore, it appears dark on T1-weighted but bright on
T2-weighted acquisitions. Gadolinium-based contrast agents, which
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lower T1 relaxation times, are often utilized to enhance brain tumor
appearance. Because several tumors compromise the brain–blood
barrier, they permit entrance of contrast agents which lower the T1 time,
making the tumor brighter on T1-weighted images. Vasogenic edema
associated with brain tumors appears bright on T2-weighted images.
Oftentimes extremely high spatial resolution is needed (e.g., for
visualization of cranial nerves), in which case the constructive
interference steady state (CISS, also called FIESTA) sequence is utilized.
If visualization hyperintense abnormalities obscured by CSF within
ventricles is needed, a specialized MRI technique called FLAIR can be
utilized to dampen the signal from the CSF. Magnetic resonance
spectroscopy (MRS) measures the levels of various metabolites in body
tissues. It can be tuned to recognize tumor cellular metabolites. The level
of these metabolites can be spatially overlaid with MRI images allowing
a better differentiation of tumor from normal tissue.
Diffusion tensor imaging enables visualization of neural fiber
directions to examine the connectivity of different regions in the brain.
Conceptually, this could be used to potentially avoid hot spots and high
doses within critical fiber tracts. fMRI measures signal changes in the
brain that are due to changing neural activity. The measurement is done
through the mechanism called blood-oxygen-level dependent (BOLD)
effect, which is based on the fact that increased neural activity requires
enhanced oxygen levels. Deoxygenated hemoglobin attenuates the MRI
signal, while in the oxygenated state it enhances the signal, leading to a
T2 signal increase related to the neural activity.
After the desired MRI scans were acquired, they are co-registered with
CT images in the treatment planning software with the help of specially
designed mutual information-seeking algorithms combined with human
input. This co-registration allows delineation of the most pertinent
regions of interest in the framework of the treatment planning CT.
After an acceptable treatment plan has been created using an
appropriate treatment planning system (TPS), the patient is positioned
for using appropriate external immobilization and three-point alignment,
following which setup verification of the relevant anatomy and/or
fiducials is performed. The simplest modality for this is the radiographic
film. Port films are compared to digitally reconstructed radiographs from
the TPS and setup corrections are applied as necessary. Electronic
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devices such as electronic portal imaging device (EPID) have substituted
radiographic film with an electronic screen. Conventionally, the
megavoltage photon beam is used to obtain the verification image. The
Compton interaction responsible for image creation results in very low
tissue contrast, making it difficult to interpret the images. Recent
technologic advances have introduced in-room imaging with kilovoltage
photon beams, in which the portion of photoelectric interactions
significantly increases, resulting in a very substantial increase in tissue
contrast and therefore image quality. X-ray sources and imaging panels
are mounted on modern linear accelerators, allowing them to acquire CT
type image sets, called cone beam CT. As a result, 3D information at the
time of the patient setup is compared with the 3D image sets on which
the treatment plans have been generated. Necessary shifts can be applied
to best match the treatment planning conditions.
Volume Definition
Treatment-planning volumes are based on reports 50 and 62 of the ICRU
(50,51). Gross tumor volume (GTV) represents grossly identifiable
disease (50,51). For glioblastoma multiforme, this includes T1-enhancing
abnormality on MRI. For nonenhancing low-grade glioma, this is usually
T2-hyperintense or FLAIR abnormality on MRI, often better visualized as
FLAIR abnormality. The clinical target volume (CTV) includes the
subclinical microscopic tumor extent as well as resection cavity. For
glioblastoma multiforme, two CTVs are delineated: (i) T2-hyperintense
abnormality plus resection cavity and 2-cm margin treated to 46 Gy and
(ii) T1-enhancing abnormality plus resection cavity and 2-cm margin
treated to 60 Gy cumulative dose (50). Uniform expansion may result in
an excessively large volume with unnecessary dose to normal
surrounding tissues. The CTV is therefore reduced around natural
barriers to tumor growth, such as the skull, ventricles, and the falx. In
addition, the CTV margin maybe limited in areas near critical organs.
The planning target volume (PTV) is also referred to as the
“dosimetric margin,” which has two components (51). The internal
margin accounts for variations in size, shape, and position of the CTV in
relation to anatomic reference points. In the CNS, this is usually not a
major component and is due mainly to physiologic variations, such as
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the possible changes in the mass effect from cerebral edema that may
increase or decrease over the course of treatment. Setup margin is added
to take into account uncertainties in patient-to-beam positioning,
although this may be reduced by utilizing appropriate immobilization
devices, Dosimetric margins as low as 3 to 5 mm are acceptable with
optimal immobilization devices. For treatment plans emphasizing
homogenous dose delivery, the maximum dose to PTV should be
generally less than 110% of the prescription dose, and 95% of the target
should receive at least the prescription dose.
Organs at Risk
Organs at risk (OARs) are critical normal structures whose relative
radiation sensitivity and proximity to the CTV may significantly
influence the prescribed dose and the treatment-planning strategy. It is
especially important to limit the risk of late toxicities by respecting the
dose tolerances of normal structures when long-term survival is
expected. The relationship between the planning organ at risk volume
(PRV) and the OAR is analogous to that of the PTV and the CTV (51).
For each OAR, when part of the organ or the whole organ is irradiated
above the accepted tolerance level, the maximum dose should be
reported (50). The volume receiving more than the maximum allowable
dose should be evaluated using the corresponding dose–volume
histogram (DVH).
Recent publications of Quantitative Analyses of Normal Tissue Effects
in the Clinic based on review of published series established
recommended dose constraints for the brain, brainstem, optic
nerves/chiasm, cochlea, and spinal cord (Table 31.2).
The spinal cord and brainstem are the two most critical normal
structures to be considered in the CNS, given the devastating
consequences that can arise from damage to these structures. Damage to
the spinal cord can result in pain, paresthesia, sensory deficits, paralysis,
Brown-Sequard syndrome, and bowel/bladder incontinence (52). With
conventional fractionation of 2 Gy per day for the full cord cross-section,
alpha–beta has been estimated to be as low as 0.87 Gy, suggesting a
strong dose-per-fraction response relationship. In addition, 50, 60, and
69 Gy have been estimated to be associated with 0.2%, 6.0%, and 50%
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rates of myelopathy, respectively. In the case of re-irradiation, a 25%
increase in spinal cord tolerance 6 months after the initial course of
conventionally fractionated radiotherapy has been proposed (53).
Although damage to the brainstem can result in symptoms similar to
those seen in the spinal cord, the brainstem is also critical in providing
motor and sensory innervation to the head and neck via the cranial
nerves, as well as the regulation of respiratory and cardiac function. A
maximal dose constraint of 54 Gy is generally considered to have a
minimal risk of causing severe neurologic effects, and small volumes (1
to 10 cc) may be irradiated to as much as 59 Gy with a continued small
risk of side effects (54). Furthermore, series on dose-escalated
radiotherapy for skull base tumors have demonstrated that the ventral
surface of the brainstem may be somewhat radioresistant, with surface
doses as high as 64 CGE and 53 CGE to the brainstem center resulting in
high rates of toxicity-free survival (55).
TABLE 31.2 Normal Tissue Tolerance of Intracranial Organs at Risk
Radiation induced optic neuropathy (RION) can result in profound and

irreversible visual loss approximately 10 to 20 months after treatment,
with a median onset of 18 months after treatment and vascular damage
representing one possible mechanism of action (56). The alpha/beta
ratio is estimated to be quite small, in some cases <0, suggesting a very
strong dose-per-fraction effect. With conventional fractionation, a dose
of 50 Gy is associated with a near-zero incidence of RION. This risk
increases to between 3% and 7% at doses of 55 to 60 Gy, and becomes
more substantial with rates of 7% to 20% reported for doses >60 Gy at
traditional fraction sizes (57). The retina is another radiosensitive vision
structure, where radiation-induced retinopathy can mimic the symptoms
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of diabetic retinopathy. The threshold dose radiation retinopathy is
estimated to be at 30 to 35 Gy, with lower doses associated with a near-
zero risk of retinopathy and >50 Gy associated with approximately a
5% chance of retinopathy. Consequentially, most protocols set 45 Gy as
the maximum dose constraint for the retina (58).
The pathogenesis of radiotherapy-induced cognitive decline may at
least partially involve a neural stem cell compartment located in the
subgranular zone of the hippocampal dentate gyrus. Preclinical and
clinical studies have demonstrated not just the importance of this neural
stem cell compartment on memory function, but also its exquisite
radiosensitivity (59). In RTOG 0933, a prospective clinical trial of whole-
brain radiotherapy for brain metastases, conformal avoidance of the
hippocampal dentate gyrus using intensity-modulated radiotherapy
reduced the rate of memory decline, as compared to historical controls
(60). These findings provided the first direct clinical evidence that the
application of advanced radiotherapy techniques to minimize
hippocampal dose may prevent radiotherapy-induced cognitive decline.
However, the precise radiobiologic dose-tolerance of the hippocampal
dentate gyrus remains unclear. Exploratory analysis of patients enrolled
on RTOG 0933 demonstrated that dose to 100% of the hippocampal
dentate gyrus correlated with severity of memory decline, suggesting
that better memory preservation might be attainable with lower
hippocampal dose (60). In a prospective study of benign and low-grade
tumor treated with photon radiotherapy without hippocampal
avoidance, >7.3 Gy in 2-Gy fractions to 40% of the hippocampal
dentate gyrus was associated with long-term impairment in list-learning
recall (61).
Temporal lobe injury (TLI) can be associated with such symptoms as
dizziness, memory impairment, disorientation, and personality changes
or with more specific symptoms such as temporal lobe epilepsy (62).
Data from studies in nasopharyngeal cancer patients has established 70
Gy as a threshold for an increased incidence of TLI (63). Some authors
treating skull base tumors have proposed a D2 cc of 74 Gy as an absolute
threshold dose (64).
Intensity-Modulated Radiation Therapy
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Intensity-modulated radiation therapy (IMRT) is an advanced form of
the 3D CRT. While CRT delivers an irregularly shaped beam of uniform
intensity, IMRT modulates the intensity of the photon beam across the
treated area by delivering multiple subfields (segments), each of
irregular shape and different photon intensities. There are three major
advantages of utilizing IMRT for CNS tumors: (i) shape dose around
concave PTVs (such as with some meningiomas); (ii) improve
homogeneity of the delivered dose to complex-shaped PTVs; (iii) permit
simultaneous integrated dose delivery using two or more PTV dose levels
(such as for glioblastoma multiforme); and (iv) improve dose
homogeneity to target in the regions where large variations of external
contours exist (such as in case of posterior fossa lesions or spinal cord
meningiomas).
These advantages of IMRT technique are achieved through inverse
planning during which dosimetric objectives are set for tumor coverage
and for OAR avoidance. An optimization algorithm is then employed to
find the optimal photon fluence that meets the predetermined dosimetric
objectives. After the optimal photon fluence has been found, another
optimization algorithm is employed to determine the optimal way (i.e.,
the shape, the number, and the intensity of segments) to deliver the
calculated fluence. In order to fully utilize the power of IMRT, the
irradiated tissue should be as static as possible during delivery, the
dosimetric objectives for planning should not be unrealistic, and great
care should be given to contour targets and OARs which include lenses,
eye globes, optic nerves, chiasm, brainstem, temporal lobes, pituitary
gland, inner ears, general brain parenchyma, and spinal cord.
Immobilization can help to reduce the necessary margins when
creating PTVs. Margins should be set based on a realistic assessment of
setup uncertainties and the quality of immobilization. During IMRT
planning, unrealistic desired objectives could lead to suboptimal plans.
For instance, if aiming to cover the PTV with a homogeneous dose of 60
Gy, while constraining the maximum dose to the adjacent, say 1 mm
distant chiasm, to 40 Gy, the software will substantially increase the
needed monitor units and generate a large number of very tiny area
segments, which might not be deliverable due to machine limitations.
Good IMRT plans can achieve better than 5%/mm dose gradient while
still preserving good target dose uniformity.
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Proton Therapy
Proton therapy is a form of particle therapy that is becoming
increasingly available. Its dosimetric advantages of sharper lateral
penumbrae and finite distal range permit greater sparing of organ at risk
in close proximity to the tumor target. This becomes particularly
important in the treatment of radioresistant tumors in eloquent
locations, such as skull base chordoma and chondrosarcoma, where
dose-escalation to 70 Gy or higher in close proximity to brainstem, optic
nerves, temporal lobes, and cochlea is required for optimal local control.
In addition, reduced integral dose, due to the finite range of proton
therapy and fewer proton beams needed to optimally treat the tumor
target, may have important implications in terms of secondary
malignancy risk reduction and adverse cognitive effects. In the setting of
craniospinal irradiation, proton therapy has been observed to have
significant clinical benefits in terms of acute toxicities, and is postulated
to minimize the risk of multiple long-term toxicities. Trials testing the
potential benefits of proton therapy for novel CNS tumor indications
remain ongoing.
SIMULATION PROCEDURES
Positioning
When simulating CNS tumor patients, patient positioning becomes very
important and appropriate position devices should be used to aid in
reproducibility and setup. The head, neck, and body should be
positioned such that the setup marks are in locatable and reproducible
positions. Marks on steeply sloping surfaces, ears, nose, lips, and chin
should be avoided whenever possible. In some settings, there is a benefit
from positioning the head on a pituitary head-board for posteriorly
located tumors (e.g., occipital lobes or posterior fossa). For patients
requiring craniospinal irradiation, it is often useful to have the patient
supine with the chin slightly extended such that the exit of the PA spine
field does not exit through the patient’s oral cavity. CT scan simulation,
3D treatment planning, and IMRT allow for different head and neck
positions in most situations as noncoplanar beams can be used to avoid
entry and exit dose to OARs.
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Immobilization
There exist a variety of commercially available head immobilization
devices, most of which use thermoplastic or other materials, such as
expandable foam or plastic beads in a vacuum bag. They are adaptable
for flexion or extension when the patient is in the supine position.
Variability of setup should not be >2 or 3 mm with a thermoplastic
mask. To obtain more accurate and/or rigid head positioning and
immobilization, a modified stereotactic aquaplast mask with
reinforcement strips may be used to help insure reproducibility and
setup.
Once the patient is placed in the appropriate positioning device, they
are scanned, typically using between 2 and 3 mm slice thicknesses. The
clinician may need to decide at the time of simulation where the
isocenter should be placed. After completion of treatment planning in
virtual reality (see subsequent text), verification films should be
obtained before treatment; these may include orthogonal radiographs to
verify the isocenter, and films of any custom-shaped portal fields.
Isocenter films (with or without portal images) are usually obtained
weekly to verify accuracy of the treatment setup. Volumetric imaging
capabilities now offer more detailed imaging verification of the patient
setup.
Generally, special custom immobilization devices are used for patients
with spinal cord tumors to ensure setup reproducibility, especially with
craniospinal irradiation patients since the match lines (areas where fields
abut) are of importance. Regardless of the immobilization device, it must
fit the physical dimensions of the CT scan or MRI scanner and be
constructed of materials compatible with the imaging modality.
Simulation
In this chapter, the reader may assume that patients are simulated in the
supine position using 3D CT scan-based planning, unless otherwise
stated. The primary body planes are transverse, sagittal, and coronal,
with body axes anterior, posterior, right, left, superior, and inferior.
Isocentric treatment machines rotate 360 degrees around a transverse
plane of the patient’s body, and treating in a coronal or sagittal plane
requires the treatment couch to be rotated.
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For CT scan simulation involving the brain, the patient is placed in the
positioning device and scanned and the isocenter or reference markers
are selected and marked on the thermoplastic mask. For intracranial
disease, a single-field or opposed-beam two-field arrangements are
usually not considered acceptable, as they deliver excessive dose to
normal tissues in the beam paths. The exception is a short course of
palliative radiation therapy to the whole brain or cervical spinal cord
using an opposed lateral beam arrangement. An optimum beam
arrangement typically consists of multiple noncoplanar beams. For
tumors involving both hemispheres of the brain, the ideal beam
arrangement is six noncoplanar beams; two on the right and left sides of
the patient (entering anterior to shoulder and posterior to shoulder), and
two superior obliques. When applicable, the contralateral uninvolved
hemisphere of the brain should be spared as much as possible. In these
cases, for patients with right-sided lesions, for example, the contralateral
beams should not be utilized, if possible. Beam exit through the thyroid
gland, eyes, lacrimal gland, and oral cavity should also be avoided as
much as possible.
Most lesions can be treated well with 6 to 10 MV photon beams. For
more lateralized tumors, it is ideal to not include contralateral beams if
possible. Typically, a homogenous dose distribution within the target
volume is desirable, with not >5% to 10% inhomogeneity in the
irradiated volume. When IMRT is used, a practical timesaving approach
uses the beam arrangement of an optimized noncoplanar 3D plan as a
starting point. This can significantly shorten the treatment-planning
effort and allows for greater freedom of optimization than a coplanar
(i.e., 2-dimensional, 2D) plan.
SPECIFIC EXAMPLES OF TREATMENT TECHNIQUES

Whole Brain Radiation Therapy
Whole brain radiation therapy evolved in the early days of radiation
therapy when precise anatomic definition of tumor was limited to plain
radiography. Nonetheless, the benefits were apparent. In the first
randomized clinical trial in brain tumors in the United States, 60 Gy
whole brain radiotherapy increased survival in patients with
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glioblastoma multiforme over steroids alone (65). With the advent of CT
and MRI, more focal radiation techniques for brain tumors became the
standard. Still, there are important clinical settings in which the brain
and/or meninges are the target for which whole brain radiation therapy
is an essential component of therapy. These clinical situations with
examples are reviewed below.
Acute Leukemia
The CNS is a known sanctuary site from leukemic chemotherapy. After
failures in the CNS and eyes were noted, CNS penetrating therapy such
as intrathecal drugs and radiation therapy became an important
component of treatment of leukemia (66). While the doses of
radiotherapy are low, in the 12 to 18 Gy range, the target remains the
entire brain, cranial meninges down to the level of C2, and the posterior
retina and optic nerves. An example of a C2-whole brain field for cranial
prophylaxis is shown in Figure 31.1A. Opposed lateral fields in an
aquaplast mask with a 2- to 3-degree posterior cant on the fields can
help spare exit through the contralateral lens. The anterior border is set
at the fleshy canthus of the eye, which corresponds to the anatomic
equator of the eye. Radio-opaque markers placed on the fleshy canthus
are very helpful for conventional simulation. For a CT simulation, the
anterior border is placed at the posterior border of the lens, and the
gantry angle is adjusted to make the beam nondivergent across the
posterior aspect of both lenses. It is very important to note that the block
be placed to ensure that the entire posterior globe be included in the
fields. At least a 1-cm margin should be included on the middle cranial
and base of skull meninges. One centimeter of flash should be provided
over the convexity, and the soft tissue of the posterior neck should be
shielded with a minimum 1-cm margin on the intracranial contents (Fig.
31.1A).
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Figure 31.1 Sample whole brain radiotherapy fields illustrating blocking for C2-whole brain fields
(A) that would be appropriate for leukemic prophylaxis and whole brain fields with a scalp block
(B) that would be appropriate for whole brain radiotherapy of metastatic disease.
Brain Metastases
The radiation therapy oncology group (RTOG) conducted a number of
trials in the early 1980s on whole brain radiotherapy for brain
metastases (67). These established a palliative benefit for whole brain
radiation therapy. More recently, whole brain radiotherapy with a
stereotactic boost showed a survival and neurologic function benefit in
selected patients with brain metastases (68). Randomized trials of
stereotactic radiosurgery (SRS) and whole brain radiation versus SRS
alone for 1 to 4 brain metastases showed equivalent survival, but
suggested a local control benefit to whole brain radiotherapy (69,70).
Traditionally, an open flashing rectangular field with the inferior
border collimated to a line connecting the superior orbital rim with the
mastoid tip was used. Increasingly, CT simulation with MLC blocking
techniques has become common, allowing relatively easy target
definition and blocking. The target in whole brain radiation is the brain
parenchyma. While posterior fossa metastases may have a higher
association with leptomeningeal spread, there is no evidence that
including the cranial meninges prevents this pattern of failure. Figure
31.1B illustrates a whole brain field that includes the brain parenchyma
with a 1-cm block margin. This typically blocks the lenses of the eyes,
but occasionally adjustment of the leaves over the lenses is necessary.
The advantage of including a “scalp block” is to avoid the tangent effect
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of the beam over the vertex scalp that often leads to a characteristic
“reverse mohawk” bald patch among surviving patients. Inhomogeneities
across the superior thinned parts of the head can also be reduced with
simple field-within-a-field techniques.
Whole brain radiation is now known to cause mild-to-moderate
memory deficits as early as 4 months after treatment (66). RTOG 0614
demonstrated a modest improvement in overall neurocognition with the
use of prophylactic memantine during whole brain radiation for brain
metastases. In addition, RTOG 0933 demonstrated that use of intensity
modulated radiotherapy during whole-brain radiotherapy to conformally
avoid the hippocampal dentate gyrus, where neural stem cells whose
neurogenic differentiation subserves memory function are believed to
reside, was associated with highly promising memory preservation
results (59,60) (Fig. 31.2). Phase III trials to confirm these promising
phase II results are ongoing through NRG Oncology. NRG CC001 is a
phase III trial of whole-brain radiotherapy plus memantine with or
without hippocampal avoidance. NRG CC003 is a randomized phase
II/III trial of prophylactic cranial irradiation with or without
hippocampal avoidance for small cell lung cancer.
Craniospinal Irradiation
Certain neoplasms will require treatment to the entire craniospinal axis.
This may include medulloblastomas and PNETs, high-grade
ependymomas, some germ cell tumors, pineoblastomas, disseminated
CNS lymphoma, and leptomeningeal carcinomatosis or gliomatosis.
Several positioning variations are used in clinical practice often in an
immobilization cast to ensure daily positional reproducibility (71).
Patients are ideally treated in the supine position with the neck extended
to avoid beams exiting the oral cavity. Conventional methods utilize
field “feathering” to reduce hot or cold spots caused by imperfect fields
matching between cranial and spine fields. This method feathered each
junction on a weekly basis with the cranial fields’ inferior border
decreasing between 5 and 10 mm. The intracranial contents and upper
one or two segments of the cervical cord are treated through opposed
lateral fields, usually positioned so that the isocenter is at midline with
the beam axes passing through the lateral canthi to minimize divergence
into the contralateral eye. The collimator and couch are rotated to create
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a straight line through the inferior portion of the brain fields that
removes the possibility of overlap with the posterior spine field. This can
be visualized with the treatment planning systems simulation software
(see subsequent text). Customized blocks protect the normal head and
neck tissues from the primary radiation beam; as mentioned above, care
must be taken not to underdose the cribriform plate. Figure 31.3A
represents a typical cranial field with blocks for the lenses and
collimator angled to match the divergence of the PA spine field. The
inferior border of the initial “short” field is placed around C2 to C3,
leaving adequate room for subsequent shifts in the match with the upper
spine field, a technique commonly referred to as “feathering the gap.”
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Figure 31.2 Volumetric arc therapy plan for conformal avoidance of the hippocampus during
whole brain radiotherapy. This IMRT plan was generated using the partial-field dual-arc planning
technique developed by Shen et al. (75). The following isodose lines are shown 35 Gy (red), 33
Gy (orange), 30 Gy (green), 25 Gy (blue), 16 Gy (purple), and 10 Gy (brown). This technique
significantly spares the hippocampus with 100% of the hippocampus receiving a dose of 8 Gy and
a maximum hippocampal dose of less than 16 Gy.
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Figure 31.3 A: Sample whole brain field with angled collimator for craniospinal radiotherapy of
medulloblastoma. B: Represents the prescription dose cloud for craniospinal radiation of
medulloblastoma. Note no loss of dose at the junction between brain and spine fields on account
of a daily three-feathered junction using the independent jaw. C: Illustrates the isodose cloud for
an IMRT medulloblastoma posterior fossa boost specifically avoiding the cochlea (shown in
green). The optic pathway is shown in aqua and the primary tumor is shown in pink.
Depending on length, the spine is treated through one or two posterior

fields. It is customary practice to maximize the field length of the upper
spinal field (40 cm at 100 cm source–skin distance [SSD]) and minimize
the length of the lower spinal field, therefore simplifying planning for
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junction shifts (see in subsequent text). If 40 cm or less of length covers
the spine inclusive of the end of the thecal sac (typically near the level of
S3, this should be confirmed by MRI), a lower spine field is not
necessary. All fields’ central axes remain fixed; it is only the fields’
lengths that are changed. Therefore, the caudal border of the lower PA
spine field should be set inferior to S3 by a length equal to the two-field
shifts, and then blocked back to S3 using asymmetric collimators.
Matching the upper border of the spine field to the lower border of the
cranial field requires strict attention to accuracy, as overlap (i.e.,
overdosing) in the upper cervical cord may have catastrophic outcomes
for the patient. In one method, the collimator for the lateral cranial
fields is angled to match the divergence of the upper border of the
adjacent spinal field, and the treatment couch is angled so that the
inferior border of the cranial field is perpendicular to the superior edge
of the spinal field (“exact-match” technique). Both the rotation of the
collimator and degree of couch rotation are calculated and typically
range from 9 to 11 degrees. The drawback to this technique is that the
couch rotation displaces the contralateral eye cephalad, so that it cannot
be blocked without blocking frontal brain tissue. This technique may
also result in underdosing of the temporal lobes and cribriform plate.
One method for craniospinal irradiation involves a 3D CT simulation
of a patient in the supine position in a wooden box that encompasses the
entire spinal canal. The patient’s cranium extends outside the end of the
box to allow for positioning, utilizing an aquaplast mask (see photo).
This method, referred to as “simulated dynamic feathering,” feathers the
gap daily as opposed to conventional methods where the fields are
feathered after five fractions. The process is as follows:
Simulation
The patient is placed on the vac bag, which provides comfort. An
aquaplast mask is used to immobilize the cranium. The patient is aligned
with the spine as straight as possible and no rotation of the cranium
before scanning. A scout is usually needed to confirm that the patient is
aligned and no adjustments are needed. An isocenter is placed in the CT
room for the cranium fields only and the mask is marked. The isocenter
is usually placed midline and will serve as a reference point for the spine
field. Ideally, the spine isocenter is placed such that the couch is moved
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as little as possible between brain and spine fields. Generally, after the
cranium fields are treated, the couch is shifted in two directions: toward
the gantry and raised to accommodate the extended SSD of the PA spine
field.
Treatment Planning
The cranial fields are designed as well as the spine field for the initial
beams. Collimator and couch are rotated to prevent the overlap between
the brain and spine fields using the treatment planning system. The
planning system allows visualization of beam divergence for all beams in
the axial, sagittal, and coronal views. Once the initial fields have been
designed, they are copied and labeled accordingly (Shift#1, 2, etc.). The
cranial field’s inferior border is increased by 5 mm and the spine field’s
superior border is decreased to match the inferior border of the brain
fields. A total of 1.5 cm shift is used for this technique, which requires
three shifts 5 mm each shift. It is important to note that the spine field
will not necessarily be 5 mm due to beam divergence as these fields are
generally treated at extended SSD’s (between 125 and 135 cm). The
following shifts are created using the same process. The number of
beams can be as many as 12 treated on a daily basis using the dynamic
method; therefore, patient comfort is important as it contributes greatly
to reproducibility. The number of shifts or junctions is physician
dependent.
Plan optimization usually involves a forward planned field in field
technique for the brain fields as well as for the spine field. However, it is
possible to optimize the spine fields using inverse planning to cool off
hot spots. The rationale for inverse planning the spine field is merely
related to time. The control points needed for the spine field are
generally higher than that of the brain fields. Figure 31.3B shows the
dose cloud for such a craniospinal plan. Figure 31.3C shows the dose
cloud for an IMRT-planned posterior fossa boost, sparing cochlea.
Documenting junction match requires placing wires on the inferior
border of brain fields before imaging the spine field for each junction
shift.
Partial Brain Radiation
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The era of 3D CRT in the 1990s allowed substantial reduction of
unnecessary radiation to normal brain. The anatomic location of the
brain atop the head also maximized the benefits of noncoplanar beams,
because vertex beam arrangements were available with a simple rotation
of the treatment couch. While the wedge requirements of noncoplanar
beam to produced homogeneous plans are more complicated, they are
solvable (72). In spite of this, the compensation requirements of such
noncoplanar arrangements are more easily handled with IMRT inverse
planning. In addition, intensity modulation can produce concave dose
distributions around critical adjacent structures such as the optic chiasm,
brainstem, and cochlea and thus provide more adequate dose sparing.
IMRT also allows differential prescription of doses and simultaneously
integrated boost plans that has made IMRT routine for contemporary
partial brain irradiation.
Low-Grade Glioma
Low-grade gliomas form a heterogeneous group of tumors that include
the most favorable pilocytic astrocytoma and the fibrillary astrocytomas
with a less favorable prognosis and propensity to progress to a higher
grade histology. Doses are 45 to 54 Gy in standard fractions with a
typical 1 to 2 cm clinical margin on the radiographically defined GTV.
Higher radiation doses have been studied, but only resulted in increased
toxicity with no survival benefit.
A helpful quantitative tool to evaluate brain plans is the conformity
index. Born from radiosurgical planning, various conformity indices have
been described. For an ideal plan, conformity indices approach 1. From a
practical point of view, the indices have value in discriminating between
generally acceptable treatment plans, since poorly conformal plans and
plans that do not cover the target are usually quite apparent to the keen
observer. The simplest conformity index can be defined as:
Conformity Index = Treatment Volume/Target Volume
When the entire body is contoured in the planning system, the

treatment volume is easily obtained from the DVH as the volume of the
body receiving the prescription dose. A conformity index <1.2 indicates
a highly conformal plan and should be an important and achievable
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planning goal.
High-Grade Glioma
Most high-grade gliomas are glioblastomas. Although temozolomide
with radiation prolongs median survival by about 2 months with a small
number of 5-year survivors (ref), most patients invariably recur,
requiring salvage therapy. While hypofractionated treatments and
smaller treatment volumes are under investigation, the radiation
standard remains 45 to 50 Gy to a clinical target including all
surrounding postoperative flair signal plus a 2-cm margin along
continuous white matter tracks within the brain with a boost to a
clinical target including the enhancing tumor or postoperative cavity
plus a 1- to 2-cm margin. It is important to adjust clinical targets along
known anatomic white matter tracks to avoid unnecessary irradiation of
the posterior fossa or contralateral brain, as both the tentorium and falx
are effective barriers to spread of glial tumors. The standard boost dose
remains 60 Gy. While radiotherapy dose-escalation demonstrated no
survival benefit, these trials were conducted prior to the widespread
adoption of concurrent and adjuvant temozolomide. The potential
survival benefit of dose-escalation with concomitant and adjuvant
temozolomide remains the subject of an ongoing NRG oncology study.
Ependymoma
Ependymomas are uncommon primary glial CNS tumors that typically
arise in the posterior fossa and cauda equina. Ependymomas in the
cauda equina are most often low-grade myxopapillary type and carry a
relatively favorable prognosis. Radiation therapy is reserved for
incompletely resected or recurrent tumors. Ependymomas account for
5% to 10% of childhood intracranial tumors, but occur as well in adults.
Standard management involves complete surgical removal. Most authors
agree that posterior fossa ependymomas should receive postoperative
radiotherapy, as recurrence rates remain high even after complete
surgical removal in this location. The addition of radiotherapy for
supratentorial ependymomas after complete surgical resection is
controversial, as this appears to be a more favorable subsite.
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Meningiomas
Meningiomas are common CNS tumors, for which radiation therapy is a
safe and effective treatment approach. Radiotherapy for meningiomas
can be challenging because they often have irregular shapes and are
located near critical structures. With the advent of IMRT, fractionated
stereotactic radiotherapy (FSRT), and SRS, radiotherapeutic options in
the management of meningiomas are now diverse. However, regardless
of the treatment modality, careful treatment planning is central, since
meningiomas are mostly benign tumors, and therefore the risk of serious
late toxicities needs to be minimized.
Fusion of a contrast-enhanced MRI with the planning CT scan provides
the optimal definition of the meningioma and adjacent OARs. For well-
demarcated lesions, the GTV and CTV are identical. Stereotactic
positioning may be useful to reduce the margin for PTV, which takes
into account the error in tumor volume delineation, errors inherent to
image fusion, and for the variation in day-to-day setup. With invasive
tumors, such as those involving the sphenoid or cavernous sinuses, there
is greater uncertainty, which must be considered in determining the
CTV.
The optimal beam arrangement is dictated by both the shape and
location of the lesion. With a large convexity lesion, for example, a
potential arrangement may be three coplanar beams angled at 120
degrees from one another (“Mercedes Star”), or a cruciform arrangement
of four coplanar beams. The couch and gantry are then rotated so that
each beam is shifted 10 degrees inferiorly with respect to the patient
(Fig. 31.2). These arrangements minimize the cross-sectional area of the
lesion within the beam’s eye view. Other suggestions for beam
arrangements are presented in the subsequent text, based on the region
of the brain. The use of IMRT may be useful for concave-shaped lesions.
With superficially located lesions, 6-MV photons are typically utilized
owing to the short buildup depth; for more deeply situated tumors, such
as cavernous sinus lesions, higher energy beams may be considered.
Pituitary Tumors
Fusion of a contrast-enhanced MRI with a contrasted planning CT scan
provides the optimum definition of the suprasellar optic apparatus and
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the extensiveness of the tumor. The GTV is the pituitary adenoma,
including any of its extension into adjacent anatomic regions. Generally,
the entire content of the sella and, if appropriate, extension into the
sphenoid or cavernous sinuses are included in the CTV. With appropriate
immobilization devices, CTV expansion of 0.5 cm, that is, 1.0 to 1.5 cm
margin to block edge is adequate to create the PTV. Stereotactic
positioning can reduce the PTV, with margins of 7 mm giving excellent
dose distribution with minimal dose to surrounding tissues. OARs to be
contoured include the optic globes, lenses, optic nerves, optic chiasm,
brainstem, and temporal lobes.
The traditional three-field approach using wedged opposed laterals
and an anterior or vertex beam superior to the eyes leads to
unacceptably high doses to the temporal lobes. IMRT may be useful to
further improve dose distribution, especially for irregularly shaped
lesions. Beam energies of at least 6 MV should be used to spare
surrounding structures, most notably the temporal lobes. Ten-megavolt
photons provide a good balance between depth dose and penumbra
width, although for stereotactic plans with small margins, 6-MV photons
may be more advantageous.
Spinal Tumors
The most favorable field arrangement will be determined by the location
and adjacent OARs, and it may be a single posteroanterior (PA) field,
opposed-lateral fields, a PA field with opposed laterals, opposed
anterior–posterior (AP/PA) fields, or oblique wedge-pair fields (73,74).
In some circumstances, IMRT may be useful to spare esophagus, heart,
lung, kidney, and bowel, especially when higher doses need to be
delivered. Some metastatic lesions may be suitable for treatment in a
single fraction with spinal radiosurgery using appropriate
immobilization and image guidance tools. In the cervical region, an
opposed-lateral beam approach minimizes the dose to the anterior neck.
When palliating a tumor in the cervicothoracic region, a split beam
approach facilitates the match with another treatment field. In this case,
the central axis is placed just above the shoulders and opposed-lateral
beams are used to treat the upper spine, and a PA field is used for the
area of the spine below the central axis. Tumors in the thoracic region
can be treated with opposed lateral beams, a three-field approach using
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a PA field and opposed lateral beams, a two-field approach using AP/PA
beams, or a posterior beam prescribed to an appropriate depth. When
treating with a single posterior beam, the depth prescription should take
into account the dose to the spinal cord to prevent accidental
overdosing. In the lumbar region, AP/PA or PA fields reduce the
exposure to the kidneys. In the sacral region, opposed lateral beams with
or without a posterior beam or a four-field approach using AP/PA and
opposed lateral beams may be useful. Comparison of various treatment
setups by means of DVHs is recommended.
ACKNOWLEDGMENTS
The authors would like to acknowledge the contributions of Lucien A Nedzi,
Kevin S. Choe, Arnold Pompos, Ezequiel Ramirez, Volker W. Stieber, Kevin
P. McMullen, Allan DeGuzman, and Edward G. Shaw to the writing of this
chapter in the previous editions of this book.
KEY POINTS
• Multimodality therapy for CNS tumors may consist of medical
therapy, surgical resection, radiation therapy, or some combination
of the above.
• The therapeutic ratio of radiation therapy for CNS tumors has
improved due to the introduction of new irradiation technologies,
such as 3D CRT, IMRT, and proton therapy, and the development
and availability of advanced imaging techniques such as MRI that
help to better delineate targets and regions of avoidance.
• Modern radiation therapy for CNS tumors requires various novel
imaging techniques that help to better understand the
dosimetrically relevant composition of the tissue in the path of the
radiation and verify the location of the target during dose delivery.
QUESTIONS
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1. (T/F) In patients diagnosed with a brain tumor, prophylactic use
of anticonvulsants should be initiated irrespective of seizure
history.
2. For radiotherapy planning of a resected high-grade glioma, the
following MRI sequence(s) should be obtained:
A. Preoperative T1-weighted sequence with contrast only
B. Postoperative T1-weighted sequence with contrast only
C. Preoperative T1-weighted sequence with contrast and
preoperative T2/FLAIR sequence only.
D. Postoperative T2/FLAIR sequence only
E. Pre- and postoperative T1-weighted sequences with contrast
and pre- and postoperative T2/FLAIR sequences only.
3. The following statements regarding radiobiologic tolerance of the
brainstem and spinal cord are true, except:
A. A maximal dose constraint of 54 Gy is generally considered to
have a minimal risk of causing severe neurologic effects.
B. 50 Gy at 2-Gy per fraction has been estimated to be associated
with a 0.2% rate of myelopathy.
C. Damage to the spinal cord can result in pain, paresthesia,
sensory deficits, paralysis, Brown-Sequard syndrome, and
bowel/bladder incontinence.
D. Series on dose-escalated radiotherapy for skull base tumors
have demonstrated that the dorsal surface of the brainstem
may be somewhat radioresistant.
4. (T/F) A radiosensitive neural stem cell compartment located in
the subgranular zone of the hippocampal dentate gyrus may be
central to radiotherapy-related memory toxicity.
5. All of the following statements are true regarding craniospinal
irradiation, except:
A. The field length of the lower spine field should be maximized,
where as the field length of the upper spine field should be
minimized.
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B. Medulloblastoma is an example of a neoplasm requiring
craniospinal irradiation.
C. When treating craniospinal irradiation in the supine position,
the neck should be extended to avoid beams exiting the oral
cavity.
D. In “exact-match” technique for matching the cranial fields to
the upper spinal field, the collimator for the lateral cranial
fields is angled to match the divergence of the upper border of
the adjacent spinal field, and the treatment couch is angled so
that the inferior border of the cranial field is perpendicular to
the superior edge of the spinal field.
ANSWERS
1. False
2. E
3. D
4. True
5. A
REFERENCES
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2014.
3. Ferlay J. GLOBOCAN 2000 [electronic resource]: Cancer Incidence,
Mortality, and Prevalence Worldwide/WHO, International Agency for
Research on Cancer. Lyon: IARC Press; 2001.
4. Connolly E. Spinal cord tumors in adults. In: Youmans Y, ed.
Neurological Surgery vol 5. Philadelphia, PA: WB Saunders;
1982:3196.
5. Sasanelli F. Primary intraspinal neoplasms in Rochester, Minnesota,
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1935–1981. Neuroepidemiology. 1983;2:156–163.
6. IARC. WHO Classification of Tumours of the Central Nervous System.
Lyon: IARC; 2007.
7. Preston-Martin S. Descriptive epidemiology of primary tumors of the
spinal cord and spinal meninges in Los Angeles County, 1972–1985.
Neuroepidemiology. 1990;9:106–111.
8. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions
of brain metastases in patients diagnosed (1973 to 2001) in the
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compression on MRI scan and implications for treatment. Clin Oncol
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21. Ruff RL, Lanska DJ. Epidural metastases in prospectively evaluated
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patients. Neurol Clin. 1998;16:449–483.
23. Ricci PE, Dungan DH. Imaging of low- and intermediate-grade
gliomas. Semin Radiat Oncol. 2001;11:103–112.
24. Munley M. Bioanatomic IMRT treatment planning with dose
function histograms. Int J Rad Oncol Biol Phys. 2002;54:126.
25. Nuutinen J, Sonninen P, Lehikoinen P, et al. Radiotherapy
treatment planning and long-term follow-up with
[(11)C]methionine PET in patients with low-grade astrocytoma. Int
26. Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided
target delineation for high-grade gliomas. Int J Radiat Oncol Biol
Phys. 2001;50:915–928.
27. Husband DJ, Grant KA, Romaniuk CS. MRI in the diagnosis and
treatment of suspected malignant spinal cord compression. Br J
Radiol. 2001;74:15–23.
28. Sarin R, Murthy V. Medical decompressive therapy for primary and
metastatic intracranial tumours. Lancet Neurol. 2003;2:357–365.
29. French LA. The use of steroids in the treatment of cerebral edema.
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30. Long DM, Hartmann JF, French LA. The response of human cerebral
edema to glucosteroid administration. An electron microscopic
study. Neurology. 1966;16:521–528.
31. Vecht CJ, Hovestadt A, Verbiest HB, et al. Dose-effect relationship
of dexamethasone on Karnofsky performance in metastatic brain
tumors: a randomized study of doses of 4, 8, and 16 mg per day.
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32. Wolfson AH, Snodgrass SM, Schwade JG, et al. The role of steroids
in the management of metastatic carcinoma to the brain. A pilot
prospective trial. Am J Clin Oncol. 1994;17:234–238.
33. Kalkanis SN, Eskandar EN, Carter BS, et al. Microvascular
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decompression surgery in the United States, 1996 to 2000: mortality
rates, morbidity rates, and the effects of hospital and surgeon
volumes. Neurosurgery. 2003;52:1251–1261; discussion 1261–1262.
34. Sorensen S, Helweg-Larsen S, Mouridsen H, et al. Effect of high-dose
dexamethasone in carcinomatous metastatic spinal cord
compression treated with radiotherapy: a randomised trial. Eur J
Cancer. 1994;30A:22–27.
35. Bilsky MH. Intensive and Postoperative Care of Intracranial Tumors.
3rd ed. New York, NY: Raven Press; 1993:309–329.
36. Heimdal K, Hirschberg H, Slettebo H, et al. High incidence of
serious side effects of high-dose dexamethasone treatment in
patients with epidural spinal cord compression. J Neurooncol.
1992;12:141–144.
37. Weissman DE, Janjan NA, Erickson B, et al. Twice-daily tapering
dexamethasone treatment during cranial radiation for newly
diagnosed brain metastases. J Neurooncol. 1991;11:235–239.
38. Maranzano E, Latini P, Beneventi S, et al. Radiotherapy without
steroids in selected metastatic spinal cord compression patients. A
phase II trial. Am J Clin Oncol. 1996;19:179–183.
39. Bell BA, Smith MA, Kean DM, et al. Brain water measured by
magnetic resonance imaging. Correlation with direct estimation and
changes after mannitol and dexamethasone. Lancet. 1987;1:66–69.
40. Quinn JA, DeAngelis LM. Neurologic emergencies in the cancer
patient. Semin Oncol. 2000;27:311–321.
41. Working Group on Status Epilepticus. Treatment of convulsive
status epilepticus. Recommendations of the Epilepsy Foundation of
America’s Working Group on Status Epilepticus. JAMA.
1993;270:854–859.
42. Forsyth PA, Weaver S, Fulton D, et al. Prophylactic anticonvulsants
in patients with brain tumour. Can J Neurol Sci. 2003;30:106–112.
43. Glantz MJ, Cole BF, Friedberg MH, et al. A randomized, blinded,
placebo-controlled trial of divalproex sodium prophylaxis in adults
with newly diagnosed brain tumors. Neurology. 1996;46:985–991.
44. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of
surgery in the treatment of single metastases to the brain. N Engl J
Med. 1990;322:494–500.
45. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single
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brain metastasis: radiotherapy alone or combined with
neurosurgery? Ann Neurol. 1993;33:583–590.
46. Mintz AH, Kestle J, Rathbone MP, et al. A randomized trial to assess
the efficacy of surgery in addition to radiotherapy in patients with a
single cerebral metastasis. Cancer. 1996;78:1470–1476.
47. Loblaw DA, Laperriere NJ. Emergency treatment of malignant
extradural spinal cord compression: an evidence-based guideline. J
Clin Oncol. 1998;16:1613–1624.
48. Young RF, Post EM, King GA. Treatment of spinal epidural
metastases. Randomized prospective comparison of laminectomy
and radiotherapy. J Neurosurg. 1980;53:741–748.
49. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive
surgical resection in the treatment of spinal cord compression
caused by metastatic cancer: a randomised trial. Lancet.
2005;366:643–648.
50. ICRU report 50. Prescribing, Recording, and Reporting Photon Beam
Therapy. Bethesda, MD; International Commission on Radiation
Units and Measurements, ICRU; 1993.
51. ICRU report 62. Prescribing, Recording, and Reporting Photon Beam
Therapy (Supplement to ICRU Report 50). Bethesda, MD; International
Commission on Radiation Units and Measurements; 1999.
1112.
53. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. The radiation
dose-response of the human spinal cord. Int J Radiat Oncol Biol Phys.
2010;76:S42–S49.
54. Mayo C, Yorke E, Merchant TE. Radiation associated brainstem
injury. Int J Radiat Oncol Biol Phys. 2010;76:S36–S41.
55. Debus J, Hug EB, Liebsch NJ, et al. Brainstem tolerance to
conformal radiotherapy of skull base tumors. Int J Radiat Oncol Biol
Phys. 1997;39:967–975.
56. Danesh-Meyer HV. Radiation-induced optic neuropathy. J Clin
Neurosci. 2008;15:95–100.
57. Mayo C, Martel MK, Marks LB, et al. Radiation dose-volume effects
of optic nerves and chiasm. Int J Radiat Oncol Biol Phys.
2010;76:S28–S35.
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58. Jeganathan VS, Wirth A, MacManus MP. Ocular risks from orbital
and periorbital radiation therapy: a critical review. Int J Radiat
Oncol Biol Phys. 2011;79:650–659.
59. Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A
comprehensive review. Radiother Oncol. 2010;97:370–376.
60. Gondi V, Pugh, SL, Tomé, WA, et al. Preservation of memory with
conformal avoidance of the hippocampal neural stem-cell
compartment during whole-brain radiotherapy for brain metastases
(RTOG 0933): a phase II multi-institutional trial. J Clin Oncol.
2014;32:3810–3816.
61. Gondi V, Hermann B, Mehta MP, et al. Hippocampal dosimetry
predicts neurocognitive function impairment after fractionated
stereotactic radiotherapy for benign or low-grade adult brain
tumors. Int J Radiat Oncol Biol Phys. 2013;85:348–354.
62. Lee AW, Ng SH, Ho JH, et al. Clinical diagnosis of late temporal
lobe necrosis following radiation therapy for nasopharyngeal
carcinoma. Cancer. 1988;61:1535–1542.
63. Lee AW, Ng WT, Hung WM, et al. Major late toxicities after
conformal radiotherapy for nasopharyngeal carcinoma-patient- and
treatment-related risk factors. Int J Radiat Oncol Biol Phys. 2009;
73:1121–1128.
64. Pehlivan B, Ares C, Lomax AJ, et al. Temporal lobe toxicity analysis
after proton radiation therapy for skull base tumors. Int J Radiat
Oncol Biol Phys. 2012;83:1432–1440.
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and/or radiotherapy in the treatment of anaplastic gliomas. J
Neurosurg. 1978;49:333–343.
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nervous system irradiation and intensive chemotherapy early in
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1972;29:381–391.
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metastases: final results of the first two studies by the Radiation
Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1980;6:1–9.
68. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation
therapy with or without stereotactic radiosurgery boost for patients
with one to three brain metastases: phase III results of the RTOG
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9508 randomised trial. Lancet. 2004;363:1665–1672.
69. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus
whole-brain radiation therapy vs stereotactic radiosurgery alone for
treatment of brain metastases: a randomized controlled trial. JAMA.
2006;295:2483–2491.
70. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain
radiotherapy versus observation after radiosurgery or surgical
resection of one to three cerebral metastases: results of the EORTC
22952–26001 study. J Clin Oncol. 2011;29:134–141.
71. Shiu AS, Chang EL, Ye JS, et al. Near simultaneous computed
tomography image-guided stereotactic spinal radiotherapy: an
emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol
Biol Phys. 2003;57:605–613.
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and orientation. Med Phys. 1993;20:1211–1218.
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Principles and Practice of Radiation Oncology. 5th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2008:765–777.
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whole-brain radiation therapy (HA-WBRT). Med Dosim.
2015:S0958–S3947.
76. Lawrence YR, Li XA, Naqa IE, et al. Radiation dose-volume effects in
the brain. Int J Radiat Oncol Biol Phys. 2010;76:S20–S27.
77. Bhandare N, Jackson A, Eisbruch A, et al. Radiation therapy and
hearing loss. Int J Radiat Oncol Biol Phys. 2010;76:S50–S57.
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32 Pediatric Malignancies
Shannon M. MacDonald and Nancy J. Tarbell
INTRODUCTION
There are several special aspects to consider for radiation treatment
planning for children. Pediatric radiation oncology differs from other
radiation subspecialties in that it involves knowledge of all anatomic
locations. Tolerances for organs at risk differ from adults due to growth
and development. There is also much greater variability in patient size
and their ability to cooperate. Pediatric malignancies are relatively rare.
As a pediatric oncology community, we rely more on the collective
experience of our field than most subspecialties. Forums and guidelines
exist through Children’s Oncology Group (COG) and the Pediatric
Radiation Oncology Society (PROS). These websites help to provide
general radiation guidelines and also the ability to communicate with
other subspecialists in pediatric oncology, enabling pediatric oncologists
to benefit from the experience of others when faced with a difficult case.
Given that approximately 80% of pediatric cancer patients will go on to
be long-term survivors, it is of paramount importance that radiation
treatment plans are devised with great care to ensure the best possibility
of local control with the lowest possible risk of long-term side effects (1).
Radiation Delivery for Children

