Professional Documents
Culture Documents
TX Planning in Rad Onc PDF
TX Planning in Rad Onc PDF
EDITION
KHAN’S
Treatment Planning in Radiation
Oncology
EDITORS
4th edition
Copyright © 2012 Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2006
Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 1998 by Lippincott
Williams & Wilkins. All rights reserved. This book is protected by copyright. No part of this book
may be reproduced or transmitted in any form or by any means, including as photocopies or
scanned-in or other electronic copies, or utilized by any information storage and retrieval system
without written permission from the copyright owner, except for brief quotations embodied in
critical articles and reviews. Materials appearing in this book prepared by individuals as part of
their official duties as U.S. government employees are not covered by the above-mentioned
copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001
Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at
lww.com (products and services).
9 8 7 6 5 4 3 2 1
Printed in China
This work is provided “as is,” and the publisher disclaims any and all warranties, express or
implied, including any warranties as to accuracy, comprehensiveness, or currency of the content
of this work.
This work is no substitute for individual patient assessment based upon healthcare professionals’
examination of each patient and consideration of, among other things, age, weight, gender,
current or prior medical conditions, medication history, laboratory data and other factors unique
to the patient. The publisher does not provide medical advice or guidance and this work is
merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible
for the use of this work including all medical judgments and for any resulting diagnosis and
treatments.
Given continuous, rapid advances in medical science and health information, independent
professional verification of medical diagnoses, indications, appropriate pharmaceutical selections
and dosages, and treatment options should be made and healthcare professionals should consult
a variety of sources. When prescribing medication, healthcare professionals are advised to
consult the product information sheet (the manufacturer’s package insert) accompanying each
drug to verify, among other things, conditions of use, warnings and side effects and identify any
changes in dosage schedule or contraindications, particularly if the medication to be
administered is new, infrequently used or has a narrow therapeutic range. To the maximum
extent permitted under applicable law, no responsibility is assumed by the publisher for any
injury and/or damage to persons or property, as a matter of products liability, negligence law or
otherwise, or from any reference to or use by any person of this work.
LWW.com
To Kathy, my wife and companion of fifty years:
Happy Anniversary, My Love.
—Faiz M. Khan
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
Fiori Alite, MD
Department of Radiation Oncology
Stritch School of Medicine
Loyola University
Maywood, Illinois
Jason Chan, MD
Resident in Training
Department of Radiation Oncology
University of California San Francisco
San Francisco, California
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
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina
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
Department of Radiation Oncology
University of California San Francisco
San Francisco, California
James A. Kavanaugh, MS
Department of Radiation Oncology
Washington University in St. Louis
Director of Satellite Services
Siteman Cancer Center
St. Louis, Missouri
Jonathan P. S. Knisely, MD
Associate Professor
Department of Radiation Medicine
Northwell Health
Hofstra University School of Medicine
Lake Success, New York
Rupesh Kotecha, MD
Resident
Department of Radiation Oncology
Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio
Shannon M. MacDonald, MD
Associate Professor of Radiation Oncology
Massachusetts General Hospital/Harvard Medical School
Francis H. Burr Proton Therapy Center
Boston, Massachusetts
Loren K. Mell, MD
Associate Professor
Department of Radiation Medicine and Applied Sciences
University of California San Diego
La Jolla, California
Manisha Palta, MD
Assistant Professor
Duke Cancer Institute
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina
Bradford A. Perez, MD
Resident
Duke Cancer Institute
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina
Kevin L. Stephans, MD
Assistant Professor
Taussig Cancer Institute
Department of Radiation Oncology
Cleveland Clinic
Cleveland, Ohio
Robert Timmerman, MD
Professor, Vice Chair
Department of Radiation Oncology
University of Texas Southwestern Medical Center
Dallas, Texas
Jordan A. Torok, MD
Resident Physician
Department of Radiation Oncology
Duke University School of Medicine
Duke Cancer Institute
Durham, North Carolina
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
Yi Wang, PhD
Instructor
Department of Radiation Oncology
Harvard Medical School
Medical Physicist
Radiation Oncology
Massachusetts General Hospital
Boston, Massachusetts
Darwin Yip, MD
Clinical Fellow
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Faiz M. Khan
John P. Gibbons
Paul W. Sperduto
Preface to First Edition
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
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
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
Julian Johnson and Albert Chang
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
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
SECTION I
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.
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
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.
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.
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
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
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.
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.
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-
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.”
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
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.
2 Imaging in Radiotherapy
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,
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
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.
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.
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.
FIGURE 2.3 Temporal aliasing artifacts when scanning a patient during respiration. Note distortion
at the lung/diaphragm interface, indicated by yellow.
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
line) at exhale (A); at inhale (B); residual artifacts due to irregular breathing (C).
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.
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.
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
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/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
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.
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
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.
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.
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.
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
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.
Segmentation
Volumes of interest can be segmented manually or automatically. In
manual segmentation, points are digitized by mouse on each transaxial
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.
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
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.
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.
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.
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.
KEY POINTS
• 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?
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
3. C
4. A
5. C
REFERENCES
1. Munzenrider JE, Pilepich M, Rene-Ferrero JB. Use of a body scanner
in radiotherapy treatment planning. Cancer. 1977;40:170–179.
2. Boyer AL, Butler EB, DiPetrillo TA, et al. Intensity-modulated
radiotherapy: Current status and issues of interest. Int J Radiat Oncol
Biol Phys. 2001;51(4):880–914.
3. Chang BK, Timmerman RD. Stereotactic body radiation therapy: a
comprehensive review. Am J Clin Oncol. 2007;30(6):637–644.
doi:10.1097/COC.0b013e3180ca7cb1.
4. Loeffler JS, Smith AR, Suit HD. The potential role of proton beams in
radiation oncology. Semin Oncol. 1997;24(6):686–695.
5. Wolbarst AB, Capasso P, Wyant AR. Medical Imaging: Essentials for
Physicians. Wiley Online Library; 2013.
6. Bushong SC. Radiologic Science for Technologists: Physics, Biology and
Protection. St. Louis, MO: Mosby; 1993.
7. Rosenow UF. Notes on the legacy of the Roentgen rays. Med Phys.
1995;22:1855–1868.
8. Siebert JA. One hundred years of medical technology. Health Phys.
1995;69:695–720.
9. Simpson DR, Lawson JD, Nath SK, et al. Utilization of advanced
imaging technologies for target delineation in radiation oncology. J
Am Coll Radiol JACR. 2009;6(12):876–883.
doi:10.1016/j.jacr.2009.08.006.
10. Pan X, Siewerdsen J, La Riviere P, et al. Anniversary Paper:
Development of x-ray computed tomography: The role of Medical
Physics and AAPM from the 1970s to present. Med Phys.
2008;35(8):3728–3739. doi:10.1118/1.2952653.
11. Schneider Ω, Bortfeld T, Schlegel W. Correlation between CT
numbers and tissue parameters needed for Monte Carlo simulations
of clinical dose distributions. Phys Med Biol. 2000;45(2):459–478.
12. Hünemohr N, Paganetti H, Greilich S, et al. Tissue decomposition
from dual energy CT data for MC based dose calculation in particle
therapy. Med Phys. 2014;41(6):061714. doi:10.1118/1.4875976.
13. Spitzer V, Ackerman MJ, Scherzinger AL, et al. The visible human
male: A technical report. J Am Med Inform Assoc. 1996;3(2):118–
130.
14. Olsen DR, Thwaites DI. Now you see it… Imaging in radiotherapy
treatment planning and delivery. Radiother Oncol. 2007;85(2):173–
175. doi:10.1016/j.radonc.2007.11.001.
15. Gao Z, Wilkins D, Eapen L, et al. A study of prostate delineation
referenced against a gold standard created from the visible human
data. Radiother Oncol. 2007;85(2):239–246.
doi:10.1016/j.radonc.2007.08.001.
16. Barrett JF, Keat N. Artifacts in CT: recognition and avoidance.
Radiographics. 2004;24(6):1679–1691. doi:10.1148/rg.246045065.
17. Balter JM, Ten Haken RK, Lawrence TS, et al. Uncertainties in CT-
based radiation therapy treatment planning associated with patient
breathing. Int J Radiat Oncol Biol Phys. 1996;36(1):167–174.
18. Chen GT, Kung JH, Beaudette KP. Artifacts in computed
tomography scanning of moving objects. Semin Radiat Oncol.
2004;14(1):19–26.
19. Vedam SS, Keall PJ, Kini VR, et al. Acquiring a four-dimensional
computed tomography dataset using an external respiratory signal.
Phys Med Biol. 2003;48(1):45–62. doi:10.1088/0031–
9155/48/1/304.
20. Ford EC, Mageras GS, Yorke E, et al. Respiration-correlated spiral
CT: a method of measuring respiratory-induced anatomic motion for
radiation treatment planning. Med Phys. 2003;30(1):88–97.
21. Low DA, Nystrom M, Kalinin E, et al. A method for the
reconstruction of four-dimensional synchronized CT scans acquired
during free breathing. Med Phys. 2003;30(6):1254–1263.
22. Pan T, Lee TY, Rietzel E, et al. 4D-CT imaging of a volume
influenced by respiratory motion on multi-slice CT. Med Phys.
2004;31(2):333–340.
23. Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography:
image formation and clinical protocol. Med Phys. 2005;32(4):874–
889.
24. Rietzel E, Chen GT, Choi NC, et al. Four-dimensional image-based
treatment planning: Target volume segmentation and dose
calculation in the presence of respiratory motion. Int J Radiat Oncol
Biol Phys. 2005;61(5):1535–1550.
25. Li T, Schreibmann E, Thorndyke B, et al. Radiation dose reduction
in four-dimensional computed tomography. Med Phys.
2005;32(12):3650–3660.
26. Ross CS, Hussy DH, Pennington EC. Analysis of movement in
intrathoracic neoplasm using ultrafast computerized tomography.
Int J Radiat Oncol Biol Phys. 1990;18:671–677.
27. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing
control (ABC) to reduce margin for breathing motion. Int J Radiat
Oncol Biol Phys. 1999;44(4):911–919.
28. Balter JM, McGinn CJ, Lawrence TS, et al. Improvement of CT-
based treatment-planning models of abdominal targets using static
exhale imaging. Int J Radiat Oncol Biol Phys. 1998;41(4):939–943.
29. Frank SJ, Kudchadker RJ, Kuban DA, et al. A volumetric trend
analysis of the prostate and seminal vesicles during a course of
intensity-modulated radiation therapy. Am J Clin Oncol.
2010;33(2):173–175. doi:10.1097/COC.0b013e3181a31c1a.
30. Jaffray DA, Siewerdsen H. Cone-beam computed tomography with
flat panel imager: initial performance characterization. Med Phys.
2000;27:1311–1323.
31. Sonke J-J, Zijp L, Remeijer P, et al. Respiratory correlated cone
beam CT. Med Phys. 2005;32(4):1176–1186.
32. Pouliot J, Bani-Hashemi A, Chen J, et al. Low-dose megavoltage
cone-beam CT for radiation therapy. Int J Radiat Oncol Biol Phys.
2005;61(2):552–560.
33. Mackie TR, Kapatoes J, Ruchala K, et al. Image guidance for precise
conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56(1):89–
105.
34. Adler JR, Chang SD, Murphy MJ, et al. The Cyberknife: a frameless
robotic system for radiosurgery. Stereotact Funct Neurosurg. 1997;
69(1–4 Pt 2):124–128.
35. Thornton AF, Sandler HM, Ten Haken RK, et al. The clinical utility
of MRI in 3-dimentional treatment planning of brain neoplasms. Int
J Radiat Oncol Biol Phys. 1992;24:767–775.
36. Korsholm, ME, Waring, LW, Edmund, JM. A criterion for the
reliable use of MRI-only radiotherapy. Radiat Oncol. 2014;9(16):1–7.
37. Jansen EPM, Dewit LGH, van Herk M, et al. Target volumes in
radiotherapy for high-grade malignant glioma of the brain.
Radiother Oncol. 2000;56(2):151–156. doi:10.1016/S0167–
8140(00)00216–4.
38. Berberat J, McNamara J, Remonda L, et al. Diffusion tensor imaging
for target volume definition in glioblastoma multiforme. Strahlenther
Onkol. 2014;190(10):939–943. doi:10.1007/s00066–014–0676–3.
39. Feng M, Balter JM, Normolle D, et al. Characterization of pancreatic
tumor motion using cine MRI: surrogates for tumor position should
be used with caution. Int J Radiat Oncol Biol Phys. 2009;74(3):884–
891. doi:10.1016/j.ijrobp.2009.02.003.
40. Padhani AR, Khoo VS, Suckling J, et al. Evaluating the effect of
rectal distension and rectal movement on prostate gland position
using cine MRI. Int J Radiat Oncol. 1999;44(3):525–533.
doi:10.1016/S0360–3016(99)00040–1.
41. Ghilezan MJ, Jaffray DA, Siewerdsen JH, et al. Prostate gland
motion assessed with cine-magnetic resonance imaging (cine-MRI).
Int J Radiat Oncol Biol Phys. 2005;62(2):406–417.
42. Orrison WW, Lewine JD, Sanders JA, et al. Functional brain
imaging. Mosby. In: Year Book. Chicago: Mosby; 1995.
43. Nakajima T, Fujita M, Watanabe H, et al. Functional mapping of the
human visual system with near-infrared spectroscopy and BOLD
functional MRI. In: Society of Magnetic Resonance Medicine. San
Francisco; 1994.
44. Cao Y, Towel V, Levin D, et al. Functional mapping of human motor
cortical activation with conventional MR imaging at 1.5 T. J Magn
Reson Imag. 1993;3:869–871.
45. Hamilton RJ, Sweeney PJ, Pelizzari CA, et al. Functional imaging in
treatment planning of brain lesions. Int J Radiat Oncol Biol Phys.
1997;37(1):181–188.
46. Nelson SJ. Multivoxel magnetic resonance spectroscopy of brain
tumors. Mol Cancer Ther. 2003;2(5):497–507.
47. Arrayeh E, Westphalen AC, Kurhanewicz J, et al. Does local
recurrence of prostate cancer after radiation therapy occur at the
site of primary tumor? Results of a longitudinal MRI and MRSI
study. Int J Radiat Oncol Biol Phys. 2012;82(5):e787–e793.
doi:10.1016/j.ijrobp.2011.11.030.
48. Narayana A, Chang J, Thakur S, et al. Use of MR spectroscopy and
functional imaging in the treatment planning of gliomas. Br J Radiol.
2007;80(953):347–354. doi:10.1259/bjr/65349468.
49. Ling CC, Humm J, Larson S, et al. Towards multidimensional
radiotherapy (MD-CRT): biological imaging and biological
conformality. Int J Radiat Oncol Biol Phys. 2000;47(3):551–560.
50. Shih HA, Harisinghani M, Zietman AL, et al. Mapping of nodal
disease in locally advanced prostate cancer: rethinking the clinical
target volume for pelvic nodal irradiation based on vascular rather
than bony anatomy. Int J Radiat Oncol Biol Phys. 2005;63(4):1262–
1269. doi:10.1016/j.ijrobp.2005.07.952.
51. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-
guided and controlled radiotherapy. Semin Radiat Oncol.
2014;24(3):196–199. doi:10.1016/j.semradonc.2014.02.008.
52. Lagendijk JJ, Raaymakers BW, Raaijmakers AJ, et al. MRI/linac
integration. Radiother Oncol. 2008;86(1):25–29.
doi:10.1016/j.radonc.2007.10.034.
53. Das SK, Ten Haken RK. Functional and molecular image guidance in
radiotherapy treatment planning optimization. Semin Radiat Oncol.
2011;21(2):111–118. doi:10.1016/j.semradonc.2010.10.002.
54. Bradley J, Thorstad WL, Mutic S, et al. Impact of FDG-PET on
radiation therapy volume delineation in non-small-cell lung cancer.
Int J Radiat Oncol Biol Phys. 2004;59(1):78–86.
doi:10.1016/j.ijrobp.2003.10.044.
55. Grosu A-L, Piert M, Weber WA, et al. Positron emission tomography
for radiation treatment planning. Strahlenther Onkol. 2005;
181(8):483–499. doi:10.1007/s00066–005–1422–7.
56. MacManus M, Nestle U, Rosenzweig KE, et al. Use of PET and
PET/CT for radiation therapy planning: IAEA expert report 2006–
2007. Radiother Oncol. 2009;91(1):85–94.
doi:10.1016/j.radonc.2008.11.008.
57. Chao KS, Bosch WR, Mutic S, et al. A novel approach to overcome
hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated
radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49(4):1171–
1182.
58. Townsend DW, Beyer T, Blodgett TM. PET/CT scanners: a hardware
approach to image fusion. Semin Nucl Med. 2003;33(3):193–204.
59. Abdelnour AF, Nehmeh SA, Pan T, et al. Phase and amplitude
binning for 4D-CT imaging. Phys Med Biol. 2007;52(12):3515–3529.
doi:10.1088/0031–9155/52/12/012.
60. Nehmeh SA, Erdi YE, Pan T, et al. Four-dimensional PET/CT
imaging of the thorax. Med Phys. 2004;31(12):3179–3186.
61. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of
validation studies on tumour assessment. Eur J Cancer.
2006;42(8):1031–1039. doi:10.1016/j.ejca.2006.01.026.
62. Shankar LK, Hoffman JM, Bacharach S, et al. Consensus
recommendations for the use of 18F-FDG PET as an indicator of
therapeutic response in patients in National Cancer Institute Trials. J
Nucl Med. 2006;47(6):1059–1066.
63. Lattanzi J, McNeeley S, Pinover W, et al. A comparison of daily CT
localization to a daily ultrasound-based system in prostate cancer.
Int J Radiat Oncol Biol Phys. 1999;43(4):719–725.
64. Langen KM, Pouliot J, Anezinos C, et al. Evaluation of ultrasound-
based prostate localization for image-guided radiotherapy. Int J
Radiat Oncol Biol Phys. 2003;57(3):635–644.
65. Simpson DR, Lawson JD, Nath SK, et al. A survey of image-guided
radiation therapy use in the United States. Cancer.
2010;116(16):3953–3960. doi:10.1002/cncr.25129.
66. Conner WG, Boone ML, Veomett R, al et. Patient repositioning and
motion detection using a video cancellation system. Int J Radiat
Oncol Biol Phys. 1975;1:147–153.
67. Bert C, Metheany KG, Doppke K, et al. A phantom evaluation of a
stereo-vision surface imaging system for radiotherapy patient setup.
Med Phys. 2005;32(9):2753–2762.
68. Bert C, Metheany KG, Doppke KP, et al. Clinical experience with a
3D surface patient setup system for alignment of partial-breast
irradiation patients. Int J Radiat Oncol Biol Phys. 2006;64(4):1265–
1274. doi:10.1016/j.ijrobp.2005.11.008.
69. Rong Y, Walston S, Welliver MX, et al. Improving intra-fractional
target position accuracy using a 3D surface surrogate for left breast
irradiation using the respiratory-gated deep-inspiration breath-hold
technique. PloS One. 2014;9(5):e97933.
doi:10.1371/journal.pone.0097933.
70. Berthelsen AK, Dobbs J, Kjellén E, et al. What’s new in target
volume definition for radiologists in ICRU Report 71? How can the
ICRU volume definitions be integrated in clinical practice? Cancer
Imaging. 2007;7:104–116. doi:10.1102/1470-7330.2007.0013.
71. ICRU 83 Prescribing, Recording and Reporting Intensity-Modulated
Photon-Beam Therapy (IMRT); 2010.
72. ICRU 78 Prescribing, Recording and Reporting Proton-Beam THerapy.
ICRU; 2007.
73. ICRU 50 Prescribing, Recording, and Reporting Photon Beam Therapy.
ICRU; 1993.
74. ICRU 62 Prescribing, Recording and Reporting Photon Beam Therapy
Supplement to ICRU Report 50; 1999.
75. Ontario Cancer Care. Contouring Nomenclature Recommendation
Report; 2014.
https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId
= 300038.
76. Santanam L, Hurkmans C, Mutic S, et al. Standardizing naming
conventions in radiation oncology. Int J Radiat Oncol Biol Phys.
2012;83(4):1344–1349.
77. Pham DL, Xu C, Prince JL. Current methods in medical image
segmentation. Annual Review of Biomedical Engineering. Vol. 2.
2000:315–337.
78. Sharp G, Fritscher KD, Pekar V, et al. Vision 20/20: perspectives on
automated image segmentation for radiotherapy. Med Phys.
2014;41(5):050902. doi:10.1118/1.4871620.
79. Leunens G, Menten J, Weltens C. Quality assessment of medical
decision making in radiation oncology: variability in target volume
delineation for brain tumors. Radiother Oncol. 1993;29:169–175.
80. McShan DL, Silverman A, Lanza DN, et al. A computerized three-
dimensional treatment planning system utilizing interactive color
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
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.
96. Milos Hasan. Shadie: A Domain-Specific Language for Volume
Rendering. Boston, MA: Massachusetts General Hospital; 2010.
miloshasan.net/Shadie/shadie.pdf.
3 Treatment Simulation
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:
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.
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.
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
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-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.
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
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).
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.
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).
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
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.
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.
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):
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).
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.,
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).
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
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
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.
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
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
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
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
through CT sections. Int J Radiat Oncol Biol Phys. 1983;9:789–797.
15. NEMA. The DICOM Standard. 2006.
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.
28. Tarver RD, Conces DJ Jr., Godwin JD. Motion artifacts on CT
simulate bronchiectasis. AJR Am J Roentgenol. 1988;151:1117–1119.
29. Vedam SS, Keall PJ, Kini VR, et al. Acquiring a four-dimensional
computed tomography dataset using an external respiratory signal.
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.
32. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing
control (ABC) to reduce margin for breathing motion. Int J Radiat
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.
42. Devic S. MRI simulation for radiotherapy treatment planning. Med
Phys. 2012;39:6701–6711.
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.
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.
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.
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.)
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
(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.
where YP(r) and (Kc(r))P are the primary energy fluence and collision
Convolution/Superposition Method
Unfortunately, Equation (4.1) is simplistic because it does not take into
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:
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.)
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.
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
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.
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
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
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):
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
the results (34). However, these issues have led to improved, high-
accuracy condensed history methods (34–36).
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.
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):
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.)
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.)
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
• 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
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.
1993;20(5):1417–1427.
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.
Australas Phys Eng Sci Med. 1992;15(4):159–178.
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.
14. Kubsad SS, Mackie TR, Gehring MA, et al. Monte Carlo and
convolution dosimetry for stereotactic radiosurgery. Int J Radiat
Oncol Biol Phys. 1990; 19(4):1027–1035.
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.
16. Metcalfe PE, Hoban PW, Murray DC. Beam hardening of 10 MV
radiotherapy x-rays: analysis using a convolution/superposition
method. Phys Med Biol. 1990;35(11):1533–1549.
17. Papanikolaou N, Mackie TR, Meger-Wells C, et al. Investigation of
the convolution method for polyenergetic spectra. Med Phys.
1993;20(5):1327–1336.
18. 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(12):1960–
1974.
19. Liu HH, Mackie TR, McCullough EC. Correcting kernel tilting and
hardening in convolution/superposition dose calculations for
clinical divergent and polychromatic photon beams. Med Phys.
1997;24(11):1729–1741.
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.
21. Mackie TR, Bielajew AF, Rogers DW, et al. Generation of photon
energy deposition kernels using the EGS Monte Carlo code. Phys
Med Biol. 1988;33(1):1–20.
22. Mohan R, Chui C, Lidofsky L. Energy and angular distributions of
photons from medical linear accelerators. Med Phys.
1985;12(5):592–597.
23. Chaney EL, Cullip TJ, Gabriel TA. A Monte Carlo study of
accelerator head scatter. Med Phys. 1994;21(9):1383–1390.
24. Lovelock DM, Chui CS, Mohan R. A Monte Carlo model of photon
beams used in radiation therapy. Med Phys. 1995;22(9):1387–1394.
25. Sharpe MB, Jaffray DA, Battista JJ, et al. Extrafocal radiation: a
unified approach to the prediction of beam penumbra and output
factors for megavoltage x-ray beams. Med Phys. 1995;22(12):2065–
2074.
26. Hoban PW, Murray DC, Round WH. Photon beam convolution using
polyenergetic energy deposition kernels. Phys Med Biol.
1994;39(4):669–685.
27. Rogers DWO, Bielajew AF. Monte Carlo techniques of electron and
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.
29. Andreo P. Monte Carlo techniques in medical radiation physics.
Phys Med Biol. 1991;36(7):861–920.
30. Bielajew AF. The Monte Carlo simulation of radiation transport. In:
Curran B, Balter J, Chetty I, eds. AAPM Monograph No. 32:
Integrating New Technologies into the Clinic: Monte Carlo and Image-
Guided Radiation Therapy. Madison, WI: Medical Physics Publishing;
2006:697.
31. Rogers DW. Fifty years of Monte Carlo simulations for medical
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
planning. Med Phys. 2007;34(12):4818–4853.
33. Kawrakow I. Accurate condensed history Monte Carlo simulation of
electron transport. I. EGSnrc, the new EGS4 version. Med Phys.
2000;27(3):485–498.
34. Bielajew AF, Rogers DWO, Jenkins TW, et al. Monte Carlo Transport
of Electrons and Photons. New York, NY: Plenum; 1988:115–137.
35. Kawrakow I, Bielajew AF. On the condensed history technique for
electron transport. Nucl Instrum Methods Phys Res B. 1998;142:253–
280.
36. Seltzer SM. Electron-photon Monte Carlo calculations: The ETRAN
code. Intl J Appl Radiat Isot. 1991;42:917–941.
37. Kawrakow I, Rogers DW, Walters BR. Large efficiency
improvements in BEAMnrc using directional bremsstrahlung
splitting. Med Phys. 2004;31(10):2883–2898.
38. Case KM, Zweifel PF. Linear Transport Theory. Reading, MA:
Addison-Wesley; 1967.
39. Bell GI, Glasstone S. Nuclear Reactor Theory. New York, NY: Van
Nostrand Reinhold Company; 1970:619.
40. Boman E, Tervo J, Vauhkonen M. Modelling the transport of
ionizing radiation using the finite element method. Phys Med Biol.
2005;50(2):265–280.
41. Borgers C. Complexity of Monte Carlo and deterministic dose-
calculation methods. Phys Med Biol. 1998;43(3):517–528.
42. Lewis EE, Miller WFJ. Computational Methods of Neutron Transport.
New York, NY: Wiley; 1984.
43. Dautray R, Lions JL. Mathematical Analysis and Numerical Methods
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.
2008;72(1):220–227.
46. Lorence L, Morel J, Valdez G. Physics Guide to CEPXS: a Multigroup
Coupled Electron-Photon Cross Section Generating Code. New Mexico:
Sandia National Laboratories: Albuquerque; 1989:110.
47. Wareing TA, McGhee JM, Morel JE, et al., Discontinuous finite
element Sn methods on 3-D unstructured grids. Nucl Sci Eng.
2001;138:256–268.
48. Eclipse Photon and Electron Algorithms Reference Guide. Varian
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.
5 Treatment Planning Algorithms:
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
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
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
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.
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.
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.
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
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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
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.
REFERENCES
1. Khan F. The Physics of Radiation Therapy. 2nd ed. Baltimore, MD:
Williams & Wilkins; 1994.
2. Perez CA, Glasgow GP. Clinical applications of brachytherapy. In:
Perez CA, Brady LW, eds. Principles and Practice of Radiation
Oncology. Philadelphia, PA: JB Lippincott Co; 1987.
3. Johns HE, Cunningham JR. The Physics of Radiology. 4th ed.
Springfield, IL: Charles C Thomas Publisher; 1983.
4. Pierquin B, Chassagne DJ, Chahbazian CM, et al. Brachytherapy. St.
Louis, MO: Warren H. Green; 1978.
5. Glasgow GP. Low dose rate brachytherapy. In: Khan F, Gerbi BJ, eds.
Treatment Planning in Radiation Oncology 3rd Ed. Philadelphia, PA:
Lippincott Williams Wilkins; 2012.
6. Attix FH. Introduction To Radiological Physics And Radiation Dosimetry.
New York, NY: John Wiley & Sons; 1986.
7. Brown E, Firestone RB, Shirley VS. Table of Radioactive Isotopes. New
York, NY: John Wiley & Sons; 1986.
8. Meisberger LL, Keller RJ, Shalek RJ. The effective attenuation in
water of the gamma rays of gold 198, iridium 192, cesium 137,
radium 226, and cobalt 60. Radiology. 1968;90:953–957.
9. Meli JA, Meigooni AS, Nath R. On the choice of phantom material
for the dosimetry of 192Ir sources. Int J Radiat Oncol Biol Phys.
1988;14:587–594.
10. Dale RG. Some theoretical derivations relating to the tissue
dosimetry of brachytherapy nuclides, with particular reference to
iodine-125. Med Phys. 1983;10:176–183.
11. Hale J. The use of interstitial radium dose-rate tables for other
radioactive isotopes. Am J Roentgenol Radium Ther Nucl Med. 1958;
79:49–53.
12. Evans RD, Noyau A. The Atomic Nucleus. New York, NY: McGraw
Hill; 1955.
13. Kornelson RO, Young ME. Brachytherapy buildup factors. Br J
Radiol. 1981;54:136.
14. Webb S, Fox RA. The dose in water surrounding point isotropic
gamma ray emitters. Br J Radiol. 1979;52:482–484.
15. Venselaar JL, van der Giessen PH, Dries WJ. Measurement and
calculation of the dose at large distances from brachytherapy
sources: Cs-137, Ir-192, and Co-60. Med Phys. 1996;23:537–543.
16. van Kleffens HJ, Star WM. Application of stereo X-ray
photogrammetry (SRM) in the determination of absorbed dose
values during intracavitary radiation therapy. Int J Radiat Oncol Biol
Phys. 1979;5:557–563.
17. Dale RG. A Monte Carlo derivation of parameters for use in the
tissue dosimetry of medium and low energy nuclides. Br J Radiol.
1982;55:748–757.
18. Park HC, Almond PR. Evaluation of the buildup effect of an 192Ir
high dose-rate brachytherapy source. Med Phys. 1992;19:1293–
1297.
19. Weaver K. Brachytherapy dose calculations: calculational
algorithms. In: Thomadsen B, ed. Categorical Course in Brachytherapy
Physics. Oak Brook, IL: Radiological Society of North America;
1997:41–49.
20. Sievert RM. Die intensitatatverteilung der primaren-strehlung in der
nahe medinizinisher radium-praparate. Acta Radiol. 1921;1:89–128.
21. Young ME, Batho HF. Dose tables for linear radium sources
calculated by an electronic computer. Br J Radiol. 1964;37:38–44.
22. Glasgow GP, Dillman LT. Specific gamma-ray constant and exposure
rate constant of 192Ir. Med Phys. 1979;6:49–52.
23. Glasgow GP. Exposure rate constants for filtered 192Ir sources. Med
Phys. 1981;8:502–503.
24. Diffey BL, Klevenhagen SC. An experimental and calculated dose
distribution in water around CDC K-type Cesium-137 sources. Phys
Med Biol. 1975;20:446–454.
25. van der Laarse R, Meertens H. An algorithm for ovoid shielding of a
cervix applicator. In: Cunningham JR, Ragan D, Van Dyk J, eds. The
Proceedings 8th International Conference on The Use of Computers in
Radiation Therapy, Toronto, Canada, July 9–12. Los Angeles, CA:
IEEE Computer Society; 1984.
26. Williamson JF. Monte Carlo and analytic calculation of absorbed
dose near 137Cs intracavitary sources. Int J Radiat Oncol Biol Phys.
1988;15:227–237.
27. Meertens H, van der Laarse R. Screens in ovoids of a Selectron
cervix applicator. Radiother Oncol. 1985;3:69–80.
28. Weeks KJ, Dennett JC. Dose calculation and measurements for a CT
compatible version of the Fletcher applicator. Int J Radiat Oncol Biol
Phys. 1990;18:1191–1198.
29. Williamson JF. Monte Carlo evaluation of specific dose constants in
water for 125I seeds. Med Phys. 1988;15:686–694.
30. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial
brachytherapy sources: recommendations of the AAPM Radiation
Therapy Committee Task Group 43. Med Phys. 1995;22:209–234.
31. Rivard MJ, Coursey BM, DeWerd LA, et al. Update of AAPM Task
Group No. 43 Report: A revised AAPM protocol for brachytherapy
dose calculations. Med Phys. 2004;31:633–674.
32. Williamson JF, Butler W, DeWerd LA, et al. Recommendations of
the American Association of Physicists in medicine regarding the
impact of implementing the 2004 Task Group 43 report on dose
specification for 103Pd and 125I interstitial brachytherapy. Med
Phys. 2005;32:1424–1439.
33. DeWerd LA, Huq MS, Das IJ, et al. Procedures for establishing and
maintaining consistent air- kerma strength standards for low-energy,
photon-emitting brachytherapy sources: recommendations of the
Calibration Laboratory Accreditation Subcommittee of the American
Association of Physics in medicine. Med Phys. 2004;31:675–681.
34. Rivard MJ, Butler WM, DeWerd LA, et al. Supplement to the 2004
update of AAPM Task Group No. 43 Report. Med Phys.
2007;34:2187–2205.
35. Chan GH, Nath R, Williamson JF. On the development of consensus
values of reference dosimetry parameters for interstitial
brachytherapy sources. Med Phys. 2004;31:1040–1045.
36. Karaiskos P, Angelopoulos A, Sakellio L et al. Monte Carlo and TLD
dosimetry of an 192Ir high dose-rate brachytherapy source. Med
Phys. 1998;25:1975–1984.
37. Heintz BH, Wallace RE, Hevezi JM. Comparison of I-125 sources
used for permanent interstitial implants. Med Phys. 2001;28:671–
682.
38. Mainegra E, Capote R, Lopez E. Dose-rate constants for 125I, 103Pd,
192Ir and 169Yb brachytherapy sources: an EGS4 Monte Carlo
study. Phys Med Biol. 1998;43:1557–1566.
39. Williamson JF. The accuracy of the line and point source
approximations in Ir-192 dosimetry. Int J Radiat Oncol Biol Phys.
1990;12:409–414.
40. Thomason C, Mackie TR, Lindstrom MJ, et al. The dose distribution
surrounding 192Ir and 137Cs seed sources. Phys Med Biol.
1991;36:475–493.
41. Mainegra E, Capote R, Lopez E. Radial dose functions for 103Pd,
125I, 169Yb and 192Ir brachytherapy sources: an EGS4 Monte Carlo
study. Phys Med Biol. 2000;45:703–717.
42. Kirov AS, Williamson JF, Meigooni AS, et al. TLD, diode, and Monte
Carlo dosimetry of an 192Ir source for high dose-rate
brachytherapy. Phys Med Biol. 1995;40:2015–2036.
43. Nath R, Meigooni AS, Muench P, et al. Anisotropy functions for
103Pd, 125I, and 192Ir interstitial brachytherapy sources. Med Phys.
1993;20:1465–1473.
44. Capote R, Mainegra E, Lopez E. Anisotropy functions for low energy
interstitial brachytherapy sources: an EGS4 Monte Carlo Study. Phys
Med Biol. 2001;46:135–150.
45. Brunet-Benkhoucha M, Verhaegen F, Lassalle S, et al. Clinical
Implementation of a digital tomosyhthesis-based seed reconstruction
algorithm for intraoperative postimplant dose evaluation in low
dose rate prostate brachytherapy. Med. Phys. 2009;36:5235–5244.
46. Corbett JF, Jezioranski JJ, Crook J, et al. The effect of seed
orientation deviations on the quality of 125I prostate implants. Phys
Med Biol. 2001;46:2785–2800.
47. Furhang EE, Anderson LL. Functional fitting of interstitial
brachytherapy dosimetry data recommended by the AAPM
Radiation Therapy Committee Task Group 43. Med Phys.
1999;26:153–160.
48. Sloboda RS, Menon GV. Experimental determination of the
anisotropy function and anisotropy factor for model 6711 I-125
seeds. Med Phys. 2000;27:1789–1799.
49. Ling CC, Schell MC, Yorke ED, et al. Two dimensional dose
distribution of 125I seeds. Med Phys. 1985;12:652–655.
50. Ling CC, Spiro IJ, Kubiatowicz DO, et al. Measurement of dose
distribution around Fletcher-Suit-Delcos colpostats using a Therados
radiation field analyzer (RFA-3). Med Phys. 1984;11:326–330.
51. Mohan R, Ding IY, Martel MK, et al. Measurements of radiation
dose distributions for shielded cervical applicators. Int J Radiat
Oncol Biol Phys. 1985;11:861–868.
52. Williamson JF. Dose calculations about shielded gynecological
colpostats. Int J Radiat Oncol Biol Phys. 1990;19:167–178.
53. Weeks KJ. Monte Carlo calculations for a new ovoid shield system
for carcinoma of the uterine cervix. Med Phys. 1998;25:2288–2292.
54. Mohan R, Ding IY, Toraskar J, et al. Computation of radiation dose
distributions for shielded cervical applicators. Int J Radiat Oncol Biol
Phys. 1985;11:823–830.
55. Russell KR, Ahnesjo A. Dose calculation in brachytherapy for a
192Ir source using a primary and scatter dose separation technique.
Phys Med Biol. 1996;1007–1024.
56. Rose ME. Elementary Theory of Angular Momentum. New York, NY:
Wiley; 1957.
57. Weeks KJ. Brachytherapy object oriented treatment planning using
three dimensional image guidance. In: Thomadsen B, ed. Categorical
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
brachytherapy sources. Med Phys. 1979;6:454–456.
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.
6 Treatment Planning Algorithms:
Electron Beams
Faiz M. Khan
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
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.
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 < +∞.
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.)
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.)
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.)
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
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 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
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.)
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
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.
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
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
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
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.
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.
26. 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.
7 Treatment Planning Algorithms:
Proton Therapy
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
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.
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.
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
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.
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
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.
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):
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).
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
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
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)
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).
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.
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
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.
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.
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 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
−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.
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.
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,
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).
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
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
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.
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.
13. Hogstrom KR, Mills MD, Almond PR. Electron beam dose
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.
8 Commissioning and Quality
Assurance
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
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
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.
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
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
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.
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
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.
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
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
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.
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 8.5 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.
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%.
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
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).
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
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.
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
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).
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
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
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:
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
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.
SUMMARY
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
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.
QUESTIONS
1. Dose calculations for an enface photon beam in a homogenous
phantom exhibit the highest absolute uncertainty in which
region?
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.
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.
REFERENCES
1. Peters LJ, O’Sullivan B, Giralt J, et al. Critical impact of radiotherapy
protocol compliance and quality in the treatment of advanced head
and neck cancer: results from TROG 02.02. J Clin Oncol.
2010;28(18):2996–3001.
2. Bogdanich W. The Radiation Boom. As Technology Surges, Radiation
Safeguards Lag. New York, NY: New York Times; 2010:A1, New York
edition.
3. Bogdanich W. The Radiation Boom. Radiation Offers New Cures, and
Ways to do Harm. New York Times; 2010:A1, New York edition.
4. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: quality
assurance of medical accelerators. Med Phys. 2009;36(9):4197–4212.
5. Wu Q, Xing L, Ezzell G, et al. Inverse treatment planning. In: Van
Dyk J, ed. The Modern Technology of Radiation Oncology: A
Compendium For Medical Physicists And Radiation Oncologists. Volume
2. Madison,WI: Medical Physics Publishing; 2005:131–183.
6. Xia P, Verhey LJ. Intensity-modulated radiation therapy. In: Van Dyk
J, ed. The Modern Technology of Radiation Oncology: A Compendium
for Medical Physicists and Radiation Oncologists. Volume 2. Madison,
WI: Medical Physics Publishing; 2005:221–258.
7. Jeraj R, Bowen S, Jallow N, et al. Molecular imaging in radiation
oncology. In: Van Dyk J, ed. The Modern Technology of Radiation
Oncology: A Compendium for Medical Physicists and Radiation
Oncologists. Volume 3. Madison, WI: Medical Physics Publishing;
2013:25–58.
8. Yorke ED, Mechalakos JG, Rosenzweig KE. Dose-volume
considerations: an update for use in treatment planning. In: Van Dyk
J, ed. The Modern Technology of Radiation Oncology: A Compendium
for Medical Physicists And Radiation Oncologists. Volume 2.
Madison,WI: Medical Physics Publishing; 2013:59–90.
9. Tol JP, Delaney AR, Dahele M, et al. Evaluation of a knowledge-
based planning solution for head and neck cancer. Int J Radiat Oncol
Biol Phys. 2015;91(3):612–620.
10. Wu QJ, Li T, Wu Q, et al. Adaptive radiation therapy: technical
components and clinical applications. Cancer J. 2011;17(3):182–
189.
11. Shafiq J, Barton M, Noble D, et al. An international review of
patient safety measures in radiotherapy practice. Radiother Oncol.
2009;92(1):15–21.
12. Gershkevitsh E, Pesznyak C, Petrovic B, et al. Dosimetric inter-
institution comparison in European radiotherapy centres: results of
IAEA supported treatment planning system audit. Acta Oncol.
2014;53;628–636.
13. 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;25:1773–1829.
14. Van Dyk J, Rosenwald J-C, Fraass B, et al. Commissioning and
Quality Assurance of Computerized Planning Systems for Radiation
Treatment of Cancer. IAEA TRS-430. Vienna, Austria: International
Atomic Energy Agency; 2004.
15. International Atomic Energy Agency. IAEA-TECDOC-1540.
Specification and Acceptance Testing of Radiotherapy Treatment
Planning Systems. Vienna, Austria: International Atomic Energy
Agency; 2007.
16. International Atomic Energy Agency. IAEA-TECDOC-1583:
Commissioning of Radiotherapy Treatment Planning Systems: Testing for
Typical External Beam Treatment Techniques. Vienna, Austria:
International Atomic Energy Agency; 2008.
17. Cho SH, Vassiliev ON, Lee S, et al. Reference photon dosimetry data
and reference phase space data for the 6 MV photon beam from
Varian Clinac 2100 series linear accelerators. Med Phys. 2005;
32:137–148.
18. Das IJ, Cheng C-W, Watts, RJ, et al. Accelerator beam data
commissioning equipment and procedures: Report of the TG-106 of
the Therapy Physics Committee of the AAPM. Med Phys. 2008;
35(9):4186–4215.
19. Das IJ, Njeh CF. Point/Counterpoint: Vendor provided machine data
should never be used as a substitute for fully commissioning a linear
accelerator. Med Phys. 2012;39:569–573.
20. 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;21:581–618.
21. Brahme A, ed. Accuracy requirements and quality assurance of
external beam therapy with photons and electrons. Acta Oncol.
1988;27(Suppl 1):5–76.
22. Williamson JF, Thomadsen BR, eds. Quality assurance for radiation
therapy: the challenges of advanced technologies symposium. Int J
Radiat Oncol Biol Phys. 2008;72(Suppl 1):S1–S214.
23. Wheatley BM. An instrument for dosage estimation with fields of
any size and any shape. Brit J Radiol. 1951;24:388–391.
24. Cunningham JR. The Gordon Richards memorial lecture: the
stampede to compute: computers in radiotherapy. J Can Assoc
Radiol. 1971;22:242–251.
25. Tsien KC. The application of automatic computing machines to
radiation treatment planning. Brit J Radiol. 1955;28:432–439.
26. Power WE, Korba A, Purdy JA, et al. Dose profiles in treatment
planning. Radiology. 1976;121(3 Pt. 1):741–742.
27. The use of computers in therapeutic radiology. Special report no. 1.
Symposium Proceedings of First International Conference of
Computers in Radiotherapy, Cambridge, UK, 1966. London: British
Institute of Radiology; 1967.
28. Haworth A, Kron T, ed. Proceedings of the XVIIth International
Conference on the Use of Computers in Radiotherapy (ICCR 2013).
Melbourne, Australia. Journal of Physics: Conference Series 489;
2014.
29. Moore KL, Kagadis GC, McNutt TR, et al. Vision 20/20: Automation
and advanced computing in clinical radiation oncology. Med Phys.
2014;41(1):010901.
30. Mijnheer B, Olszewska A, Fiorino C, et al. Quality Assurance of
Treatment Planning Systems: Practical Examples of Non-IMRT Photon
Beams. Brussels: European Society of Therapeutic Radiation
Oncology (ESTRO); 2004.
31. Bruinvis IAD, Keus RB, Lenglet WJM, et al. Quality assurance of 3D
treatment planning systems for external photon and electron beams.
Report 15 of the Netherlands Commission on Radiation Dosimetry.
Delft, The Netherlands: Netherlands Commission on Radiation
Dosimetry (NCS); 2006.
32. International Electrotechnical Commission (IEC). Medical electrical
equipment—requirements for the safety of radiotherapy treatment
planning systems. IEC 62083 (2000–11). Geneva: International
Electrotechnical Commission; 2000.
33. Ezzell GA, Burmeister JW, Dogan N, et al. IMRT commissioning:
multiple institution planning and dosimetry comparisons, a report
from AAPM Task Group No. 119. Med Phys. 2009; 36(11):5359–
5373.
34. International Commission on Radiation Units and Measurements.
ICRU Report 62. Prescribing, Recording, and Reporting Photon Beam
Therapy (Supplement to ICRU Report 50). Bethesda, MD: ICRU; 1999.
35. Verhey L, Bentel G. Patient immobilization. In: Van Dyk J, ed. The
modern technology of radiation oncology: a compendium for medical
physicists and radiation oncologists. Madison, WI: Medical Physics
Publishing; 1999:53–94.
36. Siebers JV, Keall PJ, Kawrakow I. Monte Carlo dose calculations for
external beam radiation therapy. In: Van Dyk J, ed. The modern
technology of radiation oncology: a compendium for medical physicists
and radiation oncologists. Volume 2. Madison, WI: Medical Physics
Publishing; 2005:91–130.
37. 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.
38. Papanikolaou N, Battista JJ, Boyer AL, et al. Tissue Inhomogeneity
Corrections for Megavoltage Photon Beams. Report by Task Group 65 of
the Radiation Therapy Committee of the American Association of
Physicists in Medicine. AAPM Report 85. Madison, WI: Medical
Physics Publishing; 2004.
39. Rivard MJ, Venselaar JL, Beaulieu L. The evolution of
brachytherapy treatment planning. Med Phys. 2009;36:2136–2153.
40. International Commission on Radiation Units and Measurements.
ICRU Report 42: Use of Computers in External Beam Radiotherapy
Procedures with High-Energy Photons and Electrons. Bethesda, MD:
International Commission On Radiation Units and Measurements;
1987.
41. Van Dyk J, Barnett RB, Cygler JE, et al. Commissioning and quality
assurance of treatment planning computers. Int J Radiat Oncol Biol
Phys. 1993;26:261–273.
42. Venselaar J, Welleweerd H, Mijnheer B. Tolerances for the accuracy
of photon beam dose calculations of treatment planning systems.
Radiother Oncol. 2001;60:191–201.
43. DeWerd LA, Ibbott GS, Meigooni AS, et al. A dosimetric uncertainty
analysis for photon-emitting brachytherapy sources: report of AAPM
Task Group No. 138 and GEC-ESTRO. Med Phys. 2011;38:782–801.
44. Venselaar J, Welleweerd H. Application of a test package in an
intercomparison of the photon dose calculation performance of
treatment planning systems used in a clinical setting. Radiother
Oncol. 2001;60:203–213.
45. Mackie TR. History of tomotherapy. Phys Med Biol. 2006;51:R427–
R453.
46. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-
guided and controlled radiotherapy. Semin Radiat Oncol.
2014;24:196–199.
47. Wowra B, Muacevic A, Jess-Hempen A, et al. Safety and efficacy of
outpatient gamma knife radiosurgery for multiple cerebral
metastases. Expert Rev Neurother. 2004;4:673–679.
48. Zhu TC, Palta JR. Electron contamination in 8 and 18 MV photon
beams. Med Phys. 1998;25:12–19.
49. Bedford JL, Childs PJ, Nordmark H, et al. Commissioning and
quality assurance of the Pinnacle(3) radiotherapy treatment
planning system for external beam photons. Br J Radiol.
2003;76:163–176.
50. Cadman P, McNutt T, Bzdusek K. Validation of physics
improvements for IMRT with a commercial treatment-planning
system. J Appl Clin Med Phys. 2005:6:74–86.
51. Cadman P, Bassalow R, Sidhu NP, et al. Dosimetric considerations
for validation of a sequential IMRT process with a commercial
treatment planning system. Phys Med Biol. 2002;47:3001–3010.
52. International Commission on Radiation Units and Measurements.
ICRU Report 83: Prescribing, Recording, and Reporting Photon-Beam
Intensity-Modulated Radiation Therapy (IMRT). Bethesda, MD:
International Commission On Radiation Units and Measurements;
2010.
53. Craft DL, Hong TS, Shih HA, et al. Improved planning time and plan
quality through multicriteria optimization for intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys. 2012; 82(1):e83–e90.
54. Voet PWJ, Maarten DLP, Breedveld S, et al. Toward fully automated
multicriterial plan generation: a prospective clinical study. Int J
Radiat Oncol Biol Phys. 2012;85(3):866–872.
55. Moore KL, Brame RS, Low DA, et al. Experience-based quality
control of clinical intensity-modulated radiotherapy planning. Int J
Radiat Oncol Biol Phys. 2011;81(2):545–551.
56. Zhang X, Li X, Quan EM, et al. A methodology for automatic
intensity-modulated radiation treatment planning for lung cancer.
Phys Med Biol. 2011;56:3873–3893.
57. Wu B, Ricchetti F, Sanguineti G, et al. Patient geometry-driven
information retrieval for IMRT treatment plan quality control. Med
Phys. 2009;36(12):5497–5505.
58. Good D, Lo J, Lee WR, et al. A knowledge-based approach to
improving and homogenizing intensity modulated radiation therapy
planning quality among treatment centers: an example application
to prostate cancer planning. Int J Radiat Oncol Biol Phys.
2013;87(1):176–181.
59. Appenzoller LM, Michalski JM, Thorstad WL, et al. Predicting dose-
volume histograms for organs-at-risk in IMRT planning. Med Phys.
2012;39(12):7446–7461.
60. Zhu X, Ge Y, Thongphiew D, et al. A planning quality evaluation
tool for prostate adaptive IMRT based on machine learning. Med
Phys. 2011;38(2):719–726.
61. Altman MB, Kavanaugh JA, Green OL, et al. Addressing the issues
limiting rapid contour evaluation to facilitate On-line Adaptive
Radiation Therapy (OL-ART) with MR-IGRT. Int JRadiat Oncol Biol
Phys. 2014;90(1):S860.
62. Caldwell C, Mah K. Imaging for radiation therapy planning. In: Van
Dyk J, ed. The Modern Technology of Radiation Oncology: A
Compendium for Medical Physicists and Radiation Oncologists. Volume
2. Madison, WI: Medical Physics Publishing; 2005:31–89.
63. Kessler ML. Image registration and data fusion in radiation therapy.
Br J Radiol. 2006;70:S99–S108.
64. Njeh CF. Tumor delineation: the weakest link in the search for
accuracy in radiotherapy. J Med Phys. 2008;33(4):136–140. doi:
10.4103/0971–6203.44472.
65. Khoo VS, Joon DL. New developments in MRI for target volume
delineation in radiotherapy. Br J Radiol. 2006;79:S2–S15.
66. Price PM, Green MM. Positron emission tomography imaging
approaches for external beam radiation therapies: current status and
future developments. Br J Radiol. 2011;84:S19–S34.
67. Macmanus M, Nestle U, Rosenweig KE, et al. Use of PET and
PET/CT for Radiation Therapy Planning: IAEA expert report 2006–
2007. Radiother Oncol. 2008;91:85–94.
68. Li G, Citrin D, Camphausen K, et al. Advances in 4D medical
imaging and 4D radiation therapy. Technol Cancer Res Treat.
2008;7:67–81.
69. Brock KK. Deformable registration accuracy consortium. Results of a
multi-institution deformable registration accuracy study (MIDRAS).
Int J Radiat Oncol Biol Phys. 2010;76(2):583–596.
70. Brock KK, Kessler ML, Mutic S, et al. AAPM Task Group 132: use of
image registration and data fusion algorithms and techniques in
radiotherapy treatment planning.
71. Teguh DN, Levendag PC, Voet PW, et al. Clinical validation of atlas-
based auto-segmentation of multiple target volumes and normal
tissue (swallowing/maticiation) structures in the head and neck. Int
J Radiat Oncol Biol Phys. 2011;81(4):950–957.
72. Gambacorta MA, Valentini C, Dinapoli N, et al. Clinical validation
of atlas-based auto-segmentation of pelvic volumes and normal
tissue in rectal tumors using auto-segmentation computed system.
Acta Oncologica. 2013;52:1676–1681.
73. Li T, Zhu X, Thongphlew D, et al. On-line adaptive radiation
therapy: feasibility and clinical study. J Oncol. 2010;2010:407236.
74. Noel CE, Santanam L, Parikh PJ, et al. Process-based quality
management for clinical implementation of adaptive radiotherapy.
Med Phys. 2014;41(8):081717.
75. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial
brachytherapy sources. Med Phys. 1995;22(2):209–234.
76. Rivard MJ, Coursey BM, DeWerd LA, et al. Update of AAPM Task
Group No. 43 Report: A revised AAPM protocol for brachytherapy
dose calculations. Med Phys. 2004;31(3):633–674.
77. Perez-Calatayud J, Ballester F, Das RK, et al. Report of the High
Energy Brachytherapy Source Dosimetry (HEBD) Working Group: Dose
Calculation for Photon-Emitting Brachytherapy Sources with Average
Energy Higher than 50 keV: Full Report of the AAPM and ESTRO.
College Park, MD: AAPM; 2012.
78. Rivard MJ, Beaulieu L, Mourtada F. Enhancements to
commissioning techniques and quality assurance of brachytherapy
treatment planning systems that use model-based dose calculation
algorithms. Med Phys. 2010;37:2645–2658.
79. Beaulieu L, Tedgren AC, Carrier JF, 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.
80. Paganetti H, Jiang H, Lee SY, et al. Accurate Monte Carlo
simulations for nozzle design, commissioning and quality assurance
for a proton radiation therapy facility. Med Phys. 2004;31:2107–
2118.
81. Zhu XR, Poenisch F, Sawakurchi GO, et al. Commissioning dose
computation models for spot scanning proton beams in water for a
commercially available treatment planning system. Med Phys.
2013;40(4):041723.
82. Slopsema RL, Lin L, Flampouri S, et al. Development of a golden
beam data set for the commissioning of a proton double-scatter
system in a pencil-beam dose calculation algorithm. Med Phys.
2014;41(9):091710.
83. Paganetti H. Proton Therapy Physics, Series in Medical Physics and
Biomedical Engineering. Boca Raton, FL: CRC Press; 2012.
84. International Commission on Radiation Units and Measurements.
ICRU Report 78: Prescribing, Recording, and Reporting Proton-Beam
Therapy. Bethesda, MD: International Commission On Radiation
Units and Measurements; 2007.
85. Park PC, Zhu XR, Lee AK, et al. A beam-specific planning target
volume (PTV) design for proton therapy to account for setup and
range uncertainties. Int J Radiat Oncol Biol Phys. 2012;82(2):e329–
e336.
86. Paganetti H. Range Uncertainties in proton therapy and the role of
Monte Carlo simulations. Phys Med Biol. 2012;57:R99–R117.
87. Paganetti H. Dose to water versus dose to medium in proton beam
therapy. Phys Med Biol. 2009;54(14):4399–4421.
88. 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.
89. Calcerrada Diaz-Santos N, Blasco Amaro JA, Cardiel GA, et al. The
safety and efficacy of robotic image-guided radiosurgery system
treatment for intra- and extracranial lesions: a systematic review of
the literature. Radiother Oncol. 2008;89:245–253.
90. Huq MS, Fraass BA, Dunscombe PB, et al. A method for evaluating
quality assurance needs in radiation therapy. Int J Radiat Oncol Biol
Phys. 2008;71:S170–S173.
91. Ford EC, Smith K, Terezakis S, Croog V, et al. A streamlined failure
mode and effects analysis. Med Phys. 2014;41(6):061709.
92. Sawant A, Dieterich S, Svatos M, et al. Failure mode and effects
analysis-based quality assurance for dynamic MLC tracking systems.
Med Phys. 2010;37:6466–6479.
93. Ciocca M, et al. Application of failure mode and effects analysis to
intra-operative radiation therapy using mobile electron linear
accelerators. Int J Radiat Oncol Biol Phys. 2012;82:e305–e311.
94. Mutic S, Brame RS, Oddiraju S, et al. Event (error and near-miss)
reporting and learning for process improvement in radiation
oncology. Med Phys. 2010;37:5027–5036.
95. Ford EC, Fong de Los Santos L, Pawlicki T, et al. Consensus
recommendations for incident learning database structures in
radiation oncology. Med Phys. 2012;39:7272–7290.
96. Terezakis SA, Harris KM, Ford EC, et al. An evaluation of
departmental radiation oncology incident reports: Anticipating a
national reporting system. Int J Radiat Oncol Biol Phys. 2013;
85:919–923.
97. Stern RL, Heaton R, Fraser MW, et al. Verification of monitor unit
calculations for non-IMRT clinical radiotherapy: Report of AAPM
Task Group 114. Med Phys. 2011;38(1):504–530.
98. Georg D, Nyholm T, Olofsson J, et al. Clinical evaluation of monitor
unit software and the application of action levels. Radiother Oncol.
2007;85:306–315.
99. Georg D, Stock M, Kroupa B, et al. Patient-specific IMRT verification
using independent fluence-based dose calculation software:
experimental benchmarking and initial clinical experience. Phys Med
Biol. 2007;52:4981–4992.
100. Yukihara EG, McKeever SW. Optically stimulated luminescence
(OSL) dosimetry in medicine. Phys Med Biol. 2008;53:R351–R379.
101. Jornet N, Carrasco P, Jurado D, et al. Comparison study of MOSFET
detectors and diodes for entrance in vivo dosimetry in 18 MV x-ray
beams. Med Phys. 2004;31:2534–2542.
102. Dunscombe P, McGhee P, Lederer E. Anthropomorphic phantom
measurements for the validation of a treatment planning system.
Phys Med Biol. 1996;41:399–411.
103. Van Dam J, Marinello G. Methods for In Vivo Dosimetry in External
Radiotherapy. Brussels, Belgium: ESTRO; 2006.
104. World Health Organization (WHO). Radiotherapy Risk Profile:
Technical Manual. Geneva: World Health Organization; 2008.
105. Bednarz B, Kry SF, Klein EE, et al. AAPM Task Group 158:
Measurements and calculations of doses outside the treatment
volume from External Beam Radiation Therapy.
106. International Atomic Energy Agency (IAEA). Development of
Procedures for In Vivo Dosimetry in Radiotherapy. Vienna, Austria:
International Atomic Energy Agency; 2013.
107. Van Dyk J, Purdy JA. Clinical implementation of technology and
the quality assurance process. In: Van Dyk J, ed. The Modern
Technology of Radiation Oncology: A Compendium for Medical
Physicists and Radiation Oncologists. Madison, WI: Medical Physics
Publishing; 1999:19–51.
108. Ibbott G, Ma CM, Rogers DW, et al. Anniversary paper: fifty years
of AAPM involvement in radiation dosimetry. Med Phys.
2008;35:1418–1427.
109. Schiefer H, Fogliata A, Nicolini G, et al. The Swiss IMRT dosimetry
intercomparison using a thorax phantom. Med Phys. 2010; 37:4424–
4431.
110. International Atomic Energy Agency. Comprehensive Audits of
Radiotherapy Practices: A Tool for Quality Improvement, Quality
Assurance Team for Radiation Oncology (QUATRO). Vienna, Austria:
International Atomic Energy Agency; 2007.
111. American Society for Radiation Oncology. Guidance document for
ASTRO’s Accrediation Program for Excellence (APEx). Fairfax,
Virginia: APEx Guidance document; 2015.
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
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.
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.
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.
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
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
Controlling Tradeoffs
Different objectives in IMRT planning are inherently conflicting. Clearly,
there is a tradeoff between delivering dose to the tumor and reducing
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.
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.
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:
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).
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.
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.
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:
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)).
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)).
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 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:
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
For the first and third aspects, the reader is referred to the advanced
optimization literature. The second aspect is outlined below.
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
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
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.
FIGURE 9.11 Illustration of beam collimation for IMRT delivery using multi-leaf collimators and
jaws.
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.
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
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.
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
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.
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).
Furthermore, enhancements to the sequencing algorithm have been
devised, which for example, aim to reduce tongue-and-groove effects
(14).
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.
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)).
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.
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
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).
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.
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
rates while others allow for discrete values only. All machines have a
maximum dose rate.
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.
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:
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.
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
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)).
• 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.
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.
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
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:
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
KEY POINTS
• Illustrate the need for intensity-modulation when treating concave
target volumes such as head-and-neck tumors, prostate cancer, or
spinal metastasis.
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
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
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.
REFERENCES
1. Brahme A, Roos JE, Lax I. Solution of an integral equation
encountered in radiation therapy. Phys Med Biol. 1982;27:1221–
1229.
2. Bortfeld T. IMRT: a review and preview. Phys Med Biol. 2006;
51(13):R363–R379.
3. Webb S. Intensity-modulated Radiation Therapy. Boca Raton, FL: CRC
Press; 2001.
4. Boyer A, Unkelbach J. Intensity-modulated radiation therapy
planning. In: Brahme A, ed. Comprehensive Biomedical Physics, Vol 9,
Chapter 17, Elsevier; 2014.
5. Romeijn HE, Dempsey JF, Li JG. A unifying framework for multi-
criteria fluence map optimization models. Phys Med Biol.
2004;49(10):1991–2013.
6. Nocedal J, Wright SJ. Numerical Optimization. 2nd ed. Springer;
2006.
7. Bertsekas DP. Nonlinear Programming. 2nd ed. Belmont, MA: Athena
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.
Radiother Oncol. 1994;32:163–173.
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
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
planning. Med Phys. 2009;36:2328–2239.
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.
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.
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.
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.
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
referred to the publications of Gottschalk (3) or Lomax (8).
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.
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,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
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.
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.
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
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
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.
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.
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
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)):
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.
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
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
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
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
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
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.)
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.
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.
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
2. Please select the answer choice that best completes the sentence.
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
3. Please select the answer choice that best completes the sentence.
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
4. Please select the answer choice that best completes the sentence.
Optimization in PBS treatment planning…
A. Can only be performed using MC dose calculations
B. Is far more complex than for IMRT planning
C. Is a degenerate problem
D. Is not required.
5. Please select the answer choice that best completes the sentence.
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).
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).
REFERENCES
1. Koehler AM, Schneider RJ, Sisterson JM. Range modulators for
protons and heavy ions. Nucl Instrum Meth. 1975;131:437–440.
2. Koehler AM, Schneider RJ, Sisterson JM. Flattening of proton dose
distributions for large fields radiotherapy. Med phys. 1977;4:297–
301.
3. Gottschalk B. Physics of proton interactions in matter. In: Paganetti
H, ed. Proton Therapy Physics. Boca Raton, FL: CRC Press; 2012:20–
59.
4. Goitein M. Radiation Oncology: A Physicist’s-Eye View. New York, NY:
Springer Science and Business Media; 2008.
5. Safai S, Bortfeld T, Engelsman M. Comparison between the lateral
penumbra of a collimated double-scattering beam and uncollimated
scanning beam in proton radiotherapy. Phys Med Biol.
2008;21:1729–1750.
6. Lomax AJ, Bolsi A, Albertini F, et al. Treatment planning for Pencil
Beam scanning. In: Das I, Paganetti H, eds. Principle and Practice of
Proton Beam Therapy. Madison, WI: Medical Physics Publishing Inc.;
2015:667–707.
7. Gottschalk B, Koehler AM, Schneider RJ, et al. Multiple Coulomb
scattering of 160 MeV protons. Nucl Instrum Methods B.
1993;74:467–490.
8. Lomax AJ. Charged particle therapy: The physics of interaction.
Cancer J. 2009;15:285–291.
9. Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological
effectiveness (RBE) values for proton beam therapy. Int J Radiat
Oncol Biol Phys. 2002;53:407–421.
10. Paganetti H. Relative biological effectiveness (RBE) values for
proton beam therapy. Variations as a function of biological
endpoint, dose, and linear energy transfer. Phys Med Biol.
2014;59:R419–R472.
11. Kanai T, Kawachi K, Kumamoto Y, et al. Spot scanning system for
proton radiotherapy. Med Phys. 1980;7:365–369.
12. Pedroni E, Bacher R, Blattmann H, et al. The 200 MeV proton
therapy project at PSI: Conceptual design and practical realisation.
Med Phys. 1995;22:37–53.
13. Pedroni E, Scheib S, Boehringer T, et al. Experimental
characterization and physical modelling of the dose distribution of
scanned proton beams. Phys Med Biol. 2005;50:541–561.
14. Bortfeld T, Schlegel W. An analytical approximation of depth-dose
distributions for therapeutic proton beams. Phys Med Biol.
1996;41:1331–1339.
15. Schaffner B, Pedroni E, Lomax A. Dose calculation models for
proton treatment planning using a dynamic beam delivery system:
An attempt to include density heterogeneity effects in the analytical
dose calculation. Phys Med Biol. 1999;44:27–41.
16. Soukup M, Fippel M, Alber M. A Pencil beam algorithm for intensity
modulated proton therapy derived from Monte Carlo simulations.
Phys Med Biol. 2005;50:5089–5104.
17. Szymanowski H, Oelfke U. Two-dimensional pencil beam scaling:
An improved proton dose algorithm for heterogeneous media. Phys
Med Biol. 2002;47:3313–3330.
18. Paganetti H, Schuemann J, Mohan R. Dose calculations for proton
beam therapy: Monte Carlo. In: Das I, Paganetti H, eds. Principle and
Practice of Proton Beam Therapy. Madison, WI: Medical Physics
Publishing Inc.; 2015;571–594.
19. Ferrari A, Sala PR, Fasso A, et al. FLUKA: A multi-particle transport
code, CERN Yellow Report CERN 2005–10. Geneva: CERN; INFN/TC
05/11, SLAC-R-773;2005.
20. Agostinelli S, Allison J, Amako KA, et al. GEANT4 – a simulation
toolkit. Nucl Instrum Methods Phys Res A. 2003;506:250–303.
21. Pelowitz DB. MCNPX user’s manual, version 2.5.0. Los Alamos
National Laboratory; 2005;LA-CP-05–0369.
22. Fippel M, Soukup M. A Monte Carlo dose calculation algorithm for
proton therapy. Med Phys. 2004;31:2263–2273.
23. Dementiev AV, Sobolevsky NM. SHIELD-universal Monte Carlo
hadron transport code: Scope and applications. Radiation
Measurements. 1999;30:553–557.
24. Perl J, Shin J, Schumnn J, et al. TOPAS: An innovative proton
Monte Carlo platform for research and clinical applications. Med
Phys. 2012;39:6818–6837.
25. Grassberger C, Lomax A, Paganetti H. Characterizing a proton beam
scanning system for Monte Carlo dose calculations in patients. Phys
Med Biol. 2015;60:633–645.
26. Yepes P, Randeniya S, Taddei PJ, et al. A track repeating algorithm
for fast Monte Carlo dose calculations of proton radiotherapy. Nucl
Technol. 2009;168:736–740.
27. Jia X, Schumann J, Paganetti H, et al. GPU-based fast Monte Carlo
dose calculation for proton therapy. Phys Med Biol. 2012;57:7783–
7797.
28. Mustafa A, Jackson DF. The relation between x-ray CT numbers and
charged particle stopping powers and its significance for
radiotherapy treatment planning. Phys Med Biol. 1983;2:169–176.
29. Schneider U, Pedroni E, Lomax A. The calibration of CT-Hounsfield
units for radiotherapy treatment planning. Phys Med Biol.
1996;41:111–124.
30. Schneider W, Bortfeld T, Schlegel W. Correlation between CT
numbers and tissue parameters needed for Monte Carlo simulations
of clinical dose distributions. Phys Med Biol. 2000;45:459–478.
31. Schaffner B, Pedroni E. The precision of proton range calculations in
proton radiotherapy treatment planning: Experimental verification
of the relation between CT-HU and proton stopping power. Phys
Med Biol. 1998;43:1579–1592.
32. Kruse J. Immobilisation and simulation In: Das I, Paganetti H eds.
Principle and Practice of Proton Beam Therapy. Madison, WI: Medical
Physics Publishing Inc. 2015;521–540.
33. Paganetti H. Range uncertainties in proton therapy and the role of
Monte Carlo simulations. Phys Med Biol. 2012;57:99–117.
34. Newhauser WD, Giebeler A, Langen KM, et al. Can megavoltage
computed tomography reduce proton range uncertainties in
treatment plans for patients with large metal implants? Phys Med
Biol. 2008;53:2327–2344.
35. Jaekel O, Reiss P. The influence of metal artefacts on the range of
ion beams. Phys Med Biol 2007;52:635–644.
36. Yang M, Virshup G, Clayton J, et al. Theoretical variance analysis of
single- and dual-energy computed tomography methods for
calculating proton stopping power ratios of biological tissues. Phys
Med Biol. 2010;55:1343–1362.
37. Huenemohr N, Paganetti H, Greilich S, et al. Tissue decomposition
from dual energy CT data for MC based dose calculation in particle
therapy. Med Phys. 2014;41:061714
38. Wei J, Sandison GA, Hsi WC, et al. Dosimetric impact of a CT metal
artefact suppression algorithm for proton, electron and photon
therapies. Phys Med Biol. 2006;51:5183–5197.
39. Meyer E, Raupach R, Lell M, et al. Normalized metal artifact
reduction (NMAR) in computed tomography. Med Phys.
2010;37:5482–5493.
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
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
PTV definition in ion beam therapy. Radiother Oncol. 2013;
107:227–233.
43. Park PC, Zhu XR, Lee AK, et al. A beam-specific planning target
volume (PTV) design for proton therapy to account for setup and
range uncertainties. Int J Radiat Oncol Biol Phys. 2012;82:e329–
e336.
44. Bolsi A, Lomax AJ, Pedroni E, et al. Experiences at the Paul Scherrer
Institute with a remote patient positioning procedure for high-
throughput proton radiation therapy. Int J Radiat Oncol Biol Phys.
2008;71:1581–1590.
45. Zhu XR, Poenisch F, Heng Li, et al. Field shaping: Scanning beam.
In: Das I, Paganetti H, eds. Principle and Practice of Proton Beam
Therapy. Madison, WI: Medical Physics Publishing Inc: 2015; 667–
707.
46. Schieb S, Pedroni E. Dose calculation and optimization for 3D
conformal voxel scanning. Radiat Environ Biophys. 1992;31:251–256.
47. Lomax AJ, Pedroni E, Schaffner B, et al. 3D treatment planning for
conformal proton therapy by spot scanning. Quantitative Imaging in
Oncology. 1996. Proc. 19th L H Gray Conference, (1996 BIR
publishing London) 67–71.
48. Zenklusen SM, Pedroni E, Meer D, et al. Preliminary investigations
for the option to use fast uniform scanning with compensators on a
gantry designed for IMPT. Med Phys. 2011;38:5208–5216.
49. Bortfeld T, Buerkelbach J, Boesecke R, et al. Methods of image
reconstruction from projections applied to conformation
radiotherapy. Phys Med Biol. 1990;35:1423–1434.
50. Lomax A. Intensity modulated methods for proton therapy. Phys
Med Biol. 1999;44:185–205.
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:
Medical Physics Publishing; 2010:1–18.
52. Unkelbach J, Craft D, Gorissen BL, et al. Treatment plan
optimization in proton therapy. In: Das I, Paganetti H, eds. Principle
and Practice of Proton Beam Therapy. Madison, WI: Medical Physics
Publishing Inc; 2015;623–646
53. Titt U, Mirkovic D, Sawakuchi GO, et al. Adjustment of the lateral
and longitudinal size of scanned proton beam spots using a
preabsorber to optimize penumbrae and delivery efficiency. Phys
Med Biol. 2010;55:7097–7106
54. Bues M, Newhauser WD, Titt U, et al. Therapeutic step and shoot
proton beam spot scanning with a multi-leaf collimator: A Monte
Carlo study. Radiat Prot Dosimetry 2005;115:164–169.
55. Lomax AJ, Intensity Modulated Proton Therapy In: Delaney T, Kooy
H, eds. Proton and charged particle radiotherapy. Boston, MA:
Lippincott Williams and Wilkins; 2008.
56. Deasy JO, Shephard DM, Mackie TR. Distal edge tracking: A
proposed delivery method for conformal proton therapy using
intensity modulation. In: Leavitt DD, Starkschall GS, eds. Proc XIIth
ICCR, Salt Lake City. Madison, WI: Medical Physics Publishing; 406–
409.
57. Oelfke U, Bortfeld T. Intensity modulated radiotherapy with
charged particle beams: Studies of inverse treatment planning for
rotation therapy. Med Phys. 2000;27:1246–1257.
58. Albertini F, Hug EB, Lomax AJ. The influence of the optimization
starting conditions on the robustness of intensity-modulated proton
therapy plans. Phys Med Biol. 2010;55:2863–2878.
59. Unkelbach J, Bortfeld T, Martin BC, et al. Reducing the sensitivity
of IMPT treatment plans to setup errors and range uncertainties via
probabilistic treatment planning. Med. Phys. 2009;36:149–163.
60. Unkelbach J, Chan TC, Bortfeld T. Accounting for range
uncertainties in the optimization of intensity modulated proton
therapy. Phys Med Biol. 2007;52:2755–2773.
61. Chen W, Unkelbach J, Trofimov A, et al. Including robustness in
multi-criteria optimization for intensity-modulated proton therapy.
Phys Med Biol. 2012;57:591–608.
62. Grassberger C, Trofimov A, Lomax A, et al. Variations in linear
energy transfer within clinical proton therapy fields and the
potential for biological treatment planning. Int J Radiat Oncol Biol
Phys. 2011;80:1559–1566.
63. Mohan R, Sahoo N. Uncertainties in proton therapy: Their impact
and management. In: Das I, Paganetti H, eds. Principle and Practice of
Proton Beam Therapy. Madison, WI: Medical Physics Publishing Inc;
2015:595–622.
64. Goitein M. Calculation of the uncertainty in the dose delivered
during radiation therapy. Med Phys. 1985;12:608–612.
65. Pflugfelder D, Wilkens JJ, Oelfke U. Worst case optimization: A
method to account for uncertainties in the optimization of intensity
modulated proton therapy. Phys Med Biol. 2008;53:1689–1700.
66. Fredriksson A, Forsgren A, Hardemark B. Minimax optimization for
handling range and setup uncertainties in proton therapy. Med Phys.
2011;38:1672–1684.
67. Liu W, Zhang X, Li Y, et al. Robust optimization of intensity
modulated proton therapy. Med Phys. 2012;39:1079–1091.
68. Lomax AJ. Intensity modulated proton therapy and its sensitivity to
treatment uncertainties 2: The potential effects of inter-fraction and
inter-field motions. Phys Med Biol. 2008;53:1043–1056.
69. Albertini F, Hug EB, Lomax AJ. Is it necessary to plan with safety
margins for actively scanned proton therapy? Phys Med Biol.
2011;56:4399–4413.
70. Casiraghi M, Albertini F, Lomax AJ. Advantages and limitations of
the “worst case scenario” approach in IMPT treatment planning.
Phys Med Biol. 2013;58:1323–1339.
71. Park PC, Cheung J P, Zhu X R, et al. Statistical assessment of proton
treatment plans under setup and range uncertainties. Int J Radiat
Oncol Biol Phys. 2013;86:1007–1013.
72. Lowe M, Albertini F, Aitkenhead A, et al. Incorporating the effect of
fractionation in the evaluation of proton plan robustness to set-up
errors. Submitted to Phys Med Biol. July 2015.
73. Lomax AJ, Boehringer T, Coray A, et al. Intensity modulated proton
therapy: A clinical example. Med Phys. 2001;28:317–324.
74. Albertini F, Bolsi A, Lomax AJ, Sensitivity of intensity modulated
proton therapy plans to changes in patient weight. Radiother Oncol.
2008;86:187–194.
75. Madani I, Lomax AJ, Albertini F, et al. Dose-painting intensity-
modulated proton therapy using simultaneous integrated boost for
intermediate- and high-risk meningioma. Radiat Oncol. 2015; 30:72.
76. Meier G, Leiser D, Besson R, et al. Contour scanning for pencil beam
scanned proton therapy for skull-base tumors, PTCOG54, San Diego,
CA; 2015.
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.
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
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
both setup reproducibility and intra-treatment patient monitoring.
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.
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).
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.
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).
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.
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.
FIGURE 11.6 Components of an active breathing control (ABC) system.
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
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.
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
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
REFERENCES
1. International Commission on Radiation Units and Measurements.
Prescribing, recording and reporting photon beam therapy. ICRU
Report 50. 1993.
2. International Commission on Radiation Units and Measurements.
Prescribing, recording and reporting photon beam therapy
(Supplement to ICRU Report 50). ICRU Report 62. 1999.
3. International Commission on Radiation Units and Measurements.
Prescribing, recording, and reporting photon-beam intensity-
modulated radiation therapy (IMRT). ICRU Report 83. 2010.
4. Jaffray DA, Siewerdsen JH, Wong JW, et al. Flat-panel cone-beam
computed tomography for image-guided radiation therapy. Int J
Radiat Oncol Biol Phys. 2002;53(5):1337–1349.
5. Cho PS, Johnson RH, Griffin TW. Cone-beam CT for radiotherapy
applications. Phys Med Biol. 1995;40(11):1863–1883.
6. Pouliot J, Bani-Hashemi A, Chen J, et al. Low-dose megavoltage
cone-beam CT for radiation therapy. Int J Radiat Oncol Biol Phys.
2005;61(2):552–560.
7. Smitsmans MH, de Bois J, Sonke JJ, et al. Automatic prostate
localization on cone-beam CT scans for high precision image-guided
radiotherapy. Int J Radiat Oncol Biol Phys. 2005;63(4):975–984.
8. Fallone BG. The rotating biplanar linac–magnetic resonance imaging
system. Semin Radiat Oncol. 2014;24:200–202.
9. Lagendijk JJ, Raaymakers BW, van Vulpen M. The magnetic
resonance imaging–linac system. Semin Radiat Oncol. 2014;24:207–
209.
10. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-
guided and controlled radiotherapy. Semin Radiat Oncol.
2014;24:196–199.
11. Van Herk M. Errors and margins in radiotherapy. Semin Radiat
Oncol. 2004;14:52–64.
12. Bentel GC, Marks LB, Sherouse GW, et al. The effectiveness of
immobilization during prostate irradiation. Int J Radiat Oncol Biol
Phys. 1995;31(1):143–148.
13. Song PY, Washington M, Vaida F, et al. A comparison of four
patient immobilization devices in the treatment of prostate cancer
patients with three dimensional conformal radiotherapy. Int J Radiat
Oncol Biol Phys. 1996;34(1):213–219.
14. Biggs PJ, Goitein M, Russell MD. A diagnostic X ray field
verification device for a 10 MV linear accelerator. Int J Radiat Oncol
Biol Phys. 1985;11(3):635–643.
15. Balter JM, Brock KK, Litzenberg DW, et al. Daily targeting of
intrahepatic tumors for radiotherapy. Int J Radiat Oncol Biol Phys.
2002;52(1):266–271.
16. Litzenberg D, Dawson LA, Sandler H, et al. Daily prostate targeting
using implanted radiopaque markers. Int J Radiat Oncol Biol Phys.
2002;52(3):699–703.
17. Schewe JE, Lam KL, Balter JM, et al. A room-based diagnostic
imaging system for measurement of patient setup. Med Phys.
1998;25(12):2385–2387.
18. Murphy MJ. An automatic six-degree-of-freedom image registration
algorithm for image-guided frameless stereotaxic radiosurgery. Med
Phys. 1997;24(6):857–866.
19. Shirato H, Shimizu S, Kitamura K, et al. Four-dimensional treatment
planning and fluoroscopic real-time tumor tracking radiotherapy for
moving tumor. Int J Radiat Oncol Biol Phys. 2000;48(2):435–442.
20. Shimizu S, Shirato H, Kitamura K, et al. Use of an implanted marker
and real-time tracking of the marker for the positioning of prostate
and bladder cancers. Int J Radiat Oncol Biol Phys. 2000;48(5):1591–
1597.
21. Mackie TR, Holmes T, Swerdloff S, et al. Tomotherapy: a new
concept for the delivery of dynamic conformal radiotherapy. Med
Phys. 1993;20(6):1709–1719.
22. King CR, Brooks JD, Gill H, et al. Stereotactic body radiotherapy for
localized prostate cancer: interim results of a prospective phase II
clinical trial. Int J Radiat Oncol Biol Phys. 2009;73(4):1043–1048.
23. Kamino Y, Takayama K, Kokubo M, et al. Development of a four-
dimensional image-guided radiotherapy system with a gimbaled X-
ray head. Int J Radiat Oncol Biol Phys. 2006;66(1):271–278.
24. Kupelian P, Willoughby T, Mahadevan A, et al. Multi-institutional
clinical experience with the Calypso System in localization and
continuous, real-time monitoring of the prostate gland during
external radiotherapy. Int J Rad Onc Biol Phys. 2007;67(4):1088–
1098.
25. de Kruijf WJ, Verstraete J, Neustadter D, et al. Patient positioning
based on a radioactive tracer implanted in patients with localized
prostate cancer: a performance and safety evaluation. Int J Radiat
Oncol Biol Phys. 2013;85(2):555–560.
26. Castellanos E, Ericsson MH, Sorcini B, et al. RayPilot –
Electromagnetic real-time positioning in radiotherapy of prostate
cancer – Initial clinical results. Radiotherapy and Oncology.
2012;103, Supplement 1(0):S433.
27. Ballhausen H, Li M, Hegemann NS, et al. Intra-fraction motion of
the prostate is a random walk. Phys Med Biol. 2015;60(2):549–563.
28. Fallone B. Murray B, Rathee S, et al. First MR images obtained
during megavoltage photon irradiation from a prototype integrated
linac-MR system. Med Phys. 2009;36(6):2084–2088.
29. Raaymakers BW, Lagendijk JJ, Overweg J, et al. Integrating a 1.5 T
MRI scanner with a 6 MV accelerator: proof of concept. Phys Med
Biol. 2009;54(12):N229–N237.
30. Keall PJ, Barton M, Crozier S, et al. The Australian magnetic
resonance imaging–linac program. Semin Radiat Oncol.
2014;24:203–206.
31. Poulsen PR, Cho B, Langen K, et al. Three-dimensional prostate
position estimation with a single x-ray imager utilizing the spatial
probability density. Phys Med Biol. 2008;53(16):4331–4353.
32. Keall PJ, Aun Ng J, O’Brien R, et al. The first clinical treatment with
kilovoltage intrafraction monitoring (KIM): a real-time image
guidance method. Med Phys. 2015;42(1):354–358.
33. Bert C, Metheany KG, Doppke K, et al. A phantom evaluation of a
stereo-vision surface imaging system for radiotherapy patient setup.
Med Phys. 2005;32(9):2753–2762.
34. Bel A, van Herk M, Lebesque JV. Target margins for random
geometrical treatment uncertainties in conformal radiotherapy. Med
Phys. 1996;23(9):1537–1545.
35. Remeijer P, Rasch C, Lebesque JV, et al. Margins for translational
and rotational uncertainties: a probability-based approach. Int J
Radiat Oncol Biol Phys. 2002;53(2):464–474.
36. van Herk M, Remeijer P, Lebesque JV. Inclusion of geometric
uncertainties in treatment plan evaluation. Int J Radiat Oncol Biol
Phys. 2002;52(5):1407–1422.
37. Balter JM, Brock KK, Lam KL, et al. Evaluating the influence of
setup uncertainties on treatment planning for focal liver tumors. Int
J Radiat Oncol Biol Phys. 2005;63(2):610–614.
38. de Boer HC, van Sörnsen de Koste JR, Creutzberg CL, et al.
Electronic portal image assisted reduction of systematic set-up errors
in head and neck irradiation. Radiother Oncol. 2001;61(3):299–308.
39. de Boer HC, Heijmen BJ. A protocol for the reduction of systematic
patient setup errors with minimal portal imaging workload. Int J
Radiat Oncol Biol Phys. 2001;50(5):1350–1365.
40. van Lin EN, Nijenhuis E, Huizenga H, et al. Effectiveness of couch
height–based patient set-up and an off-line correction protocol in
prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys.
2001;50(2):569–577.
41. Yan D, Vicini F, Wong J, et al. Adaptive radiation therapy. Phys Med
Biol. 1997;42(1):123–132.
42. Langen KM, Jones DT. Organ motion and its management. Int J
Radiat Oncol Biol Phys. 2001;50(1):265–278.
43. Seppenwoolde Y, Shirato H, Kitamura K, et al. Precise and real-time
measurement of 3D tumor motion in lung due to breathing and
heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol
Phys. 2002;53(4):822–834.
44. Suh Y, Dieterich S, Cho B, et al. An analysis of thoracic and
abdominal tumour motion for stereotactic body radiotherapy
patients. Phys Med Biol. 2008;53(13):3623–3640.
45. Balter JM, Sandler HM, Lam K, et al. Measurement of prostate
movement over the course of routine radiotherapy using implanted
markers. Int J Radiat Oncol Biol Phys. 1995;31(1):113–118.
46. 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. 1996;34(2):451–458.
47. Booth JT, Zavgorodni SF. Set-up error & organ motion uncertainty:
a Review. Australas Phys Eng Sci Med. 1999;22(2):29–47.
48. Crook JM, Raymond Y, Salhani D, et al. Prostate motion during
standard radiotherapy as assessed by fiducial markers. Radiother
Oncol. 1995;37(1):35–42.
49. Dawson LA, Mah K, Franssen E, et al. Target position variability
throughout prostate radiotherapy. Int J Radiat Oncol Biol Phys.
1998;42(5):1155–1161.
50. 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.
51. Padhani AR, Khoo VS, Suckling J, et al. Evaluating the effect of
rectal distension and rectal movement on prostate gland position
using cine MRI. Int J Radiat Oncol Biol Phys. 1999;44(3):525–533.
52. Roeske JC, Forman JD, Mesina CF, et al. Evaluation of changes in
the size and location of the prostate, seminal vesicles, bladder, and
rectum during a course of external beam radiation therapy. Int J
Radiat Oncol Biol Phys. 1995;33(5):1321–1329.
53. van Herk M, Bruce A, Kroes AP, et al. Quantification of organ
motion during conformal radiotherapy of the prostate by three
dimensional image registration. Int J Radiat Oncol Biol Phys.
1995;33(5):1311–1320.
54. Zimmermann FB, Molls M. Influence of organ and patient
movements on the target volume in radiotherapy of prostatic
carcinoma. Strahlenther Onkol. 1997;173(3):172–173.
55. Dawson LA, Litzenberg DW, Brock KK, et al. A comparison of
ventilatory prostate movement in four treatment positions. Int J
Radiat Oncol Biol Phys. 2000;48(2):319–323.
56. Malone S, Crook JM, Kendal WS. Respiratory-induced prostate
motion: quantification and characterization. Int J Radiat Oncol Biol
Phys. 2000;48(1):105–109.
57. Keall PJ, Mageras GS, Balter JM, et al. The management of
respiratory motion in radiation oncology report of AAPM Task
Group 76. Med Phys. 2006;33(10):3874–3900.
58. George R, Vedam SS, Chung TD, et al. The application of the
sinusoidal model to lung cancer patient respiratory motion. Med
Phys. 2005;32(9):2850–2861.
59. Allen AM, Siracuse KM, Hayman JA, et al. Evaluation of the
influence of breathing on the movement and modeling of lung
tumors. Int J Radiat Oncol Biol Phys. 2004;58(4):1251–1257.
60. Stevens CW, Munden RF, Forster KM, et al. Respiratory-driven lung
tumor motion is independent of tumor size, tumor location, and
pulmonary function. Int J Radiat Oncol Biol Phys. 2001;51(1):62–68.
61. Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography:
image formation and clinical protocol. Med Phys. 2005; 32(4):874–
889.
62. Barnes EA, Murray BR, Robinson DM, et al. Dosimetric evaluation
of lung tumor immobilization using breath hold at deep inspiration.
Int J Radiat Oncol Biol Phys. 2001. 50(4):1091–1098.
63. Chen MH, Cash EP, Danias PG, et al. Respiratory maneuvers
decrease irradiated cardiac volume in patients with left-sided breast
cancer. J Cardiovasc Magn Reson. 2002;4(2):265–271.
64. Hanley J, Debois MM, Mah D, et al. Deep inspiration breath-hold
technique for lung tumors: the potential value of target
immobilization and reduced lung density in dose escalation. Int J
Radiat Oncol Biol Phys. 1999;45(3):603–611.
65. Rosenzweig KE, Hanley J, Mah D, et al. The deep inspiration breath-
hold technique in the treatment of inoperable non–small-cell lung
cancer. Int J Radiat Oncol Biol Phys. 2000;48(1):81–87.
66. Sixel KE, Aznar MC, Ung YC. Deep inspiration breath hold to reduce
irradiated heart volume in breast cancer patients. Int J Radiat Oncol
Biol Phys. 2001. 49(1):199–204.
67. Stromberg JS, Sharpe MB, Kim LH, et al. Active breathing control
(ABC) for Hodgkin’s disease: reduction in normal tissue irradiation
with deep inspiration and implications for treatment. Int J Radiat
Oncol Biol Phys. 2000;48(3):797–806.
68. Brock KK, Hollister SJ, Dawson LA, et al. Technical note: creating a
four-dimensional model of the liver using finite element analysis.
Med Phys. 2002;29(7):1403–1405.
69. Brock KM, Balter JM, Dawson LA, et al. Automated generation of a
four-dimensional model of the liver using warping and mutual
information. Med Phys. 2003;30(6):1128–1133.
70. Brock KK, Sharpe MB, Dawson LA, et al. Accuracy of finite element
model-based multi-organ deformable image registration. Med Phys.
2005;32(6):1647–1659.
71. Brock KK, McShan DL, Ten Haken RK, et al. Inclusion of organ
deformation in dose calculations. Med Phys. 2003;30(3):290–295.
72. Shirato H, Shimizu S, Kunieda T, et al. Physical aspects of a real-
time tumor-tracking system for gated radiotherapy. Int J Radiat
Oncol Biol Phys. 2000;48(4):1187–1195.
73. Berbeco RI, Nishioka S, Shirato H, et al. Residual motion of lung
tumours in gated radiotherapy with external respiratory surrogates.
Phys Med Biol. 2005. 50(16):3655–3667.
74. Jin JY, Yin FF. Time delay measurement for linac based treatment
delivery in synchronized respiratory gating radiotherapy. Med Phys.
2005;32(5):1293–1296.
75. Ozhasoglu C, Murphy MJ. Issues in respiratory motion
compensation during external-beam radiotherapy. Int J Radiat Oncol
Biol Phys. 2002;52(5):1389–1399.
76. Vedam SS, Keall PJ, Kini VR, et al. Determining parameters for
respiration-gated radiotherapy. Med Phys. 2001;28(10):2139–2146.
77. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing
control (ABC) to reduce margin for breathing motion. Int J Radiat
Oncol Biol Phys. 1999;44(4):911–919.
78. Cheung PC, Sixel KE, Tirona R, et al. Reproducibility of lung tumor
position and reduction of lung mass within the planning target
volume using active breathing control (ABC). Int J Radiat Oncol Biol
Phys. 2003;57(5):1437–1442.
79. Dawson LA, Brock KK, Kazanjian S, et al. The reproducibility of
organ position using active breathing control (ABC) during liver
radiotherapy. Int J Radiat Oncol Biol Phys. 2001;51(5):1410–1421.
80. Dawson LA. Eccles C, Bissonnette JP, et al. Accuracy of daily image
guidance for hypofractionated liver radiotherapy with active
breathing control. Int J Radiat Oncol Biol Phys. 2005;62(4):1247–
1252.
81. Remouchamps VM, Letts N, Vicini FA, et al. Initial clinical
experience with moderate deep-inspiration breath hold using an
active breathing control device in the treatment of patients with
left-sided breast cancer using external beam radiation therapy. Int J
Radiat Oncol Biol Phys. 2003;56(3):704–715.
82. Sarrut D, Boldea V, Ayadi M, et al. Nonrigid registration method to
assess reproducibility of breath-holding with ABC in lung cancer. Int
J Radiat Oncol Biol Phys. 2005;61(2):594–607.
83. Wu J, Ruan D, Cho B, et al. Electromagnetic detection and real-time
DMLC adaptation to target rotation during radiotherapy. Int J Radiat
Oncol Biol Phys. 2012;82(3):e545–e553.
84. Ge Y, O’Brien RT, Shieh CC, et al. Toward the development of
intrafraction tumor deformation tracking using a dynamic multi-leaf
collimator. Med Phys. 2014;41(6):061703.
12 Image-Guided Radiation
Therapy
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
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
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.
FIGURE 12.1 Image guidance at various stages of the radiotherapy process.
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
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)
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.
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.
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.
2006;31:51–61.
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.
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
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).
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
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).
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.
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:
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).
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
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.
• 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.
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
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.
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
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
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.
QUESTIONS
1. On all isocentric linac machines, the kV and MV radiographic
imaging are available commercially. Which of the following
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
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
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
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.
REFERENCES
1. Park SS, Yan D, McGrath S, et al. Adaptive image-guided
radiotherapy (IGRT) eliminates the risk of biochemical failure
caused by the bias of rectal distension in prostate cancer treatment
planning: clinical evidence. Int J Radiat Oncol Biol Phys.
2012;83(3):947–952.
2. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of
accelerated hypofractionated intensity-modulated radiation therapy
for early-stage oropharyngeal cancer (RTOG 00–22). Int J Radiat
Oncol Biol Phys. 2010;76(5):1333–1338.
3. Tucker SL, Jin H, Wei X, et al. Impact of toxicity grade and scoring
system on the relationship between mean lung dose and risk of
radiation pneumonitis in a large cohort of patients with non-small
cell lung cancer. Int J Radiat Oncol Biol Phys. 2010;77(3):691–698.
4. Leibel SA, Fuks Z, Zelefsky MJ, et al. Intensity-modulated
radiotherapy. Cancer J. 2002;8(2):164–176.
5. Suit H. The Gray Lecture 2001: coming technical advances in
radiation oncology. Int J Radiat Oncol Biol Phys. 2002;53(4):798–
809.
6. Matuszak MM, Yan D, Grills I, et al. Clinical applications of
volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys.
2010;77(2):608–616.
7. Sveistrup J, af Rosenschold PM, Deasy JO, et al. Improvement in
toxicity in high risk prostate cancer patients treated with image-
guided intensity-modulated radiotherapy compared to 3D conformal
radiotherapy without daily image guidance. Radiat Oncol. 2014;9:44.
8. Mageras GS, Mechalakos J. Planning in the IGRT context: closing the
loop. Semin Radiat Oncol. 2007;17(4):268–277.
9. van Herk M. Different styles of image-guided radiotherapy. Semin
Radiat Oncol. 2007;17(4):258–267.
10. Greco C, Ling CC. Broadening the scope of image-guided
radiotherapy (IGRT). Acta Oncol. 2008;47(7):1193–1200.
11. Lagendijk JJ, Raaymakers BW, Raaijmakers AJ, et al. MRI/linac
integration. Radiother Oncol. 2008;86(1):25–29.
12. Nishio T, Miyatake A, Ogino T, et al. The development and clinical
use of a beam ON-LINE PET system mounted on a rotating gantry
port in proton therapy. Int J Radiat Oncol Biol Phys. 2010;76(1):277–
286.
13. Jarvis LA, Zhang R, Gladstone DJ, et al. Cherenkov video imaging
allows for the first visualization of radiation therapy in real time. Int
J Radiat Oncol Biol Phys. 2014;89(3):615–622.
14. Boyer AL, Antonuk L, Fenster A, et al. A review of electronic portal
imaging devices (EPIDs). Med Phys. 1992;19(1):1–16.
15. van Elmpt W, McDermott L, Nijsten S, et al. A literature review of
electronic portal imaging for radiotherapy dosimetry. Radiother
Oncol. 2008;88(3):289–309.
16. Mans A, Remeijer P, Olaciregui-Ruiz I, et al. 3D Dosimetric
verification of volumetric-modulated arc therapy by portal
dosimetry. Radiother Oncol. 2010;94(2):181–187.
17. Russo GA, Qureshi MM, Truong MT, et al. Daily orthogonal
kilovoltage imaging using a gantry-mounted on-board imaging
system results in a reduction in radiation therapy delivery errors. Int
J Radiat Oncol Biol Phys. 2012;84(3):596–601.
18. Kalender WA. Dose in x-ray computed tomography. Phys Med Biol.
2014;59(3):R129–R150.
19. Uematsu M, Fukui T, Shioda A, et al. A dual computed tomography
linear accelerator unit for stereotactic radiation therapy: a new
approach without cranially fixated stereotactic frames. Int J Radiat
Oncol Biol Phys. 1996;35(3):587–592.
20. Yenice KM, Lovelock DM, Hunt MA, et al. CT image-guided
intensity-modulated therapy for paraspinal tumors using stereotactic
immobilization. Int J Radiat Oncol Biol Phys. 2003;55(3):583–593.
21. Hua C, Lovelock DM, Mageras GS, et al. Development of a semi-
automatic alignment tool for accelerated localization of the prostate.
Int J Radiat Oncol Biol Phys. 2003;55(3):811–824.
22. Wong JR, Cheng CW, Grimm L, et al. Clinical implementation of the
world’s first primatom, a combination of CT scanner and linear
accelerator, for precise tumor targeting and treatment. Physica
Medica. 2001;17(4):271–276.
23. Court L, Rosen I, Mohan R, et al. Evaluation of mechanical precision
and alignment uncertainties for an integrated CT/LINAC system.
Med Phys. 2003;30(6):1198–1210.
24. 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(3):605–613.
25. Jaffray DA, Drake DG, Moreau M, et al. A radiographic and
tomographic imaging system integrated into a medical linear
accelerator for localization of bone and soft-tissue targets. Int J
Radiat Oncol Biol Phys. 1999;45(3):773–789.
26. Siewerdsen JH, Moseley DJ, Bakhtiar B, et al. The influence of
antiscatter grids on soft-tissue detectability in cone-beam computed
tomography with flat-panel detectors. Med Phys. 2004;31(12):3506–
3520.
27. Li G, Ballangrud A, Kuo LC, et al. Motion monitoring for cranial
frameless stereotactic radiosurgery using video-based three-
dimensional optical surface imaging. Med Phys. 2011;38(7):3981–
3994.
28. Cho PS, Rudd AD, Johnson RH. Cone-beam CT from width-
truncated projections. Comput Med Imaging Graph. 1996;20(1):49–
57.
29. Stankovic U, van Herk M, Ploeger LS, et al. Improved image quality
of cone beam CT scans for radiotherapy image guidance using fiber-
interspaced antiscatter grid. Med Phys. 2014;41(6):061910.
30. Gardner SJ, Studenski MT, Giaddui T, et al. Investigation into image
quality and dose for different patient geometries with multiple cone-
beam CT systems. Med Phys. 2014;41(3):031908.
31. Kim J, Lu W, Zhang T. Dual source and dual detector arrays
tetrahedron beam computed tomography for image guided
radiotherapy. Phys Med Biol. 2014;59(3):615–630.
32. Mackie TR, Holmes T, Swerdloff S, et al. Tomotherapy: a new
concept for the delivery of dynamic conformal radiotherapy. Med
Phys. 1993;20(6):1709–1719.
33. Ruchala KJ, Olivera GH, Schloesser EA, et al. Megavoltage CT on a
tomotherapy system. Phys Med Biol. 1999;44(10):2597–2621.
34. Forrest LJ, Mackie TR, Ruchala K, et al. The utility of megavoltage
computed tomography images from a helical tomotherapy system
for setup verification purposes. Int J Radiat Oncol Biol Phys.
2004;60(5):1639–1644.
35. Swindell W, Simpson RG, Oleson JR, et al. Computed tomography
with a linear accelerator with radiotherapy applications. Med Phys.
1983;10(4):416–420.
36. Mosleh-Shirazi MA, Evans PM, Swindell W, et al. A cone-beam
megavoltage CT scanner for treatment verification in conformal
radiotherapy. Radiother Oncol. 1998;48(3):319–328.
37. Sillanpaa J, Chang J, Mageras G, et al. Developments in
megavoltage cone beam CT with an amorphous silicon EPID:
reduction of exposure and synchronization with respiratory gating.
Med Phys. 2005;32(3):819–829.
38. Pouliot J, Bani-Hashemi A, Chen J, et al. Low-dose megavoltage
cone-beam CT for radiation therapy. Int J Radiat Oncol Biol Phys.
2005;61(2):552–560.
39. Kupelian PA, Ramsey C, Meeks SL, et al. Serial megavoltage CT
imaging during external beam radiotherapy for non-small-cell lung
cancer: observations on tumor regression during treatment. Int J
Radiat Oncol Biol Phys. 2005;63(4):1024–1028.
40. Langen KM, Meeks SL, Poole DO, et al. The use of megavoltage CT
(MVCT) images for dose recomputations. Phys Med Biol. 2005;
50(18):4259–4276.
41. Yin FF, Guan H, Lu W. A technique for on-board CT reconstruction
using both kilovoltage and megavoltage beam projections for 3D
treatment verification. Med Phys. 2005;32(9):2819–2826.
42. Blessing M, Stsepankou D, Wertz H, et al. Breath-hold target
localization with simultaneous kilovoltage/megavoltage cone-beam
computed tomography and fast reconstruction. Int J Radiat Oncol
Biol Phys. 2010;78(4):1219–1226.
43. Kolitsi Z, Panayiotakis G, Anastassopoulos V, et al. A multiple
projection method for digital tomosynthesis. Med Phys.
1992;19(4):1045–1050.
44. Godfrey DJ, Yin FF, Oldham M, et al. Digital tomosynthesis with an
on-board kilovoltage imaging device. Int J Radiat Oncol Biol Phys.
2006;65(1):8–15.
45. Santoro J, Kriminski S, Lovelock DM, et al. Evaluation of
respiration-correlated digital tomosynthesis in lung. Med Phys.
2010;37(3):1237–1245.
46. Keall PJ, Mageras GS, Balter JM, et al. The management of
respiratory motion in radiation oncology report of AAPM Task
Group 76. Med Phys. 2006;33(10):3874–3900.
47. Low DA, Nystrom M, Kalinin E, et al. A method for the
reconstruction of four-dimensional synchronized CT scans acquired
during free breathing. Med Phys. 2003;30(6):1254–1263.
48. Pan T, Lee TY, Rietzel E, et al. 4D-CT imaging of a volume
influenced by respiratory motion on multi-slice CT. Med Phys.
2004;31(2):333–340.
49. Ford EC, Mageras GS, Yorke E, et al. Respiration-correlated spiral
CT: a method of measuring respiratory-induced anatomic motion for
radiation treatment planning. Med Phys. 2003;30(1):88–97.
50. Vedam SS, Keall PJ, Kini VR, et al. Acquiring a four-dimensional
computed tomography dataset using an external respiratory signal.
Phy Med Biol. 2003;48(1):45–62.
51. Keall P. 4-dimensional computed tomography imaging and
treatment planning. Semin Radiat Oncol. 2004;14(1):81–90.
52. Mageras GS, Pevsner A, Yorke ED, et al. Measurement of lung tumor
motion using respiration-correlated CT. Int J Radiat Oncol Biol Phys.
2004;60(3):933–941.
53. Yamamoto T, Langner U, Loo BW Jr, et al. Retrospective analysis of
artifacts in four-dimensional CT images of 50 abdominal and
thoracic radiotherapy patients. Int J Radiat Oncol Biol Phys.
2008;72(4):1250–1258.
54. Li G, Caraveo M, Wei J, et al. Rapid estimation of 4DCT motion-
artifact severity based on 1D breathing-surrogate periodicity. Med
Phys. 2014;41(11):111717.
55. Lu W, Parikh PJ, Hubenschmidt JP, et al. A comparison between
amplitude sorting and phase-angle sorting using external respiratory
measurement for 4D CT. Med Phys. 2006;33(8):2964–2974.
56. Abdelnour AF, Nehmeh SA, Pan T, et al. Phase and amplitude
binning for 4D-CT imaging. Phys Med Biol. 2007;52(12):3515–3529.
57. Coolens C, Bracken J, Driscoll B, et al. Dynamic volume vs
respiratory correlated 4DCT for motion assessment in radiation
therapy simulation. Med Phys. 2012;39(5):2669–2681.
58. Hertanto A, Zhang Q, Hu YC, et al. Reduction of irregular breathing
artifacts in respiration-correlated CT images using a respiratory
motion model. Med Phys. 2012;39(6):3070–3079.
59. Thomas D, Lamb J, White B, et al. A novel fast helical 4D-CT
acquisition technique to generate low-noise sorting artifact-free
images at user-selected breathing phases. Int J Radiat Oncol Biol
Phys. 2014;89(1):191–198.
60. Sonke JJ, Zijp L, Remeijer P, et al. Respiratory correlated cone
beam CT. Med Phys. 2005;32(4):1176–1186.
61. Purdie TG, Moseley DJ, Bissonnette JP, et al. Respiration correlated
cone-beam computed tomography and 4DCT for evaluating target
motion in Stereotactic Lung Radiation Therapy. Acta Oncol.
2006;45(7):915–922.
62. Li T, Xing L, Munro P, et al. Four-dimensional cone-beam computed
tomography using an on-board imager. Med Phys. 2006;
33(10):3825–3833.
63. Rit S, Wolthaus JW, van Herk M, et al. On-the-fly motion-
compensated cone-beam CT using an a priori model of the
respiratory motion. Med Phys. 2009;36(6):2283–2296.
64. Zhang Q, Hu YC, Liu F, et al. Correction of motion artifacts in cone-
beam CT using a patient-specific respiratory motion model. Med
Phys. 2010;37(6):2901–2909.
65. Rit S, Nijkamp J, van Herk M, et al. Comparative study of
respiratory motion correction techniques in cone-beam computed
tomography. Radiother Oncol. 2011;100(3):356–359.
66. Dzyubak O, Kincaid R, Hertanto A, et al. Evaluation of tumor
localization in respiration motion-corrected cone-beam CT:
prospective study in lung. Med Phys. 2014;41(10):101918.
67. Wang D, Doddrell DM. A proposed scheme for comprehensive
characterization of the measured geometric distortion in magnetic
resonance imaging using a three-dimensional phantom. Med Phys.
2004;31(8):2212–2218.
68. Chen L, Price RA Jr, Wang L, et al. MRI-based treatment planning
for radiotherapy: dosimetric verification for prostate IMRT. Int J
Radiat Oncol Biol Phys. 2004;60(2):636–647.
69. Wang C, Chao M, Lee L, et al. MRI-based treatment planning with
electron density information mapped from CT images: a preliminary
study. Technol Cancer Res Treat. 2008;7(5):341–348.
70. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-
guided and controlled radiotherapy. Semin Radiat Oncol.
2014;24(3):196–199.
71. Raaijmakers AJ, Raaymakers BW, Lagendijk JJ. Integrating a MRI
scanner with a 6 MV radiotherapy accelerator: dose increase at
tissue-air interfaces in a lateral magnetic field due to returning
electrons. Phys Med Biol. 2005;50(7):1363–1376.
72. Jaffray DA, Carlone MC, Milosevic MF, et al. A facility for magnetic
resonance-guided radiation therapy. Semin Radiat Oncol.
2014;24(3):193–195.
73. Lagendijk JJ, Raaymakers BW, Van den Berg CA, et al. MR guidance
in radiotherapy. Phys Med Biol. 2014;59(21):R349–369.
74. Li G, Citrin D, Camphausen K, et al. Advances in 4D medical
imaging and 4D radiation therapy. Technol Cancer Res Treat.
2008;7(1):67–81.
75. Prabhakar R, Julka PK, Ganesh T, et al. Feasibility of using MRI
alone for 3D radiation treatment planning in brain tumors. Jpn J
Clin Oncol. 2007;37(6):405–411.
76. Metcalfe P, Liney GP, Holloway L, et al. The potential for an
enhanced role for MRI in radiation-therapy treatment planning.
Technol Cancer Res Treat. 2013;12(5):429–446.
77. Wang H, Balter J, Cao Y. Patient-induced susceptibility effect on
geometric distortion of clinical brain MRI for radiation treatment
planning on a 3T scanner. Phys Med Biol. 2013;58(3):465–477.
78. Dowling JA, Lambert J, Parker J, et al. An atlas-based electron
density mapping method for magnetic resonance imaging (MRI)-
alone treatment planning and adaptive MRI-based prostate radiation
therapy. Int J Radiat Oncol Biol Phys. 2012;83(1):e5–e11.
79. Plathow C, Klopp M, Schoebinger M, et al. Monitoring of lung
motion in patients with malignant pleural mesothelioma using two-
dimensional and three-dimensional dynamic magnetic resonance
imaging: comparison with spirometry. Invest Radiol.
2006;41(5):443–448.
80. Hu Y, Caruthers SD, Low DA, et al. Respiratory amplitude guided 4-
dimensional magnetic resonance imaging. Int J Radiat Oncol Biol
Phys. 2013;86(1):198–204.
81. Tryggestad E, Flammang A, Han-Oh S, et al. Respiration-based
sorting of dynamic MRI to derive representative 4D-MRI for
radiotherapy planning. Med Phys. 2013;40(5):051909.
82. Tryggestad E, Flammang A, Hales R, et al. 4D tumor centroid
tracking using orthogonal 2D dynamic MRI: implications for
radiotherapy planning. Med Phys. 2013;40(9):091712.
83. Yan S, Bowsher J, Yin FF. A line-source method for aligning on-
board and other pinhole SPECT systems. Med Phys. 2013;
40(12):122501.
84. Zhu X, Espana S, Daartz J, et al. Monitoring proton radiation
therapy with in-room PET imaging. Phys Med Biol.
2011;56(13):4041–4057.
85. Fan Q, Nanduri A, Mazin S, et al. Emission guided radiation therapy
for lung and prostate cancers: a feasibility study on a digital patient.
Med Phys. 2012;39(11):7140–7152.
86. Fontanarosa D, van der Meer S, Bamber J, et al. Review of
ultrasound image guidance in external beam radiotherapy: I.
Treatment planning and inter-fraction motion management. Phys
Med Biol. 2015;60(3):R77–R114.
87. Fuss M, Cavanaugh SX, Fuss C, et al. Daily stereotactic ultrasound
prostate targeting: inter-user variability. Technol Cancer Res Treat.
2003;2(2):161–170.
88. Scarbrough TJ, Golden NM, Ting JY, et al. Comparison of
ultrasound and implanted seed marker prostate localization
methods: Implications for image-guided radiotherapy. Int J Radiat
Oncol Biol Phys. 2006;65(2):378–387.
89. Bert C, Metheany KG, Doppke K, et al. A phantom evaluation of a
stereo-vision surface imaging system for radiotherapy patient setup.
Med Phys. 2005;32(9):2753–2762.
90. Djajaputra D, Li S. Real-time 3D surface-image-guided beam setup
in radiotherapy of breast cancer. Med Phys. 2005;32(1):65–75.
91. Zhang R, Andreozzi JM, Gladstone DJ, et al. Cherenkoscopy based
patient positioning validation and movement tracking during post-
lumpectomy whole breast radiation therapy. Phys Med Biol.
2015;60(1):L1–L14.
92. Yue NJ, Kim S, Lewis BE, et al. Optimization of couch translational
corrections to compensate for rotational and deformable target
deviations in image guided radiotherapy. Med Phys.
2008;35(10):4375–4385.
93. Lu B, Samant S, Mittauer K, et al. A further investigation of the
centroid-to-centroid method for stereotactic lung radiotherapy: a
phantom study. Med Phys. 2013;40(10):101704.
94. Hugo GD, Weiss E, Badawi A, et al. Localization accuracy of the
clinical target volume during image-guided radiotherapy of lung
cancer. Int J Radiat Oncol Biol Phys. 2011;81(2):560–567.
95. Rottmann J, Keall P, Berbeco R. Markerless EPID image guided
dynamic multi-leaf collimator tracking for lung tumors. Phys Med
Biol. 2013;58(12):4195–4204.
96. Li R, Lewis JH, Cervino LI, et al. A feasibility study of markerless
fluoroscopic gating for lung cancer radiotherapy using 4DCT
templates. Phys Med Biol. 2009;54(20):N489–N500.
97. Li R, Jia X, Lewis JH, et al. Real-time volumetric image
reconstruction and 3D tumor localization based on a single x-ray
projection image for lung cancer radiotherapy. Med Phys.
2010;37(6):2822–2826.
98. Cervino LI, Pawlicki T, Lawson JD, et al. Frame-less and mask-less
cranial stereotactic radiosurgery: a feasibility study. Phys Med Biol.
2010;55(7):1863–1873.
99. Murphy MJ. Tracking moving organs in real time. Semin Radiat
Oncol. 2004;14(1):91–100.
100. Jin JY, Yin FF, Tenn SE, et al. Use of the BrainLAB ExacTrac X-Ray
6D system in image-guided radiotherapy. Med Dosim.
2008;33(2):124–134.
101. Nakagawa K, Haga A, Shiraishi K, et al. First clinical cone-beam CT
imaging during volumetric modulated arc therapy. Radiother Oncol.
2009;90(3):422–423.
102. Ling C, Zhang P, Etmektzoglou T, et al. Acquisition of MV-scatter-
free kilovoltage CBCT images during RapidArc or VMAT. Radiother
Oncol. 2011;100(1):145–149.
103. Zhang P, Hunt M, Happersett L, et al. Incorporation of treatment
plan spatial and temporal dose patterns into a prostate
intrafractional motion management strategy. Med Phys.
2012;39(9):5429–5436.
104. Yan H, Li H, Liu Z, et al. Hybrid MV-kV 3D respiratory motion
tracking during radiation therapy with low imaging dose. Phys Med
Biol. 2012;57(24):8455–8469.
105. Azcona JD, Li R, Mok E, et al. Development and clinical evaluation
of automatic fiducial detection for tumor tracking in cine
megavoltage images during volumetric modulated arc therapy. Med
Phys. 2013;40(3):031708.
106. Solberg TD, Medin PM, Ramirez E, et al. Commissioning and initial
stereotactic ablative radiotherapy experience with Vero. J Appl Clin
Med Phys. 2014;15(2):4685.
107. Depuydt T, Verellen D, Haas O, et al. Geometric accuracy of a novel
gimbals based radiation therapy tumor tracking system. Radiother
Oncol. 2011;98(3):365–372.
108. Poels K, Depuydt T, Verellen D, et al. A complementary dual-
modality verification for tumor tracking on a gimbaled linac system.
Radiother Oncol. 2013;109(3):469–474.
109. Burghelea M, Verellen D, Gevaert T, et al. Feasibility of using the
Vero SBRT system for intracranial SRS. J Appl Clin Med Phys.
2014;15(1):4437.
110. Meeks SL, Tome WA, Willoughby TR, et al. Optically guided patient
positioning techniques. Semin Radiat Oncol. 2005;15(3):192–201.
111. Li G, Huang H, Wei J, et al. Novel Spirometry based on optical
surface imaging. Med Phys. 2015;42(4):1690.
112. Li G, Yuan A, Wei J. An analytical respiratory perturbation model
for lung motion prediction. Med Phys. 2014;41(6):473–473.
113. Balter JM, Wright JN, Newell LJ, et al. Accuracy of a wireless
localization system for radiotherapy. Int J Radiat Oncol Biol Phys.
2005;61(3):933–937.
114. Sawant A, Smith RL, Venkat RB, et al. Toward submillimeter
accuracy in the management of intrafraction motion: the integration
of real-time internal position monitoring and multileaf collimator
target tracking. Int J Radiat Oncol, Biol, Phys. 2009;74(2):575–582.
115. 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.
116. Fallone BG, Murray B, Rathee S, et al. First MR images obtained
during megavoltage photon irradiation from a prototype integrated
linac-MR system. Med Phys. 2009;36(6):2084–2088.
117. Lagendijk JJ, Raaymakers BW, van Vulpen M. The magnetic
resonance imaging-linac system. Semin Radiat Oncol.
2014;24(3):207–209.
118. Raaymakers BW, de Boer JC, Knox C, et al. Integrated megavoltage
portal imaging with a 1.5 T MRI linac. Phys Med Biol.
2011;56(19):N207–N214.
119. Kolling S, Oborn B, Keall P. Impact of the MLC on the MRI field
distortion of a prototype MRI-linac. Med Phys. 2013;40(12):121705.
120. Bjerre T, Crijns S, af Rosenschöld PM, et al. Three-dimensional MRI-
linac intra-fraction guidance using multiple orthogonal cine-MRI
planes. Phys Med Biol. 2013;58(14):4943–4950.
121. Brix L, Ringgaard S, Sorensen TS, Poulsen PR. Three-dimensional
liver motion tracking using real-time two-dimensional MRI. Med
Phys. 2014;41(4):042302.
122. Yang J, Yamamoto T, Mazin SR, et al. The potential of positron
emission tomography for intratreatment dynamic lung tumor
tracking: A phantom study. Med Phys. 2014;41(2):021718.
123. Keall PJ, Joshi S, Vedam SS, et al. Four-dimensional radiotherapy
planning for DMLC-based respiratory motion tracking. Med Phys.
2005;32(4):942–951.
124. McQuaid D, Webb S. IMRT delivery to a moving target by dynamic
MLC tracking: delivery for targets moving in two dimensions in the
beam’s eye view. Phys Med Biol. 2006;51(19):4819–4839.
125. McMahon R, Papiez L, Rangaraj D. Dynamic-MLC leaf control
utilizing on-flight intensity calculations: a robust method for real-
time IMRT delivery over moving rigid targets. Med Phys. 2007;
34(8):3211–3223.
126. Zimmerman J, Korreman S, Persson G, et al. DMLC motion tracking
of moving targets for intensity modulated arc therapy treatment: a
feasibility study. Acta Oncol. 2009;48(2):245–250.
127. Yun J, Wachowicz K, Mackenzie M, et al. First demonstration of
intrafractional tumor-tracked irradiation using 2D phantom MR
images on a prototype linac-MR. Med Phys. 2013;40(5):051718.
128. Keall PJ, Colvill E, O’Brien R, et al. The first clinical
implementation of electromagnetic transponder-guided MLC
tracking. Med Phys. 2014;41(2):020702.
129. D’Souza WD, Naqvi SA, Yu CX. Real-time intra-fraction-motion
tracking using the treatment couch: a feasibility study. Phys Med
Biol. 2005;50(17):4021–4033.
130. Buzurovic I, Yu Y, Werner-Wasik M, et al. Implementation and
experimental results of 4D tumor tracking using robotic couch. Med
Phys. 2012;39(11):6957–6967.
131. Menten MJ, Guckenberger M, Herrmann C, et al. Comparison of a
multileaf collimator tracking system and a robotic treatment couch
tracking system for organ motion compensation during
radiotherapy. Med Phys. 2012;39(11):7032–7041.
132. Kamino Y, Takayama K, Kokubo M, et al. Development of a four-
dimensional image-guided radiotherapy system with a gimbaled X-
ray head. Int J Radiat Oncol Biol Phys. 2006;66(1):271–278.
133. Akimoto M, Nakamura M, Mukumoto N, et al. Predictive
uncertainty in infrared marker-based dynamic tumor tracking with
Vero4DRT. Med Phys. 2013;40(9):091705.
134. Yin F-F, Wong J, James Balter, et al. The role of in-room kV X-ray
imaging for patient setup and target localization.
http://www.aapm.org/pubs/reports/RPT_104pdf. 2009;(1–72): Last
visited 12/15/ 2015.
135. Willoughby T, Lehmann J, Bencomo JA, et al. Quality assurance for
nonradiographic radiotherapy localization and positioning systems:
report of Task Group 147. Med Phys. 2012;39(4):1728–1747.
136. Bissonnette JP, Balter PA, Dong L, et al. Quality assurance for
image-guided radiation therapy utilizing CT-based technologies: a
report of the AAPM TG-179. Med Phys. 2012;39(4):1946–1963.
137. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: quality
assurance of medical accelerators. Med Phys. 2009;36(9):4197–
4212.
138. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body
radiation therapy: the report of AAPM Task Group 101. Med Phys.
2010;37(8):4078–4101.
139. Sharpe MB, Moseley DJ, Purdie TG, et al. The stability of
mechanical calibration for a kV cone beam computed tomography
system integrated with linear accelerator. Med Phys.
2006;33(1):136–144.
140. Mao W, Lee L, Xing L. Development of a QA phantom and
automated analysis tool for geometric quality assurance of on-board
MV and kV x-ray imaging systems. Med Phys. 2008;35(4):1497–
1506.
141. Langen KM, Papanikolaou N, Balog J, et al. QA for helical
tomotherapy: report of the AAPM Task Group 148. Med Phys.
2010;37(9):4817–4853.
142. Wang L, Kielar KN, Mok E, et al. An end-to-end examination of
geometric accuracy of IGRT using a new digital accelerator
equipped with onboard imaging system. Phys Med Biol.
2012;57(3):757–769.
143. Bissonnette JP, Moseley DJ, Jaffray DA. A quality assurance
program for image quality of cone-beam CT guidance in radiation
therapy. Med Phys. 2008;35(5):1807–1815.
144. Yoo S, Yin FF. Dosimetric feasibility of cone-beam CT-based
treatment planning compared to CT-based treatment planning. Int J
Radiat Oncol Biol Phys. 2006;66(5):1553–1561.
145. Gopal A, Samant SS. Use of a line-pair resolution phantom for
comprehensive quality assurance of electronic portal imaging
devices based on fundamental imaging metrics. Med Phys.
2009;36(6):2006–2015.
146. Gayou O, Miften M. Commissioning and clinical implementation of
a mega-voltage cone beam CT system for treatment localization.
Med Phys. 2007;34(8):3183–3192.
147. Antypas C, Pantelis E. Performance evaluation of a CyberKnife G4
image-guided robotic stereotactic radiosurgery system. Phys Med
Biol. 2008;53(17):4697–4718.
148. Jiang SB, Wolfgang J, Mageras GS. Quality assurance challenges for
motion-adaptive radiation therapy: gating, breath holding, and four-
dimensional computed tomography. Int J Radiat Oncol Biol Phys.
2008;71(1 Suppl):S103–S107.
149. Li G, Xie H, Ning H, et al. A novel 3D volumetric voxel registration
technique for volume-view-guided image registration of multiple
imaging modalities. Int J Radiat Oncol Biol Phys. 2005;63(1):261–
273.
150. Li G, Xie H, Ning H, et al. Accuracy of 3D volumetric image
registration based on CT, MR and PET/CT phantom experiments. J
Appl Clin Med Phys. 2008;9(4):2781.
151. Sharpe M, Brock KK. Quality assurance of serial 3D image
registration, fusion, and segmentation. Int J Radiat Oncol Biol Phys.
2008;71(1 Suppl):S33–S37.
152. Zhang L, Garden AS, Lo J, et al. Multiple regions-of-interest analysis
of setup uncertainties for head-and-neck cancer radiotherapy. Int J
Radiat Oncol Biol Phys. 2006;64(5):1559–1569.
153. van Kranen S, van Beek S, Rasch C, et al. Setup uncertainties of
anatomical sub-regions in head-and-neck cancer patients after
offline CBCT guidance. Int J Radiat Oncol Biol Phys.
2009;73(5):1566–1573.
154. Park SB, Rhee FC, Monroe JI, Sohn JW. Spatially weighted mutual
information image registration for image guided radiation therapy.
Med Phys. 2010;37(9):4590–4601.
155. Mencarelli A, van Beek S, Zijp LJ, et al. Automatic detection system
for multiple region of interest registration to account for posture
changes in head and neck radiotherapy. Phys Med Biol.
2014;59(8):2005–2021.
156. Li G, Yang TJ, Furtado H, et al. Clinical assessment of 2D/3D
registration accuracy in 4 major anatomic sites using on-board 2D
kilovoltage images for 6D patient setup. Technol Cancer Res Treat.
2014.
157. Pluim JP, Maintz JB, Viergever MA. Mutual-information-based
registration of medical images: a survey. IEEE Trans Med Imaging.
2003;22(8):986–1004.
158. Al-Mayah A, Moseley J, Velec M, Brock K. Toward efficient
biomechanical-based deformable image registration of lungs for
image-guided radiotherapy. Phys Med Biol. 2011;56(15):4701–4713.
159. Yang D, Brame S, El Naqa I, et al. Technical note: DIRART–A
software suite for deformable image registration and adaptive
radiotherapy research. Med Phys. 2011;38(1):67–77.
160. Saleh ZH, Apte AP, Sharp GC, et al. The distance discordance
metric—a novel approach to quantifying spatial uncertainties in
intra- and inter-patient deformable image registration. Phys Med
Biol. 2014;59(3):733–746.
161. Wijesooriya K, Weiss E, Dill V, et al. Quantifying the accuracy of
automated structure segmentation in 4D CT images using a
deformable image registration algorithm. Med Phys.
2008;35(4):1251–1260.
162. Zhang Q, Pevsner A, Hertanto A, et al. A patient-specific respiratory
model of anatomical motion for radiation treatment planning. Med
Phys. 2007;34(12):4772–4781.
163. Kruis MF, van de Kamer JB, Sonke JJ, et al. Registration accuracy
and image quality of time averaged mid-position CT scans for liver
SBRT. Radiother Oncol. 2013;109(3):404–408.
164. Wang H, Garden AS, Zhang L, et al. Performance evaluation of
automatic anatomy segmentation algorithm on repeat or four-
dimensional computed tomography images using deformable image
registration method. Int J Radiat Oncol, Biol, Phys. 2008;72(1):210–
219.
165. Hugo GD, Campbell J, Zhang T, Yan D. Cumulative lung dose for
several motion management strategies as a function of pretreatment
patient parameters. Int J Radiat Oncol Biol Phys. 2009; 74(2):593–
601.
166. Yan D, Vicini F, Wong J, Martinez A. Adaptive radiation therapy.
Phys Med Biol. 1997;42(1):123–132.
167. Yan D, Jaffray DA, Wong JW. A model to accumulate fractionated
dose in a deforming organ. Int J Radiat Oncol Biol Phys.
1999;44(3):665–675.
168. Yan C, Hugo G, Salguero FJ, et al. A method to evaluate dose errors
introduced by dose mapping processes for mass conserving
deformations. Med Phys. 2012;39(4):2119–2128.
169. Li HS, Zhong H, Kim J, et al. Direct dose mapping versus
energy/mass transfer mapping for 4D dose accumulation:
fundamental differences and dosimetric consequences. Phys Med
Biol. 2014;59(1):173–188.
170. Li G, Cohen P, Xie H, et al. A novel four-dimensional radiotherapy
planning strategy from a tumor-tracking beam’s eye view. Phys Med
Biol. 2012;57(22):7579–7598.
171. Cai J, Malhotra HK, Orton CG. A 3D-conformal technique is better
than IMRT or VMAT for lung SBRT. Med Phys. 2014;41(4):040601.
172. Qi P, Pouliot J, Roach M 3rd, et al. Offline multiple adaptive
planning strategy for concurrent irradiation of the prostate and
pelvic lymph nodes. Med Phys. 2014;41(2):021704.
173. Lalondrelle S, Huddart R, Warren-Oseni K, et al. Adaptive-
predictive organ localization using cone-beam computed
tomography for improved accuracy in external beam radiotherapy
for bladder cancer. Int J Radiat Oncol Biol Phys. 2011;79(3):705–
712.
174. Ahunbay EE, Peng C, Godley A, et al. An on-line replanning method
for head and neck adaptive radiotherapy. Med Phys.
2009;36(10):4776–4790.
175. Standard. IHE-RO: Integrating Healthcare Enterprise - Radiation
Oncology. http://wikiihenet/indexphp?title = Radiation_Oncology.
Accessed on March 20, 2015.