Modern radiation planning and delivery for pediatrics take advantage of
many of the same technologic advances in imaging, planning software
systems, and radiation modalities used for the adult population. Nearly
all treatments are planned using three-dimensional (3D) imaging and
cutting-edge modalities such as proton radiation, brachytherapy, and
intensity-modulated radiation, which are frequently used to provide
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maximal normal tissue sparing. Advances in imaging have allowed for
more precise definition of structures and areas at risk and radiation
guidelines over time have allowed for smaller margins due to improved
delineation of tumors and minimization of setup error.
Immobilization
Immobilization is often a challenge for young children. They may be
fearful of the therapy or treatment room and/or lack the ability to
understand the importance of remaining still for treatment. For young
children or those unable to tolerate treatment without sedation,
anesthesia is necessary. It is crucial for the pediatric radiation oncology
team to have a good working relationship with the pediatric anesthesia
team to ensure positioning is optimal for both teams and to provide safe
and efficient treatment. Children do not require deep sedation for
radiation therapy as the purpose of anesthesia is simply to keep the
patient from moving, therefore the use of a conscious sedative rather
than full general anesthetic requiring intubation is preferred at most
institutions. Propofol is our institution’s preference due to ease of
administration and rapid recovery. Intravenous access is required for this
type of sedation. A portacath is the most common mode of access and
many patients will have a portacath for chemotherapy administration;
some may have a Broviac catheter device that can also be used. Children
with a portacath can be accessed on Mondays prior to treatment and
have the access removed on Fridays following treatment. While
positioning is optimized for RT delivery, a good airway will supersede
this for children under anesthesia. Most children need only an oxygen
mask, but a few will require a laryngeal mask airway (LMA) or nasal
trumpet to maintain a good airway. Prone positioning is the most
challenging for achieving and maintaining a good airway, but this is still
possible for the vast majority of patients. Older children can usually
tolerate treatment without sedation. Music may be helpful for soothing
anxiety or providing distraction. For some older children that have
difficulty staying still, a low dose of a medication such as Ativan may
allow them to tolerate treatment without sedation. Select children that
cannot initially tolerate treatment do respond to coaching by nurses,
child life specialists, and even other pediatric patients going through a
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similar treatment. The ability to avoid anesthesia allows for maintenance
of a regular meal schedule, thereby limiting impact on weight loss/gain
and decreases the amount of time spent in the radiation oncology
department, permitting greater preservation of the child’s routine or
“normal” life. In addition, avoidance of anesthesia limits the strain on
hospital resources, including nursing and anesthesia staff while also
reducing time on radiation treatment machines and decreases the cost of
a radiation course.
Some immobilization devices may be uncomfortable for children or
difficult to use, as most were manufactured for adults and later adapted
for use in children. Immobilization for the treatment of brain or head-
and-neck tumors is usually accomplished with a molded thermoplastic
mask. Metallic markers can be placed on the mask to help with
localization. Some stereotactic treatments require a more rigid frame,
often with a bite block. These systems are sometimes only feasible for a
single fraction treatment and usually too difficult for children to tolerate
without sedation. Treatment to the trunk of the body or extremities will
require the placement of tattoos and it is very important to review with
parents and children the placement and permanency of these tattoos.
Vac-loc bags, leg immobilizers, or custom-made immobilization devices
are used depending upon treatment site and patient anatomy.
Respiratory gating or a four-dimensional computed tomography (4D CT)
to determine the margin needed to account for respiratory motion is
appropriate for some thoracic and abdominal locations. Image-guided
radiation therapy with daily kV quality images or cone-beam CT is
generally used to allow for a small setup margin and to improve
accuracy. The dose of radiation from setup imaging is small, but may
need to be discussed with parents in the era of a more heightened
awareness of diagnostic radiation exposure for pediatric patients (2,3).
Three-Dimensional Treatment Planning

3D planning should be used for most, if not all, pediatric radiation
treatment. Most departments obtain a CT scan in the treatment position
and fuse diagnostic magnetic resonance imaging (MRI), CT and/or
positron emission tomography (PET)/CT sequences for treatment
planning. Some radiation departments utilize MRI or PET/CT treatment
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planning scanners. As our imaging techniques have improved, margins
for error around this volume can be made smaller, thereby allowing for
full coverage of the tumor with improved avoidance of the surrounding
healthy tissues.

Intensity-modulated radiation therapy (IMRT) allows for the most
conformal photon plan with high-dose isodose lines closely surrounding
the target volume. While IMRT plans decrease high and moderate dose
to nearby structures, these plans typically result in the delivery of low-
dose radiation to a larger volume of tissue outside of the target. While
this may be a little consequence in terms of function, second malignancy
is a risk for even low-dose radiation and is a greater concern for the
pediatric population (4). Despite this concern, recent data with
reasonably long follow up indicate the risk of second malignancy for
pediatric patients treated with IMRT is still low (5).
Proton Radiation
Proton radiation is a form of particle radiation that allows for complete
sparing of tissue beyond the target volume for a given beam and often
decreased dose proximal to the target compared to photon radiation (6).
Proton therapy decreases both high- and low-dose regions outside of the
target volume. Pediatric tumors are considered one of the best
indications for this type of treatment, given the importance of sparing
developing tissue from radiation. While clinical experience for protons is
still limited relative to photon experience, many publications have
supported disease outcomes that are comparable to favorable to photons
and suggest that morbidity is less (7–12). Protons are more costly than
other external-beam radiation options. However, for children, the
avoidance of radiation to critical structures that would lead to costly
chronic medical conditions can render protons cost-effective and even
cost-saving for some patients (13,14).
PEDIATRIC DISEASE SITES/TREATMENT PLANNING
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Embryonal Tumors of the CNS
Embryonal tumors are the most common malignant brain tumors in
children. They are highly malignant small round blue cell tumors that
have a propensity to spread through the cerebrospinal fluid (CSF).
Subtypes of embryonal tumors include medulloblastoma, supratentorial
primitive neuroectodermal tumors (SPNETs), and atypical teratoid
rhabdoid tumors (ATRT). While treatment regimens differ, intensive
treatment with surgery, radiation, and chemotherapy is indicated for all
embryonal tumor subtypes for the best chance of disease control and
survival.
Medulloblastoma is the most common embryonal tumor that is located
in the cerebellum, by definition. Workup includes MRI of the brain that
characteristically shows a mass in the cerebellum filling the fourth
ventricle and causing obstructive hydrocephalus. Maximal safe resection
is recommended and additional workup includes MRI of the spine
(presurgical or 0 to 14 days after surgery) and a lumbar puncture to
obtain CSF (10 to 14 days after surgery; CSF should be obtained by LP
and should not be performed prior to surgery due to risk of herniation).
At present, a risk stratification system based on clinical factors divides
patients into two risk groups, “high-risk” and “standard-risk,” with
standard-risk defined as children over the age of 3 with ≤1.5 cm2 of
residual disease following surgery and no metastatic disease (grossly or
in CSF) and all others considered high-risk. In recent years, diffuse
anaplastic histology has been found to portend a poor prognosis and
these patients should be considered for high-risk therapy regimens (15).
Molecular profiles will likely supersede current staging and histologic
risk stratification, but at present these profiles are used to dictate
treatment only in the setting of a clinical trial (16–18). Accepted
radiation treatment for standard-risk disease is 23.4 CSI followed by a
whole posterior fossa or involved-field boost to 54 Gy. Lower CSI doses
have and are being investigated for young children (<8 years old) and
for molecularly favorable profiles (19). Standard treatment for high-risk
disease includes CSI to 36 Gy followed by whole posterior fossa or
involved-field boost to 54 Gy. Any sites of initial metastatic disease in
the spine should receive 45 Gy and metastatic lesions in the brain should
receive at least 45 Gy, sometimes a higher dose depending on location
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and the perceived risk-benefit ratio. Management for children under the
age of 3 is a bit more heterogeneous and generally consists of maximal
safe resection followed by chemotherapy, followed by delayed and
usually localized radiation therapy (20,21). In infants that present with
disseminated or refractory disease, low-dose CSI may be considered
depending on patient age and parental wishes. Disease-free survival for a
patient with standard-risk disease treated with chemotherapy and
radiation exceeds 80% (15). Cure rates for high-risk disease are less
favorable, but fall between 50% and 70% (22). Children with standard-
risk disease with anaplastic histology have a disease-free survival in
between these two groups of approximately 73% (15).
SPNETs are histologically similar to medulloblastoma but are located
outside of the cerebellum in any location of the supratentorial brain.
Pineoblastomas are a subset of SPNETs. The prognosis for patients with
this disease is worse than medulloblastoma even in the absence of
dissemination. All patients with SPNETs are therefore considered to have
“high-risk” disease, regardless of whether or not the disease is metastatic
at diagnosis, and standard CSI doses for localized or metastatic disease is
36 Gy. A dose of 54 Gy is recommended to the tumor bed plus a margin
of approximately 1 cm within anatomical boundaries. For children under
the age of 3, involved-field radiation to 50.4 to 54 Gy is generally
recommended. Similar to medulloblastoma, management for children
under the age of 3 is maximal safe resection followed by chemotherapy,
followed by delayed, and usually localized, radiation therapy.
ATRT are rare malignancies that typically affect very young children.
These tumors look similar to medulloblastoma, but have a mutation that
results in a deficiency of INI-1 protein (23). The prognosis for ATRT is
inferior to that for medulloblastoma and SPNET; however, with more
aggressive chemotherapy, 2-year progression free and overall survival
rates of 53% and 70%, respectively, can be achieved (24). The treatment
of ATRT includes maximal resection of primary disease, intense
induction chemotherapy including intrathecal chemotherapy, high-dose
chemotherapy followed by stem cell rescue (HDCSCR), and radiation
therapy. For children under the age of 3, localized radiation is
recommended. For older children, CSI followed by additional involved-
field radiation is favored due to risk of dissemination and poor prognosis
(25). The COG protocol delivers involved-field RT for all children,
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regardless of age. Although there are limited data on effective CSI dose,
given the more aggressive nature of this disease, 36 Gy is most standard
for CSI. A dose of 50.4 to 54 Gy is recommended to the involved-field.
Embryonal tumors are highly radiosensitive tumors. As a result, the
technical quality of radiation delivery significantly influences the risk of
recurrence. Treatment planning, especially CSI, must be planned with
utmost care. The craniospinal volume includes the entire brain and
spine. Care should be taken to ensure coverage of the cribriform plate
and to give a margin of at least one vertebral body below the thecal sac,
which is typically located near S2, but can vary. Adequate margin lateral
to the thecal sac is also required. It is best to confirm the location of
these regions with a neuroradiologist to ensure coverage. Most CSI
treatments are delivered with the patient in the prone position, although
supine CSI treatment is now being delivered in the supine position at
several institutions. There was some reluctance to deliver CSI in the
supine position, as clinical verification that matched spinal fields is only
possible in the prone position. However, there is also a possibility that
overconcern regarding field overlap could lead to “colder” cold spots
potentially increasing the risk of relapse. The spinal field is typically too
long to treat with just one field and typically two to three fields are
necessary. Fields are matched anterior to the spinal cord, which create a
small area of underdosing in the cord but avoids any areas of overlap or
hot spots in the cord (Fig. 32.1). Care should be taken to minimize these
areas of slight under- and overdosing and fields should be “feathered”
(match point varied during treatment) to minimize these areas and
decrease uncertainty. The use of IMRT and scanning proton techniques
allow for treatment without field matching of fields and because of the
lack of exit dose protons avoid exit dose to the thyroid, heart, lungs,
abdominal organs, and ovaries (Fig. 32.2).
The posterior fossa volume extends from the tentorium superiorly to
C1 inferiorly. Laterally the posterior fossa volume includes the entire
cerebellum and extends to the bony occiput and anteriorly this volume
includes the brainstem and lower midbrain (as defined by COG
guidelines). The involved-field volume GTV should include the tumor
bed (anything in contact with the initial tumor prior to surgery) and any
residual gross disease. Care should be taken to ensure coverage of
anything touched by the initial tumor and also to account for anatomical
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shifts following surgery. An expansion of 1 to 1.5 cm is typically used to
form the CTV for the involved-field boost.
Ependymoma
Intracranial ependymomas are brain tumors that originate from
ependymal cells lining the ventricles or from ependymal cell rests
located in the brain parenchyma. The majority (approximately two-
thirds) occur in the posterior fossa/fourth ventricle and the remainder
occur in the supratentorial brain (26). Diagnostic workup includes MRI
of the brain and spine and CSF sampling, though CSF is rarely positive
when MRIs show no evidence of metastatic disease (27). Intracranial
ependymomas are defined as classic/differentiated (WHO grade II) or
anaplastic (WHO grade III) by histology. Similar to medulloblastoma, we
are learning more and more about the genetic profiles for this disease
and molecular characteristics may play a role treatment delivery on
future clinical trials (28). The initial treatment is complete surgical
removal. Removal of the entire tumor is critical for a favorable outcome
and this has been demonstrated clearly in both small and large series.
For localized disease, the 3- to 5-year progression-free survival rates
range from 51% to 88% for gross total resection and from 0% to 54% for
subtotal resection (7,29). If complete removal is achieved, radiation to
the tumor bed plus a margin is recommended. If resection is incomplete,
a short course of chemotherapy followed by a second-look surgery in
attempt to achieve a gross total resection prior to radiation is generally
favored. Chemotherapy has not shown benefit for this disease and
cannot be used in place of RT; it is unclear if chemotherapy adds benefit
over surgery and radiation alone, but this is being investigated in a
randomized fashion on the current COG protocol, ACNS0831. Off
protocol, maximal resection and radiation is standard. Although there
are concerns about radiating very young children, localized radiation has
been proven safe and effective for children as young as 12 months of
age.
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Figure 32.1 Craniospinal irradiation requires spinal fields to be matched. Fields should be
matched anterior to spinal cord, which creates a small cold spot within the cord. To minimize this
slightly underdosed area and to minimize the uncertainty associated with matched fields, fields
are “feathered” so that this match is moved to different locations during treatment. This figure
shows field feathering.
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Figure 32.2 Proton radiation allows for complete sparing of all organs anterior to the vertebral
body. This figure shows a CSI plan for a young child. Note that the whole vertebral body is
included to ensure even dosing and avoid asymmetric growth.
Treatment planning should start with a careful review of all images

with a neuroradiologist to determine any areas of residual disease and
review all surfaces contacted by initial tumor. Infratentorial
ependymomas are notorious for extension through the foramina of
Luschka and Magendie. It is critical to determine original tumor
extension into these regions and treat these surfaces. Contouring the
preoperative volume to become familiar with both the anatomical
location of the tumor as well as ependymal and CNS structures in
contact with the tumor may be useful. Care should be taken to adjust
this volume for anatomical shifts following surgery. The GTV should
include any surface contacted by the original tumor as well as any gross
residual disease. The CTV expansion should be approximately 5 mm
with constraints for anatomical boundaries. The recommended dose to
this volume is 54 to 59.4 Gy in 30 to 33 fractions. The recently closed
and current COG protocols (ACN0121 and ACNS0831, respectively)
prescribe a total dose to 59.4 Gy, but ACNS0831 requires that critical
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structures (the spinal cord and optics) outside of the area of highest risk
be blocked after 54 Gy. It should be recognized that brainstem tolerance
is considered 54 Gy and that doses in excess of this may increase the risk
of brainstem necrosis. Many do however feel that the risk of local
recurrence after radiation warrants this additional risk. Children under
the age of 18 months or with known brainstem injury should not receive
a total dose in excess of 54 Gy. Off protocol, our institution favors a dose
of 54 Gy for patients of all ages that have undergone a gross total
resection and have infratentorial disease. Supratentorial tumors are also
treated with maximal resection followed by involved-field RT to 54 to
59.4 Gy. Again, care should be taken to define GTV as any residual
tumor and areas of the cerebrum in contact with presurgical tumor. Due
to shifts in the brain parenchyma, this is sometimes challenging and
sulci/gyri of the brain in contact with the initial tumor should be
reviewed with a neuroradiologist. Figure 32.3 shows an IMRT plan for a
patient with an infratentorial ependymoma. Supratentorial WHO grade II
tumors that are completely resected may be observed without radiation
on protocol, but should receive RT off protocol. Limited data exist for
patients with metastatic ependymoma and outcomes are very poor. Most
patients are treated with CSI to 36 Gy followed by a localized boost to
54 to 59.4 Gy. For patients with recurrence following radiation,
reirradiation has been explored and may allow for long-term survival for
some patients, but, in general, this treatment is considered palliative.
Low-Grade Astrocytoma
Though the most common pediatric brain tumor, low-grade gliomas can
be cured with surgery alone if they occur in a location amenable to
surgery with acceptable morbidity, and therefore, many do not require
radiation. Tumors that occur in the hypothalamus, thalamus, tectum,
optics, and brainstem, often require radiation, as surgical morbidity may
be unacceptable in these locations. Histologic subtypes of pediatric low-
grade gliomas include pilocytic (WHO grade I) and diffuse (WHO grade
II), with pilocytic astrocytoma accounting for the majority of tumors in
young children. Younger patients are often treated with chemotherapy to
delay radiation and for children with neurofibromatosis chemotherapy
alone may be sufficient and spontaneous regression is possible. Packer et
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al. (30) reported a 68% 3-year progression-free survival rate for children
treated with carboplatin and vincristine. Additional chemotherapeutic
agents have since been studied and also shown efficacy, but second- and
third-line regiments tend to lead to less efficacious and less durable
results. For most children with low-grade glioma, chemotherapy
typically delays progression, but radiation is usually still required for
definitive treatment. When determining the appropriate therapy, one
must also consider the cumulative morbidity of multiple regimens and
risks of functional loss from progression of tumor. Data also indicate that
young children are more likely to respond and have a durable response
than older children. Radiation provides durable control with Merchant et
al. (31,32) reporting 10-year progression-free survival rates of 74% for
conformal focal radiation.
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Figure 32.3 Intensity-modulated radiation therapy (IMRT) is one advanced technique used for the
treatment of pediatric malignancies. This figure shows beam arrangement and intensity
modulation of fields for an infratentorial ependymoma (A) and an axial image of plan and doses
(B).
Because these tumors are not highly infiltrative, only a small volume
expansion is necessary around visible tumor. The GTV should include
enhancing and nonenhancing or cystic tumor plus a small margin of
approximately 5 mm. A dose of 50.4 to 54 Gy is recommended. If tumors
contain a cystic component, it is important to monitor the cystic
component for changes during radiation therapy and adjust the plan as
needed. Although it is relatively rare for low-grade gliomas to
disseminate, for these cases, radiation volumes typically encompass the
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entire craniospinal axis to a dose of 36 Gy followed by involved-field
treatment to 45 to 54 Gy, depending on tumor location.
Pseudoprogression—enhancement and/or enlargement of tumor—may
occur following treatment, most frequently at 6 to 12 months following
delivery of radiation. Care should be taken to consider this in order to
avoid unnecessary treatment or assume tumor progression or
transformation to a more malignant process.
High-Grade Astrocytoma
High-grade gliomas of the supratentorial brain are seen much less
frequently in the pediatric population, than the adult population. Most
high-grade gliomas are localized. Maximal safe resection and radiation is
standard. Chemotherapy has been studied, but without great success and
temozolamide seems less efficacious for children than adults, perhaps
due to the relatively low frequency of MGMT deletion for childhood
tumors (33). Despite this, at present, temozolamide is often used as a
first-line chemotherapy concurrent with RT and following RT due to
absence of a more effective agent and the still relatively poor prognosis
of high-grade gliomas in children. Despite a less-favorable prognosis
compared with many other pediatric brain tumors, long-term survival is
attainable for some children, especially the very young, and some
pediatric patients with high-grade gliomas will be long-term survivors
(34).
For treatment planning, one must be careful to include areas of
contrast enhancement and T2 fluid-attenuated inversion recovery signal
abnormality for the initial GTV. Again, review of all MRI sequences with
pediatric neuroradiologist should be done. The GTV plus a generous
margin of approximately 1 to 2 cm is usually treated to 45 Gy. The
enhancing area plus a margin should receive a boost dose to bring this
region to a dose of 54 to 59.4 Gy. While anatomical boundaries such as
bone and tentorium should be respected when defining the CTV, these
tumors often cross white matter tracts and it is important to consider
this when defining tumor margins to account for microscopic spread of
disease.
Diffuse Pontine Glioma
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Diffuse infiltrating pontine gliomas (DIPG) are high-grade tumors that
arise from the pons. These tumors have a characteristic appearance on
MRI of a nonenhancing T2 bright lesion that expands the pons. Biopsy is
not necessary when this classic radiographic appearance is evident;
however, more recently and for clinical trials, pathology is obtained for
molecular profiling and sometimes drug selection (35). Radiation is
palliative but indicated to the tumor with a small margin to a dose of
approximately 54 Gy. Symptoms almost always improve promptly with
treatment, but sadly, duration of resolution or improvement of
presenting symptoms is relatively short, on the order of months. This
disease is uniformly fatal and the median survival is approximately 1
year. Dose escalations of radiation, altered fractionation, and
chemotherapy have all been explored and have failed to improve DFS or
OS (36,37). Molecular targets are currently under investigation for this
tumor, but to date no successful systemic agent has been defined.
Germinoma/Nongerminomatous Germ Cell Tumors

Pediatric intracranial germ cell tumors are rare and usually occur in
adolescents. The most common locations for these tumors are in the
pineal gland and infundibulum/suprasellar region. Rarely, they occur in
other locations of the brain, with the third most common location being
the basal ganglia. When a GCT is suspected by MRI findings, serum
tumor markers, α-fetoprotein (AFP), and β human chorionic
gonadotropin (β-HCG) should be obtained. If a lumbar puncture can be
safely performed, CSF should be obtained for cytology and tumor
markers. MRI of the spine is also standard to rule out disseminated
disease.
“Pure” germinoma are highly curable tumors with DFS rates in excess
of 90% for both localized and disseminated disease. In the United States,
chemotherapy followed by reduced-dose radiation is usually
recommended for children to reduce late side effects of radiation. Two to
four cycles of platinum-based therapy, usually carboplatin and
etoposide, are delivered. If a complete response is achieved, a dose of 21
Gy to the whole ventricles followed by a boost to 30 to 40 Gy to the
primary tumor region is delivered. If a complete response is not
achieved, a second-look surgery is recommended (if this can be safely
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performed) to ensure that a nongerminomatous component is not
present and/or higher doses of radiation may be recommended. Some
studies have explored the use of chemotherapy followed by involved-
field radiation to 30 to 40 Gy. Early reports showed promising results,
but higher rates of ventricular relapse were later reported by Alapetite et
al., resulting in a shift back to a larger low-dose volume, whole
ventricular RT, first followed by an involved-field boost (38,39). The
current COG protocol, ACNS1123, is investigating the use of pre-RT
chemotherapy with four cycles of carboplatin and etoposide followed by
very low-dose whole ventricular radiation to 18 Gy and a boost to a total
of 30 Gy to the primary tumor for localized pure germinoma following a
complete response to four cycles of carboplatin and etoposide.
The prognosis for nongerminomatous germ cell tumors is inferior to
germinoma. The standard chemotherapeutic regimen in the United
States consists of six cycles of alternating carboplatin/etoposide and
ifosfamide/etoposide followed by radiation. Patients that do not have a
complete response to chemotherapy should undergo a second-look
surgery and those that have viable tumor remaining have been shown to
have an inferior prognosis. For these unfortunate patients, HDCSCR
should be considered (40). The last COG protocol, ACNS0122, delivered
CSI to 36 Gy followed by a boost to the tumor volume to 54 Gy after six
cycles of chemotherapy. The results of this trial have not yet been
published in manuscript form, but 5-year event-free and overall survival
rates of 84% and 93%, respectively, have been reported (should be
published by time of proof). The current COG protocol, ACNS1123,
examines a “middle ground” radiation volume delivering 30.6 Gy to the
whole ventricles followed by a dose of 54 Gy to the involved field
following six cycles of carboplatin/etoposide alternating with
ifosfamide/etoposide for patients with localized nongerminomatous
germ cell tumors who have a complete response to chemotherapy.
It is critical that the involved-field volume is determined at the time of
planning CSI or whole-ventricle treatment planning to ensure the CTV
boost volume receives full dose. The whole ventricular CTV should
include the whole ventricles plus the CTV for the boost volume. Germ
cell tumors can involve the optic nerves and hypothalamus in areas that
are not part of classic CSI or whole-ventricle volumes and the CTV
volume for pineal gland tumors may extend outside of the whole-
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ventricle volume, especially for infiltrating tumors. Guidelines to assist
in contouring the whole ventricular volume, a somewhat challenging
and tedious volume, are available for the current germinoma COG
protocol (Fig. 32.4).
Figure 32.4 The whole-ventricle volume is used for treatment of microscopic disease for
germinomas. This figure shows contours in axial, sagittal, and coronal views.
CRANIOPHARYNGIOMA
Craniopharyngioma is considered a “benign” tumor and highly curable.
However, these children can suffer great morbidity from tumor
progression and/or treatment. The most common type of
craniopharyngiomas, adamantinomatous histology, is often difficult to
separate surgically from adjacent critical structures, preventing a
curative complete surgical resection. Treatment with biopsy and cyst
decompression or minimal excision followed by radiation is usually
favored as a less morbid treatment. The standard GTV for
craniopharyngiomas includes both solid and cystic components. A small
margin of 3 to 5 mm around the GTV should be given for the CTV
volume. A dose of 50.4 to 54 Gy at daily fractions of 1.8 Gy is
recommended.
Given the high likelihood of survival, minimizing late morbidity is of
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paramount importance, and modern modalities are recommended for
treatment in an attempt to decrease long-term morbidity. Intracavitary
radiation may be used for the cystic recurrence (41,42). Because of
limited penetration, this treatment is not useful for treatment of the solid
component of craniopharyngioma.
For any tumors that have a cystic component, cyst growth or change
in position may occur during radiation therapy. Since the cystic portion
of the tumor is also targeted in treatment, it is crucial to make
appropriate adjustments in the radiation plan during the course of
radiation. It is also important to recognize that dose to organs at risk
may also be altered by cystic change. CT or T2-weighted noncontrast
MRI every 7 to 14 days or daily cone-beam CT for cyst monitoring
should be strongly considered.
Wilms Tumor and Other Renal Malignancies

Wilms tumor is the most common abdominal malignancy in children.
These children generally present with an abdominal mass, but are
otherwise healthy. The North American standard is to perform surgical
resection as the initial treatment for therapeutic treatment as well as for
diagnosis, staging, and determination of subsequent therapy. COG
radiation therapy guidelines are based on both stage and pathology.
Flank radiation is recommended for patients with stages I to III
unfavorable histologies (diffuse anaplasia, focal anaplasia, CCSK, CCSK
—stages II and III) and for stage III FH. The standard dose is 10.8 Gy in
fractions of 1.8 Gy following complete removal of tumor, but higher
doses are recommended for recurrent disease, stage III DA, and
sometimes for children diagnosed at an older age. An additional 10.8 Gy
is advised for gross residual disease. Although 3D planning is useful for
delineation of the tumor bed and gross residual disease if present,
guidelines are still based in large part on bony landmarks. Respiratory
motion should be considered and a 4D CT may be useful for planning.
Respiratory gating is not typically employed, but margins for respiratory
motion are added. The initial tumor should be reproduced on planning
CT scan. Care should be taken to include or evenly dose the entire
vertebral body and to spare the contralateral kidney and ovaries for
females. AP/PA fields are typically used, but oblique fields may be of
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benefit for contralateral renal sparing in some cases. Whole abdominal
radiation (WART) to a dose of 10.5 Gy at 1.5 Gy per fraction is
recommended for positive cytology, diffuse spillage, prior biopsy, or
peritoneal seeding. If feasible, RT should be started by postoperative day
9 if and no later than postoperative day 14. Whole lung irradiation
(WLI) to 10.5 Gy is recommended for patients with pulmonary
metastases that do not resolve following chemotherapy and for patients
with pulmonary metastases at diagnosis with loss of heterozygosity for
1p16q. Brain, liver, and bone irradiation is indicated when metastases
are present.
Neuroblastoma
Neuroblastoma is the most common solid non-CNS malignancy.
Neuroblastoma occurs in very young children and usually originates
from the adrenal gland or paraspinal ganglia. Children often present
with an abdominal mass but in contrast to Wilms tumor, the other
common abdominal malignancy in children, these children are typically
very ill due to systemic involvement. Radiation therapy is not used for
favorable disease and is recommended mainly for patients with high-risk
disease or rarely for children with intermediate-risk disease refractory to
chemotherapy. At present, children with high-risk disease are treated
with chemotherapy, HDCSCR, immunotherapy, and usually surgery and
radiation for local control (43). Many children with high-risk disease
have primary tumors that cannot be resected at diagnosis and surgery is
performed after five or six cycles of systemic therapy. The standard dose
of RT recommended to the post-chemotherapy presurgical volume in
21.6 Gy. This volume should include a tumor bed (GTV) that
encompasses all areas touched by this disease but accounts for shifts in
organs following surgical resection. For children with residual disease
following surgery, a total dose of 36 Gy is recommended to areas of
gross disease. Advanced radiation techniques such as IMRT,
intraoperative radiation, and proton radiation should be considered to
minimize dose to the kidneys, liver, lung, developing bone, and other
normal structures (44). Although the dose of radiation is relatively low
compared with other disease sites, children are usually very young and
volumes may be quite large. Figure 32.5A demonstrates various
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treatment techniques for a child with high-risk neuroblastoma with
proton therapy for a fully-grown child. Note the gradient seen over the
vertebral body. For a growing child, contours or plan should be devised
so that the entire vertebral body receives a relatively homogeneous dose.
Figure 32.5B shows a proton planning volume that includes the vertebral
body to ensure homogeneous dose delivery. Radiation therapy to a dose
of 21.6 Gy is also advised for any metastatic sites persistent following
induction chemotherapy. Metastatic sites requiring RT are typically
present in the bone. Figure 32.6 shows a bony metastatic site treated
with protons. Note the low dose achieved to both the pelvis and femoral
head growth plates. This would not be possible with an alternative
modality. In the setting of multiple metastatic sites still positive after
induction chemotherapy, consideration must be given to the amount of
tissue to be irradiated, and typically children are re-evaluated after
further chemotherapy and an attempt is made to limit the number of
metastatic sites receiving radiation to three to five. Additional
indications for radiation for neuroblastoma are in an emergent setting
and include radiation to the liver for liver metastases in infants to relieve
respiratory distress after other measures have failed, and radiation for
spinal cord compression if surgical decompression is not feasible. A dose
of 1.5 Gy for three fractions is recommended to a portion of the liver
and is generally promptly effective. Care should be taken to shield the
ovaries for females. For spinal cord compression, a decision should be
made regarding dose based on additional risk factors and plans for
subsequent radiation.
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Figure 32.5 Proton plan for neuroblastoma. Part A shows a plan for a fully grown 17-year-old
child with no effort made to include the whole vertebral body. Part B shows a plan for a young
child which intentionally includes the whole vertebral body. It is important to be aware of even
doses to the vertebral bodies/bone. When using advanced techniques, it may be necessary to
adjust contours in order to facilitate homogeneous dosing.
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Figure 32.6 Treatment of a bone metastasis for a child with neuroblastoma with proton radiation.
Protons allow for excellent sparing of nearby growth plates.
Hodgkin Disease
Hodgkin disease is a highly curable lymphoma often cured with
chemotherapy alone, but sometimes requiring radiation. At present,
most patients are treated with risk-adapted therapy dictating amount of
chemotherapy and/or radiation therapy based on response to
chemotherapy (45). The radiation treatment of this disease has evolved
over many decades from large volume-extended-field radiation to
involved-field radiation and now to involved-site or involved-node
radiation therapy (46). Defining these nodal areas require the use of
both pre- and post-chemotherapy imaging. Ideally a PET-CT in the
treatment position at the time of diagnosis should be obtained, but often
this is not feasible to obtain. Information regarding the initial nodal
disease and use of fusion if position allows should be performed. The
location of nodal disease should be carefully reviewed with radiology to
assist in design of the GTV and CTV. Motion should be accounted for by
use of a 4D CT and/or additional margin for motion. Most pediatric
patients are treated if they present with initial bulky disease or do not
achieve a rapid early response. The most commonly used dose is 21 Gy
at 1.5 Gy per fraction. Given the very high cure rates seen in this
disease, extreme care must be taken to avoid long-term morbidity from
this disease and cooperative trial groups continue to determine how to
minimize radiation dose and volume for this disease (47,48).
Leukemia
In spite of the frequency of leukemia in children, with modern
chemotherapy radiation is seldom necessary. For acute lymphocytic
leukemia (ALL), radiation is employed in the setting of high-risk disease,
refractory disease, or at relapse. For patients with T-cell ALL, current
guidelines indicate radiation for patients with the following high-risk
features: WBC >50 × 109, CNS3 disease (>5 WBC/l or blasts in the
CSF), Ph + ALL, or other high-risk disease that are “slow responders”
with poor response to induction chemotherapy. Cranial radiation to a
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dose of 12 to 18 Gy, more often 12 Gy, at 1.5 Gy per fraction is the
recommended CNS dose for this disease. Testicular radiation is other site
for which radiation may be necessary, but it is now used only in the
setting of refractory or recurrent disease. The recommended dose for
testicular radiation for leukemia is 20 to 24 Gy (49).
Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma of
childhood. Two main histologies exist, embryonal and alveolar and these
tumors may occur in any location of the body. Currently, the COG
studies stratify patients into three risk groups (low, intermediate, and
high) on the basis of site, stage, histology, and group, but TNM staging is
also used. Risk stratification is highly complex, but in general risk groups
include: (1) low-risk: embryonal nonmetastatic favorable sites and
embryonal group 1 or 2 unfavorable sites, (2) intermediate-risk:
embryonal group III unfavorable sites and nonmetastatic alveolar RMS at
any site, (3) high-risk: metastatic disease.
The Intergroup Rhabdomyosarcoma Studies (IRS) enabled marked
improvement in therapy and outcomes for this disease over the past
several decades (50). At present, combined modality risk-stratified
therapy is used for children with rhabdomyosarcoma, and this represents
another disease site that requires multidisciplinary discussion regarding
best management. Radiation treatment depends on several prognostic
factors and feasibility of surgery with organ preservation. Surgery is
performed upfront for resectable tumors and may be attempted
following chemotherapy if tumors become resectable usually with the
goal of decreasing radiation dose and sometimes volume.
Contemporary treatment and the existing COG rhabdomyosarcoma
trials require 3D treatment planning to allow for full visualization of
areas at risk and target volumes. Radiation is omitted only for patients
with completely resected favorable histology disease. Following surgical
resection, 36 Gy is recommended for microscopic disease and nodal
disease is treated to a dose of 41.4 Gy. Patients with gross disease
receive a dose of 50.4 Gy. Target volumes delineate pre-chemotherapy
volume as the gross tumor volume. A margin of 1 cm around this volume
respecting anatomical boundaries is recommended to encompass
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microscopic disease.
Ewing Sarcoma
Ewing sarcoma follows rhabdomyosarcoma in its frequency in the
pediatric population. When complete surgical resection can be achieved
without unacceptable morbidity, this is the preferred treatment and
radiation is not required. Radiation therapy is indicated for inoperable
or either partially resected tumors. Radiation dose to 50.4 to 55.8 Gy to
the involved area of bone with a margin for microscopic disease is
standard. The initial extent of disease should be treated to a dose of
approximately 45 Gy adjusting for the shifting of organs or tissues after
regression of the soft tissue portion of the tumor following
chemotherapy, but not the bony component of tumor. A margin of
approximately 1.5 cm should be used around this volume to form the
CTV. Gross disease at the time of treatment along with initially involved
bone with a margin of approximately 1.5 cm should receive an
additional dose of 10.8 Gy to total 55.8 Gy with the exception of tumors
located in the vertebral body, which may receive a total dose of 45 to
55.8 Gy depending on location and ability to avoid the spinal cord due
to spinal cord tolerance.
Retinoblastoma
Retinoblastoma is a rare disease almost always diagnosed in infants or
children under the age of 3. Approximately 60% of patients will have a
nonhereditary and unilateral form of this disease and the remainder of
patients will have the hereditary form of retinoblastoma with a high
propensity for bilateral disease and subsequent malignancies, some
radiation induced and some that occur in children that have not received
radiation (51). Radiation is largely avoided because of the fear of
radiation-induced malignancies and because of the young age of these
patients, and bony growth abnormalities that will occur in the irradiated
bone following RT. Radiation is generally reserved for disease refractory
to alternative therapies (cryotherapy, laser therapy, intra-arterial
chemotherapy, intravitreal chemotherapy, and systemic chemotherapy)
in an eye with useful vision while enucleation is advised if it is thought
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that there is no meaningful visual potential. The most common
indication for treatment of the intact eye is vitreous seeding.
Postoperative radiation is delivered for advanced disease following
enucleation. A dose of 45 Gy is standard for all indications. Treatment of
the entire retina is most standard. For very localized tumors, the area of
the involved retina may be considered if alternative options exist for
anterior retinal tumor occurrence (i.e., cryotherapy or laser therapy). In
the postoperative setting, the orbit and up to the optic chiasm is
necessary in cases of frank orbital disease and high-risk pathology
features (trans-scleral extension or tumor involvement of the cut end of
the optic nerve). Plaque brachytherapy may be an option for unifocal
tumors that are located in the peripheral retina. Radiation does provide
an excellent chance at durable control of disease, but carries risks of
facial hypoplasia and radiation-induced malignancies. Proton radiation is
an excellent option for this disease to reduce exposure of tissue at risk
for a radiation-induced malignancy and to avoid severe bony growth
abnormalities (9,11). Referral to a proton center with expertise in
retinoblastoma should be considered. Figure 32.7 shows a treatment
setup utilizing an eye cup to ensure eye immobilization in addition to an
aquaplast face mask to ensure immobilization of the head. A cup similar
to a contact lens with a metal post is placed on the eye following
sedation. A small amount of suction allows for the eye to be positioned.
The metallic post can be imaged with kV x-rays for daily setup. Figure
32.8 shows a proton plan.
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Figure 32.7 Retinoblastoma treatment. A suction eye cup is used to provide reproducible eye
positioning for a child under anesthesia.
Figure 32.8 Retinoblastoma plan with protons. Protons provide excellent sparing of tissues
outside of the target area.
CONCLUSIONS
The field of radiation oncology is evolving rapidly both technologically
and biologically, and we see much improved cancer outcomes and
survival rates than we did just a few decades ago. As malignancies
become more curable and life expectancies following the diagnosis of
cancer become prolonged, the impact of our treatments on quality of life
or even secondary risks of life-threatening complications become more
apparent. We have learned a great deal from our childhood cancer
survivors. In no other subset of patients are the late effects of treatment
more apparent. Though we debate the absolute benefit of these
technologic advances in adults, there has been little argument against
using more expensive technology for our children in order to protect
healthy tissues from the adverse effects of radiation. As we continue to
learn from our experience with childhood malignancies and advance
with biologic treatments, radiation treatments will without doubt evolve
and change with continued goals of providing curative treatment while
minimizing side effects and allowing our patients to experience a good
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quality of life following the diagnosis of cancer. We hope that future
treatments will include lower-dose and smaller-volume radiation
treatments combined with less toxic biologic agents. In the meantime,
we should continue to provide the most targeted treatment possible by
delineating proper target volumes and using the appropriate technology
to deliver radiation with the optimal therapeutic ratio.
KEY POINTS
• Highly conformal therapy is indicated in the treatment of pediatric
tumors, given the importance of sparing developing tissue from
radiation. Advance modalities, such as proton therapy, should be
considered.
• Embryonal tumors of the CNS are the most common malignant
brain tumors in children. They are highly malignant but include very
curable tumors such as medulloblastoma. Currently, to achieve
high cure rates, surgery, chemotherapy, and radiation therapy are
all part of standard treatment for embryonal tumors.
• Wilms tumor and neuroblastoma are common tumors in children,
often presenting with an abdominal mass.
• Radiation for Hodgkin lymphoma has evolved over time. Children
are now treated with risk-adapted involved involved-site or
involved-node radiation therapy to relatively low doses (21 Gy).
• Rhabdomyosarcoma and Ewing sarcoma are the most frequently
encountered sarcomas in the pediatric population.
• Childhood tumors generally have high cure rates and thus great
care should be taken in the planning and treatment to decrease the
morbidity of treatment.
QUESTIONS
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1. Approximately what percentage of pediatric cancer patients will
be long-term survivors?
A. <20%
B. 20% to 50%
C. 50% to 70%
D. >70%
2. Which of the following are true about medulloblastoma?
A. Medulloblastoma is the most common embryonal tumor
B. Tumors arise in the posterior fossa
C. Chemotherapy plus radiation are used for children over 3
years of age
D. All of the above
3. All of the following are true about ependymoma EXCEPT:
A. Standard treatment includes craniospinal radiation therapy
B. Infratentorial ependymomas often extend through the
foramina of Luschka
C. The recommended dose of involved-field radiation is currently
54 to 59.4 Gy
D. Gross total resection is an important prognostic factor
4. Which of the following is NOT true regarding pediatric low-grade
gliomas?
A. They can sometimes be cured with surgery alone
B. Young patients are often treated with chemotherapy to delay
radiation therapy
C. When using radiation therapy to treat low-grade gliomas, a
large margin is needed around the visible tumor
D. Radiation often provides durable control rates for this tumor
5. Localized CNS germinoma are highly curable with therapy that
includes:
A. Two to four cycles of platinum-based therapy
B. Whole-ventricle RT plus a cone down to the primary tumor
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site
C. Dose of RT that is typically reduced after a complete response
to chemotherapy
D. All of the above
ANSWERS
1. D
2. D
3. A
4. C
5. D
REFERENCES
1. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions
in adult survivors of childhood cancer. N Engl J Med.
2006;355(15):1572–1582.
2. Brenner D, Elliston C, Hall E, et al. Estimated risks of radiation-
induced fatal cancer from pediatric CT. AJR Am J Roentgenol. 2001;
176(2):289–296.
3. Brenner DJ, Hall EJ. Computed tomography–an increasing source of
radiation exposure. N Engl J Med. 2007;357(22):2277–2284.
4. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of
3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003;56(1):83–88.
5. Casey DL, Friedman DN, Moskowitz CS, et al. Second cancer risk in
childhood cancer survivors treated with intensity-modulated
radiation therapy (IMRT). Pediatr Blood Cancer. 2014.
6. MacDonald SM, DeLaney TF, Loeffler JS. Proton beam radiation
therapy. Cancer Invest. 2006;24(2):199–208.
7. Macdonald SM, Sethi R, Lavally B, et al. Proton radiotherapy for
pediatric central nervous system ependymoma: clinical outcomes for
70 patients. Neuro Oncol. 2013;15(11):1552–1559.
8. MacDonald SM, Trofimov A, Safai S, et al. Proton radiotherapy for
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pediatric central nervous system germ cell tumors: early clinical
outcomes. Int J Radiat Oncol Biol Phys. 2011;79(1):121–129.
9. Mouw KW, Sethi RV, Yeap BY, et al. Proton radiation therapy for the
treatment of retinoblastoma. Int J Radiat Oncol, Biol Phys. 2014;
90(4):863–869.
10. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy
for pediatric Ewing’s sarcoma: initial clinical outcomes. Int J Radiat
Oncol Biol Phys. 2012;82(3):1142–1148.
11. Sethi RV, Shih HA, Yeap BY, et al. Second nonocular tumors among
survivors of retinoblastoma treated with contemporary photon and
proton radiotherapy. Cancer. 2014;120(1):126–133.
12. Yock TI, Bhat S, Szymonifka J, et al. Quality of life outcomes in
proton and photon treated pediatric brain tumor survivors.
13. Mailhot Vega R, Kim J, Hollander A, et al. Cost effectiveness of
proton versus photon radiation therapy with respect to the risk of
growth hormone deficiency in children. Cancer. 2015;121(10):1694–
1702.
14. Mailhot Vega RB, Kim J, Bussiere M, et al. Cost effectiveness of
proton therapy compared with photon therapy in the management
of pediatric medulloblastoma. Cancer. 2013;119(24):4299–4307.
15. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal
radiation therapy followed by adjuvant chemotherapy for newly
diagnosed average-risk medulloblastoma. J Clin Oncol. 2006;
24(25):4202–4208.
16. Packer RJ, Hoffman EP. Neuro-oncology: understanding the
molecular complexity of medulloblastoma. Nat Rev Neurol. 2012;
8(10):539–540.
17. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma
comprises four distinct molecular variants. J Clin Oncol. 2011;
29(11):1408–1414.
18. Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural
variation across 1000 medulloblastoma genomes. Nature. 2012;
488(7409):49–56.
19. Gajjar A, Packer RJ, Foreman NK, et al. Children’s Oncology
Group’s 2013 blueprint for research: Central nervous system tumors.
Pediatr Blood Cancer. 2013;60(6):1022–1026.
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20. Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood
medulloblastoma by postoperative chemotherapy alone. N Engl J
Med. 2005;352(10):978–986.
21. Dhall G, Grodman H, Ji L, et al. Outcome of children less than three
years old at diagnosis with non-metastatic medulloblastoma treated
with chemotherapy on the “Head Start” I and II protocols. Pediatr
Blood Cancer. 2008;50(6):1169–1175.
22. Tarbell NJ, Friedman H, Polkinghorn WR, et al. High-risk
medulloblastoma: a pediatric oncology group randomized trial of
chemotherapy before or after radiation therapy (POG 9031). J Clin
Oncol. 2013;31(23):2936–2941.
23. Biegel JA, Kalpana G, Knudsen ES, et al. The role of INI1 and the
SWI/SNF complex in the development of rhabdoid tumors: meeting
summary from the workshop on childhood atypical
teratoid/rhabdoid tumors. Cancer Res. 2002;62(1):323–328.
24. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality
treatment for children with newly diagnosed CNS atypical teratoid
rhabdoid tumor. J Clin Oncol. 2009;27(3):385–389.
25. Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/rhabdoid
tumors (ATRT): improved survival in children 3 years of age and
older with radiation therapy and high-dose alkylator-based
chemotherapy. J Clin Oncol. 2005;23(7):1491–1499.
26. Tamburrini G, D’Ercole M, Pettorini BL, et al. Survival following
treatment for intracranial ependymoma: a review. Childs Nerv Syst.
2009;25(10):1303–1312.
27. Fangusaro J, Van Den Berghe C, Tomita T, et al. Evaluating the
incidence and utility of microscopic metastatic dissemination as
diagnosed by lumbar cerebro-spinal fluid (CSF) samples in children
with newly diagnosed intracranial ependymoma. J Neurooncol.
2011;103(3):693–698.
28. Mack SC, Witt H, Wang X, et al. Emerging insights into the
ependymoma epigenome. Brain Pathol. 2013;23(2):206–209.
29. Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after
surgery for paediatric ependymoma: a prospective study. Lancet
Oncol. 2009;10(3):258–266.
30. Packer RJ, Lange B, Ater J, et al. Carboplatin and vincristine for
recurrent and newly diagnosed low-grade gliomas of childhood. J
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Clin Oncol. 1993;11(5):850–856.
31. Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal
radiation therapy for pediatric patients with low-grade glioma:
prospective evaluation of cognitive, endocrine, and hearing deficits.
J Clin Oncol. 2009;27(22):3691–3697.
32. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal
radiation therapy for pediatric low-grade glioma. J Clin Oncol. 2009;
27(22):3598–3604.
33. Lashford LS, Thiesse P, Jouvet A, et al. Temozolomide in malignant
gliomas of childhood: a United Kingdom Children’s Cancer Study
Group and French Society for Pediatric Oncology Intergroup Study.
J Clin Oncol. 2002;20(24):4684–4691.
34. Duffner PK, Krischer JP, Burger PC, et al. Treatment of infants with
malignant gliomas: the Pediatric Oncology Group experience. J
Neurooncol. 1996;28(2–3):245–256.
35. Kaye EC, Baker JN, Broniscer A. Management of diffuse intrinsic
pontine glioma in children: current and future strategies for
improving prognosis. CNS Oncology. 2014;3(6):421–431.
36. Jalali R, Raut N, Arora B, et al. Prospective evaluation of
radiotherapy with concurrent and adjuvant temozolomide in
children with newly diagnosed diffuse intrinsic pontine glioma. Int J
37. Walter AW, Gajjar A, Ochs JS, et al. Carboplatin and etoposide with
hyperfractionated radiotherapy in children with newly diagnosed
diffuse pontine gliomas: a phase I/II study. Med Pediatr Oncol.
1998;30(1):28–33.
38. Allen JC, DaRosso RC, Donahue B, et al. A phase II trial of
preirradiation carboplatin in newly diagnosed germinoma of the
central nervous system. Cancer. 1994;74(3):940–944.
39. Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome
of non-metastatic germinoma patients treated with chemotherapy
and limited field radiation: the SFOP experience. Neuro Oncol.
2010;12(12):1318–1325.
40. Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose
chemotherapy with autologous stem-cell rescue in patients with
recurrent or progressive CNS germ cell tumors. J Clin Oncol.
2004;22(10):1934–1943.
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41. Voges J, Sturm V, Lehrke R, et al. Cystic craniopharyngioma: long-
term results after intracavitary irradiation with stereotactically
applied colloidal beta-emitting radioactive sources. Neurosurgery.
1997;40(2):263–269; discussion 269–270.
42. Vanhauwaert D, Hallaert G, Baert E, et al. Treatment of cystic
craniopharyngioma by endocavitary instillation of yttrium(9)(0)
radioisotope–still a valuable treatment option. J Neurol Surg A Cent
Eur Neurosurg. 2013;74(5):307–312.
43. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with
GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J
Med. 2010;363(14):1324–1334.
44. Hattangadi JA, Rombi B, Yock TI, et al. Proton radiotherapy for
high-risk pediatric neuroblastoma: early outcomes and dose
comparison. Int J Radiat Oncol Biol Phys. 2012;83(3):1015–1022.
45. Nachman JB, Sposto R, Herzog P, et al. Randomized comparison of
low-dose involved-field radiotherapy and no radiotherapy for
children with Hodgkin’s disease who achieve a complete response to
chemotherapy. J Clin Oncol 2002;20(18):3765–3771.
46. Hoppe BS, Hoppe RT. Expert radiation oncologist interpretations of
involved-site radiation therapy guidelines in the management of
hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2015;92(1):40–45.
47. Donaldson SS. Finding the balance in pediatric Hodgkin’s
lymphoma. J Clin Oncol. 2012;30(26):3158–3159.
48. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between
radiotherapy vs no radiotherapy based on early response to VAMP
chemotherapy and survival among children with favorable-risk
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system relapse. Pediatr Hematol Oncol. 2004;21(3):279–289.
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33 Cancers of the Thorax/Lung
Gregory M. M. Videtic, Rupesh Kotecha, Neil M. Woody, and
Kevin L. Stephans
INTRODUCTION
The chest is home to a range of pathologic processes because of the
number and variety of structures it harbors. This chapter is focused on
the principles and practice of chest irradiation for primary neoplasms
such as lung cancer, malignant pleural mesothelioma, and thymoma.
Other thoracic malignancies such as esophageal cancer, primary
lymphomas and sarcomas are dealt with elsewhere in this textbook.
Radiotherapy (RT) plays a fundamental role in the management of
thoracic tumors and in doing so encompasses all the facets of oncologic
care, from cure to palliation. This chapter will review the components of
RT as they apply to the chest: the procedures and processes required for
its planning and delivery, focusing on relevant issues, including
simulation, target definition, dose and fractionation, dosimetric
planning, tolerance of normal structures, and tumor- and site-specific
treatment techniques, for example, to the pleural cavity after resection of
mesothelioma. Specialty topics in RT including the use of stereotactic
body radiation therapy (SBRT) and proton therapy will be addressed.
ANATOMY
Many of the normal structures in the thorax are very sensitive to
irradiation. It is incumbent on specialists in radiation medicine therefore
to understand the normal anatomy of the chest in order predict the acute
and late manifestations of RT on its organs and tissues. The thorax
contains the heart, lungs, and other vital structures within a skeletal
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framework that also protects some of the abdominal organs (1). The
mediastinum occupies the central space of the thorax and is defined as
the interval between the two pleural sacs. It is commonly divided into a
superior mediastinum, above the level of the pericardium, and three
lower divisions: anterior, middle, and posterior. The anterior
mediastinum lies between the sternum and pericardium and most
importantly contains the thymus. The middle mediastinum contains the
pericardium, heart, and the main bronchi and other structures of the
roots of the lungs. The posterior mediastinum, behind the pericardium,
contains the esophagus and thoracic aorta. The superior mediastinum
contains portions of the thymus, great vessels related to the heart, the
trachea, the esophagus, and occasionally aberrant thyroid tissue. The
two lungs and their pleural sacs are situated in the thoracic cavity. The
pleura is a thin serous membrane adherent to various structures. Where
it lines the thoracic wall and diaphragm, it is known as the parietal
pleura, and when it is reflected onto the lung, it is called the visceral
pleura. The latter covers the whole surface of the lung parenchyma and
track deeply into its fissures. The bronchi and pulmonary vessels, which
extend from the trachea and heart, respectively, collectively form the
root of the lung. The part of the medial surface where these structures
enter the lung is known as the hilus. The trachea extends from the
inferior end of the larynx to its point of bifurcation at a level between
the 5th and 7th vertebrae dividing into right and left main bronchi. The
esophagus extends from the lower end of the pharynx to the cardiac
opening of the stomach. The heart is situated in the middle mediastinum
and is enclosed in a fibroserous sac termed the pericardium.
DIAGNOSTIC WORKUP AND STAGING

A patient presenting with a suspected chest malignancy requires a
thorough history and physical examination as well as selected diagnostic
tests in order to confirm malignancy, identify the histologic tumor type,
determine the disease stage, all in order to direct treatment and
management decisions. There are no cancer-specific laboratory studies to
gauge the presence of the majority of thoracic tumors but certain tests
including complete blood count, serum electrolytes, and liver function
tests may point to paraneoplastic syndromes, the presence of metastatic
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disease, or cancer-associated phenomena such as malnutrition. Routine
radiologic examinations include chest x-rays and computed tomography
(CT). CT studies are valuable at identifying tumor location and size and
at staging disease but have limitations with respect to recognizing
mediastinal nodal disease or metastatic disease. 2-deoxy-2[F-18]fluoro-
D-glucose positron emission tomography [FDG-PET] scanning is now
considered standard in the staging workup of thoracic tumors. It can
help distinguish inflammatory from neoplastic disease, it is more
sensitive than CT at recognizing metastatic disease in regional lymph
nodes (LNs), and it is more accurate in determining the clinical stage of
the patient: for example, in lung cancer, up to 25% of patients judged
potentially curable were found on PET to have incurable advanced
disease (2,3). Brain imaging is frequently utilized for staging, especially
for certain diagnoses, for example, small cell lung cancer (SCLC), when
there is a large burden of intrathoracic disease or in patients who
present with neurologic symptoms. Magnetic resonance imaging (MRI) is
considered more sensitive than CT at detecting frank and occult
metastatic disease. Pulmonary function tests (such as spirometry and
diffusing capacity of the lung for carbon monoxide [DLCO]) are not
staging tools but are used to predict a patient’s tolerance to different
treatment modalities such as surgery or RT.
A range of diagnostic procedures may be employed in characterizing a
thoracic tumor (4). These include sputum cytology, percutaneous fine-
needle aspiration (FNA), bronchoscopy, mediastinosocopy, thoracentesis,
endobronchial ultrasound-guided (EBUS) FNA, thoracoscopy, and rarely,
exploratory thoracotomy. The goal in choosing any of these procedures
is to effectively and safely obtain tissues for histologic characterization,
accurately map out extent of disease in the chest (e.g., mediastinoscopy
or EBUS sampling of mediastinal LNs) and to appropriately complete the
staging.
The extent, or more formally the “stage,” of cancer at the time of
diagnosis is the key factor that defines prognosis and is a critical element
in determining appropriate treatment. The most widely accepted and
clinically validated staging system is the tumor node metastasis (TNM)
system maintained collaboratively by the American Joint Committee on
Cancer (AJCC) and the International Union for Cancer Control (UICC)
(5). The TNM system classifies cancers by the size and extent of the
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primary tumor (T), the degree of involvement of regional lymph node
(N), and the presence or absence of distant metastases (M), and more
recently, supplemented by carefully selected nonanatomic prognostic
factors for certain cancers (e.g., tumor grade, histology). Detailed lymph
node maps have been published in order to facilitate consistent and
appropriate labeling of regional thoracic (LNs). The International
Association for the Study of Lung Cancer (IASLC) lymph node map is
now the recommended means of describing regional lymph node
involvement for lung cancers (6). The seventh edition of the TNM system
is currently the accepted standard for staging patients diagnosed on or
after January 1, 2010 (7).
RT PRINCIPLES FOR THORACIC MALIGNANCIES

Introduction
There are general principles for planning thoracic RT that are valid
across a range of malignancies since it is the normal anatomy of the
thorax which imposes the most important constraints on the safe
delivery of RT. These common principles when considering planning
chest RT include the approaches to simulation, target delineation,
motion control, definition of normal tissues and organs at risk (OARs),
dose constraints, dose limiting structures, and beam setups.
Specific thoracic RT dose prescriptions are determined by the tumor
types being treated and by the particular indications for treatment,
including preoperative, postoperative, definitive [both conventional and
stereotactic], prophylactic, and palliative therapies. The primary
rationale for preoperative (also known as induction or neoadjuvant)
therapy is to facilitate complete surgical resection of disease, and yield a
negative-margin (R0) resection. In addition, preoperative RT may
“downsize” a tumor to alter the form of surgical resection required, for
example, change the operation from a pneumonectomy to lobectomy. It
may also alter patterns of locoregional failure by sterilizing micro-
metastatic disease in regional lymph node chains and potentially affect
overall survival. Preoperative RT is typically well tolerated by most
patients since their patient performance and medical status are usually
intact.
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Postoperative RT is administered to patients showing high-risk
features for locoregional recurrence after surgical resection, that is,
positive margins at the resection line (R1), gross residual disease (R2), or
regional lymph node involvement. Given that patient status is often
compromised after surgery, completing a planned course of
postoperative RT is often challenging due to patient intolerance of side
effects.
The rationale for definitive RT is to provide optimal intrathoracic
control of disease by ablating visible tumor and eradicating micro-
metastatic disease. Because of the constraints imposed by normal
thoracic structures on RT delivery, the potential doses for optimal gross
tumor control by conventional RT are often not achievable in the chest.
This has led to the pursuits of other means of dose optimization for
thoracic RT such as stereotactic delivery, integrating RT with
chemotherapy (CHT), use of altered RT dose schedules (e.g.,
hyperfractionation), and use of radiation protectants.
The most common indication for thoracic RT is in the palliation of
local symptoms attributable to advanced or metastatic disease. Since the
primary goal of palliation is symptom relief, thoracic RT schedules in
this setting tend to be short, and favor large doses per fraction with
modest total doses, since late effects are not a critical consideration in
patients with a limited life expectancy.
Regarding upfront prophylactic therapy, the primary site where this is
indicated when dealing with thoracic malignancies is the brain. Since
SCLC has a propensity for micro-metastatic spread to that organ,
prophylactic cranial irradiation (PCI) is routinely used with that
diagnosis. PCI typically involves lower total RT doses and short
treatment schedules.
Technical Factors
Simulation
RT simulation for thoracic malignancies is performed using a CT scan for
delineation of the target volumes and the OARs. In general, patients are
setup in the supine position with their arms above their head. In special
scenarios, such as for patients with superior sulcus or Pancoast tumors,
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simulation can be performed in the akimbo position. For mesothelioma
patients receiving adjuvant radiation therapy after extrapleural
pneumonectomy (EPP), the incision and drainage sites should be marked
with radiopaque material and bolus should be applied over these sites
and the chest wall at the time of simulation.
Localization
A volumetric CT scan should be acquired with a 3-mm slice thickness
from the second or third cervical vertebrae to the third or fourth lumbar
vertebrae to ensure adequate margin around the lungs for generation of
digitally reconstructed radiographs, dosimetry calculations, and planning
using noncoplanar fields (8). The liver should be included in the
simulation CT scan. Oral contrast can assist with delineation of the
esophagus. Intravenous contrast (IV) can be administered to assist with
identification of the major blood vessels, which is especially important
for patients with centrally located tumors and mediastinal LNs (9,10).
Alternatively, if a patient underwent a diagnostic CT scan of the chest
with IV contrast, this can be co-registered to a noncontrast simulation CT
scan. For patients with early-stage lung cancer undergoing SBRT, the
isocenter should be placed in the center of the primary tumor volume.
For patients undergoing treatment to a primary tumor and regional LNs,
the isocenter should be placed in the center of the mediastinum near the
carina. After placement of the isocenter and acquisition of a verification
scan, external marks are placed on the patient or immobilization device
to ensure accurate setup for treatment delivery.
Immobilization
Numerous immobilization devices are commercially available including
a simple thorax board, alpha cradle, vacuum-lock bag, and thermoplastic
mold. Patients should be positioned in a reproducible manner that is
comfortable enough to reduce intrafraction movement but reproducible
enough to minimize interfraction set-up errors. Patients undergoing
SBRT can also be immobilized using a stereotactic frame.
Motion Management
For patients undergoing treatment to thoracic sites, the effect of
respiratory motion on target movement must be accounted for at
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simulation, treatment planning, and treatment delivery (11,12). At the
time of simulation, the motion of the primary tumor should be
characterized and quantified. For the initial simulation scan, patients
should be instructed to breathe at a normal pace. Motion management
strategies are recommended for patients in whom the target motion
exceeds 5 mm in any direction and include use of a four-dimensional CT
(4DCT) scan, physical restriction of motion, breath-hold techniques, and
respiratory gating. A 4DCT scan can generate volumetric datasets
representing the various phases of the respiratory cycle (13). During
acquisition of the 4DCT, imaging data is stored relative to a respiratory
phase or amplitude either by use of an external motion detector,
infrared-based respiratory position monitor device, or a belt wrapped
around the patient’s waist (14). The 4DCT scan can reconstruct either 10
individual phase CT scans or a reduced number of scans representing
specific phases of respiration (e.g., 25%, 50%, 75%, 100%) which can be
viewed in a motion display (15). The 4DCT image dataset can also
reconstruct a maximum intensity projection (MIP) to provide a rapid and
reliable estimate of the maximum motion of the tumor through the
respiratory cycle (16). For accurate dosimetry analysis and dose
calculation, an average intensity dataset should be generated from the
4DCT (17). Physical restriction of tumor motion is most commonly
performed with application of an abdominal belt or hoop (18).
Breathhold is performed with an active breathing control device to
monitor the patient’s inspiratory and expiratory breathing patterns (19).
A respiratory gating technique uses external patient signals (such as the
movement of the chest wall) or fiducials to determine the RT delivery
time. During the course of treatment, the patient breathes at a normal
pace, but the treatment machine delivers the radiation treatment only
during a specific interval based on the position of the external signals
(14).
Target Definition and Normal Structures

Target Volumes
The International Commission on Radiation Units (ICRU) Report No. 50
outlines the definitions for treatment volumes in radiation therapy
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planning (20). For patients with thoracic malignancies, the gross tumor
volume (GTV) includes the primary tumor volume and the involved
regional LNs. Regional LNs are included in the GTV if they are
metabolically active on PET-CT (SUV = 1.5 × mean intensity of 1 cc of
the aorta volume or SUV >3), ≥1 cm in short axis on CT scan, or found
to be pathologically involved on bronchoscopy or mediastinoscopy.
Regional hilar or mediastinal LNs should also be included if there is
serial growth documented on diagnostic CT scans, two or more nodes are
visualized in a high-risk nodal station, or if nodes are visualized at the
first echelon drainage or within 1 cm of the primary tumor. The primary
tumor volume should be contoured on the lung window settings (21).
For tumors abutting the chest wall or mediastinum, the edge of the
primary tumor can be modified using mediastinal window settings.
Involved hilar and mediastinal LNs should be contoured using the
mediastinal window setting. The primary tumor volume can be
disjointed from the regional LNs and lymph node contours can be
noncontiguous.
For patients with thoracic malignancies, internal margins (IMs) and
target volumes have to be considered and are defined in ICRU Report
No. 62 (22). The IM accounts for variations in size, shape, and position
of the targets relative to the movements of respiration and is used to
generate an internal target volume (ITV). When using a 4DCT scan, there
are numerous approaches to reconstructing the image data for
determining the ITV. Ezhil et al. evaluated the generation of the ITV
using four different methods: (1) combining the GTV contours from each
of the ten respiratory phases, (2) combining the GTV contours from two
extreme respiratory phases (0% and 50%), (3) defining the GTV contour
using the MIP, and (4) defining the GTV contour using the MIP with
modification based on visual verification of contours on individual
respiratory phases (23). Based on this comparison, methods 2 and 3
underestimated the ITV, and the use of MIP with modification based on
visual verification was recommended. There are alternative methods of
generating an ITV without use of 4DCT. For example, the targets can be
contoured on end of tidal volume inhale and exhale scans to create a
composite structure to capture any possible tumor motion (24,25).
Alternatively, “slow” CT techniques (slice thickness 4 mm, index 3 mm,
revolution time 4 s/slice) can be used to better capture potential tumor
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movement (26). For patients being simulated with an active breathing
control device, at least two confirmatory scans should be acquired to
verify the position of the target during subsequent breathholds and these
scans are used to generate the ITV.
The clinical target volume (CTV) includes the GTV and adds a margin
for coverage of areas at risk for subclinical microscopic disease. For
patients undergoing SBRT, the CTV representation is equivalent to the
GTV. For patients undergoing RT for locally advanced nonsmall cell lung
cancer (NSCLC), the CTV is created from a 0.5- to 1-cm expansion
around the GTV or ITV. Data to support these RT expansions arises from
a study by Giraud et al., who examined pathologic specimens from 70
patients with NSCLC (27). They determined that the mean microscopic
extension was 2.69 and 1.48 mm for adenocarcinoma and squamous cell
carcinoma cases, respectively. Moreover, to account for 95% of
microscopic disease extension, a margin of 8 mm for adenocarcinoma
and 6 mm for squamous cell carcinoma histologies was required.
Similarly, pathologic studies have also shown that the extent of
microscopic nodal extracapsular extension is 0.7 and ≤3 mm in 95% of
nodes (28). For patients with SCLC, the CTV includes the ipsilateral hilar
LNs (lymph node station 10), if not already included in the GTV.
The planning target volume (PTV) includes the CTV and provides a
margin for motion of the target and setup reproducibility between
fraction delivery. With regard to internal motion, there should be at least
a 1-cm expansion in the superior–inferior dimension and a 0.5-cm
expansion in the axial dimension. In the free-breathing (non-ITV) setting,
an additional setup margin of at least 0.5 cm should be added to create
the final PTV.
Organs at Risk
As important as it is to accurately identify and contour the tumor
volume, defining the OARs is equally important in creating an RT
treatment plan. OARs should be outlined on all CT slices in which the
structures exist and are in the field of irradiation (29). The lungs should
be individually contoured as right and left lung structures and then
combined into a composite structure for dosimetry evaluation. The lung
contours should represent the inflated lung volume and exclude the
proximal bronchial tree, areas of atelectasis, scarring, pleural fluid, or
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large vessels. Considerable variability exists regarding the subtraction of
the GTV, CTV, or PTV from the composite lung volume with no
prospective evidence to support one particular method over another.
SBRT protocols have used the proximal bronchial tree to differentiate
central lung tumors (within 2 cm) from peripheral tumors. The proximal
bronchial tree is composed of the distal 2 cm of the trachea, carina, right
and left mainstem bronchi, right and left upper lobe bronchi, right
middle lobe bronchus, left lingular bronchus, and the right and left
lower lobe bronchi. These structures should be contoured using
mediastinal window settings with inclusion of the outer wall of the
airway.
The heart contour should include the pericardial sac extending from
the superior aspect, defined as either the ascending arch of the aorta or
the inferior aspect of the pulmonary artery passing midline, to the apex
of the heart using mediastinal window settings. The esophagus should be
contoured with inclusion of the outer edge of the muscular wall and
adventitia from the inferior edge of the cricoid cartilage to the
gastroesophageal junction on mediastinal window settings. Of note,
although oral contrast can be used for easier identification of the
esophagus, this may distort the true dimensions of the structure. The
spinal cord should be outlined on each slice as either the true spinal cord
or the extent of the bony canal from the same cranial level as the
esophagus contour (cricoid cartilage) to the bottom of the second lumbar
vertebra. For patients with superior sulcus tumors, apical tumors, or
supraclavicular nodal metastases, the brachial plexus should be
contoured. The brachial plexus is located posterior to the subclavian
vessels between the anterior and middle scalene muscles from the
interspace between the fourth and the fifth cervical vertebra to the
interspace between the first and the second thoracic vertebra. For
patients with tumors abutting the chest wall, the ribs and chest wall can
be contoured by applying a 2-cm expansion in the lateral, anterior, and
posterior dimensions from the lung contours within 3 cm of the PTV.
This should include the intercostal muscles but exclude other muscles or
the skin. For patients with lower lobe tumors, consideration should be
given to contouring the liver and kidneys, each individually and then
combined into a composite whole kidney structure. For patients with
implanted devices in the thorax, such as pacemakers and defibrillators,
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the devices should be contoured separately. Dose–volume histograms are
created to evaluate the radiation exposure to the OARs. In general, the
tolerance of each of the normal organs depends on the dose per fraction
received and the total dose prescribed to the target, but the dose
received to normal structures should be minimized. Examples of
suggested constraints for conventionally fractionated RT treatments for
thoracic malignancies are outlined in Table 33.1.
TABLE 33.1 Suggested Normal Tissue Dose Constraints for

Conventionally Fractionated External-Beam Radiotherapy (30)
Integration of PET-CT into Treatment Planning

FDG-PET has not only enhanced the accuracy of staging patients with
lung cancer, but is also useful in delineation of the primary tumor target,
distinction between atelectasis and tumor, evaluation of mediastinum,
and detection of distant metastatic disease (31). PET remains
investigational for delineation of tumor volumes in patients who
previously received CHT, RT dose escalation, or other forms of response-
adapted therapy.
PET-CT is useful in delineating the primary tumor extent, as the size
and dimensions of the primary tumor measured on PET-CT correlate
well with pathologic examination (32). There are numerous methods of
utilizing PET in contouring, including use of the absolute standardized
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uptake value (SUV) (typically 2.5) (33), a percentage of the maximum
SUV, a fixed percent intensity level of the maximum activity in the
primary tumor (typically 40% to 55%) (34), or an SUV intensity three-
standard deviations above the background level. The use of PET-CT for
delineation of the primary tumor volume also reduces variability in
target contouring between providers (35). Compared to CT scans,
however, FDG-PET tumor volumes can be larger than CT volumes since
the slower acquisition time of the PET scan captures the integral
movement of the primary tumor through respiration (36). Therefore, the
PET volume may correlate more closely with the ITV volume than the
CT-derived GTV (37). It is important to note that FDG-PET may increase
the GTV contour in cases where the adjacent tissue appears
morphologically normal but has metabolic activity concerning for
disease extension. At the same time, FDG-PET may be used to reduce the
CT-derived tumor volume when the tumor is directly adjacent to a
structure and no clear plane of separation is visualized. This is useful in
cases of atelectasis or for tumors abutting the chest wall (see Fig. 33.1)
(38).
PET/CT is especially useful in evaluation of the mediastinum, where it
has a higher sensitivity (84%) and specificity (89%) than CT scans (57%
and 82%, respectively) or endoscopic ultrasound (78% and 71%,
respectively) (39). In fact, when integrating FDG-PET findings into
radiation therapy treatment planning, significant changes to target
volume contours have been reported in 21% to 100% of cases, primarily
due to the addition of mediastinal lymph node targets (40). At the same
time, given the high negative predictive value of FDG-PET, nodal regions
without significant SUV uptake can be omitted from RT volumes.
A PET-CT scan is typically obtained during staging. This scan can be
used in planning if it can be co-registered to the simulation CT scan.
Differences in patient set-up for acquisition of each scan and these
differences must be accounted for when co-registering diagnostic to
treatment planning studies. Alternatively, PET-CT scans may be obtained
in the treatment position on a firm flat-top couch with the same
immobilization device used for radiation therapy planning to minimize
co-registration errors (41). In either setting, consistent FDG-PET window
and color settings should be utilized.
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Figure 33.1 FDG-PET improves staging accuracy for nonsmall cell lung cancer. FDG-PET
differentiates tumor from collapsed lung (A and B), and detects CT undetected node (arrow in C
and D). Blue, CT lesion; red, PET hypermetabolic lesion.
There are certain caveats to be aware of when interpreting FDG-PET

images. False-positive findings can be seen in patients with inflammatory
conditions, whereas false-negative readings may be obtained either when
LNs are below the size threshold for detection (typically <1 cm) or are
too close to the primary tumor volume (42). Moreover, in patients who
recently received CHT, the residual malignant cells may decrease their
glucose uptake, resulting in false-negative findings (40).
Elective Nodal Irradiation

Prior to the introduction of the CT scan into RT planning, lung cancer
volumes were based on anatomic landmarks and encompassed the
definable lung tumor on CXR, any clinically involved LNs, and the
regional nodes considered at risk. This approach of covering all the
mediastinal LNs, independent of confirmed metastatic involvement, is
now termed elective nodal irradiation (ENI). The treatment of clinically
uninvolved nodal groups by ENI is now controversial. In the current CT-
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based era, the concern with ENI is that it overexposes normal structures
to treat presumptive at-risk sites of disease. Furthermore, in generating
the large fields required for ENI, the total dose potentially deliverable to
the tumor is limited by the dose to normal tissues. Non–ENI-based
approaches to RT planning have become an active area of interest in
lung cancer. The specifics on ENI will be addressed in each relevant
tumor section (NSCLC, SCLC).
Treatment Planning
Dose
A range of dose/fractionation schedules is employed routinely in
thoracic RT. Guidelines have been developed for selection of dose and
fractionation in SCLC (43), definitive management of NSCLC (44–46),
postoperative RT, (47), and palliation/poor performance status (48,49).
This section includes general dose and fractionation information for
thoracic RT. Guidelines for specific disease sites and specific techniques
(e.g., SBRT) are located in their respective sections.
Standard Fractionation. Standard fractionation using doses of 1.8 to 2