176. Standard. DICOM: Digital Imaging and Communications in
Medicine, managed by the Medical Imaging & Technology Alliance -
a division of NEMA. http://medicalnemaorg/standardhtml.
Accessed on March 20, 2015: 2015.
177. Yan D. Adaptive radiotherapy: merging principle into clinical
practice. Semin Radiat Oncol. 2010;20(2):79–83.
178. Deasy JO, Blanco AI, Clark VH. CERR: a computational
environment for radiotherapy research. Med Phys. 2003;30(5):979–
985.
179. Jaffray DA. Image-guided radiation therapy: from concept to
practice. Semin Radiat Oncol. 2007;17(4):243–244.
180. Oh S, Stewart J, Moseley J, et al. Hybrid adaptive radiotherapy
with on-line MRI in cervix cancer IMRT. Radiother Oncol. 2013.
181. Yan D, Lockman D, Brabbins D, et al. An off-line strategy for
constructing a patient-specific planning target volume in adaptive
treatment process for prostate cancer. Int J Radiat Oncol Biol Phys.
2000;48(1):289–302.
182. Riboldi M, Sharp GC, Baroni G, et al. Four-dimensional targeting
error analysis in image-guided radiotherapy. Phys Med Biol.
2009;54(19):5995–6008.
183. Chen H, Wu A, Brandner ED, et al. Dosimetric evaluations of the
interplay effect in respiratory-gated intensity-modulated radiation
therapy. Med Phys. 2009;36(3):893–903.
184. Kini VR, Vedam SS, Keall PJ, et al. Patient training in respiratory-
gated radiotherapy. Med Dosim. 2003;28(1):7–11.
185. Parkhurst JM, Price GJ, Sharrock PJ, et al. Self-management of
patient body position, pose, and motion using wide-field, real-time
optical measurement feedback: results of a volunteer study. Int J
Radiat Oncol Biol Phys. 2013;87(5):904–910.
186. Mageras GS, Yorke E. Deep inspiration breath hold and respiratory
gating strategies for reducing organ motion in radiation treatment.
Semin Radiat Oncol. 2004;14(1):65–75.
187. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing
control (ABC) to reduce margin for breathing motion. Int J Radiat
Oncol, Biol, Phys. 1999;44(4):911–919.
188. Steidl P, Haberer T, Durante M, et al. Gating delays for two
respiratory motion sensors in scanned particle radiation therapy.
Phys Med Biol. 2013;58(21):N295–N302.
189. Poulsen PR, Cho B, Sawant A, et al. Detailed analysis of latencies in
image-based dynamic MLC tracking. Med Phys. 2010;37(9):4998–
5005.
190. Sharp GC, Jiang SB, Shimizu S, et al. Prediction of respiratory
tumour motion for real-time image-guided radiotherapy. Phys Med
Biol. 2004;49(3):425–440.
191. Hoisak JD, Sixel KE, Tirona R, et al. Correlation of lung tumor
motion with external surrogate indicators of respiration. Int J Radiat
Oncol Biol Phys. 2004;60(4):1298–1306.
192. van Herk M. Errors and margins in radiotherapy. Semin Radiat
Oncol. 2004;14(1):52–64.
193. van Herk M, Remeijer P, Rasch C, Lebesque JV. The probability of
correct target dosage: dose-population histograms for deriving
treatment margins in radiotherapy. Int J Radiat Oncol Biol Phys.
2000;47(4):1121–1135.
194. Nelson C, Balter P, Morice RC, et al. Evaluation of tumor position
and PTV margins using image guidance and respiratory gating. Int J
Radiat Oncol Biol Phys. 2010;76(5):1578–1585.
195. Grills IS, Hugo G, Kestin LL, et al. Image-guided radiotherapy via
daily online cone-beam CT substantially reduces margin
requirements for stereotactic lung radiotherapy. Int J Radiat Oncol
Biol Phys. 2008;70(4):1045–1056.
196. Pepin EW, Wu H, Shirato H. Dynamic gating window for
compensation of baseline shift in respiratory-gated radiation
therapy. Med Phys. 2011;38(4):1912–1918.
197. Ge J, Santanam L, Noel C, et al. Planning 4-dimensional computed
tomography (4DCT) cannot adequately represent daily
intrafractional motion of abdominal tumors. Int J Radiat Oncol Biol
Phys. 2013;85(4):999–1005.
198. Akino Y, Oh RJ, Masai N, et al. Evaluation of potential internal
target volume of liver tumors using cine-MRI. Med Phys.
2014;41(11):111704.
199. Melancon AD, O’Daniel JC, Zhang L, et al. Is a 3-mm intrafractional
margin sufficient for daily image-guided intensity-modulated
radiation therapy of prostate cancer?Radiother Oncol.
2007;85(2):251–259.
200. Tanyi JA, He T, Summers PA, et al. Assessment of planning target
volume margins for intensity-modulated radiotherapy of the
prostate gland: role of daily inter- and intrafraction motion. Int J
Radiat Oncol Biol Phys. 2010;78(5):1579–1585.
201. O’Daniel JC, Dong L, Zhang L, et al. Daily bone alignment with
limited repeat CT correction rivals daily ultrasound alignment for
prostate radiotherapy. Int J Radiat Oncol Biol Phys. 2008;71(1):274–
280.
202. Li HS, Chetty IJ, Enke CA, et al. Dosimetric consequences of
intrafraction prostate motion. Int J Radiat Oncol Biol Phys. 2008;
71(3):801–812.
203. Langen KM, Jones DT. Organ motion and its management. Int J
Radiat Oncol Biol Phys. 2001;50(1):265–278.
204. Fokdal L, Honore H, Hoyer M, et al. Impact of changes in bladder
and rectal filling volume on organ motion and dose distribution of
the bladder in radiotherapy for urinary bladder cancer. Int J Radiat
Oncol Biol Phys. 2004;59(2):436–444.
205. Li XA, Qi XS, Pitterle M, et al. Interfractional variations in patient
setup and anatomic change assessed by daily computed
tomography. Int J Radiat Oncol Biol Phys. 2007;68(2):581–591.
206. Sanguineti G, Marcenaro M, Franzone P, et al. Neoadjuvant
androgen deprivation and prostate gland shrinkage during
conformal radiotherapy. Radiother Oncol. 2003;66(2):151–157.
207. Litzenberg DW, Hadley SW, Tyagi N, et al. Synchronized dynamic
dose reconstruction. Med Phys. 2007;34(1):91–102.
208. Ramsey CR, Scaperoth D, Seibert R, et al. Image-guided helical
tomotherapy for localized prostate cancer: technique and initial
clinical observations. J Appl Clin Med Phys. 2007;8(3):2320.
209. Langen KM, Lu W, Willoughby TR, et al. Dosimetric effect of
prostate motion during helical tomotherapy. Int J Radiat Oncol Biol
Phys. 2009;74(4):1134–1142.
210. Chen L, Paskalev K, Xu X, et al. Rectal dose variation during the
course of image-guided radiation therapy of prostate cancer.
Radiother Oncol. 2010;95(2):198–202.
211. Wen N, Kumarasiri A, Nurushev T, et al. An assessment of PTV
margin based on actual accumulated dose for prostate cancer
radiotherapy. Phys Med Biol. 2013;58(21):7733–7744.
212. 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(1):125–129.
213. Chao KS, Majhail N, Huang CJ, et al. Intensity-modulated radiation
therapy reduces late salivary toxicity without compromising tumor
control in patients with oropharyngeal carcinoma: a comparison
with conventional techniques. Radiother Oncol. 2001;61(3):275–280.
214. Barker JL Jr., Garden AS, Ang KK, et al. Quantification of
volumetric and geometric changes occurring during fractionated
radiotherapy for head-and-neck cancer using an integrated
CT/linear accelerator system. Int J Radiat Oncol, Biol, Phys.
2004;59(4):960–970.
215. O’Daniel JC, Garden AS, Schwartz DL, et al. Parotid gland dose in
intensity-modulated radiotherapy for head and neck cancer: is what
you plan what you get?Int J Radiat Oncol Biol Phys.
2007;69(4):1290–1296.
216. Wu QJ, Thongphiew D, Wang Z, et al. The impact of respiratory
motion and treatment technique on stereotactic body radiation
therapy for liver cancer. Med Phys. 2008;35(4):1440–1451.
217. Kuo HC, Mah D, Chuang KS, et al. A method incorporating 4DCT
data for evaluating the dosimetric effects of respiratory motion in
single-arc IMAT. Phys Med Biol. 2010;55(12):3479–3497.
218. Zarepisheh M, Long T, Li N, et al. A DVH-guided IMRT optimization
algorithm for automatic treatment planning and adaptive
radiotherapy replanning. Med Phys. 2014;41(6):061711.
219. Olsen LA, Robinson CG, He GR, et al. Automated radiation therapy
treatment plan workflow using a commercial application
programming interface. Pract Radiat Oncol. 2014;4(6):358–367.
220. Li H, Yu L, Anastasio MA, et al. Automatic CT simulation
optimization for radiation therapy: A general strategy. Med Phys.
2014;41(3):031913.
221. Zhang P, Yorke E, Hu YC, et al. Predictive treatment management:
incorporating a predictive tumor response model into robust
prospective treatment planning for non-small cell lung cancer. Int J
Radiat Oncol Biol Phys. 2014;88(2):446–452.
222. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin
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.
13 Linac Radiosurgery: System
Requirements, Procedures, and
Testing
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
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.
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.
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
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.
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.
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.
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
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.
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.
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.
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
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 13.15 Absolute phantom and optical positioning system used for end-to-end testing, from
image acquisition through delivery.
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.
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.
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.
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).
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.
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.
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.
FIGURE 13.22 A skull-based tumor that was planned with sphere packing. Table shows the
sphere diameters and relative intensities.
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.
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.
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
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
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.
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.
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.
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.
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).
FIGURE 13.32 Checklist for time-out prior to initiation of the radiosurgical procedure.
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?
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
REFERENCES
1. Audet C, Poffenbarger B, Chang P, et al. Evaluation of volumetric
modulated arc therapy for cranial radiosurgery using multiple non-
coplanar arcs. Med Phys. 2011;38(11):5863–5872.
2. Barth NH. An inverse problem in radiation oncology. Int J Radiation
Oncology Biol Phys. 1990;18:425–431.
3. Betti OO Galmarini D, Derechinsky V. Radiosurgery with a linear
accelerator. Methodological aspects. Stereotact Funct Neurosurg.
1999;57(1–2):87–98.
4. Bolsi A, Fogliata A, Cozzi L.. Radiotherapy of small intracranial
tumours with different advanced techniques using photon and
proton beams: A treatment planning study. Radiother Oncol. 2003;
68:1–14.
5. Chang J, Yenice K, Narayana A, et al. Accuracy and feasibility of
conebeam computed tomography for stereotactic radiosurgery setup.
Med Phys. 2007;34:2077–2084.
6. Chin L, MA L, DiBiase S. Radiation necrosis following gamma knife
surgery: a case-controlled comparison of treatment parameters and
long-term clinical follow up. J Neurosurg. 2001;899–904.
7. Clark G, Popple R, Young E, et al. Feasibility of single-isocenter
volumetric modulated arc radiosurgery for treatment of Multiple
Brain Metastases. Int J Radiat Oncol Biol Phys. 2010;76(1):296–302.
8. Colombo F, Benedetti A, Pozza F. Stereotactic radiosurgery utilizing
a linear accelerator. Appl Neurophysiol. 1985;48(1–6):133–145.
9. Friedman WA, Bova FJ. The University of Florida radiosurgery
system. Surg Neurol. 1989;32(5):334–343.
10. Heilbrun M, Roberts T, Apuzzo M. Preliminary experience with
Brown-Roberts-Wells (BRW) computerized tomography stereotaxic
guidance system. J Neurosurg. 1983;59:217–222.
11. ICRU, 6. ICRU Report 62. Prescribing, recording, and reporting photon
beam therapy. International Commission on Radiation Units and
Measurements. Bethesda, MD: ICRU;1999.
12. Kjellberg R, Hanamura T, Davis KR, et al. Bragg-Peak proton-beam
therapy for arteriovenous malformations of the brain. N. Engl. J.
Med. 1983;309:269–274.
13. Leksel L. The stereotaxic method and radiosurgery of the brain. Acta
Chir Scand. 1951;102:316–319.
14. Leksell L. Cerebral radiosurgery. I. Gammathalamotomy in two
cases of intractable pain. Acta Chir Scan. 1968;134:585–589.
15. Leksell L. Stereotaxis and radiosurgery: An operative system. Thomas;
1971.
16. Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry.
1983;46(9):797–803.
17. Li L, Leigh J. Quantifying arbitrary magnetic susceptibility
distributions with MR. Magn Reson Med. 2004;51(5):1077–1082.
18. Lightstone A, Benedict S, Bova F, et al. American Association of
Physicists in Medicine Radiation Therapy Committee. Intracranial
stereotactic positioning systems: Report of the American Association
of Physicists in Medicine Radiation Therapy Committee Task Group
no. 68. Med Phys. 2005;32:2380–2398.
19. Lindquist C. Gamma Knife Radiosurgery. Semin Radiat Oncol.
1995;5(3):197–202.
20. Liu R, Wagner TH, Buatti JM, et al. Geometrically based
optimization for extracranial radiosurgery. 2004;49(6):987–996.
21. Lunsford LD, Flickinger J, Lindner G, et al. Stereotactic radiosurgery
of the brain using the first United States 201 cobalt-60 source
gamma knife. Neurosurgery. 1989;24(2):151–159.
22. Lutz W, Winston KR, Maleki N. A system for stereotactic
radiosurgery with a linear accelerator. Int J Radiat Oncol Biol Phys.
1988;14(2):373–381.
23. Ma L, Sahgal A, Larson DA, et al. Impact of millimeter-level margins
on peripheral normal brain sparing for gamma knife radiosurgery.
Int J Radiat Oncol Biol Phys. 2014;89:206–213.
24. Meeks S, Bova F, Friedman W, et al. IRLED-based patient
localization for linac radiosurgery. Int J Radiat Oncol Biol Phys.
1998;41:433–439.
25. Meeks SL, Bova FJ, Wagner TH et al. Image localization for
frameless stereotactic radiotherapy. Int J Radiat Oncol Biol Phys.
2000;46:1291–1299.
26. Mehta M. The physical, biologic, and clinical basis of radiosurgery.
Current Problems in Cancer. 1995;19(5):270–328.
27. Mould R. Mould’s Medical Anecdotes Omnibus Edition. CRC
Press;1966.
28. Paddick A. A simple scoring ratio to index the conformity of
radiosurgical treatment plans. Technical note. J Neurosurg. 2000;
93(Suppl 3):219–222.
29. Phillips MH, Singer K, Miller E, et al. Commissioning an image-
guided localization system for radiotherapy. Int J Radiat Oncol Biol
Phys. 2000;48(1):267–276.
30. Pike GB, Podgorsak EB, Peters TM, et al. Three-dimensional isodose
distributions in stereotactic radiosurgery. Stereotact Funct Neurosurg.
1990;54(55):519–524.
31. Rahimian J, Chen L, Rao A, et al. Geometrical accuracy of the
Novalis stereotactic radiosurgery system for trigeminal neuralgia. J
Neurosurg. 2004;101(Suppl 3):352–355.
32. Rice RK, Hansen JL, Svensson GK, et al. Measurements of dose
distributions in small beams of 6 MV X-rays. 1987;32(9):1087–1099.
33. Roberts T, Brown R. Technical and clinical aspects of CT-directed
stereotaxis. Appl Neurophysiol. 1980;43:170–171.
34. Ryken T, Meeks S, Pennington E, et al. Initial clinical experience
with frameless stereotactic radiosurgery: analysis of accuracy and
feasibility. Int J Radiat Oncol Biol Phys. 2001;51:1152–1158.
35. Saw CB, Ayyangar K, Suntharalingam N. Coordinate transformations
and calculation of the angular and depth parameters for a
stereotactic system. Med Phys. 1987;14(6):1042–1044.
36. Schell MC, Smith V, Larson DA, et al. Evaluation of radiosurgery
techniques with cumulative dose volume histograms in linac-based
stereotactic external beam irradiation. Int J Radiat Oncol Biol Phys.
1991;20(6):1325–1330.
37. Schell M, Bova F, Larson D, et al. “TG-42 Report on stereotactic
external beam irradiation. AAPM Report No. 54.” Stereotactic
Radiosurgery. American Association of Physicists in Medicine.
College Park: AAPM; 1995.
38. Shirashi S, Tan J, Olsen LA. Knowledge-based prediction of plan
quality metrics in intracranial stereotactic radiosurgery. Med Phys.
2015;42(3):908–917.
39. Siddon RL, Barth NH. Stereotaxic localization of intracranial targets.
Int J Radiat Oncol Biol Phys. 1987;13(8):1241–1246.
40. Tan J, Olsen L, Moore K. Knowledge-based prediction of plan
quality metrics in intracranial stereotactic radiosurgery. Med Phys.
2015;42(2):908–917.
41. Verellen D, Linthout N, Bel A, et al. Assessment of the uncertainties
in dose delivery of a commercial system for linac-based stereotactic
radiosurgery. Int J Radiat Oncol Biol Phys. 1999;44:421–433.
42. Wagner TH, Bova FJ, Friedman WA, et al. A simple and reli- able
index for scoring rival stereotactic radiosurgery plans. J Radiat
Oncol Biol Phys. 2003;57(4):1141–1149.
43. Wagner TH, Yi T, Meeks SL, et al. A geometrically based method for
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.
14 Stereotactic Ablative
Radiotherapy
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
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
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.
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).
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
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
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.
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
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.
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
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.
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
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.
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.
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
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).
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.
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
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.
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
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
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
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
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
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
REFERENCES
1. Blomgren H, Lax I, Näslund I, et al. Stereotactic high dose fraction
radiation therapy of extracranial tumors using an accelerator.
Clinical experience of the first thirty-one patients. Acta Oncol.
1995;34(6):861–870.
2. Lax I, Blomgren H, Näslund I, et al. Stereotactic radiotherapy of
malignancies in the abdomen. Methodological aspects. Acta Oncol.
1994;33(6):677–683.
3. Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS
and SBRT: are more than the 5 rs involved?. Int J Radiat Oncol Biol
Phys. 2014;88(2):254–262.
4. Brown JM, Carlson DJ, Brenner DJ. Dose escalation, not “new
biology,” can account for the efficacy of stereotactic body radiation
therapy with non-small cell lung cancer. In reply to Rao et al. Int J
Radiat Oncol Biol Phys. 2014;89(3):693–694.
5. Rao SS, Oh JH, Jackson A, et al. Dose escalation, not “new biology,”
can account for the efficacy of stereotactic body radiation therapy
with non-small cell lung cancer. In regard to Brown et al. Int J Radiat
Oncol Biol Phys. 2014;89(3):692–693.
6. Song CW, Kim MS, Cho LC, et al. Radiobiological basis of SBRT and
SRS. Int J Clin Oncol. 2014;19(4):570–578.
7. Finkelstein SE, Timmerman R, McBride WH, et al. The confluence of
stereotactic ablative radiotherapy and tumor immunology. Clin Dev
Immunol. 2011;2011:439752.
8. Park C, Papiez L, Zhang S, Story M, 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(3):847–852.
9. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates
of the abscopal effect in a patient with melanoma. N Engl J Med.
2012;366(10):925–931.
10. Stamell EF, Wolchok JD, Gnjatic S, et al. The abscopal effect
associated with a systemic anti-melanoma immune response. Int J
Radiat Oncol Biol Phys. 2013;85(2):293–295.
11. Foster R, Meyer J, Iyengar P, et al. Localization accuracy and
immobilization effectiveness of a stereotactic body frame for a
variety of treatment sites. Int J Radiat Oncol Biol Phys.
2013;87(5):911–916.
12. Negoro Y, Nagata Y, Aoki T, et al. The effectiveness of an
immobilization device in conformal radiotherapy for lung tumor:
reduction of respiratory tumor movement and evaluation of the
daily setup accuracy. Int J Radiat Oncol Biol Phys. 2001;50(4):889–
98.
13. Han K, Cheung P, Basran PS, et al. A comparison of two
immobilization systems for stereotactic body radiation therapy of
lung tumors. Radiother Oncol. 2010;95(1):103–108.
14. Shah C, Grills IS, Kestin LL, et al. Intrafraction variation of mean
tumor position during image-guided hypofractionated stereotactic
body radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys.
2012;82(5):1636–1641.
15. Boda-Heggemann J, Frauenfeld A, Weiss C, et al. Clinical outcome
of hypofractionated breath-hold image-guided SABR of primary lung
tumors and lung metastases. Radiat Oncol. 2014;9:10.
16. Eccles C, Brock KK, Bissonnette JP, et al. Reproducibility of liver
position using active breathing coordinator for liver cancer
radiotherapy. Int J Radiat Oncol Biol Phys. 2006;64(3):751–759.
17. Berbeco RI, Nishioka S, Shirato H, et al. Residual motion of lung
tumours in gated radiotherapy with external respiratory surrogates.
Phys Med Biol. 2005;50(16):3655–3667.
18. Falk M, Pommer T, Keall P, et al. Motion management during IMAT
treatment of mobile lung tumors–a comparison of MLC tracking and
gated delivery. Med Phys. 2014;41(10):101707.
19. Depuydt T, Verellen D, Haas O, et al. Geometric accuracy of a novel
gimbals based radiation therapy tumor tracking system. Radiother
Oncol. 2011;98(3):365–72.
20. Hoogeman M, Prévost JB, Nuyttens J, et al. Clinical accuracy of the
respiratory tumor tracking system of the cyberknife: assessment by
analysis of log files. Int J Radiat Oncol Biol Phys. 2009;74(1):297–
303.
21. Heinzerling JH, Anderson JF, Papiez L, et al. Four-Dimensional
Computed Tomography Scan Analysis of Tumor and Organ Motion
at Varying Levels of Abdominal Compression During Stereotactic
Treatment of Lung and Liver. Int J Radiat Oncol Biol Phys.
2008;70(5):1571–1578.
22. Keall PJ, Colvill E, O’Brien R, et al. The first clinical implementation
of electromagnetic transponder-guided MLC tracking. Med Phys.
2014;41(2):020702.
23. Papiez L, Timmerman R, DesRosiers C, et al. Extracranial
stereotactic radioablation: physical principles. Acta Oncol. 2003;
42(8):882–894.
24. Xiao Y, Papiez L, Paulus R, et al. Dosimetric evaluation of
heterogeneity corrections for RTOG 0236: stereotactic body
radiotherapy of inoperable stage I-II non-small-cell lung cancer. Int J
Radiat Oncol Biol Phys. 2009;73(4):1235–1242.
25. Disher B, Hajdok G, Gaede S, et al. An in-depth Monte Carlo study
of lateral electron disequilibrium for small fields in ultra-low density
lung: implications for modern radiation therapy. Phys Med Biol.
2012;57(6):1543–1559.
26. Lang S, Shrestha B, Graydon S, et al. Clinical application of
flattening filter free beams for extracranial stereotactic
radiotherapy. Radiother Oncol. 2013;106(2):255–259.
27. Ong CL, Verbakel WF, Dahele M, et al. Fast arc delivery for
stereotactic body radiotherapy of vertebral and lung tumors. Int J
Radiat Oncol Biol Phys. 2012;83(1):e137–e143.
28. Prendergast BM, Fiveash JB, Popple RA, et al. Flattening filter-free
linac improves treatment delivery efficiency in stereotactic body
radiation therapy. J Appl Clin Med Phys. 2013;14(3):4126.
29. Thomas EM, Popple RA, Prendergast BM, et al. Effects of flattening
filter-free and volumetric-modulated arc therapy delivery on
treatment efficiency. J Appl Clin Med Phys. 2013;14(6):4328.
30. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body
radiation therapy: the report of AAPM Task Group 101. Med Phys.
2010;37(8):4078–4101.
31. Aarup LR, Nahum AE, Zacharatou C, et al. The effect of different
lung densities on the accuracy of various radiotherapy dose
calculation methods: implications for tumour coverage. Radiother
Oncol. 2009;91(3):405–414.
32. Chen H, Lohr F, Fritz P, et al. Stereotactic, single-dose irradiation of
lung tumors: a comparison of absolute dose and dose distribution
between pencil beam and Monte Carlo algorithms based on actual
patient CT scans. Int J Radiat Oncol Biol Phys. 2010;78(3):955–963.
33. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: quality
assurance of medical accelerators. Med Phys. 2009;36(9):4197–
4212.
34. Borius PY, Debono B, Latorzeff I, et al. [Dosimetric stereotactic
radiosurgical accident: Study of 33 patients treated for brain
metastases]. Neurochirurgie. 2010;56(5):368–373.
35. Derreumaux S Etard C, Huet C, et al. Lessons from recent accidents
in radiation therapy in France. Radiat Prot Dosimetry.
2008;131(1):130–135.
36. Followill DS, S Kry. Response to Thomsen et al.: Comments on “The
Radiological Physics Center’s standard dataset for small field size
output factors”. J Appl Clin Med Phys. 2014;15(2):4841.
37. Followill DS, Kry SF, Qin L, et al. The Radiological Physics Center’s
standard dataset for small field size output factors. J Appl Clin Med
Phys. 2012;13(5):3962.
38. Solberg TD, Balter JM, Benedict SH, et al. Quality and safety
considerations in stereotactic radiosurgery and stereotactic body
radiation therapy: executive summary. Practical Radiation Oncology.
2012;2(1):2–9.
39. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J
Clin. 2014;64(1):9–29.
40. Pan H, Rose BS, Simpson DR, et al. Clinical practice patterns of lung
stereotactic body radiation therapy in the United States: a secondary
analysis. Am J Clin Oncol. 2013;36(3):269–272.
41. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation
therapy for inoperable early stage lung cancer. JAMA. 2010;
303(11):1070–1076.
42. Timmerman RD, Hu C, Michalski J, et al. Long-term results of RTOG
0236: A phase II trial of stereotactic body radiation therapy (SBRT)
in the treatment of patients with medically inoperable stage I non-
small cell lung cancer. Int J Radiat Oncol Biol Phys. 90(1):S30.
43. Timmerman RD, Paulus R, Pass HI, et al. RTOG 0618: stereotactic
body radiation therapy (SBRT) to treat operable early-stage lung
cancer patients. ASCO Meeting Abstracts. 2013;31(15 Suppl):7523.
44. Palma D, Visser O, Lagerwaard FJ, et al. Impact of introducing
stereotactic lung radiotherapy for elderly patients with stage I non-
small-cell lung cancer: a population-based time-trend analysis. J Clin
Oncol. 2010;28(35):5153–5159.
45. Videtic GM, Gaspar LE, Zamorano L, et al. Radiation Therapy
Oncology Group (RTOG) Protocol 0915: A Randomized Phase 2
Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT)
Schedules for Medically Inoperable Patients With Stage I Peripheral
Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 87(2):S3.
46. Senthi S, Haasbeek CJ, Slotman BJ, et al. Outcomes of stereotactic
ablative radiotherapy for central lung tumours: a systematic review.
Radiother Oncol. 2013;106(3):276–282.
47. Rowe BP, Boffa DJ, Wilson LD, et al. Stereotactic body radiotherapy
for central lung tumors. J Thorac Oncol. 2012;7(9):1394–1399.
48. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of
stereotactic body radiation therapy combined with erlotinib for
patients with limited but progressive metastatic non-small-cell lung
cancer. J Clin Oncol. 2014;32(34):3824–3830.
49. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA
Cancer J Clin. 2014;64(2):104–117.
50. Ercolani G, Grazi GL, Ravaioli M, et al. Liver resection for multiple
colorectal metastases: influence of parenchymal involvement and
total tumor volume, vs number or location, on long-term survival.
Arch Surg. 2002;137(10):1187–1192.
51. Welch JP, Donaldson GA. The clinical correlation of an autopsy
study of recurrent colorectal cancer. Ann Surg. 1979;189(4):496–
502.
52. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable
colorectal liver metastases downstaged by chemotherapy: a model
to predict long-term survival. Ann Surg. 2004;240(4):644–557;
discussion 657–658.
53. Fusai G, Davidson BR. Management of colorectal liver metastases.
Colorectal Dis. 2003;5(1):2–23.
54. de Baere T, Elias D, Dromain C, et al. Radiofrequency ablation of
100 hepatic metastases with a mean follow-up of more than 1 year.
AJR Am J Roentgenol. 2000;175(6):1619–1625.
55. Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial
versus intravenous fluorouracil and folinic acid for colorectal cancer
liver metastases: a multicentre randomised trial. Lancet.
2003;361(9355):368–373.
56. Solbiati L, Livraghi T, Goldberg SN, et al. Percutaneous radio-
frequency ablation of hepatic metastases from colorectal cancer:
long-term results in 117 patients. Radiology. 2001;221(1):159–166.
57. Sotsky TK, Ravikumar TS. Cryotherapy in the treatment of liver
metastases from colorectal cancer. Semin Oncol. 2002;29(2):183–
191.
58. Tandan VR, Harmantas A, Gallinger S. Long-term survival after
hepatic cryosurgery versus surgical resection for metastatic
colorectal carcinoma: a critical review of the literature. Can J Surg.
1997;40(3):175–181.
59. Vogl TJ, Müller PK, Hammerstingl R, et al. Malignant liver tumors
treated with MR imaging-guided laser-induced thermotherapy:
technique and prospective results. Radiology. 1995;196(1):257–265.
60. Vogl TJ, Straub R, Eichler K, et al. Malignant liver tumors treated
with MR imaging-guided laser-induced thermotherapy: experience
with complications in 899 patients (2,520 lesions). Radiology.
2002;225(2):367–377.
61. Haas RJ, Wicherts DA, Adam R. Oncosurgical Strategies for
Unresectable Liver Metastases, in Liver Metastases. 2009;1–13.
62. Blazer DG, Anaya DA, Abdalla EK. Destructive therapies for
colorectal cancer metastases. In: Vauthey JN, Audisio RA, Hoff PM,
et al., eds. Liver Metastases. London: Springer-Verlag; 2009:1–11.
63. Reed GB, Jr., Cox AJ, Jr. The human liver after radiation injury. A
form of veno-occlusive disease. Am J Pathol. 1966;48(4):597–611.
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
Oncologica. 2006;45(7):823–830.
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
Oncol Biol Phys. 2008;72(Suppl 1):S247–S248.
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
radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72(5):1516–1522.
75. McCammon R, Schefter TE, Gaspar LE, et al. Observation of a dose-
control relationship for lung and liver tumors after stereotactic body
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
Radiat Oncol Biol Phys. 2005;62(5):1371–1378.
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.
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
J Radiat Oncol Biol Phys. 2012;83(3):1031–1037.
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
J Radiat Oncol Biol Phys. 2013;87(5):939–945.
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.
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
cancer. Int J Radiat Oncol Biol Phys. 2010;78(3):735–742.
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
Radiat Oncol Biol Phys. 2012;82(2):940–945.
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
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 &
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.
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
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.
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
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.
FIGURE 15.2 TG-43 brachytherapy dosimetry coordinate system for dose calculations, adapted
from Rivard et al. (28).
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
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.
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
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
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).
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
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
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.
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
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
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
• 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?
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
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.
REFERENCES
1. Danlos H, Bloch P. Note sur le traitement du lupus erythematenx par
des application de radium. Ann Dermatol Syphil. 1901;2:986–988.
2. Forssell G. La lutte social contre le cancer. J Radiologie.
1931;15:621–634.
3. Aronowitz JN. Benjamin Barringer: originator of the transperineal
prostate implant. Urology. 2002;60:731–734.
4. Aronowitz JN. Dawn of prostate brachytherapy: 1915–1930. Int J
Radiat Oncol, Biol Phys. 2002;54:712–718.
5. Aronowitz JN. Buried emanation: the development of seeds for
permanent implantation. Brachytherapy. 2002;1:167–178.
6. Aronowitz JN. Ethereal fire: antecedents of radiology and
radiotherapy. Am J Roentgenology. 2007;188:904–912.
7. Aronowitz JN, Aronowitz SV, Robinson RF. Classics in
brachytherapy: margaret cleaves introduces gynecologic
brachytherapy. Brachytherapy. 2007;6:293–298.
8. Aronowitz JN. The “Golden Age” of prostate brachytherapy: a
cautionary tale. Brachytherapy. 2008;7:55–59.
9. Aronowitz JN, Robinson RF. Howard Kelly establishes gynecologic
brachytherapy in the United States. Brachytherapy. 2010;9:178–184.
10. Aronowitz JN. Don Lawrence and the “k-capture” revolution.
Brachytherapy. 2010;9:373–381.
11. Aronowitz JN. Partial breast irradiation by brachytherapy, 1927.
Brachytherapy. 2011;10:427–431.
12. Aronowitz JN. Whitmore, Henschke, and Hilaris: the reorientation
of prostate brachytherapy (1970–1987). Brachytherapy. 2012;
11:157–162.
13. Aronowitz JN. Robert Abbe: early American brachytherapist.
Brachytherapy. 2012;11:421–428.
14. Aronowitz JN, Rivard MJ. The phylogeny of permanent prostate
brachytherapy. J Contemp Brachytherapy. 2013;5:89–92.
15. Aronowitz JN, Rivard MJ. The evolution of computerized treatment
planning for brachytherapy: American contributions. J Contemp
Brachytherapy. 2014;11:85–90.
16. Aronowitz JN. Introduction of transperineal image-guided prostate
brachytherapy. Int J Radiat Oncol Biol Phys. 2014;89:907–915.
17. International Commission on Radiation Units and Measurements
(ICRU). Dose and Volume Specification for Reporting Intracavitary
Therapy in Gynecology, Report No. 38. Bethesda, MD: ICRU; 1985.
18. Bogdanich W. At V.A. Hospital, A Rogue Cancer Unit. New York, NY:
The New York Times; 2009.
19. Venselaar J, Perez-Calatayud J. A Practical Guide to Quality Control
of Brachytherapy Equipment. 1st ed. Brussels, Belgium: European
Guidelines for Quality Assurance in Radiotherapy: Booklet No. 8;
2004. http://www.estro-
education.org/publications/Documents/Booklet_n8.pdf.
20. Nath R, Anderson LL, Meli JA, et al. Code of practice for
brachytherapy physics: report of the AAPM Radiation Therapy
Committee Task Group No. 56. Med Phys. 1997;24:1557–1598.
21. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant
brachytherapy: report of the American association of physicists in
medicine task group No. 64. Med Phys. 1999;26:2054–2076.
22. Thomadsen BR. Achieving Quality in Brachytherapy. Bristol and
Philadelphia: Medical Science Series, Institute of Physics Publishing;
2000.
23. Kennedy AS, Nutting C, Coldwell D, et al. Pathologic response and
microdosimetry of 90Y microspheres in man: review of four
explanted whole livers. Int J Radiat Oncol Biol Phys. 2004;60:1552–
1563.
24. Dezarn WA, Cessna JT, DeWerd LA, et al. Recommendations of the
American Association of Physicists in Medicine on dosimetry,
imaging, and quality assurance procedures for 90Y microsphere
brachytherapy in the treatment of hepatic malignancies. Med Phys.
2011;38:4824–4845.
25. Dinsmore M, Harte KJ, Sliski AP, et al. A new miniature x-ray
source for interstitial radiosurgery: device description. Med Phys.
1996;23:45–52.
26. Rivard MJ, Davis SD, DeWerd LA, et al. Calculated and measured
brachytherapy dosimetry parameters in water for the Xoft Axxent X-
Ray source: an electronic brachytherapy source. Med Phys.
2006;33:4020–4032.
27. Garcia-Martinez T, Chan JP, Perez-Calatayud J, et al. Dosimetric
characteristics of a new unit for electronic skin brachytherapy.
J Contemp Brachytherapy. 2014;6:45–53.
28. Rivard MJ, Butler WM, DeWerd LA, et al. Update of AAPM Task
Group No. 43 Report: a revised AAPM protocol for brachytherapy
dose calculations. Med Phys. 2004;31:633–674.
29. Rivard MJ, Butler WM, DeWerd LA, et al. Supplement to the 2004
update of the AAPM Task Group No. 43 Report: a revised AAPM
protocol for brachytherapy dose calculations. Med Phys.
2007;34:2187–2205.
30. Ballester F, Granero D, Perez-Calatayud J, et al. Evaluation of high-
energy brachytherapy source electronic disequilibrium and dose
from emitted electrons. Med Phys. 2009;36:4250–4256.
31. Anderson LL, Presser JE. Classical systems I for temporary
interstitial implants. In: Williamson JF, Thomadsen BR, Nath R, eds.
Brachytherapy Physics, AAPM Summer School. Madison, WI: Medical
Physics Publishing; 1995.
32. Gillin MJ, Albano KS, Erickson B. Classical systems II for planar and
volume temporary interstitial implants. In: Williamson JF,
Thomadsen BR, Nath R, eds. Brachytherapy Physics, AAPM Summer
School. Madison, WI: Medical Physics Publishing; 1995.
33. Gillin MJ, Mourtada F. Systems 1B: Manchester planar and volume
implants and the Paris system. In: Thomadsen BR, Rivard MJ, Butler
WM, eds. Brachytherapy Physics, 2nd ed. Joint AAPM/America
Brachytherapy Society Summer School. Madison, WI: Medical Physics
Publishing; 2005.
34. Zwicker RD. Quimby-based brachytherapy systems. In: Thomadsen
BR, Rivard MJ, Butler WM, eds. Brachytherapy Physics, 2nd ed. Joint
AAPM/America Brachytherapy Society Summer School. Madison, WI:
Medical Physics Publishing; 2005.
35. Meisberger LL, Keller RJ, Shalek RJ. The effective attenuation in
water of the gamma rays of gold-198, iridium-192, cesium-137,
radium-226, and cobalt-60. Radiology. 1968;90:953–957.
36. Rivard MJ, Venselaar JL, Beaulieu L. The evolution of
brachytherapy treatment planning. Med Phys. 2009;36:2136–2153.
37. Failla G. Radium technique at the Memorial Hospital, New York.
Arch Radiol Electrother. 1920;25:3–19.
38. Davis BJ, Horwitz EM, Lee WR, et al. American Brachytherapy
Society consensus guidelines for transrectal ultrasound-guided
permanent prostate brachytherapy. Brachytherapy. 2012;11:6–19.
39. Nath R, Bice WS Jr, Butler WM, et al. AAPM recommendations on
dose prescription and reporting methods for permanent interstitial
brachytherapy for prostate cancer: report of Task Group 137. Med
Phys. 2009;36:5310–5322.
40. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial
brachytherapy sources: recommendations of the AAPM Radiation
Therapy Committee Task Group No. 43. Med Phys. 1995;22:209–
234.
41. Eaton DJ. Highly cited papers in Medical Physics. Med Phys.
2014;41:080401.
42. Paterson R, Parker HM. A dosage system for interstitial radium
therapy. Br J Radiol. 1938:11:252–266.
43. Quimby EH, Castro V. The calculation of dosage in interstitial
radium therapy. Am J Roentgenol Radium Ther Nucl Med. 1953;
70:739–759.
44. Shalek RJ, Stovall M. The M. D. Anderson method for the
computation of isodose curves around interstitial and intracavitary
radiation sources. I. Dose from linear sources. Am J Roentgenol
Radium Ther Nucl Med. 1968;102:662–672.
45. Dale RG. Some theoretical derivations relating to the tissue
dosimetry of brachytherapy nuclides, with particular reference to
iodine-125. Med Phys. 1983;10:176–183.
46. Dale R. Revisions to radial dose function data for 125I and 131Cs.
Med Phys. 1986;13:963–964.
47. Anderson LL, Nath R, Weaver KA. Interstitial Collaborative Working
Group (ICWG). Interstitial Brachytherapy: Physical, Biological, and
Clinical Considerations. New York, NY: Raven Press; 1990.
48. Rivard MJ, Chiu-Tsao ST, Finger PT, et al. Comparison of dose
calculation methods for brachytherapy of intraocular tumors. Med
Phys. 2011;38:306–316.
49. Ibbott GS, Ma CM, Rogers DW, et al. Fifty years of AAPM
involvement in radiation dosimetry. Med Phys. 2008;35:1418–1427.
50. Meigooni AS, Mishra V, Panth H, et al. Instrumentation and
dosimeter-size artifacts in quantitative thermoluminescence
dosimetry of low-dose fields. Med Phys. 1995;22:555–561.
51. Williamson JF, Rivard MJ. Quantitative dosimetry methods for
brachytherapy. In: Thomadsen BR, Rivard MJ, Butler WM, eds.
Brachytherapy Physics. 2nd ed. Madison, WI: Medical Physics;
2005:233–294.
52. Williamson JF, Rivard MJ. Thermoluminescent detector and Monte
Carlo techniques for reference-quality brachytherapy dosimetry. In:
Rogers DWO, Cygler JE, eds. Clinical Dosimetry for Radiotherapy:
AAPM Summer School. Madison, WI: Medical Physics; 2009:403–
436.
53. Stovall MA, Shalek RJ. Study of explicit distributions of radiation in
interstitial implantations. I. Method of calculation with automatic
digital computer. Radiology. 1962;78:950–954.
54. Rivard MJ, Granero D, Perez-Calatayud J, et al. Influence of photon
energy spectra from brachytherapy sources on Monte Carlo
simulations of kerma and dose rates in water and air. Med Phys.
2010;37:869–876.
55. Ellett WH, Brownell GL, Reddy AR. An assessment of Monte Carlo
calculations to determine gamma ray dose from internal emitters.
Phys Med Biol. 1968;13:219–230.
56. Krishnaswamy V. Calculation of the dose distribution about
californium-252 needles in tissue. Radiology. 1971;98:155–160.
57. Williamson JF. Brachytherapy technology and physics practice since
1950: a half-century of progress. Phys Med Biol. 2006;51:R303–
R325.
58. Thomadsen BR, Williamson JF, Rivard MJ, et al. Anniversary Paper:
Past and current issues, and trends in brachytherapy physics. Med
Phys. 2008;35:4708–4723.
59. Rivard MJ, Butler WM, DeWerd LA, et al. Erratum: update of AAPM
Task Group No. 43 Report: a revised AAPM protocol for
brachytherapy dose calculations [Med. Phys. 31, 633–674 (2004)].
Med Phys. 2004;31:3532–3533.
60. Rivard MJ, Butler WM, DeWerd LA, et al. Erratum: supplement to
the 2004 update of the AAPM Task Group No. 43 Report [Med.
Phys. 34, 2187–2205 (2007)]. Med Phys. 2010;37:2396.
61. Rivard MJ. Refinements to the geometry factor used in the AAPM
Task Group Report No. 43 necessary for brachytherapy dosimetry
calculations. Med Phys. 1999;26:2445–2450.
62. Rivard MJ, Melhus CS, Granero D, et al. An approach to using
conventional brachytherapy software for clinical treatment planning
of complex, Monte Carlo-based brachytherapy dose distributions.
Med Phys. 2009;36:1968–1975.
63. 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;27:634–642.
64. Williamson, Butler W, Dewerd LA, et al. Recommendations of the
American Association of Physicists in Medicine regarding the impact
of implementing the 2004 Task Group 43 report on dose
specification for 103Pd and 125I interstitial brachytherapy. Med Phys.
2005;32:1424–1439.
65. Rivard MJ, Nath R. Interstitial brachytherapy dosimetry update.
Rad Prot Dosim. 2006;120:64–69.
66. DeWerd LA, Huq MS, Das IJ, et al. Procedures for establishing and
maintaining consistent air-kerma strength standards for low energy,
photon-emitting brachytherapy sources: recommendations of the
Calibration Laboratory Accreditation Subcommittee of the American
Association of Physicists in Medicine. Med Phys. 2004;31:675–681.
67. Butler WM, Bice WS Jr, DeWerd LA, et al. Third-party
brachytherapy source calibrations and physicist responsibilities:
report of the AAPM Low Energy Brachytherapy Source Calibration
Working Group. Med Phys. 2008;35:3860–3865.
68. Williamson JF, Coursey BM, DeWerd LA, et al. Dosimetric
prerequisites for routine clinical use of new low energy photon
interstitial brachytherapy sources. Med Phys. 1998;25:2269–2270.
69. Rosenzweig DP, Schell MC, Yu Y. Toward a statistically relevant
calibration end point for prostate seed implants. Med Phys. 2000;
27:144–150.
70. Ramos LI, Monge RM. Sampling size in the verification of
manufacturer-supplied air kerma strengths. Med Phys.
2005;32:3375–3378.
71. Wan S, Joshi CP, Carnes G, et al. Evaluation of an automated seed
loader for seed calibration in prostate brachytherapy. J Appl Clin
Med Phys. 2006;7:115–125.
72. Yue NJ, Haffty BG, Yue J, et al. On the assay of brachytherapy
sources. Med Phys. 2007;34:1975–1982.
73. Seltzer SM, Lamperti PJ, Loevinger R, et al. New national air-kerma-
strength standards for 125I and 103Pd brachytherapy seeds. J Res Natl
Inst Stand Technol. 2003;108:337–358.
74. Kubo H. Exposure contribution from Ti K x rays produced in the
titanium capsule of the clinical 125I seed. Med Phys. 1985;12:215–
220.
75. Kubo HD, Coursey BM, Hanson WF, et al. Report of the ad hoc
committee of the AAPM Radiation Therapy Committee on 125I
sealed source dosimetry. Int J Radiat Oncol Biol Phys. 1998;40:697–
702.
76. Williamson JF, Coursey BM, DeWard LA, et al. On the use of
apparent activity (Aapp) for treatment planning of 125I and 103Pd
interstitial brachytherapy sources: recommendations of the
American Association of Physicists in Medicine radiation therapy
committee subcommittee on low-energy brachytherapy source
dosimetry. Med Phys. 1999;26:2529–2530.
77. NRC Information Notice 2009–17. Reportable Medical Events
Involving Treatment Delivery Errors Caused by Confusion of Units for
the Specification of Brachytherapy Sources. Washington, DC: Nuclear
Regulatory Commission; 2009.
http://pbadupws.nrc.gov/docs/ML0807/ML080710054.pdf
78. Nath R, et al. Specification of Brachytherapy Source Strength: Report of
AAPM Task Group No. 32. Melville, NY: American Institute of
Physics; 1987.
79. Pouliot J, Lessard E, Hsu I. Advanced 3D planning. In: Thomadsen
BR, Rivard MJ, Butler WM, eds. Brachytherapy Physics, 2nd ed. Joint
AAPM/American Brachytherapy Society Summer School. Madison, WI:
Medical Physics Publishing; 2005.
80. Li Z. Quality review of brachytherapy treatment systems. In:
Thomadsen BR, Rivard MJ, Butler WM, eds. Brachytherapy Physics,
2nd ed. Joint AAPM/America Brachytherapy Society Summer School.
Madison, WI: Medical Physics Publishing; 2005.
81. Weeks KJ, Dennett JC. Dose calculations and measurements for a
CT-compatible version of the Fletcher applicator. Int J Radiat Oncol
Biol Phys. 1990;18:1191–1198.
82. Fellner C, Pötter 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;5:53–62.
83. Harris T, Hunter RJ, Skoczny J, et al. The variance of bladder and
rectal doses calculated from orthogonal and simple stereo films in
cervix high-dose-rate brachytherapy. Brachytherapy. 2007;6:304–
310.
84. Kim RY, Pareek P. Radiography-based treatment planning compared
with computed tomography (CT)-based treatment planning for
intracavitary brachytherapy in cancer of the cervix: analysis of dose-
volume histograms. Brachytherapy. 2003;2:200–206.
85. Shin KH, Kim TH, Cho JK, et al. CT-guided intracavitary
radiotherapy for cervical cancer: comparison of conventional point
A plan with clinical target volume-based three-dimensional plan
using dose-volume parameters. Int J Radiat Oncol Biol Phys. 2005;
62:197–204.
86. Pötter R, Haie-Meder C, Van Limbergen E, et al. Recommendations
from Gynaecological (GYN) GEC-ESTRO Working Group (II):
concepts and terms in 3D image-based treatment planning in cervix
cancer – 3D dose volume parameters and aspects of 3D imaged-
based anatomy, radiation physics, radiobiology. Radiother Oncol.
2006;78:67–77.
87. 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;68:491–498.
88. Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and
rectum dose defined from MRI based treatment planning for cervix
cancer brachytherapy: comparison of dose-volume histograms for
organ contours and organ wall, comparison with ICRU rectum and
bladder reference points. Radiother Oncol. 2003;68:269–276.
89. Haie-Meder C, Pötter 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;74:235–245.
90. Kirisits C, Pötter R, Lang S, et al. Dose and volume parameters for
MRI treatment planning in intracavitary brachytherapy for cervical
cancer. Int J Radiat Oncol Biol Phys. 2002;62:901–911.
91. DeWerd LA, Ibbott GS, Meigooni AS, et al. A dosimetric uncertainty
analysis for photon-emitting brachytherapy sources: report of AAPM
Task Group No. 138 and GEC-ESTRO. Med Phys. 2011; 38:782–801.
92. Kirisits C, Rivard MJ, Baltas D, et al. Review of clinical
brachytherapy uncertainties: analysis guidelines of GEC-ESTRO and
the AAPM. Radiotherapy Oncol. 2014;110:199–212.
93. International Commission on Radiation Units and Measurements
(ICRU). Dose and Volume Specification for Reporting Interstitial
Therapy, Report No. 58. Bethesda, MD: ICRU; 1997.
94. Horwitz EM. ABS brachytherapy consensus guidelines.
Brachytherapy. 2012;11:4–5.
95. Williamson JF, Coursey BM, DeWerd LA, et al. Guidance to users of
Nycomed Amersham and North American Scientific, Inc. I-125
interstitial sources: recommendations of the American Association of
Physicists in Medicine Radiation Therapy Committee Ad Hoc
Subcommittee Low-Energy Seed Dosimetry. Med Phys. 1999;26:570–
573.
96. Rivard MJ, Butler WM, Devlin PM, et al. American brachytherapy
society recommends no change for prostate permanent implant dose
prescriptions using iodine-125 or palladium-103. Brachytherapy.
2007;6:34–37.
97. Beyer D, Nath R, Butler W, et al. American brachytherapy society
recommendations for clinical implementation of NIST-1999
standards for 103palladium brachytherapy. Int J Radiat Oncol Biol
Phys. 2000;47: 273–275.
98. Lee LJ, Das IJ, Higgins SA, et al. American brachytherapy society
consensus guidelines for penile locally advanced carcinoma of the
cervix. Part III: low-dose-rate and pulsed-dose-rate brachytherapy.
Brachytherapy. 2012;11:53–57.
99. Nag S, Orton C, Young D, et al. The American brachytherapy society
survey of brachytherapy practice for carcinoma of the cervix in the
United States. Gynecol Oncol. 1999;73:111–118.
100. 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;60:1160–1172.
101. Crook JM, Haie-Meder C, Demanes DJ, et al. American
Brachytherapy Society–Groupe Européen de Curiethérapie–
European Society of Therapeutic Radiation Oncology (ABS-GEC-
ESTRO) consensus statement for penile brachytherapy.
Brachytherapy. 2103;12:191–198.
102. Holloway CL, Delaney TF, Alektiar KM, et al. American
Brachytherapy Society (ABS) consensus statement for sarcoma
brachytherapy. Brachytherapy. 2013;12:179–190.
103. Pignol JP, Keller B, Rakovitch E, et al. First report of a permanent
breast 103Pd seed implant as adjuvant radiation treatment for early-
stage breast cancer. Int J Radiat Oncol Biol Phys. 2006;64:176–181.
104. Pignol JP, Rakovitch E, Keller BM, et al. Tolerance and acceptance
results of a palladium-103 permanent breast seed implant Phase I/II
study. Int J Radiat Oncol Biol Phys. 2009;73:1482–1488.
105. Afsharpour H, Pignol JP, Keller B, et al. Influence of breast
composition and interseed attenuation in dose calculations for post-
implant assessment of permanent breast 103Pd seed implant. Phys
Med Biol. 2010;55l:4547–4561.
106. Keller B, Sankreacha R, Rakovitch E, et al. A permanent breast seed
implant as partial breast radiation therapy for early-stage patients: a
comparison of palladium-103 and iodine-125 isotopes based on
radiation safety considerations. Int J Radiat Oncol Biol Phys.
2005;62:358–365.
107. Keller BM, Pignol JP, Rakovitch E, et al. A radiation badge survey
for family members living with patients treated with a 103Pd
permanent breast seed implant. Int J Radiat Oncol Biol Phys.
2008;70:267–271.
108. Jansen N, Deneufbourg JM, Nickers P. Adjuvant stereotactic
permanent seed breast implant: A boost series in view of partial
breast irradiation. Int J Radiat Oncol Biol Phys. 2007;67:1052–1058.
109. Ostertag CB, Kreth FW. Interstitial iodine-125 radiosurgery for
cerebral metastases. Br J Neurosurg. 1995;9:593–604.
110. Schulder M, Black PM, Shrieve DC, et al. Permanent low-activity
iodine-125 implants for cerebral metastases. J Neurooncol. 1997;
33:213–221.
111. Bogart JA, Ungureanu C, Shihadeh E, et al. Resection and
permanent I-125 brachytherapy without whole brain irradiation for
solitary brain metastasis from nonsmall cell lung carcinoma.
J Neurooncol. 1999;44:53–57.
112. Lee W, Daly BD, DiPetrillo TA, et al. Limited resection for non-small
cell lung cancer: Observed local control with implantation of I-125
brachytherapy seeds. Ann Thorac Surg. 2003;75:237–243.
113. Fernando HC, Landreneau RJ, Mandrekar SJ, et al. Impact of
brachytherapy on local recurrence rates after sublobar resection:
results from ACOSOG Z4032 (alliance), a phase III randomized trial
for high-risk operable non–small-cell lung cancer. J Clin Oncol.
2003;32:2456–2462.
114. Nag S, Quivey JM, Earle JD, et al. The American Brachytherapy
Society recommendations for brachytherapy of uveal melanomas. Int
J Radiat Oncol Biol Phys. 2003;56:544–555.
115. Simpson ER, Gallie B, Iaperriere N, et al. The American
Brachytherapy Society consensus guidelines for plaque
brachytherapy of uveal melanoma and retinoblastoma.
Brachytherapy. 2014;13:1–14.
116. Astrahan MA. Improved treatment planning for COMS eye plaques.
Int J Radiat Oncol Biol Phys. 2005;61:1227–1242.
117. Rivard MJ, Melhus CS, Sioshansi S, et al. The impact of prescription
depth, dose rate, plaque size, and source loading on the central axis
using 103Pd, 125I, and 131Cs. Brachytherapy. 2008;7:327–335.
118. Rivard MJ, Chiu-Tsao ST, Finger PT, et al. Comparison of dose
calculation methods for brachytherapy of intraocular tumors. Med
Phys. 2011;38:306–316.
119. Chiu-Tsao ST, Astrahan MA, Finger PT, et al. Dosimetry of 125I and
103Pd COMS eye plaques for intraocular tumors: report of Task
Group 129 by the AAPM and ABS. Med Phys. 2012;39:6161–6184.
120. Lesperance M, Martinov M, Thomson RM. Monte Carlo dosimetry
for 103Pd, 125I, and 131Cs ocular brachytherapy with various plaque
models using an eye phantom. Med Phys. 2014;41:031706.
121. Aryal P, Molloy JA, Rivard MJ. Independent dosimetric assessment
of the model EP917 episcleral brachytherapy plaque. Med Phys.
2014;41:092102.
122. Nath R, Gray L, Park CH. Dose distributions around cylindrical
241Am sources for a clinical intracavitary applicator. Med Phys.
1987;14:809–817.
123. Ballester F, Granero D, Perez-Calatayud J, et al. Study of
encapsulated 170Tm sources for their potential use in brachytherapy.
Med Phys. 2010;37:1629–1637.
124. Enger SA, Amours MD, Beaulieu L. Modeling a hypothetical 170Tm
source for brachytherapy applications. Med Phys. 2011;38:5307–
5310.
125. Enger SA, Lundqvist H, Amours MD, et al. Exploring 57Co as a new
isotope for brachytherapy applications. Med Phys. 2012;39:2342–
2345.
126. Enger SA, Fisher DR, Flynn RT. Gadolinium-153 as a brachytherapy
isotope. Phys Med Biol. 2013;58:957–964.
127. Nuttens VE, Lucas S. AAPM TG-43U1 formalism adaptation and
Monte Carlo dosimetry simulations of multiple-radionuclide
brachytherapy sources. Med Phys. 2006;33:1101–1107.
128. Nuttens VE, Lucas S. Determination of the prescription dose for
biradionuclide permanent prostate brachytherapy. Med Phys.
2008;35:5451–5462.
129. Villeneuve M, Leclerc G, Lessard E, et al. Relationship between
isotope half-life and prostate edema for optimal prostate dose
coverage in permanent seed implants. Med Phys. 2008;35:1970–
1977.
130. Wang JZ, Mayr NA, Nag S, et al. Effect of edema, relative biological
effectiveness, and dose heterogeneity on prostate brachytherapy.
Med Phys. 2006;33:1025–1032.
131. Schlea CC, Stoddard DH. Californium isotopes proposed for
intracavitary and interstitial radiation therapy with neutrons.
Nature. 1965;206:1058–1059.
132. Liu H, Wang Q, Wan X, et al. Californium-252 neutron
brachytherapy combined with external beam radiotherapy for
esophageal cancer: Long-term treatment results. Brachytherapy.
2014;13:514–521.
133. Lin L, Patel RR, Thomadsen BR, et al. The use of directional
interstitial sources to improve dosimetry in breast brachytherapy.
Med Phys. 2008;35:240–247.
134. Rivard MJ. Monte Carlo radiation dose simulations and dosimetric
comparison of the model 6711 and 9011 125I brachytherapy sources.
Med Phys. 2009;36:486–491.
135. Kennedy RM, Davis SD, Micka JA, et al. Experimental and Monte
Carlo determination of the TG-43 dosimetric parameters for the
model 9011 THINSeed™ brachytherapy source. Med Phys.
2010;37:1681–1688.
136. Meigooni AS, Awan SB, Rachabatthula V, et al. Treatment-planning
considerations for prostate implants with the new linear
RadioCoilTM 103Pd brachytherapy source. J Appl Clin Med Phys.
2005;6:23–36.
137. Meigooni AS, Awan SB, Dou K. Feasibility of calibrating elongated
brachytherapy sources using a well-type ionization chamber. Med
Phys. 2006;33:4184–4189.
138. Bannon EA, Yang Y, Rivard MJ. Accuracy assessment of the
superposition principle for evaluating dose distributions of
elongated and curved 103Pd and 192Ir brachytherapy sources. Med
Phys. 2011; 38:2957–2963.
139. Rivard MJ, Reed JL, DeWerd LA. 103Pd strings: Monte Carlo
assessment of a new approach to brachytherapy source design. Med
Phys. 2014;41:011716.
140. Reed JL, Rivard MJ, Micka JA, et al. Experimental and Monte Carlo
dosimetric characterization of a 1 cm 103Pd brachytherapy source.
Brachytherapy. 2014;13:657–667.
141. Dempsey JF, Williams JA, Stubbs JB, et al. Dosimetric properties of
a novel brachytherapy balloon applicator for the treatment of
malignant brain-tumor resection-cavity margins. Int J Radiat Oncol
Biol Phys. 1998;42:421–429.
142. Monroe JI, Dempsey JF, Dorton JA, et al. Experimental validation
of dose calculation algorithms for the GliaSite™ RTS, a novel 125I
liquid-filled balloon brachytherapy applicator. Med Phys.
2001;28:73–85.
143. Rogers LR, Rock JP, Sills AK, et al. Results of a phase II trial of the
GliaSite radiation therapy system for the treatment of newly
diagnosed, resected single brain metastases. J Neurosurg.
2006;105:375–384.
144. Rivard MJ, Evans DA, Kay I. A technical evaluation of the
Nucletron FIRST® system: conformance of a remote afterloading
brachytherapy seed implantation system to manufacturer
specifications and AAPM Task Group report recommendations. J
Appl Clin Med Phys. 2005;6:22–50.
145. Fichtinger G, Burdette EC, Tanacs A, et al. Robotically assisted
prostate brachytherapy with transrectal ultrasound guidance –
Phantom experiments. Brachytherapy. 2006;5:14–26.
146. Podder TK, Beaulieu L, Caldwell B, et al. AAPM and GEC-ESTRO
guidelines for image-guided robotic brachytherapy: report of Task
Group 192. Med Phys. 2014;41:101501.
147. Holupka EJ, Meskell PM, Burdette EC, et al. An automatic seed
finder for brachytherapy CT postplans based on the Hough
transform. Med Phys. 2004;31:2672–2679.
148. Mahdavi SS, Spadinger I, Chng N, et al. Semiautomatic
segmentation for prostate brachytherapy: dosimetric evaluation.
Brachytherapy. 2013;12:65–76.
149. De Brabandere M, Hoskin P, Haustermans K, et al. Prostate
postimplant dosimetry: interobserver variability in seed localisation,
contouring and fusion. Radiother Oncol. 2012;104:192–198.
150. Sabater S, Andres I, Sevillano M, et al. Dose accumulation during
vaginal cuff brachytherapy based on rigid/deformable registration
vs. single plan addition. Brachytherapy. 2014;13:343–351.
151. Kim H, Huq MS, Houser C, et al. Mapping of dose distribution from
IMRT onto MRI-guided high dose rate brachytherapy using
deformable image registration for cervical cancer treatments:
preliminary study with commercially available software. J Contemp
Brachytherapy. 2014;6:178–184.
152. Rivard MJ, Ghadyani HR, Bastien AD, et al. Multi-axis dose
accumulation of noninvasive image-guided breast brachytherapy
through biomechanical modeling of tissue deformation using the
finite element method. J Contemp Brachytherapy. 2015;7:55–71.
153. Siebert FA, Venselaar JLM, Hellebust TP, et al. Dose-rate to water
calibrations for brachytherapy sources from the end-user
perspective. Metrologia.2012;49:S249-S252.
154. Aubineau-Lanièce I, Chauvenet B, Cutarella D, et al. LNE–LNHB air-
kerma and absorbed dose to water primary standards for low dose-
rate 125I brachytherapy sources. Metrologia. 2012;49:S189–S192.
155. Toni MP, Pimpinella M, Pinto M, et al. Direct determination of the
absorbed dose to water from 125I low dose-rate brachytherapy seeds
using the new absorbed dose primary standard developed at ENEA-
INMRI. Metrologia. 2012;49:S193–S197.
156. Schneider T. The PTB primary standard for the absorbed-dose to
water for I-125 interstitial brachytherapy sources. Metrologia.
2012;49:S198–S202.
157. L. Beaulieu, Carlsson Tedgren A, Carrier JF, 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;39:6208–6236.
158. Chibani O, Williamson JF. MCPI: a sub-minute Monte Carlo dose
calculation engine for prostate implants. Med Phys. 2005;32:3688–
3698.
159. Wang R, Sloboda RS. Brachytherapy scatter dose calculation in
heterogeneous media: I. A microbeam ray-tracing method for the
single-scatter contribution. Phys Med Biol. 2007;52:5619–5636.
160. Landry G, Reniers B, Murrer L, et al. Sensitivity of low energy
brachytherapy Monte Carlo dose calculations to uncertainties in
human tissue composition. Med Phys. 2010;37:5188–5198.
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.
16 High Dose-Rate Brachytherapy
Treatment Planning
Bruce R. Thomadsen
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
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
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
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
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.
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
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.
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
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),
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
OPTIMIZATION
In brachytherapy, “optimization” generally connotes determination of
some aspects of an application in order to achieve particular goals. For
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
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
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,
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,
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
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
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.
FIGURE 16.6 Three dwell positions around a point, based on an example case from van der
Laarse.
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
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
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.
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.
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
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).
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.
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.
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.
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.
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
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.
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
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.
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).
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 16.13 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.
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.
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
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,
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
prescription dose matches the target.
The peripheral uniformity number (PUN) also addresses the conformity
at the target but at the periphery, specifying (54)
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
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.
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):
For any of these checks, the source strength should come from a
separate table rather than from the treatment plan.
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:
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 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.
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
PLANNING AN IMPLANT
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.
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
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.
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
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
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
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
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.)
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
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.