Gy per fraction has an established role in preoperative, definitive, and
postoperative RT in the chest. Doses of 45 to 50 Gy in the preoperative
setting are standard (50,51). In the definitive setting, doses of 60 to 70
Gy are standard depending on the clinical setting (52,53). In the
postoperative setting, doses of 50 to 60 Gy in 1.8 to 2 Gy fractions are
routine (47,54,55). Generally the postoperative bed is treated to a dose
of 50 Gy with a focal boost to a dose of 60 Gy to areas of extracapsular
extension or resected bulky nodes. For areas of gross disease total doses
of 66 to 70 Gy can be considered if normal tissue constraints can be met.
Hyperfractionation and Hypofractionation. Hyperfractionation is

utilized in definitive thoracic RT. Hyperfractionation to a total dose of
69.6 Gy in 1.2-Gy fractions given BID (twice-daily) with an interfraction
interval of ≥6 hours has been employed in NSCLC and may be superior
to standard fractionation when concurrent CHT is not used (56,57).
Accelerated hyperfractionation to total dose of 45 to 54 Gy given BID is
routine in SCLC (58,59). In NSCLC, continuous hyperfractionated
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accelerated RT (CHART) to a dose of 54 Gy in 36 fractions given at 1.5
Gy TID (thrice-daily) has been shown to be superior compared to
standard once-daily fractionation in the absence of CHT (60–62).
Accelerated hypofractionation may also provide advantages, for
example, 40 to 45 Gy in 15 fractions are associated with comparable
responses to standard fractionation (63,64). Other hypofractionated
regimens including split-course regimens are also feasible and efficacious
(65). A meta-analysis of clinical trials has suggested a 2.5% overall
survival benefit at 5 years for the use of altered fractionation (66).
Palliation. The primary role of thoracic RT in metastatic lung cancer is

the palliation of symptoms prior to the initiation of systemic CHT, or in
patients who are unable to receive systemic therapy at all. In the United
States, 30 Gy in 10 fractions is commonly utilized. However, multiple
prospective randomized trials of different dose/fractionation schedules
have shown that thoracic symptoms can be treated safely and effectively
with 1- or 2-fraction (e.g., 17 Gy at 8.5 Gy per fraction 1 week apart)
schedules, with no overall benefit to higher RT doses for symptom relief.
Selected patients with good performance status may see modest survival
benefits from higher-dose palliative regimens (30 Gy/10 fraction
equivalent or higher) but at the expense of moderately higher
esophageal toxicity (49). Although these randomized clinical trials of
palliative RT for lung cancer have been conducted in patients with
NSCLC, the treatment approaches and results from such studies are
readily applicable to the patient with symptoms related to SCLC (67).
Technical Factors
Beam Energy
Appropriate beam energy is critical in the treatment planning of thoracic
RT. A 6 MV photon beam energy is generally the preferred choice to
provide optimal PTV coverage, particularly near lung tissue density
interfaces. With higher-energy beams, high-energy secondary electrons
travel resulting in dose loss in the boundary region (68–70). This effect
may not always be well represented in computerized treatment planning
with heterogeneity calculation (71). In addition, higher-energy beam
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neutron contamination is also introduced. Despite these limitations,
higher-energy beams no higher than 10 MV may be occasionally helpful
to provide improved dose homogeneity particularly in AP/PA
arrangements where tissue density is more consistent.
Heterogeneity
The chest is unique relative to other body sites as the lungs have
significantly less electron density and thus significantly less attenuation
of an RT beam occurs than in other surrounding tissues. These
differences have the effect of changing the dose distribution substantially
if the heterogeneity of tissue densities is not considered. Traditional
thoracic RT was performed without heterogeneity correction but as these
corrections are now available in modern computer treatment planning
systems they are considered routine practice. Several algorithms for
heterogeneity correction are presently available although
convolution/superposition algorithms (C/S) are most common.
Corrections with pencil beam algorithms which were historically used
have been shown to have reduced accuracy relative to other options
(72). Caution should be used when switching between homogeneous
planning and accounting for heterogeneity (see Fig. 33.2). Conversion
factors have been suggested to adjust RT prescription dose but these
conversions may be different between algorithms within a type and
between types (72,73). Monte Carlo algorithms which are increasingly
becoming available in commercial planning systems may be particularly
distinct from prior algorithms (74). It is notable that when heterogeneity
corrections are applied, PTV surface dose decreases due to increased
range of secondary electrons. This effect can be particularly pronounced
with high-energy beams (68,75).
Intensity-Modulated RT
Since its initial development in the 1980s, 3D conformal RT (3D-CRT)
has long been a standard technique for dose delivery in lung cancer. This
technique, while powerful, may not provide optimal sparing of nearby
normal tissues. Several dosimetric studies have suggested that intensity-
modulated radiation therapy (IMRT) can result in statistically significant
improvements in dose distributions (76–78). Retrospective data by Li et
al. comparing 3D-CRT to IMRT did show reduction in locoregional
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failure and improvement in overall survival with IMRT without
improvement in the distant metastatic rate. Unfortunately, prospective
comparisons have not been performed and are unlikely to be
forthcoming to validate the results of this retrospective comparison.
Based on available data, controversy remains regarding the routine use
of IMRT, particularly for lung cancer (79,80). First, some postulate that
the mediastinal coverage to high dose with 3D-CRT may be aiding in
controlling microscopic mediastinal spread. The higher conformality
with IMRT could potentially reduce this incidental coverage. Second,
IMRT is associated with a lower V20 and mean lung dose but is also
associated with a higher low dose (V5) and the effect of this low dose
cloud on lung toxicity has not been well elucidated (78,80). Finally,
there is a concern of motion interplay effect where tumor motion and
MLC leaf motion could interact to perturb the expected dose
distribution. However, studies have suggested this effect is likely to be
small (81,82). Despite these concerns, sufficient experience exists to
suggest that IMRT may be safely and effectively employed in thoracic
malignancies and may be particularly appropriate when normal tissue
constraints cannot be met with 3D-CRT. While a clear role for IMRT in
all patients has not been observed, IMRT may be beneficial to achieve
dose escalation although the optimal strategy for such dose escalation
has not been determined (83).
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Figure 33.2 Tissue heterogeneity correction in lung cancer planning. A: Impact of heterogeneity
correction on planning target volume (PTV) coverage in a patient with a tumor in the right lower
lobe. This figure shows a remarkable underdosage of PTV in a plan generated by the traditional
homogeneous prescription method with heterogeneity corrections (right panel) and the current
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heterogeneity-corrected prescription method (left panel) in the (a) sagittal and (b) coronal planes.
Isodose lines are color-coded as follows: red, 76.Gy; orange, 66 Gy (prescribed dose); yellow, 60
Gy; green, 20 Gy. B: Impact of calculation algorithm on isodose distribution a lung treatment plan
(two fields, 15-MV photons show isodose lines calculated with Monte Carlo (MC, solid line) and an
equivalent path-length–based algorithm (EPL, dashed line). Figure 33.2B (left panel) shows that
MC and EPL have almost same isodose distribution when heterogeneity correction is not turned
on (i.e., the lung tissue is treated homogeneously), while Figure 33.2B (right panel) depicts
remarkable overestimation of 95% isodose surface of the EPL-based dose computation
comparing to that of MC calculation. (Courtesy of Indrin Chetty, Henry Ford Hospital, Detroit,
Michigan.)
SPECIAL TOPICS IN RT DELIVERY

Stereotactic Body Radiation Therapy
SBRT is a radiation technique that allows for the precise delivery of large
fractions of radiation by multiple beams guided by a set of coordinates
relating to the direct position of the tumor rather than external marks or
anatomical structures. Given the high hypofractionated radiation doses
and small treatment margins involved SBRT requires both careful
definition of target and nontarget structures, as well as precise
management of target motion and treatment set-up (84).
Indications
While medically inoperable stage I NSCLC remains the primary
indication, SBRT is also utilized in the treatment of lung oligometastases
(85), thoracic re-irradiation (86–93), poor-risk stage I SCLC (94,95), and
is under investigation for operable stage I NSCLC (96,97) as well as
potentially as a boost to conventionally fractionated radiation in locally
advanced NSCLC (98,99).
Treatment Planning
SBRT requires careful immobilization of the patient followed by
management of target motion so that it is limited to <5 to 10 mm. This
may be accomplished by abdominal compression, respiratory gating
using either controlled breathhold or external surrogates, or tumor
tracking/respiratory modeling. Tumor motion should be assessed by
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either fluoroscopy or 4DCT imaging at simulation, and verified by cone-
beam CT (CBCT) or other imaging during treatment.
In lung SBRT, a PTV can be created from a fixed expansion (1 cm
superior–inferior, 5 mm axially) off the contoured GTV (100).
Alternatively it may be derived from the union of multi-phasic CT GTVs
(free-breathing, inhale, exhale) or 4DCT images into an ITV, which is
then expanded uniformly by 5 mm yielding the PTV (84). Expansion of
the 4DCT ITV typically results in a smaller PTV, and likely more
consistently represents the actual tumor motion as well as center of mass
(101).
Beam arrangements may consist of six or more noncoplanar open
beams, IMRT beams, noncoplanar volumetric arcs (typically at least 3
arcs each offset by 30 to 40 degrees), intensity-modulated arc therapy,
or alternatively particle-based therapy. The use of IMRT in the treatment
of small moving lung targets is controversial due to concerns of potential
underdosing, though IMRT is allowed by recent protocols such as
Radiation Therapy Oncology Group (RTOG) 0813 and reported
outcomes with IMRT have been on par with other techniques (102).
Planning should utilize collapsed cone convolution or Monte Carlo
algorithms, as there is a suggestion that pencil beam algorithms may
compromise tumor control due to potential for more variable
underdosing (103). Planning should focus on maximizing conformality
and rapid dose fall-off. Heterogeneity is acceptable and may be desirable
for purposes of faster fall-off provided critical serial structures are not
overexposed. Per its protocol design, RTOG 0236 utilized homogeneous
treatment planning prescribing 60 Gy in 3 fractions (see Fig. 33.3). This
has been estimated to correlate with a heterogeneity corrected
prescription of 54 Gy in 3 fractions (74), however, care should be taken
in interpreting this as the correction is based on estimates of attaining
95% coverage of the PTV periphery whereas other parameters such as
mean dose to the GTV, ITV, and PTV may vary considerably,
furthermore this correction is also sensitive to tumor size and location
(104).
Dose
SBRT prescriptions can range from 30 to 60 Gy in 1 to 8 fractions. Early
series established a correlation with delivery of biologically equivalent
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dose (BED) of at least 100 to 105 Gy10 to improved LC (105,106), and
reported excellent safety and tumor control regardless of tumor location.
In the United States, clinical practice favors the results of the Indiana
University phase I dose-escalation studies which ultimately formed the
basis for RTOG 0236 (107). In the phase II setting, these researchers
found this dose was associated with a grade 3 or higher toxicity rate
exceeding 50% in patients whose tumor fell within 2 cm of the proximal
bronchial tree, which they termed “central” tumors (108). While this has
caused concern regarding the safety of treating “central” tumors it is
noted that Japanese series utilizing a lower dose per fraction (10 to 12
Gy) did not report variability of toxicity by location (105,109,110).
Subsequent publications from the Netherlands validated 60 Gy in 8
fractions even for very large central tumors (111), and several United
States retrospective series similarly demonstrated the safety of SBRT for
central lung lesions with fraction sizes of up to 10 Gy/fraction
(112,113). Recently RTOG 0813, a dose-escalation for SBRT of central
lung tumors escalating dose from 50 up to 60 Gy in 5 fractions was
completed reaching the highest dose level without interruption (84).
Normal tissue constraints are still evolving with increased SBRT
experience. Early experiences used few normal tissue constraints
focusing purely on conformality. More recently constraints have
emerged from early experience (113,114), though still need to be
validated in larger settings. Normal tissue constraints should be based on
appropriate protocols for the target being treated such as RTOG 0236,
0813, 0915, or large institutional experiences (see Table 33.2).
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Figure 33.3 Representative dose distribution for a lung SBRT plan. The patient is a 75-year-old
male with medically inoperable adenocarcinoma of the right upper lobe, T1aN0M0, stage IA,
treated with 60 Gy in 3 fractions (per RTOG 0236) delivered by dynamic arcs. Motion
management was by abdominal compression. Image guidance was by an infrared-based x-ray
positioning system. Overall treatment time was 8 days. PTV = GTV + 1 cm superior/inferior and
0.5-cm radial expansion. Green color fill is the GTV, yellow color filled-ring represents a 2-cm
planning structure to limit dose spillage, light blue line is 30 Gy, yellow line is 60 Gy.
Treatment Delivery
Image guidance during treatment initially consisted of bony registration
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followed by port films, though modern approaches typically rely on
CBCT. Free-breathing CT may not represent the true tumor center of
mass due to respiratory motion, and a pitfall can be created by matching
free-breathing CT to CBCT tumor at time of treatment, potentially
introducing systematic error that occasionally exceeds the PTV
expansion (101). One should either use the average CT as the reference
for matching, or otherwise localize only to bony anatomy if using a free-
breathing image while verifying that the CBCT tumor falls within the
ITV.
Outcomes
Local control (LC) of the index lesion after lung SBRT is typically defined
as the absence of tumor progression within 1 cm of the primary tumor
site (100), and has historically ranged from 90% to 98%
(97,100,105,109,110,117–119), consistent with prospective surgical
series showing a locoregional failure rate of 5% to 7% for lobectomy,
and 8% to 17% for sub-lobar resection (120,121). A pooled meta-
analysis of 40 SBRT studies totaling 4,850 patients and 23 surgical
studies (lobar or sub-lobar resection, 7,071 patients in total) likewise
suggests no significant differences in LC (119). SBRT is well tolerated
even in the medically inoperable population. Pulmonary function is well
conserved with generally <3% risk of radiation pneumonitis, and even
patients with extremely compromised pulmonary function exhibiting OS
outcomes at or above the mean (122–124), suggesting there is no lower
limit to pulmonary function for SBRT provided patients are medically
stable. Neuropathic pain and rib fractures may occur with 10% to 15%
of treatments of targets abutting the chest wall, though symptoms are
generally modest and potentially less common than in surgical series
(125,126). Skin ulcers (127), brachial plexopathy (128), and bronchial
(129) or esophageal fistulas (130) have been reported, though they are
extremely uncommon and risk is modifiable during the planning process
when identified.
TABLE 33.2 Suggested Normal Tissue Dose Constraints for Lung

SBRT Based on a Range of Dose/Fractionation Schedules (115,116)
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Endobronchial Brachytherapy
Endobronchial brachytherapy is a useful method of achieving palliation
in a patient with recurrent centrally located obstructing tumor and who
has had previous definitive RT. In most reports rates of relief from
hemoptysis and obstructive symptoms are high, while cough is less
frequently improved (48,131–133). A range of dose regimens have been
used, with most using weekly dosing such as 7 Gy × 3. Potential
complications include pneumothorax from the endobronchial catheter,
as well as 5% to 10% risk of high-grade hemoptysis due to the
combination of cumulative treatment dose and recurrence of resistant
central disease. Mesh-based brachytherapy sewn to the surgical staple
line has also been investigated in conjunction with sub-lobar resection of
early-stage NSCLC, but was associated with increased risk of
complications without improving recurrence rates (121).
Protons
There is currently a growing interest in the applications of particle
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therapies, and in particular protons, to the management of thoracic
tumors due to contemporary advances in the manufacturing, price
profile, and availability of dedicated clinically oriented proton-
generating accelerators. What has made proton-based therapy
theoretically attractive for treatment of tumors as compared to x-ray
based therapies is that, in contrast to photons and electrons that deposit
most of their energy near the patient surface and deliver lower doses of
RT at the depth of the primary lung tumor or sites of nodal metastases,
the physical properties of proton therapy allow energy to be deposited at
a specific depth that is known as the Bragg peak. After this depth,
protons are able to achieve a rapid energy fall-off, allowing normal
tissues beyond the tumor depth to receive little or no irradiation dose.
Therefore, normal tissues on the distal side of the target volume can be
more or less spared, compared with photon beams where there will
always be an exit dose through the patient. With the current increased
availability of proton centers, some clinicians suggest that for chest
tumors (e.g., lung cancer), proton therapy may have a particularly strong
rationale. In this setting, the prime driver for considering protons is the
purported advantages it would provide in normal tissue sparing as
opposed to an intrinsic improvement in cancer control. Given its range
of highly sensitive structures, the thorax would seem an appropriate
setting for testing protons’ clinical impact. By manipulating the physical
properties of the Bragg peak, proton therapy could preferentially reduce
dose to normal critical structures such as the lungs, esophagus, heart,
brachial plexus, and spinal cord, all of which may ultimately be able to
lead to a reduction in acute and late toxicities from the treatment and
influence morbidity and mortality. If there is the potential for decreased
toxicities, some clinicians also suggest that proton therapy may also
facilitate RT dose escalation with the goal of improved local tumor
control, which potentially could influence overall survival (134,135).
There are specific RT-related challenges in the use of proton beams in
the chest. Protons are significantly more sensitive compared to photon
beams to a variety of uncertainties such as respiratory motion, changes
in patient positioning, and tumor shrinkage. This creates more technical
challenges in planning and delivery of RT. This added complexity could
introduce more challenges in delivering RT (e.g., interruptions due to re-
planning; set-up errors) and makes its use limited to large treatment
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centers (136). At present, the use of protons for thoracic cancers remains
investigational. For example, an ongoing clinical research trial [RTOG
1308] is a randomized phase III trial of proton versus photon
chemoradiotherapy in locally advanced lung NSCLC with a primary
endpoint of overall survival (135).
LUNG CANCER
Introduction
In 2014, an estimated 221,200 new cases of lung cancer were diagnosed
in the United States, with an estimate of 159,260 lung cancer-related
deaths (137). NSCLC represents about 75% to 85% of lung cancer
diagnosis (137), while SCLC make up approximately 10% to 15% (138).
Although the use of the TNM staging system is standard for NSCLC,
SCLC has traditionally been classified as either limited (LSCLC) or
extensive stage (ESCLC), with disease confined to a hemithorax
considered limited and all other presentations considered extensive. The
AJCC now recommends that TNM staging be normative for SCLC (5).
The primary risk factor for lung cancer is a history of smoking. Risk may
increase by contributions from exposure asbestos and other industrial
irritants. Successful promotion of smoking cessation is largely credited
with recent decreases in the incidence and mortality rates of lung
cancer, particularly in men (139).
NSCLC
Stage I
Stage I NSCLC comprises only 10% to 15% of all lung cancer diagnoses.
The standard of care for stage I disease is surgical lobectomy, which
results in excellent LC (95%) and overall survival, ranging from 60% to
80% (120). Given the risk factors associated with NSCLC, however,
many patients cannot tolerate surgical resection. These patients
historically fare poorly with observation (140), and were treated with
either 3D-CRT to doses ranging from 60 to 74 Gy in conventional
fractionation, though as high as 100 Gy has been investigated
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(141–143). Recent advances in technology such as SBRT are now
achieving LC rates in the medically inoperable population approaching
those of surgical resection (100,105,119), along with excellent LC and
overall survival in limited use in the operable population (96,97). The
reader is referred to the section on SBRT for further details. More
hypofractionated courses in conventional RT such as 60 Gy in 15
fractions have been recently described as both safe and effective (144).
Stage II
Stage II NSCLC is even less common than stage I (137), and almost
universally treated surgically as the need for nodal coverage typically
prevents radiation doses from reaching levels which would attain
equivalent LC (51,142,145). Patients unable to tolerate surgical resection
can be treated with concurrent or sequential chemoradiotherapy, or RT
alone if unable to tolerate the additional of CHT. Similar dose and
targeting strategies as those discussed below for stage III disease apply
here as well.
Stage III
Preoperative RT
Stage III is the most challenging NSCLC presentation due to its tumor
and nodal heterogeneity. A decision point in the management of many
stage III patients is the role, if any, of surgery in combination with CHT
and RT (known collectively as trimodality therapy when all three are
employed together). Much like stage II disease, the LC achieved with
definitive chemoradiotherapy does not reach the levels attained by the
addition of surgical resection due to limitations of normal tissue toxicity
on radiation dose for fields, including significant portions of the
mediastinum (142,145). However, the predominant cause of mortality in
lung cancer is distant metastatic failure, hence bringing into question the
role of any local therapy. Two randomized trials in this patient
population have compared definitive chemoradiotherapy to induction
chemoradiotherapy followed by surgical resection. The Intergroup 0139
study randomized 396 patients with technically resectable surgically
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staged IIIA (N2) NSCLC to either (1) definitive RT to 61 Gy concurrent
with 2 cycles of CHT or (2) the same CHT concurrent with RT to 45 Gy
followed by resection. There was no benefit to overall survival afforded
by the surgery despite progression free survival being improved (146). A
second randomized study, EORTC 08941, showed no difference in either
of these survival endpoints for trimodality therapy compared to
chemoradiotherapy (147).
For those who receive trimodality therapy the most common induction
regimen is 45 Gy in 25 fractions with concurrent CHT (148). Recent
phase II trials are exploring the safety, efficacy and outcomes for dose
escalated RT (60 Gy/30 fractions) in this setting (149,150).
Definitive RT
The standard of care for nonoperative treatment of stage III NSCLC is
concurrent CHT and RT given as 60 Gy in 30 fractions (see Figure 33.4)
based on the most current phase III randomized study showing no
advantage, and potentially some detriment, to dose escalation beyond
60 Gy in 30 fractions (83). RTOG 0617 randomly assigned 544 patients
to receive either 60 Gy in 30 fractions or 74 Gy in 37 fractions, with or
without the addition of cetuximab to standard CHT. There was an
unexpected overall survival detriment to high-dose radiation, and
notably also a decrease in LC. The addition of cetuximab likewise
increased toxicity without benefit to overall survival. Finally, altered
fractionation does not appear to have significant benefit in the setting of
concurrent CHT (151). For patients who cannot tolerate concurrent CHT
with RT, sequential therapy is recommended. When delivering
sequential therapy or RT alone there may be a benefit to dose escalation
(152–154).
In the definitive setting, ENI is not recommended (44,155,156). While
local failure inside the high-dose volume is a significant contributor to
treatment failure, recurrence in omitted potential elective nodal regions
has been low in both retrospective and prospective series (145,155,157).
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Figure 33.4 Representative coronal CT image from the treatment plan of a 77-year-old male with
adenocarcinoma of the right upper lobe of the lung with biopsy-proven involvement of only lymph
node station [4R], T2bN2M0, stage IIIA. The final target (thick red line) represents a non-ENI
approach with 4DCT simulation and PET-fusion at the time of planning. Total dose delivered was
60 Gy in 30 fractions with 10-MV photons via a three-field approach prescribed to the 99%
isodose line with daily CBCT for image guidance.
Early randomized trials examined the role of PCI in both NSCLC and
SCLC and did find that rates of brain metastasis were reduced in both
diseases, however unlike in SCLC where PCI improved survival (158), a
modern randomized study in NSCLC showed no benefit despite some
reduction in the frequency of future brain metastasis (159).
Postoperative RT
While four randomized trials have confirmed a survival advantage for
the addition of adjuvant CHT for resected stages II to III NSCLC
(160–164), adjuvant radiation has a more limited range of indications.
In N2+ disease the Lung Cancer Study Group (included in postoperative
radiation [PORT] meta-analysis) demonstrated improved LC for PORT
without a survival detriment (165,166). A sub-set analysis of a
randomized adjuvant CHT study (167, and reviews of the surveillance,
epidemiology, and end results (SEER), and National Cancer Database
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also suggest the potential for a survival advantage when modern
techniques and smaller fields are utilized in the setting of resected stage
III NSCLC (168,169).
PORT is typically delivered sequentially after completion of CHT,
however in the setting of positive margins concurrent delivery is an
alternative (55). The target volume for PORT is the bronchial stump and
hilum, as well as known clinically and pathologically involved
mediastinal nodal stations. Intervening nodal stations may be covered as
well. Recommended dose is 50 Gy in 25 fractions for patients with
negative margins. Dose should be increased to 54 to 60 Gy in 27 to 30
fractions for close or positive margins.
Stage IV
The primary role of radiation in metastatic NSCLC is the palliation of
symptoms prior to the initiation of systemic CHT, or in patients who are
unable to receive systemic therapy at all. The reader is referred to the
section on palliative dose schedules in the section “Treatment Planning”
above.
SCLC
Limited Disease
Thoracic RT
Dose/Fractionation. The current standard of care in the United States

for the dose and fractionation of thoracic RT in LSCLC is 45 Gy given as
twice-daily (BID) fractions of 1.5 Gy for a total of 30 fractions over 3
weeks based on the result of the most current randomized phase III study
(Intergroup 0096) (58). Two current randomized studies are addressing
the question of dose-escalated thoracic RT and its impact on overall
survival. CONVERT (Concurrent ONce-daily VErsus twice-daily RT) is a
European phase III trial in which patients were randomized to either 45
Gy/1.5 Gy BID in 30 fractions or to 66 Gy in 33 once-daily fractions,
both starting with the second cycle of CHT. The trial completed accrual
in 2013 and results are pending. In North America, CALGB 30610/RTOG
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0538 is an ongoing phase III trial in which patients were to be
randomized to one of two experimental arms: either 70 Gy/2 Gy once-
daily over 7 weeks or 61.2 Gy/1.8 Gy once-daily over 16 days followed
by 1.8 Gy twice-daily for 9 days; versus the standard comparator arm of
45 Gy/1.5 Gy BID. In 2013 after planned interim analysis, and without
differences between the arms, the 61.2 Gy arm was dropped from the
study in order to facilitate accrual but not because of any statistically
significant differences in events between the arms.
Timing/Sequencing/Duration. In fit patients, thoracic RT should be

administered with the start of CHT, rather than after greater than 2
cycles of CHT, since its early initiation is associated with improved
survival as shown in a range of randomized trials and three major meta-
analyses (170–172). Within the concept of “time-to-treatment” start,
overall treatment duration may in fact be the most important factor
associated with LC and overall survival in LSCLC (170). De Ruysscher et
al. have promoted the concept of SER, an acronym for the “Start of any
treatment until the End of RT,” in the treatment of LSCLC. Their analysis
suggests the SER is the most important predictor with respect to
outcomes. The biologic rationale for this observation is that shortening
the overall time of RT delivery (i.e., acceleration) reduces the potential
for triggering accelerated repopulation in SCLC stem cells which could
lead to resistant cells.
Treatment Volume. In 1987, a randomized clinical trial addressing the

specific question of treatment volume in SCLC was published by the
Southwest Oncology Group (SWOG) (173). Patients were randomized to
a pre-CHT versus a post-CHT target designed at the time of RT planning
and the study showed that the RT target can be restricted to the residual
visible tumor (post-CHT target) without increasing the risk of local
failure.
With respect to current controversies of non-ENI target design, there
has been a prospective study from van Loon et al. (174), which showed
that omission of ENI by PET-based selective nodal irradiation in LSCLC
resulted in a 3% rate of out-of-target nodal failures. A recent report from
the International Atomic Energy Agency (IAEA) on ENI in SCLC still
suggests caution in restricting target coverage in the absence of high
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level evidence (175).
Extensive Disease
Thoracic RT
In incurable ESCLC, the role of thoracic RT is conventionally for relief
and palliation of local symptoms. In 1999, a novel role for thoracic RT in
advanced stage SCLC patients was published by Jeremic et al. (59). In
this phase III study, ESCLC patients who had received induction CHT
and had shown response were randomized to either accelerated
hyperfractionated thoracic RT (50.4 Gy/36 BID fractions over 18 days)
and concurrent low-dose daily CHT or to CHT alone. The 5-year survival
rate for those receiving the thoracic RT compared to those not receiving
it was 9.1% versus 3.7%, respectively, and was statistically significant.
These results did not prompt widespread introduction of thoracic RT in
the case of ESCLC patients. Recently Slotman et al. (176) reported the
results a phase III trial looking at the survival of ESCLC patients
receiving thoracic RT along with PCI compared to PCI only for those
who respond after the completion of 4 to 6 cycles of CHT. Thoracic RT
consisted of 30 Gy in 10 fractions. Overall survival at 1 year was not
significantly different between groups: 33% for the thoracic RT group
versus 28% for the control group. In North America RTOG 0937 is an
ongoing randomized phase II study comparing PCI alone to PCI and
consolidative RT to the chest and to limited numbers of partially
responding distant metastases (177). The trial’s primary end-point is to
determine 1-year overall and median survival rates in each arm.
PCI in LSCLC and ESCLC

Indications
PCI is considered standard of care for LSCLC patients. In 1999, Auperin
et al. published a meta-analysis of completed randomized trials of PCI in
SCLC (158) and reported that it yields a 25.3% decreased incidence of
brain metastases at 3 years with absolute improvements in overall and
disease-free survivals in the PCI group by 5.4% and 8.8%, respectively,
compared to patients not receiving PCI. In 2007, the EORTC reported the
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results of a phase III trial in which ESCLC patients were randomized to
PCI or observation after CHT (178). At 1 year, the PCI patients were
found to have a significantly lower rate of symptomatic brain metastases
but, more strikingly, improved 1-year (27% vs. 13%) survivals compared
to the patients in the no-PCI arm. This finding has led to the
recommendation that PCI be offered to any ESCLC patient who shows a
response to CHT.
Dose and Toxicity in PCI

The total doses used in PCI are modest. A dose of 25 Gy in 10 fractions
delivered by opposed lateral fields remains the standard of care in LSCLC
based on phase III data showing no benefits to dose escalation (179).
Doses in ESCLC are more variable. PCI-related neurocognitive toxicities
appear self-limited and dose-dependent (180). That said, in efforts to
maximally reduce any neurocognitive toxicities in LSCLC patients there
are currently proposals for trials to reduce toxicity in PCI. The approach
in these trials has been extrapolated from similar studies but looking at
the effect of whole brain RT in patients with frank brain metastases For
example, RTOG 0933 was a nonrandomized phase II trial using IMRT to
deliver hippocampal-avoidance whole brain RT (HA-WBRT) (181). The
hippocampus is felt to be critical in maintaining short-term memory. The
RTOG has proposed a trial that involves randomizing SCLC patients to
standard PCI versus PCI with hippocampal-avoidance.
MESOTHELIOMA
Introduction
Malignant pleural mesothelioma (MPM) is an uncommon tumor strongly
associated with asbestos exposure. MPM is staged according to the AJCC
staging system (182). Medically fit potentially resectable patients are
treated surgically with extra-pleural pneumonectomy (EPP) or with
pleurectomy and decortication (P/D). Controversy exists regarding the
optimal surgical approach but combined modality treatment can have
good outcomes in favorable patients (183–186). Studies suggest that any
surgical resection is preferable to RT alone from an LC standpoint (187).
Patients who are unresectable are treated palliatively with CHT and RT
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as needed (188).
Indications
There have been two conventional indications for RT for MPM: (1) as
adjuvant therapy following definitive surgical resection with EPP, or (2)
for palliation of symptoms. Also, IMRT-based consolidation treatment
after P/D is increasingly used, and definitive RT can also be employed in
very selected clinical scenarios (187,189–191). RT prophylaxis to drain
or biopsy sites is a controversial indication due to conflicting results
from a small number of randomized trials, with the most current
suggesting rates of surgical track recurrences are not improved by its
addition (192,193).
Simulation
For mesothelioma it is crucial to encompass the entire extent of the
pleural surface within the CT simulation scan. Particular attention to the
lower border of the scan is critical as the diaphragm can extend as low
as the third lumbar vertebra (L3) and this recess is a common site of
failure (194). All scars and drain sites should be identified with
radiopaque wire. Clinicians should consider application of bolus to drain
sites or areas of chest wall invasion. After P/D, the standard principles of
thoracic RT should be followed.
Target Volume
After EPP, the CTV for adjuvant RT is defined as the entire resected
pleural surfaces (chest wall, pericardium, diaphragmatic crural
insertions, any reconstructed diaphragm, ipsilateral hilum, and
mediastinal boundary). Surgical clips can aid in the delineation of the
medial aspect of the diaphragm, inferior diaphragmatic insertion, and
sterno-pericardial recess in particular. IMRT studies have suggested this
sterno-pericardial recess is a particular site of recurrence (187). A boost
to the ipsilateral mediastinum can be applied in the setting of resected
N2 disease. Sites of positive margins need to be defined as feasible for a
boost volume. CTV to PTV expansion with rigid immobilization is
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typically 5 mm to 10 mm. An example of the resulting PTV is showing in
Figure 33.5. After P/D, the CTV includes the rind of residual pleura (if
present) and the chest wall of the entire hemithorax including the
insertion of the diaphragm. This CTV is typically expanded by 8 mm to
form the PTV for planning (190).
Dose/Fractionation
In the adjuvant setting, 54 Gy at 2 Gy per fraction is standard following
R0 resection (see Figure 33.5). In cases of positive margin or
pathologically involved mediastinal nodes, a boost to a total dose of 60
Gy in 2-Gy fractions is recommended (194,195). Following P/D or as
definitive RT, doses of 45 to 50.4 Gy have been employed with
acceptable toxicity and control (190). For palliative treatment, minimal
doses of 40 Gy and at least 4 Gy per fraction appear to be associated
with improved symptom control, compared to conventional palliative
schedules, such as 30 Gy in 10 fractions (196–198).
Treatment Planning
Adjuvant RT following EPP was historically performed with AP/PA fields
and electrons to supplement dose in key areas (194). IMRT is now
recommended in this setting as it allows for better sparing of normal
tissues and outcomes do not appear to be inferior to conventional field
arrangements (199). Rates of severe pulmonary toxicity with IMRT,
however, may be higher than expected due to the delivery approach
selected (195,200,201). To minimize the risk of pulmonary toxicity,
dosimetrists need to avoid beam entry through the remaining lung and
to restrict the mean lung dose of that lung to 10 Gy or less, with ≤8.5
Gy preferred. Following P/D, only an IMRT approach is indicated, with
emphasis on mean lung and spinal cord tolerances in planning
(187,190,191).
THYMOMA
Indications
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Thymomas represent the most common tumor in the anterior
mediastinum (202,203). Most patients present with localized disease and
surgical resection provide histologic conformation of the diagnosis and is
often curative as a single modality. In addition to the completeness of
surgical resection, the Masaoka stage and specific histologic
classification of the tumor are important prognostic factors (204–206).
Adjuvant therapy is the most common RT indication and is
recommended for patients who present with stages III to IVa. Definitive
RT is offered to the occasional patient who is medically inoperable or
who has tumors which are surgically unresectable. Patients with
Masaoka stage I thymomas (macroscopically and microscopically
encapsulated) should undergo surgical resection alone. Local recurrences
are rare (<5%) and patients may be salvaged with repeat excision
(207). There is no role for postoperative RT for these patients. Likewise,
for Masaoka stage II disease (microscopic transcapsular invasion or
macroscopic invasion into surrounding fatty tissue with or without
adherence to the mediastinal pleura or pericardium), contemporary
studies have failed to demonstrate an LC benefit to adjuvant RT.
Adjuvant RT is recommended for patients with stage III thymomas
(macroscopic invasion into nearby organs such as the pericardium, great
vessels, or lung) since only 50% of patients undergo complete surgical
resection and the local recurrence remains considerable even in this
setting (208–211). Thymic carcinomas are considerably rarer than
thymomas, and patients often present with locally advanced disease
(207). Patients often undergo multimodality treatment including upfront
surgical resection with adjuvant CHT and RT (212,213). Adjuvant RT
may provide a locoregional control and possible survival benefit in
patients with resected thymic carcinomas, although data from different
retrospective reviews are conflicting (207,214).
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Figure 33.5 A: Representative axial, coronal, and sagittal images from the treatment plan and (B)
the DVH for a 40-year-old male with right thoracic epithelioid mesothelioma treated with 3 cycles
induction chemotherapy, then a right extrapleural pneumonectomy followed by adjuvant right
pleural space IMRT-based radiotherapy (54 Gy in 27 fractions). The mean lung dose is 7.99 Gy.
Postoperative RT
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A dose of 45 to 50 Gy is recommended for adjuvant RT in the setting of
a negative or close-margin resection. For patients with a microscopically
involved resection margin, a dose of 54 to 60 Gy is recommended (see
Figure 33.6). A dose of 60 to 70 Gy is recommended for patients with
gross residual disease. Patients undergoing adjuvant RT for a resected
thymic carcinoma typically receive 60 Gy after complete surgical
resection. The postoperative CTV should be referenced off of the
available presurgical imaging and incorporate relevant operative
findings. In other words, the CTV should include the visible surgical clips
in the tumor bed, reflect the tumor bed as derived from the preoperative
extent of disease, and include other areas at risk for subclinical
microscopic disease. In patients with a positive resection margin, the
radiation oncologist should discuss the findings with the surgeon and
pathologist to ensure adequate coverage of the at-risk regions. Typically,
a 0.5 cm to 1-cm margin is added to the CTV (or ITV) to generate the
PTV.
Preoperative RT
Typically, a dose of 45 to 50 Gy is recommended in the preoperative
setting, delivered in conventional fraction sizes of 1.8 to 2.0 Gy/fraction.
ENI is not warranted in patients with thymomas (215). The GTV consists
of the visible tumor volume, generated from all available studies
including CT scans and FDG-PET scans. A CTV can be generated with a
0.5- to 1-cm margin to account for extension of microscopic disease. If a
4DCT scan is acquired at the time of simulation, an ITV can be generated
(see general principles section). Typically, a 0.5- to 1-cm margin is
added to the CTV (or ITV) to generate the PTV.
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Figure 33.6 Representative axial CT image from the treatment plan of a 63-year-old female with
resected Masaoka stage III thymoma with lung invasion, WHO type B2 with focal B3, who
received adjuvant RT to a dose of 60 Gy in 30 fractions delivered with 10 MV photons via a five-
field 3D coplanar field setup. The CTV is represented by the shaded red volume and
representative isodose lines and their corresponding doses are provided.
Treatment Planning
Patients should be treated with 3D-CRT or IMRT planning techniques to
maximize the conformality of the treatment volume and minimize the
dose to the surrounding thoracic structures (210). A radiation beam
arrangement should be chosen based on patient anatomy, extent of the
RT target volume, and proximity to OARs. Classic field set-ups include:
anterior/posterior fields with anterior weighting or a wedged-pair field.
KEY POINTS
• The treatment of thoracic malignancies with RT is very challenging
because of the limitations in safe delivery of dose imposed by the
range of highly sensitive normal structures in the thorax.
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• Lung cancer is the most common thoracic malignancy and also kills
more cancer patients than any other because the majority of
patients are essentially incurable at presentation. Improvements in
RT dose and delivery are currently very limited in terms of
modifying the natural history of this cancer and palliative therapy is
the most common RT indication.
• Technologic and planning improvements in RT delivery, such as
IMRT, motion management, 4DCT, and the use of DVHs, have
enhanced our understanding of the benefits and side effect
potential of treatment to the chest.
• SBRT has created a new paradigm of RT care by offering medically
inoperable lung cancer patients with early-stage disease the
possibility of safe and effective cure.
• Ongoing refinements in RT delivery, such as particle therapies, are
geared toward minimizing toxicity in potentially curable patients.
QUESTIONS
1. When discussing the concept of heterogeneity in the planning and
delivery and radiotherapy for lung cancer, one is referring to:
A. The number of different organs in the thorax
B. The range of beams >10 MV that must be used in planning
C. The variable PTV margin used for different cancers.
D. The idea that the electron density of the lung needs to be
taken into account to correctly predict dose delivered.
2. Lung SBRT is used in medically inoperable early-stage lung
cancer patients. When considering the requirements for SBRT
delivery, the physician must:
A. Employ a means of managing the tumor motion
B. Deliver the therapy over a minimum of 3 weeks
C. Ensure that no tumors near the tracheobronchial tree are
treated with this approach
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D. Always use protons for normal tissue sparing
3. The following terms and concepts are all associated with a 4DCT
simulation of a thoracic malignancy, except:
A. Time
B. Tumor size
C. Internal target volume
D. Breathing cycle
4. Radiotherapy dose escalation in the treatment of stage III non-
small lung cancer has been studied in randomized studies and
has been shown to:
A. Be only effective in small cell lung cancer
B. Be only effective with the drug cetuximab
C. Ineffective because doses greater than 60 Gy have poorer
overall survival
D. Ineffective because doses greater than 60 Gy have increased
esophageal toxicity
5. Elective nodal irradiation (ENI) is no longer recommended in the
management of lung cancers. The reason is:
A. It limits the amount of radiotherapy that can be delivered to
the ITV
B. It was carried out before heterogeneity corrections were used
in dose calculations
C. PET-based planning suggests low failure rates in lymph nodes
not included in the target
D. DVHs measure lung toxicity better for 3D than 2D plans
ANSWERS
1. D
2. A
3. B 4DCT relates to time and image collection and has nothing
to do with the tumor size. 4DCT allows characterization of
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motion, hence it has a relationship in helping to define the
ITV.
4. C RTOG 0617, which randomized patients to 60 Gy versus
74 Gy showed a decrement in survival in the dose-
escalated (high dose, 74 Gy) arm.
5. C PET permits better determination of at-risk/involved
lymph nodes when designing the GTV and phase II data
suggest no elevated failure rates in nontargeted nodes with
PET-based planning.
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radiation in partial responders: a southwest oncology group study. J
Clin Oncol. 1987;5:592–600.
174. van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal
irradiation on basis of (18)FDG-PET scans in limited-disease small-
cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys.
2010;77:329–336.
175. Videtic GM, Belderbos JS, Spring Kong FM, et al. Report from the
international atomic energy agency (IAEA) consultants’ meeting on
elective nodal irradiation in lung cancer: small-cell lung cancer
(SCLC). Int J Radiat Oncol Biol Phys. 2008;72:327–334.
176. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic
radiotherapy for extensive stage small-cell lung cancer: a phase 3
randomised controlled trial. Lancet. 2015;385:36–42.
177. Gore EM. Randomized phase II study comparing prophylactic
cranial irradiation alone to prophylactic cranial irradiation and
consolidative extra-cranial irradiation for extensive disease small
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cell lung cancer (ED-SCLC). 2014.
178. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial
irradiation in extensive small-cell lung cancer. N Engl J Med.
2007;357:664–672.
179. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus
higher-dose prophylactic cranial irradiation (PCI) in patients with
limited-stage small-cell lung cancer in complete remission after
chemotherapy and thoracic radiotherapy (PCI 99–01, EORTC
22003–08004, RTOG 0212, and IFCT 99–01): a randomised clinical
trial. Lancet Oncol. 2009;10:467–474.
180. Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II
randomized trial radiation therapy oncology group (RTOG) 0212:
impact of different total doses and schedules of prophylactic cranial
irradiation on chronic neurotoxicity and quality of life for patients
with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol
Phys. 2011;81:77–84.
181. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with
conformal avoidance of the hippocampal neural stem-cell
compartment during whole-brain radiotherapy for brain metastases
(RTOG 0933): a phase II multi-institutional trial. J Clin Oncol.
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182. Anonymous. Pleural mesothelioma. In: Edge S, Byrd D, Compton C,
et al, eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY:
Springer; 2010:325.
183. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins,
extrapleural nodal status, and cell type determine postoperative
long-term survival in trimodality therapy of malignant pleural
mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg.
1999;117:54–63; discussion 63–65.
184. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy
versus pleurectomy/decortication in the surgical management of
malignant pleural mesothelioma: results in 663 patients. J Thorac
Cardiovasc Surg. 2008;135:620–626, 626.e1–e3.
185. Lang-Lazdunski L, Bille A, Lal R, et al. Pleurectomy/decortication is
superior to extrapleural pneumonectomy in the multimodality
management of patients with malignant pleural mesothelioma. J
Thorac Oncol. 2012;7:737–743.
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186. Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural
pneumonectomy versus no extra-pleural pneumonectomy for
patients with malignant pleural mesothelioma: clinical outcomes of
the mesothelioma and radical surgery (MARS) randomised
feasibility study. Lancet Oncol. 2011;12:763–772.
187. Rimner A, Spratt DE, Zauderer MG, et al. Failure patterns after
hemithoracic pleural intensity modulated radiation therapy for
malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys.
2014;90:394–401.
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pemetrexed in combination with cisplatin versus cisplatin alone in
patients with malignant pleural mesothelioma. J Clin Oncol.
2003;21:2636–2644.
189. Baldini EH. Radiation therapy options for malignant pleural
mesothelioma. Semin Thorac Cardiovasc Surg. 2009;21:159–163.
190. Rosenzweig KE, Zauderer MG, Laser B, et al. Pleural intensity-
modulated radiotherapy for malignant pleural mesothelioma. Int J
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therapy after pleurectomy/decortication for malignant pleural
mesothelioma. Int J Radiat Oncol Biol Phys. 2005;63:1045–1052.
192. O’Rourke N, Garcia JC, Paul J, et al. A randomised controlled trial
of intervention site radiotherapy in malignant pleural mesothelioma.
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invasive diagnostic procedures in patients with pleural
mesothelioma. A randomized trial of local radiotherapy. Chest.
1995;108:754–758.
194. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of
surgical resection and adjuvant high-dose hemithoracic radiation for
malignant pleural mesothelioma. J Thorac Cardiovasc Surg.
2001;122:788–795.
195. Allen AM, Czerminska M, Janne PA, et al. Fatal pneumonitis
associated with intensity-modulated radiation therapy for
mesothelioma. Int J Radiat Oncol Biol Phys. 2006;65:640–645.
196. Ball DL, Cruickshank DG. The treatment of malignant mesothelioma
of the pleura: review of a 5-year experience, with special reference
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to radiotherapy. Am J Clin Oncol. 1990;13:4–9.
197. de Graaf-Strukowska L, van der Zee J, van Putten W, et al. Factors
influencing the outcome of radiotherapy in malignant mesothelioma
of the pleura–a single-institution experience with 189 patients. Int J
198. Gordon W Jr, Antman KH, Greenberger JS, et al. Radiation therapy
in the management of patients with mesothelioma. Int J Radiat
Oncol Biol Phys. 1982;8:19–25.
199. Gomez DR, Hong DS, Allen PK, et al. Patterns of failure, toxicity,
and survival after extrapleural pneumonectomy and hemithoracic
intensity-modulated radiation therapy for malignant pleural
mesothelioma. J Thorac Oncol. 2013;8:238–245.
200. Miles EF, Larrier NA, Kelsey CR, et al. Intensity-modulated
radiotherapy for resected mesothelioma: the Duke experience. Int J
201. Rice DC, Stevens CW, Correa AM, et al. Outcomes after extrapleural
pneumonectomy and intensity-modulated radiation therapy for
malignant pleural mesothelioma. Ann Thorac Surg. 2007;84:1685–
1692; discussion 1692–1693.
202. Azarow KS, Pearl RH, Zurcher R, et al. Primary mediastinal masses.
A comparison of adult and pediatric populations. J Thorac
Cardiovasc Surg. 1993;106:67–72.
203. Cowen D, Hannoun-Levi JM, Resbeut M, et al. Natural history and
treatment of malignant thymoma. Oncology (Williston Park).
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204. Zhu G, He S, Fu X, et al. Radiotherapy and prognostic factors for
thymoma: a retrospective study of 175 patients. Int J Radiat Oncol
Biol Phys. 2004;60:1113–1119.
205. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and
long-term results after thymoma resection: a series of 307 patients. J
Thorac Cardiovasc Surg. 1996;112:376–384.
206. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of
thymomas with special reference to their clinical stages. Cancer.
1981;48:2485–2492.
207. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a
clinical study of 1320 patients from Japan. Ann Thorac Surg.
2003;76:878–884; discussion 884–885.
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208. Myojin M, Choi NC, Wright CD, et al. Stage III thymoma: pattern of
failure after surgery and postoperative radiotherapy and its
implication for future study. Int J Radiat Oncol Biol Phys.
2000;46:927–933.
209. Strobel P, Bauer A, Puppe B, et al. Tumor recurrence and survival
in patients treated for thymomas and thymic squamous cell
carcinomas: a retrospective analysis. J Clin Oncol. 2004;22:1501–
1509.
210. Fan C, Feng Q, Chen Y, et al. Postoperative radiotherapy for
completely resected Masaoka stage III thymoma: a retrospective
study of 65 cases from a single institution. Radiat Oncol. 2013;
8:199.717X-8–199.
211. Chang JH, Kim HJ, Wu HG, et al. Postoperative radiotherapy for
completely resected stage II or III thymoma. J Thorac Oncol.
2011;6:1282–1286.
212. Hsu HC, Huang EY, Wang CJ, et al. Postoperative radiotherapy in
thymic carcinoma: treatment results and prognostic factors. Int J
213. Ruffini E, Van Raemdonck D, Detterbeck F, et al. Management of
thymic tumors: a survey of current practice among members of the
European society of thoracic surgeons. J Thorac Oncol. 2011;6:614–
623.
214. Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic
carcinoma: a cohort study of patients from the European society of
thoracic surgeons database. J Thorac Oncol. 2014;9:541–548.
215. Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma:
analysis of clinicopathologic features, treatment, and outcome.
J Thorac Cardiovasc Surg. 1997;113:55–63.
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34 Soft Tissue and Bone Sarcomas
Yen-Lin Chen and Thomas F. DeLaney
INTRODUCTION
Sarcomas are rare malignant tumors of mesenchymal cell origin that can
arise from connective tissues throughout the body, including bone, soft
tissue, and the peripheral nervous system (1). In 2015, the estimated
number of new soft tissue sarcoma diagnoses in the United States is
11,930 and the number of new bone sarcoma diagnoses is 2,970,
accounting for <1% of all malignancies. The age distribution of sarcoma
is bimodal in nature with a peak at young age (in the top 5 most
common causes of cancer death ages <20 and 20 to 39) and a peak after
60 years of age (2). Soft tissue sarcomas can arise in any portion of the
body: 46% lower extremities, 18% trunk/body wall, 13% upper
extremities, 13% retroperitoneum, and 9% head and neck (3).
Because of the rarity of bone and soft tissue sarcomas, clinical
outcomes have been shown to be better when patients are evaluated and
managed by centers with multidisciplinary expertise in the treatment of
sarcomas including orthopedic surgery, surgical oncology, radiation
oncology, medical/pediatric oncology, radiology, and pathology. A
South Sweden Health Care Region study, for example, showed that in
375 patients with soft tissue sarcoma, patients not referred at any time
to a tumor center had 2.4-fold higher local recurrence rates, and those
referred only after definitive surgery had 1.3-fold higher local recurrence
rates (4). Other studies suggest that multidisciplinary management of
both bone and soft tissue sarcomas, especially at high-volume academic
centers, helps overcome specialty bias and facilitates better adherence to
guidelines for sarcoma management (5–10) while lack of access to
centers of expertise can increase mortality from sarcoma (11).
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Radiation therapy (RT) plays a central role in the management of soft
tissue sarcomas in most anatomic sites, both for improving local control
as well as preserving limb or organ function, and in challenging bone
sarcoma sites such as head and neck, spine, and pelvis. This chapter will
go into three major subcategories of sarcomas that pose unique
considerations from the standpoint of radiation planning: truncal and
extremity soft tissue sarcoma, retroperitoneal sarcoma, and bone
sarcomas. Ablative treatments for oligometastatic sarcoma are
increasingly used and will also be discussed.
TRUNCAL AND EXTREMITY SOFT TISSUE SARCOMA

Natural History
Truncal and extremity soft tissue sarcomas present most commonly as a
painless mass; rarely there is pain, edema, or paresthesia. Due to the
rarity of these tumors, delay in diagnosis can be significant. Rapid
appearance or growth of a preexisting lump may be symptoms that
would typically be alarming for possible malignancy.
Within a normal extremity, the muscles are separated into
compartments by major intermuscular septae. Between the muscles
within the same compartment, muscles are separated by minor septae.
Sarcomas tend to grow longitudinally along the axis of the compartment
and radially within the confines of the major fascial barrier of the
compartment rather than cross into neighboring compartment until quite
late in their natural history. Radially the tumor compresses the
surrounding muscles and tissue and results in zones with a mixture of
sarcoma cells, atrophic muscles, and edema, a “pseudocapsule” that can
be appreciated during resection. Between the muscles within a
compartment, the sarcoma can permeate the minor intermuscular septae
for a distance away from the gross tumor. The minor septae and
pseudocapsule, however, are not true barriers to microscopic spread, and
removal along the pseudocapsule is likely to leave microscopic disease
behind. Therefore, the minimal resection margin for resection alone for a
sarcoma is considered to be the major compartmental fascia,
interosseous membrane (tibia–fibula, ulna–radius), peritoneum,
perineurium, or adventitia of an organ, or at least a centimeter beyond
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the mass into surrounding fat.
Soft tissue sarcomas of the trunk and extremities rarely metastasize to
lymph nodes with the exception of a few histologic subtypes: clear cell
sarcoma, angiosarcoma, rhabdomyosarcoma, epithelioid sarcoma, and
synovial sarcoma. Sentinel lymph node mapping is quite controversial
for these histologies. Generally, unless lymph nodes are clinically
involved or pathologically show high-risk features (extracapsular
extension, multiple lymph nodes, or lymph nodes greater than 3 cm),
elective nodal RT to lymph nodes is rarely used. PET may be useful in
these lymphotropic sarcomas.
Figure 34.1 MRI images showing a T2bN0M0 grade 3 lower extremity soft tissue sarcoma (top
left coronal, top right axial). The tumor involves the medial compartment of the upper thigh and
abuts the deep femoral artery and vein and approaches but does not invade the femur. Note the
extensive peritumoral edema on the sagittal images (two lower panels).
Most sarcomas metastasize to the lungs. Myxoid liposarcoma and clear

cell sarcoma can have unusual sites of spread, including bone marrow,
spine, and soft tissue. Therefore, magnetic resonance imaging (MRI)
imaging for bone metastases may be useful (12). Brain metastases are
overall rare and tend to be a late event in patients with lung metastases
or wide spread systemic disease.
Diagnosis and Staging

When a soft tissue sarcoma is suspected, anatomic imaging prior to
biopsy or resection is recommended. MRI is the preferred modality to
image soft tissue sarcomas of the trunk and extremities because of
superior tissue definition of tumor from individual muscles (13,14).
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Figure 34.1 shows an MRI of a T2b high-grade sarcoma involving the
medial compartment of the upper thigh.
Definitive diagnosis of a truncal or extremity sarcoma is best
established by a core biopsy with low complication rate and high
accuracy (15,16). Incisional biopsy is sometimes done if a histologic
diagnosis cannot be made on the core biopsy sample. If necessary, the
incision used to biopsy a sarcoma needs to be carefully placed directly
over the tumor and longitudinally over the limb. Transverse incisions or
incision or biopsy tracks through unaffected compartments can violate
compartments otherwise not likely to be involved by direct tumor
extension: sarcoma cells can seed these areas and unnecessarily increase
the radiation target volume and surgical procedure. Excisional biopsy is
also rarely recommended without an attempt at core biopsy. Because the
entire incision or excisional scar as well as associate ecchymoses must be
removed entirely, doing so may result in loss of major neurovascular
supply, loss of major muscles necessary for the function of the limb, or
skin/soft tissue defects too large to reconstruct satisfactorily. Therefore,
the biopsy approach may dramatically affect the treatment approach and
outcomes for patients with STS and is best undertaken at a sarcoma
treatment center. The Musculoskeletal Tumor Society evaluated 329
biopsies of primary soft tissue sarcomas in 1982 and 597 cases in 1992
and found that when biopsy was done in a referring institution instead of
a sarcoma treatment center, the rate of errors, complications, need for a
more complicated resection, increased disability, loss of function, local
recurrence, or death were two to twelve times higher (17,18). For
patients receiving RT, details of the biopsy technique can significantly
affect target definition and radiation planning: although uninvolved skin
should be avoided, it is important to adequately dose (avoid bolus) for
an initially unplanned incision/excisional biopsy track must be
adequately dosed to the surface at areas at high risk of having tumor cell
contamination.
Once a biopsy has been obtained, key findings on pathology include
the histologic subtype and grading. There are over 100 different
histologic subtypes of soft sarcomas, named based on the presumed
normal tissue of origin that the tumor most closely resembles (1). The
most common soft tissue sarcomas include GI stromal tumors (19),
undifferentiated or unclassified soft tissue sarcoma (previously named
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malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial
sarcoma, and malignant peripheral nerve sheath tumor (MPNST). Some
sarcomas are identified through unique chromosome translocations:
Ewing sarcoma, desmoplastic small round cell tumor, myxoid and round
cell liposarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell
sarcoma, extraskeletal myxoid chondrosarcoma, and
dermatofibrosarcoma protuberans, among others. While most of the soft
tissue sarcomas behave similarly, there are some notable exceptions in
local aggressiveness and patterns of spread. Differentiating between the
various subtypes of sarcoma is important for prognosis and
individualization of treatment. For example, superficial
myxofibrosarcoma is much more infiltrative than other soft tissue
sarcomas, particularly in the subcutaneous tissue, and may be
challenging to visualize and predict the distance of microscopic spread,
even on MRI (20). As a result, definition of clinical target volume (CTV)
for preoperative radiation treatment planning may be difficult, and
surgical margins may be difficult to clear. Hence, staged surgery to clear
margins followed by postoperative RT may be a more rational strategy
for superficial myxofibrosarcoma (20–23) than preoperative RT.
Angiosarcoma of the skin, often associated with prior RT, can be
multicentric in presentation with great propensity for dermal, lymph
node, and distant metastases and pose challenges in both radiation
treatment target design and dose. Epithelioid and synovial sarcoma can
have discontinuous spread (24–27).
Histologic grade of sarcoma is generally done using the French
Federation of Cancer Centers (FNCLCC) Sarcoma Group system into
grades 1, 2, and 3 (1). For soft tissue sarcomas, distant metastasis is best
predicted by grade (28–31) and size (32). Staging studies for soft tissue
sarcomas include chest x-ray or chest CT (the latter for primary tumor
>5 cm, deep tumors, intermediate/high grade). Abdominal CT is
recommended for myxoid liposarcoma because of risk of extrapulmonary
spread. At present, there are no conclusive studies on the use of PET for
primary STS imaging or staging (33,34).
Tables 34.1 and 34.2 show the AJCC seventh edition staging system
for soft tissue sarcomas.
TABLE 34.1 American Joint Committee on Cancer Staging TNM
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Classification for Soft-Tissue Sarcomas
Treatment Options and Prognosis

Amputation versus Limb Salvage
The primary goals of treatment for truncal and extremity soft tissue
sarcoma are survival free of disease and preservation of extremities,
organs, mobility, and function. A seminal prospective trial at the NCI in
the 1970s randomized 43 patients with high-grade soft tissue sarcoma to
limb salvage surgery with postoperative RT (5,000 rads to the entire
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anatomic area at risk and 6,000 to 7,000 rads to the tumor bed) versus
amputation, both arms with chemotherapy. At 5 years, the investigators
found no statistical difference in local recurrence (4 vs. none P2 =
0.06), disease-free survival (DFS) (71% vs. 78% at 5 years P2 = 0.75) or
overall survival (83% vs. 88% P2 = 0.99) between the limb salvage
group or the amputation group, respectively (35). This trial
demonstrated that limb salvage was a viable option for extremity STS.
TABLE 34.2 American Joint Committee on Cancer Staging

Classification for Soft-Tissue Sarcomas—Stage Groupings
Whereas primary amputation may still be indicated for advanced

sarcomas for which a functional limb after limb-conserving therapy is
not feasible (e.g., severe peripheral vascular disease, diabetes, other
comorbidities, involvement of a major nerve plexus or artery,
involvement of multiple compartments, or near-circumferential
subcutaneous involvement for which reconstruction may not be possible,
among others), in the majority of cases limb-conserving therapy is
preferred. For limb salvage, primary tumors are widely excised, ideally
en bloc without tumor cut-through and with a cuff of normal tissue
around the tumor. The generally recommended margin for STS is at least
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1 cm. Resections that are done through the pseudocapsule or otherwise
intralesional, piecemeal, or subtotal in nature are suboptimal and are
associated with higher local failure. Local control can vary as much as
47% versus 87% in patients with and without tumor violation (36).
However, for deep tumors near neurovascular structures, bones, or
other critical structures, acceptable margins may be much smaller (1 to 2
mm) if the specimen is removed with the involved natural anatomic
barriers such as fascia of the compartment. Soft tissue sarcomas
generally do not cross compartmental fascia or periosteum with the
exception of extremely advanced cases or where violation of the barrier
has occurred through biopsy or prior procedures. Major nerves are
usually preserved if possible, with nerve sheath as a margin. The
exception is in neurogenic tumors such as MPNST where it may be
necessary to resect the involved nerve to minimize risk of leaving
macroscopic or diffuse microscopic disease. Margins along abutting bone
can be cleared by stripping the involved periosteum. Generally periosteal
stripping should be limited to tumors directly abutting the periosteum,
especially in weight-bearing bones such as the femur, because of dose-
related pathologic fracture. If periosteal stripping is necessary for tumors
directly abutting bone and stripping is required, some surgeons may
recommend prophylactic fixation. There is also a clear dose effect with
radiation and fractures after limb-sparing resection and RT (37–40).
Major arteries involved sometimes may be resected for better surgical
margin and reconstructed, whereas veins generally are not. Surgical
wounds may be closed primarily or require rotational or free tissue flaps;
the use of flap reconstruction does not appear to adversely affect
postoperative function or health status outcomes (41,42). A
multidisciplinary discussion of the anticipated surgical approach,
including stripping of periosteum, vascular resection, reconstruction
options, and potential margins of concern can help inform radiation
planning, both in the preoperative and postoperative settings.
Importance of Radiation Therapy in Limb Conserving

Therapy
Following promising single institutional experiences combining RT with
conservative surgery in sarcomas (43), an NCI study randomized 141
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patients after limb salvage surgery for STS to RT plus chemotherapy
versus chemotherapy alone without RT. At 9.6 years of follow-up, there
was a highly significant decrease in local recurrence rate with RT (one
LR) versus without RT (17 LR, P2 = 0.0001). The impact of RT on LR
was significant in both high-grade and low-grade sarcomas, though there
was no difference in distant metastasis or OS (44).
A trial of adjuvant brachytherapy (BRT) versus no BRT after complete
excision of extremity or trunk sarcoma using iridium-192 implant to 42
to 45 Gy over 4 to 5 days found 5-year local control rate of 82% versus
69% (P = 0.04). Within the high-grade sarcoma patients, local control
was 89% (BRT) versus 66% (no BRT) (P = 0.0025). In contrast to the
NCI trial, BRT did not affect local control for low-grade sarcomas (P =
0.49). As in the other studies, use of adjuvant RT did not impact distant
metastasis or disease-specific survival (30). Neither this nor the NCI trial
comparing limb-conserving surgery with or without RT was powered to
detect a survival difference (30,44). However, analysis of 2,606 soft
tissue sarcoma in the Surveillance, Epidemiology, and End Results
(SEER) database found on multivariate analysis that RT was associated
with 20% and 30% survival advantage for the matched and unmatched
cohorts (P ≤ 0.02) (42,45). Other studies suggest that local recurrence
can be directly associated with worse survival (Gronchi et al., 2009).
The most consistent prognostic factor for local recurrence is a positive
or uncertain surgical margins (28). In patients who initially undergo a
nononcologic resection or an R1 resection, as high as 35% to 67% of
these patients may have residual sarcoma and benefit from re-resection
for local control even with the routine use of adjuvant RT (46–50). RT
may be given preoperatively or postoperatively in conjunction with re-
resection to yield high local control rates.
However, in some patients, re-resection after an initially unplanned
excision may not be feasible due to medical or functional considerations;
in these patients, RT to median doses of 66 Gy has been shown to have a
reasonably high 10-year local control rate of 86% (51). It appears that if
the margin cannot be cleared, higher RT dose may help improve local
control. A large series of 154 STS patients, for example, found that high
doses >64 Gy appear to improve local control rate to 85% versus 66.1%
with doses ≤64 Gy (P < 0.04) (52).
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Surgery Only for STS
There is likely a subset of patients with STS who may not require RT.
Large population-based studies and single institution studies suggest that
there may be some patients, for example, those with T1 or low-grade
tumors, who may not benefit from adjuvant RT (53–56). In a prospective
trial of selected patients with T1 STS, 84% of patients were able to have
R0 resection and were treated with surgery alone with isolated local
recurrence of 10.6% at 10 years (55). In a series of 74 patients treated
with function-sparing surgery without RT, 10-year local control rate was
93%: those with margins <1 cm had 87% LC compared with 100% for
those with margins ≥1 cm (P = 0.04), rates comparable to that
reported with RT (56). Memorial Sloan Kettering Cancer Center
developed a nomogram based on 684 patients with extremity sarcoma
treated with limb-sparing surgery alone that includes age, size, margin
status, grade, and histology as five independent predictors of recurrence
(53). In practice, surgical excision alone is reserved for cases with low-
grade, superficial tumors ≤5 cm in size, high-grade tumors that are
entirely intramuscular for which widely negative margins can be
achieved.
Radiation Only for STS

For patients who cannot undergo surgery or for whom limb salvage is
not feasible but amputation is unacceptable, RT alone may be an option.
A study of 112 patients treated with RT to a median dose of 64 Gy for
gross unresected disease found 5-year local control of 45%. The LC
differed based on size: LC was 51% for tumors <5 cm, 45% for tumors 5
to 10 cm, and only 9% for tumors greater than 10 cm. Doses greater
than 63 Gy were associated with better LC but doses >68 Gy were
associated with higher complication rates (27% vs. less than 8% for dose
<68 Gy) (57).
Sequencing of Radiation Therapy: Preoperative versus

Postoperative Radiation Therapy
There are theoretical advantages and disadvantages to preoperative
versus postoperative RT: preoperative RT allows for clear tumor
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definition and areas at risk, potential reduction of seeding, sterilizes the
tumor, and allows for more conservative surgical margins whereas
postoperative RT allows for evaluation of the entire tumor and surgical
margins and potentially may allow omission of RT in selected cases. A
number of retrospective studies of preoperative or postoperative RT for
STS have shown comparable outcomes. There was higher late RT-related
complications with postoperative RT. Higher wound complication rates
are seen with preoperative RT (ranging from 27% to 37%) than with
postoperative RT (ranging from 8% to 29.3%) (43,58–61).
The only phase III randomized clinical trial to compare preoperative
RT versus postoperative RT was conducted by NCI Canada (CAN-NCIC-
SR2). One hundred and ninety patients with extremity STS, mostly
intermediate or high grade, were randomized to preoperative RT with 50
Gy (with postoperative boost of 16 to 20 Gy if positive margins) versus
postoperative RT to 50 Gy covering an initial large field covering the
incision plus a 16 to 20 Gy cone down to the tumor bed. The tumor
volumes were 5 cm proximal and distal to the tissues at risk followed by
reduction to 2 cm around the initial tumor bed. The primary end point
was acute wound healing complications defined as wound healing
requiring deep packing, prolonged wound dressings, secondary surgery,
or hospital admission within 120 days of resection. A planned interim
analysis found highly significantly more acute wound healing
complications with preoperative RT (35%) versus postoperative RT
(17%), and the study was terminated early (62), however, a long-term
follow-up found a statistically nonsignificant trend toward greater rates
of fibrosis (48.2% vs. 31.5%), joint stiffness (23.25% vs. 17.8%), and
edema (23.2% vs. 15.5%). These predicted for lower functional scores as
measured by the Musculoskeletal Tumor Rating Scale (MSTS) and the
Toronto Extremity Salvage Score (TESS) (P < 0.01). Field size was
greater with postoperative RT versus preoperative RT and was the only
significant predictor of fibrosis and joint stiffness and a trend for edema
(P = 0.002, P = 0.006, and P = 0.06, respectively) (63). Because of the
reduction of late effects as well as other potential advantages of
preoperative RT (decreasing the necessary surgical margin and reduce
seeding), preoperative RT is generally preferred for most intermediate to
high-grade truncal or extremity STS.
There are some exceptions to this preference: patients with infiltrative
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subcutaneous myxofibrosarcoma where defining the margins and
appropriate preoperative target volume may be challenging, surgery first
may help define the margins for postoperative RT. Patients who are
obese, diabetic, or whose subcutaneous tissue may not be spared and
likely at higher risk of acute wound healing problems may be better
served with postoperative RT after complete healing (64).
Treatment Planning
Radiation treatment planning for truncal and soft tissue sarcoma
requires a careful consideration and understanding of the patient’s
comorbidities, natural history of the sarcoma subtype, available
diagnostic imaging, any anticipated reconstruction and normal structures
and potential impact on limb function. Because sarcomas can involve
many different anatomic compartments of the limb, immobilization is
the most important first step in treatment planning.
Good immobilization is necessary to reproducibly position the affect
limb. A variety of devices may be used to achieve this ranging from
standard plastic supports with Velcro straps, to individually formed casts
from polyurethane foam (Niewald et al., 1990), thermoplastic shell,
vacuum pillow on adaptable baseplates (65,66), or other variations
thereof (67). Immobilization across movable joints adjacent to the
involved portion of the extremity can eliminate one of the largest
variables in positioning. Whenever possible, the immobilization should
minimize soft tissue distortion of the affected portion of the limb. For
proximal medial thigh lesions, frog-leg position and scrotal sling can
help reduce skin folds and dose to the scrotum/perineum; in some cases
the ipsilateral leg benefits from the frog-leg positioning while in other
cases the contralateral leg benefits. One should consider potential beam
arrangements at the time of the immobilization so that the desired dose
can be delivered as conformally as possible to the target and the
uninvolved limb can be positioned to avoid exit dose or clearance
problems with the gantry head. For the sarcomas that occupy the near
entirety of an anterior or posterior compartment, for example, elevation
of the contralateral leg may allow for straight-forward opposed lateral
beams, whereas those in the medial/lateral compartments or only a
small portion of the cross section of the limb can benefit from anterior,
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posterior, obliques, or other angles that would be better conform the
dose and therefore the contralateral leg may be best left in the neutral
position. Each case must be individualized to optimize treatment
planning options. Figure 34.3 shows the treatment set-up and an
intensity-modulated radiation therapy (IMRT) plan for a medial thigh
sarcoma. Figures 34.4 to 34.6 show the preoperative treatment set-up
and plan for a high-grade calf synovial sarcoma (Fig. 34.4), the set-up
digitally reconstructed radiograph (DRR), and postoperative boost (Fig.
34.6). Figure 34.12 shows an IMRT plan for a synovial sarcoma
involving a long length in the medial aspect of a foot where the dose
shaping allowed maximal avoidance of high dose to the weight-bearing
bones of the foot.
Figure 34.2 High-grade thigh sarcoma after preoperative chemoRT showing extensive internal
necrosis.
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Figure 34.3 A: Treatment set-up for T2bN0M0 proximal lower extremity high-grade sarcoma.
Custom accuform cushion, thermoplast food mold, and foot plate allow for reproducible
immobilization of the right leg for daily treatment. B: Shows IMRT plan for T2BN0M0 grade 3
lower extremity sarcoma involving the medial compartment of the proximal thigh. Prescribed dose
(in orange) covers the CTV, which is limited to the affected compartmental fascia and the
periosteum of the adjacent femur. Dose to the femur is limited to the affected side. Dose to
uninvolved soft tissue is minimized and a strip of soft tissue and skin laterally (at least 3 cm) is
kept free of dose.
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Figure 34.4 Custom immobilization and set up (A and B) for a T2BN0M0 grade 3 pleomorphic
sarcoma of the right calf treated with preoperative radiation treatment. C, D and E: show the axial,
sagittal, and coronal images of GTV (solid red) and CTV (shaded magenta) and dose distribution
from a 3D conformal photon plan. Note that the CTV is confined to the fascia and the tibia rather
than extending uniformly to the skin or the fibia to allow for dose drop off at the uninvolved
subcutaneous tissue laterally and the pretibial soft tissue anteriorly. F: shows the dose volume
histogram with L knee dose V50 < 50%. (continued)
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For the upper extremity, the patient can lie prone or supine with the
arm elevated or akimbo away from the trunk with the patient positioned
toward the contralateral edge of the table to reduce risk of gantry
interference. Supination or pronation of the forearm may affect the
tumor’s position within the forearm and optimal beam arrangements.
For the hand and fingers, custom bolus may be built into the
immobilization if dose build-up is desired because it may otherwise be
difficult to add bolus after the planning without affecting treatment set-
up. Figures 34.7 and 34.8 show the MRI, immobilization, and IMRT plan
for a high-grade sarcoma involving the deltoid muscle at the humeral
head/shoulder joint. Figure 34.11 shows a high-grade sarcoma involving
the second metacarpal and the custom immobilization with built-in
bolus dorsal to the lesion, and a 3D conformal plan to allow some
superficial sparing while achieving adequate dose to the dorsal aspect of
the lesion.
The use of bolus, especially for preoperative RT, is limited to cases
where skin or superficial spread may be of concern (e.g., angiosarcoma
of the skin). Generally even for CTV close to but not involving superficial
subcutaneous tissue or skin, it is not necessary to bring full dose to cover
the planning target volume (PTV) expansion to the skin.
When treating any patient who has had initial incision or excision of
the tumor, marking the surgical scar and drain sites with radio-opaque
wires is important for target definition. These areas are potential sites of
contamination and should be included in the initial 50 Gy of the target.
CT-based simulation is preferred in most cases to allow for 3D
conformal therapy. When CT-based simulation with conformal blocking
was introduced in sarcoma, it was found to reduce volume of tissue
receiving target dose by greater than 20% in four of five patients with
thigh sarcomas compared with 2D (68,69). Nowadays, CT simulation
also allows for fusion with MRI for better target definition.

Based on the natural patterns of growth of sarcoma, traditional margins
have included as much as 5- to 10-cm longitudinal margin (reflecting the
greater risk of microscopic spread of sarcomas along the axis of the
involved compartment) and 2 to 3 cm of radial margin (reflecting a 1-cm
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margin generally considered to be the optimal surgical margin plus a
margin to account for target uncertainty in the era before MRI, daily set-
up uncertainty, and beam penumbra). The National Cancer Institute
(NCI) Canada randomized trial of preop versus postop RT utilized 5-cm
longitudinal margins and 2-cm radial margins for the first 50 Gy and 2
cm around the tumor bed for the boost (62). The local control was high
with these margins.
Figure 34.5 Orthogonal daily imaging with KV imaging.
However, the advent of MRI generated great interest in refining these

margins. When satellite tumor cells in resected high-grade sarcoma
specimens were correlated with MRI signals, it was found that T2 MRI
peritumoral signal abnormalities ranged from 0 to 7.1 cm beyond the
gross tumor, T1 contrast enhancement abnormalities ranged from 0 to
5.3 cm, but sarcoma cells could be identified beyond the gross tumor in
10/15 cases: of those, 6 cases had cells within 1 cm of the gross tumor
but 4 cases had cells >1 cm and up to maximum of 4 cm from the gross
tumor. The presence of microscopic spread did not correlate with tumor
size or MRI peritumoral changes (70). A recent review of patients treated
preoperatively with CT- and MRI-planned RT used post gadolinium
contrast enhancement T1 MRI images to define the gross target volume
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(GTV). The GTV was expanded with 1 to 1.5 cm radially and 3.5 cm
longitudinally to form the CTV respecting fascial barriers. PTV expansion
was 5 to 7 mm and prescribed at least 95% of the dose. At 5 years of
follow-up, local control was 88.5%. Of the three patients who had local
failure as first relapse all had positive margins. Two additional patients
(all with margin <1 mm) had late local failure after distant metastasis.
There were no local failures with margins ≥1 mm. The authors
concluded that with preoperative RT, these margins seem to be
appropriate for most patients (71). Because inter- and intraobserver
variability for gross tumor definition in sarcoma can be quite significant,
peer review in target definition for sarcoma is recommended (72).
RTOG 0630 evaluated the use of MRI fusion and image-guided
radiation treatment (IGRT) to further reduce both CTV and PTV. In this
trial the GTV was defined by T1 contrast–enhanced MRI sequences,
ideally with image fusion. The GTV was then expanded 3 cm
longitudinally for high-grade sarcomas and 2 cm longitudinally for low-
grade sarcomas or more to encompass suspicious peritumoral edema on
MRI T2 sequences, but confined to the end of a compartment plus a 1-
cm margin. The radial expansion was 1.5 cm for high-grade tumors and
1 cm for low-grade sarcomas, confined to intact fascial barrier or
uninvolved bone or skin or subcutaneous tissue. IGRT using either daily
orthogonal imaging or CBCT was required for PTV of 0.5 cm; without
IGRT, a 1-cm PTV was required (73).
A companion study was made based on RTOG 0630 to assess the
variability of preoperative GTV and CTV target volume definition
between radiation oncologist. It was found that there was near perfect
agreement in the GTV and CTV of a lower extremity case among 10
sarcoma radiation oncologists but there was more variation in the CTV
definition for an upper extremity case (74). Another companion study
found that there was also good agreement in the definitive of suspicious
edema using T2-weighted MRI images of high-grade extremity sarcomas
among sarcoma radiation oncologists (75). Therefore, a consensus atlas
for preop RT GTV and CTV target definition was developed by the RTOG
sarcoma radiation oncologists to guide target definition for this trial. The
key recommendations of the atlas included: MRI fusion be performed
when possible with CT planning to better delineate the GTV; high-grade
large STS should include GTV plus 3-cm margins longitudinally and be
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confined by the end of a compartment; and radial margins would be 1.5
cm in areas not confined by intact fascial barrier, bone, or skin surface
(73). At the final report of the results of RTOG 0630, local control using
these margins and IGRT was high with 5 local failures out of 79
evaluable patients (treated with IGRT without concurrent
chemotherapy), all of which were in field, none marginal. Grade ≥2 late
toxicity at 2 years was 10.5%, which compared favorably with those
seen in the NCIC trial (62,76). A deformable RTOG Consensus Atlas of
Musculoskeletal Anatomy (CAMAS) of the compartments and structures
of the lower extremities was also developed as a part of this trial and
may become a useful tool for designing anatomically appropriate target
volumes (77).
As noted before, certain tumor histologies such as acral
myxoinflammatory fibrosarcoma or superficial myxofibrosarcoma, or in
cases where fascial planes have been violated, more generous margins
may be necessary (23,78,79). Careful consideration of the biopsy, prior
surgical details (if any), and the histologic subtype and compartment
involved are necessary to adequately cover the target at risk.
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Figure 34.6 Postoperative boost with 16 Gy for calf sarcoma after resection with positive margins
along the neurovascular bundle. A: Axial. B: Sagittal. C: Coronal. D: DVH showing attempt to
conform the boost dose while sparing a strip of medial soft tissue. E: Note the metal artifact from
the plate, seen on the DRR AP film, which was placed at the time of the resection for stabilization
of the tibia to prevent fracture due to periosteal stripping. F: Daily surface imaging combined with
weekly CBCT allowed for use of 5 mm for PTV.
Figure 34.7 Grade 2 leiomyosarcoma involving the deltoid muscle. A: Note the extensive
suspicious peritumoral edema along the deltoid muscle from origin to insertion. B: Immobilization
with custom immobilization to reproducibly position the shoulder and the right arm.
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Figure 34.8 A: Preoperative IMRT plan for deltoid sarcoma using daily CBCT for IGRT to allow for
a 5-mm PTV (dark purple) around the CTV (red). The longitudinal margins of this target fan out
around the insertion points of deltoid and include suspicious peritumoral edema that extends
around the humerus. B: Axial isodose plan. C: Sagittal. D: Coronal. E: Dose–volume histogram
shows that less than 50% of the humerus and right shoulder joint receives full dose.
Dose and Fractionation

Preoperative RT
50 Gy in 2 Gy per fraction is a standard dose fractionation given
preoperatively to the volumes as detailed above followed by at least 3
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weeks of recovery prior to resection. In chemoradiation protocols used
for high-grade sarcomas at some centers, a 10% reduction in dose or a
change from 2 Gy per fraction to 1.8 Gy per fraction (to 50.4 Gy) is
commonly done to reduce the potentially added impact of chemotherapy
on already high acute wound healing complication rates. Timing from
completion of chemoradiation to surgery is also adjusted to 5 weeks
(80).
Boost for Positive Margin or Gross Disease

(BRT boost in more detail below) can deliver 16 Gy as low-dose rate or a
high-dose rate (14 Gy twice daily × 4 days or 25 Gy for gross residual
disease). Intraoperative electron RT of 10 to 15 Gy given either after or
preceding external beam radiation therapy (EBRT) has also been used for
boost with high local control rates without increase in acute or late
morbidity (81–85). It is unclear whether given the long interval between
preoperative RT and postoperative recovery whether EBRT is beneficial
as a modality for boosting a positive margin. Some studies found modest
or no impact of EBRT boost on local control but higher risk of fracture,
fibrosis, edema, and joint stiffness from the high cumulative dose
(86,87).
Hypofractionation
There is limited experience using hypofractionation in sarcoma. A series
on 60 patients with median size 12-cm tumor treated with chemotherapy
and either hypofractionated 3DRT with 35 Gy in 10 fractions or standard
46 to 50 Gy in 23 to 25 fractions found that those treated with
hypofractionation had significantly superior local control rate, DFS, and
cause-specific survival compared with conventional fractionation (88).
Another study reported the use of preoperative stereotactic body
radiation therapy (SBRT) for 13 patients with high-grade extremity
sarcomas using expansion of 0.5 cm radially and 3 cm longitudinally to a
dose of 35 Gy in 5 fractions or 40 Gy in 5 fractions for deeper tumors.
Maximum skin dose was constrained to 46 Gy. Surgery was done at a
median of 37 days after SBRT. All patients had negative margins and
4/13 required planned vacuum-assisted wound closure but no other
wound complications. This initial experience warrants further follow-up
(89).
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Treatment Set-up and Uncertainties
Proper positioning for extremity sarcomas can be challenging even with
immobilization. A study evaluated 236 treatments in 15 patients with
extremity sarcoma to assess whether surface imaging could improve
patient positioning and reduce the necessary CTV (67). Intrafraction
motion is small (2.1-mm mean 3D vector shift 1.3-mm systematic and
random errors). However, the mean interfraction error was 7.6 mm and
systematic and random errors were 3 to 4 mm in each direction. The
required PTV margins were 1 cm, 1.2 cm, and 1.3 cm in the anterior–
posterior, superior–inferior, and lateral directions, respectively. With
surface alignment the mean root mean square (RMS) errors for
uncorrected position were 4.7 mm and were reduced to 2.2 mm with 4
degrees of freedom surface alignment and down to 1.7 mm for 5 degrees
of freedom surface alignment. Based on this, the author’s institution uses
daily surface imaging with weekly cone beam CT (67). Another study
registered planning CT with CBCT acquired before delivery of image-
guided IMRT and found that a uniform 5-mm PTV margin was necessary
to cover intrafractional and interfractional systematic error and random
error (90). RTOG 0630 required the use of either daily kV or MV
orthogonal imaging or CBCT pretreatment to allow for use of 5 mm as
PTV (76). 5-mm PTV, however, is not adequate if set-up is checked with
only weekly KV or MV portal imaging, particularly in the lower
extremity. Figure 34.9 shows CBCT for daily alignment for a sarcoma
involving the shoulder joint to allow sparing of the joint.
Other uncertainties may come from changes in the sarcoma with
preoperative therapy. Adaptation of the plan may be necessary for
sarcomas. Imaging of STS after preoperative RT can show either
enlargement or shrinkage. In one study 20% of cases had an increase in
tumor volume but all cases had clear surgical margins and no local
recurrence. In 80% of tumors, maximal diameter was reduced by 13.5%
and median volume reduction was 33% (91). Another study quantified
tumor volume on T1 gadolinium–enhanced sequences and correlated to
pathologic response; median decrease in tumor volume was 13.8% for
nonmyxoid low-grade sarcomas, 82.1% for myxoid liposarcomas, and
<1% for high-grade sarcomas, despite a variety of pathologic responses
(92). Careful attention must be paid to potential changes in tumor size,
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whether by clinical examination and measurement of the circumference
of the limb at the site of the tumor, evaluation of larger than expected
changes in patient set-up, or review of surface or CBCT used for image
guidance for changes. Reevaluation of the initial radiation treatment
plan may be necessary if the plan no longer adequately covers the target.
Figure 34.10 shows an example where 3D plan for a tumor anticipated
to potentially swell (due to chemoradiation) was more robust than an
IMRT plan. Allowing flash for tumors anticipated to potentially swell
from induction chemotherapy may help reduce the need for replanning.
Other Radiation Modalities