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
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
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.
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
5. C
6. A, B, C, and D
7. B and D
REFERENCES
1. Das RK, Thomadsen BR. High dose rate brachytherapy sources and
delivery systems. In: Thomadsen BR, Rivard MJ, Butler WM, eds.
Brachytherapy Physics, 2nd ed. Madison, WI: Medical Physics
Publishing; 2005.
2. Das RK, Thomadsen BR. High dose rate brachytherapy. In: Webster
J, ed. Encyclopedia of Medical Devices and Instrumentation. Hoboken,
NJ: John Wiley & Sons; 2006.
3. Thomadsen BR, Shahabi S, Buchler DA. Differential loadings of
brachytherapy templates. Endocurietherapy/Hypertherm Oncol.
1990;6:197–202.
4. Thomadsen BR, Shahabi S, Stitt JA, et al. High dose rate
intracavitary brachytherapy for carcinoma of the cervix: the
Madison system: II. Procedural and physical considerations. Int J
Radiat Oncol Biol Phys. 1992;24(2):349–357.
5. King CC, Stockstill TF, Bloomer WD, et al. Point dose variations with
time in brachytherapy for cervical carcinoma. Med Phys.
1992;19:777.
6. Gao S, Delclos ME, Tomas LC, et al. High-dose-rate remote
afterloaders for intraoperative radiation therapy. AORN J.
2007;86(5):827–836; quiz 837–840.
7. van den Aardweg GJ, Hopewell JW. The kinetics of repair for
sublethal radiation-induced damage in the pig epidermis: an
interpretation based on a fast and a slow component of repair.
Radiother Oncol. 1992;23(2):94–104.
8. Fowler JF. Repair between dose fractions: a simpler method of
analyzing and reporting apparently biexponential repair. Radiat Res.
2002;158(2):141–151.
9. Han I, Malviya V, Chuba P, et al. Multifractionated high-dose-rate
brachytherapy with concomitant daily teletherapy for cervical
cancer. Gynecol Oncol. 1996;63(1):71–77.
10. Bentzen SM, Constine LS, Deasy JO. Quantitative analyses of normal
tissue effects in the clinic (QUANTEC): an introduction to the
scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S3–
S9.
11. Dale RG. The application of the linear-quadratic dose-effect
equation to fractionated and protracted radiotherapy. Br J Radiol.
1985; 58(690):515–528.
12. Orton CG, Seyedsadr M, Somnay A. Comparison of high and low
dose rate remote afterloading for cervix cancer and the importance
of fractionation. Int J Radiat Oncol Biol Phys. 1991;21(6):1425–1434.
13. Ezzell G. Optimization in brachytherapy. In: Thomadsen BR, Rivard
MJ, Butler W, eds. Brachytherapy Physics, 2nd ed. Madison, WI:
Medical Physics Publishing; 2005.
14. Ezzell G, Luthmann RW. Clinical implementation of dwell time
optimization techniques. In: Williamson JF, Thomadsen BR, Nath R,
eds. Brachytherapy Physics, 2nd ed. Madison, WI: Medical Physics
Publishing; 1995.
15. Edmundson GK. Geometry based optimization for stepping source
implants. In: Martinez AA, Orton CG, Mould RF, eds. Brachytherapy
HDR and LDR. Columbia, MD: Nucletron Corporation; 1990:184–
192.
16. Shewchuk JR. An Introduction to the Conjugate Gradient Method
Without the Agonizing Pain. Pittsburgh, PA: Carnegie Mellon
University; 1994.
17. Holmes T, Mackie TR, Simpkin D, et al. A unified approach to the
optimization of brachytherapy and external beam dosimetry. Int J
Radiat Oncol Biol Phys. 1991;20(4):859–873.
18. Thomadsen B, Houdek P, van der Laarse R. Treatment planning and
optimization. In: Nag S, ed. Textbook and High Dose Rate
Brachytherapy. Armonk, NY: Futura Publishing Co; 1994.
19. van der Laarse R, Edmundson GK, Luthmann RW, et al.
Optimization of HDR brachytherapy dose distributions. Activity.
1991;5:94–101.
20. Lessard E, Pouliot J. Inverse planning anatomy-based dose
optimization for HDR-brachytherapy of the prostate using fast
simulated annealing algorithm and dedicated objective function.
Med Phys. 2001;28(5):773–779.
21. Lessard E. Development and clinical introduction of an inverse
planning dose optimization by simulated annealing (IPSA) for high
dose rate brachytherapy (Thesis abstract). Med Phys. 2004;31:2935.
22. Hsu IC, Lessard E, Weinberg V, et al. Comparison of inverse
planning simulated annealing and geometrical optimization for
prostate high-dose-rate brachytherapy. Brachytherapy.
2004;3(3):147–152.
23. Yu Y, Schell MC. A genetic algorithm for the optimization of
prostate implants. Med Phys. 1996;23(12):2085–2091.
24. Yang G, Reinstein LE, Pai S, et al. A new genetic algorithm
technique in optimization of permanent 125I prostate implants. Med
Phys. 1998;25(12):2308–2315.
25. Pouliot J, Lessard E, Hsu I-C. Advanced 3D planning. In: Thomadsen
BR, Rivard MJ, Butler W, eds. Brachytherapy Physics, 2nd ed.
Madison, WI: Medical Physics Publishing; 2005.
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.
Int J Radiat Oncol Biol Phys. 2010;78(1):276–279.
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.
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
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.
46. Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and
rectum dose defined from MRI based treatment planning for cervix
cancer brachytherapy: comparison of dose-volume histograms for
organ contours and organ wall, comparison with ICRU rectum and
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.
Radiother Oncol. 1998;47:85–90.
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
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.
Int J Radiat Oncol Biol Phys. 1998;40(2):515–524.
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.
63. International Commission on Radiation Units and Measurements.
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.
66. Twombly GH, Rosh R. A new method for applying radium in the
vagina in cases of carcinoma of the uterine cervix. Cancer. 1955;
8:1016–1020.
67. Chassagne D. La plesiocurietherapie des cancers du cavum avec
support-moule et Yridium 192. Annales de Radiologie. 1963;6:719–
726.
68. Lewis GC. Acrylic molds for vaginal radium application. Radiology.
1963;80:282–284.
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.
70. Bertoni F, Bertoni G, Bignardi M. Vaginal molds for intracavitary: a
new method of preparation. Int J Radiat Oncol Biol Phys.
1983;9(10):1579–1582.
71. Pearcey RG, Petereit DG. Post-operative high dose rate
brachytherapy in patients with low to intermediate risk endometrial
cancer. Radiother Oncol. 2000;56(1):17–22.
72. Paterson R. A dosage system for gamma ray therapy: Part I
[Clinical]. Br J Radiol. 1934;7:592–612.
73. Parker H. A dosage system for gamma ray therapy. Part II: physical
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.
Madison, WI: Medical Physics Publishing; 1997.
78. Pierquin B, Dutreix A. For a new methodology in curietherapy: the
system of Paris (endo- and plesioradiotherapy with non-radioactive
preparation). A preliminary note. Ann Radiol (Paris). 1966;9(9):757–
760.
79. 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.
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.
John A. Antolak
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
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
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
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.
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
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.
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
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.
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
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
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
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
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.
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.
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.
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.
Similarly, there is a similar rule for the air gap factor (12).
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
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
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.
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.
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 17.14 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.
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.
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.
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
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
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.
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
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
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
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
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.
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
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-
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.
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
considered.
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.
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
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
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:
http://medicalphysicsweb.org/cws/article/opinion/53380, accessed
on April 2, 2015
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.
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.
16. Hogstrom KR, Mills MD, Almond PR. Electron beam dose
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
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.
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
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
Radiat Oncol Biol Phys. 2004;59(2):602–617.
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
radiotherapy. Phys Med Biol. 2012;57(11):3259–3272.
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
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.
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
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
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.
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
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.
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
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.
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,
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.
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
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)
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
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)
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
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.
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
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
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
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
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.
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.
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
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
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
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
through CT sections. Int J Radiat Oncol Biol Phys. 1983;9:789–797.
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.
6. Lomax AJ. Intensity modulated proton therapy and its sensitivity to
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.
19 Role of Protons Versus Photons
in Modern Radiotherapy: Clinical
Perspective
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
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
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
studies with protons, but there are currently no operating carbon or
other heavy charged ion facilities 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
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.)
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
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
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,
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).
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.
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
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.
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).
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).
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
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
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
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
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
REFERENCES
1. Hong T, DeLaney TF. Principles of Radiation Therapy. In: Gorroll
AH, Mulley AG Jr, eds. Primary Care Medicine. New York, NY:
Wolters Kluwer; 2014:705–709.
2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab
for squamous-cell carcinoma of the head and neck. N Engl J Med.
2006;354(6):567–578.
3. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates
of the abscopal effect in a patient with melanoma. N Engl J Med.
2012;366(10):925–931.
4. Goitein M. Radiation Oncology: A Physicists-Eye View. New York, NY:
Springer; 2008.
5. Jermann M. Particle therapy facilities in operation. (website:
http://www.ptcog.ch/)
6. Goitein M, Jermann M. The relative costs of proton and X-ray
radiation therapy. Clin Oncol (R Coll Radiol). 2003;15:S37–S50.
7. Peeters A, Grutters JP, Pijls-Johannesma M, et al. How costly is
particle therapy? Cost analysis of external beam radiotherapy with
carbon-ions, protons and photons. Radiother Oncol. 2010;95(1):45–
53.
8. Mansur DB. Incorporating a compact proton therapy unit into an
existing National Cancer Institute-designated comprehensive cancer
center. Expert Rev Anticancer Ther. 2014;14(9):1001–1005.
9. Lundkvist J, Ekman M, Ericsson SR, et al., Economic evaluation of
proton radiation therapy in the treatment of breast cancer. Radiother
Oncol. 2005;75(2):179–185.
10. Lundkvist J, Ekman M, Ericsson SR, et al., Cost-effectiveness of
proton radiation in the treatment of childhood medulloblastoma.
Cancer. 2005;103(4):793–801.
11. Lundkvist J, Ekman M, Ericsson SR, et al. Proton therapy of cancer:
potential clinical advantages and cost-effectiveness. Acta Oncol.
2005;44(8):850–861.
12. Tsujii H, Kamada R, Debus J. Overview of experience with heavier
charged particle radiotherapy. In: DeLaney TF, Kooy HM, eds.
Proton and Charged Particle Radiotherapy. Philadelphia, PA:
Lippincott Williams & Wilkins; 2008: 115–124.
13. Maor MH, Errington RD, Caplan RJ, et al. Fast-neutron therapy in
advanced head and neck cancer: a collaborative international
randomized trial. Int J Radiat Oncol Biol Phys. 1995;32(3):599–604.
14. Rosenberg AE, Nielsen GP, Keel SB, et al. Chondrosarcoma of the
base of the skull: a clinicopathologic study of 200 cases with
emphasis on its distinction from chordoma. Am J Surg Pathol.
1999;23:1370–1378.
15. Brahme A. Recent advances in light ion radiation therapy. Int J
Radiat Oncol Biol Phys. 2004;58(2):603–616.
16. Wilson RR. Radiological uses of fast protons. Radiology. 1946;
47:487–491.
17. Lawrence JH, Tobias CA, BORN JL, et al. Pituitary irradiation with
high-energy proton beams: A preliminary report. Cancer Res.
1958;18:121–139.
18. Falkmer S, Fors B, Larsson B, et al. Pilot study on proton irradiation
of human carcinoma. Acta Radiol. 1962;58:33–51.
19. Kjellberg RN, Shintani A, Frantz AG, et al. Proton-beam therapy in
acromegaly. N Engl J Med. 1968;278:689–695.
20. Kjellberg RN, Hanamura T, Davis KR, et al. Bragg peak proton-beam
therapy for arteriovenous malformations of the brain. N Engl J Med.
1983;309:269–274.
21. Gragoudas E, Goitein M, Koehler AM, et al. Proton irradiation of
small choroidal malignant melanomas. Am J Opthalmol.
1977;83:665–673.
22. Austin-Seymour M, Munzenrider J, Goitein M, et al. Fractionated
proton radiation therapy of chordoma and low grade
chondrosarcoma of the base of skull. J Neurosurg. 1989;70:13–17.
23. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate
cancer: the results of a randomized comparative trial of high dose
irradiation boosting with conformal protons compared with
conventional dose irradiation using photons alone. Int J Radiat Oncol
Biol Phys. 1995;32:3–12.
24. Noel G, Habrand JL, Jauffret E, et al. Radiation therapy for
chordoma and chondrosarcoma of the skull base and the cervical
spine. Prognostic factors and patterns of failure. Strahlenther Onkol.
2003;179(4):241–248.
25. Egger E, Zografos L, Schalenbourg A, et al. Eye retention after
proton beam radiotherapy for uveal melanoma. Int J Radiat Oncol
Biol Phys. 2003;55(4):867–880.
26. Slater JM, Archambeau JO, Miller DW, et al. The proton treatment
center at Loma Linda University Medical Center: rationale for and
description of its development. Int J Radiat Oncol Biol Phys.
1992;22(2):383–389.
27. Koehler AM, Schneider RJ, Sisterson JM. Range modulators for
protons and heavy ions. Nucl Instrum Methods. 1975;131:437–440.
28. Koehler AM, Schneider RJ, Sisterson JM. Flattening of proton dose
distributions for large-field radiotherapy. Med Phys. 1977; 4(4):297–
301.
29. Gottschalk B, Wagner M. Contoured scatterer for proton dose
flattening. Harvard Cyclotron Laboratory report, 1989.
30. Goitein M. Compensation for inhomogeneities in charged particle
radiotherapy using computed tomography. Int J Radiat Oncol Biol
Phys. 1978;4:499–508.
31. Urie M, Goitein M, Wagner M. Compensating for heterogeneities in
proton radiation therapy. Phys Med Biol. 1984;29(5):553–566.
32. Wagner MS. Automated range compensation for proton therapy.
Med Phys. 1982;9(5):749–752.
33. Larsson B. Pre-therapeutic physical experiments with high energy
protons. Br J Radiol. 1961;34:143–151.
34. Kanai T, Kawachi K, Kumamoto Y, et al. Spot scanning system for
proton radiotherapy. Med Phys. 1980;7(4):365–369.
35. Verhey LJ, Koehler AM, McDonald JC, et al. The determination of
absorbed dose in a proton beam for purposes of charged-particle
radiation therapy. Radiat Res. 1979;79(1):34–54.
36. Verhey LJ, Goitein M, McNulty P, Munzenrider JE, Suit HD. Precise
positioning of patients for radiation therapy. Int J Radiat Oncol Biol
Phys. 1982;8(2):289–294.
37. Goitein M, Miller T. Planning proton therapy of the eye. Med Phys.
1983;10(3):275–283.
38. Niemierko A, Goitein M. Calculation of normal tissue complication
probability and dose-volume histogram reduction schemes for
tissues with a critical element architecture. Radiother Oncol.
1991;20(3):166–176.
39. Goitein M, Abrams M, Rowell D, Pollari H, Wiles J. Multi-
dimensional treatment planning: II. Beam’s eye-view, back
projection, and projection through CT sections. Int J Radiat Oncol
Biol Phys. 1983;9(6):789–797.
40. Goitein M, Abrams M. Multi-dimensional treatment planning: I.
Delineation of anatomy. Int J Radiat Oncol Biol Phys. 1983;9(6):777–
787.
41. Goitein M. Calculation of the uncertainty in the dose delivered
during radiation therapy. Med Phys. 1985;12(5):608–612.
42. von Essen CF, Blattmann H, Bodendoerfer G, et al. The Piotron: II.
Methods and initial results of dynamic pion therapy in phase II
studies. Int J Radiat Oncol Biol Phys. 1985;11(2):217–226.
43. Lomax AJ, Boehringer T, Coray A, et al. Intensity modulated proton
therapy: a clinical example. Med Phys. 2001;28(3):317–324.
44. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of
conventional-dose vs high-dose conformal radiation therapy in
clinically localized adenocarcinoma of the prostate: a randomized
controlled trial. JAMA. 2005;294(10):1233–1239.
45. Trofimov A, Nguyen PL, Coen JJ, et al. Radiotherapy treatment of
early-stage prostate cancer with IMRT and protons: A treatment
planning comparison. Int J Radiat Oncol Biol Phys. 2007;18:18.
46. Weber DC, Trofimov AV, Delaney TF, Bortfeld T. A treatment
planning comparison of intensity modulated photon and proton
therapy for paraspinal sarcomas. Int J Radiat Oncol Biol Phys.
2004;58:1596–1606.
47. Safai S, Trofimov A, Adams JA, Engelsman M, Bortfeld T. The
rationale for intensity-modulated proton therapy in geometrically
challenging cases. Phys Med Biol. 2013;58(18):6337–653.
48. Plastaras JP, Berman AT, Freedman GM. Special cases for proton
beam radiotherapy: re-irradiation, lymphoma, and breast cancer.
Semin Oncol. 2014;41(6):807–819.
49. Winkfield KM, Niemierko A, Bussiere MR, et al. Modeling
intracranial second tumor risk and estimates of clinical toxicity with
various radiation therapy techniques for patients with pituitary
adenoma. Technol Cancer Res Treat. 2011;10(3):243–251.
50. Jagsi R, DeLaney TF, Donelan K, Tarbell NJ. Real-time rationing of
scarce resources: the Northeast Proton Therapy Center experience. J
Clin Oncol. 2004;22(11):2246–2250.
51. Bekelman JE, Asch DA, Tochner Z, et al. Principles and reality of
proton therapy treatment allocation. Int J Radiat Oncol Biol Phys.
2014;89(3):499–508.
52. Chang AL, Yock TK, Mahajan A, et al. Pediatric proton therapy:
patterns of care across the United States. Int J Particle Therapy.
2014;1(2):357–367.
53. Brown AP, Barney CL, Grosshans DR, et al. Proton beam
craniospinal irradiation reduces acute toxicity for adults with
medulloblastoma. Int J Radiat Oncol Biol Phys. 2013;86(2):277–284.
54. Ladra MM, Edgington SK, Mahajan A, et al. A dosimetric
comparison of proton and intensity modulated radiation therapy in
pediatric rhabdomyosarcoma patients enrolled on a prospective
phase II proton study. Radiother Oncol. 2014;113(1):77–83.
55. Merchant TE, Rose SR, Bosley C, Wu S, Xiong X, Lustig RH. Growth
hormone secretion after conformal radiation therapy in pediatric
patients with localized brain tumors. J Clin Oncol.
2011;29(36):4776–4780.
56. Chung CS, Yock TI, Nelson K, Xu Y, Keating NL, Tarbell NJ.
Incidence of second malignancies among patients treated with
proton versus photon radiation. Int J Radiat Oncol Biol Phys.
2013;87(1):46–52.
57. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of
the incidence of radiation-induced second cancer by using proton
beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol
Phys. 2002;54:284–289.
58. Paganetti H, Athar BS, Moteabbed M, et al. Assessment of radiation-
induced second cancer risks in proton therapy and IMRT for organs
inside the primary radiation field. Phys Med Biol. 2012;57(19):6047–
6061.
59. Taddei PJ, Khater N, Zhang R, et al. Inter-institutional comparison
of personalized risk assessments for second malignant neoplasms for
a 13-year-old girl receiving proton versus photon craniospinal
irradiation. Cancers (Basel). 2015;7(1):407–426.
60. Berrington de Gonzalez, A, Curtis RE, Kry SF, Gilbert E, et al.
Proportion of second cancers attributable to radiotherapy treatment
in adults: a cohort study in the US SEER cancer registries. Lancet
Oncol. 2011;12(4):353–360.
61. Kuttesch Jr, JF, Wexler LH, Marcus RB, et al. Second malignancies
after Ewing’s sarcoma: radiation dose-dependency of secondary
sarcomas. J Clin Oncol. 1996;14:2818–2815.
62. Kasper HB, Raeke L, Indelicato DJ, et al. The pediatric proton
consortium registry: a multi-institutional collaboration in U.S.
proton centers. Int J of Particle Therapy. 2014;1(2):323–333.
63. Mailhot Vega RB, Kim J, Bussière M, et al. Cost effectiveness of
proton therapy compared with photon therapy in the management
of pediatric medulloblastoma. Cancer. 2013;119(24):4299–307.
64. Amin NP, Sher DJ, Konski AA. Systematic review of the cost
effectiveness of radiation therapy for prostate cancer from 2003 to
2013. Appl Health Econ Health Policy. 2014;12(4):391–408.
65. Patel S, Kostaras X, Parliament M, et al. Recommendations for the
referral of patients for proton-beam therapy, an Alberta Health
Services report: a model for Canada? Curr Oncol. 2014;21(5):251–
262.
66. Newhauser WD, Zhang R, Jones TG, et al. Reducing the cost of
proton radiation therapy: the feasibility of a streamlined treatment
technique for prostate cancer. Cancers (Basel). 2015;7(2):688–705.
67. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker
study of preoperative short course chemoradiation with proton
beam therapy and capecitabine followed by early surgery for
resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol
Phys. 2014;89(4):830–838.
68. American College of Radiology(ACR)-American Society for
Therapeutic Radiology(ASTRO) Practice Parameter for the
Performance of Proton Beam Radiation Therapy. Available online at:
http://www.acr.org/
∼/media/7BEBF7E77E1141578CB8722F997BDE9B.pdf. 2014.
69. American College of Radiology.(ACR)-Americal Association of
Physicists in Medicine (AAPM) technical standard for the
performance of proton beam radiation therapy,
http://www.acr.org/
∼/media/7C781C89623F47D4A2DA85178C721A68.pdf, Editor.
2013.
70. ASTRO Model Policy: Proton Beam Therapy. 2014:
http://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimburs
71. DeLaney TF, Kooy HM, eds. Proton and Charged Particle
Radiotherapy. Philadelphia, PA: Lippincott Williams and Wilkins;
2007.
72. Schulz-Ertner D, Jakel O, Schlegel W. Radiation therapy with
charged particles. Semin Radiat Oncol. 2006;16(4):249–259.
73. Brada M, Pijls-Johannesma M, De Ruysscher D. Proton therapy in
clinical practice: current clinical evidence. J Clin Oncol. 2007;
25(8):965–970.
74. Allison RR, Sibata C, Patel R. Future radiation therapy: photons,
protons and particles. Future Oncol. 2013;9(4):493–504.
75. Loeffler JS, Durante M. Charged particle therapy–optimization,
challenges and future directions. Nat Rev Clin Oncol. 2013;
10(7):411–424.
76. Foote RL, Stafford SL, Petersen IA, et al. The clinical case for proton
beam therapy. Radiat Oncol. 2012;7:174.
77. Williams TM, Maier A. Role of stereotactic body radiation therapy
and proton/carbon nuclei therapies. Cancer J. 2013;19(3):272–281.
78. Merchant TE, Farr JB. Proton beam therapy: a fad or a new
standard of care. Curr Opin Pediatr. 2014;26(1):3–8.
79. Mitin T, Zietman AL. Promise and pitfalls of heavy-particle therapy.
J Clin Oncol. 2014;32(26):2855–2863.
80. Delaney TF. Proton therapy in the clinic. Front Radiat Ther Oncol.
2011;43:465–485.
81. 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.
82. MacDonald SM, Safai S, Trofimov A, et al. Proton radiotherapy for
childhood ependymoma: initial clinical outcomes and dose
comparisons. Int J Radiat Oncol Biol Phys. 2008;71(4):979–986.
83. Yock TI, Schneider R, Friedmann A, et al. Proton radiotherapy for
orbital rhabdomyosarcoma: clinical outcome and a dosimetric
comparison with photons. Int J Radiat Oncol Biol Phys.
2005;63(4):1161–1168.
84. Kozak KR, Adams J, Krejcarek SJ, Tarbell NJ, Yock TI. A dosimetric
comparison of proton and intensity-modulated photon radiotherapy
for pediatric parameningeal rhabdomyosarcomas. Int J Radiat Oncol
Biol Phys. 2009;74(1):179–186.
85. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy
for pediatric ewing’s sarcoma: initial clinical outcomes. Int J Radiat
Oncol Biol Phys. 2011;82(3):1142–1148.
86. Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for
pediatric medulloblastoma and supratentorial primitive
neuroectodermal tumors: outcomes for very young children treated
with upfront chemotherapy. Int J Radiat Oncol Biol Phys.
2013;87(1):120–126.
87. Hattangadi-Gluth JA, Chapman PH, Kim D, et al. Single-fraction
proton beam stereotactic radiosurgery for cerebral arteriovenous
malformations. Int J Radiat Oncol Biol Phys. 2014;89(2):338–346.
88. Weber DC, Schneider R, Goitein G, et al. Spot scanning-based
proton therapy for intracranial meningioma: long-term results from
the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys.
2012;83(3):865–871.
89. Tran E, Ma R, Paton K, Blackmore E, Pickles T. Outcomes of proton
radiation therapy for peripapillary choroidal melanoma at the BC
Cancer Agency. Int J Radiat Oncol Biol Phys. 2012;83(5):1425–1431.
90. Krema H, Somani S, Sahgal A, et al. Stereotactic radiotherapy for
treatment of juxtapapillary choroidal melanoma: 3-year follow-up.
Br J Ophthalmol. 2009;93(9):1172–1176.
91. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull
base. Strahlenther Onkol. 1999;175(Suppl 2):57–63.
92. Chen YL, Liebsch N, Kobayashi W, et al. Definitive high dose proton
based radiotherapy for unresected mobile spine and sacral
chordomas. Spine. 2013;38(15):E930–E936.
93. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of
Phase II study of high dose photon/proton radiotherapy in the
management of spine chordomas, chondrosarcomas, and other
sarcomas. J Surg Oncol. 2014;110(2):115–122.
94. Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based
radiotherapy for unresectable or incompletely resected
osteosarcoma. Cancer. 2011;117(19):4522–4530.
95. Kandula S, Zhu X, Garden AS, et al. Spot-scanning beam proton
therapy vs intensity-modulated radiation therapy for ipsilateral head
and neck malignancies: a treatment planning comparison. Med
Dosim. 2013;38(4):390–394.
96. Swisher-McClure SD, Chang C, Teo K, Lin A. Postoperative radiation
therapy (RT) for salivary gland carcinoma: a comparison of intensity
modulated radiation therapy (IMRT) and proton treatment
techniques. Int J Radiat Oncol Biol Phys. 2012;84(3S):S838.
97. Chan AW, Adams JA, Weyman E, et al. A phase II trial of proton
beam with chemotherapy for nasopharyngeal carcinoma. Int J
Radiat Oncol Biol Phys. 2012;84(3):S151–S152.
98. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton
therapy with concurrent chemotherapy for unresectable stage III
nonsmall cell lung cancer. Cancer. 2011;117(20):4707–4713.
99. Ishikawa H, Hashimoto T, Moriwaki T, et al. Proton beam therapy
combined with concurrent chemotherapy for esophageal cancer.
Anticancer Res. 2015;35(3):1757–1762.
100. Mizumoto M, Okumura T, Hashimoto T, et al. Proton beam therapy
for hepatocellular carcinoma: a comparison of three treatment
protocols. Int J Radiat Oncol Biol Phys. 2011;81(4):1039–1045.
101. Bush DA, Kayali Z, Grove R, Slater JD. The safety and efficacy of
high-dose proton beam radiotherapy for hepatocellular carcinoma: a
phase 2 prospective trial. Cancer. 2011;117(13):3053–3059.
102. Hong TS, DeLaney TF, Mamon HJ, et al. A prospective feasibility
study of respiratory-gated proton beam therapy for liver tumors.
Pract Radiat Oncol. 2014;4(5):316–322.
103. Bush DA, Slater JD, Garberoglio C, et al. Partial breast irradiation
delivered with proton beam: results of a phase II trial. Clin Breast
Cancer. 2011;11(4):241–245.
104. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-
volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010; 76(3
Suppl):S77–S85.
105. Mihailidis DN. Proton therapy for breast cancer after mastectomy:
early outcomes of a prospective clinical trial. Int J Radiat Oncol Biol
Phys. 2014;88(3):754.
106. Mehta M, Gondi V, et al. NRG-BN001: randomized Phase II Trial of
Hypofractionated Dose-Escalated Photon IMRT or Proton Beam
Therapy Versus Conventional Photon Irradiation With Concomitant
and Adjuvant Temozolamide in Patients with Newly Diagnosed
Glioblastoma. Philadelphia, PA: NRG Oncology;. Available at:
https://www.nrgoncology.org/Clinical-Trials/NRG-BN001 2015
107. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated
radiotherapy for prostate cancer: patterns of care and early toxicity.
J Natl Cancer Inst. 2013;105(1):25–32.
108. Efstathiou J, Bekelman JE, Massachusetts General Hospital;
University of Pennsylvania; National Cancer Institute. Proton
therapy vs. IMRT for low or intermediate risk prostate cancer
(PARTIQoL). ClinicalTrials.gov. Available at:
https://clinicaltrials.gov/ct2/show/NCT01617161 Identifier:
NCT01611761, 2015.
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.
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
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.
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
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:
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:
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.
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.
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
equation becomes:
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.
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.
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).
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.
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
Radiat Oncol Biol Phys. 2011;79:1188–1195.
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
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.
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
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).
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
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.
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
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
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.
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):
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.
Examples
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:
Tumor solution. Before the break the BED is (using Equation 20.13):
Therefore:
Solving this for d gives:
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.
or
Solving for d gives:
or
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.
or
or
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:
SOLUTION
According to Equation 20.16, the remainder of the treatments should be
delivered at a dose/fraction dc given by:
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.
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):
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
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
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
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.
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.
REFERENCES
1. Coutard H. Roentgen therapy of epitheliomas of tonsillar regions,
hypopharynx, and larynx from 1920 to 1926. Am J Roentgenol.
1932;28:313–331.
2. Chadwick KH, Leenhouts HP. A molecular theory of cell survival.
Phys Med Biol. 1973;18:78–87.
3. Wouters BG, Begg AC. Irradiation-induced damage and DNA damage
response. In: Joiner M, van der Kogel A, eds. Basic Clinical
Radiobiology. 4th ed. London: Hodder Arnold; 2009:11–26.
4. Tubiana M, Dutreix J, Wambersie A. Introduction to radiobiology.
Bristol, PA: Taylor & Francis; 1990:97–104.
5. Fowler JF. The radiobiology of prostate cancer. Acta Oncol. 2005;
44:265–276.
6. Thames HD. On the origin of dose fractionation regimens in
radiotherapy. Semin Radiat Oncol. 1992;2:3–9.
7. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction
size on tumour control in patients with early-stage breast cancer
after local tumour excision: long-term results of a randomised trial.
Lancet Oncol. 2006;7:467–471.
8. Cox JD. Clinical perspectives of recent developments in
fractionation. Semin Radiat Oncol. 1992;2:10–15.
9. Fowler JF. Intercomparisons of new and old schedules in
fractionated radiotherapy. Semin Radiat Oncol. 1992;2:67–72.
10. Saunders MI, Dische S. Continuous, hyperfractionated, accelerated
radiotherapy (CHART). Semin Radiat Oncol. 1992;2:41–44.
11. Stuschke M, Thames H. Hyperfractionation: where do we stand?
Radiother Oncol. 1998;46:131–133.
12. Kaanders J, Van Der Kogel A, Ang KK. Altered fractionation: limited
by mucosal reactions? Radiother Oncol. 1998;50:247–260.
13. Wilson EM, Williams JF, Lyn BE, et al. Comparison of two
dimensional and three dimensional radiotherapy treatment planning
in locally advanced non-small cell lung cancer treated with
continuous hyperfractionated accelerated radiotherapy weekend
less. Radiother Oncol. 2005;74:307–314.
14. Khoo VS, Dearnaley DP. Question of dose, fractionation and
technique: ingredients for testing hypofractionation in prostate
cancer—the CHHiP trial. Clin Oncol. 2008;20:12–14.
15. Stuschke M, Thames HD. Hyperfractionated radiotherapy of human
tumors: overview of the randomized clinical trials. Int J Radiat Oncol
Phys Biol. 1997;37:259–267.
16. Miles EF, Lee WR. Hypofractionation for prostate cancer: a critical
review. Semin Radiat Oncol. 2008;18;41–47.
17. Haviland JS, Owen JR, Dewar JA, et al. The UK standardisation of
breast radiotherapy (START) trials of radiotherapy
hypofractionation for treatment of early breast cancer: 10-year
follow-up results of two randomised controlled trials. Lancet Oncol.
2013;14:1086–1094.
18. Lyman JT. Complication probabilities as assessed from dose-volume
histograms. Radiat Res. 1985;104:S13–S19.
19. 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 Phys
Biol. 1991;21:137–146.
20. Mohan R, Mageras GS, Baldwin B, et al. Clinically relevant
optimization of 3-D conformal treatments. Med Phys. 1992;19:933–
944.
21. Niemierko A, Goitein M. Calculation of normal tissue complication
probability and dose–volume histogram reduction schemes for tissue
with a critical element architecture. Radiother Oncol. 1991;20:161–
176.
22. Niemierko A. Reporting and analyzing dose distributions: a concept
of equivalent uniform dose. Med Phys. 1997;24:103–110.
23. Kwa S, Theuws J, Wagenaar A, et al. Evaluation of two dose-volume
histogram reduction models for the prediction of radiation
pneumonitis. Radiother Oncol. 1998;48:61–69.
24. Moiseenko V, Battista J, Van Dyk J. Normal tissue complication
probabilities: dependence on choice of biological model and dose-
volume histogram reduction scheme. Int J Radiat Oncol Biol Phys.
2000;46:983–993.
25. Wang JZ, Li XA, D’Souza WD, et al. Impact of prolonged fraction
delivery times on tumor control: a note of caution for intensity-
modulated radiation therapy (IMRT). Int J Radiat Oncol Phys Biol.
2003;57:543–552.
26. Liao Y, Joiner M, Huang Y, et al. Hypofractionation: what does it
mean for prostate cancer treatment? Int J Radiat Oncol Phys Biol.
2010;76:260–268.
27. Fyles AW, Milosevic M, Wong R, et al. Oxygen predicts radiation
response and survival in patients with cervix cancer. Radiother
Oncol. 1998;48:149–156.
28. Stadler P, Becker A, Feldmann HJ, et al. Influence of the hypoxic
subvolume on the survival of patients with head and neck cancer.
Int J Radiat Oncol Biol Phys. 1999;44:749–754.
29. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and
neck cancer: changes during radiotherapy and impact on treatment
outcome. Radiother Oncol. 1999;53:113–117.
30. Nahum AE, Movsas B, Horwitz EM, et al. Incorporating clinical
measurements of hypoxia into tumor local control modeling of
prostate cancer: implications for the α/β ratio. Int J Radiat Oncol Biol
Phys. 2003;57:391–401.
31. Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of
tumor oxygenation in 397 head and neck tumors after primary
radiation therapy. An international multi-center study. Radiother
Oncol. 2005;77:18–24.
32. Movsas B, Chapman JD, Hanlon AL, et al. A hypoxic ratio of
prostate pO2/muscle pO2 predicts for biochemical failure in prostate
cancer patients. Urology. 2002;60:634–639.
33. Hall EJ. Radiobiology for the Radiologist. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2000:112–123.
34. Chapman JD, Gillespie CJ, Reuvers AP, et al. The inactivation of
Chinese hamster cells by x-rays: the effects of chemical modifiers on
single- and double-events. Rad Res. 1975;64:365–375.
35. Palcic B, Skarsgard LD. Reduced oxygen enhancement ratio at low
doses of radiation. Rad Res. 1984;100:328–329.
36. Orton C. In regard to Nahum et al. (Int J Radiat Oncol Biol Phys.
2003;57:391–401): incorporating clinical measurements of hypoxia
into tumor control modeling of prostate cancer: implications for the
α/β ratio. Int J Radiat Oncol Biol Phys. 2004;58:1637.
37. Nahum AE, Chapman JD. In response to Dr. Orton. Int J Radiat
Oncol Biol Phys. 2004;58:1637–1639.
38. DaS,u A, Denekamp J. New insights into factors influencing the
clinically relevant oxygen enhancement ratio. Radiother Oncol.
1998;46:269–277.
39. DaS,u A, Denekamp J. Superfractionation as a potential hypoxic cell
radiosensitizer: prediction of an optimal dose per fraction. Int J
Radiat Oncol Biol Phys. 1999;43:1083–1094.
40. 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.
41. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated
tumor clonogen repopulation during radiation therapy. Acta Oncol.
1988;27:131–146.
42. Bentzen S, Thames HD. Clinical evidence for tumor clonogen
regeneration: interpretations of the data. Radiother Oncol.
1991;22:161–166.
43. Hall EJ. Radiobiology for the Radiologist. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2000:51–66.
44. Bentzen SM, Saunders MI, Dische S, et al. Radiotherapy-related
early morbidity in head and neck cancer: quantitative clinical
radiobiology as deduced from the CHART trial. Radiother Oncol.
2001;60:123–135.
45. Saunders MI, Rojas A, Lyn BE, et al. Experience with dose escalation
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–
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
Radiat Oncol Biol Phys. 2004;58:871–875.
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–
S2.
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.
21 Radiobiology of Stereotactic
Radiosurgery and Stereotactic
Ablative Radiotherapy
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
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.
Figure 21.1 A schematic representation of the current understanding of the mechanism of action
for SRS/SBRT.
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).
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
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.
• 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
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
REFERENCES
1. Gray LH, Conger AO, Ebert M, et al. The concentration of oxygen
dissolved in tissues at the time of irradiation as a factor in
radiotherapy. Br J Radiol. 1953;26:638–648.
2. Hall E. Radiobiology for the radiobiologist. 5th ed. Philadelphia, PA: JB
Lippincott; 2000.
3. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931–
10934.
4. Folkman J. Role of angiogenesis in tumor growth and metastasis.
Semin Oncol. 2002;29:15–18.
5. Denekamp J. Review article: Angiogenesis, neovascular proliferation
and vascular pathophysiology as targets for cancer therapy.
Br J Radiol. 1993;66:181–196.
6. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to
radiotherapy regulated by endothelial apoptosis. Science. 2003;
300:1155–1159.
7. Moeller BJ, Cao Y, Li CY, et al. Radiation activates HIF-1 to regulate
vascular radiosensitivity in tumors: role of reoxygenation, free
radicals and stress granules. Cancer Cell. 2004;5:429–441.
8. Semenza G. HIF-1 inhibitors for cancer therapy: from gene
expression to drug discovery. Curr Pharm Des. 2009;15:3839–3843.
9. Colbert LE, Fisher SB, Balci S, et al. High nuclear hypoxia-inducible
factor 1 alpha expression is a predictor of distant recurrence in
patients with resected pancreatic adenocarcinoma. Int J Radiat Oncol
Biol Phys. 2015;91(3):631–639.
10. Lee HJ, Yoon C, Park DJ, et al. Inhibition of vascular endothelial
growth factor A and hypoxia-inducible factor 1α maximizes the
effects of radiation in sarcoma mouse models through destruction of
tumor vasculature. Int J Radiat Oncol Biol Phys. 2015;91(3):621–630.
11. Sperduto PW. A review of stereotactic radiosurgery in the
management of brain metastases. Technol Cancer Res Treat.
2003;2:105–110.
12. Kim YJ, Cho KH, Kim JY, et al. Single-dose versus fractionated
stereotactic radiotherapy for brain metastases. Int J Radiat Oncol Biol
Phys. 2010;81:483–489.
13. Timmerman R, Paulus R, Galvin J, et al. Stereo-tactic body
radiotherapy to treat medically inoperable early stage lung cancer
patients. J Am Med Assoc. 2010;303(11):1070–1076.
14. Nagata Y. Stereotactic body radiotherapy for early stage lung
cancer. Cancer Res Treat. 2013;45:155–161.
15. Jang WI, Kim MS, Bae SH, et al. High-dose stereotactic body
radiotherapy correlates increased local control and overall survival
in patients with inoperable hepatocellular carcinoma. Radiat Oncol.
2013;8:250–262.
16. Folkert MR, Bilsky MH, Tom AK, et al. Outcome and toxicity for
hypofractionated and single-fraction image-guided stereotactic
radiosurgery for sarcomas metastasizing to the spine. Int J Radiat
Oncol Biol Phys. 2014;88:1085–1091.
17. Cho LC, Fonteyne V, DeNeve W, et al. Stereotactic body
radiotherapy. In: Levitt SH, et al., eds. Technical Basis of Radiation
Therapy; Practical Clinical Application. Springer; 2012;363–400.
18. Kocher M, Treuer H, Voges J, et al. Computer simulation of
cytotoxic and vascular effects of radiosurgery in solid and necrotic
brain metastases. Radiother Oncol. 2000;54:149–156.
19. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is
appropriate to model high dose per fraction effects in radiosurgery.
Semin Radiat Oncol. 2008;18:240–243.
20. Song CW, Park HJ, Griffin RJ, et al. Radiobiology of stereotactic
radiosurgery and stereotactic body radiation therapy. In: Levitt SH,
et al., eds. Technical Basis of Radiation Therapy; Practical Clinical
Application. Springer: 2012:51–61.
21. Park HJ, Griffin RJ, Hui S, et al. Radiation-induced vascular damage
in tumors: implications of vascular damage in ablative
hypofractionated radiotherapy (SBRT and SRS). Radiat Res.
2012;177:311–327.
22. Song CW, Kim MS, Cho LC, et al. Radiobiological basis of SBRT and
SRS. Int J Clin Oncol. 2014;19:570–578.
23. Song CW, Park I, Cho LC, et al. Is there indirect cell death involved
in response of tumor to SRS and SBRT? Int J Radiat Oncol Biol Phys.
2014; 89: 924–925.
24. Brown JM, Diehn M, Loo BW. Stereotactic ablative radiotherapy
should be combined with a hypoxic cell radiosensitizer. Int J Radiat
Oncol Biol Phys. 2010;78:323–327.
25. Monte UD. Does the cell number 109 still really fit one gram of
tumor tissue? Cell Cycle. 2009;8(3):505–506.
26. Leith JT, Cook S, Choughle P, et al. Intrinsic and extrinsic
characteristics of human tumors relevant to radiosurgery:
comparative cellular radiosensitivity and hypoxic percentages. Acta
Neurochir Supp. 1994;62:18–27.
27. Song CW, Lee YJ, Griffin RJ, et al. Indirect Tumor Cell Death by
High-Dose Hypofractionated Irradiation: Implication for SBRT and
SRS. Intl J Radiat Oncol Biol Phys. 2015;93(1):166–172.
28. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor
cells with PD-1 on tumor-specific T cells as a mechanism of immune
evasion: implications for tumor immunotherapy. Cancer Immunol
Immnother. 2005;54:307–314.
29. Matsumura S, Wang B, Kawashima N, et al. Radiation induced
CXCL16 release by breast cancer cells attracts effector T cells.
J Immunol. 2008;181:3009–3107.
30. Seung SK, Curti BD, Drittenden M, et al. Phase I study of
stereotactic body radiotherapy and interleukin-2: tumor and
immunological responses. Sci Transl Med. 2012;4:137–174.
31. Kaur P, Asea A. Radiation-induced effects and the immune system
in cancer. Front Oncol. 2012;2:10–11.
32. Lugada AA, Moran JP, Gerbe SA, et al. Local radiation therapy of
B16 melanoma tumors increases the generation of tumor antigen-
specific effector cells that traffic to the tumor. J Immunol.
2005;174:7516–7523.
33. Finkelstein SE, Timmerman R, McBride WH, et al. The confluence of
stereotactic ablative radiotherapy and tumor immunology. Clin Dev
Immunol. 2011;2011:7–13.
34. Sridharan V, Schoenfield JD. Immune effects of targeted radiation
therapy for cancer. Disc Med. 2015;19(104):219–228.
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.
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.
22 Tolerance of Normal Tissue to
Therapeutic Radiation
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
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
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.
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
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).
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
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).
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
seems to be <5%, after 5 years of completing radiotherapy, when the
brachial plexus is limited to 60 Gy.
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–
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.
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
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.
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.
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
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.
• 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%
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
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).
REFERENCES
1. Halperin EC, Perez CA, Brady, LW. Preface to the first edition. In:
Halperin EC, Perez CA, Brady LW, eds. Perez and Brady’s Principles
and Practice of Radiation Oncology. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2008:xxi.
2. Rubin P, Cassarett G. A direction for clinical radiation pathology. In:
Vaeth JM, et al., eds. Frontiers of Radiation Therapy and Oncology VI.
Baltimore, MD: University Park Press; 1972:1–16.
3. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to
therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–
22.
4. Marks LB, Ten Haken RK, Martel MK. Guest editor’s introduction to
QUANTEC: a users guide. Int J Radiat Oncol Biol Phys. 2010;76(3
Suppl):S1–S2.
5. Bentzen SM, Constine LS, Deasy JO, et al. Quantitative Analyses of
Normal Tissue Effects in the Clinic (QUANTEC): an introduction to
the scientific issues. Int J Radiat Oncol Biol Phys. 2010; 76(3
Suppl):S3–S9.
6. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
complication probability models in the clinic. Int J Radiat Oncol Biol
Phys. 2010;76(3 Suppl):S10–S19.
7. Lawrence YR, Li XA, el Naqa I, et al. Radiation dose-volume effects
in the brain. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S20–S27.
8. 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(3
Suppl):S28–S35.
9. Mayo C, Yorke E, Merchant TE. Radiation associated brainstem
injury. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S36–S41.
10. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-
volume effects in the spinal cord. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S42–S49.
11. Bhandare N, Jackson A, Eisbruch A, et al. Radiation therapy and
hearing loss. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S50–S57.
12. Deasy JO, Moiseenko V, Marks L, et al. Radiotherapy dose-volume
effects on salivary gland function. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S58–S63.
13. Rancati T, Schwarz M, Allen AM, et al. Radiation dose-volume
effects in the larynx and pharynx. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S64–S69.
14. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume
effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76(3
Suppl):S70–S76.
15. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume
effects in the heart. Int J Radiat Oncol Biol Phys. 2010;76 (3
Suppl):S77–S85.
16. Werner-Wasik M, Yorke E, Deasy J, et al. Radiation dose-volume
effects in the esophagus. Int J Radiat Oncol Biol Phys. 2010;76(3
Suppl):S86–S93.
17. Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-associated liver
injury. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S94–S100.
18. Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume
effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S101–S107.
19. Dawson LA, Kavanagh BD, Paulino AC, et al. Radiation-associated
kidney injury. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S108–
S115.
20. Viswanathan AN, Yorke ED, Marks LB, et al. Radiation dose-volume
effects of the urinary bladder. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S116–S122.
21. Michalski JM, Gay H, Jackson A, et al. Radiation dose-volume
effects in radiation-induced rectal injury. Int J Radiat Oncol Biol
Phys. 2010;76(3 Suppl):S123–S129.
22. Roach M 3rd, Nam J, Gagliardi G, et al. Radiation dose-volume
effects and the penile bulb. Int J Radiat Oncol Biol Phys. 2010; 76(3
Suppl):S130–S134.
23. Jaffray DA, Lindsay PE, Brock KK, et al. Accurate accumulation of
dose for improved understanding of radiation effects in normal
tissue. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S135–S139.
24. Jeraj R, Cao Y, Ten Haken RK, et al. Imaging for assessment of
radiation-induced normal tissue effects. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S140–S144.
25. Bentzen SM, Parliament M, Deasy JO, et al. Biomarkers and
surrogate endpoints for normal-tissue effects of radiation therapy:
the importance of dose-volume effects. Int J Radiat Oncol Biol Phys.
2010;76(3 Suppl):S145–S150.
26. Deasy JO, Bentzen SM, Jackson A, et al. Improving normal tissue
complication probability models: the need to adopt a “data-pooling”
culture. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S151–S154.
27. 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(3 Suppl):S155–S160.
28. Veninga T, Langendijk HA, Slotman BJ, et al. Reirradiation of
primary brain tumours: survival, clinical response and prognostic
factors. Radiother Oncol. 2001;59:127–137.
29. Mayer R, Sminia P. Reirradiation tolerance of the human brain. Int J
Radiat Oncol Biol Phys. 2008;70(5):1350–1360.
30. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the
central nervous system. Int J Radiat Oncol Biol Phys. 1995;31:1093–
1112.
31. Parsons F. Chapter 1: The effect of radiation on normal tissues in
management of head and neck cancer. In: Million R, Cassisi N, eds.
Management of Head and Neck Cancer: A Multidisciplinary Approach.
Philadelphia, PA: Lippincott; 1984:183–184.
32. Parsons JT, Fitzgerald CR, Hood CI, et al. The effects of irradiation
on the eye and optic nerve. Int J Radiat Oncol Biol Phys. 1983;9609–
9622.
33. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation retinopathy
after external-beam irradiation: analysis of time-dose factors. Int J
Radiat Oncol Biol Phys. 1994;30(4):765–773.
34. Monroe AT, Bhandare N, Morris CG, et al. Preventing radiation
retinopathy with hyperfractionation. Int J Radiat Oncol Biol Phys.
2005;61(3):856–864.
35. Takeda A, Shigematsu N, Suzuki S, et al. Late retinal complications
of radiation therapy for nasal and paranasal malignancies:
relationship between irradiated-dose area and severity. Int J Radiat
Oncol Biol Phys. 1999;44(3):599–605.
36. Chan SH, Ng WT, Kam KL, et al. Sensorineural hearing loss after
treatment of nasopharyngeal carcinoma: a longitudinal analysis. Int
J Radiat Oncol Biol Phys. 2009;73(5):1335–1342.
37. Blanco AI, Chao KSC, El Naqa I, et al. Dose-volume modeling of
salivary function in patients with head-and-neck cancer receiving
radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:1055–1069.
38. Eisbruch A, Kim KM, Terrell JE, et al. Xerostomia and its predictors
following parotid-sparing irradiation of head-and-neck cancer. Int J
Radiat Oncol Biol Phys. 2001;50:695–704.
39. Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular
bone complications. Cancer Treat Rev. 2002;28(1):65–74.
40. Ben-David MA, Diamante M, Radawski JD, et al. Lack of
osteoradionecrosis of the mandible after intensity-modulated
radiotherapy for head and neck cancer: likely contributions of both
dental care and improved dose distributions. Int J Radiat Oncol Biol
Phys. 2007;68(2):396–402.
41. Gomez DR, Zelefsky MJ, Wolden SL, et al. Osteoradionecrosis
(ORN) of the Mandible in Head/Neck Cancer Treated with Intensity
Modulated Radiation Therapy (IMRT). Int J Radiat Oncol Biol Phys.
2008;72(1 Suppl):S410.
42. Gomez DR, Zhung JE, Gomez J, et al. Intensity-modulated
radiotherapy in postoperative treatment of oral cavity cancers. Int J
Radiat Oncol Biol Phys. 2009;73(4):1096–1103.
43. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of
accelerated hypofractionated intensity-modulated radiation therapy
for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat
Oncol Biol Phys. 2010;76(5):1333–1338.
44. Lee IJ, Koom WS, Lee CG, et al. Risk factors and dose-effect
relationship for mandibular osteoradionecrosis in oral and
oropharyngeal cancer patients. Int J Radiat Oncol Biol Phys. 2009;
75(4):1084–1091.
45. Feng FY, Kim HM, Lyden TH, et al. Intensity-modulated
radiotherapy of head and neck cancer aiming to reduce dysphagia:
Early dose–effect relationships for the swallowing structures. Int J
Radiat Oncol Biol Phys. 2007;68:1289–1298.
46. Sanguineti G, Adapala P, Endres EJ, et al. Dosimetric predictors of
laryngeal edema. Int J Radiat Oncol Biol Phys. 2007;68:741–749.
47. Bajrovic A, Rades D, Fehlauer F, et al. Is there a life-long risk of
brachial plexopathy after radiotherapy of supraclavicular lymph
nodes in breast cancer patients? Radiother Oncol. 2004;71(3):297–
301.
48. Johansson S, Svensson H, Denekamp J. Dose response and latency
for radiation-induced fibrosis, edema, and neuropathy in breast
cancer patients. Int J Radiat Oncol Biol Phys. 2002;52(5):1207–1219.
49. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus
injury: follow-up of two different fractionation schedules. Radiother
Oncol. 1990;18(3):213–220.
50. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume
histogram analysis for pneumonitis after 3D treatment for non-small
cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 1999; 45:323–
329.
51. Bradley J, Deasy JO, Bentzen S, et al. Dosimetric correlates for
acute esophagitis in patients treated with radiotherapy for lung
carcinoma. Int J Radiat Oncol Biol Phys. 2004;58:1108–1113.
52. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced
esophageal toxicity in patients with non-small cell lung cancer
treated with three-dimensional conformal radiotherapy. Int J Radiat
Oncol Biol Phys. 2003;55:337–341.
53. Kim TH, Cho KH, Pyo HR, et al. Dose–volumetric parameters of
acute esophageal toxicity in patients with lung cancer treated with
three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol
Phys. 2005;62:995–1002.
54. RTOG Protocol. Available at:
http://rtog.org/members/protocols/0617/0617.pdf. Last accessed
September 20, 2010.
55. RTOG Protocol. Available at:
http://rtog.org/members/protocols/0436/0436.pdf. Last accessed
September 20, 2010.
56. RTOG Protocol. Available at:
http://rtog.org/members/protocols/0623/0623.pdf. Last accessed
September 20, 2010.
57. Martel MK, Sahijdak WM, Ten Haken RK, et al. Fraction size and
dose parameters related to the incidence of pericardial effusions. Int
J Radiat Oncol Biol Phys. 1998;40:155–161.
58. Wei X, Liu HH, Tucker SL, et al. Risk factors for pericardial effusion
in inoperable esophageal cancer patients treated with definitive
chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2008;70:707–
714.
59. Gagliardi G, Lax I, Ottolenghi A, et al. Long-term cardiac mortality
after radiotherapy of breast cancer – application of the relative
seriality model. Br J Radiol. 1996;69:839–846.
60. Eriksson F, Gagliardi G, Liedberg A, et al. Long-term cardiac
mortality following radiation therapy for Hodgkin’s disease:
Analysis with the relative seriality model. Radiother Oncol.
2000;55:153–162.
61. Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol
Phys. 1995;31:1249–1256.
62. Baglan KL, Frazier RC, Yan D, et al. The dose-volume relationship of
acute small bowel toxicity from concurrent 5-FU-based
chemotherapy and radiation therapy for rectal cancer. Int J Radiat
Oncol Biol Phys. 2002;52:176–183.
63. Robertson JM, Lockman D, Yan D, et al. The dose-volume
relationship of small bowel irradiation and acute grade 3 diarrhea
during chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol
Phys. 2008;70:413–418.
64. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute
gastrointestinal toxicity in women receiving intensity modulated
whole-pelvic radiation therapy. Radiother Oncol. 2003;69:201–207.
65. RTOG Protocol. Available at:
http://rtog.org/members/protocols/0415/0415.pdf. Last accessed
September 20, 2010.
66. Shipley WU, Bae K, Efstathiou JA, et al. Late Pelvic Toxicity
Following Bladder-Sparing Therapy in Patients With Invasive
Bladder Cancer: Analysis of RTOG 89-03, 95-06, 97-06, 99-06. Int J
Radiat Oncol Biol Phys. 2007;69(3 Suppl):S8.
67. Roach M, Winter K, Michalski JM, et al. Penile bulb dose and
impotence after three-dimensional conformal radiotherapy for
prostate cancer on RTOG 9406: Findings from a prospective, multi-
institutional, phase I/II dose-escalation study. Int J Radiat Oncol Biol
Phys. 2004;60:1351–1356.
68. Grigsby PW, Roberts HL, Perez CA. Femoral neck fracture following
groin irradiation. Int J Radiat Oncol Biol Phys. 1995;32(1):63–67.
69. Katz A, Eifel PJ, Jhingran A, et al. The role of radiation therapy in
preventing regional recurrences of invasive squamous cell
carcinoma of the vulva. Int J Radiat Oncol Biol Phys.
2003;57(2):409–418.
70. Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after
androgen deprivation for prostate cancer. N Engl J Med. 2005;
352:154–164.
71. Fiorino C, Valdagni R, Rancati T, et al. Dose-volume effects for
normal tissues in external radiotherapy: pelvis. Radiother Oncol.
2009;93(2):153–167.
72. Bedford JL, Khoo VS, Webb S, et al. Optimization of coplanar six-
field techniques for conformal radiotherapy of the prostate. Int J
Radiat Oncol Biol Phys. 2000;46(1):231–238.
73. Marion CM, Zelefsky MJ, Paoli J, et al. Predictors of late femoral
head toxicity after high-dose 3D-conformal radiotherapy and
intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys.
2002;54(2 Suppl):S111.
74. Jereczek-Fossa BA, Vavassori A, Fodor C, et al. Dose escalation for
prostate cancer using the three-dimensional conformal dynamic arc
technique: analysis of 542 consecutive patients. Int J Radiat Oncol
Biol Phys. 2008;71(3):784–794.
75. Timmerman RD. An overview of hypofractionation and introduction
to this issue of seminars in radiation oncology. Semin Radiat Oncol.
2008;18(4):215–222.
76. RTOG Protocol 0539. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed January 11, 2014.
77. RTOG Protocol 0825. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed January 11, 2014.
78. RTOG Protocol 0837. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed January 11, 2014.
79. RTOG Protocol 0848. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed January 11, 2014.
80. Zhung J, Melian E, Rusu I, et al. Evaluation of RTOG guidelines for
Monte Carlo-based lung SBRT planning. Int J Radiat Oncol Biol Phys.
2012;84(3 Suppl):(abstr 1089).
81. Bhandare N, Moiseenko V, Song WY, et al. Severe dry eye syndrome
after radiotherapy for head-and-neck tumors. Int J Radiat Oncol Biol
Phys. 2012;82(4):1501–1508.
82. Parsons JT, Bova FJ, Mendenhall WM, et al. Response of the normal
eye to high dose radiotherapy. Oncology (Williston Park).
1996;10(6):837–847; discussion 847–838, 851–832.
83. Rønjom MF, Brink C, Bentzen SM, et al. Hypothyroidism after
primary radiotherapy for head and neck squamous cell carcinoma:
normal tissue complication probability modeling with latent time
correction. Radiother Oncol. 2013;109(2):317–322.
84. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease
in women after radiotherapy for breast cancer. N Engl J Med.
2013;368(11):987–998.
85. RTOG Protocol 1005. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
86. RTOG Protocol 1304. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
87. Grimm J, LaCouture T, Croce R, et al. Dose tolerance limits and
dose volume histogram evaluation for stereotactic body
radiotherapy. J Appl Clin Med Phys. 2011;12(2):3368.
88. RTOG Protocol 7361. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
89. RTOG Protocol 0631. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
90. RTOG Protocol 0915. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
91. RTOG Protocol 0813. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
92. RTOG Protocol 0618. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
93. RTOG Protocol 0417. Available at:
http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Last
accessed March 7, 2014.
94. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation
tolerance of the optic nerves and chiasm after stereotactic
radiosurgery. Int J Radiat Oncol Biol Phys. 2003;55(5):1177–1181.
95. Leber KA, Bergloff J, Pendl G. Dose-response tolerance of the visual
pathways and cranial nerves of the cavernous sinus to stereotactic
radiosurgery. J Neurosurg. 1998;88(1):43–50.
96. Mould RF, Schulz RA, Bucholz RD, et al. Robotic Radiosurgery -
Volume 1. Sunnyvale, CA: Cyberknife Society Press; 2005.
97. Sahgal A, Larson D, Chang E. Stereotactic body radiosurgery for
spinal metastases: a critical review. Int J Radiat Oncol Biol Phys.
2008;71(3):652–665.
98. Gomez DR, Hunt MA, Jackson A, et al. Low rate of thoracic toxicity
in palliative paraspinal single-fraction stereotactic body radiation
therapy. Radiother Oncol. 2009;93(3):414–418.
99. Kavanagh BD, Schefter TE, Cardenes HR, et al. Interim analysis of a
prospective phase I/II trial of SBRT for liver metastases. Acta Oncol.
2006;45(7):848–855.
100. Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following
stereotactic body radiation therapy for stage I non-small-cell lung
cancer: who’s at risk? Int J Radiat Oncol Biol Phys. 2008;
72(5):1283–1286.
101. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy
for unresectable adenocarcinoma of the pancreas. Cancer. 2009;
115(3):665–672.
102. Fuller DB, Lee C. CyberKnife radiosurgery for low & intermediate
risk prostate cancer: emulating HDR brachytherapy dosimetry.
2008. Available at:
http://clinicaltrials.gov/ct2/show/NCT00643617. Last accessed
January 5, 2015.
103. Meier R, Kaplan I, Sanda M. CyberKnife radiosurgery for organ-
confined prostate cancer: homogenous dose distribution. 2008.
Available at: http://clinicaltrials.gov/ct2/show/NCT00643994. Last
accessed January 5, 2015.
104. Heron DE, Ferris RL, Karamouzis M, et al. Stereotactic body
radiotherapy for recurrent squamous cell carcinoma of the head and
neck: results of a phase I dose-escalation trial. Int J Radiat Oncol Biol
Phys. 2009;75(5):1493–1500.
105. Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume
receiving >30 Gy predicts risk of severe pain and/or rib fracture
after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol
Phys. 2010;76(3):796–801.
106. Chang J, Balter P, Dong L, et al. Stereotactic body radiation therapy
in centrally and superiorly located stage I or isolated recurrent non–
small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(4):967–
971.
107. Choi BO, Choi IB, Jang HS, et al. Stereotactic body radiation
therapy with or without transarterial chemoembolization for
patients with primary hepatocellular carcinoma: preliminary
analysis. BMC Cancer. 2008;8:351.
108. Takayama K, Nagata Y, Negoro Y, et al. Treatment planning of
stereotactic radiotherapy for solitary lung tumor. Int J Radiat Oncol
Biol Phys. 2005;61(5):1565–1571.
109. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a
phase I/II study of 48 Gy of stereotactic body radiotherapy in 4
fractions for primary lung cancer using a stereotactic body frame.
Int J Radiat Oncol Biol Phys. 2005;63(5):1427–1431.
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.
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.
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
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
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.
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
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
Biologic Models
Biologic models are an alternative method of evaluating treatment plans
that use the complete DVH as well as other information to predict
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.
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
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
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
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
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).
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
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
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
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”.
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
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
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
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.
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.)
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.
• 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
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
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”).
REFERENCES
1. Allen Li X, Alber M, Deasy JO, et al. The use and QA of biologically
related models for treatment planning: short report of the TG-166 of
the therapy physics committee of the AAPM. Med Phys.
2012;39:1386–1409.
http://www.aapm.org/pubs/reports/RPT_166.pdf
2. Timmerman R, Bastasch M, Saha D, et al. Stereotactic body radiation
therapy: normal tissue and tumor control effects with large dose per
fraction. Front Radiat Ther Oncol. 2011;43:382–394.
3. Schultz DB, Diehn M, Loo BW Jr. To SABR or not to SABR?
Indications and contraindications for stereotactic ablative
radiotherapy in the treatment of early-stage, oligometastatic or
oligoprogressive non-small cell lung cancer. Semin Radiat Oncol.
2015;25:78–86.
4. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
complication probability models in the clinic. Int J Radiat Oncol Biol
Phys. 2010;76(3 Suppl):S10–S19.
5. Wu Q, Mohan R, Morris M, et al. Simultaneous integrated boost
intensity-modulated radiotherapy for locally advanced head-and-
neck squamous cell carcinomas. I: dosimetric results. Int J Radiat
Oncol Biol Phys. 2003;56:573–585.
6. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-
volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010;
76(3 Suppl):S42–S49.
7. Moore KL, Schmidt R, Moiseenko V, et al Quantifying unnecessary
normal tissue complication risks due to suboptimal planning: a
secondary study of RTOG 0126. Int J Radiat Oncol Biol Phys.
2015;92:228–235.
8. Widesott L, Pierelli A, Fiorino C, et al. Helical tomotherapy vs.
intensity-modulated proton therapy for whole pelvis irradiation in
high-risk prostate cancer patients: dosimetric, normal tissue
complication probability, and generalized equivalent uniform dose
analysis. Int J Radiat Oncol Biol Phys. 2011;80:1589–1600.