Brachytherapy
BRT has particular appeal compared to EBRT, especially prior to the
availability of 3D and IMRT techniques: targeted dose distribution with
the treatment field defined at the time of resection with the surgeon, low
integral dose and short treatment times. The American Brachytherapy
Society consensus statement for sarcoma brachytherapy provides a
comprehensive guide to the use of this technique in soft tissue sarcomas:
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Figure 34.9 CBCT used for daily treatment alignment. In this case the CBCT was superior to
surface imaging for ensuring dose conformality around the right shoulder joint. A: Coronal. B:
Sagittal. C: Axial. D: Couch correction based on CBCT alignment. E: Vision RT surface imaging.
BRT is most often accomplished as interstitial implants by passing

hollow needles through the skin and soft tissue at least 1 to 2 cm away
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from the wound incision. The catheters are placed 1 to 1.5 cm apart in
parallel or perpendicular to the incision depending on the curvature of
the extremity so as to avoid distortion of the catheters postoperatively.
The CTV should encompass the entire area at risk as either a single plane
or multiple planes. Surgeons usually can help place radio-opaque clips to
allow visualization for planning. Catheters are then sutured and
anchored to the external skin with fixation buttons. Tissue expanders,
gel foam, drains, or inflatable material may be used to protect normal
tissues. Once the wound is healed, catheters are numbered for correct
identification and the positions of the catheters at the skin are marked to
ensure consistent depth between fractions. Patients are planned
postoperatively using CT simulation with “dummy ribbons” which help
identify potential source positions. The quality of implant is measured as
D90 (dose to 90% of the CTV), V100 (percent of CTV receiving 100%
isodose), and V150. Surgical incision is limited to <100% isodose and
source should not be closer than 0.5 cm from the skin surface.
Figure 34.10 Planning needs to take into consideration potential changes in tumor between
simulation and start of treatment or potentially during treatment. In the example, a 15-cm chest
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wall sarcoma was planned using both IMRT and 3D. On CBCT and clinical assessment at the
verification simulation, the tumor had increased significantly in size after the first cycle of
interdigitated MAID (mesna,adriamycin, ifosfamide, and dacarbazine). A: IMRT plan showing
before (top left) and after (bottom left) the tumor swelling and the shortfall in blue (bottom
right). B: DVH comparison of tumor coverage with IMRT on the initial and replanning CT shows
decreased PTV and CTV coverages using an IMRT plan. C: 3D CRT plan showing before (top
left) and after (bottom left) the tumor swelling. D: DVH comparison of tumor coverage with 3D
CRT with adequate flash had no PTV or CTV shortfall.
BRT treatments for extremity sarcomas are most commonly delivered

using iridium-192 seeds as low-dose rate or as high-dose rate; the latter
avoids radiation exposure to the personnel and can be given as an
outpatient. For LDR, the prescription is delivered to the lowest
continuous isodose rate line covering CTV (usually 5 mm from the plane
of the implant) at a dose of 45 to 50 Gy over 4 to 6 days at 0.45 to 0.5
Gy/hr, or to 15 to 25 Gy over 2 to 3 days at 0.45 to 0.5 Gy/hr with 45 to
50 Gy of EBRT. For HDR, the recommended prescription dose is 30 to 54
Gy over 4 to 7 days at 2 to 4 Gy BID, or 12 to 20 Gy over 2 to 3 days at
2 to 4 Gy BID, with 6-hour intervals. Pulse dose rate (PDR) is a way to
use remote after-loading delivering dose in short bursts at hourly doses
that is radiobiologically comparable to LDR. To limit the impact of
wound healing, time to source loading more than 5 days and good
implant geometry can help lower wound healing complication (93).
There are no randomized comparisons between EBRT versus BRT as
monotherapy, or EBRT versus EBRT plus BRT as a boost. The American
Brachytherapy Society (ABS) guidelines on brachytherapy recommend
BRT monotherapy be reserved for sarcomas resected with negative
margins or pediatrics or previously irradiated patients, but for >5 cm,
high grade, or incompletely resected or recurrent but not previously
irradiated sarcomas, EBRT to the larger volume at risk with BRT as a
boost may provide better coverage (94). The randomized phase III trial
mentioned above showed that for high-grade tumors local control was
higher versus no surgery alone (89% vs. 66%), although it is unclear
why the same advantage was not seen in low-grade sarcomas (30).
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Growing evidence suggests that IMRT can potentially provide better
dosimetric normal tissue sparing and tumor coverage than 3D RT for
extremity soft tissue sarcomas. A study found that using a tight margin
at the soft tissue/bone interface in patients with tumors approaching but
not directly involving the femur, a 5-field coplanar IMRT plan can result
in better bone sparing than a 3D conformal plan with two to three beams
with wedges or partial transmission blocks as compensators (95).
Compared to 3D CRT, IMRT reduced the volume of surrounding soft
tissues excluding the PTV receiving prescription dose by 78%, the
volume of femur receiving full prescription by 57%, D05 in femur by
about 2.2 Gy, mean dose to femur by about 2.4 Gy, volume of
surrounding soft tissue by 13%, volume of skin by 45%, hot spots on the
skin, and mean dose to the skin by 14%, all statistically significant. In a
follow-up study of 41 patients with primary STS treated with limb-
sparing surgery and adjuvant IMRT (7 preoperatively to a median dose
of 50 Gy and 34 postoperatively to a median dose of 63 Gy) acute and
late toxicities appeared to be acceptable and local control was high at
94% at 5 years (96,97). Complication rates were acceptable: 9.8%
noninfectious wound complications; 7.l3% grade 2 and 2.4% grade 3
infectious wound complications. Two patients had bone fracture (4.8%)
without periosteal stripping or bone resection. Grade 1 or 2 joint
stiffness occurred in 46.3%, grade 1 or 2 edema in 31.7%, and grade 1
or 2 nerve damage in 26.7% (96).
A prospective phase II trial of image-guided IMRT (IG-IMRT) for
extremity sarcoma to conform dose and avoid normal tissues (skin flaps
for wound closure, bone, or other uninvolved tissue) in 70 patients (59
evaluable), found that wound complication rate was 30.5% (comparable
to the NCIC SR2 trial) but primary closure was more often with IMRT
than the NCIC SR2 trial (93.2% vs. 71.4%) and there were no fractures.
Local control rate was high with only 6.8% local recurrence at 49
months of follow-up (98).
A comparison of IMRT versus EBRT in 319 patients found higher local
control rate at 5 years (92% vs. 85%) despite higher-grade lesions and
more close/positive margins with lower grade ≥2 radiation dermatitis
(31% vs. 49%). However, 3.5% of patients had grade ≥2 neuropathy
compared to fractionation but overall risk was low (99). A comparison of
IMRT (10 with preoperative 50 Gy and 53 with postoperative RT 63 Gy)
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versus adjuvant BRT with LDR to 45 Gy for high-grade extremity STS
found local control was better with IMRT (92% vs. 81%, P = 0.04) and
that IMRT was the only predictor of improved local control on
multivariate analysis despite worse features (positive/close margins <1
mm, large tumors >10 cm, and bone/nerve stripping/resection) (100).
The authors suggest that IMRT should be the treatment of choice for
primary high-grade extremity sarcoma. Longer follow-up will be
necessary to see if indeed IMRT is superior to other techniques, though
these initial studies are promising.
Some aspects unique to IMRT that warrant attention include
potentially greater dose inhomogeneity and hot spots, which may cause
unanticipated acute toxicity, for example, in soft tissue, skin, or nerves.
For sarcomas not involving skin yet close to the skin, a 3- to 5-mm rind
of skin may need to be contoured and used as a planning objective to
avoid hot spots in the soft tissue critical for wound healing. Another
concern is the use of multiple beams (often 5 or more) in IMRT, which
bathes a larger circumference of the extremity with low-dose radiation
and whether that affects edema and secondary malignancy rates. For
large fields, it may be necessary to divide fields into subfields (95).
Ultimately, the choice of modality should be individualized for each
patient, the type of CTV to be covered, the normal tissue to be avoided.
Collaboration with the orthopedic surgeon to define potential tissue,
which will be critical to wound closure, may also be helpful. In upper
thigh/groin sarcomas closer to the pelvis, IMRT may significantly reduce
dose to vulva, perineum, anus, rectum, and femoral heads. Around the
shoulder complex, IMRT may help reduce dose to the brachial plexus.
Around paraspinal muscles, chest wall, or other truncal (nonvisceral)
sarcomas, IMRT may be helpful for reduction of dose to spinal cord,
lung, and other internal organ dose while conforming dose to potentially
complex, irregular target volumes than the more convex targets in distal
extremities. In the distal parts of the extremities (including hands, feet,
fingers, toes), 3D conformal therapy may be quite adequate while IMRT
may not be necessary.
Proton Radiotherapy
At this point, proton therapy’s role in extremity and truncal soft tissue
sarcoma is not established. Generally, because of the marked reduction
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in integral dose, protons can be considered and are accepted on most
protocols for children with soft tissue sarcomas. Young adults with
hip/truncal sarcoma may also benefit from proton beam therapy to spare
reproductive, pelvic, or other critical organs, but the long-term benefits
remain to be studied.
Dose Constraints and Complications

Consistently, limb-conserving therapy with adjuvant radiation has shown
high local control rates as discussed above. Patients overall enjoy good,
long-term quality of life with limb-conserving therapy, though across
different anatomic sites, functional outcomes can vary. A quality of life
study evaluating 149 patients with deep soft tissue sarcomas and 58
patients with superficial sarcomas found that treatment of superficial
sarcomas does not significantly affect function as assessed with the
Musculoskeletal Tumor Society (MSTS 1993) score or the Toronto
Extremity Salvage Score (TESS); however, treatment of deep soft tissue
sarcomas leads to significant reduction of both scores. Gait handicap,
limping, dressing, sitting, bending, and bathing affect function
depending on the location of the tumor (101).
Acute complications during preoperative or postoperative treatment
include skin reactions that are generally self-limited. Aside from groin
sites or superficial or contaminated tumors requiring bolus, attention to
the skin and subcutaneous dose for deep tumors generally allows
patients to complete treatment without severe desquamation. The most
common acute complication with preoperative RT is wound healing
delay. Lower extremity STS is associated with higher acute wound
complication rates (32%) compared to upper extremity STS (17%)
(102,103). Medial compartments are associated with higher wound
reoperation and edema and nerve damage more frequently in the
posterior compartment (104). Proximity of target volumes to the skin
surface of <3 mm is associated with preoperative RT, in addition to
diabetes, tumor >10 cm, and vascular zed flap/split-thickness skin graft
closure (105). Tumors in the adductor compartment, high grade,
proximal lower extremity, smoking, and obesity are other additional
predictors for wound complication (106). A study showed a trend
toward higher wound healing complication rate for those who had
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surgery after 6 weeks versus <4 weeks (28% vs. 34%, P = 0.08) (107).
General recommendations for dose constraint in radiation treatment for
STS include sparing a minimum of 3 cm strip of uninvolved soft tissue
(2D and 3D concept), avoiding entrance or exit through the contralateral
extremity, genital organs or perineum for tumors in the upper thigh and
pelvic region, avoidance of bolus unless necessary (though in some
postoperative cases adequate skin flash and build-up may be desirable to
cover potential contamination), and limiting hot spots. Skin care
throughout and after radiation treatment, gentle handling of tissue,
planned reconstruction with vascularized flaps, meticulous hemostasis,
avoidance of wound closure under tension, minimizing dead space by
using rotational or free tissue transfers, wound drainage, compression
dressings, immobilization of the limb until adequate initial wound
healing, and omitting postoperative RT for a subgroup of patients
without tumor cut-through or any residual viable tumors are some of the
ways that have been recommended to reduce wound healing
complication (108).
Late effects in soft tissue is related to both volume and dose of RT.
RTOG 0630 is encouraging that careful tailoring of preoperative RT
target volume using MRI sequences and standardizing target volumes for
STS, combined with IGRT to allow reduced PTV, can reduce late effects
including fibrosis, edema, and joint stiffness compared to larger volumes
used in the past (76). As shown in the NCIC SR2 trial, late effects are
greater with postoperative RT versus preoperative RT (62,63). A recently
completed VORTEX study in the United Kingdom randomized
postoperative sarcoma patients to either a larger versus a smaller
postoperative clinical target volume (109). Whether postoperative target
volume can be safely reduced awaits the results of this study.
Bone fractures after adjuvant RT in limb salvage patients can be quite
morbid and tend to occur within long bones with an average time to
fracture of 4 years, with the majority within 5 years of treatment (39).
These fractures have a high nonunion rate and can be quite morbid.
Overall fractures these are infrequent: 4.5% to 7.6% from preop RT in
the 2D to 3D era (38,58,104,110), 3.4% with BRT (93), 4% to 6.4% with
IMRT (97,103). One of the dose parameters found to correlate with
fracture is V40. The risk of RT-induced fracture appears to be reduced if
V40 <64%. Mean dose to bone <37 Gy or maximum dose anywhere
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along length of bone <59 Gy are also significantly associated with lower
risk of fracture (38). Mean dose to bone greater than 40 Gy and femoral
neck location has also been associated with higher risk of fracture (40).
A nomogram to predict radiation-associated fracture of the femur for
STS using variables including periosteal stripping <10 cm versus 10 to
20 or >20 cm, sex (female worse than male), age at surgery, anterior
compartment worse than adductor or posterior compartment, tumor size,
high radiation dose was found to have high sensitivity and specificity in
predicting pathologic fracture risk (39). Confining the CTV to bone when
there is no radiographic evidence of invasion and optimizing these
dosimetric parameters as well as prophylactic intramedullary fixation for
high-risk patients may help reduce this morbid effect.
Reirradiation
In patients with recurrent tumor after prior RT, reirradiation if the
recurrence is amenable to conservative excision can be considered;
however, high morbidity can be seen with additional course of RT (111).
In a study of 14 patients undergoing reirradiation (13 with EBRT with or
without BRT and one with BRT), for recurrent extremity or trunk STS,
50% of patients had serious complications leading to reoperation of
permanent impairment of limb function and only 1 remained disease-
free without complications (111–114). Another series found that
retreatment dose (median 49.5 Gy) and cumulative dose 100 Gy (93 to
120 Gy) salvaged 36% of patients but 60% had wound complication
(113). A study of 26 patients using after loading BRT (192IR) prescribed
between 50 and 80 cGy an hour to 0.5 cm from the implant to a mean
dose of 47.2 Gy after mean prior EBRT of 55.6 Gy found 19% had
complications and found local control in 52% of patients. Reirradiation
of patients with recurrent STS therefore must carefully balance the
higher risks of complications and the functional outcomes of the
salvaged limb versus amputation. The difficulty of salvaging recurrent
STS confirms the importance of optimizing upfront management of these
patients.
RETROPERITONEAL SARCOMAS
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Natural History and Treatment
Retroperitoneal sarcomas (RPS) comprise ∼15% of soft tissue (3). Their
size, typically >10 cm, and the complex retroperitoneal anatomy (see
Fig. 34.1) make treatment challenging (42). Wide surgical margins are
not achievable; narrowly negative margins are achieved in ∼60% to
70% of patients (115) although local recurrence (LR) is frequent even
with negative margins (116). Conventional EBRT is problematic because
the required target dose may exceed small bowel, kidney, and liver
tolerance. Many RPS deaths are from uncontrolled locoregional disease,
although intermediate and high-grade RPS have significant rates of
distant metastases (117). Although patients with high-grade RPS are at
risk for distant recurrence, there is no level-one evidence that adjuvant
chemotherapy mitigates this risk (118). Given the uncertain benefit of
adjuvant chemotherapy for RPS, it remains investigational (118).
Because of many RPS deaths are related to locoregional disease,
improvements in local tumor control (LC) might improve overall
survival, currently ∼50% at 5 years, although RPS can recur even after
5 years (119,120), illustrated by the Toronto report of 5- and 10-year
survival rates of 36% and 14%, respectively and 5-year locoregional
relapse-free rate of 28% at 5 years dropping to only 9% at 10 years
(119).
RPS poses significant surgical challenges. Incomplete (R2) resections
are not curative. There is clear benefit with macroscopically complete
(R0 or R1) resection (120–122), the standard for localized, operable RPS
(123). Satisfactory margins may require en-bloc removal of adjacent
viscera (42). Approximately 30% to 40% of gross total RPS resections
have microscopically (+) margins, although their prognostic
significance is unclear, in part reflecting pathologic margin assessment
limitations related to specimen sampling and the complex and variable
anatomy (116). Given these limitations, even patients with (–) margins
are at risk for relapse and prognostic factor studies do not demonstrate a
clear association between margin status and LR (116,120).
There is no level-one evidence that postoperative radiation improves
LC after R0/R1 resections (124). Many groups do not administer
postoperative EBRT after R1 resection, concerned about potential
toxicity to fixed bowel in the tumor bed (125,126). In a small trial
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conducted at the U.S. NCI, 35 patients were randomized to receive (1)
postoperative EBRT 50 to 55 Gy (35 to 40 Gy to an extended field +15
Gy to boost field) or (2) misonidazole plus electron IORT and
postoperative EBRT (35 to 40 Gy) (127). LR rate was 6/15 (40%) with
IORT plus EBRT versus 16/20 (80%) with EBRT alone (P < 0.001).
Significant radiation-related enteritis occurred in 10/20 patients
receiving only higher-dose EBRT compared to 2/15 with IORT and
lower-dose EBRT (P < 0.05), although peripheral neuropathy rates were
higher in the IORT + EBRT group, attributed to overlapping IORT fields
and misonidazole. Given the small sample size, toxicity, and relatively
high-LR rates in both arms, the trial is not considered definitive and has
not changed the standard of care. Nevertheless, several other reports of
IORT + EBRT suggest high rates of LC with higher radiation doses
achievable with IORT (128–130). IORT, generally one 10 to 15 Gy
fraction, can, however, be associated with neural injury or ureteral
stricture (131).
Some retrospective reports suggest that EBRT improves LC (123) or
delays LR (119), while others report no value (120,132). In general,
these reports, primarily of postoperative EBRT, include small patient
numbers and contain little information on the treatment selection
criteria.
Although both pre- and postoperative EBRT are options, a recent
international expert panel agreed (126) that preoperative RT is well-
tolerated, has potential advantages (133,134), and is preferable to
postoperative RT. The advantages for preoperative irradiation include
displacement of much small bowel from the CTV (discussed below) by
the tumor itself, resulting in less toxicity, (2) better gross tumor
delineation for radiotherapy planning, (3) potential for higher-dose
delivery to portions of tumor, (4) potentially lower risk of
intraperitoneal dissemination of otherwise viable tumor at surgery, and
(5) possibly higher biologic effectiveness of preoperative radiotherapy.
Disadvantages of postoperative irradiation include bowel frequently
falling back into the RT target area after tumor resection (Fig. 34.2);
potentially lower bowel mobility due to postoperative adhesion
formation (resulting in greater dose to fixed loops of bowel than they
were mobile and moving in and out of the treatment field); and the
appropriate dose may be 60 to 66 Gy (i.e., the dose used for
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postoperative extremity sarcoma radiation), which is often not tolerable
to large abdominopelvic volumes; and the target volume is more difficult
to delineate. While preoperative irradiation also has potential
disadvantages including limited histologic sampling, delay of definitive
surgery, and the quandary posed by positive margins following
preoperative RT (86), the expert consensus panel endorsed preoperative
radiation when RT was to be employed.
In a series of preoperative radiation for RPS from Toronto (135),
although the radiation volume was large (median 7.3 L), preoperative
EBRT (median dose, 45 Gy) was associated with EORTC/RTOG acute
toxicity scores <2. In a phase I trial from M.D. Anderson, patients
received preoperative EBRT in escalating doses combined with low-dose
infusional doxorubicin (136). At the maximum dose of 50.4 Gy,
preoperative chemoradiation was well tolerated, with only 18% of
participants having grade 3 or 4 nausea. Similarly, a recent series of 31
patients treated with 50 Gy of preoperative RT at Brigham and Women’s
Hospital reported a >grade 3 acute GI toxicity rate of only 3% (137).
The low toxicity of preoperative EBRT to these large volumes likely
relates to tumor displacement of much of the bowel from the CTV.
In reports on preoperative EBRT, outcomes appear improved
compared to those expected with surgery alone (138). However, absent
level-one data, it is not possible to determine whether this improvement
is real or from selection or other confounding factors. A randomized
study of preoperative radiation versus surgery alone conducted by the
American College of Surgeons Oncology Group (ACOSOG) was
terminated early because of poor accrual. A similar EORTC-led study is
currently underway, accruing well, and will hopefully define the role of
preoperative EBRT (https://clinicaltrials.gov/ct2/show/NCT01344018).
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Figure 34.11 A: CT-guided biopsy of a high-grade fibrosarcoma of the second metacarpal.
Custom immobilization device is shown in B: lateral view C: AP view. D: Coronal isodose plan for
3D CRT. E: Axial isodose plan.
In a dosimetric study, intensity-modulated photons (IMRT) were

superior to 3D conformal photons for RPS (139). Bossi et al. (140)
delivered preoperative IMRT (50 Gy) to a limited CTV encompassing the
posterior abdominal wall region at higher risk for relapse in patients
with retroperitoneal liposarcomas; at 27-month median follow-up, 2/18
patients so treated had an LR. Tzeng et al. (141) safely delivered dose-
painted, dose-escalated preoperative IMRT of 45 Gy to a standard risk
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volume and 57.5 Gy to the high-risk posterior RPS margin where
surgical margins were predicted to be positive; the actuarial risk of LR at
2 years was 20%. In an effort to further reduce LR, DeLaney et al. are
conducting a phase I/II study with IMRT and IMPT cohorts testing the
hypotheses that further dose escalation to this high-risk margin is
possible with advanced preoperative dose-painting radiation techniques;
although protons have a lower integral dose (up to ∼60% lower (142)),
conformal IMRT might also safely allow permit dose escalation
(https://clinicaltrials.gov/ct2/show/NCT01659203).
Management Guidelines
Given the rarity of RPS, most radiation, surgical, and medical oncologists
do not have extensive experience with treating it. Studies have shown
better outcomes for patients with sarcoma who are managed at centers
with experience (143). For this reason, multidisciplinary consultation at
high-volume sarcoma centers is recommended for patients with RPS.
Furthermore, both a surgical oncologist and radiation oncologist should
assess the patient at the time of diagnosis and prior to definitive
management. Consultation with a medical oncologist may also be
advisable, especially if the histology is high grade. It is ideal for
multimodality experts to assess the patient together, but multimodality
management conferences or tumor boards are another appropriate forum
in which to discuss management following individual consultations.
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Figure 34.12 Treatment set-up and plans for foot sarcoma. A: MRI images showing axials on top
and coronal and sagittal on bottom. B and C: Immobilization using a supportive ankle mold. D:
IMRT plan allowing for maximal sparing of uninvolved bone from high dose both pre- and
postoperatively.
Because level-one evidence for the use of RT for retroperitoneal

sarcoma is not available, treatment recommendations may be guided by
patient eligibility for ongoing clinical trials, including those mentioned
above, as well as practice guidelines such as those published by the
National Comprehensive Cancer Network. When preoperative radiation
is recommended, the patient must be deemed a surgical candidate, the
tumor must be resectable with intent for macroscopic complete
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resection, and there should be no symptoms requiring urgent immediate
resection, such as bowel obstruction. The patient must have localized
tumor and be judged a suitable candidate for RT to the prescription dose
of 50.4 Gy with acceptable toxicity (defined by the ability to meet
normal organ constraints).
For preoperative radiation planning/treatment, patients are
immobilized with arms elevated. 4D CT simulation is performed for
lesions above the pelvic brim where tumor motion may occur (144). For
RT planning, gross tumor volume (GTV) is defined by CT or MRI T1 plus
contrast images (126). If 4D CT showed GTV motion, an iGTV is defined
capturing motion. The average risk CTV1 is anatomically constrained 1-
to 1.5-cm expansion on the GTV or iGTV with edited reduction at bone,
renal, and hepatic interfaces (0 mm), bowel and air cavity (5 mm), and
skin (3 mm) (126). CTV1 is expanded fully into retroperitoneal muscles
but not beyond the peritoneal compartment or intact fascia. For RPS
extending into the thigh through inguinal canal, the inferior margin
would be 3 cm below the GTV and thigh radial margin would be 1.5 cm
(i.e., similar to extremity sarcoma), but not beyond the compartment,
intact fascia, or bone. There have been studies looking at radiation
exclusively to a high-risk posterior target volume (140) or as a dose–
escalated boost to that volume (140), to typically include tumor margin
along posterior retroperitoneal musculature, ipsilateral prevertebral
space, major vessels, or organs to be left in situ after surgery, including
∼1.5 cm of the GTV abutting the anticipated positive margin and
expanding 5 to 10 mm into the tissues at risk (2). Weekly cone-beam CT
scans demonstrated changes in tumor size and position over the course
of treatment and can be important for positional verification and
assessing the need for adaptive replanning (144).
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Figure 34.13 Axial (A) and coronal CT (B) scans of a patient with a dedifferentiated liposarcoma.
Figure 34.14 Axial (A) and coronal (B) images from postoperative CT scan on a patient with a
dedifferentiated liposarcoma, illustrating the problem of bowel falling into the anatomic region
previously occupied by tumor, and making postoperative radiation very difficult to deliver because
of the large volume of bowel that would be in the postoperative radiation fields.
Intraoperative radiation can be considered for a boost to the high-risk

retroperitoneal margin at the time of surgery (128–130). Postoperative
radiation may be added after intraoperative radiation has been given a
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patient who did not receive preoperative radiation, but in patients who
have not received intraoperative radiation, postoperative radiation if
often not feasible without exceeding bowel constraints and is not given
in many sarcoma centers. Figures 34.13 to 34.15 show images of a case
of retroperitoneal sarcoma and the use of preoperative radiation with
differential dose painting of standard clinical risk target volume and
high-risk target volume using IMRT and protons.
Figure 34.15 Standard clinical risk target volume (CTV1) and high-risk boost region (CTV2) in a
patient with undifferentiated pleomorphic sarcoma of the retroperitoneum receiving preoperative
radiation to 50.4 GyRBE to CTV1 and 57.4 GyRBE to CTV2 with scanned beam protons.
BONE SARCOMAS
Primary bone sarcomas are uncommon, with an estimated 2,970 new
cases in the United States in 2016 (2). Because these tumors are
relatively uncommon and present in a variety of anatomic locations,
most clinicians see these tumors infrequently. Because successful
treatment with good functional outcome may require specialized surgical
expertise including complex reconstructive techniques, aggressive
chemotherapy, and sophisticated radiation techniques, referral to centers
with experienced multidisciplinary sarcoma teams is the most
appropriate management strategy.
The common histologic subtypes in order of frequency include
osteosarcomas, chondrosarcomas, Ewing sarcoma, and chordoma.
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Chemotherapy is a critical component of all patients with Ewing
sarcoma and most patients with intermediate and high-grade
osteosarcomas. In contrast, chondrosarcomas and chordomas respond
poorly to chemotherapy, which is not commonly used as a component of
primary treatment. Surgery is the preferred treatment for the primary
site in the majority of patients and results in very high rates of local
control in patients with extremity tumors. In the case of primary
extremity osteosarcomas, for example, the rate of local control with
chemotherapy and surgical resection is over 90% (145). In contrast,
osteosarcoma lesions of the head and neck, spine, and pelvis, local
control with surgery and chemotherapy is less favorable. The local
recurrence rate for lesions in the pelvis was 70% in 67 patients reported
by the Cooperative Osteosarcoma Study Group, with recurrence
developing in 31 of 50 (62%) who underwent resection and 16 (94%) of
17 who did not (146). Of 22 patients with spinal osteosarcomas reported
by Ozaki et al. (147), 15 (68%) experienced local failure. For patients
with head and neck osteosarcoma, local control is achieved in
approximately 50% of patients, with the mandible the most favorable
site, followed by the maxilla and then extragnathic sites (zygoma, orbit,
nasoethmoid, and cranial bones) (148,149).
Radiotherapy can be useful in helping to secure local control in these
unfavorable sites, which include pelvis, sacrum, spine, and craniofacial
tumors (146,150). Radiation can be employed as neoadjuvant
(preoperative), adjuvant (postoperative or intraoperative), or primary
local therapy depending upon the site and type of tumor, the availability
and acceptability of the surgical option, and the efficacy of the
chemotherapy. Neoadjuvant (preoperative) radiotherapy can be
delivered prior to resection of spine (151) or pelvic sarcomas (152).
Adjuvant radiation is employed for patients with bone sarcomas with
positive or inadequate margins and in selected other situations that
might include presentation with a pathologic fracture (153), poor
histologic response to chemotherapy (154), or intralesional excision of
or intramedullary rod placement through a radiographically or
cytologically benign-appearing lesion later found to be sarcoma on
review of final pathologic material. Radiotherapy as the primary local
therapy without surgery is used for medically inoperable patients, for
patients with axial Ewing sarcomas or extremity Ewing sarcomas where
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surgery would compromise function (155), and for patients with primary
bone tumors involving the upper sacrum (37,156), portions of the pelvis,
the base of skull, and the ethmoid/sphenoid sinus region where
complete resection is either not technically possible or acceptable to the
patient (158,159).
Ewing sarcomas are quite radiation sensitive, and the original
description of this tumor by James Ewing made note of the fact that the
radiation sensitivity of this tumor was one of the features distinguishing
it from other bone sarcomas (160). Unresected tumors or gross residual
disease is usually treated with 55.8 Gy in association with chemotherapy
(155). Consideration of higher doses for high-risk bulky axial tumors
may be appropriate. Vertebral lesions, because of spinal cord constraints,
have often been treated to doses of 45 to 50 Gy. Microscopic residual
disease is usually treated to 50.4 Gy.
Chondrosarcomas and osteogenic sarcomas require doses of
approximately 66 Gy for control of microscopic residual disease and
doses of >70 Gy for control of gross residual disease (151). Because
most osteosarcomas are treated in conjunction with chemotherapy, the
MGH has managed patients (particularly younger patients) with
unresectable or gross residual osteosarcoma with induction
chemotherapy with using adriamycin, platinum, and methotrexate per
established protocols and then, after ∼12 weeks of chemotherapy,
deliver radiation of 72 Gy in 40 fractions of 1.8 Gy daily via shrinking
field technique concurrent with chemotherapy, generally
ifosfamide/etoposide (150). Chondrosarcomas in patients with gross
disease have been generally managed with 70 to 77.4 Gy at 1.8 to 2 Gy
tissues (151). Chordomas require doses of ∼70 Gy for microscopic
residual disease and doses of >75 Gy for control of gross residual
disease (151).
Chapter 19 provides additional discussion of the use of protons for
osteosarcomas, chondrosarcomas, Ewing sarcoma, and chordoma, and
the readers are referred to that chapter for these clinical results. Some
additional important experience with photons includes that from The
Princess Margaret Hospital and colleagues in Toronto who reported on
60 patients who underwent surgery and photons for extracranial high-
risk CS (161). Preoperative RT (median dose 50 Gy) and postoperative
RT (median dose 60 Gy) were used in 40% and 60% of the patients,
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respectively. Sites included pelvis/lower extremity (48%), chest wall
(22%), spine/paraspinal (17%), and head and neck (13%). Median
follow-up was 75 months. The crude local control rate was 90%. Patients
with R0, R1, and R2 resections had local control rates of 100%, 94%,
and 42%, respectively.
SBRT FOR SARCOMAS

The most common sites of metastasis for most soft tissue and bone
sarcomas are the lungs, followed by bone and soft tissue. Although
pulmonary metastatic disease is generally incurable, lung
metastasectomy in patients with lung metastases has shown a not-
insignificant percentage of patients surviving long-term (7% to 18%) and
3-year oversurvival ranging from 23% to 71% (19,162–172). However,
not all patients are medically operable; reports of pulmonary
metastasectomy found that up to 1/3 of patients were not surgical
candidates. Recently SBRT has been shown to be a feasible and effective
option for local control. This topic is addressed in more detail elsewhere
in the book but we will briefly describe the key studies related to
sarcomas. A study of 50 patients with five or fewer lung metastases
including sarcomas treated to 50 Gy in 5 Gy per fraction found 83%
local control of treated lesions with 2% grade 3 toxicity (173). The first
study of SBRT for PM from STS primary reported high local lesion
control of 97% at 3 years for 67/69 patients who received 50 Gy in 10
fractions (BED 2 Gy = 62.5). None had grade ≥3 toxicity with median
survival of 2.1 years (0.8 to 11.5 years) with SBRT versus 0.6 years
without SBRT (P = 0.002) (174). Another study using SBRT of 54 Gy in
3 to 4 fractions in 16 high-grade sarcoma patients found 94% local
control at 43 months without any radiation pneumonitis or esophagitis
to be safe and effective in pulmonary metastases in soft tissue sarcoma
(175). Other studies since have found SBRT to be safe and effective for
pulmonary metastases from both bone and soft tissue sarcomas
(176–178). SBRT therefore should be considered among the options
available for sarcoma patients with pulmonary lung metastases (Fig.
34.17).
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Figure 34.17 SBRT plan 50 Gy in 10 Gy per fraction × 5 fractions for a patient with a solitary lung
metastasis who had recurred after bilateral pulmonary metastasectomy and deemed not to be a
candidate for reoperation.
KEY POINTS
• Soft tissue and bone sarcomas are rare malignancies that can
arise from connective tissue throughout the body. Proper
assessment and management by experienced centers are
associated with optimal outcomes.
• Adjuvant radiotherapy either as preoperative RT or postoperative
RT combined with wide surgical excision leads to high local control
rate with good functional outcomes in truncal and extremity soft
tissue sarcoma.
• Optimal treatment of truncal and extremity soft tissue sarcoma
require careful assessment of the feasibility of limb salvage, the
planned surgical approach, the role and sequencing of adjuvant RT,
and potential acute and late effects.
• The use of customized immobilization, advanced imaging and
consensus atlas for target volume definition, and image guidance in
RT delivery can reduce the RT field. A recent trial showed that
these modern techniques of preoperative RT is associated with
decreased late effects.
• For retroperitoneal sarcoma, preoperative RT is the preferred
approach in combination with resection because of high recurrence
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rate with surgery alone. Simultaneous integrated boost is a strategy
to escalate the dose to the high-risk retroperitoneal margin.
• For bone sarcomas, advanced techniques such as protons allow
adequate dose to be achieved for high local control.
• Stereotactic radiotherapy can offer an ablative, nonsurgical option
for the management of oligometastases from bone and soft tissue
sarcoma.
QUESTIONS
1. What bone constraints have been found to be significantly
associated with reduced risk of fractures after adjuvant RT for
extremity soft tissue sarcomas near or abutting long bones?
A. Mean bone dose <45 Gy
B. V40 <64%
C. Max dose <70
D. V50 <30%
2. What PTV is recommended when IGRT is not used?
A. 3 mm
B. 5 mm
C. 10 mm or more
D. 0 mm
3. Preoperative RT compared to postoperative RT for extremity
sarcoma is associated with:
A. Higher rate of fibrosis, joint stiffness, and edema
B. Higher rate of acute wound complications
C. Lower rate of fibrosis, joint stiffness and edema
D. Both B and C
4. For interstitial brachytherapy in soft tissue sarcoma, implant
loading is most optimal for reducing wound necrosis:
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A. >5 days after catheter placement
B. Intraoperatively
C. One day postoperatively
D. There is no limitation
5. When radiation therapy is employed for retroperitoneal sarcoma,
the preferred approach is:
A. Brachytherapy
B. SBRT
C. Preoperative radiation
D. Postoperative radiation
ANSWERS
1. B
2. C
3. D
4. A
5. C
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Ewing. Proceedings of the New York Pathological Society, 1921. CA
Cancer J Clin. 1972;22(2):95–98.
161. Goda JS, Ferguson PC, O’Sullivan B, et al. High-risk extracranial
chondrosarcoma: Long-term results of surgery and radiation
therapy. Cancer. 2011;117:2513–2519.
162. Toussi MS, Bagheri R, Dayani M, et al. Pulmonary metastasectomy
and repeat metastasectomy for soft-tissue sarcoma. Asian Cardiovasc
Thorac Ann. 2013;21(4):437–442.
163. Rehders A, Hosch SB, Scheunemann P, et al. Benefit of surgical
treatment of lung metastasis in soft tissue sarcoma. Arch Surg.
2007;142(1):70–75; discussion 76.
164. Liebl LS, Elson F, Quaas A, et al. Value of repeat resection for
survival in pulmonary metastases from soft tissue sarcoma.
Anticancer Res. 2007;27(4C):2897–2902.
165. Pfannschmidt J, Klode J, Muley T, et al. Pulmonary metastasectomy
in patients with soft tissue sarcomas: experiences in 50 patients.
Thorac Cardiovasc Surg. 2006;54(7):489–492.
166. Weiser MR, Downey RJ, Leung DH, et al. Repeat resection of
pulmonary metastases in patients with soft-tissue sarcoma. J Am Coll
Surg. 2000;191(2):184–190; discussion 190–191.
167. Billingsley KG, Lewis JJ, Leung DH, et al. Multifactorial analysis of
the survival of patients with distant metastasis arising from primary
extremity sarcoma. Cancer. 1999;85(2):389–395.
168. Billingsley KG, Burt ME, Jara E, et al. Pulmonary metastases from
soft tissue sarcoma: analysis of patterns of diseases and
postmetastasis survival. Ann Surg. 1999;229(5):602–610; discussion
610–612.
169. Temeck BK, Wexler LH, Steinberg SM, et al. Reoperative pulmonary
metastasectomy for sarcomatous pediatric histologies. Ann Thorac
Surg. 1998;66(3):908–912; discussion 913.
170. van Geel AN, Pastorino U, Jauch KW, et al. Surgical treatment of
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lung metastases: The European Organization for Research and
Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of
255 patients. Cancer. 1996;77(4):675–682.
171. Pogrebniak HW, Pass HI. Initial and reoperative pulmonary
metastasectomy: indications, technique, and results. Semin Surg
Oncol. 1993;9(2):142–149.
172. Johnston MR. Median sternotomy for resection of pulmonary
metastases. J Thorac Cardiovasc Surg. 1983;85(4):516–522.
173. Okunieff P, Petersen AL, Philip A, et al. Stereotactic Body Radiation
Therapy (SBRT) for lung metastases. Acta Oncol. 2006;45(7):808–
817.
174. Dhakal S, Corbin KS, Milano MT, et al. Stereotactic body
radiotherapy for pulmonary metastases from soft-tissue sarcomas:
excellent local lesion control and improved patient survival. Int J
175. Mehta N, Selch M, Wang PC, et al. Safety and efficacy of
stereotactic body radiation therapy in the treatment of pulmonary
metastases from high grade sarcoma. Sarcoma. 2013;2013:360214.
176. Brown LC, Lester RA, Grams MP, et al. Stereotactic body
radiotherapy for metastatic and recurrent ewing sarcoma and
osteosarcoma. Sarcoma. 2014;2014:418270.
177. Frakulli R, Salvi F, Balestrini D, et al. Stereotactic radiotherapy in
the treatment of lung metastases from bone and soft-tissue
sarcomas. Anticancer Res. 2015;35(10):5581–5586.
178. Navarria P, Ascolese AM, Cozzi L, et al. Stereotactic body radiation
therapy for lung metastases from soft tissue sarcoma. Eur J Cancer.
2015;51(5):668–674.
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Index
Note: Page numbers followed by f indicate figures; those followed