9. Kong FM, Ten Haken RK, Schipper MJ, et al, High-dose radiation
improved local tumor control and overall survival in patients with
inoperable/unresectable non-small –cell lung cancer: long term
results of a radiation dose escalation study. Int J Radiat Oncol Biol
Phys. 2005;63:324–333.
10. Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-
escalation study using three-dimensional conformal radiation
therapy in the treatment of inoperable nonsmall cell lung
carcinoma. Cancer. 2005;103:2118–2127.
11. Long T, Matuszak M, Feng M, et al. Sensitivity analysis for
lexicographic ordering in radiation therapy treatment planning.
Med Phys. 2012;39:3445–3455.
12. Spalding AC, Jee KW, Vineberg K, et al. Potential for dose-
escalation and reduction of risk in pancreatic cancer using IMRT
optimization with lexicographic ordering and gEUD-based cost
functions. Med Phys. 2007;34:521–529.
13. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 7th ed.
Philadelphia, PA: Lippincott, Williams and Wilkins; 2012.
14. Joiner M, van der Kogel A. Basic Clinical Radiobiology. 4th ed.
London: Hodder Arnold; 2009.
15. Fowler JF. The linear-quadratic formula and progress in
fractionated radiotherapy. Br J Radiol. 1989;62:679–694.
16. Nahum AE. The radiobiology of hypofractionation. Clin Oncol (R
Coll Radiol). 2015;27:260–269.
17. Chapman JD. Can the two mechanisms of tumor cell killing by
radiation be exploited for therapeutic gain? J Radiat Res. 2014;
55:2–9.
18. Thames HD, Hendry JH. Fractionation in Radiotherapy. London:
Taylor and Francis; 1987.
19. Bentzen SM, Joiner MC. Chapter 9: The linear-quadratic approach
in clinical practice. In: Joiner M, van der Kogel A, eds. Basic Clinical
Radiobiology. 4th ed. London: Hodder Arnold; 2009.
20. Joiner MC, Bentzen SM. Chapter 8: Fractionation: the linear-
quadratic approach. In: Joiner M, van der Kogel A, eds. Basic
Clinical Radiobiology. 4th ed. London: Hodder Arnold; 2009.
21. Bentzen SM, Dörr W, Gahbauer R, et al. Bioeffect modeling and
equieffective dose concepts in radiation oncology – terminology,
quantities and units. Radiother Oncol. 2012;105:266–268.
22. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy
of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43:1095–
1101.
23. Munro TR, Gilbert CW. The relation between tumour lethal doses
and the radiosensitivity of tumour cells. Br J Radiol. 1961;34:246–
251.
24. Fowler JF, Toma-Dasu I, Dasu A. Is the α/β ratio for prostate
tumours really low and does it vary with the level of risk at
diagnosis? Anticancer Res. 2013;33:1009–1011.
25. Michalski JM, Gay H, Jackson A, et al. Radiation dose-volume
effects in radiation-induced rectal injury. Int J Radiat Oncol Biol
Phys. 2010;76(3 Suppl):S123–S129.
26. Henderson DR, Tree AC, van As NJ. Stereotactic body radiotherapy
for prostate cancer. Clin Oncol. 2015;27:270–279.
27. Brenner DJ. The linear-quadratic model is an appropriate
methodology for determining isoeffective doses at large doses per
fraction. Semin Radiat Onc. 2008;18:234–239.
28. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is
inappropriate to model high dose per fraction effects in
radiosurgery. Semin Radiat Oncol. 2008;18:240–243.
29. 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.
30. Tucker SL, Li M, Xu T, et al. Incorporating single-nucleotide
polymorphisms into the Lyman model to improve prediction of
radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2013;85:251–
257.
31. Brahme A. Dosimetric precision requirements in radiation therapy.
Acta Radiol Oncol. 1984;23:379–391.
32. Goitein M. Causes and consequences of inhomogeneous dose
distributions in radiation therapy. Int J Radiat Oncol Biol Phys.
1986;12:701–704.
33. Goitein M. The probability of controlling an inhomogeneously
irradiated tumor. In Zink S ed. Evaluation of Treatment Planning for
Particle Beam Radiotherapy, NCI Contract Report. Bethesday, MD:
National Cancer Institute; 1987.
34. Bentzen SM, Thames HD. Tumor volume and local control
probability: clinical data and radiobiological interpretations. Int J
Radiat Oncol Biol Phys. 1996;36:247–251.
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.
Radiother Oncol. 1993;29:140–147.
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
Oncol. 1992;25:251–260.
39. Dutreix J, Tubiana M, Dutreix A. An approach to the interpretation
of clinical data on the tumor control probability-dose relationship.
Radiother Oncol. 1988;11:239–248.
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.
1994;39:1895–1914.
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
Radiat Oncol Biol Phys. 1991;22:241–246.
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,
eds. Basic Clinical Radiobiology. 4th ed. London: Hodder Arnold;
2009:207–216.
48. Wouters BG, Koritzinsky M. The tumour microenvironment and
cellular hypoxia responses In: Michael Joiner, Albert van derKogel,
eds. Basic Clinical Radiobiology. 4th ed. London: Hodder Arnold;
2009:217–232.
49. Popple RA, Ove R, Shen S. Tumor control probability for selective
boosting of hypoxic subvolumes, including the effect of
reoxygenation. Int J Radiat Oncol Biol Phys. 2002;54:921–927.
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.
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.
65. Niemierko A, Goitein M. Calculation of normal tissue complication
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.
Radiother Oncol. 1993;26:226–237.
68. Jackson A, Kutcher GJ, Yorke ED. Probability of radiation-induced
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;
62:249–262.
70. 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.
71. Burman C, Kutcher GJ, Emami B, et al. Fitting normal tissue
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.
76. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
complication probability models in the clinic. Int J Radiat Oncol Biol
Phys. 2010;76:S10–S19.
77. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the
central nervous system. Int J Radiat Oncol Biol Phys. 1995;31:1093–
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
Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol
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.
Int J Radiat Oncol Biol Phys. 2008;70:1124–1129.
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
J Radiat Oncol Biol Phys. 2006;66:296–304.
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.
2012;39:7446–7461.
93. Deasy JO, Bentzen SM, Jackson A, et al. Improving normal tissue
complication probability models: the need to adopt a “data pooling”
culture. Int J Radiat Oncol Biol Phys. 2010;76:S151–S154.
SECTION II
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
(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
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
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
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
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,
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
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).
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
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.
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.
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
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.
DIAGNOSTIC EVALUATION
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).
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
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
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).
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.
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
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
deaths from this disease, highlighting the unfavorable prognosis of this
cancer at any stage and the need for more effective therapies.
DIAGNOSTIC EVALUATION
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
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
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.
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,
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.
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).
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.
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).
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.
DIAGNOSTIC EVALUATION
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–
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.
Radiotherapy Target
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
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
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).
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
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.
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
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).
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
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.
DIAGNOSTIC EVALUATION
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
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.
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.
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
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
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.
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
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).
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
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
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
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
for esophageal and gastric cancers in the Linxian general population
trial cohort in China. Int J Cancer. 2005;113:456–463.
6. Gholipour C, Shalchi RA, Abbasi M. A histopathological study of
esophageal cancer on the western side of the Caspian littoral from
1994 to 2003. Dis Esophagus. 2008;21:322–327.
7. Cancer AJCo. AJCC Cancer Staging Manual. 7th ed. New York, NY:
Springer; 2010.
8. Lightdale CJ, Kulkarni KG. Role of endoscopic ultrasonography in
the staging and follow-up of esophageal cancer. J Clin Oncol.
2005;23:4483–4489.
9. van Vliet EP, Heijenbrok-Kal MH, Hunink MG, et al. Staging
investigations for oesophageal cancer: a meta-analysis. Br J Cancer.
2008;98:547–557.
10. Flamen P, Lerut A, Van Cutsem E, et al. Utility of positron emission
tomography for the staging of patients with potentially operable
esophageal carcinoma. J Clin Oncol. 2000;18:3202–3210.
11. Gschossmann JM, Bonner JA, Foote RL, et al. Malignant
tracheoesophageal fistula in patients with esophageal cancer.
Cancer. 1993;72:1513–1521.
12. Yamada S, Takai Y, Ogawa Y, et al. Radiotherapy for malignant
fistula to other tract. Cancer. 1989;64:1026–1028.
13. Burt M, Diehl W, Martini N, et al. Malignant esophagorespiratory
fistula: management options and survival. Ann Thorac Surg.
1991;52:1222–1228; discussion 8–9.
14. Rice TW, Rusch VW, Apperson-Hansen C, et al. Worldwide
esophageal cancer collaboration. Dis Esophagus. 2009;22:1–8.
15. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy
after surgery compared with surgery alone for adenocarcinoma of
the stomach or gastroesophageal junction. N Engl J Med. 2001;
345:725–730.
16. Adelstein DJ, Rice TW, Rybicki LA, et al. Mature results from a
phase II trial of postoperative concurrent chemoradiotherapy for
poor prognosis cancer of the esophagus and gastroesophageal
junction. J Thorac Oncol. 2009;4:1264–1269.
17. Chen J, Pan J, Liu J, et al. Postoperative radiation therapy with or
without concurrent chemotherapy for node-positive thoracic
esophageal squamous cell carcinoma. Int J Radiat Oncol Biol Phys.
2013;86:671–677.
18. Fok M, Sham JS, Choy D, et al. Postoperative radiotherapy for
carcinoma of the esophagus: a prospective, randomized controlled
study. Surgery. 1993;113:138–147.
19. Teniere P, Hay JM, Fingerhut A, et al. Postoperative radiation
therapy does not increase survival after curative resection for
squamous cell carcinoma of the middle and lower esophagus as
shown by a multicenter controlled trial. French University
Association for Surgical Research. Surg Gynecol Obstet.
1991;173:123–130.
20. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative
chemoradiotherapy for esophageal or junctional cancer. N Engl J
Med. 2012;366:2074–2084.
21. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus
chemoradiotherapy followed by surgery for stage I and II
esophageal cancer: final analysis of randomized controlled phase III
trial FFCD 9901. J Clin Oncol. 2014;32:2416–2422.
22. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and
without surgery in patients with locally advanced squamous cell
carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317.
23. Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by
surgery compared with chemoradiation alone in squamous cancer of
the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–1168.
24. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of
locally advanced esophageal cancer: long-term follow-up of a
prospective randomized trial (RTOG 85–01). Radiation Therapy
Oncology Group. JAMA. 1999;281:1623–1627.
25. Corn BW, Coia LR, Chu JC, et al. Significance of prone positioning
in planning treatment for esophageal cancer. Int J Radiat Oncol Biol
Phys. 1991;21:1303–1309.
26. Patel AA, Wolfgang JA, Niemierko A, et al. Implications of
respiratory motion as measured by four-dimensional computed
tomography for radiation treatment planning of esophageal cancer.
Int J Radiat Oncol Biol Phys. 2009;74:290–296.
27. Dieleman EM, Senan S, Vincent A, et al. Four-dimensional
computed tomographic analysis of esophageal mobility during
normal respiration. Int J Radiat Oncol Biol Phys. 2007;67:775–780.
28. Thomas E, Crellin A, Harris K, et al. The role of endoscopic
ultrasound (EUS) in planning radiotherapy target volumes for
oesophageal cancer. Radiother Oncol. 2004;73:149–151.
29. Konski A, Doss M, Milestone B, et al. The integration of 18-fluoro-
deoxy-glucose positron emission tomography and endoscopic
ultrasound in the treatment-planning process for esophageal
carcinoma. Int J Radiat Oncol Biol Phys. 2005;61:1123–1128.
30. Vrieze O, Haustermans K, De Wever W, et al. Is there a role for
FGD-PET in radiotherapy planning in esophageal carcinoma?
Radiother Oncol. 2004;73:269–275.
31. Muijs CT, Beukema JC, Woutersen D, et al. Clinical validation of
FDG-PET/CT in the radiation treatment planning for patients with
oesophageal cancer. Radiother Oncol. 2014;113:188–192.
32. Sannohe Y, Hiratsuka R, Doki K. Lymph node metastases in cancer
of the thoracic esophagus. Am J Surg. 1981;141:216–218.
33. Mandard AM, Chasle J, Marnay J, et al. Autopsy findings in 111
cases of esophageal cancer. Cancer. 1981;48:329–335.
34. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy
and radiotherapy compared with radiotherapy alone in patients
with cancer of the esophagus. N Engl J Med. 1992;326:1593–1598.
35. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation
Therapy Oncology Group 94–05) phase III trial of combined-
modality therapy for esophageal cancer: high-dose versus standard-
dose radiation therapy. J Clin Oncol. 2002;20:1167–1174.
36. Gao XS, Qiao X, Wu F, et al. Pathological analysis of clinical target
volume margin for radiotherapy in patients with esophageal and
gastroesophageal junction carcinoma. Int J Radiat Oncol Biol Phys.
2007;67:389–396.
37. Oppedijk V, van der Gaast A, van Lanschot JJ, et al. Patterns of
recurrence after surgery alone versus preoperative
chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol.
2014; 32:385–391.
38. Huang W, Li B, Gong H, et al. Pattern of lymph node metastases and
its implication in radiotherapeutic clinical target volume in patients
with thoracic esophageal squamous cell carcinoma: A report of 1077
cases. Radiother Oncol. 2010;95:229–233.
39. Akiyama H, Tsurumaru M, Udagawa H, et al. Radical lymph node
dissection for cancer of the thoracic esophagus. Ann Surg.
1994;220:364–372; discussion 72–73.
40. Meier I, Merkel S, Papadopoulos T, et al. Adenocarcinoma of the
esophagogastric junction: the pattern of metastatic lymph node
dissemination as a rationale for elective lymphatic target volume
definition. Int J Radiat Oncol Biol Phys. 2008;70:1408–1417.
41. Yu E, Dar R, Rodrigues GB, et al. Is extended volume external beam
radiation therapy covering the anastomotic site beneficial in post-
esophagectomy high risk patients? Radiother Oncol. 2004;73:141–
148.
42. Tucker SL, Liu HH, Wang S, et al. Dose-volume modeling of the risk
of postoperative pulmonary complications among esophageal cancer
patients treated with concurrent chemoradiotherapy followed by
surgery. Int J Radiat Oncol Biol Phys. 2006;66:754–761.
43. Wang SL, Liao Z, Vaporciyan AA, et al. Investigation of clinical and
dosimetric factors associated with postoperative pulmonary
complications in esophageal cancer patients treated with concurrent
chemoradiotherapy followed by surgery. Int J Radiat Oncol Biol Phys.
2006;64:692–699.
44. Chandra A, Guerrero TM, Liu HH, et al. Feasibility of using
intensity-modulated radiotherapy to improve lung sparing in
treatment planning for distal esophageal cancer. Radiother Oncol
2005;77:247–253.
45. Mayo CS, Urie MM, Fitzgerald TJ, et al. Hybrid IMRT for treatment
of cancers of the lung and esophagus. Int J Radiat Oncol Biol Phys.
2008;71:1408–1418.
46. Chen YJ, Liu A, Han C, et al. Helical tomotherapy for radiotherapy
in esophageal cancer: a preferred plan with better conformal target
coverage and more homogeneous dose distribution. Med Dosim.
2007;32:166–171.
47. Hsu FM, Lee YC, Lee JM, et al. Association of clinical and
dosimetric factors with postoperative pulmonary complications in
esophageal cancer patients receiving intensity-modulated radiation
therapy and concurrent chemotherapy followed by thoracic
esophagectomy. Ann Surg Oncol. 2009;16:1669–1677.
48. Lin SH, Wang L, Myles B, et al. Propensity score-based comparison
of long-term outcomes with 3-dimensional conformal radiotherapy
vs intensity-modulated radiotherapy for esophageal cancer. Int J
Radiat Oncol Biol Phys. 2012;84:1078–1085.
49. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus
chemoradiotherapy followed by surgery for resectable cancer of the
oesophagus: a randomised controlled phase III trial. Lancet Oncol.
2005;6:659–668.
50. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy
followed by surgery compared with surgery alone in squamous-cell
cancer of the esophagus. N Engl J Med. 1997;337:161–167.
51. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of
trimodality therapy with cisplatin, fluorouracil, radiotherapy, and
surgery compared with surgery alone for esophageal cancer: CALGB
9781. J Clin Oncol. 2008;26:1086–1092.
52. Walsh TN, Noonan N, Hollywood D, et al. A comparison of
multimodal therapy and surgery for esophageal adenocarcinoma.
N Engl J Med. 1996;335:462–467.
53. Merkow RP, Bilimoria KY, Keswani RN, et al. Treatment trends, risk
of lymph node metastasis, and outcomes for localized esophageal
cancer. J Nat Cancer Inst. 2014;106:pii: dju133.
54. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA
Cancer J Clin. 2015;65(2):87–108.
55. Powell J, McConkey CC. Increasing incidence of adenocarcinoma of
the gastric cardia and adjacent sites. Br J Cancer. 1990;62:440–443.
56. Siewert JR, Stein HJ. Classification of adenocarcinoma of the
oesophagogastric junction. Br J Surg. 1998;85:1457–1459.
57. Yoshida S, Tanaka S, Kunihiro K, et al. Diagnostic ability of high-
frequency ultrasound probe sonography in staging early gastric
cancer, especially for submucosal invasion. Abdom Imaging.
2005;30:518–523.
58. Saito N, Takeshita K, Habu H, et al. The use of endoscopic
ultrasound in determining the depth of cancer invasion in patients
with gastric cancer. Surg Endosc. 1991;5:14–19.
59. Ganpathi IS, So JB, Ho KY. Endoscopic ultrasonography for gastric
cancer: does it influence treatment? Surg Endosc. 2006;20:559–562.
60. Kim SJ, Kim HH, Kim YH, et al. Peritoneal metastasis: detection
with 16- or 64-detector row CT in patients undergoing surgery for
gastric cancer. Radiology. 2009;253:407–415.
61. Chen J, Cheong JH, Yun MJ, et al. Improvement in preoperative
staging of gastric adenocarcinoma with positron emission
tomography. Cancer. 2005;103:2383–2390.
62. Smyth E, Schoder H, Strong VE, et al. A prospective evaluation of
the utility of 2-deoxy-2-[(18) F]fluoro-D-glucose positron emission
tomography and computed tomography in staging locally advanced
gastric cancer. Cancer. 2012;118:5481–5488.
63. Mukai K, Ishida Y, Okajima K, et al. Usefulness of preoperative
FDG-PET for detection of gastric cancer. Gastric Cancer. 2006;
9:192–196.
64. Kim SK, Kang KW, Lee JS, et al. Assessment of lymph node
metastases using 18F-FDG PET in patients with advanced gastric
cancer. Eur J Nucl Med Mol Imaging. 2006;33:148–155.
65. Stahl A, Ott K, Weber WA, et al. FDG PET imaging of locally
advanced gastric carcinomas: correlation with endoscopic and
histopathological findings. Eur J Nucl Med Mol Imaging.
2003;30:288–295.
66. Yoshioka T, Yamaguchi K, Kubota K, et al. Evaluation of 18F-FDG
PET in patients with advanced, metastatic, or recurrent gastric
cancer. J Nucl Med. 2003;44:690–699.
67. Sarela AI, Lefkowitz R, Brennan MF, et al. Selection of patients with
gastric adenocarcinoma for laparoscopic staging. Am J Surg.
2006;191:134–138.
68. Power DG, Schattner MA, Gerdes H, et al. Endoscopic ultrasound
can improve the selection for laparoscopy in patients with localized
gastric cancer. J Am Coll Surg. 2009;208:173–178.
69. Leake PA, Cardoso R, Seevaratnam R, et al. A systematic review of
the accuracy and indications for diagnostic laparoscopy prior to
curative-intent resection of gastric cancer. Gastric Cancer. 2012;
15(Suppl 1):S38–S47.
70. Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of
failure in a re-operation series (second or symptomatic look)
clinicopathologic correlation and implications for adjuvant therapy.
Int J Radiat Oncol Biol Phys. 1982;8:1–11.
71. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of
SWOG-directed intergroup study 0116: a phase III trial of adjuvant
radiochemotherapy versus observation after curative gastric cancer
resection. J Clin Oncol. 2012;30:2327–2333.
72. Hundahl SA, Macdonald JS, Benedetti J, et al. Surgical treatment
variation in a prospective, randomized trial of chemoradiotherapy
in gastric cancer: the effect of undertreatment. Ann Surg Oncol.
2002;9:278–286.
73. Kim S, Lim DH, Lee J, et al. An observational study suggesting
clinical benefit for adjuvant postoperative chemoradiation in a
population of over 500 cases after gastric resection with D2 nodal
dissection for adenocarcinoma of the stomach. Int J Radiat Oncol
Biol Phys. 2005;63:1279–1285.
74. Park SH, Sohn TS, Lee J, et al. Phase III trial to compare adjuvant
chemotherapy with capecitabine and cisplatin versus concurrent
chemoradiotherapy in gastric cancer: Final report of the adjuvant
chemoradiotherapy in stomach tumors trial, including survival and
subset analyses. J Clin Oncol. 2015;33(28):3130–3136.
75. Cunningham D, Allum WH, Stenning SP, et al. Perioperative
chemotherapy versus surgery alone for resectable gastroesophageal
cancer. N Engl J Med. 2006;355:11–20.
76. Xiong BH, Cheng Y, Ma L, et al. An updated meta-analysis of
randomized controlled trial assessing the effect of neoadjuvant
chemotherapy in advanced gastric cancer. Cancer Invest. 2014;
32:272–284.
77. Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative
chemoradiation in patients with localized gastric adenocarcinoma
(RTOG 9904): quality of combined modality therapy and pathologic
response. J Clin Oncol. 2006;24:3953–3958.
78. Moertel CG, Childs DS Jr., Reitemeier RJ, et al. Combined 5-
fluorouracil and supervoltage radiation therapy of locally
unresectable gastrointestinal cancer. Lancet. 1969;2:865–867.
79. A comparison of combination chemotherapy and combined
modality therapy for locally advanced gastric carcinoma.
Gastrointestinal Tumor Study Group. Cancer. 1982;49:1771–1777.
80. Yamashita H, Okuma K, Takahashi W, et al. Four-dimensional
measurement of the displacement of metal clips or postoperative
surgical staples during 320-multislice computed tomography
scanning of gastric cancer. Radiat Oncol. 2012;7:137.
81. Wang J, Lin SH, Dong L, et al. Quantifying the interfractional
displacement of the gastroesophageal junction during radiation
therapy for esophageal cancer. Int J Radiat Oncol Biol Phys.
2012;83:e273–e280.
82. Wo JY, Yoon SS, Guimaraes AR, et al. Gastric lymph node
contouring atlas: A tool to aid in clinical target volume definition in
3-dimensional treatment planning for gastric cancer. Pract Radiat
Oncol. 2013;3:e11–e19.
83. Smalley SR, Gunderson L, Tepper J, et al. Gastric surgical adjuvant
radiotherapy consensus report: rationale and treatment
implementation. Int J Radiat Oncol Biol Phys. 2002;52:283–293.
84. Leong T, Willis D, Joon DL, et al. 3D conformal radiotherapy for
gastric cancer–results of a comparative planning study. Radiother
Oncol. 2005;74:301–306.
85. Ringash J, Khaksart SJ, Oza A, et al. Post-operative
radiochemotherapy for gastric cancer: adoption and adaptation. Clin
Oncol. 2005;17:91–95.
86. Ringash J, Perkins G, Brierley J, et al. IMRT for adjuvant radiation
in gastric cancer: a preferred plan? Int J Radiat Oncol Biol Phys.
2005;63:732–738.
87. Dahele M, Skinner M, Schultz B, et al. Adjuvant radiotherapy for
gastric cancer: A dosimetric comparison of 3-dimensional conformal
radiotherapy, tomotherapy and conventional intensity modulated
radiotherapy treatment plans. Med Dosim. 2010;35:115–121.
88. Wieland P, Dobler B, Mai S, et al. IMRT for postoperative treatment
of gastric cancer: covering large target volumes in the upper
abdomen: a comparison of a step-and-shoot and an arc therapy
approach. Int J Radiat Oncol Biol Phys. 2004;59:1236–1244.
89. Trip AK, Nijkamp J, van Tinteren H, et al. IMRT limits
nephrotoxicity after chemoradiotherapy for gastric cancer. Radiother
Oncol. 2014;112:289–294.
90. Chakravarty T, Crane CH, Ajani JA, et al. Intensity-modulated
radiation therapy with concurrent chemotherapy as preoperative
treatment for localized gastric adenocarcinoma. Int J Radiat Oncol
Biol Phys. 2012;83:581–586.
91. Schwartz GK, Winter K, Minsky BD, et al. Randomized phase II trial
evaluating two paclitaxel and cisplatin-containing chemoradiation
regimens as adjuvant therapy in resected gastric cancer (RTOG-
0114). J Clin Oncol. 2009;27:1956–1962.
92. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a
randomized phase III trial comparing adjuvant chemotherapy with
S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol
2011;29:4387–4393.
93. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus
oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-
year follow-up of an open-label, randomised phase 3 trial. Lancet
Oncol. 2014;15:1389–1396.
94. NCCN Guidelines Pancreatic Adenocarcinoma (Version 1.2015).
Available at:
http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
Accessed February 24, 2015
95. Vargas R, Nino-Murcia M, Trueblood W, et al. MDCT in Pancreatic
adenocarcinoma: prediction of vascular invasion and resectability
using a multiphasic technique with curved planar reformations. AJR
Am J Roentgenol. 2004;182:419–425.
96. Zimny M. Diagnostic imaging of pancreatic cancer–the role of PET.
Front Radiat Ther Oncol. 2004;38:67–75.
97. Kauhanen SP, Komar G, Seppanen MP, et al. A prospective
diagnostic accuracy study of 18F-fluorodeoxyglucose positron
emission tomography/computed tomography, multidetector row
computed tomography, and magnetic resonance imaging in primary
diagnosis and staging of pancreatic cancer. Ann Surg. 2009;250:957–
963.
98. Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after
curative resection of pancreatic carcinoma. Cancer. 1990;66:56–61.
99. Tepper J, Nardi G, Sutt H. Carcinoma of the pancreas: review of
MGH experience from 1963 to 1973. Analysis of surgical failure and
implications for radiation therapy. Cancer. 1976;37:1519–1524.
100. Further evidence of effective adjuvant combined radiation and
chemotherapy following curative resection of pancreatic cancer.
Gastrointestinal Tumor Study Group. Cancer. 1987;59:2006–2010.
101. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of
chemoradiotherapy and chemotherapy after resection of pancreatic
cancer. N Eng J Med. 2004;350:1200–1210.
102. Smeenk HG, van Eijck CH, Hop WC, et al. Long-term survival and
metastatic pattern of pancreatic and periampullary cancer after
adjuvant chemoradiation or observation: long-term results of
EORTC trial 40891. Ann Surg. 2007;246:734–740.
103. Hsu CC, Herman JM, Corsini MM, et al. Adjuvant chemoradiation
for pancreatic adenocarcinoma: the Johns Hopkins Hospital-Mayo
Clinic collaborative study. Ann Surg Oncol. 2010;17:981–990.
104. Corsini MM, Miller RC, Haddock MG, et al. Adjuvant radiotherapy
and chemotherapy for pancreatic carcinoma: the Mayo Clinic
experience (1975–2005). J Clin Oncol. 2008;26:3511–3516.
105. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and
postoperative chemoradiation strategies in patients treated with
pancreaticoduodenectomy for adenocarcinoma of the pancreas. J
Clin Oncol. 1997;15:928–937.
106. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation
and pancreaticoduodenectomy for adenocarcinoma of the pancreas.
Arch Surg. 1992;127:1335–1339.
107. Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of
preoperative radiation therapy and chemotherapy for patients with
localized, resectable adenocarcinoma of the pancreas: an Eastern
Cooperative Oncology Group Study. J Clin Oncol. 1998;16:317–323.
108. Lowy AM, Lee JE, Pisters PW, et al. Prospective, randomized trial of
octreotide to prevent pancreatic fistula after
pancreaticoduodenectomy for malignant disease. Ann Surg.
1997;226:632–641.
109. Ujiki MB, Talamonti MS. Guidelines for the surgical management of
pancreatic adenocarcinoma. Semin Oncol. 2007;34:311–320.
110. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of
chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a
locally advanced pancreatic cancer (LAPC) controlled after 4
months of gemcitabine with or without erlotinib: Final results of the
international phase III LAP 07 study. ASCO Meeting Abstracts.
2013;31:LBA4003.
111. Klaassen DJ, MacIntyre JM, Catton GE, et al. Treatment of locally
unresectable cancer of the stomach and pancreas: a randomized
comparison of 5-fluorouracil alone with radiation plus concurrent
and maintenance 5-fluorouracil–an Eastern Cooperative Oncology
Group study. J Clin Oncol. 1985;3:373–378.
112. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally
unresectable pancreatic carcinoma: a randomized comparison of
high dose (6000 rads) radiation alone, moderate dose radiation
(4000 rads + 5-fluorouracil), and high dose radiation + 5-
fluorouracil: The Gastrointestinal Tumor Study Group. Cancer.
1981;48:1705–1710.
113. Treatment of locally unresectable carcinoma of the pancreas:
comparison of combined-modality therapy (chemotherapy plus
radiotherapy) to chemotherapy alone. J Natl Cancer Inst.
1988;80:751–755.
114. Loehrer PJ, Powell ME, Cardenes HR, et al. A randomized phase III
study of gemcitabine in combination with radiation therapy versus
gemcitabine alone in patients with localized, unresectable
pancreatic cancer: E4201. ASCO Meeting Abstracts. 2008;26:4506.
115. Shinchi H, Takao S, Noma H, et al. Length and quality of survival
after external-beam radiotherapy with concurrent continuous 5-
fluorouracil infusion for locally unresectable pancreatic cancer. Int J
Radiat Oncol Biol Phys. 2002;53:146–150.
116. Goodman KA, Regine WF, Dawson LA, et al. Radiation Therapy
Oncology Group consensus panel guidelines for the delineation of
the clinical target volume in the postoperative treatment of
pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012; 83:901–
908.
117. Brunner TB, Merkel S, Grabenbauer GG, et al. Definition of elective
lymphatic target volume in ductal carcinoma of the pancreatic head
based on histopathologic analysis. Int J Radiat Oncol Biol Phys.
2005;62:1021–1029.
118. Kao GD, Whittington R, Coia L. Anatomy of the celiac axis and
superior mesenteric artery and its significance in radiation therapy.
Int J Radiat Oncol Biol Phys. 1993;25:131–134.
119. Nagakawa T, Kobayashi H, Ueno K, et al. Clinical study of
lymphatic flow to the paraaortic lymph nodes in carcinoma of the
head of the pancreas. Cancer. 1994;73:1155–1162.
120. Kayahara M, Nagakawa T, Ohta T, et al. Analysis of paraaortic
lymph node involvement in pancreatic carcinoma: a significant
indication for surgery? Cancer. 1999;85:583–590.
121. Tokuuye K, Sumi M, Kagami Y, et al. Small-field radiotherapy in
combination with concomitant chemotherapy for locally advanced
pancreatic carcinoma. Radiother Oncol. 2003;67:327–330.
122. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy
for unresectable adenocarcinoma of the pancreas. Cancer.
2009;115:665–672.
123. Moningi S, Dholakia AS, Raman SP, et al. The role of stereotactic
body radiation therapy for pancreatic cancer: a single-institution
experience. Ann Surg Oncol. 2015;22(7):2352–2358.
124. Dholakia AS, Chang DT, Goodman KA, et al. A phase 2 multicenter
study to evaluate gemcitabine and fractionated stereotactic body
radiation therapy for locally advanced pancreatic adenocarcinoma.
Int J Radiat Oncol Biol Phys. 2013;87:S28.
125. 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;86:516–522.
126. Seo Y, Kim MS, Yoo S, et al. Stereotactic body radiation therapy
boost in locally advanced pancreatic cancer. Int J Radiat Oncol Biol
Phys. 2009;75:1456–1461.
127. Bussels B, Goethals L, Feron M, et al. Respiration-induced
movement of the upper abdominal organs: a pitfall for the three-
dimensional conformal radiation treatment of pancreatic cancer.
Radiother Oncol. 2003;68:69–74.
128. Feng M, Balter JM, Normolle D, et al. Characterization of
pancreatic tumor motion using cine MRI: surrogates for tumor
position should be used with caution. Int J Radiat Oncol Biol Phys.
2009;74:884–891.
129. Jayachandran P, Minn AY, Van Dam J, et al. Interfractional
uncertainty in the treatment of pancreatic cancer with radiation. Int
J Radiat Oncol Biol Phys. 2010;76:603–607.
130. Higgins PD, Sohn JW, Fine RM, et al. Three-dimensional conformal
pancreas treatment: comparison of four- to six-field techniques. Int J
Radiat Oncol Biol Phys. 1995;31:605–609.
131. Ben-Josef E, Shields AF, Vaishampayan U, et al. Intensity-
modulated radiotherapy (IMRT) and concurrent capecitabine for
pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;59:454–459.
132. Milano MT, Chmura SJ, Garofalo MC, et al. Intensity-modulated
radiotherapy in treatment of pancreatic and bile duct malignancies:
toxicity and clinical outcome. Int J Radiat Oncol Biol Phys.
2004;59:445–453.
133. van der Geld YG, van Triest B, Verbakel WF, et al. Evaluation of
four-dimensional computed tomography-based intensity-modulated
and respiratory-gated radiotherapy techniques for pancreatic
carcinoma. Int J Radiat Oncol Biol Phys. 2008;72:1215–1220.
134. Brown MW, Ning H, Arora B, et al. A dosimetric analysis of dose
escalation using two intensity-modulated radiation therapy
techniques in locally advanced pancreatic carcinoma. Int J Radiat
Oncol Biol Phys. 2006;65:274–283.
135. Fuss M, Wong A, Fuller CD, et al. Image-guided intensity-modulated
radiotherapy for pancreatic carcinoma. Gastrointest Cancer Res.
2007;1:2–11.
136. 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 2015;121(7):1128–1137.
137. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus
gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;
364:1817–1825.
138. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in
pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J
Med. 2013;369:1691–1703.
139. Faris JE, Blaszkowsky LS, McDermott S, et al. FOLFIRINOX in
locally advanced pancreatic cancer: the Massachusetts General
Hospital Cancer Center experience. Oncologist. 2013;18:543–548.
140. Boone BA, Steve J, Krasinskas AM, et al. Outcomes with
FOLFIRINOX for borderline resectable and locally unresectable
pancreatic cancer. J Surg Oncol. 2013;108:236–241.
141. Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and
surgical implications of neoadjuvant treatment with FOLFIRINOX
for locally advanced and borderline resectable pancreatic cancer.
Ann Surg. 2015;261:12–17.
142. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with
capecitabine versus fluorouracil for locally advanced rectal cancer: a
randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol.
2012;13:579–588.
143. Meta-analysis Group In Cancer, Piedbois P, Rougier P, et al.
Efficacy of intravenous continuous infusion of fluorouracil
compared with bolus administration in advanced colorectal cancer.
J Clin Oncol. 1998;16:301–308.
144. Li CP, Chao Y, Chi KH, et al. Concurrent chemoradiotherapy
treatment of locally advanced pancreatic cancer: gemcitabine versus
5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol
Phys. 2003;57:98–104.
145. Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or
capecitabine-based chemoradiotherapy for locally advanced
pancreatic cancer (SCALOP): a multicentre, randomised, phase
2 trial. Lancet Oncol. 2013;14:317–326.
146. Crane CH, Wolff RA, Abbruzzese JL, et al. Combining gemcitabine
with radiation in pancreatic cancer: understanding important
variables influencing the therapeutic index. Semin Oncol.
2001;28:25–33.
147. Kim NK, Kim MJ, Yun SH, et al. Comparative study of transrectal
ultrasonography, pelvic computerized tomography, and magnetic
resonance imaging in preoperative staging of rectal cancer. Dis
Colon Rectum. 1999;42:770–775.
148. MERCURY Study Group. Diagnostic accuracy of preoperative
magnetic resonance imaging in predicting curative resection of
rectal cancer: prospective observational study. BMJ. 2006;
333(7572):779.
149. MERCURY Study Group. Extramural depth of tumor invasion at
thin-section MR in patients with rectal cancer: results of the
MERCURY study. Radiology. 2007;243:132–139.
150. Calvo FA, Domper M, Matute R, et al. 18F-FDG positron emission
tomography staging and restaging in rectal cancer treated with
preoperative chemoradiation. Int J Radiat Oncol Biol Phys.
2004;58:528–535.
151. Prolongation of the disease-free interval in surgically treated rectal
carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med.
1985;312:1465–1472.
152. Douglass HO Jr., Moertel CG, Mayer RJ, et al. Survival after
postoperative combination treatment of rectal cancer. N Engl J Med.
1986;315:1294–1295.
153. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical
adjuvant therapy for high-risk rectal carcinoma. N Engl J Med.
1991;324:709–715.
154. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus
postoperative chemoradiotherapy for rectal cancer. N Engl J Med.
2004;351:1731–1740.
155. Sauer R, Liersch T, Merkel S, et al. Preoperative versus
postoperative chemoradiotherapy for locally advanced rectal cancer:
results of the German CAO/ARO/AIO-94 randomized phase III trial
after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926–
1933.
156. van Gijn W, Marijnen CAM, Nagtegaal ID, et al. Preoperative
radiotherapy combined with total mesorectal excision for resectable
rectal cancer: 12-year follow-up of the multicentre, randomised
controlled TME trial. Lancet Oncol. 2011;12:575–582.
157. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term
results of a randomized trial comparing preoperative short-course
radiotherapy with preoperative conventionally fractionated
chemoradiation for rectal cancer. Br J Surg. 2006;93:1215–1223.
158. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-
course radiotherapy versus long-course chemoradiation comparing
rates of local recurrence in patients with T3 rectal cancer: Trans-
Tasman Radiation Oncology Group trial 01.04. J Clin Oncol
2012;30:3827–333.
159. Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III
study comparing preoperative radiotherapy with chemoradiotherapy
in nonresectable rectal cancer. J Clin Oncol. 2008;26:3687–3694.
160. Willett CG, Tepper JE, Skates SJ, et al. Adjuvant postoperative
radiation therapy for colonic carcinoma. Ann Surg. 1987;206:694–
698.
161. Willett CG, Goldberg S, Shellito PC, et al. Does postoperative
irradiation play a role in the adjuvant therapy of stage T4 colon
cancer? Cancer J Sci Am. 1999;5:242–247.
162. Martenson JA Jr., Willett CG, Sargent DJ, et al. Phase III study of
adjuvant chemotherapy and radiation therapy compared with
chemotherapy alone in the surgical adjuvant treatment of colon
cancer: results of intergroup protocol 0130. J Clin Oncol.
2004;22:3277–3283.
163. Baglan KL, Frazier RC, Yan D, et al. The dose-volume relationship
of acute small bowel toxicity from concurrent 5-FU-based
chemotherapy and radiation therapy for rectal cancer. Int J Radiat
Oncol Biol Phys. 2002;52:176–183.
164. Robertson JM, Lockman D, Yan D, et al. The dose-volume
relationship of small bowel irradiation and acute grade 3 diarrhea
during chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol
Phys. 2008;70:413–418.
165. Tho LM, Glegg M, Paterson J, et al. Acute small bowel toxicity and
preoperative chemoradiotherapy for rectal cancer: investigating
dose-volume relationships and role for inverse planning. Int J Radiat
Oncol Biol Phys. 2006;66:505–513.
166. Gallagher MJ, Brereton HD, Rostock RA, et al. A prospective study
of treatment techniques to minimize the volume of pelvic small
bowel with reduction of acute and late effects associated with pelvic
irradiation. Int J Radiat Oncol Biol Phys. 1986;12:1565–1573.
167. Martin J, Fitzpatrick K, Horan G, et al. Treatment with a belly-
board device significantly reduces the volume of small bowel
irradiated and results in low acute toxicity in adjuvant radiotherapy
for gynecologic cancer: results of a prospective study. Radiother
Oncol. 2005;74:267–274.
168. Olofsen-van Acht M, van den Berg H, Quint S, et al. Reduction of
irradiated small bowel volume and accurate patient positioning by
use of a bellyboard device in pelvic radiotherapy of gynecological
cancer patients. Radiother Oncol. 2001;59:87–93.
169. Pinkawa M, Gagel B, Demirel C, et al. Dose-volume histogram
evaluation of prone and supine patient position in external beam
radiotherapy for cervical and endometrial cancer. Radiother Oncol.
2003;69:99–105.
170. Kim TH, Chie EK, Kim DY, et al. Comparison of the belly board
device method and the distended bladder method for reducing
irradiated small bowel volumes in preoperative radiotherapy of
rectal cancer patients. Int J Radiat Oncol Biol Phys. 2005;62:769–
775.
171. Moossa AR, Ree PC, Marks JE, et al. Factors influencing local
recurrence after abdominoperineal resection for cancer of the
rectum and rectosigmoid. Br J Surg. 1975;62:727–730.
172. Roberson SH, Heron HC, Kerman HD, et al. Is anterior resection of
the rectosigmoid safe after preoperative radiation? Dis Colon Rectum.
1985;28:254–259.
173. Ciatto S, Pacini P. Radiation therapy of recurrences of carcinoma of
the rectum and sigmoid after surgery. Acta Radiol Oncol.
1982;21:105–109.
174. Schild SE, Martenson JA Jr, Gunderson LL, et al. Postoperative
adjuvant therapy of rectal cancer: an analysis of disease control,
survival, and prognostic factors. Int J Radiat Oncol Biol Phys.
1989;17:55–62.
175. Bassi MC, Turri L, Sacchetti G, et al. FDG-PET/CT imaging for
staging and target volume delineation in preoperative conformal
radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys.
2008;70:1423–1426.
176. Anderson C, Koshy M, Staley C, et al. PET-CT fusion in radiation
management of patients with anorectal tumors. Int J Radiat Oncol
Biol Phys. 2007;69:155–162.
177. Hruby G, Barton M, Miles S, et al. Sites of local recurrence after
surgery, with or without chemotherapy, for rectal cancer:
implications for radiotherapy field design. Int J Radiat Oncol Biol
Phys. 2003;55:138–143.
178. Syk E, Torkzad MR, Blomqvist L, et al. Local recurrence in rectal
cancer: anatomic localization and effect on radiation target. Int J
Radiat Oncol Biol Phys. 2008;72:658–664.
179. Yu TK, Bhosale PR, Crane CH, et al. Patterns of locoregional
recurrence after surgery and radiotherapy or chemoradiation for
rectal cancer. Int J Radiat Oncol Biol Phys. 2008;71:1175–1180.
180. Chao KS, Lin M. Lymphangiogram-assisted lymph node target
delineation for patients with gynecologic malignancies. Int J Radiat
Oncol Biol Phys. 2002;54:1147–1152.
181. Myerson R, Drzymala R. Technical aspects of image-based
treatment planning of rectal carcinoma. Semin Radiat Oncol. 2003;
13:433–440.
182. Roels S, Duthoy W, Haustermans K, et al. Definition and delineation
of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol
Phys. 2006;65:1129–1142.
183. Sanfilippo NJ, Crane CH, Skibber J, et al. T4 rectal cancer treated
with preoperative chemoradiation to the posterior pelvis followed
by multivisceral resection: patterns of failure and limitations of
treatment. Int J Radiat Oncol Biol Phys. 2001;51:176–183.
184. Taylor N, Crane C, Skibber J, et al. Elective groin irradiation is not
indicated for patients with adenocarcinoma of the rectum extending
to the anal canal. Int J Radiat Oncol Biol Phys. 2001;51:741–747.
185. Robertson JM, Campbell JP, Yan D. Generic planning target margin
for rectal cancer treatment setup variation. Int J Radiat Oncol Biol
Phys. 2009;74:1470–1475.
186. Tournel K, De Ridder M, Engels B, et al. Assessment of
intrafractional movement and internal motion in radiotherapy of
rectal cancer using megavoltage computed tomography. Int J Radiat
Oncol Biol Phys. 2008;71:934–939.
187. Grigsby PW, Roberts HL, Perez CA. Femoral neck fracture following
groin irradiation. Int J Radiat Oncol Biol Phys. 1995;32:63–67.
188. Brizel HE, Tepperman BS. Postoperative adjuvant irradiation for
adenocarcinoma of the rectum and sigmoid. Am J Clin Oncol.
1984;7:679–685.
189. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant
therapy for rectal cancer by combining protracted-infusion
fluorouracil with radiation therapy after curative surgery. N Engl J
Med. 1994;331:502–507.
190. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative
radiotherapy combined with total mesorectal excision for resectable
rectal cancer. N Engl J Med. 2001;345:638–646.
191. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative
multimodality therapy improves disease-free survival in patients
with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;
27:5124–5130.
192. Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target
volumes for conformal therapy in anorectal cancer: a radiation
therapy oncology group consensus panel contouring atlas. Int J
Radiat Oncol Biol Phys. 2009;74:824–830.
193. Nuyttens JJ, Robertson JM, Yan D, et al. The variability of the
clinical target volume for rectal cancer due to internal organ motion
during adjuvant treatment. Int J Radiat Oncol Biol Phys.
2002;53:497–503.
194. Engels B, De Ridder M, Tournel K, et al. Preoperative helical
tomotherapy and megavoltage computed tomography for rectal
cancer: impact on the irradiated volume of small bowel. Int J Radiat
Oncol Biol Phys. 2009;74:1476–1480.
195. Guerrero Urbano MT, Henrys AJ, Adams EJ, et al. Intensity-
modulated radiotherapy in patients with locally advanced rectal
cancer reduces volume of bowel treated to high dose levels. Int J
Radiat Oncol Biol Phys. 2006;65:907–916.
196. Duthoy W, De Gersem W, Vergote K, et al. Clinical implementation
of intensity-modulated arc therapy (IMAT) for rectal cancer. Int J
Radiat Oncol Biol Phys. 2004;60:794–806.
197. Mok H, Crane CH, Palmer MB, et al. Intensity modulated radiation
therapy (IMRT): differences in target volumes and improvement in
clinically relevant doses to small bowel in rectal carcinoma. Radiat
Oncol. 2011;6:63.
198. De Ridder M, Tournel K, Van Nieuwenhove Y, et al. Phase II study
of preoperative helical tomotherapy for rectal cancer. Int J Radiat
Oncol Biol Phys. 2008;70:728–734.
199. Freedman GM, Meropol NJ, Sigurdson ER, et al. Phase I trial of
preoperative hypofractionated intensity-modulated radiotherapy
with incorporated boost and oral capecitabine in locally advanced
rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67:1389–1393.
200. Aristu JJ, Arbea L, Rodriguez J, et al. Phase I-II trial of concurrent
capecitabine and oxaliplatin with preoperative intensity-modulated
radiotherapy in patients with locally advanced rectal cancer. Int J
Radiat Oncol Biol Phys. 2008;71:748–755.
201. Samuelian JM, Callister MD, Ashman JB, et al. Reduced acute
bowel toxicity in patients treated with intensity-modulated
radiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2012;
82:1981–1987.
202. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of
fluorouracil-based chemotherapy regimens plus radiotherapy in
postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol.
2006;24:3542–3547.
203. Hofheinz R-D, Wenz F, Post S, et al. Chemoradiotherapy with
capecitabine versus fluorouracil for locally advanced rectal cancer: a
randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol
2012;13:579–588.
204. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and
oxaliplatin in the preoperative multimodality treatment of rectal
cancer: surgical end points from national surgical adjuvant breast
and Bowel Project Trial R-04. J Clin Oncol. 2014;32(18):1927–1934.
205. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to
preoperative chemoradiation with or without oxaliplatin in locally
advanced rectal cancer: pathologic results of the STAR-01
randomized phase III trial. J Clin Oncol. 2011;29:2773–2780.
206. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Clinical outcome of
the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer.
J Clin Oncol 2012;30:4558–4565.
207. Klotz R, Pamukcoglu T, Souilliard D. Transitional cloacogenic
carcinoma of the anal canal. Clinicopathologic study of three
hundred seventy-three cases. Cancer 1967;20:1727–1745.
208. Frost D, Richards P, Montague E, Giacco G, et al. Epidermoid
cancer of the anorectum. Cancer 1984;53:1285–1293.
209. Nigro N, Vaitkevicius V, Considine B. Combined therapy for cancer
of the anal canal: a preliminary report. Dis Colon Rectum.
1974;17:354–356.
210. Epidermoid anal cancer: results from the UKCCCR randomised trial
of radiotherapy alone versus radiotherapy, 5-fluorouracil, and
mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-
ordinating Committee on Cancer Research. Lancet. 1996;348:1049–
1054.
211. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant
radiotherapy and chemotherapy is superior to radiotherapy alone in
the treatment of locally advanced anal cancer: results of a phase III
randomized trial of the European Organization for Research and
Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative
Groups. J Clin Oncol. 1997;15:2040–2049.
212. Flam M, John M, Pajak T, et al. Role of mitomycin in combination
with fluorouracil and radiotherapy, and of salvage chemoradiation
in the definitive nonsurgical treatment of epidermoid carcinoma of
the anal canal: results of a phase III randomized intergroup study. J
Clin Oncol. 1996;14:2527–2539.
213. Ajani J, Winter K, Gunderson L, et al. Fluorouracil, mitomycin, and
radiotherapy vs fluorouracil, cisplatin, and radiotherapy for
carcinoma of the anal canal: a randomized controlled trial. JAMA.
2008;299:1914–1921.
214. James R, Glynne-Jones R, Meadows H, et al. Mitomycin or cisplatin
chemoradiation with or without maintenance chemotherapy for
treatment of squamous-cell carcinoma of the anus (ACT II): a
randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol.
2013;14:516–524.
215. Peiffert D, Tournier-Rangeard L, Gérard J-P, et al. Induction
chemotherapy and dose intensification of the radiation boost in
locally advanced anal canal carcinoma: final analysis of the
randomized UNICANCER ACCORD 03 trial. J Clin Oncol.
2012;30:1941–1948.
216. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics
Review 1975–2010. National Cancer Institute; Bethesda, MD.
217. Hoppe R, Phillips TL, Roach M. Leibel and Phillips Textbook of
Radiation Oncology: Expert Consult: Elsevier Health Sciences; 2010.
218. Winton E, Heriot A, Ng M, et al. The impact of 18-
fluorodeoxyglucose positron emission tomography on the staging,
management and outcome of anal cancer. Br J Cancer.
2009;100:693–700.
219. Cotter S, Grigsby P, Siegel B, et al. FDG-PET/CT in the evaluation
of anal carcinoma. Int J Radiat Oncol Biol Phys. 2006;65:720–725.
220. Trautmann T, Zuger J. Positron Emission Tomography for
pretreatment staging and posttreatment evaluation in cancer of the
anal canal. Mol Imaging Biol. 2005;7:309–313.
221. Nguyen B, Joon D, Khoo V, et al. Assessing the impact of FDG-PET
in the management of anal cancer. Radiother Oncol. 2008;87:376–
82.
222. Krengli M, Milia M, Turri L, et al. FDG-PET/CT imaging for staging
and target volume delineation in conformal radiotherapy of anal
carcinoma. Radiat Oncol. 2010;5:10.
223. Jones D. ICRU Report 50—prescribing, recording and reporting
photon beam therapy. Med Phys. 1994;21:833–834.
224. Ortholan C, Resbeut M, Hannoun-Levi J-M, et al. Anal canal cancer:
management of inguinal nodes and benefit of prophylactic inguinal
irradiation (CORS-03 Study). Int J Radiat Oncol Biol Phys.
2012;82:1988–1995.
225. Godlewski G, Prudhomme M. Embryology and anatomy of the
anorectum. Basis of surgery. Surg Clin North Am. 2000;80:319–343.
226. Ng M, Leong T, Chander S, et al. Australasian Gastrointestinal Trials
Group (AGITG) contouring atlas and planning guidelines for
intensity-modulated radiotherapy in anal cancer. Int J Radiat Oncol
Biol Phys. 2012;83:1455–1462.
227. Gay H, Barthold H, O’Meara E, et al. Pelvic normal tissue
contouring guidelines for radiation therapy: a Radiation Therapy
Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys.
2012;83:e353–e362.
228. Myerson R, Garofalo M, El Naqa I, et al. Elective clinical target
volumes for conformal therapy in anorectal cancer: a radiation
therapy oncology group consensus panel contouring atlas. Int J
Radiat Oncol Biol Phys. 2009;74:824–830.
229. Pepek J, Willett C, Wu Q, et al. Intensity-modulated radiation
therapy for anal malignancies: a preliminary toxicity and disease
outcomes analysis. Int J Radiat Oncol Biol Phys. 2010;78:1413–1419.
230. Bazan J, Hara W, Hsu A, et al. Intensity-modulated radiation
therapy versus conventional radiation therapy for squamous cell
carcinoma of the anal canal. Cancer. 2011;117:3342–3351.
231. Brooks C, Lee Y, Aitken K, et al. Organ-sparing Intensity-modulated
radiotherapy for anal cancer using the ACTII schedule: a comparison
of conventional and intensity-modulated radiotherapy plans. Clin
Oncol (R Coll Radiol). 2013;25:155–161.
232. Kachnic L, Winter K, Myerson R, et al. RTOG 0529: a phase 2
evaluation of dose-painted intensity modulated radiation therapy in
combination with 5-fluorouracil and mitomycin-C for the reduction
of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol
Biol Phys. 2013;86:27–33.
233. Milano M, Jani A, Farrey K, et al. Intensity-modulated radiation
therapy (IMRT) in the treatment of anal cancer: toxicity and clinical
outcome. Int J Radiat Oncol Biol Phys. 2005;63:354–361.
234. Kachnic L, Tsai H, Coen J, et al. Dose-painted intensity-modulated
radiation therapy for anal cancer: a multi-institutional report of
acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys.
2012;82:153–158.
235. DeFoe S, Beriwal S, Jones H, et al. Concurrent chemotherapy and
intensity-modulated radiation therapy for anal carcinoma–clinical
outcomes in a large National Cancer Institute-designated integrated
cancer centre network. Clin Oncol (R Coll Radiol). 2012;24:424–431.
236. Vieillot S, Fenoglietto P, Lemanski C, et al. IMRT for locally
advanced anal cancer: clinical experience of the Montpellier Cancer
Center. Radiat Oncol. 2012;7:45.
237. Dasgupta T, Rothenstein D, Chou J, et al. Intensity-modulated
radiotherapy vs. conventional radiotherapy in the treatment of anal
squamous cell carcinoma: a propensity score analysis. Radiother
Oncol. 2013;107:189–194.
238. Mitchell M, Abboud M, Eng C, et al. Intensity-modulated radiation
therapy with concurrent chemotherapy for anal cancer: outcomes
and toxicity. Am J Clin Oncol. 2014;37(5):461–466.
239. Devisetty K, Mell L, Salama J, et al. A multi-institutional acute
gastrointestinal toxicity analysis of anal cancer patients treated with
concurrent intensity-modulated radiation therapy (IMRT) and
chemotherapy. Radiother Oncol. 2009;93:298–301.
240. DeFoe S, Kabolizadeh P, Heron D, et al. Dosimetric parameters
predictive of acute gastrointestinal toxicity in patients with anal
carcinoma treated with concurrent chemotherapy and intensity-
modulated radiation therapy. Oncology. 2013;85:1–7.
241. 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.
242. Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume
effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys.
2010;76:S101–S107.
243. Viswanathan AN, Yorke ED, Marks LB, et al. Radiation dose-volume
effects of the urinary bladder. Int J Radiat Oncol Biol Phys.
2010;76:S116–S122.
244. Marks LB, Carroll PR, Dugan TC, et al. The response of the urinary
bladder, urethra, and ureter to radiation and chemotherapy. Int J
Radiat Oncol Biol Phys. 1995;31:1257–1280.
245. Baxter NN, Habermann EB, Tepper JE, et al. Risk of pelvic fractures
in older women following pelvic irradiation. JAMA. 2005;294:2587–
2593.
246. Bedford JL, Khoo VS, Webb S, et al. Optimization of coplanar six-
field techniques for conformal radiotherapy of the prostate. Int J
Radiat Oncol Biol Phys. 2000;46:231–238.
247. Bentzen AG, Balteskard L, Wanderas EH, et al. Impaired health-
related quality of life after chemoradiotherapy for anal cancer: late
effects in a national cohort of 128 survivors. Acta Oncol.
2013;52:736–744.
248. Das P, Cantor SB, Parker CL, et al. Long-term quality of life after
radiotherapy for the treatment of anal cancer. Cancer.
2010;116:822–829.
249. John M, Pajak T, Flam M, et al. Dose escalation in chemoradiation
for anal cancer: preliminary results of RTOG 92–08. Cancer J Sci
Am. 1996;2:205–211.
250. Weber DC, Kurtz JM, Allal AS. The impact of gap duration on local
control in anal canal carcinoma treated by split-course radiotherapy
and concomitant chemotherapy. Int J Radiat Oncol Biol Phys.
2001;50:675–680.
251. Rich TA, Ajani JA, Morrison WH, et al. Chemoradiation therapy for
anal cancer: radiation plus continuous infusion of 5-fluorouracil
with or without cisplatin. Radiother Oncol. 1993;27:209–215.
252. Hu K, Minsky BD, Cohen AM, et al. 30 Gy may be an adequate dose
in patients with anal cancer treated with excisional biopsy followed
by combined-modality therapy. J Surg Oncol. 1999;70:71–77.
253. Hatfield P, Cooper R, Sebag-Montefiore D. Involved-field, low-dose
chemoradiotherapy for early-stage anal carcinoma. Int J Radiat
Oncol Biol Phys. 2008;70:419–424.
254. Ferrigno R, Nakamura RA, Dos Santos Novaes PE, et al.
Radiochemotherapy in the conservative treatment of anal canal
carcinoma: retrospective analysis of results and radiation dose
effectiveness. Int J Radiat Oncol Biol Phys. 2005;61:1136–1142.
255. Constantinou EC, Daly W, Fung CY, et al. Time-dose considerations
in the treatment of anal cancer. Int J Radiat Oncol Biol Phys.
1997;39:651–657.
256. Salama JK, Mell LK, Schomas DA, et al. Concurrent chemotherapy
and intensity-modulated radiation therapy for anal canal cancer
patients: a multicenter experience. J Clin Oncol. 2007;25:4581–
4586.
257. Brown PD, Kline RW, Petersen IA, et al. Irradiation of the inguinal
lymph nodes in patients of differing body habitus: a comparison of
techniques and resulting normal tissue complication probabilities.
Med Dosim. 2004;29:217–222.
258. Watson BA, Tatro DS, Ten Haken RK, et al. Use of segmental boost
fields in the irradiation of inguinal lymphatic nodes. Med Dosim.
1999;24:27–32.
259. Dittmer PH, Randall ME. A technique for inguinal node boost using
photon fields defined by asymmetric collimator jaws. Radiother
Oncol. 2001;59:61–64.
260. Hung A, Crane C, Delclos M, et al. Cisplatin-based combined
modality therapy for anal carcinoma: a wider therapeutic index.
Cancer. 2003;97:1195–1202.
261. Gerard JP, Ayzac L, Hun D, et al. Treatment of anal canal
carcinoma with high dose radiation therapy and concomitant
fluorouracil-cisplatinum. Long-term results in 95 patients. Radiother
Oncol. 1998;46:249–256.
262. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US
GI intergroup RTOG 98–11 phase III trial for anal carcinoma:
survival, relapse, and colostomy failure with concurrent
chemoradiation involving fluorouracil/mitomycin versus
fluorouracil/cisplatin. J Clin Oncol. 2012;30:4344–4351.
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
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,
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.
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
(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.
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
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
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.
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).
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
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
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.
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.
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
Phys. 2008;71:428–434.
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
Radiat Oncol Biol Phys. 2011;79:348–355.
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
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
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.
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.
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
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
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,
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.
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
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.
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
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
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).
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.
Interstitial Brachytherapy
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).
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.
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.
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
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
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
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
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
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.
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
and sexuality in women with a history of cervical cancer. N Engl J
Med. 1999;340(18):1383–1389.
7. Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic
radiation therapy versus no further therapy in selected patients with
stage IB carcinoma of the cervix after radical hysterectomy and
pelvic lymphadenectomy: a Gynecologic Oncology Group Study.
Gynecol Oncol. 1999;73(2):177–183.
8. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent
chemotherapy and pelvic radiation therapy compared with pelvic
radiation therapy alone as adjuvant therapy after radical surgery in
high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;
18(8):1606–1613.
9. Rose PG, Ali S, Watkins E, et al. Long-term follow-up of a
randomized trial comparing concurrent single agent cisplatin,
cisplatin-based combination chemotherapy, or hydroxyurea during
pelvic irradiation for locally advanced cervical cancer: a Gynecologic
Oncology Group Study. J Clin Oncol. 2007;25(19):2804–2810.
10. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of
fluorouracil plus cisplatin versus hydroxyurea as an adjunct to
radiation therapy in stage IIB-IVA carcinoma of the cervix with
negative para-aortic lymph nodes: a Gynecologic Oncology Group
and Southwest Oncology Group study. J Clin Oncol.
1999;17(5):1339–1348.
11. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent
chemotherapy compared with pelvic and para-aortic radiation for
high-risk cervical cancer. N Engl J Med. 1999;340(15):1137–1143.
12. Ungar L, Palfalvi L, Novak Z. Primary pelvic exenteration in cervical
cancer patients. Gynecol Oncol. 2008;111(2 Suppl):S9–S12.
13. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and
adjuvant hysterectomy compared with radiation and adjuvant
hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med.
1999;340(15):1154–1161.
14. Keys HM, Bundy BN, Stehman FB, Okagaki T, et al. Radiation
therapy with and without extrafascial hysterectomy for bulky stage
IB cervical carcinoma: a randomized trial of the Gynecologic
Oncology Group. Gynecol Oncol. 2003;89(3):343–353.
15. Rotman M, Pajak TF, Choi K, et al. Prophylactic extended-field
irradiation of para-aortic lymph nodes in stages IIB and bulky IB
and IIA cervical carcinomas. Ten-year treatment results of RTOG
79–20. JAMA. 1995;274(5):387–393.
16. Kinsella TJ, Bloomer WD, Lavin PT, et al. Stage II endometrial
carcinoma: 10-year follow-up of combined radiation and surgical
treatment. Gynecol Oncol. 1980;10(3):290–297.
17. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic
lymphadenectomy vs. no lymphadenectomy in early-stage
endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst.
2008;100(23):1707–1716.
18. group As, Kitchener H, Swart AM, et al. Efficacy of systematic pelvic
lymphadenectomy in endometrial cancer (MRC ASTEC trial): a
randomised study. Lancet. 2009;373(9658):125–136.
19. Phelan C, Montag AG, Rotmensch J, et al. Outcome and
management of pathological stage I endometrial carcinoma patients
with involvement of the lower uterine segment. Gynecol Oncol.
2001;83(3):513–517.
20. Aalders J, Abeler V, Kolstad P, et al. Postoperative external
irradiation and prognostic parameters in stage I endometrial
carcinoma: clinical and histopathologic study of 540 patients. Obstet
Gynecol. 1980;56(4):419–427.
21. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and
postoperative radiotherapy versus surgery alone for patients with
stage-1 endometrial carcinoma: multicentre randomised trial.
PORTEC Study Group. Post Operative Radiation Therapy in
Endometrial Carcinoma. Lancet. 2000;355(9213):1404–1411.
22. Group AES, Blake P, Swart AM, et al. Adjuvant external beam
radiotherapy in the treatment of endometrial cancer (MRC ASTEC
and NCIC CTG EN.5 randomised trials): pooled trial results,
systematic review, and meta-analysis. Lancet. 2009;373(9658):137–
146.
23. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery
with or without adjunctive external pelvic radiation therapy in
intermediate risk endometrial adenocarcinoma: a Gynecologic
Oncology Group study. Gynecol Oncol. 2004;92(3):744–751.
24. Lee CM, Szabo A, Shrieve DC, et al. Frequency and effect of
adjuvant radiation therapy among women with stage I endometrial
adenocarcinoma. JAMA. 2006;295(4):389–397.
25. Wright JD, Fiorelli J, Kansler AL, et al. Optimizing the management
of stage II endometrial cancer: the role of radical hysterectomy and
radiation. Am J Obstet Gynecol. 2009; 200(4):419e1–e7.
26. Naumann RW, Coleman RL. The use of adjuvant radiation therapy
in early endometrial cancer by members of the Society of
Gynecologic Oncologists in 2005. Gynecol Oncol. 2007;105(1):7–12.
27. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus
pelvic external beam radiotherapy for patients with endometrial
cancer of high-intermediate risk (PORTEC-2): an open-label, non-
inferiority, randomised trial. Lancet. 2010;375(9717):816–823.
28. Randall ME, Wilder J, Greven K, et al. Role of intracavitary cuff
boost after adjuvant external irradiation in early endometrial
carcinoma. Int J Radiat Oncol Biol Phys. 1990;19(1):49–54.
29. Soper JT, Creasman WT, Clarke-Pearson DL, et al. Intraperitoneal
chromic phosphate P 32 suspension therapy of malignant peritoneal
cytology in endometrial carcinoma. Am J Obstet Gynecol.
1985;153(2):191–196.
30. Connell PP, Rotmensch J, Waggoner S, et al. The significance of
adnexal involvement in endometrial carcinoma. Gynecol Oncol.
1999;74(1):74–79.
31. Greven KM, Lanciano RM, Corn B, et al. Pathologic stage III
endometrial carcinoma. Prognostic factors and patterns of
recurrence. Cancer. 1993;71(11):3697–3702.
32. Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of
whole-abdominal irradiation versus doxorubicin and cisplatin
chemotherapy in advanced endometrial carcinoma: a Gynecologic
Oncology Group Study. J Clin Oncol. 2006;24(1):36–44.
33. Tewari KS, Filiaci VL, Spirtos NM, et al. Association of number of
positive nodes and cervical stroma invasion with outcome of
advanced endometrial cancer treated with chemotherapy or whole
abdominal irradiation: a Gynecologic Oncology Group study.
Gynecol Oncol. 2012;125(1):87–93.
34. Mundt AJ, McBride R, Rotmensch J, et al. Significant pelvic
recurrence in high-risk pathologic stage I–IV endometrial carcinoma
patients after adjuvant chemotherapy alone: implications for
adjuvant radiation therapy. Int J Radiat Oncol Biol Phys.
2001;50(5):1145–1153.
35. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III
trial in advanced endometrial carcinoma of surgery and volume
directed radiation followed by cisplatin and doxorubicin with or
without paclitaxel: a Gynecologic Oncology Group study. Gynecol
Oncol. 2009;112(3):543–552.
36. Murphy KT, Rotmensch J, Yamada SD, Mundt AJ. Outcome and
patterns of failure in pathologic stages I-IV clear-cell carcinoma of
the endometrium: implications for adjuvant radiation therapy. Int J
Radiat Oncol Biol Phys. 2003;55(5):1272–1276.
37. Wolfson AH, Brady MF, Rocereto T, et al. A gynecologic oncology
group randomized phase III trial of whole abdominal irradiation
(WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical
therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol
Oncol. 2007;107(2):177–185.
38. Young RC, Walton LA, Ellenberg SS, et al. Adjuvant therapy in stage
I and stage II epithelial ovarian cancer. Results of two prospective
randomized trials. N Engl J Med. 1990;322(15):1021–1027.
39. Young RC, Brady MF, Nieberg RK, et al. Adjuvant treatment for
early ovarian cancer: a randomized phase III trial of intraperitoneal
32P or intravenous cyclophosphamide and cisplatin–a gynecologic
oncology group study. J Clin Oncol. 2003;21(23):4350–4355.
40. Martinez A, Schray MF, Howes AE, et al . Postoperative radiation
therapy for epithelial ovarian cancer: the curative role based on a
24-year experience. J Clin Oncol. 1985;3(7):901–911.
41. Fuller DB, Sause WT, Plenk HP, et al. Analysis of postoperative
radiation therapy in stage I through III epithelial ovarian carcinoma.
J Clin Oncol. 1987;5(6):897–905.
42. Smith JP, Rutledge FN, Delclos L. Postoperative treatment of early
cancer of the ovary: a random trial between postoperative
irradiation and chemotherapy. Natl Cancer Inst Monogr.
1975;42:149–153.
43. Varia MA, Stehman FB, Bundy BN, et al. Intraperitoneal radioactive
phosphorus (32P) versus observation after negative second-look
laparotomy for stage III ovarian carcinoma: a randomized trial of
the Gynecologic Oncology Group. J Clin Oncol. 2003;21(15):2849–
2855.
44. Sorbe B. Consolidation treatment of advanced ovarian carcinoma
with radiotherapy after induction chemotherapy. Int J Gynecol
Cancer. 2003;13 Suppl 2:192–195.
45. Dinniwell R, Lock M, Pintilie M, et al. Consolidative
abdominopelvic radiotherapy after surgery and
carboplatin/paclitaxel chemotherapy for epithelial ovarian cancer.
Int J Radiat Oncol Biol Phys. 2005;62(1):104–110.
46. Burke TW, Stringer CA, Gershenson DM, et al. Radical wide excision
and selective inguinal node dissection for squamous cell carcinoma
of the vulva. Gynecol Oncol. 1990;38(3):328–332.
47. 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):309–314.
48. Gaffney DK, Du Bois A, Narayan K, et al. Patterns of care for
radiotherapy in vulvar cancer: a Gynecologic Cancer Intergroup
study. Int J Gynecol Cancer. 2009;19(1):163–167.
49. Stehman FB, Bundy BN, Thomas G, et al. Groin dissection versus
groin radiation in carcinoma of the vulva: a Gynecologic Oncology
Group study. Int J Radiat Oncol Biol Phys. 1992;24(2):389–396.
50. Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy versus
pelvic node resection for carcinoma of the vulva with positive groin
nodes. Obstet Gynecol. 1986;68(6):733–740.
51. Acosta AA, Given FT, Frazier AB, et al. Preoperative radiation
therapy in the management of squamous cell carcinoma of the
vulva: preliminary report. Am J Obstet Gynecol. 1978;132(2):198–
206.
52. Boronow RC. Combined therapy as an alternative to exenteration
for locally advanced vulvo-vaginal cancer: rationale and results.
Cancer. 1982;49(6):1085–1091.
53. Landoni F, Maneo A, Zanetta G, et al. Concurrent preoperative
chemotherapy with 5-fluorouracil and mitomycin C and
radiotherapy (FUMIR) followed by limited surgery in locally
advanced and recurrent vulvar carcinoma. Gynecol Oncol.
1996;61(3):321–327.
54. Thomas G, Dembo A, DePetrillo A, et al. Concurrent radiation and
chemotherapy in vulvar carcinoma. Gynecol Oncol. 1989; 34(3):263–
267.
55. Moore DH, Thomas GM, Montana GS, et al. Preoperative
chemoradiation for advanced vulvar cancer: a phase II study of the
Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys.
1998;42(1):79–85.
56. Gallup DG, Talledo OE, Shah KJ, et al. Invasive squamous cell
carcinoma of the vagina: a 14-year study. Obstet Gynecol.
1987;69(5):782–785.
57. Chyle V, Zagars GK, Wheeler JA, et al. Definitive radiotherapy for
carcinoma of the vagina: outcome and prognostic factors. Int J
Radiat Oncol Biol Phys. 1996;35(5):891–905.
58. Perez CA, Korba A, Sharma S. Dosimetric considerations in
irradiation of carcinoma of the vagina. Int J Radiat Oncol Biol Phys.
1977;2(7–8):639–649.
59. Frank SJ, Jhingran A, Levenback C, et al. Definitive radiation
therapy for squamous cell carcinoma of the vagina. Int J Radiat
Oncol Biol Phys. 2005;62(1):138–147.
60. Eifel PJ, Moughan J, Erickson B, et al. Patterns of radiotherapy
practice for patients with carcinoma of the uterine cervix: a patterns
of care study. Int J Radiat Oncol Biol Phys. 2004;60(4):1144–1153.
61. Chao KS, Williamson JF, Grigsby PW, et al. Uterosacral space
involvement in locally advanced carcinoma of the uterine cervix. Int
J Radiat Oncol Biol Phys. 1998;40(2):397–403.
62. Tyagi N, Lewis JH, Yashar CM, et al. Daily online cone beam
computed tomography to assess interfractional motion in patients
with intact cervical cancer. Int J Radiat Oncol Biol Phys.
2011;80(1):273–280.
63. Beadle BM, Jhingran A, Salehpour M, et al. Cervix regression and
motion during the course of external beam chemoradiation for
cervical cancer. Int J Radiat Oncol Biol Phys. 2009;73(1):235–241.
64. Finlay MH, Ackerman I, Tirona RG, et al. Use of CT simulation for
treatment of cervical cancer to assess the adequacy of lymph node
coverage of conventional pelvic fields based on bony landmarks. Int
J Radiat Oncol Biol Phys. 2006;64(1):205–259.
65. Zunino S, Rosato O, Lucino S, et al. Anatomic study of the pelvis in
carcinoma of the uterine cervix as related to the box technique. Int J
Radiat Oncol Biol Phys. 1999;44(1):53–59.
66. Grigsby P, Winter K, Komaki R, et al. Long-term follow-up of RTOG
88–05: twice-daily external irradiation with brachytherapy for
carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2002;54(1):51–
57.
67. MacLeod C, Bernshaw D, Leung S, et al. Accelerated
hyperfractionated radiotherapy for locally advanced cervix cancer.
Int J Radiat Oncol Biol Phys. 1999;44(3):519–524.
68. Kavanagh BD, Gieschen HL, Schmidt-Ullrich RK, et al. A pilot study
of concomitant boost accelerated superfractionated radiotherapy for
stage III cancer of the uterine cervix. Int J Radiat Oncol Biol Phys.
1997;38(3):561–568.
69. Carrascosa LA, Yashar CM, Paris KJ, et al. Palliation of pelvic and
head and neck cancer with paclitaxel and a novel radiotherapy
regimen. J Palliat Med. 2007;10(4):877–881.
70. Onsrud M, Hagen B, Strickert T. 10-Gy single-fraction pelvic
irradiation for palliation and life prolongation in patients with
cancer of the cervix and corpus uteri. Gynecol Oncol.
2001;82(1):167–171.
71. Perez CA, Grigsby PW, Chao KS, et al. Tumor size, irradiation dose,
and long-term outcome of carcinoma of uterine cervix. Int J Radiat
Oncol Biol Phys. 1998;41(2):307–317.
72. Wolfson AH, Abdel-Wahab M, Markoe AM, et al. A quantitative
assessment of standard vs. customized midline shield construction
for invasive cervical carcinoma. Int J Radiat Oncol Biol Phys.
1997;37(1):237–242.
73. Heron DE, Gerszten K, Selvaraj RN, et al. Conventional 3D
conformal versus intensity-modulated radiotherapy for the adjuvant
treatment of gynecologic malignancies: a comparative dosimetric
study of dose-volume histograms. Gynecol Oncol. 2003;91(1):39–45.
74. McIntyre JF, Eifel PJ, Levenback C, et al. Ureteral stricture as a late
complication of radiotherapy for stage IB carcinoma of the uterine
cervix. Cancer. 1995;75(3):836–843.
75. Roeske JC, Lujan A, Rotmensch J, et al. Intensity-modulated whole
pelvic radiation therapy in patients with gynecologic malignancies.
Int J Radiat Oncol Biol Phys. 2000;48(5):1613–1621.
76. Ahamad A, D’Souza W, Salehpour M, et al. Intensity-modulated
radiation therapy after hysterectomy: comparison with conventional
treatment and sensitivity of the normal-tissue-sparing effect to
margin size. Int J Radiat Oncol Biol Phys. 2005;62(4):1117–1124.
77. Mell LK, Tiryaki H, Ahn KH, et al. Dosimetric comparison of bone
marrow-sparing intensity-modulated radiotherapy versus
conventional techniques for treatment of cervical cancer. Int J
Radiat Oncol Biol Phys. 2008;71(5):1504–1510.
78. Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of
acute hematologic toxicity in cervical cancer patients treated with
concurrent cisplatin and intensity-modulated pelvic radiotherapy.
Int J Radiat Oncol Biol Phys. 2006;66(5):1356–1365.
79. ICRU. International Commission on Radiation Units and
Measurements Report Number 50: prescribing, recording and
reporting photon beam therapy. Washington, DC: 1993.
80. Simpson DR, Lawson JD, Nath SK, et al. Utilization of advanced
imaging technologies for target delineation in radiation oncology. J
Am Coll Radiol. 2009;6(12):876–883.
81. Miller TR, Grigsby PW. Measurement of tumor volume by PET to
evaluate prognosis in patients with advanced cervical cancer treated
by radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(2):353–
359.
82. 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 Phys. 2008;71(2):428–434.
83. Taylor A, Rockall AG, Reznek RH, et al. Mapping pelvic lymph
nodes: guidelines for delineation in intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys. 2005;63(5):1604–1612.
84. D’Souza WD, Ahamad AA, Iyer RB, et al. Feasibility of dose
escalation using intensity-modulated radiotherapy in
posthysterectomy cervical carcinoma. Int J Radiat Oncol Biol Phys.
2005;61(4):1062–1070.
85. Mutic S, Malyapa RS, Grigsby PW, et al. PET-guided IMRT for
cervical carcinoma with positive para-aortic lymph nodes-a dose-
escalation treatment planning study. Int J Radiat Oncol Biol Phys.
2003;55(1):28–35.
86. Low DA, Grigsby PW, Dempsey JF, et al. Applicator-guided
intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys.
2002;52(5):1400–1406.
87. Chan P MM, Paterson J, et al. Cervical cancer not suitable for
brachytherapy: case study. In: Mundt AJ, Roeske JC, ed. Intensity
Modulated Radiation Therapy: A Clinical Perspective. Hamilton,
Canada: BC Decker Inc; 2005:518–522.
88. Kidd EA, Siegel BA, Dehdashti F, et al. Clinical outcomes of
definitive intensity-modulated radiation therapy with
fluorodeoxyglucose-positron emission tomography simulation in
patients with locally advanced cervical cancer. Int J Radiat Oncol
Biol Phys. 2010; 77(4):1085–1091.
89. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated whole
pelvic radiotherapy in women with gynecologic malignancies. Int J
Radiat Oncol Biol Phys. 2002;52(5):1330–1337.
90. Hasselle MD, Rose BS, Kochanski JD, et al. Clinical outcomes of
intensity-modulated pelvic radiation therapy for carcinoma of the
cervix. Int J Radiat Oncol Biol Phys. 2011;80(5):1436–1445.
91. Liang Y, Messer K, Rose BS, et al. Impact of bone marrow radiation
dose on acute hematologic toxicity in cervical cancer: principal
component analysis on high dimensional data. Int J Radiat Oncol
Biol Phys. 2010;78(3):912–919.
92. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic
gastrointestinal toxicity in gynecology patients treated with
intensity-modulated whole pelvic radiation therapy. Int J Radiat
Oncol Biol Phys. 2003;56(5):1354–1360.
93. Brixey CJ, Roeske JC, Lujan AE, et al. Impact of intensity-modulated
radiotherapy on acute hematologic toxicity in women with
gynecologic malignancies. Int J Radiat Oncol Biol Phys.
2002;54(5):1388–1396.
94. Beriwal S, Jain SK, Heron DE, et al. Clinical outcome with adjuvant
treatment of endometrial carcinoma using intensity-modulated
radiation therapy. Gynecol Oncol. 2006;102(2):195–199.
95. Jhingran A, Winter K, Portelance L, et al. A phase II study of
intensity modulated radiation therapy to the pelvis for postoperative
patients with endometrial carcinoma: radiation therapy oncology
group trial 0418. Int J Radiat Oncol Biol Phys. 2012;84(1):e23–e28.
96. International Radiotherapy Technologies and Oncology Consortium
(IRTOC). International evaluation of radiotherapy technology
effectiveness in cervical cancer (INTERTECC): a Phase II/III clinical
trial of IMRT with concurrent cisplatin for stage I-IVA cervical
carcinoma.
http://radonc.ucsd.edu/irtoc/intertecc/intertecc1001.asp
97. 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. 2011;79(3):800–807.
98. Simpson DR, Song WY, Moiseenko V, et al. Normal tissue
complication probablity analysis of acute gastrointestinal toxicity in
cervical cancer patients undergoing intensity modulated radiation
therapy and concurrent cisplatin [abstract]. Int J Radiat Oncol Biol
Phys. 2010;78:S141–S142.
99. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute
gastrointestinal toxicity in women receiving intensity-modulated
whole-pelvic radiation therapy. Radiother Oncol. 2003;69(2):201–
207.
100. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated
radiation therapy (IMRT) reduces small bowel, rectum, and bladder
doses in patients with cervical cancer receiving pelvic and para-
aortic irradiation. Int J Radiat Oncol Biol Phys. 2001;51(1):261–266.
101. 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(3):935–943.
102. Hermesse J, Devillers M, Deneufbourg JM, Nickers P. Can intensity-
modulated radiation therapy of the paraaortic region overcome the
problems of critical organ tolerance? Strahlenther Onkol. 2005;
181(3):185–190.
103. Ahmed RS, Kim RY, Duan J, et al. IMRT dose escalation for positive
para-aortic lymph nodes in patients with locally advanced cervical
cancer while reducing dose to bone marrow and other organs at
risk. Int J Radiat Oncol Biol Phys. 2004;60(2):505–512.
104. Salama JK, Mundt AJ, Roeske J, et al. Preliminary outcome and
toxicity report of extended-field, intensity-modulated radiation
therapy for gynecologic malignancies. Int J Radiat Oncol Biol Phys.
2006;65(4):1170–1176.
105. Gerszten K, Colonello K, Heron DE, et al. Feasibility of concurrent
cisplatin and extended field radiation therapy (EFRT) using
intensity-modulated radiotherapy (IMRT) for carcinoma of the
cervix. Gynecol Oncol. 2006;102(2):182–188.
106. Vargo JA, Kim H, Choi S, Sukumvanich P, Olawaiye AB, Kelley JL,
Edwards RP, Comerci JT, Beriwal S. Extended field intensity
modulated radiation therapy with concomitant boost for lymph
node-positive cervical cancer: analysis of regional control and
recurrence patterns in the positron emission tomography/computed
tomography era. Int J Radiat Oncol Biol Phys. 2014;90(5):1091–1098
doi: 10.1016/j.ijrobp.2014.08.013.
107. Du XL, Sheng XG, Jiang T, et al. Intensity-modulated radiation
therapy versus para-aortic field radiotherapy to treat para-aortic
lymph node metastasis in cervical cancer: prospective study. Croat
Med J. 2010;51(3):229–236.
108. Moran MS, Castrucci WA, Ahmad M, et al. Clinical utility of the
modified segmental boost technique for treatment of the pelvis and
inguinal nodes. Int J Radiat Oncol Biol Phys. 2010;76(4):1026–1036.
109. Koh WJ, Chiu M, Stelzer KJ, et al. Femoral vessel depth and the
implications for groin node radiation. Int J Radiat Oncol Biol Phys.
1993;27(4):969–974.
110. Petereit DG, Mehta MP, Buchler DA, et al. Inguinofemoral radiation
of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if
proper radiation technique is used. Int J Radiat Oncol Biol Phys.
1993;27(4):963–967.
111. Dusenbery KE, Carlson JW, LaPorte RM, et al. Radical vulvectomy
with postoperative irradiation for vulvar cancer: therapeutic
implications of a central block. Int J Radiat Oncol Biol Phys.
1994;29(5):989–998.
112. Beriwal S, Heron DE, Kim H, et al. Intensity-modulated
radiotherapy for the treatment of vulvar carcinoma: a comparative
dosimetric study with early clinical outcome. Int J Radiat Oncol Biol
Phys. 2006;64(5):1395–1400.
113. Ahmad M, Song H, Moran M, et al. IMRT of whole pelvis and
inguinal nodes: evaluation of dose distributions produced by an
inverse treatment planning system. Int J Radiat Oncol Biol Phys.
2004;60(Suppl):S484–S485.
114. Beriwal S, Coon D, Heron DE, et al. Preoperative intensity-
modulated radiotherapy and chemotherapy for locally advanced
vulvar carcinoma. Gynecol Oncol. 2008;109(2):291–295.
115. Dembo AJ, Van Dyk J, Japp B, et al. Whole abdominal irradiation
by a moving-strip technique for patients with ovarian cancer. Int J
Radiat Oncol Biol Phys. 1979;5(11–12):1933–1942.
116. Randall ME, Barrett RJ, Spirtos NM, et al. Chemotherapy, early
surgical reassessment, and hyperfractionated abdominal
radiotherapy in stage III ovarian cancer: results of a gynecologic
oncology group study. Int J Radiat Oncol Biol Phys 1996;34(1):139–
147.
117. Hong L, Alektiar K, Chui C, et al. IMRT of large fields: whole-
abdomen irradiation. Int J Radiat Oncol Biol Phys. 2002;54(1):278–
289.
118. Duthoy W, De Gersem W, Vergote K, et al. Whole abdominopelvic
radiotherapy (WAPRT) using intensity-modulated arc therapy
(IMAT): first clinical experience. Int J Radiat Oncol Biol Phys.
2003;57(4):1019–1032.
119. Wong E, D’Souza DP, Chen JZ, et al. Intensity-modulated arc
therapy for treatment of high-risk endometrial malignancies. Int J
Radiat Oncol Biol Phys. 2005;61(3):830–841.
120. Pan H, Simpson DR, Mell LK, et al. A survey of stereotactic body
radiotherapy use in the United States. Cancer. 2011;117(19):4566–
4572.
121. Choi CW, Cho CK, Yoo SY, et al. Image-guided stereotactic body
radiation therapy in patients with isolated para-aortic lymph node
metastases from uterine cervical and corpus cancer. Int J Radiat
Oncol Biol Phys. 2009;74(1):147–153.
122. Molla M, Escude L, Nouet P, et al. Fractionated stereotactic
radiotherapy boost for gynecologic tumors: an alternative to
brachytherapy? Int J Radiat Oncol Biol Phys. 2005;62(1):118–124.
123. Jorcano S, Molla M, Escude L, et al. Hypofractionated extracranial
stereotactic radiotherapy boost for gynecologic tumors: a promising
alternative to high-dose rate brachytherapy. Technol Cancer Res
Treat. 2010;9(5):509–514.
124. Tod MC MW. A dosage system for use in the treatment of cancer of
the uterine cervix. Br J Radiol. 1938;11:809–813.
125. Henschke UK. “Afterloading” applicator for radiation therapy of
carcinoma of the uterus. Radiology. 1960;74:834–836.
126. Dimopoulos JC, Kirisits C, Petric P, et al. The Vienna applicator for
combined intracavitary and interstitial brachytherapy of cervical
cancer: clinical feasibility and preliminary results. Int J Radiat Oncol
Biol Phys. 2006;66(1):83–90.
127. Fleming P, Nisar Syed AM, Neblett D, et al. Description of an
afterloading 192Ir interstitial-intracavitary technique in the
treatment of carcinoma of the vagina. Obstet Gynecol.
1980;55(4):525–530.
128. Martinez A, Cox RS, Edmundson GK. A multiple-site perineal
applicator (MUPIT) for treatment of prostatic, anorectal, and
gynecologic malignancies. Int J Radiat Oncol Biol Phys.
1984;10(2):297–305.
129. Heyman J RO, Benner S, Reuterwall O. The Radiumhemmet
experience with radiotherapy in cancer of the corpus of the uterus.
Acta Radiol. 1941;22:11–98.
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
J Radiat Oncol Biol Phys. 2013;87(4):840–846.
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:
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
Radiat Oncol Biol Phys. 1992;24(2):335–348.
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.
2004;59(5):1424–1431.
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
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
Phys. 1995;32(5):1301–1307.
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–
48.
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–
67.
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.
153. Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and
rectum dose defined from MRI based treatment planning for cervix
cancer brachytherapy: comparison of dose-volume histograms for
organ contours and organ wall, comparison with ICRU rectum and
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.
Radiother Oncol. 2006;79(1):80–86.
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
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.
Int J Radiat Oncol Biol Phys. 2002;54(4):1140–1146.
168. Mutic S, Grigsby PW, Low DA, et al. PET-guided three-dimensional
treatment planning of intracavitary gynecologic implants. Int J
Radiat Oncol Biol Phys. 2002;52(4):1104–1110.
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
gynecologic malignancies. Int J Radiat Oncol Biol Phys.
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
Radiat Oncol Biol Phys. 1983;9(12):1897–1903.
172. 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(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.
Int J Radiat Oncol Biol Phys. 1998;40(2):415–420.
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
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.
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
Phys. 2010;37(11):5787–5791.
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.
26A Cancer of the Genitourinary
Tract: Prostate Cancer
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
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.
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
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.
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.
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
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.
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
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.
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
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.
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
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.
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.
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
(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
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.
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.
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).
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.
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.
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.
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.
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
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.
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).
Dose Fractionation
Prophylactic dose to the pelvic LN is 1.8 Gy/fx to 45 Gy. At UCSF,
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
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
hypofractionation or stereotactic radiotherapy for prostate cancer should
be considered experimental and is most appropriately utilized as part of
prospective clinical trials (95).
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
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
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).
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.
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.
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
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
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
REFERENCES
1. Siegel R, Ma J, Zou Z, et al. Cancer statistics. CA Cancer J Clin. 2014;
64(1):9–29.
2. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA
screening in the US prostate cancer mortality decline. Cancer Causes
Control. 2008;19(2):175–181.
3. Etzioni R, Gulati R, Falcon S, et al. Impact of PSA screening on the
incidence of advanced stage prostate cancer in the United States: a
surveillance modeling approach. Med Decis Making. 2008;28(3);323–
331.
4. Golimbu M, Morales P, Al-Askari S, et al. Extended pelvic
lymphadenectomy for prostatic cancer. J Urol. 1979;121(5):617–
620.
5. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing
conventional-dose with high-dose conformal radiation therapy in
early-stage adenocarcinoma of the prostate: Long-term results from
Proton Radiation Oncology Group/American College Of Radiology
95—09. J Clin Oncol. 2010;28(7):1106–1111.
6. Kuban DA, Levy LB, Cheung MR, et al. Long-term failure patterns
and survival in a randomized dose-escalation trial for prostate
cancer. Who dies of disease? Int J Radiat Oncol. 2011;79(5):1310–
1317.
7. Kalbasi A, Li J, Berman A, et al. Dose-escalated irradiation and
overall survival in men with nonmetastatic prostate cancer. JAMA
Oncol. 2015;1(7):897–906.
8. Cahlon O, Hunt M, Zelefsky MJ. Intensity-modulated radiation
therapy: supportive data for prostate cancer. Semin Radiat Oncol.
2008;18(1):48–57.
9. Talcott JA, Rossi C, Shipley WU, et al. Patient-reported long-term
outcomes after conventional and high-dose combined proton and
photon radiation for early prostate cancer. JAMA.
2010;303(11):1046–1053.
10. de Crevoisier R, Tucker SL, Dong L, et al. Increased risk of
biochemical and local failure in patients with distended rectum on
the planning CT for prostate cancer radiotherapy. Int J Radiat Oncol
Biol Phys. 2005;62(4):965–973.
11. Presti JC Jr, O’Dowd GJ, Miller MC, et al. Extended peripheral zone
biopsy schemes increase cancer detection rates and minimize
variance in prostate specific antigen and age related cancer rates:
results of a community multi-practice study. J Urol. 2003;
169(1):125–129.
12. Scattoni V, Zlotta A, Montironi R, et al. Extended and saturation
prostatic biopsy in the diagnosis and characterisation of prostate
cancer: a critical analysis of the literature. Eur Urol.
2007;52(5):1309–1322.
13. Djavan B, Ravery V, Zlotta A, et al. Prospective evaluation of
prostate cancer detected on biopsies 1, 2, 3 and 4: when should we
stop? J Urol. 2001;166(5):1679–1683.
14. Rastinehad AR, Turkbey B, Salami SS, et al. Improving detection of
clinically significant prostate cancer: magnetic resonance
imaging/transrectal ultrasound fusion guided prostate biopsy. J
Urol. 2014;191(6):1749–1754.
15. Lin GA, Aaronson DS, Knight SJ, et al. Patient Decision Aids for
Prostate Cancer Treatment: a systematic review of the literature. CA
Cancer J Clin. 2009;59(6):379–390.
16. Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of
California, San Francisco Cancer of the Prostate Risk Assessment
score: a straightforward and reliable preoperative predictor of
disease recurrence after radical prostatectomy. J Urol.
2005;173(6):1938–1942.
17. Cooperberg MR, Davicioni E, Crisan A, et al. Combined value of
validated clinical and genomic risk stratification tools for predicting
prostate cancer mortality in a high-risk prostatectomy cohort. Eur
Urol. 2014;67(2):326–333.
18. Edge S, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging
Manual, 7th ed. New York, NY: Springer-Verlag; 2010.
19. Stock C, Hruza M, Cresswell J, et al. Transrectal ultrasound-guided
biopsy of the prostate: development of the procedure, current
clinical practice, and introduction of self-embedding as a new way
of processing biopsy cores. J Endourol. 2008;22(6):1321–1329.
20. Hricak H, Dooms GC, Jeffrey RB, et al. Prostatic carcinoma: staging
by clinical assessment, CT, and MR imaging. Radiology.
1987;162(2)331–336.
21. Abuzallouf S, Dayes I, Lukka H. Baseline staging of newly diagnosed
prostate cancer: a summary of the literature. J Urol. 2004; 171(6 Pt
1):2122–2127.
22. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic
adenocarcinoma by combined histological grading and clinical
staging. J Urol. 1974;111(1):58–64.
23. Chism DB, Hanlon AL, Troncoso P, et al. The Gleason score shift:
score four and seven years ago. Int J Radiat Oncol Biol Phys.
2003;56(5):1241–1247.
24. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy
or watchful waiting in early prostate cancer. N Engl J Med.
2014;370(10);932–942.
25. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus
observation for localized prostate cancer. N Engl J Med. 367(3):203–
213.
26. Klotz L, Vesprini, D. Sethukavalan P, et al. Long-term follow-up of a
large active surveillance cohort of patients with prostate cancer. J
Clin Oncol. 2015;33(3):272–277.
27. Lane JA, Donovan JL, Davis M, et al. Active monitoring, radical
prostatectomy, or radiotherapy for localised prostate cancer: study
design and diagnostic and baseline results of the ProtecT
randomised phase 3 trial. Lancet Oncol. 2014;15(10):1109–1118.
28. Cooperberg MR, Broering JM, Carroll PR. Time trends and local
variation in primary treatment of localized prostate cancer. J Clin
Oncol. 2010;28(7):1117–1123.
29. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function
after radical prostatectomy for clinically localized prostate cancer:
the Prostate Cancer Outcomes Study. JAMA. 2000;283(3):354–360.
30. Sanda MG, Dunn RL, Michalaski J, et al. Quality of life and
satisfaction with outcome among prostate cancer survivors. N Engl J
Med. 2008;358:1250–1261.
31. Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after
open or robotic prostatectomy, cryoablation or brachytherapy for
localized prostate cancer. J Urol. 2010;183(5):1822–1828.
32. Trabulsi EJ, Guillonneau B. Laparoscopic radical prostatectomy. J
Urol. 2005;173(4):1072–1079.
33. Vickers AJ, Savage CJ, Hruza M, et al. The surgical learning curve
for laparoscopic radical prostatectomy: a retrospective cohort study.
Lancet Oncol. 2009;10(5):475–480.
34. Roach M 3rd, Pickett B, Rosenthal SA, et al. Defining treatment
margins for six field conformal irradiation of localized prostate
cancer. Int J Radiat Oncol Biol Phys. 1994;28(1):267–275.
35. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients
with locally advanced prostate cancer treated with radiotherapy and
goserelin. N Engl J Med. 1997;337(5):295–300.
36. Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy
oncology group (RTOG) trial 86–10 of androgen deprivation
adjuvant to definitive radiotherapy in locally advanced carcinoma of
the prostate. Int J Radiat Oncol Biol Phys. 2001;50(5):1243–1252.
37. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term
adjuvant androgen deprivation after neoadjuvant hormonal
cytoreduction and radiotherapy in locally advanced carcinoma of
the prostate: the radiation therapy oncology group protocol 92–02. J
Clin Oncol. 2003;21(21):3972–3978.
38. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of
androgen suppression in the treatment of prostate cancer. N Engl J
Med. 2009;360(24):2516–2527.
39. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or
without radiotherapy, in locally advanced prostate cancer (SPCG-
7/SFUO-3): an open randomised phase III trial. Lancet.
2009;373(9660):301–308.
40. McGowan DG, Hunt D, Jones CU, et al. Short-term endocrine
therapy prior to and during radiation therapy improves overall
survival in patients with T1b-T2b adenocarcinoma of the prostate
and PSA ≤ 20: Initial results of RTOG 94–08. Int J Radiat Oncol.
2010;77(1):1.
41. Burri RJ, Stone NN, Unger P, et al. Long-term outcome and toxicity
of salvage brachytherapy for local failure after initial radiotherapy
for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;77(5):1338–
1344.
42. Nguyen PL, Chen RC, Clark JA, et al Patient-reported quality of life
after salvage brachytherapy for radio-recurrent prostate cancer: a
prospective Phase II study. Brachytherapy. 2009;8(4):345–352.
43. Jabbari S, Hsu IC, Kawakami J, et al. High-dose-rate brachytherapy
for localized prostate adenocarcinoma post abdominoperineal
resection of the rectum and pelvic irradiation: technique and
experience. Brachytherapy. 2009;8(4):339–344.
44. D’Amico AV, Chen MH, Renshaw AA, et al. Androgen suppression
and radiation vs. radiation alone for prostate cancer: a randomized
trial. JAMA 2008;299:289–295.
45. Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-
term androgen deprivation for localized prostate cancer. N Engl J
Med. 2011;365:107–118.
46. Yamada Y, Kollmeier MA, Pei X, et al. A Phase II study of salvage
high-dose-rate brachytherapy for the treatment of locally recurrent
prostate cancer after definitive external beam radiotherapy.
Brachytherapy. 2014;13(2):111–116.
47. Robinson JW, Donnelly BJ, Siever JE, et al. A randomized trial of
external beam radiotherapy versus cryoablation in patients with
localized prostate cancer: quality of life outcomes. Cancer.
2009;115(20):4695–4704.
48. McLaughlin PW, Troyer S, Berri S, et al. Functional anatomy of the
prostate: Implications for treatment planning. Int J Radiat Oncol Biol
Phys. 2005;63(2):479–491.
49. Rosenthal SA, Roach M 3rd, Goldsmith BJ, et al. Immobilization
improves the reproducibility of patient positioning during six-field
conformal radiation therapy for prostate carcinoma. Int J Radiat
Oncol Biol Phys. 1993;27(4):921–926.
50. Kneebone A, Gebski V, Hogendoorn N, et al. A randomized trial
evaluating rigid immobilization for pelvic irradiation. Int J Radiat
Oncol Biol Phys. 2003;56(4):1105–1111.
51. Malone S, Szanto J, Perry G, et al. A prospective comparison of
three systems of patient immobilization for prostate radiotherapy.
Int J Radiat Oncol Biol Phys.2000;48(3):657–665.
52. Wachter S, Gerstner N, Dorner D, et al. The influence of a rectal
balloon tube as internal immobilization device on variations of
volumes and dose-volume histograms during treatment course of
conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol
Phys. 2002;52(1):91–100.
53. Lattanzi J, McNeely S, Hanlon A, et al. Daily CT localization for
correcting portal errors in the treatment of prostate cancer. Int J
Radiat Oncol Biol Phys. 1998;41(5):1079–1086.
54. Lattanzi J, McNeeley S, Pinover W, et al. A comparison of daily CT
localization to a daily ultrasound-based system in prostate cancer.
Int J Radiat Oncol Biol Phys. 1999;43(4):719–725.
55. Sandler HM, Bree RL, McLaughlin PW, et al. Localization of the
prostatic apex for radiation therapy using implanted markers. Int J
Radiat Oncol Biol Phys. 1993;27(4):915–919.
56. Vigneault E, Pouliot J, Laverdière J, et al. Electronic portal imaging
device detection of radioopaque markers for the evaluation of
prostate position during megavoltage irradiation: a clinical study.
Int J Radiat Oncol Biol Phys. 1997;37(1):205–212.
57. Litzenberg DW, Willoughby TR, Balter JM, et al Positional stability
of electromagnetic transponders used for prostate localization and
continuous, real-time tracking. Int J Radiat Oncol Biol Phys.
2007;68(4):1199–1206.
58. Willoughby TR, Kupelian PA, Pouliot J, et al. Target localization
and real-time tracking using the Calypso 4D localization system in
patients with localized prostate cancer. Int J Radiat Oncol Biol Phys.
2006;65(2):528–534.
59. Kupelian PA, Langen KM, Willoughby TR, et al. Image-guided
radiotherapy for localized prostate cancer: treating a moving target.
Semin Radiat Oncol. 2008;18(1):58–66.
60. Ten Haken RK, Forman JD, Heimburger DK, et al. Treatment
planning issues related to prostate movement in response to
differential filling of the rectum and bladder. Int J Radiat Oncol Biol
Phys. 1991;20(6):1317–1324.
61. Dawson LA, Litzenberg DW, Brock KK, et al. A comparison of
ventilatory prostate movement in four treatment positions. Int J
Radiat Oncol. 2000;48(2):319–323.
62. Litzenberg D, Dawson LA, Sandler H, et al. Daily prostate targeting
using implanted radiopaque markers. Int J Radiat Oncol Biol Phys.
2002;52(3):699–703.
63. Bayley AJ, Catton CN, Haycocks T, et al. A randomized trial of
supine vs. prone positioning in patients undergoing escalated dose
conformal radiotherapy for prostate cancer. Radiother Oncol.
2004;70(1):37–44.
64. Diaz A, Roach M 3rd, Marquez C, et al. Indications for and the
significance of seminal vesicle irradiation during 3D conformal
radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol
Phys. 1994;30(2):323–329.
65. Kestin L, Goldstein N, Vicini F, et al. Treatment of prostate cancer
with radiotherapy: should the entire seminal vesicles be included in
the clinical target volume? Int J Radiat Oncol Biol Phys.
2002;54(3):686–697.
66. Mukamel E, DeKernion JB, Hannah J, et al. The incidence and
significance of seminal vesicle invasion in patients with
adenocarcinoma of the prostate. Cancer. 1987;59(8):1535–1538.
67. Lawton CA, DeSilvio M, Roach M 3rd, et al. An update of the phase
III trial comparing whole pelvic to prostate only radiotherapy and
neoadjuvant to adjuvant total androgen suppression: updated
analysis of rtog 94–13, with emphasis on unexpected
hormone/radiation interactions. Int J Radiat Oncol Biol Phys.
2007;69(3):646–655.
68. Wang D, Lawton C. Pelvic lymph node irradiation for prostate
cancer: who, why, and when? Semin Radiat Oncol. 2008;18(1):35–
40.
69. Lawton CA, Michalski J, El-Naqa I, et al. Variation in the definition
of clinical target volumes for pelvic nodal conformal radiation
therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2009;
74(2):377–382.
70. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation
oncology specialists reach consensus on pelvic lymph node volumes
for high-risk prostate cancer. Int J Radiat Oncol Biol Phys.
2009;74(2):383–387.
71. Langen KM, Jones DT. Organ motion and its management. Int J
Radiat Oncol Biol Phys. 2001;50(1):265–278.
72. Ten Haken RK, Perez-Tamayo C, Tesser RJ, et al. Boost treatment of
the prostate using shaped, fixed fields. Int J Radiat Oncol Biol Phys.
1989;16(1):193–200.
73. Marsh LH, Ten Haken RK, Sandler HM. A customized non-axial
external beam technique for treatment of prostate carcinomas. Med
Dosim. 1992;17(3):123–127.
74. Roach M 3rd, Nam J, Gagliardi G, et al. Radiation dose-volume
effects and the penile bulb. Int J Radiat Oncol Biol Phys. 2010; 76(3
Suppl):S130–S134.
75. Roach M 3rd, Pickett B, Holland J, et al. The role of the
urethrogram during simulation for localized prostate cancer. Int J
Radiat Oncol Biol Phys. 1993;25(2):299–307.
76. Schild SE, Wong W, The role of retrograde urethrography in the
planning of prostate cancer radiotherapy. Med Dosim. 1997;
22(2):83–86.
77. McLaughlin PW, Evans C, Feng M, et al. Radiographic and anatomic
basis for prostate contouring errors and methods to improve
prostate contouring accuracy. Int J Radiat Oncol. 2010; 76(2):369–
378.
78. Zelefsky MJ, Happersett L, Leibel SA, et al. The effect of treatment
positioning on normal tissue dose in patients with prostate cancer
treated with three-dimensional conformal radiotherapy. Int J Radiat
Oncol Biol Phys. 1997;37(1):13–19.
79. Ryu JK, Winter K, Michalski JM, et al. Interim report of toxicity
from 3D conformal radiation therapy (3D-CRT) for prostate cancer
on 3DOG/RTOG 9406, level III (79.2 Gy). Int J Radiat Oncol Biol
Phys. 54(4):1036–1046.
80. Roach M 3rd, DeSilvio M, Valicenti R, et al. Whole-pelvis, “mini-
pelvis,” or prostate-only external beam radiotherapy after
neoadjuvant and concurrent hormonal therapy in patients treated in
the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol
Biol Phys. 2006;66:647–653.
81. Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in
radiotherapy for localized prostate cancer: results of the Dutch
multicenter randomized phase III trial comparing 68 Gy of
radiotherapy with 78 Gy. J Clin Oncol. 2006;24(13):1990–1996.
82. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation
side-effects of conformal and conventional radiotherapy in prostate
cancer: A randomised trial. Lancet. 1999;353(9149):267–272.
83. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated
intensity-modulated radiotherapy (70 Gy at 2.5 Gy Per Fraction) for
localized prostate cancer: Cleveland Clinic Experience. Int J Radiat
Oncol Biol Phys. 2007;68(5);1424–1430.
84. Marzi S, Saracino B, Petrongari MG, et al. Modeling of alpha/beta
for late rectal toxicity from a randomized phase II study:
conventional versus hypofractionated scheme for localized prostate
cancer. J Exp Clin Cancer Res. 2009;28:117.
85. Arcangeli G, Saracino B, Gomellini S, et al. A Prospective phase III
randomized trial of hypofractionation versus conventional
fractionation in patients with high-risk prostate cancer. Int J Radiat
Oncol Biol Phys. 2010;78(1):11–18.
86. Lukka H, Hayter C, Julian JA, et al. Randomized trial comparing
two fractionation schedules for patients with localized prostate
cancer. J Clin Oncol. 2005;23(25):6132–6138.
87. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU Radiation
oncology specialists reach consensus on pelvic lymph node volumes
for high-risk prostate cancer. Int J Radiat Oncol Biol Phys.
2009;74:383–387.
88. Miles EF, Lee WR. Hypofractionation for prostate cancer: a critical
review. Semin Radiat Oncol. 2008;18(1):41–47.
89. Fowler JF. The radiobiology of prostate cancer including new
aspects of fractionated radiotherapy. Acta Oncol. 2005;44(3):265–
276.
90. Ritter M. Rationale, conduct, and outcome using hypofractionated
radiotherapy in prostate cancer. Semin Radiat Oncol.
2008;18(4):249–256.
91. Proust-Lima C, Taylor JM, Sécher S, et al. Confirmation of a low α/
β ratio for prostate cancer treated by external beam radiation
therapy alone using a post-treatment repeated-measures model for
PSA dynamics. Int J. Radiat Oncol Biol Phys. 2011;79(1):195–201.
92. Madsen BL, Hsi RA, Pham HT, et al Stereotactic hypofractionated
accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five
fractions for localized disease: first clinical trial results. Int J Radiat
Oncol Biol Phys. 2007;67(4):1099–1105.
93. King CR, Brooks JD, Gill H, et al. Stereotactic body radiotherapy for
localized prostate cancer: interim results of a prospective phase II
clinical trial. Int J Radiat Oncol Biol Phys. 2009; 73(4):1043–1048.
94. 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.
95. Buyyounouski MK, Price RA Jr, Harris EE, et al. Stereotactic body
radiotherapy for primary management of early-stage, low- to
intermediate-risk prostate cancer: report of the American Society for
Therapeutic Radiology and Oncology Emerging Technology
Committee. Int J Radiat Oncol Biol Phys. 2010;76(5):1297–1304.
96. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy
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
Radiat Oncol Biol Phys. 2004;59(3):674–683.
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
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.
Int J Radiat Oncol Biol Phys. 2010;76(2):361–368.
110. Wiltshire KL, Brock KK, Haider MA, et al. Anatomic boundaries of
the clinical target volume (Prostate Bed) after radical prostatectomy.
Int J Radiat Oncol Biol Phys. 2007;69(4):1090–1099.
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
and intensity-modulated radiotherapy for localized prostate cancer.
Int J Radiat Oncol Biol Phys. 2008;70:1124–1129.
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
Radiat Oncol Biol Phys. 2008;70:67–74.
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–
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.
129. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial
brachytherapy sources: recommendations of the AAPM Radiation
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.
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
cancer. J Clin Oncol. 2003;21(24):4568–4571.
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.
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.
Int J Radiat Oncol Biol Phys. 1992;23:81–87.
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.
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
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.
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).
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,
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.
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
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
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%
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.
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
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
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
Radiat Oncol Biol Phys. 2013;85(2):363–369.
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).
Int J Radiat Oncol Biol Phys. 2011;79(1):172–178.
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
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.
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
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.
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).
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
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
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.
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
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).
• 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
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
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
1. Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA Cancer J
Clin. 2010;60(5):277–300.
2. Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CA Cancer
J Clin. 2005;55(1):10–30.
3. Forman D, Pike MC, Davey G, et al. Aetiology of testicular cancer:
association with congenital abnormalities, age at puberty, infertility,
and exercise. BMJ. 1994;308(6941):1393–1399.
4. Sokoloff MH, Joyce GF, Wise M. Testis Cancer. J Urol. 2007;
177(6):2030–2041.
5. Dearnaley DP, Huddart R, Horwich A. Regular review: managing
testicular cancer. BMJ. 2001;322(7302):1583–1588.
6. Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the
status of cancer, 1975–2001, with a special feature regarding
survival. Cancer. 2004;101(1):3–27.
7. Wilkinson PM, Read G. International Germ Cell Consensus
Classification: a prognostic factor-based staging system for
metastatic germ cell cancers. International Germ Cell Cancer
Collaborative Group. J Clin Oncol. 1997;15:594–603.
8. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual,
7th ed. New York, NY; Springer Publishers. 2010.
9. Ulbright TM, Amin MB, Young RH. Tumors of the Testis. Adnexa;
1999.
10. Warde PR, Chung P, Sturgeon J, et al. Should surveillance be
considered the standard of care in stage I seminoma? ASCO Meeting
Abstracts. 2005;23(16_suppl):4520.
11. Tyldesley S, Voduc D, Mckenzie M, et al. Surveillance of stage I
testicular seminoma: British Columbia Cancer Agency Experience
1992 to 2002. Urology. 2006;67(3):594–598.
12. Horwich A, Alsanjari N, A’hern R, et al. Surveillance following
orchidectomy for stage I testicular seminoma. Br J Cancer. 1992;
65(5):775.
13. Germà-Lluch J. Clinical pattern and therapeutic results achieved in
1490 patients with germ-cell tumours of the testis: the experience of
the Spanish Germ-Cell Cancer Group (GG). Eur Urol. 2002;
42(6):553–562.
14. Maase von der H, Specht L, Jacobsen GK, et al. Surveillance
following orchidectomy for stage I seminoma of the testis. Eur J
Cancer. 1993;29(14):1931–1934.
15. Daugaard G, Petersen PM, Rørth M. Surveillance in stage I testicular
cancer. APMIS. 2003;111(1):76–83; discussion 83–85.
16. Fossa SD, Oldenburg J, Dahl AA. Short and longterm morbidity
after treatment for testicular cancer. BJU Int. 2009;104(9b):1418–
1422.
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
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.
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.
Int J Radiat Oncol Biol Phys. 1993;27(1):3–9.
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.
42. Bauman GS, Venkatesan VM, Ago CT, et al. Postoperative
radiotherapy for stage I/II seminoma: results for 212 patients. Int J
Radiat Oncol Biol Phys. 1998;42(2):313–317.
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.
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
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.
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
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.
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
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.
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
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))
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,
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
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.
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
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
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 27.7 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
whether radiotherapy is robustly delivered.
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.
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
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
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
5. A
REFERENCES
1. Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO
classification of lymphoid neoplasms and beyond: evolving concepts
and practical applications. Blood. 2011;117(19):5019–5032.
2. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large
B-cell lymphoma identified by gene expression profiling. Nature.
2000;403(6769):503–511.
3. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2
and BCL6 expression predicts outcome in diffuse large B-cell
lymphoma. Blood. 2013;121(12):2253–2263.
4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for
initial evaluation, staging, and response assessment of Hodgkin and
non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol.
2014;32(27):3059–3068.
5. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s
disease. International Prognostic Factors Project on Advanced
Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–1514.
6. A predictive model for aggressive non-Hodgkin’s lymphoma. The
international non-Hodgkin’s lymphoma prognostic factors project. N
Engl J Med. 1993;329(14):987–994.
7. Sehn LH, Berry B, Chhanabhai M, et al. The revised International
Prognostic Index (R-IPI) is a better predictor of outcome than the
standard IPI for patients with diffuse large B-cell lymphoma treated
with R-CHOP. Blood. 2007;109(5):1857–1861.
8. Gallamini A, Rigacci L, Merli F, et al. The predictive value of
positron emission tomography scanning performed after two courses
of standard therapy on treatment outcome in advanced stage
Hodgkin’s disease. Haematologica. 2006;91(4):475–481.
9. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of
chemotherapy predicts treatment failure and progression-free
survival in Hodgkin lymphoma. Blood. 2006;107(1):52–59.
10. Hutchings M, Mikhaeel NG, Fields PA, et al. Prognostic value of
interim FDG-PET after two or three cycles of chemotherapy in
Hodgkin lymphoma. Ann Oncol. 2005;16(7):1160–1168.
11. Safar V, Dupuis J, Itti E, et al. Interim [18 F]fluorodeoxyglucose
positron emission tomography scan in diffuse large B-cell lymphoma
treated with anthracycline-based chemotherapy plus rituximab. J
Clin Oncol. 2012;30(2):184–190.
12. Yang DH, Min JJ, Song HC, et al. Prognostic significance of interim
(1)(8)F-FDG PET/CT after three or four cycles of R-CHOP
chemotherapy in the treatment of diffuse large B-cell lymphoma.
Eur J Cancer. 2011;47(9):1312–1318.
13. Mikhaeel NG, Hutchings M, Fields PA, et al. FDG-PET after two to
three cycles of chemotherapy predicts progression-free and overall
survival in high-grade non-Hodgkin lymphoma. Ann Oncol.
2005;16(9):1514–1523.
14. Haioun C, Itti E, Rahmouni A, et al. [18 F]fluoro-2-deoxy-D-glucose
positron emission tomography (FDG-PET) in aggressive lymphoma:
an early prognostic tool for predicting patient outcome. Blood.
2005;106(4):1376–1381.
15. Pregno P, Chiappella A, Bello M, et al. Interim 18-FDG-PET/CT
failed to predict the outcome in diffuse large B-cell lymphoma
patients treated at the diagnosis with rituximab-CHOP. Blood.
2012;119(9):2066–2073.
16. Cashen AF, Dehdashti F, Luo J, et al. 18 F-FDG PET/CT for early
response assessment in diffuse large B-cell lymphoma: poor
predictive value of international harmonization project
interpretation. J Nucl Med. 2011;52(3):386–392.
17. Yoo C, Lee DH, Kim JE, et al. Limited role of interim PET/CT in
patients with diffuse large B-cell lymphoma treated with R-CHOP.
Ann Hematol. 2011;90(7):797–802.
18. Halasz LM, Jacene HA, Catalano PJ, et al. Combined modality
treatment for PET-positive non-Hodgkin lymphoma: favorable
outcomes of combined modality treatment for patients with non-
Hodgkin lymphoma and positive interim or postchemotherapy FDG-
PET. Int J Radiat Oncol Biol Phys. 2012;83(5):e647–e654.
19. Dabaja BS, Hess K, Shihadeh F, et al. Positron emission
tomography/computed tomography findings during therapy predict
outcome in patients with diffuse large B-cell lymphoma treated with
chemotherapy alone but not in those who receive consolidation
radiation. Int J Radiat Oncol Biol Phys. 2014;89(2):384–391.
20. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity
in patients with early-stage Hodgkin’s lymphoma. N Engl J Med.
2010;363(7):640–652.
21. Eich HT, Diehl V, Gorgen H, et al. Intensified chemotherapy and
dose-reduced involved-field radiotherapy in patients with early
unfavorable Hodgkin’s lymphoma: final analysis of the German
Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199–
4206.
22. Raemaekers JM, Andre MP, Federico M, et al. Omitting
radiotherapy in early positron emission tomography-negative stage
I/II Hodgkin lymphoma is associated with an increased risk of early
relapse: Clinical results of the preplanned interim analysis of the
randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;
32(12):1188–1194.
23. Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-
directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med.
2015;372(17):1598–1607.
24. Borchmann P, Haverkamp H, Diehl V, et al. Eight cycles of
escalated-dose BEACOPP compared with four cycles of escalated-
dose BEACOPP followed by four cycles of baseline-dose BEACOPP
with or without radiotherapy in patients with advanced-stage
Hodgkin’s lymphoma: final analysis of the HD12 trial of the German
Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234–4242.
25. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity
chemotherapy and PET-guided radiotherapy in patients with
advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised,
open-label, phase 3 non-inferiority trial. Lancet.
2012;379(9828):1791–1799.
26. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without
radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s
lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin
Oncol. 2004;22(15):3032–3038.
27. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone
compared with chemotherapy plus radiotherapy for localized
intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J
Med. 1998;339(1):21–26.
28. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus
radiotherapy for localized aggressive lymphoma. N Engl J Med.
2005;352(12):1197–1205.
29. Bonnet C, Fillet G, Mounier N, et al. CHOP alone compared with
CHOP plus radiotherapy for localized aggressive lymphoma in
elderly patients: a study by the Groupe d’Etude des Lymphomes de
l’Adulte. J Clin Oncol. 2007;25(7):787–792.
30. Phan J, Mazloom A, Medeiros LJ, et al. Benefit of consolidative
radiation therapy in patients with diffuse large B-cell lymphoma
treated with R-CHOP chemotherapy. J Clin Oncol.
2010;28(27):4170–4176.
31. Dabaja BS, Vanderplas AM, Crosby-Thompson AL, et al. Radiation
for diffuse large B-cell lymphoma in the rituximab era: Analysis of
the National Comprehensive Cancer Network lymphoma outcomes
project. Cancer. 2015;121(7):1032–1039.
32. Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky
disease in elderly patients with aggressive B-cell lymphoma. J Clin
Oncol. 2014;32(11):1112–1118.
33. Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and
II low-grade follicular lymphoma? Results of a long-term follow-up
study of patients treated at Stanford University. J Clin Oncol.
1996;14(4):1282–1290.
34. Goda JS, Le LW, Lapperriere NJ, et al. Localized orbital mucosa-
associated lymphoma tissue lymphoma managed with primary
radiation therapy: efficacy and toxicity. Int J Radiat Oncol Biol Phys.
2011;81(4):e659–e666.
35. Tsang RW, Gospodarowicz MK, Pintilie M, et al. Stage I and II
MALT lymphoma: results of treatment with radiotherapy. Int J
Radiat Oncol Biol Phys. 2001;50(5):1258–1264.
36. Akhtari M, Reddy JP, Pinnix C, et al. Primary cutaneous B-cell
lymphoma (Non-Leg Type) has excellent outcomes even after very
low dose radiation as single-modality therapy. Leuk Lymphoma.
2015:1–13.
37. Haas RL, Poortmans P, de Jong D, et al. High response rates and
lasting remissions after low-dose involved field radiotherapy in
indolent lymphomas. J Clin Oncol. 2003;21(13):2474–2480.
38. Haas RL, Poortmans P, de Jong D, et al. Effective palliation by low
dose local radiotherapy for recurrent and/or chemotherapy
refractory non-follicular lymphoma patients. Eur J Cancer. 2005;
41(12):1724–1730.
39. Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy
radiotherapy for patients with indolent lymphoma (FORT): a
randomised phase 3 non-inferiority trial. Lancet Oncol.
2014;15(4):457–463.
40. Biswas T, Culakova E, Friedberg JW, et al. Involved field radiation
therapy following high dose chemotherapy and autologous stem cell
transplant benefits local control and survival in refractory or
recurrent Hodgkin lymphoma. Radiother Oncol. 2012;103(3):367–
372.
41. Hoppe BS, Moskowitz CH, Filippa DA, et al. Involved-field
radiotherapy before high-dose therapy and autologous stem-cell
rescue in diffuse large-cell lymphoma: long-term disease control and
toxicity. J Clin Oncol. 2008;26(11):1858–1864.
42. Goda JS, Massey C, Kuruvilla J, et al. Role of salvage radiation
therapy for patients with relapsed or refractory Hodgkin lymphoma
who failed autologous stem cell transplant. Int J Radiat Oncol Biol
Phys. 2012;84(3):e329–e335.
43. Yahalom J, Mauch P. The involved field is back: issues in
delineating the radiation field in Hodgkin’s disease. Ann Oncol.
2002;13(Suppl 1):79–83.
44. Goodman KA, Toner S, Hunt M, et al. Intensity-modulated
radiotherapy for lymphoma involving the mediastinum. Int J Radiat
Oncol Biol Phys. 2005;62(1):198–206.
45. MacDonald S, Bernard S, Balogh A, et al. Electronic compensation
using multileaf collimation for involved field radiation to the neck
and mediastinum in non-Hodgkin’s lymphoma and Hodgkin’s
lymphoma. Med Dosim. 2005;30(2):59–64.
46. Yahalom J. Transformation in the use of radiation therapy of
Hodgkin lymphoma: new concepts and indications lead to modern
field design and are assisted by PET imaging and intensity
modulated radiation therapy (IMRT). Eur J Haematol Suppl.
2005(66):90–97.
47. Girinsky T, Pichenot C, Beaudre A, et al. Is intensity-modulated
radiotherapy better than conventional radiation treatment and
three-dimensional conformal radiotherapy for mediastinal masses in
patients with Hodgkin’s disease, and is there a role for beam
orientation optimization and dose constraints assigned to virtual
volumes? Int J Radiat Oncol Biol Phys. 2006;64(1):218–226.
48. Ghalibafian M, Beaudre A, Girinsky T. Heart and coronary artery
protection in patients with mediastinal Hodgkin lymphoma treated
with intensity-modulated radiotherapy: dose constraints to virtual
volumes or to organs at risk? Radiother Oncol. 2008;87(1):82–88.
49. Campbell BA, Voss N, Pickles T, et al. Involved-nodal radiation
therapy as a component of combination therapy for limited-stage
Hodgkin’s lymphoma: a question of field size. J Clin Oncol.
2008;26(32):5170–5174.
50. Girinsky T, Specht L, Ghalibafian M, et al. The conundrum of
Hodgkin lymphoma nodes: to be or not to be included in the
involved node radiation fields. The EORTC-GELA lymphoma group
guidelines. Radiother Oncol. 2008;88(2):202–210.
51. Girinsky T, van der Maazen R, Specht L, et al. Involved-node
radiotherapy (INRT) in patients with early Hodgkin lymphoma:
concepts and guidelines. Radiother Oncol. 2006;79(3):270–277.
52. Weber DC, Peguret N, Dipasquale G, et al. Involved-node and
involved-field volumetric modulated arc vs. fixed beam intensity-
modulated radiotherapy for female patients with early-stage supra-
diaphragmatic Hodgkin lymphoma: a comparative planning study.
Int J Radiat Oncol Biol Phys. 2009;75(5):1578–1586.
53. Weber DC, Johanson S, Peguret N, et al. Predicted risk of radiation-
induced cancers after involved field and involved node radiotherapy
with or without intensity modulation for early-stage Hodgkin
lymphoma in female patients. Int J Radiat Oncol Biol Phys.
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
from the International Lymphoma Radiation Oncology Group. Int J
Radiat Oncol Biol Phys. 2014;89(1):49–58.
55. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for
Hodgkin lymphoma: field and dose guidelines from the international
lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol
Phys. 2014;89(4):854–862.
56. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for
extranodal lymphomas: field and dose guidelines from the
international lymphoma radiation oncology group. Int J Radiat
Oncol Biol Phys. 2015;92(1):11–31.
57. 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(2):527–530.
58. Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for
primary cutaneous lymphomas: field and dose guidelines from the
international lymphoma radiation oncology group. Int J Radiat
Oncol Biol Phys. 2015;92(1):32–39.
59. Wilson LD, Kacinski BM, Jones GW. Local superficial radiotherapy
in the management of minimal stage IA cutaneous T-cell lymphoma
(Mycosis Fungoides). Int J Radiat Oncol Biol Phys. 1998;40(1):109–
115.
60. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative
radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat
Oncol Biol Phys. 2009;74(1):154–158.
61. Dabaja BS, Rebueno NC, Mazloom A, et al. Radiation for Hodgkin’s
lymphoma in young female patients: a new technique to avoid the
breasts and decrease the dose to the heart. Int J Radiat Oncol Biol
Phys. 2011;79(2):503–507.
62. Hoppe BS, Flampouri S, Su Z, et al. Effective dose reduction to
cardiac structures using protons compared with 3DCRT and IMRT in
mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys.
2012;84(2):449–455.
63. Koo CW, Shah-Patel LR, Baer JW, et al. Cost-effectiveness and
patient tolerance of low-attenuation oral contrast material: milk
versus VoLumen. AJR Am J Roentgenol. 2008;190(5):1307–1313.
64. Kriz J, Spickermann M, Lehrich P, et al. Breath-hold technique in
conventional APPA or intensity-modulated radiotherapy for
Hodgkin’s lymphoma: comparison of ILROG IS-RT and the GHSG IF-
RT. Strahlenther Onkol. 2015;191:717–725.
65. Aznar MC, Maraldo MV, Schut DA, et al. Minimizing late effects for
patients with mediastinal Hodgkin lymphoma: deep inspiration
breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys.
2015;92(1):169–174.
66. Petersen PM, Aznar MC, Berthelsen AK, et al. Prospective phase II
trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of
deep inspiration breath-hold. Acta Oncol. 2015;54(1):60–66.
67. Charpentier AM, Conrad T, Sykes J, et al. Active breathing control
for patients receiving mediastinal radiation therapy for lymphoma:
Impact on normal tissue dose. Pract Radiat Oncol. 2014;4(3):174–
180.
68. Schneider U, Sumila M, Robotka J, et al. Radiation-induced second
malignancies after involved-node radiotherapy with deep-
inspiration breath-hold technique for early stage Hodgkin
Lymphoma: a dosimetric study. Radiat Oncol. 2014;9:58.
69. Voong KR, McSpadden K, Pinnix CC, et al. Dosimetric advantages of
a “butterfly” technique for intensity-modulated radiation therapy for
young female patients with mediastinal Hodgkin’s lymphoma.
Radiat Oncol. 2014;9:94.
70. Matoba M, Oota K, Toyoda I, et al. Usefulness of 4D-CT for
radiation treatment planning of gastric MZBCL/MALT. J Radiat Res.
2012;53(2):333–337.
71. Maraldo MV, Brodin NP, Aznar MC, et al. Estimated risk of
cardiovascular disease and secondary cancers with modern highly
conformal radiotherapy for early-stage mediastinal Hodgkin
lymphoma. Ann Oncol. 2013;24(8):2113–2118.
72. Filippi AR, Ragona R, Piva C, et al. Optimized volumetric
modulated arc therapy versus 3D-CRT for early stage mediastinal
Hodgkin lymphoma without axillary involvement: a comparison of
second cancers and heart disease risk. Int J Radiat Oncol Biol Phys.
2015;92(1):161–168.