by t indicate tables.
A
AAPM. See American Association of Physicists in Medicine (AAPM)
AAPM Report 23, 309
AAPM Report 39, 41
AAPM Task Group 25, 291, 294
AAPM Task Group 70, 309
AAPM TG-43 formalism, 247–248, 248f, 471
Abdomen, 500f, 501
radiation-induced toxicity of, 371
ABS. See American Brachytherapy Society (ABS)
ABS Guidelines Definitive Radiation Therapy
for cervical cancer HDR intracavitary brachytherapy, 441t
for cervical cancer LDR intracavitary brachytherapy, 440t
Abscopal effect, 358
Absolute dosimetry
in scanned proton fields, 321
in scattered proton fields, 319–320
Accelerated fractionation, 346–347
Accelerated hyperfractionation, 347
Accelerated partial breast irradiation (APBI)
patient selection for, 562
treatment planning for, 562–563
Accelerator-mounted imaging systems, 7–8
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Acceptance testing
for IMRT, 105
process proposed IAEA, 105–106
in quality assurance, 41, 103, 105–106
ACOSOG Z0011 study, 556–557
Active breathing control (ABC) system, 173
components of, 173f
Acuros XB implementation of BTE, 55–56, 56f, 57f
Acute esophagitis, 370
Acute leukemia, 576–577
Acute lymphocytic leukemia (ALL), 593
ADEPT, 517
ADEPT trial, 517
Adjuvant radiation therapy (ART), for prostate cancer, 467–468
ADT. See Androgen deprivation therapy (ADT)
Adult medulloblastoma craniospinal irradiation, 333
Air gap factor method, 296
AJCC TNM staging system
for bladder cancer, 480t
for testicular cancer, 487t
Algorithms, for treatment planning, 100–101
brachytherapy, 61–74
calculation, 101
clinical application of, 102–103
computer programs for, 101, 102t
development and implementation, 101–103
IAEA TRS-430 questionnaire, 102t
photon dose calculations, 46–57
conditions of charged particle equilibrium, 49
discrete ordinates method, 54–57
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
Monte Carlo (MC) technique, 53–54
patient representation in, 46–47
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
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superposition/convolution, 49–52
radiation database for, 101–102
radiation therapy process and, 99f
ALL. See Acute lymphocytic leukemia (ALL)
American Association of Physicists in Medicine (AAPM), 9, 66, 98, 247,
249
American Brachytherapy Society (ABS), 251, 439
guidelines interstitial HDR brachytherapy for gynecologic cancer,
445t
American College of Surgeons Oncology Group (ACOSOG), 638
American Society for Radiation Oncology (ASTRO), 9
recommendations regarding proton beam therapy, 332
Anal cancer, 413–418
chemotherapy for, 418
diagnostic evaluation of, 413
treatment options for, 413
normal tissue tolerances in, 415–416
radiotherapy dose, 416
radiotherapy fields and techniques, 416, 418
radiotherapy target in, 414–415
simulation, 413–414
Analog simulations, 53
Anaplastic thyroid cancer (ATC), 518, 518f
Androgen deprivation therapy (ADT)
for prostate cancer, 457–458
Angular density of electrons, 54
APBI. See Accelerated partial breast irradiation (APBI)
Aperture generation methods, 139
Applicators
for cervical cancer intracavitary insertions, 281f
electron, 291, 291f
in HDR brachytherapy, 260
for orthovoltage unit, 529, 529f
Arc therapy for IMRT, 141–143
VMAT plan optimization, approaches to, 143
VMAT treatment planning problem, 141–143
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Artifacts
of CT, 14
light breathing, 15f
temporal aliasing, 14, 15f
MRI, 17
ASTRO. See American Society for Radiation Oncology (ASTRO)
Astrocytoma
high-grade, 590
low-grade, 589–590
ATC. See Anaplastic thyroid cancer (ATC)
ATRT. See Atypical teratoid rhabdoid tumors (ATRT)
Attenuator (compensator), cross-sectional schematic of, 530f
Attila, 55
Atypical teratoid rhabdoid tumors (ATRT), 587
Automated image registration, 22–23, 23f
Automated image segmentation, of multiple repeat CT data set, 189f
Axial computed tomography image
from IMRT plan, 465f
of seminal vesicles, 462f
Axillary region, 498f
B
BAO. See Beam angle optimization (BAO)
Basal cell carcinomas, 534–536, 545f
Beam angle optimization (BAO), 145–146
Beam modeling, 152–153
Beam shaping, 134–135
Beamlets, 124
Beam’s eye views (BEV), 21–22
image of thoracic tumor, 22f
BED. See Biological equivalent dose (BED)
Benign, 333
Bethe–Bloch equation, 150
BEV. See Beam’s eye views (BEV)
Biochemical failure, 381
Biochemical relapse-free survival (bRFS), 468
Biological equivalent dose (BED), 380
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basic fallacies of, 368
caution of, 368
dose/fractionation, 368
in high dose-rate brachytherapy, 263–264
prostate, 468–469
dose fractionation, 468–469
target volume definition, 468
treatment technique, 469
Biologically effective dose (BED) model, 347–349
Bixels, 124
Bladder, radiation-induced toxicity of, 371–372
Bladder cancer
bladder-sparing approaches, 481–482. See also Prostate cancer
diagnosis of, 479–480
nonbladder sparing treatment approaches for, 481
overview, 479
postoperative radiotherapy for, 483
prognosis of, 483–484
risk stratification in, 479
RTOG protocols for invasive, 482t
staging in, 479–480, 480t
Bladder cancer (continued)
survival rate after radical cystectomy for, 482t
treatment options for, 480–482
bladder field, 482–483
tumor boost, 483
whole bladder field in, 482–483, 483f
Blood-oxygen-level dependent (BOLD) effect, 573
Boltzmann transport equations (BTEs), 54–55
Acuros XB implementation of, 55–56
Boltzmann–Fokker–Planck transport equation, 56
Bolus, 300–301
Bone Sarcomas, 640
BP. See Bragg peak (BP)
Brachial plexopathy, 370
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Brachial plexus, radiation-induced toxicity of, 370
Brachytherapy, 632–633
Boltzmann transport technique in, 71–73, 73f
defined, 244
dose distributions
asymmetric, 68–69, 69f
three-dimensional, 69–71, 70f, 71f
dose rate calculation
around encapsulated cylindrical source, 65–66, 65f
around line source, 64–65, 65f
around point source, 62–64, 62f, 63f
Boltzmann transport technique, 71–73, 73f
future directions in, 73–74
Monte Carlo transport technique, 71–73, 73f
three-dimensional, 68–69, 69–71, 69f, 70f, 71f
two-dimensional formalism, 66–68
electronic, 533, 534f
encapsulation in low energy problem and, 66
endobronchial, 608
equipment, 6
in gynecologic cancers, 438–445
interstitial, 443–445
intracavitary, 438–443
low-dose rate. See Low-dose rate (LDR) brachytherapy
Monte Carlo transport technique in, 71–73
for prostate cancer, 458
quality assurance of, 111–112
radial dose function, 67
radioisotope, 533
for skin cancer, 533
sources, 245
three-dimensional treatment planning, 69–71
treatment planning algorithms in, 61–74
Bragg peak (BP), 88, 150, 151, 152, 207, 326, 608
protons, 327f
Brain
anatomy of, 569
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radiation necrosis of, 368
Brain metastases, 577
Brainstem
dose-volume histograms of, 324f
Breast
anatomy of, 550–553, 551f
blood supply in, 552f
conservation, 554
Breast cancer, 335
breast anatomy, 550–553, 551f
blood vessels, 550, 552f
lymphatic drainage, 550–553, 552f
clinical presentation of, 553–554
dose and fractionation
breast conservation, 561–562
mastectomy scar boost, 562
postmastectomy, 562
tumor bed boost, 562
epidemiology of, 553
helical tomotherapy for, 561
histologic subtypes of, 553–554
IBC, 554
IMRT for, 561
noninvasive, 553
overview, 550
partial breast irradiation
patient selection
for breast conservation, 554
for omission of radiotherapy, 554
for postmastectomy, 554
simulation for, 554–556
breathhold, 555–556, 556f
postmastectomy, 555
prone, 555
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supine intact breast, 555
treatment planning for
breast conservation, 556–557
chest wall, tangent fields for, 557, 558f
dose modulation, 559, 561
intact breast, tangent fields for, 557, 558f
internal mammary nodal coverage, 558f, 559
nodal targets, inclusion of, 557, 558f
normal tissue dose constraints, 561
posterior axillary field, 559
postmastectomy, 557
supraclavicular/axillary field, 559, 560f
three-field dual isocenter, 558f, 559
three-field single isocenter, 557, 558f, 559
treatment imaging, 561
volume modulated arc therapy (VMAT) for, 561
Breast conservation
dose and fractionation, 561–562
Breast implant, differential dose-volume histogram for, 276f
Breast setup, in-house simulation, 33f
Breathing movement, 172–173
Bremsstrahlung, 47
production, 289
splitting, 53
bRFS. See Biochemical relapse-free survival (bRFS)
BTEs. See Boltzmann transport equations (BTEs)
C
California Endocurietherapy Center (CEC), 445
Cancers
anal, 413–418
bladder, 479–484
cervical, 426–427
colorectal, 408–413
esophageal, 397–401
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gastric, 401–404
head and neck, 509–525
ovarian, 428–429
pancreatic, 404–408
prostate, 123f, 453–473
skin, 527–546
survival curves for, 341f, 344f
testicular, 486–491
thyroid, 518
uterine, 427–428
vaginal, 429–430
vulvar, 429
Carbon ions therapy, 6, 327–328
CBCT. See Cone-beam computed tomography (CBCT)
CBCT image quality, limitations of, 180
CEC. See California Endocurietherapy Center (CEC)
Cell survival models, 379–382, 380f
Central nervous system, radiation-induced toxicity of, 368–369
brain, 368
brainstem, 368
chiasm and optic nerves, 369
spinal cord, 368–369
Central nervous system tumors
adult medulloblastoma craniospinal irradiation, 333
craniospinal irradiation, 577–580
diffusion tensor imaging, 573
dosimetric margins in, 573
embryonal tumors, 586–587, 588f
ependymomas, 581–582
general management of, 571–572
high-grade gliomas in, 581
high-resolution CT scan for, 572
immobilization in, 576
IMRT for, 575
intracranial meningioma, 333
low-grade gliomas in, 580–581
magnetic resonance spectroscopy for, 573
booksmedicos.org
medical therapy for, 571–572
meningiomas, 581
metastatic, epidemiology of, 569, 571
MRI for, 572–573
multimodality imaging in, 572–575
partial brain radiation in, 580
PBT for, 333
benign, 333
pituitary tumors, 581
positioning in, 575–576
primary, epidemiology of, 569
proton therapy for, 575
simulation, 576, 580
spinal tumors, 582
staging of, 571
surgical therapy for, 572
treatment planning for, 580
volume definition, 573
WHO grades of, 569, 570t
whole brain radiation therapy in, 576–580
workup for, 571
Central ray
difference profiles, 108f–109f
doses along, 109f
percentage depth doses, 107f
Cervical cancer. See also Breast cancer
ABS guidelines interstitial HDR brachytherapy for, 445t
interstitial HDR brachytherapy guidelines for, 445t
midline blocks used in patients with, 432f
PET-guided brachytherapy planning for, 443, 443f
radiotherapeutic management of, 426–427
tandem and ovoid applicator used for, 438, 438f
Charged particle equilibrium (CPE), 49
Charged-particle beams, 5–6
carbon ion, 6
electrons beams, 5–6
proton beam, 6
booksmedicos.org
CHART. See Continuous hyperfractionated accelerated radiotherapy
(CHART)
CHARTWEL, 347
Chemotherapy
for anal cancer, 418
for colorectal cancer, 412
for gastric cancer, 404
for testicular cancer, 488
Chiasm and optic nerves, radiation-induced toxicity of, 369
Children’s Oncology Group (COG), 585
Child–Turcotte–Pugh (CTP) Class, 237
Chondrosarcoma, 333–334, 642
Chordomas, 334
CI. See Coverage index (CI)
Cisplatin-based chemotherapy, for cochlea, 369
Clinical proton field, 96
Clinical target volume (CTV)
in central nervous system tumors, 573
defined, 3
dumbbell-shaped, 461f
example of double-scattered field delivery, 323f
in HDR, 264
problem of geometric variation and, 168
in prostate, 458–460, 461f
in seminal vesicles, 460
in thorax cancers, 601
uncertainty of, 3–4
CN. See Conformation number (CN)
Cochlea, radiation damage to, 369
COG. See Children’s Oncology Group (COG)
Collimator scatter, 48
Collimators
circular, 529f
multi-leaf, 134–135, 135f
Colorectal cancer, 408–413
diagnostic evaluation, 408–409
booksmedicos.org
prognosis of, 413
radiotherapy fields and techniques for, 411–412
normal tissue tolerances in, 411
radiotherapy target in, 410
Commissioning, 103. See also Quality assurance (QA)
defined, 98
in IGRT, 187–188
in QA, 103, 106–111
automated and knowledge-based planning, 110
autosegmentation, 111
image registration, 110–111
IMRT, 109–110
of other components, 107t
photon beams, 106–109, 107f, 107t, 108f, 109f
for SBRT, 233–234
for skin cancer, 528
Compton scatter, 47–48
Computed tomography angiography (CTA), 208–209
Computed tomography (CT), 12–16, 209–213
acquisition for treatment planning, 13–14
acquisition modes, 14
artifacts of, 14
light breathing, 15f
temporal aliasing, 14, 15f
for brain patient, 37f
cone-beam, 16
fiducial rod system, 209–210, 209f
four-dimensional (4D) CT scanning, 15–16
gantry tilt, 210f
of human abdomen, 14f
image, breast patient, 32f
imaging moving anatomy, 14–15
linear attenuation coefficient, 12
booksmedicos.org
phantoms, 210–211, 212f, 213
scan for masked-based system, 210, 211f
tables, 210
volumetric imaging in treatment room, 16
Winston–Lutz phantom and, 212f
Computed tomography simulator
defined, 7
for treatment planning, 7
virtual simulation and, 7
Condensed history electron transport technique, 53
Cone beam CT, 573
Cone-beam computed tomography (CBCT), 16
Conformation number (CN), 278
Contamination electrons, 49
Continuous hyperfractionated accelerated radiotherapy (CHART), 347
Contour irregularity, in pencil beam models, 81
Conventional fractionation, 346
Convolution/superposition method, 49–50, 50f
Cooper ligaments, 550
Cord/brainstem buffer, 523f
Coulomb scattering, 288–289
Coverage index (CI), 277
CPE. See Charged particle equilibrium (CPE)
Craniopharyngioma, 591–595
Craniospinal irradiation, 577–580
CT. See Computed tomography (CT)
CT scanners, for treatment planning, 7
CT simulation
defined, 29
immobilization devices and, 32, 35f
process, 32–34
CTA. See Computed tomography angiography (CTA)
CT-compatible testicular shield, 500f
CTLA-4. See Cytotoxic T-lymphocyte-associated antigen (CTLA-4)
CT-simulator, 7, 41
wide bore, 34f
CTV. See Clinical target volume (CTV)
booksmedicos.org
Cu-ATSM, 19
Cutaneous melanoma, skin cancer, 536
CyberKnife™ system, 183–184, 184f
Cytotoxic T-lymphocyte-associated antigen (CTLA-4), 358
D
4D computed tomography imaging, 32, 181–182
respiration-correlated 4D CBCT, 182
respiration-correlated 4DCT, 181–182
3D conformal radiation therapy (CRT), 8
2D photons, 329
3D photons, 329
2D radiographic imaging, 178–179
3D tomographic imaging, 179–181
digital tomosynthesis, 181
hybrid cone-beam CT, 181
kV cone-beam CT, 179–180
kV helical CT, 179–180
MV cone-beam CT, 180–181
MV helical CT, 180–181
DAO. See Direct aperture optimization (DAO)
DCIS. See Ductal in situ carcinoma (DCIS)
Dedifferentiated liposarcoma, 640f
Deformable image registration (DIR), 23–24
in IGRT, 188
Delta rays, 48
Depth-dose distribution
central axis, 80
Depth-dose electron beams, 6
DET. See Distal edge tracking (DET)
Deterministic approaches, to optimization, 265–268
convergent searches, 266
heuristic approaches, 265–266
point-dose optimization, 266–267
polynomial optimization, 267–268
DICOM. See Digital Imaging and Communications in Medicine
(DICOM)
booksmedicos.org
Diffuse infiltrating pontine gliomas (DIPG), 590
Diffuse large B-cell lymphoma (DLBCL), 494–495, 496
Diffusion tensor imaging (DTI), 17
Digital Imaging and Communications in Medicine (DICOM)
in IGRT, 189
Digital tomosynthesis (DTS), 181
Digitally reconstructed radiographs (DRRs), 21–22
beam’s eye views and, 21–22
images, 463f
DIPG. See Diffuse infiltrating pontine gliomas (DIPG)
DIR. See Deformable image registration (DIR)
Direct aperture optimization (DAO) methods, 124, 137–141
aperture generation methods, 139
approximate dose calculation, 140
FMO + sequencing approach, limitations of, 137–138
gradient-based leaf position optimization, 139–140
local leaf position optimization, 139–141
optimize leaf positions, 140–141, 140f
for step-and-shoot IMRT, 138–139
stochastic search methods, 139
Discrete ordinates method, 54–57
Acuros XB implementation of BTE, 55–56
photon beam calculations, transport equations for, 55
transport equations, derivation of, 54–55
Distal edge tracking (DET), 162
Distance optimization, in HDR brachytherapy, 266
DLA. See Dose limiting annulus (DLA)
DLBCL. See Diffuse large B-cell lymphoma (DLBCL)
DMLC. See Dynamic multileaf collimator (DMLC)
DNR. See Dose nonuniformity ratio (DNR)
Dose calculations, 153–155
engine, 152
Monte Carlo method, 154–155
primary dose, 152, 155f
quality assurance in, 101
secondary dose, 152–153, 155f
Dose distributions
booksmedicos.org
asymmetric, 68–69, 69f
three-dimensional, 69–71, 70f, 71f
Dose index, 279
Dose limiting annulus (DLA), 522f
Dose nonuniformity ratio (DNR), 277
Dose planning, radiosurgery, 214–216, 215f, 216f
Dose rate calculation, in brachytherapy
around encapsulated cylindrical source, 65–66, 65f
around line source, 64–65, 65f
around point source, 62–64, 62f, 63f
Boltzmann transport technique, 71–73, 73f
future directions in, 73–74
Monte Carlo transport technique, 71–73, 73f
three-dimensional, 68–69, 69–71, 69f, 70f, 71f
two-dimensional formalism, 66–68
Dose-deposition matrix, 125
Dose–volume effects, 129–130
dose–volume histogram, 130
equivalent uniform dose (EUD), 129–130
Dose–volume histograms (DVH), 130, 377, 378–382
and cell survival models, 380–382, 380f
constraints for OAR, 462t
for HDR brachytherapy, 275–276, 275f, 276f
for HDR prostate implant, 275f
for head and neck (H&N) cancers, 520t, 521t
ideal target, 378–379, 379f
for mandible, 380f
for normal organ (parotid), 379f
for parotid glands and brainstem, 324f
for PTV, 381–382, 382f
Dosimetrists, 10
Dosimetry checks, 114–115
Double scattering, in scattered proton fields, 317–319
DRRs. See Digitally reconstructed radiographs (DRRs)
DTI. See Diffusion tensor imaging (DTI)
DTS. See Digital tomosynthesis (DTS)
booksmedicos.org
Ductal in situ carcinoma (DCIS), 553
DVH. See Dose–volume histograms (DVH)
Dwell positions
around point, 266f
in HDR brachytherapy, 283–284
simulate line source, 284f
Dwell times, 259
Dwell weights, 259
Dynamic delivery, IMRT, 137, 137f
Dynamic multileaf collimator (DMLC), 186–187
E
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 554
Eastern Cooperative Oncology Group (ECOG), 517
EBCTCG. See Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG)
EBRT. See External-beam radiation therapy (EBRT)
Eclipse Electron Monte Carlo, 292
ECOG. See Eastern Cooperative Oncology Group (ECOG)
ECOMP. See Electronic tissue compensation (ECOMP)
Effective point source, 295
vs. virtual point source, 295–296
EFRT. See Extended field radiotherapy (EFRT)
EI. See External volume index (EI)
Elective nodal irradiation (ENI), 603
Electromagnetic field tracking system, 185f
Electron arc therapy, for skin cancer, 532–533
dwell factor for, 533
electron beam geometry and setup, 532
monitor unit for, 532–533
Electron beam radiotherapy
basic physics and properties of, 288–296
air gap factor, 296
effective point source, 295, 296
field shaping, 290–295, 291f
isodose distributions, 290, 290f, 291f, 292f
percent depth dose, 289–290, 289f, 293f
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shielding, 290–295
virtual point source, 295, 296
bolus in, 300–301
calibration and monitor units in, 301–302
central axis percentage depth-dose, change in, 290–295
with change in beam energy, 296–298, 297f, 298f
with change in field size, 292–294, 293f, 294f
with change in SSD, 294–295, 295f
electron arc therapy, 309
electron dose prescription in, 302
electron–electron field junctions for, 304–306, 305f, 306f, 307f
energy mixing in, 309
en-face beams, 302–303
future, 310
heterogeneities and, 299–300, 299f
in irregular fields, 296
mixing with photon beams
monitor unit verification, 309
total skin electron irradiation, 309
overview, 288
photon–electron field junctions for, 306–308, 308f
skin collimation in, 303–304, 304f
on sloping surface, 296–298, 297f, 298f
surface irregularities and, 298–299, 298f
total limb irradiation in, 309
Electron beams, 5–6
block, 532t
commissioning of, 111
range of depth of 90% isodose lines of, 513t
for skin cancer, 530–531, 530f, 531t
Electron contamination, 52
Electron dose calculations, sample criteria of acceptability for, 104t
Electron Gamma Shower (EGS4) code, 53
Electron transport, 48–49
Electron Transport (ETRAN) code, 53
Electronic brachytherapy, 533, 534f
booksmedicos.org
Electronic portal imaging devices (EPIDs), 8, 169, 178
in CNS tumor, 573
in MV CBCT, 180–181
Electronic tissue compensation (ECOMP), 561
Elekta Synergy™ unit, 180f
Embryonal tumors of CNS, 586–587, 588f
Emission tomography, 18–19
PET in radiation planning, 18–19
PET/CT scanners, 19
Endobronchial brachytherapy, 608
Energy layer, 152
Energy loss, in IMPT, 150–151
En-face beams, 302–303
ENI. See Elective nodal irradiation (ENI)
EORTC 10981-22023 AMAROS trial, 557
EORTC-GELA group, 498
Ependymomas, 333, 581–582, 587–589
EPIDs. See Electronic portal imaging devices (EPIDs)
EQD2. See Equivalent dose in 2-Gy fractions (EQD2)
Equieffective dose, 381
Equipments, for treatment planning, 5–10
accelerator-mounted imaging systems, 7–8
computers, 8
external beam units, 5–6
charged-particle beams, 5–6
x-ray beams, 5
patient load vs. treatment units, 6–7
brachytherapy equipment, 6
imaging equipment, 6
PET/CT, 7
simulator, 7
Equivalent dose in 2-Gy fractions (EQD2), 381–382, 382f
Equivalent uniform dose (EUD), 129–130, 385–386
ERD. See Extrapolated response dose (ERD)
Erectile dysfunction, 372
Esophageal cancer, 335, 397–401
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prognosis of, 401
radiotherapy fields and techniques for, 401
treatment planning of, 398–400
CT-based, 399
PET imaging, 399–400
radiotherapy dose in, 400
radiotherapy target, 398–399
simulation, 398
Esophageal tumors, 399
Esophagus, radiation-induced toxicity of, 370
ESTRO. See European Society for Therapeutic Radiology and Oncology
(ESTRO)
EUD. See Equivalent uniform dose (EUD)
Euler angles, 70
European Society for Therapeutic Radiology and Oncology (ESTRO),
249
Ewing’s sarcoma, 333, 594, 641
Exit beam, 531–532
Extended field radiotherapy (EFRT), 434–436
External beam dose calculation algorithm, 102t
External beam units, 5–6
charged-particle beams, 5–6
x-ray beams, 5
low-energy megavoltage, 5
medium- or high-energy megavoltage, 5
External volume index (EI), 278
External-beam radiation therapy (EBRT)
for gynecologic cancers, 430–438
for prostate cancer, 457
Extrafocal radiation, 48
Extranodal lymphomas, 498–499
Extranodal marginal zone lymphoma, 497
Extrapolated response dose (ERD), 348
Eye shields, 291
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F
Failure mode and effects analysis (FMEA), 113
Fault tree analysis (FTA), 113
FDG. See Fluorodeoxyglucose (FDG)
Femoral head, radiation-induced toxicity of, 372
Fermi–Eyges multiple scattering theory, in pencil beam models, 78–80
Fiducial rod system, 209–210, 209f
Field of view (FOV), 14
Field-shaping devices, 319
Figures of merit, HDR treatment planning, 276–278
conformity number, 278
dose outside target, 278
dose uniformity, 277
target coverage, 276–277
Five-fraction thoracic stereotactic body irradiation, guidelines in, 372t
FLAIR, 573
Fletcher–Suit–Delclos device, 438
Fluence map, for IMRT, 124–125, 125f
aperture decomposition of, 135–136, 135f
Fluorodeoxyglucose (FDG), 7
Fluoroscopic imaging, with implant fiducials, 183–184
FMEA. See Failure mode and effects analysis (FMEA)
fMRI. See Functional MRI (fMRI)
Follicular lymphoma, 497
Four-dimensional (4D) CT scanning, 15–16
FOV. See Field of view (FOV)
Fractionation, 227, 340–352
accelerated, 346–347
accelerated hyperfractionation, 347
BED model for, 347–349
cell survival curves, 340–341
conventional, 346
with dose per fraction, 342f
hyperfractionation, 346
hypofractionation, 347
linear quadratic theory, 340–341, 341f
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LQ model in clinical practice, 349–352
overview, 340
rationale for, 341–346
redistribution, 345–346
reoxygenation and oxygen effect, 343–344
repair, 342–343
repopulation, 344–345, 344f, 345f
schemes with typical parameters, 346t
strategies, 346–347
in testicular cancer, 490
FSaII fibrosarcoma tumor, radiation survival curves of, 357f
FTA. See Fault tree analysis (FTA)
Functional MRI (fMRI), 17, 18f
G
Gamma rays, PET and, 18
GammaKnife, 205, 205f, 206, 221, 222
Gantry angles, in SBRT, 230t
Gastric cancer, 401–404
diagnostic evaluation, 402
prognosis in, 404
radiotherapy fields and techniques in, 403–404
CT-based, 402
PET imaging, 402
radiotherapy dose in, 403–404
radiotherapy target, 403
Gastrointestinal tract cancer
anal cancer, 413–418
diagnostic evaluation of, 413
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normal tissue tolerances in, 415–416
colorectal cancer, 408–413
prognosis of, 413
radiotherapy fields and techniques for, 411–412
esophageal cancer, 397–401
prognosis of, 401
radiotherapy fields and techniques for, 401
gastric cancer, 401–404
diagnostic evaluation, 402
prognosis in, 404
overview, 397
pancreatic cancer, 404–408
diagnostic evaluation of, 404–405
prognosis of, 408
Gating, 32
Gaussian pencil-beam model, 92, 94–95
Gaussian proton pencil-beam model, 91–96
Gaussian spread, 90–91, 91f
GBBS. See Grid-based Boltzmann solvers (GBBS)
GBD. See Golden beam data (GBD)
GCIG. See Gynecologic Cancer Intergroup (GCIG)
GEC-ESTRO. See Group Européen de Curiethérapie-European Society
booksmedicos.org
for Therapeutic Radiology and Oncology (GEC-ESTRO)
Genitourinary tract cancer
bladder cancer, 479–484
prostate cancer, 453–473
testicular cancer, 486–491
Geometric optimization, in HDR brachytherapy, 265–266
Germ cell tumors, pediatric intracranial, 590–591
Germinomas, 590–591, 591f
Gleason grade, in prostate cancer, 455
Glioblastoma, 335
GOG. See Gynecologic Oncology Group (GOG)
GOG 122 trial, 428
GOG 150 trial, 428
Gold eye shields, 546f
Gold fiducial marker seeds, 460f
Golden beam data (GBD), 98
Gradient calculation, in IMRT, 132–134
gradient descent, improvements to, 133–134
convexity, 134
including second derivatives, 133–134
nonnegativity constraint, handling of, 133
Gradient descent method, 132
Gradient-based leaf position optimization, 139–140
Gradients, radiosurgery, 206–207, 207f
Grid-based Boltzmann solvers (GBBS), 73
Gross disease, 632
Gross tumor volume (GTV), 168
defined, 3, 168
in prostate, 458–460
PTV vs., 219
in thorax cancers, 600–601
Group Européen de Curiethérapie-European Society for Therapeutic
Radiology and Oncology (GEC-ESTRO), 441, 442f
GTV. See Gross tumor volume (GTV)
Gynecologic Cancer Intergroup (GCIG), 436
Gynecologic cancers
booksmedicos.org
brachytherapy in, 438–445
interstitial, 443–445
intracavitary, 438–443
cervical cancer, 426–427
clinical outcome studies in, 434
computerized dosimetry in, 445
extended field radiotherapy for, 434–436
external-beam therapy for, 430–438
ovarian cancer, 428–429
overview, 426
pelvic-inguinal radiotherapy, 436–437
radiotherapy techniques for, 430–445
stereotactic body radiotherapy for, 437–438
uterine cancer, 427–428
vaginal cancer, 429–430
vulvar cancer, 429
whole abdominal radiotherapy for, 437
whole pelvic radiotherapy, 430–434, 434f
Gynecologic Oncology Group (GOG), 426
H
Harmonic peripheral dose (HPD), 277
Harmonic treatment dose (HTD), 277
HCC. See Hepatocellular carcinoma (HCC)
HDR iridium-192 (Ir-192) brachytherapy, 471–472
Head and neck
radiation-induced toxicity of, 369–370
skin cancer with perineural invasion, 536
Head and neck (H&N) cancers, 123f
ART and, 523–524
defining dose volume histogram for, 520t, 521t
dose distribution for, 523f
dose limiting annulus (DLA), 522f
IGRT and, 523–524
IMRT for, 509–510
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incidence of, 509
larynx (cT1N0) for, 510f
normal tissue dose constraints for standard fractionation
adjuvant/definitive radiation therapy, 519t–520t
novel radiation therapy and, 524–525
overview, 509
target volumes by dose and disease site for, 512t–517t
treatment of, 509–524
dose constraints for, 518–519
dosimetric considerations for, 519t–520t, 519–521, 521t
future, 524–525
general principles for, 509–510
organs at risk for, 518–519
physics challenges, 521–523
recommendations for, 510, 517–518
tumor site and gross tumor volume (GTVp) delineations of, 511t–
512t
Heart, radiation-induced toxicity of, 370–371
Hepatocellular carcinoma (HCC), for SBRT, 237–240, 335
metastases, 240
pancreas, 239–240
prostate, 238–239, 239f
spine, 237–238, 238f
Heuristic approaches, to optimization, 265–266
HIF-1α. See Hypoxia-inducible factor 1-alpha (HIF-1α)
High dose rate (HDR) brachytherapy. See also Low-dose rate (LDR)
brachytherapy
absolute dose to reference location in, 270, 273
advantages, 259–260
biological equivalent dose in, 263–264
disadvantages, 260
dose limitations, 273
dose prescription, 270, 273
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dose–volume histograms (DVH), 275–276, 275f, 276f
equivalent treatments for, 264t
general considerations of, 259–260
inhomogeneity correction using discrete-ordinates algorithm, 272f
maximum contiguous dose in, 274
maximum significant dose in, 273–274
optimization in, 264–270
for cervical cancer intracavitary applications, 268, 270, 271f
convergent searches for, 266
deterministic approaches to, 265–268
distance, 266
geometric, 265–266
inhomogeneity correction, 270, 272f
manual, 268, 269f
point-dose, 266–267
polynomial, 267–268
stochastic approaches to, 268
volume, 266
planning for implantation, 280–284
appliance selection and placement, 281–283
breast implant, 283f
dwell positions, 283–284, 284f
interstitial implants, 282–283, 283f
intracavitary insertions, 281–282, 281f
planar implant, 283f
quality assurance for, 278–280
indicators of reasonableness, 278–280
interstitial implants, 279–280
intraluminal tests for, 278–279
pretreatment checks in, 280
tandem and ovoids in, 279
treatment unit programming in, 280
unified index in, 280
radiobiological considerations of, 260–264
fractionation, 262–263
prescription doses, 262–264
therapeutic ratio, 260–262
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relative doses to specified volumes in, 273
tandem and ovoid applicator used for, 438f
treatment plan evaluation, 270–278
figures of merit, 276–278
quantitative assessment of implants, 274–276
visual evaluation, 273–274
vs. LDR brachytherapy, 259–260
High dose rate techniques, in gynecologic cancer, 439–442
High-dose region, 275
High-energy electron beams, 288. See also Electron beam radiotherapy
High-grade astrocytoma, 590
High-grade gliomas, 581
Hilus, 598
Histogram reduction, 385–386
HL. See Hodgkin’s lymphomas (HL)
Hodgkin’s disease, 593
Hodgkin’s lymphomas (HL), 494
combined modality for, 496
indications for radiotherapy in, 496
prognostic factors for early stage, 495t
Hogstrom algorithm, for calculation of dose distribution, 82f
HPD. See Harmonic peripheral dose (HPD)
HTD. See Harmonic treatment dose (HTD)
Hybrid cone-beam CT, 181
Hyperfractionation, 346, 604
accelerated, 347
Hypofractionation, 347, 604, 632
Hypoxia-inducible factor 1-alpha (HIF-1α), 356–357, 358f, 358f
I
IAEA. See International Atomic Energy Agency (IAEA)
IBC. See Inflammatory breast cancer (IBC)
ICI. See Immune checkpoint inhibitor (ICI)
ICRU. See International Commission on Radiation Units and
Measurements (ICRU)
booksmedicos.org
ICRU Report 50, 302
ICRU Report 62, 302
ICRU Report 71, 302
ICRU Report 83, 109
IDC. See Invasive ductal carcinoma (IDC)
IEC. See International Electrotechnical Commission (IEC)
IFRT. See Involved field radiotherapy (IFRT)
IGCCG. See International Germ Cell Cancer Collaborative Group
(IGCCG)
IGRT. See Image-guided radiation therapy (IGRT)
ILC. See Invasive lobular carcinoma (ILC)
Image fusion techniques, 110, 214
Image registration, 22–24, 110–111
automated, 22–23, 23f
deformable image registration, 23–24, 24f
in IGRT, 188
Image-guided radiation therapy (IGRT), 5, 377
anatomic variations in, 191–195, 193f
commissioning in, 187–188
correcting dosimetric deviations in, 193–195
correction strategies in, 190–195
3D conformal radiotherapy, 177
data management, 189
DMLC in, 186–187
dosimetric consequences in, 191–195
facilitating tools, 189
future prospective, 195
image guidance, 178f
image registration, 188
information technology infrastructure for, 189
inter-fractional imaging modalities, 178–183
magnetic resonance imaging, 182
optical surface imaging, 183
patient position correction, 183
positron emission tomography, 182–183
respiration-correlated (4D) computed tomography imaging, 181–
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182
tomographic imaging, 179–181
ultrasound, 183
interfractional setup error correction, 190
management of intrafractional tumor motion, 190
mobile treatment couch approach in, 187
and motion compensation, 183–187
movable gantry approach in, 187
online vs. offline corrections, 190
overview, 177–178
population-based and individualized margins, 190–191
prototype MRI-guided real-time volumetric tracking system for, 186f
real-time electromagnetic localization and tracking in, 185
requirements and considerations of, 187–189
selection of technology in, 189
setup error in, 192f
Imaging, 12–25. See also specific class of imaging techniques
bi-planar image-based target definition, 207–209
computed tomography, 12–16
CT, 209–213
data sets used in treatment, 12–25, 13f
acquired images, 12–20
processed images, 21–25
emission tomography, 18–19
equipment for, 6
magnetic resonance imaging, 16–18
modalities in radiation therapy, 13f
MRI, 213–215
overview of, 12
process, 21–25
automated image registration, 22–23, 23f
beam’s eye views of, 21–22, 22f
deformable image registration (DIR), 23–24, 24f
digitally reconstructed radiographs (DRRs), 21–22
image registration, 22
scientific visualization challenges, 25
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segmentation, 21
segmentation nomenclature, 21, 21t
volume visualization, 24–25, 24f
projection, 19
quality assurance images, 20
response, 19
simulation images in, 19–20
surface, 20, 20f
ultrasound, 20, 183
video, 20
volumetric, 12
Imaging and Radiation Oncology Core (IROC), 233
Immobilization, 169
for children, 585–586
Immune checkpoint inhibitor (ICI), 358
Immunotherapy, 357–358
IMPT. See Intensity-modulated proton therapy (IMPT)
IMRT. See Intensity-modulated radiation therapy (IMRT)
Inflammatory breast cancer (IBC), 554
Inhomogeneity correction, in HDR brachytherapy, 270, 272f
INRT. See Involved node radiotherapy (INRT)
Integral depth dose curves, 15
Intensity modulation
for IGRT, 5
for IMRT, 5
Intensity-modulated fields
delivery of, 127, 129f
illustration of, 127f
Intensity-modulated proton therapy (IMPT), 147, 150–164
individual fields and, 161f
nuclear interactions, 151
LET, 151
RBE, 151
pencil beam scanning, 151–152, 152f
proton interactions, basic physics of, 150–151
energy loss, 150–151
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scattering, 150–151
treatment planning process, 152–163
beam modeling, 152–153
beam selection, 157–158
dose calculations, 153–155
evaluation of, 162–163
field shaping, 158–162
imaging for, 155–156
optimization, 158–162
plan design, 157–158
structure definition, 156–157
treatment to sacral chordoma, 163f
Intensity-modulated radiation therapy (IMRT, 634–635
acceptance testing for, 109–110
applications of, 122, 124
arc therapy for, 141–143
VMAT plan optimization, approaches to, 143
VMAT treatment planning problem, 141–143
axial computed tomography image, 465f
beam angle optimization, 145–146
central nervous system tumors, 575
clinical outcome models in, 130, 143–145
concave target volumes, 122, 123f
controlling tradeoffs, 127–128
direct aperture optimization methods, 137–141
FMO + sequencing approach, limitations of, 137–138
local leaf position optimization, 139–141
for step-and-shoot IMRT, 138–139
dose distribution, 128f
dose-deposition matrix, 125
dose-volume effects, 129–130
dose-volume histogram (DVH), 130
equivalent uniform dose (EUD), 129–130
for endometrial nodal disease, 315f
fluence map for, 124–125, 125f
optimization, 127–132
gradient calculation in, 132–134
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gradient descent, improvements to, 133–134
nonnegativity constraint, handling of, 133
for head and neck cancers, 509–510
head-and-neck cancer, 123f
integrating uncertainty in, 146–147
intensity-modulated fields, delivery of, 127, 129f
leaf sequencing for, 134–137
aperture decomposition of fluence maps, 135–136, 135f
beam shaping, 134–135
multi-leaf collimators, 134–135, 135f
as optimization problem, 136
sliding window sequencing, 135–136, 136f
step-and-shoot delivery vs. dynamic delivery, 136–137, 137f
optimization algorithms for, 130–132
basic gradient descent method, 132
handling of constraints via penalty functions, 132, 132f
visualization of fluence map, 131, 131f, 132f
organ motion in, 146–147
for pediatric malignancies, 586, 589f
plan for head-and-neck cancer, 127f
planning as optimization problem, formulation of, 125–126
prostate cancer, 123f
proton therapy in age of, 329–334
acute toxicity, 330, 330f
ASTRO recommendations, 332
clinical results with, 333–334
cost-effectiveness, 331–332
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331
spinal metastasis with, 123f
for thorax cancers, 604, 606
treatment plan, 126, 127f
Interfractional IGRT imaging modalities, 178–183
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patient position correction, 183
positron emission tomography, 182–183
respiration-correlated (4D) computed tomography imaging, 181–182
respiration-correlated 4D CBCT, 182
respiration-correlated 4DCT, 181–182
tomographic imaging, 179–181
digital tomosynthesis, 181
hybrid cone-beam CT, 181
kV cone-beam CT, 179–180
kV helical CT, 179–180
MV cone-beam CT, 180–181
MV helical CT, 180–181
ultrasound, 183
Interfractional setup error correction, IGRT, 190
Interfractional tumor motion, dosimetric effects, 192–193
Internal mammary chain (IMC) electron field, 306–307
Internal target volume (ITV), 146
International Atomic Energy Agency (IAEA), 98
International Commission on Radiation Units and Measurements
(ICRU), 4
equieffective dose, 381
margins, 4f
recommendations for interstitial implant, 274, 277
tumor volumes and definitions, 459t
volumes, 4f
International cooperative group trial (INTERTECC), 434
International Electrotechnical Commission (IEC), 105
International Germ Cell Cancer Collaborative Group (IGCCG), 488
International Lymphoma Radiation Oncology Group (ILROG), 498, 499
Interstitial brachytherapy
Interstitial implants
figures of merit, 276–278
booksmedicos.org
in high dose-rate brachytherapy, 282–283, 283f
ICRU recommendations for, 277
Interstitial prostate implant, isotopes used for, 471t
INTERTECC. See International cooperative group trial (INTERTECC)
Intracavitary brachytherapy
dosimetry for tandem and ovoid insertion, 439f
Intracavitary insertions, in high dose-rate brachytherapy, 281–282
Intracranial meningioma, 333
Intra-fractional real-time imaging and motion compensation, 183–187
electromagnetic localization and tracking, real-time, 185
fluoroscopic imaging with implant fiducials in, 183–184
MRI real-time cine imaging, 186
MRI real-time volumetric imaging, 186
optical fiducial motion surrogates, 184
PET real-time imaging, 186
tumor motion compensation, real-time, 186–187
video-based optical surface imaging, 185
Intrafractional tumor motion, in IGRT
dosimetric effects due, 193
management of, 190
Intraperitoneal 32P, 428–429
Intrarectal balloon device, for stablize prostate position, 459f
Intratreatment prostate movement, 171f
Invasive ductal carcinoma (IDC), 553
Invasive lobular carcinoma (ILC), 553
Inverse planning, 8
Involved field radiotherapy (IFRT), 497, 498f
Involved node radiotherapy (INRT), 497–498
Involved site radiotherapy (ISRT), 498
Ipilimumab, 358
IROC. See Imaging and Radiation Oncology Core (IROC)
Isodose distributions, 290, 290f, 291f
ISRT. See Involved site radiotherapy (ISRT)
ITV. See Internal target volume (ITV)
booksmedicos.org
K
Kerma, in low-dose-rate brachytherapy, 247, 248, 250
Kernel spatial variance, 52, 52f
Kidney, 371
L
Lacrimal gland, 369
Larynx, radiation-induced toxicity of, 370
Larynx (cT1N0) cancer treatment field, 510f
Late salivary dysfunction, 369
Lateral spread parameter (σ) in pencil beam models, 79–80, 79f, 80f
Late-responding normal tissues, 342, 342f, 344
LCIS. See Lobular carcinoma in situ (LCIS)
Leaf sequencing, for IMRT, 134–137
aperture decomposition of fluence maps, 135–136, 135f
beam shaping, 134–135
defined, 135
multi-leaf collimators, 134–135, 135f
as optimization problem, 136
sliding window sequencing, 135–136, 136f
step-and-shoot delivery vs. dynamic delivery, 136–137, 137f
Lentigo maligna, 536
LET. See Linear energy transfer (LET)
Leukemia, 593
acute, 576–577
Linac radiosurgery. See also Radiosurgery
dose planning in, 215–216
historic development of, 203–205
imaging
CT, 209–213
MRI, 213–215
localization of, 206–207
overview, 203
planning of, 206–207
prescription isodose, 216–219
PTV vs. GTV, 219
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system criteria for, 221–223
treatment, 206–207
delivery, 219–221
margin, 219
procedure, 223–224
Linear energy transfer (LET), 151
Linear quadratic (LQ) model, 349–352, 380
to SRS/SAbR, 358–359
Linear-quadratic cell-survival curve, 341f
Liver, radiation-induced toxicity of, 371
Liver metastases, SBRT for, 236–237
LKB model, 384, 385
Lobular carcinoma in situ (LCIS), 553
Localization technology, 169
Low dose rate techniques, in gynecologic cancer, 439–442
Low dose-rate permanent implants, of prostate, 71
Low-dose rate (LDR) brachytherapy. See also High dose rate (HDR)
brachytherapy
basic physics concepts in, 245–250
penetrability of radionuclides, 245
developments in, 244
dosimetry, 247–249
equivalent treatments for, 264t
future developments, 252–253
overview, 244
radionuclides in, 245
physical properties of, 245t
sources, 245, 245t, 246f
calibrations, 249–250
TG-43 formalism, 247–248, 248f
treatment planning for, 250–252, 252t
vs. high dose-rate brachytherapy, 259–260
Low-dose region, 274
Low-energy megavoltage x-ray beams, 5
Low-grade astrocytoma, 589–590
Low-grade gliomas, 580–581
Lugano classification, staging system for primary nodal lymphomas
booksmedicos.org
from, 495t
Lung cancer, 234–236, 335, 609–611. See also Thorax/lung cancers
diagnosis and staging for, 598–599
early stage, 234–235
NSCLC, 609–610
PBT for, 335
RTOG trials in, 234–235
SCLC, 610–611
tissue heterogeneity correction in, 605f
Lung lesions, SBRT couch and gantry angles for, 230t
Lungs
QUANTEC recommendations for, 387
SBRT for
normal tissue dose constraints for, 608t
prospective trials in, 234–235
tumor
PBT for, 335
SBRT of central, 235f
Lymph node
target volume in, 460–461
visualization, 18
Lymphatic drainage of breast, 552f
Lymphomas
indications for treatment, 495–497
combined modality therapy, 496
radiation alone, 496–497
relapsed/refractory setting, 497
Lugano classification, staging system, 495t
overview, 494
radiation therapy techniques
extranodal lymphomas, 498–499
field design, history of, 497–498
individualized patient care, 504
involved site radiotherapy, 498
motion management, 500–501
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on-board imaging, 501–502
planning, 502–504
staging in, 494–495, 495t
Lymphotropic nanoparticle-enhanced magnetic resonance imaging, 18
M
MA20 and EORTC 22922 trials, 556
Magnetic resonance angiography (MRA), 208
Magnetic resonance imaging (MRI), 16–18, 182, 213–215
artifacts, 17
basics of, 16–18
for brain patient, 37f
functional, 17, 18f
lymph node visualization, 18
magnetic resonance spectroscopic imaging, 17–18
in radiation therapy, 18
scan of patient with liver tumor, 17f
target delineation with, 17
in treatment room, 18
Magnetic resonance spectroscopic imaging, 17–18
Malignant pleural mesothelioma (MPM), 613
Malignant spinal cord compression (MSCC), 569, 571
Mandible, osteoradionecrosis risk in, 369–370
Mantle cell lymphoma, 495
Manual reoptimization, in HDR brachytherapy, 268
Martinez Universal Perineal Interstitial Template (MUPIT), 439
Mask function, in dose computation models, 51
Mass stopping power, 88–89
Mastectomy scar boost, 562
Matched peripheral dose, 275
Mathematical pencil beams (MPB), 94
Maximum contiguous dose (MCD), 274
Maximum significant dose (MSD), 273–274
MCD. See Maximum contiguous dose (MCD)
MCNP. See Monte Carlo N-Particle Transport code (MCNP)
MCO. See Multicriteria optimization (MCO)
booksmedicos.org
MCS. See Multiple Coulomb scattering (MCS)
MD Anderson Dose Escalation trial, 466t
Mean central dose, 274
Mean peripheral dose (MPD), 275
Mean proton range, 89
Mediastinal lymphoma, limited radiation fields for, 498f
Mediastinum, 500
Medical physicist, 9–10
roles and responsibilities of, 10t
Medium- or high-energy megavoltage x-ray beams, 5
Medulloblastoma, 333, 586–587
Megavoltage cone-beam CT (MV CBCT), 180–181
Megavoltage helical CT, 180–181
Megavoltage photon production, 47, 48f
Melanoma in situ. See Lentigo maligna
Memorial Sloan Kettering Cancer Center, 402, 437, 469, 471, 489
Meningiomas, 581
Merkel cell carcinoma, 536–537
Metal-oxide semiconductor field-effect transistor (MOSFET), 115
MF. See Mycosis fungoides (MF)
Mid-pelvic computed tomography (CT) image, 432f
MLC. See Multi-leaf collimators (MLC)
Mobile treatment couch approach, in IGRT, 187
Model-based photon dose calculations
algorithms for, 46–57
Monte Carlo method in, 53–54
basic radiation physics for, 47–49
electron transport, 48–49
booksmedicos.org
megavoltage photon production, 47, 48f
history of, 46
Monte Carlo dose calculations, 154–155
Monte Carlo (MC) method
analog simulations, 53
in brachytherapy, 71–73
condensed histories, 53
for proton transport in patient, 94–96
of radiation transport, 53–54
radiotherapy dose calculations, 53–54
for treatment planning of photon and electron beams, 83
variance reduction techniques, 53
Monte Carlo N-Particle Transport code (MCNP), 53, 72
MOSFET. See Metal-oxide semiconductor field-effect transistor
(MOSFET)
Motorized wedge, dose profiles, 108f
Movable gantry approach, in IGRT, 187
MPB. See Mathematical pencil beams (MPB)
MPD. See Mean peripheral dose (MPD)
MPM. See Malignant pleural mesothelioma (MPM)
MRA. See Magnetic resonance angiography (MRA)
MRI. See Magnetic resonance imaging (MRI)
MSCC. See Malignant spinal cord compression (MSCC)
MSD. See Maximum significant dose (MSD)
Multicriteria optimization (MCO), 321
Multi-leaf collimators (MLC), 108, 134–135, 134f, 135f
cross-beam profiles under, 109f
Multiple Coulomb scattering (MCS), 150–151, 289
MUPIT. See Martinez Universal Perineal Interstitial Template (MUPIT)
Muscle invasive disease, 481–482
MV CBCT. See Megavoltage cone-beam CT (MV CBCT)
Mycosis fungoides (MF), 537–541
radiation therapy indications, 537
radiation treatment techniques, 537–541
local radiation therapy, 537–538
total-skin electron therapy (TSET), 538, 538f–539f, 540–541
booksmedicos.org
Myxoid liposarcoma, 623
N
National Comprehensive Cancer Network (NCCN), 534, 639
National Institute of Standards and Technology (NIST), 249
Guidelines (NISTG-99), 471
NCCN. See National Comprehensive Cancer Network (NCCN)
Neuroblastoma, 592–593, 592f, 593f
NHLs. See Non-Hodgkin lymphomas (NHLs)
NIST. See National Institute of Standards and Technology (NIST)
Nongerminomatous germ cell tumors, 590–591
Non-Hodgkin lymphomas (NHLs), 494
combined modality for, 496
Noninvasive breast cancer, 553
Non-radiographic imaging
ultrasound imaging, 183
Nonseminomatous germ cell tumors (NSGCT), 486
Nonsmall cell lung cancer (NSCLC), 327, 601, 604, 606, 609–610
Normal organ volume, 21t
Normal tissue complication probability (NTCP), 130, 378–380
nonuniform irradiation, 385–386
parallel organs in, 385, 388
serial organs in, 385
statistical models, 388
supporting data for, 386–390
uniform irradiation, 385–386
Normal tissue dose constraints
for conventionally fractionated external-beam radiotherapy, 602t
for lung SBRT, 608t
Normal tissue tolerances
in anal cancer, 415–416
basic facts about, 367–368
in colorectal cancer, 411
in esophageal cancer, 399
in gastric cancer, 403
booksmedicos.org
for hypofractionated regimens, 365t–367t
of intracranial OAR, 574t
in pancreatic cancer, 406
for standard fractionation, 364t
variable impacts, 363t
NSCLC. See Nonsmall cell lung cancer (NSCLC)
NSGCT. See Nonseminomatous germ cell tumors (NSGCT)
NTCP. See Normal tissue complication probability (NTCP)
O
OAR. See Organs at risk (OAR)
OER. See Oxygen enhancement ratio (OER)
Optic structures
QUANTEC recommendations for, 388
Optical fiducial motion, 184
Optical surface imaging (OSI), 183
Optically stimulated luminescence (OSL), 115
Optimization, in HDR brachytherapy, 264–270
for cervical cancer intracavitary applications, 268, 270, 271f
convergent searches for, 266
deterministic approaches to, 265–268
distance, 266
geometric, 265–266
inhomogeneity correction, 270, 272f
manual, 268, 269f
point-dose, 266–267
polynomial, 267–268
stochastic approaches to, 268
volume, 266
Organs at risk (OAR), 168
in central nervous system tumors, 574–575
delineation, 443f
DVH constraints for, 462t
in head and neck cancers, 518–519
normal tissue tolerance of intracranial, 574t
in thorax cancers, 601–602
ORN. See Osteoradionecrosis (ORN)
booksmedicos.org
orthovoltage x-ray unit, 529f
OSI. See Optical surface imaging (OSI)
OSL. See Optically stimulated luminescence (OSL)
Osteogenic sarcomas, 642
Osteoradionecrosis (ORN), 369–370
Outpatient treatment, in HDR brachytherapy, 260
Ovarian cancer, radiotherapeutic management of, 428–429
Oxygen enhancement ratio (OER), 343–344, 344f
P
Palliation, 604
Pancreas, SBRT for, 239–240
Pancreatic cancer, 404–408
chemotherapy for, 407f, 408
diagnostic evaluation of, 404–405
prognosis of, 408
normal tissue tolerances, 406
radiotherapy target, 405–406
simulation, 405
Parallel organs, in NTCP models, 388
Pareto-optimal treatment plans, 144
Pareto-surface navigation methods, 144–145
Parietal pleura, 598
Parotid glands
dose-volume histograms of, 324f
Partial brain radiation, 580
Passive scattering (PS), 150
Patient and organ movement, 168–174
geometric variation problem, 168
position correction, 169–170
adaptive, 170–174
off-line, 170
booksmedicos.org
online, 169–170
positioning systems and, 169
setup variations and, 169
CTV and GTV, 169
minimizing impact of, 169
Patient load vs. treatment units, 6–7
Patient position
immobilization, 169
localization technology, 169
PBS. See Pencil-beam scanning (PBS)
PBT. See Proton beam therapy (PBT)
PCA3. See Prostate cancer antigen 3 (PCA3)
PDD. See Percentage depth dose (PDD); Percentage depth doses (PDD)
Pediatric malignancies
anesthesia in, 585
craniopharyngioma, 591–595
ependymoma, 333
Ewing’s sarcoma, 333, 594
Hodgkin’s disease, 593
immobilization, 585–586
IMRT for, 586, 589f
leukemia, 593
medulloblastoma, 333
neuroblastoma, 592–593, 592f, 593f
overview, 585–586
PBT for, 333
pediatric disease sites/treatment planning for
diffuse infiltrating pontine gliomas (DIPG), 590
embryonal tumors of CNS, 586–587, 588f
ependymomas, 587–589
germinoma/nongerminomatous germ cell tumors, 590–591
high-grade astrocytoma, 590
low-grade astrocytoma, 589–590
proton radiation for, 586, 588f
radiation delivery for children, 585
retinoblastoma, 333, 594–595, 594f, 595f
rhabdomyosarcoma, 333, 594
booksmedicos.org
supratentorial primitive neuroectodermal tumors, 333
three-dimensional treatment planning for, 586
Wilms’ tumor, 592
Pediatric Radiation Oncology Society (PROS), 585
Pelvic fields, 482–483
Pelvic-inguinal radiotherapy, gynecologic cancers, 436–437
Pelvis, radiation-induced toxicity of, 371–372
Pencil beam models
based on multiple scattering theory, 78–80
beam characterization in, 79–80
central axis distribution calculation, 80, 81
computer algorithm in, 82–83
in contour irregularity, 81
coordinate systems for, 79f
Gaussian function and, 79
Gaussian proton, 91–96
isodose distribution, 81, 81f
calculated vs. measured, 81f
lateral spread parameter (σ) in, 79–80, 79f, 80f
limitations of, 80–82
Monte Carlo (MC) methods and, 83
success of, 80–82
in tissue heterogeneities, 81–82, 82f
Pencil-beam scanning (PBS), 150, 151–152, 152f, 157f
field shaping for, 158–162
advanced optimization, 162
Bragg peak placement, 158
field-modifying devices, 161
fluence optimization, 158–161, 159f
irradiation of chest wall, 322f
optimization for, 158f
Pencil-beam scattered field implementation, 93–94
Penile bulb, 372
Percentage depth dose (PDD), 530
Percentage depth doses (PDD), 289–290, 289f
absolute difference, 107f
central ray, 107f
booksmedicos.org
Perineural invasion, head and neck skin cancer with, 536
Peripheral dose, 274
Peripheral uniformity number (PUN), 278
Peripheral-mean ratio (PMR), 275
PET. See Positron emission tomography (PET)
PET/CT. See Positron emission tomography/computed tomography
(PET/CT)
Phantom
heterogeneities, 52
modeling primary photons incident on, 50–51, 51f
ray-tracing, incident energy fluence through, 51–52, 51f
Pharyngeal constrictors, 370
Phase-space file, 53
Photon beam calculations, transport equations for, 55
Photon dose calculations
algorithms for, 46–57
Monte Carlo (MC) technique, 53–54
basic radiation physics for, 47–49
electron transport, 48–49
megavoltage photon production, 47, 48f
history of, 46
Photon dose calculations, sample criteria of acceptability for, 104t
Physical pencil beam (PPB), 94
Physicist, medical, 9–10
Physicist assistant, 10
Pituitary tumors, 581
booksmedicos.org
PIVOT. See Prostate Cancer Intervention Versus Observation Trial
(PIVOT)
Plane films, stereotactic system for, 208f
Planning target volume (PTV), 4
in prostate, 458–460
in SBRT, 230
PMR. See Peripheral-mean ratio (PMR)
Point-dose optimization, in HDR brachytherapy, 266–267
Polynomial optimization, in HDR brachytherapy, 267–268
Position correction, 169–170
adaptive, 170–174
adjustment, 169–170, 170f
decision, 169
measurement systems, 169
off-line, 170
online, 169–170
strategies for, 169–170, 170–172
Positioning
in central nervous system tumors, 575–576
in HDR brachytherapy, 259
systems, 169
Positron emission tomography (PET)
PET/CT scanners, 19
in radiation planning, 18–19
Positron emission tomography/computed tomography (PET/CT), 7, 42,
43, 43f
Postoperative Radiotherapy for Endometrial Carcinoma (PORTEC)-3
trial, 427
Postorchiectomy radiotherapy, in testicular cancer, 488
PPB. See Physical pencil beam (PPB)
Prescription isodose, radiosurgery, 216–219, 217f, 218f, 220f, 220f
Primary dose calculation, 152, 155f
Prioritized optimization, IMRT, 143–144
Probabilistic approach, for IMRT planning, 146–147
Projection imaging, 19
booksmedicos.org
PROS. See Pediatric Radiation Oncology Society (PROS)
Prospective gated image acquisition, 40
Prostate cancer, 123f, 453–473
BED, 468–469
treatment technique, 469
clinical anatomy
anatomy, 453
local growth patterns, 453
regional and distant metastasis, 453
clinical assessment
bone scan for, 455
CT, 454–455
diagnosis, 454
Gleason grade for, 455
MRI for, 455
PET for, 455
PSA screening, 456
risk stratification, 454, 455t, 456t
for staging, 454–455, 454t
ultrasound, 454
dose fractionation for, 466–467
field setup for
immobilization, 461
localization, 461
simulation, 461
interstitial prostate implant isotopes used for, 471t
PBT for, 335–336
radiation therapy in, 453–454
radioisotope implant for, 469–472
indications, 469
isotopes and dose, 471–472, 471t
target volume definition, 469–471
recurrence risk group by NCCN criteria, 455t
booksmedicos.org
RT dose for, 468
SBRT for, 238–239, 239f
target volume in, 458–461
lymph node, 460–461
prostate, 458–460
seminal vesicles, 460
transperineal prostate brachytherapy, 470f
treatment options for
active surveillance, 456–457
androgen deprivation therapy, 457–458
brachytherapy, 458
cryotherapy, 458
external beam radiation therapy, 457
other local therapies, 458
radical prostatectomy, 457
treatment algorithms, 456
watchful waiting, 456
treatment planning for
adjuvant/salvage EBRT, 467–468
EBRT in, 458–467
prostate bed, 468–469
radioisotope implant, 469–472
treatment technique for, 461–466
Prostate cancer antigen 3 (PCA3), 456
Prostate Cancer Intervention Versus Observation Trial (PIVOT), 456
Prostate movement
dominant modes of, 171f
intratreatment, 171f
Prostate-specific antigen (PSA), 381
Proton beam penumbra, 314–315, 315f
Proton beam radiotherapy, 635
absolute dosimetry, 321
clinical case analysis, 321–324
clinical properties of proton beam, 313–316
field-shaping devices in, 319
multi-criteria optimization in, 321
overview, 313
booksmedicos.org
proton beam penumbra, 314–315, 315f
proton fields generation, 316–321
accelerators for, 316–317
scanned proton fields, 320–321
scattered proton fields, 317–320
range-compensators in, 314f
SOBP field in, 317–318, 319
Proton beam therapy (PBT), 6
and advanced technology photon therapy, 329–334
in age of IMRT, 329–334
acute toxicity, 330
in bone and soft tissue sarcomas, 333–334
in ocular tumors, 333
in pediatric tumors, 333
development of, 328–329
for head and neck tumors, 334–336
breast cancer, 335
esophageal cancer, 335
glioblastoma, 335
hepatocellular carcinoma, 335
lung cancer, 335
prostate, 335–336
history of, 328
for nasopharyngeal carcinoma, 334
for parotid gland carcinoma, 334
Proton fields generation, 316–321
accelerators for, 316–317
scanned proton fields, 320–321
multicriteria optimization in, 321
booksmedicos.org
scattered proton fields, 317–320
absolute dosimetry in, 319–320
double scattering, 317–319
field-shaping devices and, 319
single scattering, 317
Proton lateral spread, dose computation, 90–91, 90f, 91f
Proton therapy, dose computation algorithm
dose distribution models, 91
dose to medium, 89–90, 90f
Gaussian proton pencil-beam model, 91–96
mass stopping power in, 88–89
physics of proton transport in medium and, 86–91
proton interaction in, 86–87
energy lose in, 87
inelastic, 87
proton lateral spread and, 90–91, 90f, 91f
relative biological effectiveness in, 87–88, 88f
scattered field implementation in, 92–93, 93f
pencil-beam, 94
scattered proton field composition, 93–94
water-equivalent depth and proton range, 89, 89f
Proton transport, Monte Carlo method for, 94–96
Protons, 326–327
Bragg peaks, 327f
for thorax/lung cancer, 608–609
vs. 2D photons, 329
PS. See Passive scattering (PS)
PSA. See Prostate-specific antigen (PSA)
PTV. See Planning target volume (PTV)
PUN. See Peripheral uniformity number (PUN)
Q
QA. See Quality assurance (QA)
QC. See Quality control (QC)
Quality assurance (QA)
acceptance testing, 103, 105–106
administration, 116
booksmedicos.org
beam-related information, display, 101
of brachytherapy, 111–112
commissioning of other components, 112, 112t
proton therapy, 111–112
special techniques, 112
commissioning in, 103, 106–111
automated and knowledge-based planning, 110
autosegmentation, 111
image registration, 110–111
IMRT, 109–110
of other components, 107t
photon beams, 106–109, 107f, 107t, 108f, 109f
conventional simulator, 41
current status, 98, 100
defined, 98
dose calculation, 101
dosimetry checks in, 114–115
errors in, 112–113
future possibilities, 100
for high dose rate brachytherapy, 278–280
indicators of reasonableness, 278–280
interstitial implants, 279–280
intraluminal tests for, 278–279
pretreatment checks in, 280
tandem and ovoids in, 279
treatment unit programming in, 280
unified index in, 280
historical perspective, 98, 100
for IGRT, 187–188
imaging and treatment isocenters, 187
imaging quality, 187
motion detection, 187–188
images, 19f, 20
initial dose calculation tests, 107t
methods for patient-specific, 114
patient data, 100–101
patient-specific tests in, 114
booksmedicos.org
program and system documentation in, 113
and quality control, 112–116
reproducibility tests in, 114
risk management, 112
for SBRT, 233–234
system specifications, 103–105, 104t
sources of uncertainties, 103–104
suggested tolerances, 104–105
terminology associated with, 103
of total radiation therapy planning process, 115
treatment planning process, 100–101
user training in, 113–114
Quality assurance team in radiation oncology (QUATRO), 115
Quality audits, 115
Quality control (QC), 103
defined, 98
and quality assurance, 112–116
QUANTEC. See Quantitative analysis of normal tissue effects in the
clinic (QUANTEC)
Quantitative analysis of normal tissue effects in the clinic (QUANTEC),
362, 363
Quasi-Newton methods, 134
QUATRO. See Quality assurance team in radiation oncology (QUATRO)
R
Radial dose function, 67
Radiation oncologist, 9
Radiation retinopathy, in retina, 369
Radiation Therapy Oncology Group (RTOG), 115, 427
protocols for invasive bladder cancer, 482t
Radiation therapy planning process, QA of, 115
Radiation-induced liver disease (RILD), 236, 371
Radiation-induced optic neuropathy (RION), 369
Radiation-induced renal dysfunction, 371
Radiation modalities, 632–633
Radioisotope brachytherapy, 533
Radiosurgery
booksmedicos.org
of arterial venous malformations, 206
checklist for time-out prior to, 223f
defined, 203
dose planning in, 214–216
gradients, 206–207, 207f
historic development of, 203–205
imaging in
CT, 209–213
MRI, 213–215
overview, 203
particle-beam treatments and, 207
planning of, 206–207
prescription isodose, 216–219
PTV vs. GTV, 219
single dose therapy vs. fractionated therapy, 204f
system criteria for, 221–223
treatment, 206–207
delivery, 219–221
errors, 222f
margin, 219
procedure, 223–224, 223f
ring-based SRS procedure, checklist for, 223, 224f
Radiosurgery beamline, single-scattered proton beam, 316f
Radiotherapy. See also Radiosurgery
overview, 326–338, 327f
proton beam therapy
development of, 328–329
history of, 328
proton therapy in age of IMRT, 329–334
acute toxicity, 330
in bone and soft tissue sarcomas, 333–334
booksmedicos.org
in ocular tumors, 333
in pediatric tumors, 333
protons vs. photons role in, 326–336
Radiotherapy dose
for anal cancer, 416
for colorectal cancer, 411
in esophageal cancer, 400
in gastric cancer, 403–404
in pancreatic cancer, 406
Radiotherapy target
in anal cancer, 414–415
in colorectal cancer, 410
in esophageal cancer, 398–399
of gastric cancer, 403
of pancreatic cancer, 405–406
Range straggling, 150
Ray line geometries, in dose computation, 78
Ray-tracing, 91
incident energy fluence through phantom, 51–52, 51f
RBE. See Relative biologic effect (RBE)
RC-CBCT. See Respiration-correlated CBCT (RC-CBCT)
RCCT. See Respiration-correlated CT (RCCT)
Real-time electromagnetic localization and tracking, 185
Real-time tumor motion compensation
dynamic multileaf collimator approach, 186–187
in IGRT, 186–187
mobile treatment couch approach, 187
movable gantry approach, 187
RECIST. See Response Evaluation Criteria in Solid Tumors (RECIST)
Rectum, 387–388
Relative biologic effect (RBE), 151, 327
in proton dose, 87–88
Relative dose homogeneity index, 277
booksmedicos.org
Reproducibility tests, in QA, 114
Respiration-correlated CBCT (RC-CBCT), 182
Respiration-correlated CT (RCCT), 181–182
Response Evaluation Criteria in Solid Tumors (RECIST), 19
Retina, radiation retinopathy in, 369
Retinoblastoma, 333, 594–595, 594f, 595f
Retroperitoneal sarcomas
history and treatment, 636–638
management guidelines, 638–640
Retrospective image reconstruction, 40
Rhabdomyosarcoma, 333, 594
Rigid image registration, in IGRT, 188
RILD. See Radiation-induced liver disease (RILD)
RION. See Radiation-induced optic neuropathy (RION)
Risk management, 112
Risk probability number (RPN), 113
RPN. See Risk probability number (RPN)
RTOG. See Radiation Therapy Oncology Group (RTOG)
RTOG 0236 study, 231, 234
S
SBRT. See Stereotactic body radiation therapy (SBRT)
Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), 456
Scanned proton fields, 320–321
multicriteria optimization in, 321
Scattered proton fields, 317–320
absolute dosimetry in, 319–320
composition, 93–94
double scattering, 317–319
field-shaping devices and, 319
single scattering, 317
Scatter/scattering
from beam modifiers, 48
Compton, 47–48
wedges, 51
SCLC. See Small cell lung cancer (SCLC)
booksmedicos.org
Secondary dose calculation, 152–153, 155f
Sensorineural hearing loss (SNHL), 369
Serial organs, in NTCP models, 385
SFUD. See Single field, uniform dose (SFUD)
Shaped field, 158
SIB. See Simultaneous integrated boost (SIB)
Sievert integral, 65–66
Simulation
of anal cancer, 413–414
analog, 53
in bladder cancer, 482–483
for breast cancer, 554–556
in central nervous system tumors, 576, 580
of colorectal cancer, 409–410
of esophageal cancer, 398
of gastric cancer, 402–403
images, 19–20, 19f
in lymphomas, 499–500
of pancreatic cancer, 405
of prostate cancer, 461
Simulator, 7
acceptance testing for conventional, 41
computed tomography, 7
specifications of conventional, 7
Simultaneous integrated boost (SIB), 378
Single field, uniform dose (SFUD), 160, 160f
Single intensity-modulated field, 127f
Single scattering, in scattered proton fields, 317
Skin cancer
clinical considerations for, 541–544, 542f–546f
electron beam therapy for, 530–531, 532
extent and size of, 527
overview, 527
photon beam therapy for, 532
radiation delivery modalities for, 528–541
basal and squamous cell carcinomas, 534–536
booksmedicos.org
calibration, 528
commissioning, 528
cutaneous melanoma, 536
electron arc therapy, 532–533
electron beam therapy, 530–531
electronic and radioisotope brachytherapy, 533
exit beam, (field defining devices, field shaping, and protection)
from, 531–532
fractionation schedules, 534, 535t
Merkel cell carcinoma, 536–537
mycosis fungoides, 537–541
orthovoltage dose, 535t
superficial and orthovoltage therapy, 528–530
treatment setup, aspects of, 533–534
staging, 527–528
steps in planning irradiation for, 527
target volume determination in, 527–528
Skin collimation, 303–304, 304f
Skull base chordoma, 333–334
Sliding window decomposition, 135, 135f
Sliding window sequencing, 135–136, 136f
Small cell lung cancer (SCLC), 610–611
Small-bowel toxicity, 371
SNHL. See Sensorineural hearing loss (SNHL)
SOBP. See Spread-out Bragg peak (SOBP)
Soft-tissue and bone sarcomas
diagnosis of, 623–624
dose and fractionation, 632
dose constraints and complications, 635–636
grade 2 leiomyosarcoma, 631f
history and treatment, 636–638
history, 622–623
intensity-modulated radiation therapy, 634–635
management guidelines, 638–640
orthogonal daily imaging, 629f
SBRT for, 642
staging for, 623–624, 624t
booksmedicos.org
standard clinical risk target volume (CTV1), 641f
treatment planning, 626–628
treatment set-up and plans for foot sarcoma, 639f
treatment set-up for T2bN0M0, 627f
treatment set-up and uncertainties, 632
SPCG-4. See Scandinavian Prostate Cancer Group Study Number 4
(SPCG-4)
SPG. See Sum of positive gradients (SPG)
Sphere packing, 206
Spinal cord
injury, irradiation cause, 368–369
QUANTEC recommendations for, 386–387
Spinal tumors, 582
Spine, SBRT for, 237–238, 238f
SPNETs. See Supratentorial primitive neuroectodermal tumors
(SPNETs)
Spread-out Bragg peak (SOBP), 151f, 152
absolute dose calculations for, 88f, 94
in proton beam radiotherapy, 317–318, 319
scattered proton field composition and, 93–94
Squamous cell carcinomas, 534–536, 541–546, 542f–546f
SRS/SAbR, radiobiology of
cell survival curves, 357f
HIF-1α, role of, 356–357, 358f, 358f
indirect cell death from vascular damage by, 355–357, 357f
linear quadratic model applicability to, 358–359
mechanism of action for, 357f
overview, 355
radiation-induced immune enhancement with, 357–358
VEGF, role of, 356–357, 358f, 358f
Staffing, 8–10
ACR standards for, 9t
dosimetrists, 10
medical physicist, 9–10
booksmedicos.org
radiation oncologist, 9
requirements for clinical radiation therapy, 9t
Standard clinical risk target volume (CTV1), 641f
Standard fractionation
abdomen, 371
central nervous system, 368–369
head and neck, 369–370
hypofractionation and, 372
normal tissue tolerance for, 365t–367t
pelvis, 371–372
thorax, 370–371, 603–604
Step-and-shoot IMRT, 136–137
Stepping source device, 259
Stereoscopic optical surface imaging, 183
Stereotactic body radiation therapy (SBRT)
beams eye view (BEV) for lung, 231f
body frame for, 229f
of central lung tumor, 235f
commissioning for, 233–234
couch and gantry angles, for lung lesions, 230t
dosimetry, 230–233
in early stage lung cancer, 234–235
fusion of planning CT scan to cone beam CT scan, 228f
growth in number of radiation oncology articles dealing with, 378f
for gynecologic cancers, 437–438
for HCC, 237–240
metastases, 240
pancreas, 239–240
prostate, 238–239
spine, 237–238
for liver, 236–237
axial, coronal, and sagittal isodoses, 237f
of liver metastases, 236–237
of lungs
prospective trials in, 234–235
normal tissue dose constraints for, 232t
overview, 227
booksmedicos.org
PTV in, 230
rationale and goals of, 227–228
simulations, 228–230
for thorax/lung cancers, 606
use of, 372
vacuum cushion for, 229f
Stochastic search methods, 139
Stomach, late radiation-induced toxicity, 371
Stopping power, dose computation, 88–89
Streaming term, 55
Subtotal nodal lymph node irradiation (STLNI), 497f
Sum of positive gradients (SPG), 136
Superficial and orthovoltage therapy, for skin cancer, 528–530
backscatter factors, 529
monitor unit calculation, 530
relative exposure factor, 529
stand-In/Off and attenuator correction, 529
treatment units, 528–529, 529f
Superposition/convolution algorithm, for photon dose calculation, 49–
52
under conditions of charged particle equilibrium, 49
convolution/superposition method, 49–50, 50f
Supraclavicular and axillary nodal fields, 559, 560f
Supratentorial primitive neuroectodermal tumors (SPNETs), 333, 587
Surface imaging, 20, 20f
Symmetric chordoma wrapping, 323f
Symptomatic radiation pneumonitis, 370
T
Tangent fields for intact breast, 557, 558f
Target organ volume, 21t
booksmedicos.org
Target volume
assessment of, 3–4
defined, 3
Task Group 43 (TG43), 66–67
TCP. See Tumor control probability (TCP)
TDLU. See Terminal ductal lobular units (TDLU)
Tele-radium device, 204, 204f
Terma, 50, 51–52
Terminal ductal lobular units (TDLU), 550
Testicular cancer
AJCC TNM staging system for, 487t
diagnosis of, 486
dosage in, 490
fractionation in, 490
overview, 486
para-aortic fields for stage I, 489–490, 490f
postorchiectomy radiotherapy, 488
radiation treatment fields for, 489–490
treatment options for, 486–489
chemotherapy, 488, 491t
observation/active surveillance, 488
radiotherapy, 488
stage I seminoma, 488, 491t
stage II seminoma, 488–489, 491t
treatment planning for, 489
Therapeutic ratio, 260–262
Thermoluminescent dosimeters (TLDs), 67, 114–115
Thermoplastic immobilization mask, 499f
Thorax
anatomy of, 598
cancer. See Thorax/lung cancers
Thorax/lung cancers
in CTV, 601
diagnostic workup for, 598–599
booksmedicos.org
GTV in, 600–601
in ITV, 601
lung cancer, 609–611
NSCLC, 609–610
SCLC, 610–611
malignant pleural mesothelioma, 613
overview, 598
protons for, 608–609
in PTV, 601
RT delivery for
dose, 606–607
indications, 606
outcomes, 607–609
SBRT, 606, 607f
treatment delivery, 607
treatment planning, 606, 610f
RT principles for, 599–606
beam energy, 604
constraints for conventionally fractionated RT treatments, 602t
dose/fractionation, 603–604
elective nodal irradiation, 603
FDG-PET in, 602–603, 603f
heterogeneity, 604
immobilization, 600
IMRT, 604, 606
localization, 600
motion management, 600
organs at risk, 601–602
simulation, 600
target volumes, 600–601
staging, 598–599
thymomas, 613–614
tissue heterogeneity correction in, 605f
Thymomas, 613–614
indications, 613–614
postoperative RT, 614
preoperative RT, 614
booksmedicos.org
treatment planning, 614
Thyroid, radiation-induced toxicity of, 370
Thyroid cancer, 518
Tissue heterogeneities
correction in lung cancer, 605f
in pencil beam models, 81–82, 82f
TLDs. See Thermoluminescent dosimeters (TLDs)
Tomotherapy, 141, 181f
Total nodal irradiation (TNI), 497f
Total skin electron irradiation (TSEI), 309
Total-skin electron therapy (TSET), 538, 538f–539f, 540–541, 540f,
540t
Transperineal prostate brachytherapy, 470f
Transurethral resection of bladder tumor (TURBT), 479, 480
Treatment plan evaluation
biologic indices in, 382–386
NTCP models, 384–386
TCP models, 382–384
dose escalation protocols, design of, 386–390
dose-volume histograms in, 378–382
in HDR brachytherapy, 270–278
visual evaluation, 273–274
overview, 377–378
parallel model to clinical complication data, 389–390
Treatment planning, 3–10. See also Algorithms, for treatment planning
for adjuvant/salvage EBRT, 467–468
radical prostatectomy, 467–468
algorithms in brachytherapy, 61–74
for anal cancer, 413–418
for bladder cancer, 482–483
for brachytherapy, 6
for central nervous system tumors, 580
for colorectal cancer, 409–413
booksmedicos.org
CT scanners for, 7
3D systems for, 8
for EBRT, 458–467
field setup, 461
treatment technique, 461–466
electron beams, 288–310
bolus in, 300–301
calibration, 301–302
electron–electron field junctions, 304–306
energy mixing, 309
en-face beams, 302–303
heterogeneities, 299–300
in irregular fields, 296
mixing with, 309–310
monitor units of, 301–302
photon–electron field junctions, 306–308
skin collimation, 303–304
on sloping surface, 296–298
surface irregularities and, 298–299
equipments to optimize, 5–10
accelerator-mounted imaging systems, 7–8
brachytherapy equipment, 6
computers, 8
external beam units, 5–6
imaging equipment, 6
patient load vs. treatment units, 6–7
PET/CT, 7
simulator, 6–7
of esophageal cancer, 398–400
field shaping in, 7
of gastric cancer, 402–403
high dose-rate brachytherapy, 259–284
IMPT for, 150–164
intensity modulation in, 5
booksmedicos.org
inverse planning, 8
isodose planning, 9
for pancreatic cancer, 405–408
for prostate bed, 468–469
for radioisotope implant, 469–472
indications, 469
isotopes and dose, 471–472, 471t
for rectal cancers, 409–412
staffing and, 8–10
ACR standards for, 9t
dosimetrists, 10
medical physicist, 9–10
radiation oncologist, 9
requirements for clinical radiation therapy, 9t
target volume assessment and, 3–4
for testicular cancer, 489
treatment planning algorithms in, 61–74
treatment volume in, 4–5
Treatment planning algorithms
calculation, 101
clinical application of, 102–103
computer programs for, 101, 102t
development and implementation, 101–103
IAEA TRS-430 questionnaire, 102t
radiation database for, 101–102
radiation therapy process and, 99f
Treatment simulation, 29
anatomical and traditional approach in, 29–31
CT-simulation process, 32–34
4D CT-simulation process, 39–41, 40f
defined, 29
overview, 29
typical radiotherapy simulator and, 30f
typical simulation portal and, 31f
verification simulation, 31
booksmedicos.org
virtual simulation, 29
CT-simulator and, 31–32
process, 35–39
Treatment units vs. patient load, 6–7
TSEI. See Total skin electron irradiation (TSEI)
TSET. See Total-skin electron therapy (TSET)
Tumor bed boost, 562
Tumor boost, 483
Tumor cells, FDG and, 7
Tumor control probability (TCP), 130, 382–384
Tumor node metastasis (TNM) system, 599
Tumor volumes and definitions, by ICRU, 459t
U
Ultrasound imaging, 20, 20f, 183
Ultrasound transducer, 183
UN. See Uniformity number (UN)
Uniformity number (UN), 277
User training, in QA, 113–114
Uterine cancer
customized implant plans for, 444f
V
Vaginal cancer, radiotherapeutic management of, 429–430
Varian linear accelerator, 54f
Varian TrueBeam™ unit, 180f
Variance reduction techniques, 53
Vascular endothelial growth factor (VEGF), 356–357, 358f, 358f
VEGF. See Vascular endothelial growth factor (VEGF)
Verification simulation, 31, 34f
process, 34f, 35–39
VERO™ system, 184f, 187
Vesicourethral anastomosis (VUA), 468
Video imaging, 20
Video-based 3d optical surface imaging, 185
Vienna ring applicator, 444f
booksmedicos.org
Virtual point source, 295
vs. effective point source, 295–296
Virtual simulation, 7, 29
based on three-dimensional reconstruction, 32f, 36f
CT-simulator and, 31–32, 34f
isocenter placement during, 36f
precaution in, 39–40
process, 35–39
spatial resolution and, 39
Visceral pleura, 598
VMAT. See Volumetric modulated arc therapy (VMAT)
Volume effect, 129–130
Volume optimization, in HDR brachytherapy, 266
Volume visualization, 24–25, 24f
Volumetric arc therapy plan, during whole brain radiation therapy,
578f
Volumetric imaging, 12
MRI real-time, 186
in treatment room, 16
Volumetric modulated arc therapy (VMAT), 124, 177
DICOM specification of, 142
illustration of, 142–143, 143f
for IMRT, 141–143
plan optimization, 143
treatment planning problem, 141–143
Voxels, 125
VUA. See Vesicourethral anastomosis (VUA)
Vulvar cancer, radiotherapeutic management of, 429
W
WAFAC. See Wide-angle free-air chamber (WAFAC)
WART. See Whole abdominal radiotherapy (WART)
Whole abdominal radiotherapy (WART)
for gynecologic cancers, 437
isodose distributions from intensity-modulated, 437f
Whole brain radiation therapy, 576–580, 5779f
blocking for C2-whole brain fields, 577f
booksmedicos.org
volumetric arc therapy plan, 578f
Whole pelvic field, 482–483
Whole pelvic radiotherapy, for gynecologic cancers, 430–434, 434f
Wide-angle free-air chamber (WAFAC), 250, 250f
Wilms’ tumor, 592
Worst-case approach, for IMRT planning, 146–147
X
X-ray beams
low-energy megavoltage, 5
medium- or high-energy megavoltage, 5
booksmedicos.org

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FOURTH

Faiz M. Khan, PhD

John P. Gibbons, PhD

Paul W. Sperduto, MD, MPP, FASTRO

Copyright © 2016 Wolters Kluwer

Library of Congress Cataloging-in-Publication Data

To my wife Nicole, for her continued patience and support

Judy A. Adams, CMD

John A. Antolak, PhD

James M. Balter, PhD

Christopher Beltran, PhD

Rachel C. Blitzblau, MD, PhD

Stefan Both, PhD

Frank J. Bova, PhD, FACR, FAAPM, FAAPM

Albert Chang, MD, PhD

George T. Y. Chen, PhD

Yen-Lin Evelyn Chen, MD

James C. L. Chow, PhD

Thomas F. DeLaney, MD, FASTRO

Lei Dong, PhD

Bahman Emami, MD, FACR, FASTRO

Robert L. Foote, MD, FASTRO

Ryan D. Foster, PhD

Yolanda I. Garces, MD, MS

John P. Gibbons Jr, PhD

Eli Glatstein, MD, FASTRO

Paul J. Keall, PhD

Faiz M. Khan, PhD

Eric E. Klein, PhD

Hanne M. Kooy, PhD

Gerald Kutcher, PhD

Guang Li, PhD, DABR

Tony Lomax, PhD

Gig S. Mageras, PhD

Amit Maity, MD, PhD

Charles Mayo, PhD

Minesh P. Mehta, MD, FASTRO

Dimitris N. Mihailidis, PhD, FAAPM, FACMP, CAMC

Radhe Mohan, PhD

Yvonne M. Mowery, MD, PhD

Arno J. Mundt, MD, FACRO, FASTRO

Sasa Mutic, PhD, FAAPM

Colin G. Orton, PhD

Niko Papanikolaou, PhD

Anthony Paravati, MD, MBA

Charles A. Pelizzari, PhD

John P. Plastaras, MD, PhD

Ezequiel Ramirez, MSRS, CMD, RT(R)(T)

Mark J. Rivard, PhD, FAAPM

Gregory C. Sharp, PhD

Chang W. Song, PhD

Paul W. Sperduto, MD, MPP, FASTRO

Kenneth R. Stevens Jr, MD

Alexander Sun, MD, FRCPC

Nancy J. Tarbell, MD, FASTRO

Bruce R. Thomadsen, PhD

Wolfgang A. Tomé, PhD, FAAPM

Jan Unkelbach, PhD

Gregory M. M. Videtic, MD, CM, FRPC

Kenneth J. Weeks, PhD

Christopher G. Willett, MD, FASTRO

John A. Wolfgang, PhD

Neil M. Woody, MD, MS