73. Pinnix CC, Smith GL, Milgrom S, et al. Predictors of radiation
pneumonitis in patients receiving intensity modulated radiation
therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol
Biol Phys. 2015;92(1):175–182.
74. Cella L, Liuzzi R, D’Avino V, et al. Pulmonary damage in Hodgkin’s
lymphoma patients treated with sequential chemo-radiotherapy:
predictors of radiation-induced lung injury. Acta Oncol.
2014;53(5):613–619.
75. Fox AM, Dosoretz AP, Mauch PM, et al. Predictive factors for
radiation pneumonitis in Hodgkin lymphoma patients receiving
combined-modality therapy. Int J Radiat Oncol Biol Phys. 2012;
83(1):277–283.
76. Koh ES, Sun A, Tran TH, et al. Clinical dose-volume histogram
analysis in predicting radiation pneumonitis in Hodgkin’s
lymphoma. Int J Radiat Oncol Biol Phys. 2006;66(1):223–228.
77. Galper SL, Yu JB, Mauch PM, et al. Clinically significant cardiac
disease in patients with Hodgkin lymphoma treated with
mediastinal irradiation. Blood. 2011;117(2):412–418.
78. Maraldo MV, Brodin NP, Vogelius IR, et al. Risk of developing
cardiovascular disease after involved node radiotherapy versus
mantle field for Hodgkin lymphoma. Int J Radiat Oncol Biol Phys.
2012;83(4):1232–1237.
79. Schellong G, Riepenhausen M, Bruch C, et al. Late valvular and
other cardiac diseases after different doses of mediastinal
radiotherapy for Hodgkin disease in children and adolescents: report
from the longitudinal GPOH follow-up project of the German-
Austrian DAL-HD studies. Pediatr Blood Cancer. 2010;55(6):1145–
1152.
80. Cella L, Conson M, Pressello MC, et al. Hodgkin’s lymphoma
emerging radiation treatment techniques: trade-offs between late
radio-induced toxicities and secondary malignant neoplasms. Radiat
Oncol. 2013;8:22.
81. Darby SC, Ewertz M, Hall P. Ischemic heart disease after breast
cancer radiotherapy. N Engl J Med. 2013;368(26):2527.
82. Travis LB, Hill DA, Dores GM, et al. Breast cancer following
radiotherapy and chemotherapy among young women with Hodgkin
disease. JAMA. 2003;290(4):465–475.
83. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation
dose, chemotherapy, and hormonal factors in breast cancer
following Hodgkin’s disease. J Natl Cancer Inst. 2003;95(13):971–
980.
84. Sachs RK, Brenner DJ. Solid tumor risks after high doses of ionizing
radiation. Proc Natl Acad Sci U S A. 2005;102(37):13040–13045.
85. Hodgson DC, Koh ES, Tran TH, et al. Individualized estimates of
second cancer risks after contemporary radiation therapy for
Hodgkin lymphoma. Cancer. 2007;110(11):2576–2586.
86. De Bruin ML, Sparidans J, van’t Veer MB, et al. Breast cancer risk in
female survivors of Hodgkin’s lymphoma: lower risk after smaller
radiation volumes. J Clin Oncol. 2009;27(26):4239–4246.
87. Chera BS, Rodriguez C, Morris CG, et al. Dosimetric comparison of
three different involved nodal irradiation techniques for stage II
Hodgkin’s lymphoma patients: conventional radiotherapy, intensity-
modulated radiotherapy, and three-dimensional proton
radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75(4):1173–1180.
88. Andolino DL, Hoene T, Xiao L, et al. Dosimetric comparison of
involved-field three-dimensional conformal photon radiotherapy
and breast-sparing proton therapy for the treatment of Hodgkin’s
lymphoma in female pediatric patients. Int J Radiat Oncol Biol Phys.
2011;81(4):e667–e671.
89. Li J, Dabaja B, Reed V, et al. Rationale for and preliminary results
of proton beam therapy for mediastinal lymphoma. Int J Radiat
Oncol Biol Phys. 2011;81(1):167–174.
90. Hoppe BS, Flampouri S, Su Z, et al. Consolidative involved-node
proton therapy for Stage IA-IIIB mediastinal Hodgkin lymphoma:
preliminary dosimetric outcomes from a Phase II study. Int J Radiat
Oncol Biol Phys. 2012;83(1):260–267.
91. Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin lymphoma, version
2.2015. J Natl Compr Canc Netw. 2015;13(5):554–586.
92. Zhang R, Howell RM, Homann K, et al. Predicted risks of radiogenic
cardiac toxicity in two pediatric patients undergoing photon or
proton radiotherapy. Radiat Oncol. 2013;8(1):184.
93. Zeng C, Plastaras JP, James P, et al. Proton Beam Scanning for
Mediastinal Lymphoma: Dosimetric Evaluation and 4D Robustness
Assessment. 54th Annual Conference of the Particle Therapy Co-
operative Oncology Group San Diego, 2015.
94. Zeng C, Plastaras JP, Tochner ZA, et al. Proton pencil beam
scanning for mediastinal lymphoma: the impact of interplay
between target motion and beam scanning. Phys Med Biol.
2015;60(7):3013–3029.0
95. Hill-Kayser CE, Plastaras JP, Tochner Z, et al. The case for
combined-modality therapy for limited-stage Hodgkin’s disease.
Oncologist. 2012;17(8):1006–1010.
96. Swerdlow AJ, Cooke R, Bates A, et al. Breast cancer risk after
supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in
England and Wales: a national cohort study. J Clin Oncol.
2012;30(22):2745–2752.
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.
TREATMENT
General Principles
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).
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.
TABLE 28.1 Primary Tumor Site and Gross Tumor Volume (GTVp)
Delineations
TABLE 28.2 Target Volumes by Dose and Disease Site for the N0
through N3 Neck
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,
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
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.
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.
• 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
• 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.
IMRT quality assurance (QA) measurements are carried out for each
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 28.7 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).
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?
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.
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J
Clin. 2015;65(1):5–29.
2. Scoccianti C, Cecchini M, Anderson AS, et al. European Code against
Cancer 4th Edition: Alcohol drinking and cancer. Cancer Epidemiol.
2015; pii: S1877-7821(15)00023-5.
3. Garces Y, Offord KP, Croghan IT, et al. Tobacco use among radiation
oncology outpatients (Abstract 1027). Paper presented at: American
Society of Clinical Oncology 2004 July 15. J Clin Oncol.
2004;22:14S.
4. Prokhorov AV, Hudmon KS, Marani S, et al. Engaging physicians and
pharmacists in providing smoking cessation counseling. Arch Intern
Med. 2010;170(18):1640–1646.
5. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and
Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD:
U.S. Department of Health and Human Services Public Health
Service May 2008; 2008.
6. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of
low-dose isotretinoin for prevention of second primary tumors in
stage I and II head and neck cancer patients. J Natl Cancer Inst.
2006;98(7):441–450.
7. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal
association between human papillomavirus and a subset of head and
neck cancers. J Natl Cancer Inst. 2000;92(9):709–720.
8. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide
trends in incidence rates for oral cavity and oropharyngeal cancers. J
Clin Oncol. 2013;31(36):4550–4559.
9. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV
infection in the United States, 2009–2010. JAMA. 2012;307(7):693–
703.
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.
Int J Radiat Oncol Biol Phys. 2010;78(2):461–466.
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
Radiat Oncol Biol Phys. 2014;89(5):958–963.
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
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.
Int J Radiat Oncol Biol Phys. 2009;73(3):795–801.
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
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.
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.
29 Cancers of the Skin, Including
Mycosis Fungoides
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
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:
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
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
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.
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.
Figure 29.4 Isodose curves for 6-, 9-, and 12-MeV electrons, 8 × 8-cm field, showing greater skin
sparing for lower-energy 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
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.
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
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).
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.
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).
Fractionation Schedules
The National Comprehensive Cancer Network (NCCN) has published
recommended dose-fractionation schedules for curative treatment of skin
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.
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
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.
Cutaneous Melanoma
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.
Mycosis Fungoides
Mycosis fungoides (MF) is a low-grade, non-Hodgkin T-cell lymphoma
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).
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.)
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.
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.
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).
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.
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.
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.
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
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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
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.
REFERENCES
1. American Joint Committee on Cancer. AJCC Cancer Staging
Handbook. 2010.
2. Oncology NCPG. Squamous Cell Skin Cancer. 2015.
3. Chow JCL, Jiang R. Bone and mucosal dosimetry in skin radiation
therapy: a Monte Carlo study using kilovoltage photon and
megavoltage electron beams. Phys Med Biol. 2012;57:3885–3899.
4. Strydom W, Parker W, Olivares M. Electron beams: physical and
clinical aspects. Radiation Oncology Physics: A Handbook for Teachers
and Students. 2005:273–299.
5. Khan F, Doppke K, Hogstrom K, et al. Clinical Electron-Beam
Dosimetry (AAPM Report No. 32). 1991.
6. Chow JCL, Grigorov GN. Effect of electron beam obliquity on lateral
buildup ratio: a Monte Carlo dosimetry evaluation. Phys Med Biol.
2007;52:3965–3977.
7. Shiu AS, Tung SS, Gastorf RJ, et al. Dosimetric evaluation of lead
and tungsten eye shields in electron beam treatment. Int J Radiat
Oncol Biol Phys. 1996;35:599–604.
8. Amdur RJ, Kalbaugh KJ, Ewald LM, et al. Radiation therapy for skin
cancer near the eye: kilovoltage x-rays versus electrons. Int J Radiat
Oncol Biol Phys. 1992;23:769–779.
9. Chow JCL, Jiang R. Monte Carlo calculation of monitor unit for
electron arc therapy. Med Phys. 2010;37:1571–1578.
10. Park CC, Yom SS, Podgorsak MB, et al. American Society for
Therapeutic Radiology and Oncology (ASTRO) Emerging
Technology Committee report on electronic brachytherapy. Int J
Radiat Oncol Biol Phys. 2010;76:963–972.
11. Evans MD, Podgorsak EB, Pla M, et al. Dosimetric characteristics of
surface applicators for high dose-rate brachytherapy (Abstract). Med
Phys. 1995;22:671.
12. Guix B, Finestres F, Tello J, et al. Treatment of skin carcinomas of
the face by high-dose-rate brachytherapy and custom-made surface
molds. Int J Radiat Oncol Biol Phys. 2000;47:95–102.
13. Sabbas AM, Kulidzhanov FG, Presser J, et al. HDR brachytherapy
with surface applicators: technical considerations and dosimetry.
Technol Cancer Res Treat. 2004;3:259–267.
14. Granero D, Pérez-Calatayud J, Gimeno J, et al. Design and
evaluation of a HDR skin applicator with flattening filter. Med Phys.
2008;35:495–503.
15. Sayler E, Eldredge-Hindy H, Dinome J, et al. Clinical
implementation and failure mode and effects analysis of HDR skin
brachytherapy using Valencia and Leipzig surface applicators.
Brachytherapy. 2015;14:293–299.
16. Köhler-Brock A, Prager W, Pohlmann S, et al. [The indications for
and results of HDR afterloading therapy in diseases of the skin and
mucosa with standardized surface applicators (the Leipzig
applicator)]. Strahlenther Onkol. 1999;175:170–174.
17. Tormo A, Celada F, Rodriguez S, et al. Non-melanoma skin cancer
treated with HDR Valencia applicator: clinical outcomes. J Contemp
Brachytherapy. 2014;6:167–172.
18. 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.
19. NCCN Clinical Practice Guidelines. Oncology. Merkel Cell Carcinoma.
2015.
20. Oncology NCPG. Melanoma. 2015.
21. Newman JC, Leffell DJ. Correlation of embryonic fusion planes with
the anatomical distribution of basal cell carcinoma. Dermatol Surg.
2007;33:957–964; discussion 965.
22. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Skin cancer of the
head and neck with perineural invasion. Am J Clin Oncol.
2007;30:93–96.
23. Garcia-Serra A, Hinerman RW, Mendenhall WM, et al. Carcinoma of
the skin with perineural invasion. Head Neck. 2003;25:1027–1033.
24. Gluck I, Ibrahim M, Popovtzer A, et al. Skin cancer of the head and
neck with perineural invasion: defining the clinical target volumes
based on the pattern of failure. Int J Radiat Oncol Biol Phys.
2009;74:38–46.
25. Oxenberg J, Kane JM 3rd. The role of radiation therapy in
melanoma. Surg Clin North Am. 2014;94:1031–1047.
26. Berk LB. Radiation therapy as primary and adjuvant treatment for
local and regional melanoma radiobiology of melanoma. Cancer
Control. 2008;15:233–238.
27. Hedblad MA, Mallbris L. Grenz ray treatment of lentigo maligna and
early lentigo maligna melanoma. J Am Acad Dermatol. 2012; 67:60–
68.
28. Guitera P, Moloney FJ, Menzies SW, et al. Improving management
and patient care in lentigo maligna by mapping with in vivo
confocal microscopy. JAMA Dermatol. 2013;149:692–698.
29. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant
radiotherapy versus observation alone for patients at risk of lymph-
node field relapse after therapeutic lymphadenectomy for
melanoma: a randomised trial. Lancet Oncol. 2012;13:589–597.
30. Ballo MT, Ang KK. Radiation therapy for malignant melanoma. Surg
Clin North Am. 2003;83:323–342.
31. Ballo MT, Ang KK. Radiotherapy for cutaneous malignant
melanoma: rationale and indications. Oncology (Williston Park).
2004; 18:99–107; discussion 107–110, 113–114.
32. Boyer JD, Zitelli JA, Brodland DG, et al. Local control of primary
Merkel cell carcinoma: review of 45 cases treated with Mohs
micrographic surgery with and without adjuvant radiation. J Am
Acad Dermatol. 2002;47:885–892.
33. Mortier L, Mirabel X, Fournier C, et al. Radiotherapy alone for
primary Merkel cell carcinoma. Arch Dermatol. 2003;139:1587–
1590.
34. Longo MI, Nghiem P. Merkel cell carcinoma treatment with
radiation: a good case despite no prospective studies. Arch Dermatol.
2003;139:1641–1643.
35. Medina-Franco H, Urist MM, Fiveash J, et al. Multimodality
treatment of Merkel cell carcinoma: case series and literature review
of 1024 cases. Ann Surg Oncol. 2001;8:204–208.
36. Mendenhall WM, Mendenhall CM, Mendenhall NP. Merkel cell
carcinoma. Laryngoscope. 2004;114:906–910.
37. McAfee WJ, Morris CG, Mendenhall CM, et al. Merkel cell
carcinoma: treatment and outcomes. Cancer. 2005;104:1761–1764.
38. Clark JR, Veness MJ, Gilbert R, et al. Merkel cell carcinoma of the
head and neck: is adjuvant radiotherapy necessary? Head Neck.
2007;29:249–257.
39. Ghadjar P, Kaanders JH, Poortmans P, et al. The essential role of
radiotherapy in the treatment of Merkel cell carcinoma: a study
from the rare cancer network. Int J Radiat Oncol Biol Phys.
2011;81:e583–e591.
40. Hoeller U, Mueller T, Schubert T, et al. Regional nodal relapse in
surgically staged Merkel cell carcinoma. Strahlenther Onkol. 2015;
191:51–58.
41. Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional
radiotherapy versus observation in stage I merkel cell carcinoma: a
multicentric prospective randomized study. Ann Oncol.
2012;23:1074–1080.
42. Hoppe RT. Mycosis fungoides: radiation therapy. Dermatol Ther.
2003;16:347–354.
43. Smith BD, Wilson LD. Management of mycosis fungoides: part 2.
Treatment. Oncology (Williston Park). 2003;17:1419–1428;
discussion 1430, 1433.
44. Smith BD, Wilson LD. Cutaneous lymphomas. Semin Radiat Oncol.
2007;17:158–168.
45. Cotter GW, Baglan RJ, Wasserman TH, et al. Palliative radiation
treatment of cutaneous mycosis fungoides—a dose response. Int J
Radiat Oncol Biol Phys. 1983;9:1477–1480.
46. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative
radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat
Oncol Biol Phys. 2009;74:154–158.
47. Thomas TO, Agrawal P, Guitart J, et al. Outcome of patients treated
with a single-fraction dose of palliative radiation for cutaneous T-
cell lymphoma. Int J Radiat Oncol Biol Phys. 2013;85:747–753.
48. Karzmark C, Anderson J, Fessenden P, et al. Total skin electron
therapy: technique and dosimetry. AAPM Report #23. 1988.
49. Trump J, Wright K, Evans W, et al. High energy electrons for the
treatment of extensive superficial malignant lesions. Am J Roentgenol
Radium Ther Nucl Med. 1953;69:623–629.
50. 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.
51. Karzmark CJ, Loevinger R, Steele RE, et al. A technique for large-
field, superficial electron therapy. Radiology. 1960;74:633–644.
52. Page V, Gardner A, Karzmark CJ. Patient dosimetry in the electron
treatment of large superficial lesions. Radiology. 1970;94:635–641.
53. Jones GW, Kacinski BM, Wilson LD, et al. Total skin electron
radiation in the management of mycosis fungoides: Consensus of the
European Organization for Research and Treatment of Cancer
(EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol.
2002; 47:364–370.
54. Million RR. Radiotherapy for carcinoma of the eyelid. Int J Radiat
Oncol Biol Phys. 1996;34:507.
55. Schlienger P, Brunin F, Desjardins L, et al. External radiotherapy for
carcinoma of the eyelid: report of 850 cases treated. Int J Radiat
Oncol Biol Phys. 1996;34:277–287.
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
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
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).
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.
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
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
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
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).
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
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
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.
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
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.
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.
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
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.
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
upper extremity lymphedema.
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
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).
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
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.
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
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.
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.
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,
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
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.
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?
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
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
1. Jatoi I, Chen BE, Anderson WF, et al. Breast cancer mortality trends
in the United States according to estrogen receptor status and age at
diagnosis. J Clin Oncol. 2007;25(13):1683–1690.
2. Blumgart EI, Uren RF, Nielsen PM, et al. Predicting lymphatic
drainage patterns and primary tumour location in patients with
breast cancer. Breast Cancer Res Treat. 2011;130(2):699–705.
3. Estourgie SH, Nieweg OE, Olmos RA, et al. Lymphatic drainage
patterns from the breast. Ann Surg. 2004;239(2):232–237.
4. Kawase K, Gayed IW, Hunt KK, et al. Use of lymphoscintigraphy
defines lymphatic drainage patterns before sentinel lymph node
biopsy for breast cancer. J Am Coll Surg. 2006;203(1):64–72.
5. Handley RS, Thackray AC. Invasion of the internal mammary lymph
glands in carcinoma of the breast. Br J Cancer. 1947; 1(1):15–20.
6. Danforth DN Jr, Findlay PA, McDonald HD, et al. Complete axillary
lymph node dissection for stage I-II carcinoma of the breast. J Clin
Oncol. 1986;4(5):655–662.
7. Wang H, Mao XY, Zhao TT, et al. Study on the skip metastasis of
axillary lymph nodes in breast cancer and their relation with Gli1
expression. Tumour Biol. 2012;33(6):1943–1950.
8. Stibbe EP. The internal mammary lymphatic glands. J Anat.
1918;52(Pt 3):257–264.
9. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA:
American Cancer Society; 2015.
10. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics
Review, 1975–2011. Bethesda, MD: National Cancer Institute; 2014.
11. U.S. Preventive Services Task Force. Screening for breast cancer:
U.S. Preventive Services Task Force recommendation statement. Ann
Intern Med. 2009;151(10):716–726.
12. Smith RA, Manassaram-Baptiste D, Brooks D, et al. Cancer screening
in the United States, 2015: a review of current American Cancer
Society guidelines and current issues in cancer screening. CA Cancer
J Clin. 2015;65(1):30–54.
13. Bevers TB, Anderson BO, Bonaccio E, et al; National Comprehensive
Cancer Network. NCCN clinical practice guidelines in oncology:
breast cancer screening and diagnosis. J Natl Compr Canc Netw.
2009;7(10):1060–1096.
14. Collaborative Group on Hormonal Factors in Breast Cancer.
Menarche, menopause, and breast cancer risk: individual participant
meta-analysis, including 118 964 women with breast cancer from
117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–1151.
15. Reeves GK, Pirie K, Green J, et al. Reproductive factors and specific
histological types of breast cancer: prospective study and meta-
analysis. Br J Cancer. 2009;100(3):538–544.
16. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast
cancer. Epidemiol Rev. 1993;15(1):36–47.
17. Beral V; Million Women Study Collaborators. Breast cancer and
hormone-replacement therapy in the Million Women Study. Lancet.
2003;362(9382):419–427.
18. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal
hormone therapy and health outcomes during the intervention and
extended poststopping phases of the Women’s Health Initiative
randomized trials. JAMA. 2013;310(13):1353–1368.
19. Collaborative Group on Hormonal Factors in Breast Cancer. Breast
cancer and hormonal contraceptives: collaborative reanalysis of
individual data on 53 297 women with breast cancer and 100 239
women without breast cancer from 54 epidemiological studies.
Lancet. 1996;347(9017):1713–1727.
20. Drooger JC, Hooning MJ, Seynaeve CM, et al. Diagnostic and
therapeutic ionizing radiation and the risk of a first and second
primary breast cancer, with special attention for BRCA1 and BRCA2
mutation carriers: a critical review of the literature. Cancer Treat
Rev. 2015;41(2):187–196.
21. Preston DL, Mattsson A, Holmberg E, et al. Radiation effects on
breast cancer risk: a pooled analysis of eight cohorts. Radiat Res.
2002;158(2):220–235.
22. Henderson TO, Amsterdam A, Bhatia S, et al. Systematic review:
surveillance for breast cancer in women treated with chest radiation
for childhood, adolescent, or young adult cancer. Ann Intern Med.
2010;152(7):444–455; w144–w154.
23. Collaborative Group on Hormonal Factors in Breast Cancer. Familial
breast cancer: collaborative reanalysis of individual data from 52
epidemiological studies including 58,209 women with breast cancer
and 101,986 women without the disease. Lancet.
2001;358(9291):1389–1399.
24. Nicoletto MO, Donach M, De Nicolo A, et al. BRCA-1 and BRCA-2
mutations as prognostic factors in clinical practice and genetic
counselling. Cancer Treat Rev. 2001;27(5):295–304.
25. Carter RF. BRCA1, BRCA2 and breast cancer: a concise clinical
review. Clin Invest Med. 2001;24(3):147–157.
26. NCCN Guidelines version 2.2014. Genetic/Familial High-Risk
Assessment: Breast and Ovarian 2014. Available from:
http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf
27. Fisher B, Slack NH, Ausman RK et al. Location of breast carcinoma
and prognosis. Surg Gynecol Obstet. 1969;129(4):705–716.
28. Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in
breast cancer. College of American Pathologists Consensus
Statement 1999. Arch Pathol Lab Med. 2000;124(7):966–978.
29. Jemal A, Ward E, Thun MJ. Recent trends in breast cancer
incidence rates by age and tumor characteristics among U.S.
women. Breast Cancer Res. 2007;9(3):R28.
30. Sariego J. Patterns of breast cancer presentation in the United
States: does geography matter?Am Surg. 2009;75(7):545–549;
discussion 549–550.
31. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl
Cancer Inst Monogr. 2010;2010(41):139–141.
32. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of
the breast. N Engl J Med. 2004;350(14):1430–1441.
33. Jorns J, Sabel MS, Pang JC. Lobular neoplasia: morphology and
management. Arch Pathol Lab Med. 2014;138(10):1344–1349.
34. Pestalozzi BC, Zahrieh D, Mallon E, et al. Distinct clinical and
prognostic features of infiltrating lobular carcinoma of the breast:
combined results of 15 International Breast Cancer Study Group
clinical trials. J Clin Oncol. 2008;26(18):3006–3014.
35. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a
randomized trial comparing total mastectomy, lumpectomy, and
lumpectomy plus irradiation for the treatment of invasive breast
cancer. N Engl J Med. 2002;347(16):1233–1241.
36. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast
cancer in women with ductal carcinoma in situ: an update of the
National Surgical Adjuvant Breast and Bowel Project experience.
Semin Oncol. 2001;28(4):400–418.
37. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby
S, McGale P, et al. Effect of radiotherapy after breast-conserving
surgery on 10-year recurrence and 15-year breast cancer death:
meta-analysis of individual patient data for 10,801 women in 17
randomised trials. Lancet. 2011;378(9804):1707–1716.
38. Fleck R, McNeese MD, Ellerbroek NA, et al. Consequences of breast
irradiation in patients with pre-existing collagen vascular diseases.
Int J Radiat Oncol Biol Phys. 1989;17(4):829–833.
39. Cao JQ, Truong PT, Olivotto IA, et al. Should women younger than
40 years of age with invasive breast cancer have a mastectomy? 15-
year outcomes in a population-based cohort. Int J Radiat Oncol Biol
Phys. 2014;90(3):509–517.
40. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group),
McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy
and axillary surgery on 10-year recurrence and 20-year breast
cancer mortality: meta-analysis of individual patient data for 8135
women in 22 randomised trials. Lancet. 2014;383(9935):2127–2135.
41. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative
radiotherapy in high-risk postmenopausal breast-cancer patients
given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group
DBCG 82 c randomised trial. Lancet. 1999;353(9165):1641–1648.
42. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative
radiotherapy in high-risk premenopausal women with breast cancer
who receive adjuvant chemotherapy. Danish Breast Cancer
Cooperative Group 82b Trial. N Engl J Med. 1997;337(14):949–955.
43. Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation
therapy in patients with high-risk breast cancer receiving adjuvant
chemotherapy: 20-year results of the British Columbia randomized
trial. J Natl Cancer Inst. 2005;97(2):116–126.
44. NCCN Guidelines version 1.2015; Breast Cancer. 2015; Available
from:
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
45. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the
treatment of women with early breast cancer: highlights of the St
Gallen International Expert Consensus on the Primary Therapy of
Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206–2223.
46. Belkacemi Y, Fourquet A, Cutuli B, et al. Radiotherapy for invasive
breast cancer: guidelines for clinical practice from the French expert
review board of Nice/Saint-Paul de Vence. Crit Rev Oncol Hematol.
2011;79(2):91–102.
47. Wenz F, Sperk E, Budach W, et al. DEGRO practical guidelines for
radiotherapy of breast cancer IV: radiotherapy following
mastectomy for invasive breast cancer. Strahlenther Onkol. 2014;
190(8):705–714.
48. Souchon R, Sautter-Bihl ML, Sedlmayer F, et al. Radiation
oncologists’ view on the zurich consensus. Breast Care (Basel).
2013;8(6):448–452.
49. Rowell NP. Radiotherapy to the chest wall following mastectomy
for node-negative breast cancer: a systematic review. Radiother
Oncol. 2009;91(1):23–32.
50. Katz A, Strom EA, Buchholz TA, et al. The influence of pathologic
tumor characteristics on locoregional recurrence rates following
mastectomy. Int J Radiat Oncol Biol Phys. 2001;50(3):735–742.
51. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus
tamoxifen with or without irradiation in women age 70 years or
older with early breast cancer: long-term follow-up of CALGB 9343.
J Clin Oncol. 2013;31(19):2382–2387.
52. Hughes LL, Wang M, Page DL, et al. Local excision alone without
irradiation for ductal carcinoma in situ of the breast: a trial of the
Eastern Cooperative Oncology Group. J Clin Oncol.
2009;27(32):5319–5324.
53. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective
randomized trial for good-risk ductal carcinoma in situ comparing
radiotherapy with observation. J Clin Oncol. 2015;33(7):709–715.
54. Hartsell WF, Kelly CA, Schneider L, et al. A single isocenter three-
field breast irradiation technique using an empiric simulation and
asymmetric collimator. Med Dosim. 1994;19(3):169–173.
55. Alonso-Basanta M, Ko J, Babcock M, et al. Coverage of axillary
lymph nodes in supine vs. prone breast radiotherapy. Int J Radiat
Oncol Biol Phys. 2009;73(3):745–751.
56. Griem KL, Fetherston P, Kuznetsova M, et al. Three-dimensional
photon dosimetry: a comparison of treatment of the intact breast in
the supine and prone position. Int J Radiat Oncol Biol Phys.
2003;57(3):891–899.
57. Lymberis SC, deWyngaert JK, Parhar P, et al. Prospective
assessment of optimal individual position (prone versus supine) for
breast radiotherapy: volumetric and dosimetric correlations in 100
patients. Int J Radiat Oncol Biol Phys. 2012;84(4):902–909.
58. Kirby AM, Evans PM, Donovan EM, et al. Prone versus supine
positioning for whole and partial-breast radiotherapy: a comparison
of non-target tissue dosimetry. Radiother Oncol. 2010;96(2):178–
184.
59. Krengli M, Masini L, Caltavuturo T, et al. Prone versus supine
position for adjuvant breast radiotherapy: a prospective study in
patients with pendulous breasts. Radiat Oncol. 2013;8:232.
60. Mitchell J, Formenti SC, DeWyngaert JK. Interfraction and
intrafraction setup variability for prone breast radiation therapy. Int
J Radiat Oncol Biol Phys. 2010;76(5):1571–1577.
61. Hayden AJ, Rains M, Tiver K. Deep inspiration breath hold
technique reduces heart dose from radiotherapy for left-sided breast
cancer. J Med Imaging Radiat Oncol. 2012;56(4):464–472.
62. Swanson T, Grills I, Ye H, et al. Six-year experience routinely using
moderate deep inspiration breath-hold for the reduction of cardiac
dose in left-sided breast irradiation for patients with early-stage or
locally advanced breast cancer. Am J Clin Oncol. 2013;36(1):24–30.
63. Velker VM, Rodrigues GB, Dinniwell R, et al. Creation of RTOG
compliant patient CT-atlases for automated atlas based contouring
of local regional breast and high-risk prostate cancers. Radiat Oncol.
2013;8:188.
64. Li XA, Tai A, Arthur DW, et al. Variability of target and normal
structure delineation for breast cancer radiotherapy: an RTOG
Multi-Institutional and Multiobserver Study. Int J Radiat Oncol Biol
Phys. 2009;73(3):944–951.
65. White J, Tai D, Arthur T, et al. Breast Cancer Atlas for Radiation
Treatment Planning: Consensus Definitions. Book Breast Cancer Atlas
for Radiation Therapy Planning. R.T.O.G. (RTOG), Editor.
66. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: an
intergroup trial of regional nodal irradiation in early breast cancer.
J Clin Oncol. 2011;29(18_suppl):LBA1003.
67. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or
surgery of the axilla after a positive sentinel node in breast cancer
(EORTC 10981–22023 AMAROS): a randomised, multicentre, open-
label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303–
1310.
68. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no
axillary dissection in women with invasive breast cancer and
sentinel node metastasis: a randomized clinical trial. JAMA.
2011;305(6):569–575.
69. Robinson KA, Pockaj BA, Wasif N, et al. Have the American College
of Surgeons Oncology Group Z0011 trial results influenced the
number of lymph nodes removed during sentinel lymph node
dissection? Am J Surg. 2014;208(6):1060–1064; discussion 1063–
1064.
70. Jagsi R, Chadha M, Moni J, et al. Radiation field design in the
ACOSOG Z0011 (Alliance) Trial. J Clin Oncol. 2014;32(32):3600–
3606.
71. Hennequin C, Bossard N, Servagi-Vernat S, et al. Ten-year survival
results of a randomized trial of irradiation of internal mammary
nodes after mastectomy. Int J Radiat Oncol Biol Phys.
2013;86(5):860–866.
72. Arthur DW, Arnfield MR, Warwicke LA, et al. Internal mammary
node coverage: an investigation of presently accepted techniques. Int
J Radiat Oncol Biol Phys. 2000;48(1):139–146.
73. Pierce LJ, Butler JB, Martel MK, et al. Postmastectomy radiotherapy
of the chest wall: dosimetric comparison of common techniques. Int
J Radiat Oncol Biol Phys. 2002;52(5):1220–1230.
74. Sonnik D, Selvaraj RN, Faul C, et al. Treatment techniques for 3D
conformal radiation to breast and chest wall including the internal
mammary chain. Med Dosim. 2007;32(1):7–12.
75. Oh JL, Buchholz TA. Internal mammary node radiation: a proposed
technique to spare cardiac toxicity. J Clin Oncol. 2009; 27(31):e172–
e173.
76. Kutcher GJ, Smith AR, Fowble BL, et al. Treatment planning for
primary breast cancer: a patterns of care study. Int J Radiat Oncol
Biol Phys. 1996;36(3):731–737.
77. Solin LJ, Chu JC, Sontag MR, et al. Three-dimensional photon
treatment planning of the intact breast. Int J Radiat Oncol Biol Phys.
1991;21(1):193–203.
78. Garavaglia G, Porepp C, Jozefowsky M. Improved dose distribution
homogeneity in conservative breast cancer irradiation. Radiother
Oncol. 1991;22(4):245–247.
79. Beavis AW. Treatment planning challenges in breast irradiation: the
ideal and the practical. Clin Oncol (R Coll Radiol). 2006; 18(3):200–
209.
80. Mageras GS, Mohan R, Burman C, et al. Compensators for three-
dimensional treatment planning. Med Phys. 1991. 18(2):133–140.
81. Hansen VN, Evans PM, Shentall GS, et al. Dosimetric evaluation of
compensation in radiotherapy of the breast: MLC intensity
modulation and physical compensators. Radiother Oncol. 1997;
42(3):249–256.
82. Lief EP, Hunt MA, Hong LX, et al. Radiation therapy of large intact
breasts using a beam spoiler or photons with mixed energies. Med
Dosim. 2007;32(4):246–253.
83. Ramsey CR, Chase D, Scaperoth D, et al. Improved dose
homogeneity to the intact breast using three-dimensional treatment
planning: technical considerations. Med Dosim. 2000;25(1):1–6.
84. Donovan E, Bleakley N, Denholm E, et al. Randomised trial of
standard 2D radiotherapy (RT) versus intensity modulated
radiotherapy (IMRT) in patients prescribed breast radiotherapy.
Radiother Oncol. 2007;82(3):254–264.
85. Barnett GC, Wilkinson JS, Moody AM, et al. Randomized controlled
trial of forward-planned intensity modulated radiotherapy for early
breast cancer: interim results at 2 years. Int J Radiat Oncol Biol Phys.
2012;82(2):715–723.
86. Mukesh MB, Barnett GC, Wilkinson JS, et al. Randomized controlled
trial of intensity-modulated radiotherapy for early breast cancer: 5-
year results confirm superior overall cosmesis. J Clin Oncol.
2013;31(36):4488-4495.
87. Pignol J-P, Olivotto I, Rakovitch E, et al. A multicenter randomized
trial of breast intensity-modulated radiation therapy to reduce acute
radiation dermatitis. J Clin Oncol. 2008;26(13):2085–2092.
88. Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy
results in significant decrease in clinical toxicities compared with
conventional wedge-based breast radiotherapy. Int J Radiat Oncol
Biol Phys. 2007;68(5):1375–1380.
89. McDonald MW, Godette KD, Butker EK, et al. Long-term outcomes
of IMRT for breast cancer: a single-institution cohort analysis. Int J
Radiat Oncol Biol Phys. 2008;72(4):1031–1040.
90. Lohr F, El-Haddad M, Dobler B, et al. Potential effect of robust and
simple IMRT approach for left-sided breast cancer on cardiac
mortality. Int J Radiat Oncol Biol Phys. 2009;74(1):73–80.
91. Beckham WA, Popescu CC, Patenaude VV, et al. Is multibeam IMRT
better than standard treatment for patients with left-sided breast
cancer? Int J Radiat Oncol Biol Phys. 2007;69(3):918–924.
92. Hong L, Hunt M, Chui C, et al. Intensity-modulated tangential beam
irradiation of the intact breast. Int J Radiat Oncol Biol Phys.
1999;44(5):1155–1164.
93. Bhatnagar A, Brandner E, Sonnik D, et al. Intensity modulated
radiation therapy (IMRT) reduces the dose to the contralateral
breast when compared to convention tangential fields for primary
breast irradiation. Breast Cancer Res Treat. 2006;96(1):41–46.
94. Freedman GM, Anderson PR, Li J, et al. Intensity modulated
radiation therapy (IMRT) decreases acute skin toxicity for women
receiving radiation for breast cancer. Am J Clin Oncol.
2006;29(1):66–70.
95. Mast ME, van Kempen-Harteveld L,Heijenbrok MW, et al. Left-sided
breast cancer radiotherapy with and without breath-hold: Does
IMRT reduce the cardiac dose even further? Radiother Oncol.
2013;108(2):248–253.
96. Coon AB, Dickler A, Kirk MC, et al. Tomotherapy and multifield
intensity-modulated radiotherapy planning reduce cardiac doses in
left-sided breast cancer patients with unfavorable cardiac anatomy.
Int J Radiat Oncol Biol Phys. 2010;78(1):104–110.
97. Hahn C, Kavanagh B, Bhatnagar A et al. Choosing wisely: the
American Society for Radiation Oncology’s top 5 list. Pract Radiat
Oncol. 2014;4(6):349–355.
98. ASTRO releases list of five radiation oncology treatments to
question as part of national Choosing Wisely® campaign. 2013
[cited 2015 2/19/2015]; Available from:
http://www.choosingwisely.org/astro-releases-list-of-five-radiation-
oncology-treatments-to-question-as-part-of-national-choosing-wisely-
campaign/
99. McCormick B, Hunt M. Intensity-modulated radiation therapy for
breast: is it for everyone? Semin Radiat Oncol. 2011;21(1):51–54.
100. Teh BS, Lu HH, Sobremonte S, et al. The potential use of intensity
modulated radiotherapy (IMRT) in women with pectus excavatum
desiring breast-conserving therapy. Breast J. 2001;7(4):233–239.
101. Cendales R, Vasquez J, Arbelaez JC, et al. Intensity modulated
radiotherapy (IMRT) with simultaneous integrated boost (SIB) in a
patient with left breast cancer and pectus excavatum. Clin Transl
Oncol. 2012;14(10):747–754.
102. Caudell JJ, De Los Santos JF, Keene KS, et al. A dosimetric
comparison of electronic compensation, conventional intensity
modulated radiotherapy, and tomotherapy in patients with early-
stage carcinoma of the left breast. Int J Radiat Oncol Biol Phys.
2007;68(5):1505–1511.
103. Al-Rahbi ZS,Ravichandran R, Binukumar JP, et al. A dosimetric
comparison of radiotherapy techniques in the treatment of
carcinoma of breast. J Cancer Ther. 2013;4(11 a):10–17.
104. Gokula K, Earnest A, Wong LC. Meta-analysis of incidence of early
lung toxicity in 3-dimensional conformal irradiation of breast
carcinomas. Radiat Oncol. 2013;8:268.
105. Blom Goldman U,Wennberg B, Svane G, et al. Reduction of
radiation pneumonitis by V20-constraints in breast cancer. Radiat
Oncol. 2010;5:99.
106. Lind PA, Wennberg B, Gagliardi G, et al. Pulmonary complications
following different radiotherapy techniques for breast cancer, and
the association to irradiated lung volume and dose. Breast Cancer
Res Treat. 2001;68(3):199–210.
107. Blitzblau RC, Horton JK. Treatment planning technique in patients
receiving postmastectomy radiation therapy. Pract Radiat Oncol.
2013;3(4):241–248.
108. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in
long-term survivors of breast cancer who participated in trials of
radiotherapy. J Clin Oncol. 1994;12(3):447–453.
109. Gyenes G, Rutqvist LE, Liedberg A, et al. Long-term cardiac
morbidity and mortality in a randomized trial of pre- and
postoperative radiation therapy versus surgery alone in primary
breast cancer. Radiother Oncol. 1998;48(2):185–190.
110. Favourable and unfavourable effects on long-term survival of
radiotherapy for early breast cancer: an overview of the randomised
trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet.
2000;355(9217):1757–1770.
111. Giordano SH, Kuo YF, Freeman JL, et al. Risk of cardiac death after
adjuvant radiotherapy for breast cancer. J Natl Cancer Inst.
2005;97(6):419–424.
112. Rutter CE, Chagpar AB, Evans SB. Breast cancer laterality does not
influence survival in a large modern cohort: implications for
radiation-related cardiac mortality. Int J Radiat Oncol Biol Phys.
2014;90(2):329–334.
113. Darby SC, McGale P, Taylor CW, et al. Long-term mortality from
heart disease and lung cancer after radiotherapy for early breast
cancer: prospective cohort study of about 300,000 women in US
SEER cancer registries. Lancet Oncol. 2005;6(8):557–565.
114. Gagliardi G,Constine LS, Moiseenko V, et al. Radiation dose-volume
effects in the heart. Int J Radiat Oncol Biol Phys. 2010;76(3
Suppl):S77–S85.
115. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease
in women after radiotherapy for breast cancer. N Engl J Med.
2013;368(11):987–998.
116. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of
hypofractionated radiation therapy for breast cancer. N Engl J Med.
2010;362(6):513–520.
117. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of
Breast Radiotherapy (START) trials of radiotherapy
hypofractionation for treatment of early breast cancer: 10-year
follow-up results of two randomised controlled trials. Lancet Oncol.
2013;14(11):1086–1094.
118. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole
breast irradiation: an American Society for Radiation Oncology
(ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys.
2011;81(1):59–68.
119. FAST Trialists group, Agrawal RK, Alhasso A, et al. First results of
the randomised UK FAST Trial of radiotherapy hypofractionation for
treatment of early breast cancer (CRUKE/04/015). Radiother Oncol.
2011;100(1):93–100.
120. Koukourakis MI, Panteliadou M, Abatzoglou IM, et al.
Postmastectomy hypofractionated and accelerated radiation therapy
with (and without) subcutaneous amifostine cytoprotection. Int J
Radiat Oncol Biol Phys. 2013;85(1):e7–e13.
121. Holloway CL, Panet-Raymond V, Olivotto I. Hypofractionation
should be the new ‘standard’ for radiation therapy after breast
conserving surgery. Breast. 2010;19(3):163–167.
122. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in
the conservative treatment of early breast cancer: results of a
randomized clinical trial in Lyon, France. J Clin Oncol.
1997;15(3):963–968.
123. Polgar C, Fodor J, Orosz Z, et al. Electron and high-dose-rate
brachytherapy boost in the conservative treatment of stage I-II
breast cancer first results of the randomized Budapest boost trial.
Strahlenther Onkol. 2002;178(11):615–623.
124. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher
radiation dose on local control and survival in breast-conserving
therapy of early breast cancer: 10-year results of the randomized
boost versus no boost EORTC 22881–10882 trial. J Clin Oncol.
2007;25(22):3259–3265.
125. Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young
women with ductal carcinoma in situ: a multicentre, retrospective
study of the Rare Cancer Network. Lancet Oncol. 2006;7(8):652–656.
126. Freedman GM, White JR, Arthur DW, et al. Accelerated
fractionation with a concurrent boost for early stage breast cancer.
Radiother Oncol. 2013;106(1):15–20.
127. Gilliland MD, Barton RM, Copeland EM 3rd. The implications of
local recurrence of breast cancer as the first site of therapeutic
failure. Ann Surg. 1983;197(3):284–287.
128. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional
failure in patients with operable breast cancer treated by
mastectomy and adjuvant chemotherapy with or without tamoxifen
and without radiotherapy: results from five National Surgical
Adjuvant Breast and Bowel Project randomized clinical trials. J Clin
Oncol. 2004;22(21):4247–4254.
129. Panoff JE, Takita C, Hurley J, et al. Higher chest wall dose results
in improved locoregional outcome in patients receiving
postmastectomy radiation. Int J Radiat Oncol Biol Phys.
2012;82(3):1192–1199.
130. Fowble B, Solin LJ, Schultz DJ, et al. Breast recurrence following
conservative surgery and radiation: patterns of failure, prognosis,
and pathologic findings from mastectomy specimens with
implications for treatment. Int J Radiat Oncol Biol Phys. 1990;
19(4):833–842.
131. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-
conserving surgery in small breast carcinoma: long-term results of a
randomized trial. Ann Oncol. 2001;12(7):997–1003.
132. Liljegren G, Holmberg L, Bergh J, et al. 10-Year results after sector
resection with or without postoperative radiotherapy for stage I
breast cancer: a randomized trial. J Clin Oncol. 1999;17(8):2326–
2333.
133. Fisher ER, Anderson S, Redmond C, et al. Ipsilateral breast tumor
recurrence and survival following lumpectomy and irradiation:
pathological findings from NSABP protocol B-06. Semin Surg Oncol.
1992;8(3):161–166.
134. Clark RM, McCulloch PB, Levine MN, et al. Randomized clinical
trial to assess the effectiveness of breast irradiation following
lumpectomy and axillary dissection for node-negative breast cancer.
J Natl Cancer Inst. 1992;84(9):683–689.
135. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial
breast irradiation consensus statement from the American Society
for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys.
2009;74(4):987–1001.
136. Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and
toxicity results from RAPID: a randomized trial of accelerated
partial breast irradiation using three-dimensional conformal
external beam radiation therapy. J Clin Oncol. 2013;31(32):4038–
4045.
137. Shah C, Wilkinson JB, Lanni T, et al. Five-year outcomes and
toxicities using 3-dimensional conformal external beam radiation
therapy to deliver accelerated partial breast irradiation. Clin Breast
Cancer. 2013;13(3):206–211.
138. Berrang TS, Olivotto I, Kim DH, et al. Three-year outcomes of a
Canadian multicenter study of accelerated partial breast irradiation
using conformal radiation therapy. Int J Radiat Oncol Biol Phys.
2011;81(5):1220–1227.
139. Kim Y, Parda DS, Trombetta MG, et al. Dosimetric comparison of
partial and whole breast external beam irradiation in the treatment
of early stage breast cancer. Med Phys. 2007;34(12):4640–4648.
140. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast
irradiation using intensity-modulated radiotherapy versus whole
breast irradiation: 5-year survival analysis of a phase 3 randomised
controlled trial. Eur J Cancer. 2015;51(4):451–463.
141. Liss AL, Ben-David MA, Jagsi R, et al. Decline of cosmetic outcomes
following accelerated partial breast irradiation using intensity
modulated radiation therapy: results of a single-institution
prospective clinical trial. Int J Radiat Oncol Biol Phys. 2014;
89(1):96–102.
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
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.
31 Cancers of the Central Nervous
System
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.
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).
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
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
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.
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
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%
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).
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.
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.
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.
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).
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
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
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.”
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.
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.
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
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.
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
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.
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
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
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
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.
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
1. American CS. Cancer Facts and Figures. Atlanta, GA: American Cancer
Society; 2010.
2. CBTRUS. CBTRUS Statistical Report: Primary Brain and Central
Nervous System Tumors Diagnosed in the United States in 2007–2011.
Hinsdale, IL: Central Brain Tumor Registry of the United States;
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,
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
Metropolitan Detroit Cancer Surveillance System. J Clin Oncol.
2004;22:2865–2872.
9. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain
metastases in a cohort of patients with carcinoma of the breast,
colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–2705.
10. Byrne TN. Spinal cord compression from epidural metastases. N Engl
J Med. 1992;327:614–619.
11. Gerszten P. Current surgical management of metastatic spinal
disease. Oncology. 2000;14:1013–1024.
12. Loblaw DA, Laperriere NJ, Mackillop WJ. A population-based study
of malignant spinal cord compression in Ontario. Clin Oncol (R Coll
Radiol). 2003;15:211–217.
13. Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the
spine. Spine (Phila Pa 1976). 1985;10:19–20.
14. Bilsky MH, Lis E, Raizer J, et al. The diagnosis and treatment of
metastatic spinal tumor. Oncologist. 1999;4:459–469.
15. Healey JH, Brown HK. Complications of bone metastases: surgical
management. Cancer. 2000;88:2940–2951.
16. Wong DA, Fornasier VL, MacNab I. Spinal metastases: the obvious,
the occult, and the impostors. Spine (Phila Pa 1976). 1990;15:1–4.
17. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression
from metastatic tumor: diagnosis and treatment. Ann Neurol.
1978;3:40–51.
18. Patchell RA. A randomized trial of direct decompressive surgical
resection in the treatment of spinal cord compression caused by
metastasis. J Clin Oncol. 2003;21(1):67–86.
19. Pigott KH, Baddeley H, Maher EJ. Pattern of disease in spinal cord
compression on MRI scan and implications for treatment. Clin Oncol
(R Coll Radiol). 1994;6:7–10.
20. O’Rourke T, George CB, Redmond J 3rd, et al. Spinal computed
tomography and computed tomographic metrizamide myelography
in the early diagnosis of metastatic disease. J Clin Oncol.
1986;4:576–583.
21. Ruff RL, Lanska DJ. Epidural metastases in prospectively evaluated
veterans with cancer and back pain. Cancer. 1989;63:2234–2241.
22. Schiff D, Batchelor T, Wen PY. Neurologic emergencies in cancer
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
J Radiat Oncol Biol Phys. 2000;48:43–52.
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.
Bull N Y Acad Med. 1966;42:301–311.
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.
Neurology. 1994;44:675–680.
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
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
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.
52. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the
central nervous system. Int J Radiat Oncol Biol Phys. 1995;31:1093–
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.
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.
65. Walker MD, Alexander E, Hunt WE, et al. Evaluation of BCNU
and/or radiotherapy in the treatment of anaplastic gliomas. J
Neurosurg. 1978;49:333–343.
66. Aur RJ, Simone JV, Hustu HO, et al. A comparative study of central
nervous system irradiation and intensive chemotherapy early in
remission of childhood acute lymphocytic leukemia. Cancer.
1972;29:381–391.
67. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain
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
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.
72. Sherouse GW. A mathematical basis for selection of wedge angle
and orientation. Med Phys. 1993;20:1211–1218.
73. JM M. Spinal canal. In: Haperin EC, Perez CA, Brady LW, eds.
Principles and Practice of Radiation Oncology. 5th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2008:765–777.
74. Minehan KJ, Shaw EG, Scheithauer BW, et al. Spinal cord
astrocytoma: pathological and treatment considerations. J
Neurosurg. 1995;83:590–595.
75. Shen J, Bender E, Yaparpalvi R, et al. An efficient Volumetric Arc
Therapy treatment planning approach for hippocampal-avoidance
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.
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).
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
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).
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).
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.
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.
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.
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
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.
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
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.
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
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.
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
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.
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.
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
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
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
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.
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
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
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
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
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.
Radiother Oncol. 2014;113(1):89–94.
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.
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
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
Radiat Oncol Biol Phys. 2010;77(1):113–118.
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.
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
Hodgkin lymphoma. JAMA. 2012;307(24):2609–2616.
49. Unal S, Yetgin S, Cetin M, et al. The prognosis and survival of
childhood acute lymphoblastic leukemia with central nervous
system relapse. Pediatr Hematol Oncol. 2004;21(3):279–289.
50. Raney B, Stoner J, Anderson J, et al. Impact of tumor viability at
second-look procedures performed before completing treatment on
the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV,
1991–1997: a report from the children’s oncology group. J Pediatr
Surg 2010;45(11):2160–2168.
51. Poulaki V, Mukai S. Retinoblastoma: genetics and pathology. Int
Ophthalmol Clin. 2009;49(1):155–164.
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
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.
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,
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
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).
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
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,
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.
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.
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
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
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).
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
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.)
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
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
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).
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
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.
Protons
There is currently a growing interest in the applications of particle
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
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
(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
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).
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
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
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.
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
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
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
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).
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
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.
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.
• 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
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
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.
REFERENCES
1. O’Rahilly R, Müller F, Carpenter S, et al. Basic Human Anatomy: A
Regional Study of Human Structure. Hanover, NH: Dartmouth Medical
School; 2004.
2. Vansteenkiste JF, Stroobants SG. The role of positron emission
tomography with 18 F-fluoro-2-deoxy-D-glucose in respiratory
oncology. Eur Respir J. 2001;17:802–820.
3. Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative
staging of non-small-cell lung cancer with positron-emission
tomography. N Engl J Med. 2000;343:254–261.
4. Rengan R, Chetty IJ, Decker R, et al. Lung cancer. In: Perez CA,
Halperin EC, Brady LW, et al., eds. Perez & Brady’s Principles and
Practice of Radiation Oncology. 6th ed. Philadelphia, PA: Wolters
Kluwer, Lippincott, Wilkins and Williams; 2013.
5. Thorax. In: Edge S, Byrd D, Compton C, et al., eds. AJCC Cancer
Staging Handbook. 7th ed. Chicago, IL: Springer; 2010:299.
6. Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer
staging project: a proposal for a new international lymph node map
in the forthcoming seventh edition of the TNM classification for lung
cancer. J Thorac Oncol. 2009;4:568–577.
7. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging
system for lung cancer. Ann Thorac Cardiovasc Surg. 2009;15:4–9.
8. Senan S, De Ruysscher D, Giraud P, et al. Literature-based
recommendations for treatment planning and execution in high-dose
radiotherapy for lung cancer. Radiother Oncol. 2004;71:139–146.
9. Cascade PN, Gross BH, Kazerooni EA, et al. Variability in the
detection of enlarged mediastinal lymph nodes in staging lung
cancer: a comparison of contrast-enhanced and unenhanced CT. AJR
Am J Roentgenol. 1998;170:927–931.
10. Patz EF Jr, Erasmus JJ, McAdams HP, et al. Lung cancer staging and
management: comparison of contrast-enhanced and non-enhanced
helical CT of the thorax. Radiology. 1999;212:56–60.
11. Seppenwoolde Y, Shirato H, Kitamura K, et al. Precise and real-time
measurement of 3D tumor motion in lung due to breathing and
heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol
Phys. 2002;53:822–834.
12. Mageras GS, Pevsner A, Yorke ED, et al. Measurement of lung tumor
motion using respiration-correlated CT. Int J Radiat Oncol Biol Phys.
2004;60:933–941.
13. Underberg RW, Lagerwaard FJ, Cuijpers JP, et al. Four-dimensional
CT scans for treatment planning in stereotactic radiotherapy for
stage I lung cancer. Int J Radiat Oncol Biol Phys. 2004;60:1283–
1290.
14. Keall PJ, Mageras GS, Balter JM, et al. The management of
respiratory motion in radiation oncology report of AAPM task group
76. Med Phys. 2006;33:3874–3900.
15. Rosu M, Balter JM, Chetty IJ, et al. How extensive of a 4D dataset is
needed to estimate cumulative dose distribution plan evaluation
metrics in conformal lung therapy? Med Phys. 2007;34:233–245.
16. Underberg RW, Lagerwaard FJ, Slotman BJ, et al. Use of maximum
intensity projections (MIP) for target volume generation in 4DCT
scans for lung cancer. Int J Radiat Oncol Biol Phys. 2005;63:253–260.
17. Glide-Hurst CK, Hugo GD, Liang J, et al. A simplified method of
four-dimensional dose accumulation using the mean patient density
representation. Med Phys. 2008;35:5269–5277.
18. Negoro Y, Nagata Y, Aoki T, et al. The effectiveness of an
immobilization device in conformal radiotherapy for lung tumor:
reduction of respiratory tumor movement and evaluation of the
daily setup accuracy. Int J Radiat Oncol Biol Phys. 2001;50:889–898.
19. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing
control (ABC) to reduce margin for breathing motion. Int J Radiat
Oncol Biol Phys. 1999;44:911–919.
20. International Commission on Radiation Units and Measurements.
ICRU report 50. Prescribing, recording, and reporting photon beam
therapy. 1993.
21. Harris KM, Adams H, Lloyd DC, et al. The effect on apparent size of
simulated pulmonary nodules of using three standard CT window
settings. Clin Radiol. 1993;47:241–244.
22. International Commission on Radiation Units and Measurements.
ICRU report 62. Prescribing, recording and reporting photon beam
therapy (supplement to ICRU report 50). 1999.
23. Ezhil M, Vedam S, Balter P, et al. Determination of patient-specific
internal gross tumor volumes for lung cancer using four-dimensional
computed tomography. Radiat Oncol. 2009;4:4.
24. Balter JM, Ten Haken RK, Lawrence TS, et al. Uncertainties in CT-
based radiation therapy treatment planning associated with patient
breathing. Int J Radiat Oncol Biol Phys. 1996;36:167–174.
25. Shih HA, Jiang SB, Aljarrah KM, et al. Internal target volume
determined with expansion margins beyond composite gross tumor
volume in three-dimensional conformal radiotherapy for lung
cancer. Int J Radiat Oncol Biol Phys. 2004;60:613–622.
26. Lagerwaard FJ, Van Sornsen den Koste JR, Nijssen-Visser MR, et al.
Multiple “slow” CT scans for incorporating lung tumor mobility in
radiotherapy planning. Int J Radiat Oncol Biol Phys. 2001;51:932–
937.
27. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic
tumor extension in non-small-cell lung cancer for three-dimensional
conformal radiotherapy planning. Int J Radiat Oncol Biol Phys.
2000;48:1015–1024.
28. Yuan S, Meng X, Yu J, et al. Determining optimal clinical target
volume margins on the basis of microscopic extracapsular extension
of metastatic nodes in patients with non-small-cell lung cancer. Int J
Radiat Oncol Biol Phys. 2007;67:727–734.
29. Kong FS, Ritter T, Quint DJ, et al. Consideration of dose limits for
organs at risk of thoracic radiotherapy: atlas for lung, proximal
bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int
J Radiat Oncol Biol Phys. 2011;81:1442–1457.
30. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
complication probability models in the clinic. Int J Radiat Oncol Biol
Phys. 2010;76:S10–S19.
31. MacManus M, Nestle U, Rosenzweig KE, et al. Use of PET and
PET/CT for radiation therapy planning: IAEA expert report 2006–
2007. Radiother Oncol. 2009;91:85–94.
32. Yu HM, Liu YF, Hou M, et al. Evaluation of gross tumor size using
CT, 18 F-FDG PET, integrated 18 F-FDG PET/CT and pathological
analysis in non-small cell lung cancer. Eur J Radiol. 2009;72:104–
113.
33. Hong R, Halama J, Bova D, et al. Correlation of PET standard
uptake value and CT window-level thresholds for target delineation
in CT-based radiation treatment planning. Int J Radiat Oncol Biol
Phys. 2007;67:720–726.
34. Yaremko B, Riauka T, Robinson D, et al. Thresholding in PET
images of static and moving targets. Phys Med Biol. 2005;50:5969–
5982.
35. Caldwell CB, Mah K, Ung YC, et al. Observer variation in contouring
gross tumor volume in patients with poorly defined non-small-cell
lung tumors on CT: the impact of 18FDG-hybrid PET fusion. Int J
Radiat Oncol Biol Phys. 2001;51:923–931.
36. Nestle U, Kremp S, Schaefer-Schuler A, et al. Comparison of
different methods for delineation of 18 F-FDG PET-positive tissue
for target volume definition in radiotherapy of patients with non-
small cell lung cancer. J Nucl Med. 2005;46:1342–1348.
37. De Ruysscher D, Wanders S, Minken A, et al. Effects of radiotherapy
planning with a dedicated combined PET-CT-simulator of patients
with non-small cell lung cancer on dose limiting normal tissues and
radiation dose-escalation: a planning study. Radiother Oncol.
2005;77:5–10.
38. Lavrenkov K, Partridge M, Cook G, et al. Positron emission
tomography for target volume definition in the treatment of non-
small cell lung cancer. Radiother Oncol. 2005;77:1–4.
39. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-
small cell lung cancer: a review of the current evidence. Chest.
2003;123:137S–146S.
40. Nestle U, Kremp S, Grosu AL. Practical integration of [18 F]-FDG-
PET and PET-CT in the planning of radiotherapy for non-small cell
lung cancer (NSCLC): the technical basis, ICRU-target volumes,
problems, perspectives. Radiother Oncol. 2006;81:209–225.
41. Grgic A, Nestle U, Schaefer-Schuler A, et al. FDG-PET-based
radiotherapy planning in lung cancer: optimum breathing protocol
and patient positioning–an intraindividual comparison. Int J Radiat
Oncol Biol Phys. 2009;73:103–111.
42. Rodriguez Fernandez A, Gomez Rio M, Llamas Elvira JM, et al.
Diagnosis efficacy of structural (CT) and functional (FDG-PET)
imaging methods in the thoracic and extrathoracic staging of non-
small cell lung cancer. Clin Transl Oncol. 2007;9:32–39.
43. Kong FM, Lally BE, Chang JY, et al. ACR appropriateness criteria(R)
radiation therapy for small-cell lung cancer. Am J Clin Oncol.
2013;36:206–213.
44. Chang JY, Kestin LL, Barriger RB, et al. ACR appropriateness
criteria(R) nonsurgical treatment for locally advanced non-small-cell
lung cancer: good performance status/definitive intent. Oncology
(Williston Park). 2014;28:706–710,10, 712, 714 passim.
45. De Ruysscher D, Faivre-Finn C, Nestle U, et al. European
organisation for research and treatment of cancer recommendations
for planning and delivery of high-dose, high-precision radiotherapy
for lung cancer. J Clin Oncol. 2010;28:5301–5310.
46. Gewanter RM, Rosenzweig KE, Chang JY, et al. ACR
appropriateness criteria: nonsurgical treatment for non-small-cell
lung cancer: Good performance status/definitive intent. Curr Probl
Cancer. 2010;34:228–249.
47. Decker RH, Langer CJ, Rosenzweig KE, et al. ACR appropriateness
criteria(R) postoperative adjuvant therapy in non-small cell lung
cancer. Am J Clin Oncol. 2011;34:537–544.
48. Rosenzweig KE, Chang JY, Chetty IJ, et al. ACR appropriateness
criteria nonsurgical treatment for non-small-cell lung cancer: poor
performance status or palliative intent. J Am Coll Radiol.
2013;10:654–664.
49. Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic
radiotherapy in lung cancer: an American Society for Radiation
Oncology evidence-based clinical practice guideline. Pract Radiat
Oncol. 2011;1:60–71.
50. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation
and surgical resection for superior sulcus non-small-cell lung
carcinomas: long-term results of southwest oncology group trial
9416 (intergroup trial 0160). J Clin Oncol. 2007;25:313–318.
51. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus
chemotherapy with or without surgical resection for stage III non-
small-cell lung cancer: a phase III randomised controlled trial.
Lancet. 2009;374:379–386.
52. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study
of various irradiation doses and fractionation schedules in the
treatment of inoperable non-oat-cell carcinoma of the lung.
Preliminary report by the radiation therapy oncology group. Cancer.
1980;45:2744–2753.
53. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the
patterns of failure in patients with unresectable non-oat cell
carcinoma of the lung treated with definitive radiotherapy. Report
by the radiation therapy oncology group. Cancer. 1987;59:1874–
1881.
54. Bradley JD, Paulus R, Graham MV, et al. Phase II trial of
postoperative adjuvant paclitaxel/carboplatin and thoracic
radiotherapy in resected stage II and IIIA non-small-cell lung cancer:
promising long-term results of the radiation therapy oncology
group–RTOG 9705. J Clin Oncol. 2005;23:3480–3487.
55. Keller SM, Adak S, Wagner H, et al. A randomized trial of
postoperative adjuvant therapy in patients with completely resected
stage II or IIIA non-small-cell lung cancer. Eastern cooperative
oncology group. N Engl J Med. 2000;343:1217–1222.
56. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent
chemoradiation for stage III non-small cell lung cancer: randomized
phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–1460.
57. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial
of hyperfractionated radiation therapy with total doses of 60.0 Gy to
79.2 Gy: possible survival benefit with greater than or equal to 69.6
Gy in favorable patients with radiation therapy oncology group
stage III non-small-cell lung carcinoma: report of radiation therapy
oncology group 83–11. J Clin Oncol. 1990;8:1543–1555.
58. Tarrasa AT, Kim K, Blum R, et al. Twice-daily compared with once-
daily thoracic radiotherapy in limited small-cell lung cancer treated
concurrently with cisplatin and etoposide. N Engl J Med.
1999;340:265–271.
59. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy
in the combined-modality treatment of patients with extensive
disease small-cell lung cancer: a randomized study. J Clin Oncol.
1999;17:2092–2099.
60. Saunders M, Dische S, Barrett A, et al. Continuous,
hyperfractionated, accelerated radiotherapy (CHART) versus
conventional radiotherapy in non-small cell lung cancer: mature
data from the randomised multicentre trial. CHART steering
committee. Radiother Oncol. 1999;52:137–148.
61. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy
regimens of paclitaxel and carboplatin for locally advanced non-
small-cell lung cancer: a randomized phase II locally advanced
multi-modality protocol. J Clin Oncol. 2005;23:5883–5891.
62. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated
accelerated radiotherapy (CHART) versus conventional radiotherapy
in non-small-cell lung cancer: a randomised multicentre trial.
CHART steering committee. Lancet. 1997;350:161–165.
63. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated
radiation therapy compared to conventionally fractionated radiation
therapy for the treatment of inoperable non-small cell lung cancer.
Radiat Oncol. 2012;7:33. 717X-7–33.
64. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic
irradiation in the combined modality treatment of limited-stage
small-cell lung cancer. The national cancer institute of Canada
clinical trials group. J Clin Oncol. 1993;11:336–344.
65. Slotman BJ, Njo KH, de Jonge A, et al. Hypofractionated radiation
therapy in unresectable stage III non-small cell lung cancer. Cancer.
1993;72:1885–1893.
66. Mauguen A, Le Pechoux C, Saunders MI, et al. Hyperfractionated or
accelerated radiotherapy in lung cancer: an individual patient data
meta-analysis. J Clin Oncol. 2012;30:2788–2797.
67. Videtic GM. The role of radiation therapy in small cell lung cancer.
Curr Oncol Rep. 2013;15:405–410.
68. Ekstrand KE, Barnes WH. Pitfalls in the use of high energy X rays to
treat tumors in the lung. Int J Radiat Oncol Biol Phys. 1990;18:249–
252.
69. Yorke E, Harisiadis L, Wessels B, et al. Dosimetric considerations in
radiation therapy of coin lesions of the lung. Int J Radiat Oncol Biol
Phys. 1996;34:481–487.
70. Miller RC, Bonner JA, Kline RW. Impact of beam energy and field
margin on penumbra at lung tumor-lung parenchyma interfaces. Int
J Radiat Oncol Biol Phys. 1998;41:707–713.
71. Wang L, Yorke E, Desobry G, et al. Dosimetric advantage of using 6
MV over 15 MV photons in conformal therapy of lung cancer: Monte
Carlo studies in patient geometries. J Appl Clin Med Phys.
2002;3:51–59.
72. Vanderstraeten B, Reynaert N, Paelinck L, et al. Accuracy of patient
dose calculation for lung IMRT: a comparison of Monte Carlo,
convolution/superposition, and pencil beam computations. Med
Phys. 2006;33:3149–3158.
73. Knoos T, Wieslander E, Cozzi L, et al. Comparison of dose
calculation algorithms for treatment planning in external photon
beam therapy for clinical situations. Phys Med Biol. 2006;51:5785–
5807.
74. Li J, Galvin J, Harrison A, et al. Dosimetric verification using Monte
Carlo calculations for tissue heterogeneity-corrected conformal
treatment plans following RTOG 0813 dosimetric criteria for lung
cancer stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys.
2012;84:508–513.
75. Klein EE, Morrison A, Purdy JA, et al. A volumetric study of
measurements and calculations of lung density corrections for 6 and
18 MV photons. Int J Radiat Oncol Biol Phys. 1997;37:1163–1170.
76. Derycke S, De Gersem WR, Van Duyse BB, et al. Conformal
radiotherapy of stage III non-small cell lung cancer: a class solution
involving non-coplanar intensity-modulated beams. Int J Radiat
Oncol Biol Phys. 1998;41:771–777.
77. Grills IS, Yan D, Martinez AA, et al. Potential for reduced toxicity
and dose escalation in the treatment of inoperable non-small-cell
lung cancer: a comparison of intensity-modulated radiation therapy
(IMRT), 3D conformal radiation, and elective nodal irradiation. Int J
Radiat Oncol Biol Phys. 2003;57:875–890.
78. Liu HH, Wang X, Dong L, et al. Feasibility of sparing lung and other
thoracic structures with intensity-modulated radiotherapy for non-
small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004; 58:1268–
1279.
79. Bezjak A, Rumble RB, Rodrigues G, et al. Intensity-modulated
radiotherapy in the treatment of lung cancer. Clin Oncol (R Coll
Radiol). 2012;24:508–520.
80. Chan C, Lang S, Rowbottom C, et al. Intensity-modulated
radiotherapy for lung cancer: current status and future
developments. J Thorac Oncol 2014;9:1598–1608.
81. Li HS, Chetty IJ, Solberg TD. Quantifying the interplay effect in
prostate IMRT delivery using a convolution-based method. Med
Phys. 2008;35:1703–1710.
82. Chui C, Yorke E, Hong L. The effects of intra-fraction organ motion
on the delivery of intensity-modulated field with a multileaf
collimator. Med Phys. 2003;30:1736–1746.
83. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-
dose conformal radiotherapy with concurrent and consolidation
carboplatin plus paclitaxel with or without cetuximab for patients
with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a
randomised, two-by-two factorial phase 3 study. Lancet Oncol.
2015;16(2):187–199.
84.
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?
study=0813
85. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy
for oligometastases. Lancet Oncol. 2013;14:e28–e37.
86. Peulen H, Karlsson K, Lindberg K, et al. Toxicity after reirradiation
of pulmonary tumours with stereotactic body radiotherapy.
Radiother Oncol. 2011;101:260–266.
87. Trakul N, Harris JP, Le QT, et al. Stereotactic ablative radiotherapy
for reirradiation of locally recurrent lung tumors. J Thorac Oncol.
2012;7:1462–1465.
88. Liu H, Zhang X, Vinogradskiy YY, et al. Predicting radiation
pneumonitis after stereotactic ablative radiation therapy in patients
previously treated with conventional thoracic radiation therapy. Int
J Radiat Oncol Biol Phys. 2012;84:1017–1023.
89. Reyngold M, Wu AJ, McLane A, et al. Toxicity and outcomes of
thoracic re-irradiation using stereotactic body radiation therapy
(SBRT). Radiat Oncol. 2013;8:99.
90. Valakh V, Miyamoto C, Micaily B, et al. Repeat stereotactic body
radiation therapy for patients with pulmonary malignancies who
had previously received SBRT to the same or an adjacent tumor site.
J Cancer Res Ther. 2013;9:680–685.
91. Trovo M, Minatel E, Durofil E, et al. Stereotactic body radiation
therapy for re-irradiation of persistent or recurrent non-small cell
lung cancer. Int J Radiat Oncol Biol Phys. 2014;88:1114–1119.
92. Hearn JW, Videtic GM, Djemil T, et al. Salvage stereotactic body
radiation therapy (SBRT) for local failure after primary lung SBRT.
Int J Radiat Oncol Biol Phys. 2014:90;402–406.
93. Parks J, Kloecker G, Woo S, et al. Stereotactic body radiation
therapy as salvage for intrathoracic recurrence in patients with
previously irradiated locally advanced non-small cell lung cancer.
Am J Clin Oncol. 2014.
94. Videtic GM, Stephans KL, Woody NM, et al. Stereotactic body
radiation therapy-based treatment model for stage I medically
inoperable small cell lung cancer. Pract Radiat Oncol. 2013;3:301–
306.
95. Shioyama Y, Nakamura K, Sasaki T, et al. Clinical results of
stereotactic body radiotherapy for stage I small-cell lung cancer: a
single institutional experience. J Radiat Res. 2013;54:108–112.
96. Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy
(SBRT) for operable stage I non-small-cell lung cancer: can SBRT be
comparable to surgery? Int J Radiat Oncol Biol Phys. 2011;81:1352–
1358.
97. Lagerwaard FJ, Verstegen NE, Haasbeek CJ, et al. Outcomes of
stereotactic ablative radiotherapy in patients with potentially
operable stage I non-small cell lung cancer. Int J Radiat Oncol Biol
Phys. 2012;83:348–353.
98. Feddock J, Arnold SM, Shelton BJ, et al. Stereotactic body radiation
therapy can be used safely to boost residual disease in locally
advanced non-small cell lung cancer: a prospective study. Int J
Radiat Oncol Biol Phys 2013;85:1325–1331.
99. Karam SD, Horne ZD, Hong RL, et al. Dose escalation with
stereotactic body radiation therapy boost for locally advanced non
small cell lung cancer. Radiat Oncol. 2013;8:179.
100. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation
therapy for inoperable early stage lung cancer. JAMA 2010;
303:1070–1076.
101. Wang L, Hayes S, Paskalev K, et al. Dosimetric comparison of
stereotactic body radiotherapy using 4D CT and multiphase CT
images for treatment planning of lung cancer: evaluation of the
impact on daily dose coverage. Radiother Oncol. 2009;91:314–324.
102. Videtic GM, Stephans K, Reddy C, et al. Intensity-modulated
radiotherapy-based stereotactic body radiotherapy for medically
inoperable early-stage lung cancer: excellent local control. Int J
Radiat Oncol Biol Phys. 2010;77:344–349.
103. Latifi K, Oliver J, Baker R, et al. Study of 201 non-small cell lung
cancer patients given stereotactic ablative radiation therapy shows
local control dependence on dose calculation algorithm. Int J Radiat
Oncol Biol Phys. 2014;88:1108–1113.
104. Zhuang T, Djemil T, Qi P, et al. Dose calculation differences
between Monte Carlo and pencil beam depend on the tumor
locations and volumes for lung stereotactic body radiation therapy.
J Appl Clin Med Phys. 2013;14:4011.
105. Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic
radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer:
updated results of 257 patients in a Japanese multi-institutional
study. J Thorac Oncol. 2007;2:S94–S100.
106. Kestin L, Grills I, Guckenberger M, et al. Dose-response relationship
with clinical outcome for lung stereotactic body radiotherapy
(SBRT) delivered via online image guidance. Radiother Oncol.
2014;110:499–504.
107. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic
radioablation: results of a phase I study in medically inoperable
stage I non-small cell lung cancer. Chest. 2003;124:1946–1955.
108. 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;24:4833–4839.
109. Uematsu M, Shioda A, Suda A, et al. Computed tomography-guided
frameless stereotactic radiotherapy for stage I non-small cell lung
cancer: a 5-year experience. Int J Radiat Oncol Biol Phys.
2001;51:666–670.
110. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a
phase I/II study of 48 Gy of stereotactic body radiotherapy in 4
fractions for primary lung cancer using a stereotactic body frame.
Int J Radiat Oncol Biol Phys. 2005;63:1427–1431.
111. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, et al. Outcomes of
stereotactic ablative radiotherapy for centrally located early-stage
lung cancer. J Thorac Oncol 2011;6:2036–2043.
112. Senthi S, Haasbeek CJ, Slotman BJ, et al. Outcomes of stereotactic
ablative radiotherapy for central lung tumours: a systematic review.
Radiother Oncol. 2013;106:276–282.
113. Chang JY, Li QQ, Xu QY, et al. Stereotactic ablative radiation
therapy for centrally located early stage or isolated parenchymal
recurrences of non-small cell lung cancer: how to fly in a “no fly
zone”. Int J Radiat Oncoly, Biol Phys. 2014;88:1120–1128.
114. Timmerman R, Bastasch M, Saha D, et al. Optimizing dose and
fractionation for stereotactic body radiation therapy. Normal tissue
and tumor control effects with large dose per fraction. Front Radiat
Ther Oncol. 2007;40:352–365.
115. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body
radiation therapy: the report of AAPM task group 101. Med Phys.
2010;37:4078–4101.
116. Timmerman RD, Park C, Kavanagh BD. The north American
experience with stereotactic body radiation therapy in non-small
cell lung cancer. J Thorac Oncol. 2007;2:101–112.
117. Lagerwaard FJ, Haasbeek CJ, Smit EF, et al. Outcomes of risk-
adapted fractionated stereotactic radiotherapy for stage I non-small-
cell lung cancer. Int J Radiat Oncol Biol Phys. 2008; 70:685–692.
118. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body
radiation therapy for early-stage non-small-cell lung carcinoma:
Four-year results of a prospective phase II study. Int J Radiat Oncol
Biol Phys. 2009;75:677–682.
119. Zheng X, Schipper M, Kidwell K, et al. Survival outcome after
stereotactic body radiation therapy and surgery for stage I non-small
cell lung cancer: A meta-analysis. Int J Radiat Oncol Biol Phys.
2014;90:603–611.
120. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus
limited resection for T1 N0 non-small cell lung cancer. lung cancer
study group. Ann Thorac Surg. 1995;60:615–622; discussion 622–
633.
121. Fernando HC, Landreneau RJ, Mandrekar SJ, et al. Impact of
brachytherapy on local recurrence rates after sublobar resection:
results from ACOSOG Z4032 (alliance), a phase III randomized trial
for high-risk operable non-small-cell lung cancer. J Clin Oncol.
2014;32:2456–2462.
122. Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of
pulmonary function test (PFT) changes after stereotactic body
radiotherapy (SBRT) for stage I lung cancer in medically inoperable
patients. J Thorac Oncol. 2009;4:838–844.
123. Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary
function as a predictor for survival and decline in pulmonary
function over time in patients undergoing stereotactic body
radiotherapy for the treatment of stage I non-small-cell lung cancer.
Int J Radiat Oncol Biol Phys. 2008;72:404–409.
124. Stanic S, Paulus R, Timmerman RD, et al. No clinically significant
changes in pulmonary function following stereotactic body radiation
therapy for early- stage peripheral non-small cell lung cancer: an
analysis of RTOG 0236. Int J Radiat Oncol Biol Phys. 2014;88:1092–
1099.
125. Voroney JP, Hope A, Dahele MR, et al. Chest wall pain and rib
fracture after stereotactic radiotherapy for peripheral non-small cell
lung cancer. J Thorac Oncol. 2009;4:1035–1037.
126. Stephans KL, Djemil T, Tendulkar RD, et al. Prediction of chest wall
toxicity from lung stereotactic body radiotherapy (SBRT). Int J
Radiat Oncol Biol Phys. 2012;82:974–980.
127. Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following
stereotactic body radiation therapy for stage I non-small-cell lung
cancer: Who’s at risk? Int J Radiat Oncol Biol Phys. 2008;72:1283–
1286.
128. Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy
from stereotactic body radiotherapy in early-stage NSCLC: Dose-
limiting toxicity in apical tumor sites. Radiother Oncol.
2009;93:408–413.
129. Corradetti MN, Haas AR, Rengan R. Central-airway necrosis after
stereotactic body-radiation therapy. New Engl J Med. 2012;
366:2327–2329.
130. Stephans KL, Djemil T, Diaconu C, et al. Esophageal dose tolerance
to hypofractionated stereotactic body radiation therapy: risk factors
for late toxicity. Int J Radiat Oncol Biol Phys. 2014;90:197–202.
131. Gejerman G, Mullokandov EA, Bagiella E, et al. Endobronchial
brachytherapy and external-beam radiotherapy in patients with
endobronchial obstruction and extrabronchial extension.
Brachytherapy. 2002;1:204–210.
132. Ung YC, Yu E, Falkson C, et al. The role of high-dose-rate
brachytherapy in the palliation of symptoms in patients with non-
small-cell lung cancer: a systematic review. Brachytherapy.
2006;5:189–202.
133. de Aquino Gorayeb MM, Gregorio MG, de Oliveira EQ, et al. High-
dose-rate brachytherapy in symptom palliation due to malignant
endobronchial obstruction: a quantitative assessment. Brachytherapy.
2013;12:471–478.
134. Schild SE, Rule WG, Ashman JB, et al. Proton beam therapy for
locally advanced lung cancer: a review. World J Clin Oncol.
2014;5:568–575.
135.
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?
study=1308
136. Engelsman M, Schwarz M, Dong L. Physics controversies in proton
therapy. Semin Radiat Oncol. 2013;23:88–96.
137. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J
Clin. 2015;65:5–29.
138. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology
of small-cell lung cancer in the united states over the last 30 years:
analysis of the surveillance, epidemiologic, and end results
database. J Clin Oncol. 2006;24:4539–4544.
139. Edwards BK, Noone AM, Mariotto AB, et al. Annual report to the
nation on the status of cancer, 1975–2010, featuring prevalence of
comorbidity and impact on survival among persons with lung,
colorectal, breast, or prostate cancer. Cancer. 2014;120:1290–1314.
140. McGarry RC, Song G, des Rosiers P, et al. Observation-only
management of early stage, medically inoperable lung cancer: poor
outcome. Chest. 2002;121:1155–1158.
141. Noordijk EM, vd Poest Clement E, Hermans J, et al. Radiotherapy
as an alternative to surgery in elderly patients with resectable lung
cancer. Radiother Oncol. 1988;13:83–89.
142. Sibley GS, Mundt AJ, Shapiro C, et al. The treatment of stage III
non small cell lung cancer using high dose conformal radiotherapy.
Int J Radiat Oncol Biol Phys. 1995;33:1001–1007.
143. Manon RR, Jaradat H, Patel R, et al. Potential for radiation therapy
technology innovations to permit dose escalation for non-small-cell
lung cancer. Clin Lung Cancer. 2005;7:107–113.
144. Soliman H, Cheung P, Yeung L, et al. Accelerated hypofractionated
radiotherapy for early-stage non-small-cell lung cancer: long-term
results. Int J Radiat Oncol Biol Phys. 2011;79:459–465.
145. Machtay M, Paulus R, Moughan J, et al. Defining local-regional
control and its importance in locally advanced non-small cell lung
carcinoma. J Thorac Oncol. 2012;7:716–722.
146. Albain KS, Swann RS, Rusch VR, et al. Phase III study of concurrent
chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by
surgical resection for stage IIIA(pN2) non-small cell lung cancer
(NSCLC): Outcomes update of north American intergroup 0139
(RTOG 9309). J Clin Oncol (Meeting Abstracts). 2005;23:7014.
147. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized
controlled trial of resection versus radiotherapy after induction
chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl
Cancer Inst. 2007;99:442–450.
148. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent
cisplatin/etoposide plus chest radiotherapy followed by surgery for
stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results
of southwest oncology group phase II study 8805. J Clin Oncol.
1995;13:1880–1892.
149. Edelman MJ, Suntharalingam M, Burrows W, et al. Phase I/II trial
of hyperfractionated radiation and chemotherapy followed by
surgery in stage III lung cancer. Ann Thorac Surg. 2008;86:903–910.
150. Suntharalingam M, Paulus R, Edelman MJ, et al. Radiation therapy
oncology group protocol 02–29: a phase II trial of neoadjuvant
therapy with concurrent chemotherapy and full-dose radiation
therapy followed by surgical resection and consolidative therapy for
locally advanced non-small cell carcinoma of the lung. Int J Radiat
Oncol Biol Phys. 2012;84:456–463.
151. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent
chemoradiation for stage III non-small cell lung cancer: randomized
phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–1460.
152. Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-
escalation study using three-dimensional conformal radiotherapy in
the treatment of inoperable non small cell lung carcinoma. Cancer.
2005;103:2118–2127.
153. Narayan S, Henning GT, Ten Haken RK, et al. Results following
treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation
study for non-small cell lung cancer. Lung Cancer. 2004;44:79–88.
154. Bradley JD, Moughan J, Graham MV, et al. A phase I/II radiation
dose escalation study with concurrent chemotherapy for patients
with inoperable stages I to III non-small-cell lung cancer: phase I
results of RTOG 0117. Int J Radiat Oncol Biol Phys. 2010;77:367–
372.
155. Rosenzweig KE, Sura S, Jackson A, et al. Involved-field radiation
therapy for inoperable non small-cell lung cancer. J Clin Oncol.
2007;25:5557–5561.
156. Belderbos JS, Kepka L, Spring Kong FM, et al. Report from the
international atomic energy agency (IAEA) consultants’ meeting on
elective nodal irradiation in lung cancer: non-small-cell lung cancer
(NSCLC). Int J Radiat Oncol Biol Phys. 2008;72:335–342.
157. Yuan S, Sun X, Li M, et al. A randomized study of involved-field
irradiation versus elective nodal irradiation in combination with
concurrent chemotherapy for inoperable stage III non small cell lung
cancer. Am J Clin Oncol. 2007;30:239–244.
158. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial
irradiation for patients with small-cell lung cancer in complete
remission. Prophylactic cranial irradiation overview collaborative
group. N Engl J Med. 1999;341:476–484.
159. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of
prophylactic cranial irradiation versus observation in patients with
locally advanced non-small-cell lung cancer: primary analysis of
radiation therapy oncology group study RTOG 0214. J Clin Oncol.
2011;29:272–278.
160. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin
vs. observation in resected non-small-cell lung cancer. N Engl J Med.
2005;352:2589–2597.
161. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus
cisplatin versus observation in patients with completely resected
stage IB-IIIA non-small-cell lung cancer (adjuvant navelbine
international trialist association [ANITA]): A randomised controlled
trial. Lancet Oncol. 2006;7:719–727.
162. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin
evaluation: a pooled analysis by the LACE collaborative group. J
Clin Oncol. 2008;26:3552–3559.
163. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant
paclitaxel plus carboplatin compared with observation in stage IB
non-small-cell lung cancer: CALGB 9633 with the cancer and
leukemia group B, radiation therapy oncology group, and north
central cancer treatment group study groups. J Clin Oncol.
2008;26:5043–5051.
164. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the
international adjuvant lung cancer trial evaluating adjuvant
cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol.
2010;28:35–42.
165. Weisenberger. Effects of postoperative mediastinal radiation on
completely resected stage II and stage III epidermoid cancer of the
lung. The lung cancer study group. N Engl J Med. 1986;315:1377–
1381.
166. PORT Meta-Analysis Trialists Group. Postoperative radiotherapy for
non-small cell lung cancer. Cochrane Database Syst Rev. 2003;
(1):CD002142.
167. Douillard J, Rosell R, De Lena M, et al. Impact of postoperative
radiation therapy on survival in patients with complete resection
and stage I, II, or IIIA non-small-cell lung cancer treated with
adjuvant chemotherapy: the adjuvant navelbine international trialist
association (ANITA) randomized trial. Int J Radiat Oncol Biol Phys.
2008;72:695–701.
168. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative
radiotherapy for stage II or III non-small-cell lung cancer using the
surveillance, epidemiology, and end results database. J Clin Oncol.
2006;24:2998–3006.
169. Robinson CG, Patel AP, Bradley JD, et al. Postoperative
radiotherapy for pathologic N2 non–small-cell lung cancer treated
with adjuvant chemotherapy: a review of the national cancer data
base. J Clin Oncol. 2015;33:870–876.
170. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time
between the first day of chemotherapy and the last day of chest
radiation is the most important predictor of survival in limited-
disease small-cell lung cancer. J Clin Oncol. 2006;24:1057–1063.
171. Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al. Early versus
late chest radiotherapy for limited stage small cell lung cancer.
Cochrane Database Syst Rev. 2005;(1):CD004700.
172. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating
the timing of thoracic radiation therapy in combined modality
therapy for limited-stage small-cell lung cancer. J Clin Oncol.
2004;22:4837–4845.
173. Kies MS, Mira JG, Crowley JJ, et al. Multimodal therapy for limited
small-cell lung cancer: A randomized study of induction
combination chemotherapy with or without thoracic radiation in
complete responders; and with wide-field versus reduced-field
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
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.
2014;32:3810–3816.
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.
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.
188. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of
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
Radiat Oncol Biol Phys. 2012;83:1278–1283.
191. Gupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation
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.
Radiother Oncol. 2007;84:18–22.
193. Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after
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
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
Radiat Oncol Biol Phys. 1999;43:511–516.
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
Radiat Oncol Biol Phys. 2008;71:1143–1150.
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).
1998;12:1001–1005; discussion 1006.
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.
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
Radiat Oncol Biol Phys. 2002;52:801–805.
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.
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).
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.
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).
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,
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.
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.
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)
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.
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.
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.
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).
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,
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.
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
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.
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
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.
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
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
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
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).
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.
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.
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.
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.
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.
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
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,
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.
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
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:
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
REFERENCES
1. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al. World Health
Organization Classification of Tumours of Soft tissue and Bone. Vol 4.
Lyon: IARC Press; 2002.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J
Clin. 2015;65(1):5–29.
3. Lawrence W Jr, Donegan WL, Natarajan N, et al. Adult soft tissue
sarcomas. A pattern of care survey of the American College of
Surgeons. Ann Surg. 1987;205(4):349–359.
4. Gustafson P, Dreinhofer KE, Rydholm A. Soft tissue sarcoma should
be treated at a tumor center. A comparison of quality of surgery in
375 patients. Acta Orthop Scand. 1994;65(1):47–50.
5. Sherman KL, Wayne JD, Chung J, et al. Assessment of multimodality
therapy use for extremity sarcoma in the United States. J Surg Oncol.
2014;109(5):395–404.
6. Wasif N, Smith CA, Tamurian RM, et al. Influence of physician
specialty on treatment recommendations in the multidisciplinary
management of soft tissue sarcoma of the extremities. JAMA Surg.
2013;148(7):632–639.
7. Sherman KL, Wayne JD, Bilimoria KY. Overcoming specialty bias:
another important reason for multidisciplinary management of soft
tissue sarcoma. JAMA Surg. 2013;148(7):640.
8. Perrier L, Buja A, Mastrangelo G, et al. Clinicians’ adherence versus
non adherence to practice guidelines in the management of patients
with sarcoma: a cost-effectiveness assessment in two European
regions. BMC Health Serv Res. 2012;12:82.
9. Gadgeel SM, Harlan LC, Zeruto CA, et al. Patterns of care in a
population-based sample of soft tissue sarcoma patients in the
United States. Cancer. 2009;115(12):2744–2754.
10. Stiller CA, Passmore SJ, Kroll ME, et al. Patterns of care and
survival for patients aged under 40 years with bone sarcoma in
Britain, 1980–1994. Br J Cancer. 2006;94(1):22–29.
11. Alamanda VK, Song Y, Schwartz HS, et al. Racial disparities in
extremity soft-tissue sarcoma outcomes: a nationwide analysis. Am J
Clin Oncol. 2015;38(6):595–599.
12. Schwab JH, Boland PJ, Antonescu C, et al. Spinal metastases from
myxoid liposarcoma warrant screening with magnetic resonance
imaging. Cancer. 2007;110(8):1815–1822.
13. Sundaram M, McGuire MH, Herbold DR. Magnetic resonance
imaging of soft tissue masses: an evaluation of fifty-three
histologically proven tumors. Magn Reson Imaging. 1988;6(3):237–
248.
14. Demas BE, Heelan RT, Lane J, et al. Soft-tissue sarcomas of the
extremities: comparison of MR and CT in determining the extent of
disease. AJR Am J Roentgenol. 1988;150(3):615–620.
15. Strauss DC, Qureshi YA, Hayes AJ, et al. The role of core needle
biopsy in the diagnosis of suspected soft tissue tumours. J Surg
Oncol. 2010;102(5):523–529.
16. Delaney TF. Diagnosis of sarcoma by core biopsy. J Surg Oncol.
2006;94(1):1–2.
17. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy,
revisited. Members of the Musculoskeletal Tumor Society. J Bone
Joint Surg Am. 1996;78(5):656–663.
18. Mankin HJ, Lange TA, Spanier SS. The hazards of biopsy in patients
with malignant primary bone and soft-tissue tumors. J Bone Joint
Surg Am. 1982;64(8):1121–1127.
19. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung
metastasectomy: prognostic analyses based on 5206 cases. J Thorac
Cardiovasc Surg. 1997;113(1):37–49.
20. Kikuta K, Kubota D, Yoshida A, et al. An analysis of factors related
to the tail-like pattern of myxofibrosarcoma seen on MRI. Skeletal
Radiol. 2015;44(1):55–62.
21. Iwata S, Yonemoto T, Araki A, et al. Impact of infiltrative growth on
the outcome of patients with undifferentiated pleomorphic sarcoma
and myxofibrosarcoma. J Surg Oncol. 2014;110(6):707–711.
22. Look Hong NJ, Hornicek FJ, Raskin KA, et al. Prognostic factors and
outcomes of patients with myxofibrosarcoma. Ann Surg Oncol.
2013;20(1):80–86.
23. Riouallon G, Larousserie F, Pluot E, et al. Superficial
myxofibrosarcoma: assessment of recurrence risk according to the
surgical margin following resection. A series of 21 patients. Orthop
Traumatol Surg Res. 2013;99(4):473–477.
24. Baratti D, Pennacchioli E, Casali PG, et al. Epithelioid sarcoma:
prognostic factors and survival in a series of patients treated at a
single institution.Ann Surg Oncol. 2007;14(12):3542–3551.
25. Levy A, Le Péchoux C, Terrier P, et al. Epithelioid sarcoma: need for
a multimodal approach to maximize the chances of curative
conservative treatment. Ann Surg Oncol. 2014;21(1):269–276.
26. Sakharpe A, Lahat G, Gulamhusein T, et al. Epithelioid sarcoma and
unclassified sarcoma with epithelioid features: clinicopathological
variables, molecular markers, and a new experimental model.
Oncologist. 2011;16(4):512–522.
27. Song S, Park J, Kim HJ, et al. Effects of adjuvant radiotherapy in
patients with synovial sarcoma. Am J Clin Oncol. 2014.
28. Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for
patients with localized soft-tissue sarcoma treated with conservation
surgery and radiation therapy: an analysis of 1225 patients. Cancer.
2003;97(10):2530–2543.
29. Ramanathan RC, A’Hern R, Fisher C, et al. Modified staging system
for extremity soft tissue sarcomas. Ann Surg Oncol. 1999;6(1):57–69.
30. Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic
factors in 1,041 patients with localized soft tissue sarcomas of the
extremities. J Clin Oncol. 1996;14(5):1679–1689.
31. Rööser B, Attewell R, Berg NO, et al. Prognostication in soft tissue
sarcoma. A model with four risk factors. Cancer. 1988;61(4):817–
823.
32. Suit HD, Mankin HJ, Wood WC, et al. Treatment of the patient with
stage M0 soft tissue sarcoma. J Clin Oncol. 1988;6(5):854–862.
33. Eary JF, Conrad EU, O’Sullivan J, et al. Sarcoma mid-therapy [F-
18]fluorodeoxyglucose positron emission tomography (FDG PET)
and patient outcome. J Bone Joint Surg Am. 2014;96(2):152–158.
34. Roberge D, Vakilian S, Alabed YZ, et al. FDG PET/CT in initial
staging of adult soft-tissue sarcoma. Sarcoma. 2012;2012:960194.
35. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-
tissue sarcomas of the extremities: prospective randomized
evaluations of (1) limb-sparing surgery plus radiation therapy
compared with amputation and (2) the role of adjuvant
chemotherapy. Ann Surg. 1982;196(3):305–315.
36. Tanabe KK, Pollock RE, Ellis LM, et al. Influence of surgical margins
on outcome in patients with preoperatively irradiated extremity soft
tissue sarcomas. Cancer. 1994;73(6):1652–1659.
37. Cannon CP, Ballo MT, Zagars GK, et al. Complications of combined
modality treatment of primary lower extremity soft-tissue sarcomas.
Cancer. 2006;107(10):2455–2461.
38. Dickie CI, Parent AL, Griffin AM, et al. Bone fractures following
external beam radiotherapy and limb-preservation surgery for lower
extremity soft tissue sarcoma: relationship to irradiated bone length,
volume, tumor location and dose. Int J Radiat Oncol Biol Phys.
2009;75(4):1119–1124.
39. Gortzak Y, Lockwood GA, Mahendra A, et al. Prediction of
pathologic fracture risk of the femur after combined modality
treatment of soft tissue sarcoma of the thigh. Cancer.
2010;116(6):1553–1559.
40. Pak D, Vineberg KA, Griffith KA, et al. Dose–effect relationships for
femoral fractures after multimodality limb-sparing therapy of soft-
tissue sarcomas of the proximal lower extremity. Int J Radiat Oncol
Biol Phys. 2012;83(4):1257–1263.
41. Davidge KM, Wunder J, Tomlinson G, et al. Function and health
status outcomes following soft tissue reconstruction for limb
preservation in extremity soft tissue sarcoma. Ann Surg Oncol.
2010;17(4):1052–1062.
42. Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in
a retrospectively reviewed single-institution case series of
retroperitoneal soft tissue sarcoma patients. J Clin Oncol.
2009;27(1):24–30.
43. Suit HD, Mankin HJ, Wood WC, et al. Preoperative, intraoperative,
and postoperative radiation in the treatment of primary soft tissue
sarcoma. Cancer. 1985;55(11):2659–2667.
44. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study
of the benefit of adjuvant radiation therapy in the treatment of soft
tissue sarcomas of the extremity. J Clin Oncol. 1998;16(1):197–203.
45. Kachare SD, Brinkley J, Vohra NA, et al. Radiotherapy associated
with improved survival for high-grade sarcoma of the extremity. J
Surg Oncol. 2015;112(4):338–343.
46. Goodlad JR, Fletcher CD, Smith MA. Surgical resection of primary
soft-tissue sarcoma. Incidence of residual tumour in 95 patients
needing re-excision after local resection. J Bone Joint Surg Br.
1996;78(4):658–661.
47. Manoso MW, Frassica DA, Deune EG, et al. Outcomes of re-excision
after unplanned excisions of soft-tissue sarcomas. J Surg Oncol.
2005;91(3):153–158.
48. Noria S, Davis A, Kandel R, et al. Residual disease following
unplanned excision of soft-tissue sarcoma of an extremity. J Bone
Joint Surg Am. 1996;78(5):650–655.
49. Zagars GK, Ballo MT, Pisters PW, et al. Surgical margins and
reresection in the management of patients with soft tissue sarcoma
using conservative surgery and radiation therapy. Cancer.
2003;97(10):2544–2553.
50. Zornig C, Peiper M, Schroder S. Re-excision of soft tissue sarcoma
after inadequate initial operation. Br J Surg. 1995;82(2):278–279.
51. Kepka L, Suit HD, Goldberg SI, et al. Results of radiation therapy
performed after unplanned surgery (without re-excision) for soft
tissue sarcomas. J Surg Oncol. 2005;92(1):39–45.
52. Delaney TF, Kepka L, Goldberg SI, et al. Radiation therapy for
control of soft-tissue sarcomas resected with positive margins. Int J
Radiat Oncol Biol Phys. 2007;67(5):1460–1469.
53. Cahlon O, Brannon MF, Jia X, et al. A postoperative nomogram for
local recurrence risk in extremity soft tissue sarcomas after limb-
sparing surgery without adjuvant radiation. Ann Surg. 2012;
255(2):343–347.
54. Al-Refaie WB, Habermann EB, Jensen EH, et al. Surgery alone is
adequate treatment for early stage soft tissue sarcoma of the
extremity. Br J Surg. 2010;97(5):707–713.
55. Pisters PW, Pollock RE, Lewis VO, et al. Long-term results of
prospective trial of surgery alone with selective use of radiation for
patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg.
2007;246(4):675–681; discussion 681–682.
56. Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after
function-sparing surgery without radiotherapy for soft tissue
sarcoma of the extremities and trunk. J Clin Oncol.
1999;17(10):3252–3259.
57. Kepka L, DeLaney TF, Suit HD, et al. Results of radiation therapy for
unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys.
2005;63(3):852–859.
58. Brant TA, Parsons JT, Marcus RB Jr, et al. Preoperative irradiation
for soft tissue sarcomas of the trunk and extremities in adults. Int J
Radiat Oncol Biol Phys. 1990;19(4):899–906.
59. Cheng EY, Dusenbery KE, Winters MR, et al. Soft tissue sarcomas:
preoperative versus postoperative radiotherapy. J Surg Oncol.
1996;61(2):90–99.
60. Zagars GK, Ballo MT, Pisters PW, et al. Preoperative vs.
postoperative radiation therapy for soft tissue sarcoma: a
retrospective comparative evaluation of disease outcome. Int J
Radiat Oncol Biol Phys. 2003;56(2):482–488.
61. Kuklo TR, Temple HT, Owens BD, et al. Preoperative versus
postoperative radiation therapy for soft-tissue sarcomas. Am J
Orthop (Belle Mead NJ). 2005;34(2):75–80.
62. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus
postoperative radiotherapy in soft-tissue sarcoma of the limbs: a
randomised trial. The Lancet. 2002;359(9325):2235–2241.
63. Davis A, O’Sullivan B, Turcotte R, et al. Late radiation morbidity
following randomization to preoperative versus postoperative
radiotherapy in extremity soft tissue sarcoma. Radiother Oncol.
2005;75(1):48–53.
64. Baldini EH, Abrams RA, Bosch W, et al. Retroperitoneal sarcoma
target volume and organ at risk contour delineation agreement
among NRG sarcoma radiation oncologists. Int J Radiat Oncol Biol
Phys. 2015;92(5):1053–1059.
65. Dickie CI, Parent A, Griffin A, et al. A device and procedure for
immobilization of patients receiving limb-preserving radiotherapy
for soft tissue sarcoma. Med Dosim. 2009;34(3):243–249.
66. Niewald M, Berberich W, Schnabel K, et al. [A simple method for
positioning and fixing the extremities during the radiotherapy of
soft-tissue sarcomas]. Strahlenther Onkol. 1990;166(4):295–296.
67. Gierga DP, Turcotte JC, Tong LW, et al. Analysis of setup
uncertainties for extremity sarcoma patients using surface imaging.
Pract Radiat Oncol. 2014;4(4):261–266.
68. Robinson MH, Bidmead AM, Harmer CL. Value of conformal
planning in the radiotherapy of soft tissue sarcoma. Clin Oncol (R
Coll Radiol). 1992;4(5):290–293.
69. Ward I, Haycocks T, Sharpe M, et al. Volume-based radiotherapy
targeting in soft tissue sarcoma. Cancer Treat Res. 2004;120:17–42.
70. White LM, Wunder JS, Bell RS, et al. Histologic assessment of
peritumoral edema in soft tissue sarcoma. Int J Radiat Oncol Biol
Phys. 2005;61(5):1439–1445.
71. Kim B, Chen YL, Kirsch DG, et al. An effective preoperative three-
dimensional radiotherapy target volume for extremity soft tissue
sarcoma and the effect of margin width on local control. Int J Radiat
Oncol Biol Phys. 2010;77(3):843–850.
72. Roberge D, Skamene T, Turcotte RE, et al. Inter- and intra-observer
variation in soft-tissue sarcoma target definition. Cancer Radiother.
2011;15(5):421–425.
73. Wang D, Bosch W, Roberge D, et al. RTOG sarcoma radiation
oncologists reach consensus on gross tumor volume and clinical
target volume on computed tomographic images for preoperative
radiotherapy of primary soft tissue sarcoma of extremity in
Radiation Therapy Oncology Group studies. Int J Radiat Oncol Biol
Phys. 2011;81(4):e525–e528.
74. Wang D, Bosch W, Kirsch DG, et al. Variation in the gross tumor
volume and clinical target volume for preoperative radiotherapy of
primary large high-grade soft tissue sarcoma of the extremity among
RTOG sarcoma radiation oncologists. Int J Radiat Oncol Biol Phys.
2011;81(5):e775–e780.
75. Bahig H, Roberge D, Bosch W, et al. Agreement among RTOG
sarcoma radiation oncologists in contouring suspicious peritumoral
edema for preoperative radiation therapy of soft tissue sarcoma of
the extremity. Int J Radiat Oncol Biol Phys. 2013;86(2):298–303.
76. Wang D, Zhang Q, Eisenberg BL, et al. Significant reduction of late
toxicities in patients with extremity sarcoma treated with image-
guided radiation therapy to a reduced target volume: results of
Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol.
2015;33(20):2231–2238.
77. Finkelstein SE, Trotti A, Letson G, et al. Deformable imaging
capability for the Radiation Therapy Oncology Group (RTOG)
Consensus Atlas of Musculoskeletal Anatomy (CAMAS) for soft
tissue sarcoma of the lower extremities. Pract Radiat Oncol. 2013;3(2
suppl 1):S7.
78. Haglund KE, Raut CP, Nascimento AF, et al. Recurrence patterns
and survival for patients with intermediate- and high-grade
myxofibrosarcoma. Int J Radiat Oncol Biol Phys. 2012;82(1):361–
367.
79. Tejwani A, Kobayashi W, Chen YL, et al. Management of acral
myxoinflammatory fibroblastic sarcoma. Cancer.
2010;116(24):5733–5739.
80. DeLaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy
and radiotherapy for large extremity soft-tissue sarcomas. Int J
Radiat Oncol Biol Phys. 2003;56(4):1117–1127.
81. Azinovic I, Martinez Monge R, Javier Aristu J, et al. Intraoperative
radiotherapy electron boost followed by moderate doses of external
beam radiotherapy in resected soft-tissue sarcoma of the extremities.
Radiother Oncol. 2003;67(3):331–337.
82. Calvo FA, Sole CV, Polo A, et al. Limb-sparing management with
surgical resection, external-beam and intraoperative electron-beam
radiation therapy boost for patients with primary soft tissue sarcoma
of the extremity: a multicentric pooled analysis of long-term
outcomes. Strahlenther Onkol. 2014;190(10):891–898.
83. Kunos C, Colussi V, Getty P, et al. Intraoperative electron
radiotherapy for extremity sarcomas does not increase acute or late
morbidity. Clin Orthop Relat Res. 2006;446:247–252.
84. Oertel S, Treiber M, Zahlten-Hinguranage A, et al. Intraoperative
electron boost radiation followed by moderate doses of external
beam radiotherapy in limb-sparing treatment of patients with
extremity soft-tissue sarcoma. Int J Radiat Oncol Biol Phys.
2006;64(5):1416–1423.
85. Roeder F, Lehner B, Saleh-Ebrahimi L, et al. Intraoperative electron
radiation therapy combined with external beam radiation therapy
and limb sparing surgery in extremity soft tissue sarcoma: a
retrospective single center analysis of 183 cases. Radiother Oncol.
2015;pii:S0167–S8140(15)00619-2.
86. Al Yami A, Griffin AM, Ferguson PC, et al. Positive surgical margins
in soft tissue sarcoma treated with preoperative radiation: is a
postoperative boost necessary? Int J Radiat Oncol Biol Phys.
2010;77(4):1191–1197.
87. Pan E, Goldberg SI, Chen YL, et al. Role of post-operative radiation
boost for soft tissue sarcomas with positive margins following pre-
operative radiation and surgery. J Surg Oncol. 2014; 110(7):817–
822.
88. Dincbas FO, Oksuz DC, Yetmen O, et al. Neoadjuvant treatment
with preoperative radiotherapy for extremity soft tissue sarcomas:
long-term results from a single institution in Turkey. Asian Pac J
Cancer Prev. 2014;15(4):1775–1781.
89. Kubicek GJ, LaCouture T, Kaden M, et al. Preoperative radiosurgery
for soft tissue sarcoma. Am J Clin Oncol. 2015.
90. Dickie CI, Parent AL, Chung PW, et al. Measuring interfractional
and intrafractional motion with cone beam computed tomography
and an optical localization system for lower extremity soft tissue
sarcoma patients treated with preoperative intensity-modulated
radiation therapy. Int J Radiat Oncol Biol Phys. 2010;78(5):1437–
1444.
91. le Grange F, Cassoni AM, Seddon BM, Tumour volume changes
following pre-operative radiotherapy in borderline resectable limb
and trunk soft tissue sarcoma. Eur J Surg Oncol. 2014;40(4):394–
401.
92. Roberge D, Skamene T, Nahal A, et al. Radiological and
pathological response following pre-operative radiotherapy for soft-
tissue sarcoma. Radiother Oncol. 2010;97(3):404–407.
93. Alektiar KM, Zelefsky MJ, Brennan MF. Morbidity of adjuvant
brachytherapy in soft tissue sarcoma of the extremity and superficial
trunk. Int J Radiat Oncol Biol Phys. 2000;47(5):1273–1279.
94. Holloway CL, Delaney TF, Alektiar KM, et al. American
Brachytherapy Society (ABS) consensus statement for sarcoma
brachytherapy. Brachytherapy. 2013;12(3):179–190.
95. Hong L, Alektiar KM, Hunt M, et al. Intensity-modulated
radiotherapy for soft tissue sarcoma of the thigh. Int J Radiat Oncol
Biol Phys. 2004;59(3):752–759.
96. Alektiar KM, Brennan MF, Healey JH, et al. Impact of intensity-
modulated radiation therapy on local control in primary soft-tissue
sarcoma of the extremity. J Clin Oncol. 2008;26(20):3440–3444.
97. Alektiar KM, Hong L, Brennan MF, et al. Intensity modulated
radiation therapy for primary soft tissue sarcoma of the extremity:
preliminary results. Int J Radiat Oncol Biol Phys. 2007;68(2):458–
464.
98. O’Sullivan B, Griffin AM, Dickie CI, et al. Phase 2 study of
preoperative image-guided intensity-modulated radiation therapy to
reduce wound and combined modality morbidities in lower
extremity soft tissue sarcoma. Cancer. 2013;119(10):1878–1884.
99. Folkert MR, Singer S, Brennan MF, et al. Comparison of local
recurrence with conventional and intensity-modulated radiation
therapy for primary soft-tissue sarcomas of the extremity. J Clin
Oncol. 2014;32(29):3236–3241.
100. Alektiar KM, Brennan MF, Singer S. Local control comparison of
adjuvant brachytherapy to intensity-modulated radiotherapy in
primary high-grade sarcoma of the extremity. Cancer.
2011;117(14):3229–3234.
101. Gerrand CH, Wunder JS, Kandel RA, et al. The influence of
anatomic location on functional outcome in lower-extremity soft-
tissue sarcoma. Ann Surg Oncol. 2004;11(5):476–482.
102. Tseng JF, Ballo MT, Langstein HN, et al. The effect of preoperative
radiotherapy and reconstructive surgery on wound complications
after resection of extremity soft-tissue sarcomas. Ann Surg Oncol.
2006;13(9):1209–1215.
103. Alektiar KM, Brennan MF, Singer S. Influence of site on the
therapeutic ratio of adjuvant radiotherapy in soft-tissue sarcoma of
the extremity. Int J Radiat Oncol Biol Phys. 2005;63(1):202–208.
104. Rimner A, Brennan MF, Zhang Z, et al. Influence of compartmental
involvement on the patterns of morbidity in soft tissue sarcoma of
the thigh. Cancer. 2009;115(1):149–157.
105. Baldini EH, Lapidus MR, Wang Q, et al. Predictors for major wound
complications following preoperative radiotherapy and surgery for
soft-tissue sarcoma of the extremities and trunk: importance of
tumor proximity to skin surface. Ann Surg Oncol. 2013;20(5):1494–
1499.
106. Moore J, Isler M, Barry J, et al. Major wound complication risk
factors following soft tissue sarcoma resection. Eur J Surg Oncol.
2014;40(12):1671–1676.
107. Griffin AM, Dickie CI, Catton CN, et al. The influence of time
interval between preoperative radiation and surgical resection on
the development of wound healing complications in extremity soft
tissue sarcoma. Ann Surg Oncol. 2015;22(9):2824–2830.
108. DeLaney TF, Harmon DC, Beghardt MC. Local treatment for
primary soft tissue sarcoma of the extremities and chest wall.
UpToDate. Last updated Feb 5, 2016.
109. ClinicalTrials.gov. Radiation therapy in treating patients who have
undergone surgery for soft tissue sarcoma of the arms, hands, legs,
or feet. https://clinicaltrials.gov/ct2/show/NCT00423618. Last
updated August 9, 2013.
110. McGee L, Indelicato DJ, Dagan R, et al. Long-term results following
postoperative radiotherapy for soft tissue sarcomas of the extremity.
Int J Radiat Oncol Biol Phys. 2012;84(4):1003–1009.
111. Torres MA, Ballo MT, Butler CE, et al. Management of locally
recurrent soft-tissue sarcoma after prior surgery and radiation
therapy. Int J Radiat Oncol Biol Phys. 2007;67(4):1124–1129.
112. Indelicato DJ, Meadows K, Gibbs CP Jr, et al. Effectiveness and
morbidity associated with reirradiation in conservative salvage
management of recurrent soft-tissue sarcoma. Int J Radiat Oncol Biol
Phys. 2009;73(1):267–272.
113. Catton C, Davis A, Bell R, et al. Soft tissue sarcoma of the
extremity. Limb salvage after failure of combined conservative
therapy. Radiother Oncol. 1996;41(3):209–214.
114. Pearlstone DB, Janjan NA, Feig BW, et al. Re-resection with
brachytherapy for locally recurrent soft tissue sarcoma arising in a
previously radiated field. Cancer J Sci Am. 1999;5(1):26–33.
115. Bonvalot S, Rivoire M, Castaing M, et al. Primary retroperitoneal
sarcomas: a multivariate analysis of surgical factors associated with
local control. J Clin Oncol. 2009;27(1):31–37.
116. Stojadinovic A, Leung DH, Hoos A, et al. Analysis of the prognostic
significance of microscopic margins in 2,084 localized primary adult
soft tissue sarcomas. Ann Surg. 2002;235(3):424–434.
117. Tan MC, Brennan MF, Kuk D, et al. Histology-based classification
predicts pattern of recurrence and improves risk stratification in
primary retroperitoneal sarcoma. Ann Surg. 2016;263(3):593–600.
118. Miura JT, Charlson J, Gamblin TC, et al. Impact of chemotherapy
on survival in surgically resected retroperitoneal sarcoma. Eur J Surg
Oncol. 2015;41:1386–1392.
119. Catton CN, O’Sullivan R, Kotwall C, et al. Outcome and prognosis in
retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys.
1994;29(5):1005–1010.
120. Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal soft-tissue
sarcoma: analysis of 500 patients treated and followed at a single
institution. Ann Surg. 1998;228(3):355–365.
121. Bevilacqua RG, Rogatko A, Hajdu SI, et al. Prognostic factors in
primary retroperitoneal soft-tissue sarcomas. Arch Surg.
1991;126(3):328–334.
122. Singer S, Antonescu CR, Riedel E, et al. Histologic subtype and
margin of resection predict pattern of recurrence and survival for
retroperitoneal liposarcoma. Ann Surg. 2003;238(3):358–370.
123. Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in
retroperitoneal sarcoma: a multivariate analysis of a series of 165
patients of the French Cancer Center Federation Sarcoma Group.
Cancer. 2001;92(2):359–368.
124. Nussbaum DP, Speicher PJ, Gulack BC, et al. Long-term oncologic
outcomes after neoadjuvant radiation therapy for retroperitoneal
sarcomas. Ann Surg. 2015;262(1):163–170.
125. Gilbeau L, Kantor G, Stoeckle E, et al. Surgical resection and
radiotherapy for primary retroperitoneal soft tissue sarcoma.
Radiother Oncol. 2002;65(3):137–143.
126. Siegel RL, Fedewa SA, Miller KD, et al. Cancer statistics for
Hispanics/Latinos, 2015.CA Cancer J Clin. 2015;65(6):457–480.
127. Sindelar WF, Kinsella TJ, Chen PW, et al. Intraoperative
radiotherapy in retroperitoneal sarcomas. Final results of a
prospective, randomized, clinical trial. Arch Surg. 1993;128(4):402–
410.
128. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of
intraoperative electron beam radiotherapy for primary and
recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol
Phys. 2001;50(1):127–131.
129. Yoon SS, Chen YL, Kirsch DG, et al. Proton-beam, intensity-
modulated, and/or intraoperative electron radiation therapy
combined with aggressive anterior surgical resection for
retroperitoneal sarcomas. Ann Surg Oncol. 2010;17(6):1515–1529.
130. Stucky CC, Wasif N, Ashman JB, et al. Excellent local control with
preoperative radiation therapy, surgical resection, and intra-
operative electron radiation therapy for retroperitoneal sarcoma. J
Surg Oncol. 2014;109(8):798–803.
131. Shaw EG, Gunderson LL, Martin JK, et al. Peripheral nerve and
ureteral tolerance to intraoperative radiation therapy: clinical and
dose-response analysis. Radiother Oncol. 1990;18(3):247–255.
132. Karakousis CP, Velez AF, Gerstenbluth R, et al. Resectability and
survival in retroperitoneal sarcomas. Ann Surg Oncol.
1996;3(2):150–158.
133. Pisters PW, O’Sullivan B. Retroperitoneal sarcomas: combined
modality treatment approaches. Curr Opin Oncol. 2002;14(4):400–
405.
134. Nielsen OS, O’Sullivan B. Retroperitoneal soft tissue sarcomas: a
treatment challenge and a call for randomized trials. Radiother
Oncol. 2002;65(3):133–136.
135. Jones JJ, Catton CN, O’Sullivan B, et al. Initial results of a trial of
preoperative external-beam radiation therapy and postoperative
brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol.
2002;9(4):346–354.
136. Pisters PW, Ballo MT, Fenstermacher MJ, et al. Phase I trial of
preoperative concurrent doxorubicin and radiation therapy, surgical
resection, and intraoperative electron-beam radiation therapy for
patients with localized retroperitoneal sarcoma. J Clin Oncol.
2003;21(16):3092–3097.
137. Mak KS, Mannarino EG, Lee LK, et al. Bowel bag dose-volume
parameters and acute gastrointestinal (GI) toxicity during
preoperative radiation therapy (RT) for retroperitoneal sarcoma
(RPS). Int J Radiat Oncol Biol Phys. 2014;90(1):S117–S118.
138. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA
Cancer J Clin. 2015;65(2):87–108.
139. Koshy M, Landry JC, Lawson JD, et al. Potential for toxicity
reduction using intensity modulated radiation therapy (IMRT) for
retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys. 2003;57(2
suppl):S448–S449.
140. Bossi A, De Wever I, Van Limbergen E, et al. Intensity modulated
radiation-therapy for preoperative posterior abdominal wall
irradiation of retroperitoneal liposarcomas. Int J Radiat Oncol Biol
Phys. 2007;67:164–170.
141. Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation
therapy with selective dose escalation to the margin at risk for
retroperitoneal sarcoma. Cancer. 2006;107(2):371–379.
142. Goitein M. Radiation Oncology: A Physicist’s-Eye View. New York,
NY: Springer; 2008.
143. Gutierrez JC, Perez EA, Moffat FL, et al. Should soft tissue sarcomas
be treated at high-volume centers? An analysis of 4205 patients.
Ann Surg. 2007;245(6):952–958.
144. Wong P, Dickie C, Lee D, et al. Spatial and volumetric changes of
retroperitoneal sarcomas during pre-operative radiotherapy.
Radiother Oncol. 2014;112(2):308–313.
145. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in
high-grade osteosarcoma of the extremities or trunk: an analysis of
1,702 patients treated on neoadjuvant cooperative osteosarcoma
study group protocols. J Clin Oncol. 2002;20(3):776–790.
146. Ozaki T, Flege S, Kevric M, et al. Osteosarcoma of the pelvis:
experience of the Cooperative Osteosarcoma Study Group. J Clin
Oncol. 2003;21(2):334–341.
147. Ozaki T, Flege S, Liljenqvist U, et al. Osteosarcoma of the spine:
experience of the Cooperative Osteosarcoma Study Group. Cancer.
2002;94(4):1069–1077.
148. Kassir RR, Rassekh CH, Kinsella JB, et al. Osteosarcoma of the head
and neck: meta-analysis of nonrandomized studies. Laryngoscope.
1997;107(1):56–61.
149. Jasnau S, Meyer U, Potratz J, et al. Craniofacial osteosarcoma
experience of the cooperative German-Austrian-Swiss osteosarcoma
study group. Oral Oncol. 2007;26:26.
150. Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based
radiotherapy for unresectable or incompletely resected
osteosarcoma. Cancer. 2011;117(19):4522–4530.
151. DeLaney, TF, Liebsch NJ, Pedlow FX, et al. Phase II study of high-
dose photon/proton radiotherapy in the management of spine
sarcomas. Int J Radiat Oncol Biol Phys. 2009;74(3):732–739.
152. Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr
Blood Cancer. 2004;42(5):465–470.
153. Scully SP, Ghert MA, Zurakowski D, et al. Pathologic fracture in
osteosarcoma: prognostic importance and treatment implications. J
Bone Joint Surg Am. 2002;84-A(1):49–57.
154. Picci P, Sangiorgi L, Bahamonde L, et al. Risk factors for local
recurrences after limb-salvage surgery for high-grade osteosarcoma
of the extremities. Ann Oncol. 1997;8(9):899–903.
155. Sailer SL. The role of radiation therapy in localized Ewing’ sarcoma.
Semin Radiat Oncol. 1997;7(3):225–235.
156. Hug EB, Fitzek MM, Liebsch NJ, et al. Locally challenging osteo-
and chondrogenic tumors of the axial skeleton: results of combined
proton and photon radiation therapy using three-dimensional
treatment planning. Int J Radiat Oncol Biol Phys. 1995;31(3):467–
476.
157. Chen YL, Liebsch N, Kobayashi W, et al. Definitive high-dose proton
based radiotherapy for unresected mobile spine and sacral
chordomas. Spine. 2013;38:E930–E936.
158. Hug EB. Review of skull base chordomas: prognostic factors and
long-term results of proton-beam radiotherapy. Neurosurg Focus.
2001;10(3):E11.
159. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull
base. Strahlenther Onkol. 1999;175(suppl 2):57–63.
160. Ewing J. Classics in oncology. Diffuse endothelioma of bone. James
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
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
Radiat Oncol Biol Phys. 2012;82(2):940–945.
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.
Index
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 Task Group 100, 113
AAPM Task Group 101, 233
AAPM Task Group 166, 377
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
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
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
treatment planning for, 413–418
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
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
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
treatment planning for, 482–483
bladder field, 482–483
simulation, 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
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
radiation necrosis of, 368
Brain metastases, 577
Brainstem
dose-volume histograms of, 324f
radiation-induced toxicity of, 368
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, 562
treatment planning for, 562–563
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
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
patient selection for, 554
treatment planning for, 556–557
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
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
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
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
chemotherapy for, 412
diagnostic evaluation, 408–409
prognosis of, 413
radiotherapy fields and techniques for, 411–412
treatment options for, 409
treatment planning for, 409–413
normal tissue tolerances in, 411
radiotherapy dose, 411
radiotherapy target in, 410
simulation, 409–410
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
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)
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)
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
asymmetric, 68–69, 69f
in high dose-rate brachytherapy, 273–274
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)
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
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
basic physics and properties of, 288–296
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
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
chemotherapy for, 401
diagnostic evaluation, 397–398
prognosis of, 401
radiotherapy fields and techniques for, 401
treatment options for, 398
treatment planning of, 398–400
CT-based, 399
normal tissue tolerances in, 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
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
in high dose-rate brachytherapy, 262–263
hyperfractionation, 346
hypofractionation, 347
linear quadratic theory, 340–341, 341f
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
chemotherapy for, 404
diagnostic evaluation, 402
prognosis in, 404
radiotherapy fields and techniques in, 403–404
treatment options for, 402
treatment planning of, 402–403
CT-based, 402
normal tissue tolerances in, 403
PET imaging, 402
radiotherapy dose in, 403–404
radiotherapy target, 403
simulation, 402–403
Gastrointestinal tract cancer
anal cancer, 413–418
chemotherapy for, 418
diagnostic evaluation of, 413
treatment options for, 413
treatment planning for, 413–418
normal tissue tolerances in, 415–416
colorectal cancer, 408–413
chemotherapy for, 412
diagnostic evaluation, 408–409
prognosis of, 413
radiotherapy fields and techniques for, 411–412
treatment options for, 409
treatment planning for, 409–412
esophageal cancer, 397–401
chemotherapy for, 401
diagnostic evaluation, 397–398
prognosis of, 401
radiotherapy fields and techniques for, 401
treatment options for, 398
treatment planning of, 398–400
gastric cancer, 401–404
chemotherapy for, 404
diagnostic evaluation, 402
prognosis in, 404
radiotherapy fields and techniques in, 403–404
treatment options for, 402
treatment planning of, 402–403
overview, 397
pancreatic cancer, 404–408
chemotherapy for, 408
diagnostic evaluation of, 404–405
prognosis of, 408
treatment options for, 405
treatment planning for, 405–408
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
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
in central nervous system tumors, 573
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
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
radiotherapeutic management of, 426–430
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
epidemiology of, 509
IGRT and, 523–524
IMRT for, 509–510
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
radiation-induced toxicity of, 369–370
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
conformity number, 278
disadvantages, 260
dose limitations, 273
dose outside target, 278
dose prescription, 270, 273
dose uniformity, 277
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
relative doses to specified volumes in, 273
tandem and ovoid applicator used for, 438f
treatment plan evaluation, 270–278
dose prescription, 270, 273
figures of merit, 276–278
quantitative assessment of implants, 274–276
target coverage, 276–277
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)
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
2D radiographic imaging, 178–179
magnetic resonance imaging, 182
optical surface imaging, 183
patient position correction, 183
positron emission tomography, 182–183
respiration-correlated (4D) computed tomography imaging, 181–
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
quality assurance for, 187–188
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
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
in central nervous system tumors, 576
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
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
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
2D radiographic imaging, 178–179
magnetic resonance imaging, 182
optical surface imaging, 183
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
in thorax cancers, 601
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
in gynecologic cancers, 443–445
Interstitial implants
figures of merit, 276–278
conformity number, 278
dose outside target, 278
dose uniformity, 277
target coverage, 276–277
in high dose-rate brachytherapy, 282–283, 283f
ICRU recommendations for, 277
quantitative assessment of implants, 274–276
Interstitial prostate implant, isotopes used for, 471t
INTERTECC. See International cooperative group trial (INTERTECC)
Intracavitary brachytherapy
dosimetry for tandem and ovoid insertion, 439f
in gynecologic cancers, 438–443
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)
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
bi-planar image-based target definition, 207–209
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
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
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
radiation-induced toxicity of, 370
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
prognosis of, 494–495
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
on-board imaging, 501–502
planning, 502–504
simulation, 499–500
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)
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
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 method in, 53–54
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
superposition/convolution, 49–52
basic radiation physics for, 47–49
Compton scatter, 47–48
electron transport, 48–49
megavoltage photon production, 47, 48f
history of, 46
patient representation in, 46–47
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
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
magnetic resonance imaging, 182
optical surface imaging, 183
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
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)
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
treatment options for, 405
treatment planning for, 405–408
normal tissue tolerances, 406
radiotherapy dose, 406
radiotherapy fields and techniques in, 406–408
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
radiation-induced toxicity of, 369
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
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
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
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
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
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
superposition/convolution, 49–52
basic radiation physics for, 47–49
Compton scatter, 47–48
electron transport, 48–49
megavoltage photon production, 47, 48f
history of, 46
patient representation in, 46–47
Photon dose calculations, sample criteria of acceptability for, 104t
Physical pencil beam (PPB), 94
Physicist, medical, 9–10
roles and responsibilities of, 10t
Physicist assistant, 10
Pituitary tumors, 581
PIVOT. See Prostate Cancer Intervention Versus Observation Trial
(PIVOT)
Plane films, stereotactic system for, 208f
Planning target volume (PTV), 4
in central nervous system tumors, 573
in prostate, 458–460
in SBRT, 230
in thorax cancers, 601
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
PROS. See Pediatric Radiation Oncology Society (PROS)
Prospective gated image acquisition, 40
Prostate cancer, 123f, 453–473
BED, 468–469
dose fractionation, 468–469
target volume definition, 468
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
epidemiology of, 453
field setup for
immobilization, 461
localization, 461
simulation, 461
interstitial prostate implant isotopes used for, 471t
PBT for, 335–336
prognosis of, 472–473
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
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
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
ASTRO recommendations, 332
in bone and soft tissue sarcomas, 333–334
in central nervous system tumors, 333
clinical results with, 333–334
cost-effectiveness, 331–332
in ocular tumors, 333
in pediatric tumors, 333
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331
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
absolute dosimetry, 321
multicriteria optimization in, 321
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
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
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
of arterial venous malformations, 206
bi-planar image-based target definition, 207–209
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
localization of, 206–207
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
ASTRO recommendations, 332
in bone and soft tissue sarcomas, 333–334
in central nervous system tumors, 333
clinical results with, 333–334
cost-effectiveness, 331–332
in ocular tumors, 333
in pediatric tumors, 333
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331
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
radiation-induced toxicity of, 371
Relative biologic effect (RBE), 151, 327
in proton dose, 87–88
Relative dose homogeneity index, 277
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
absolute dosimetry, 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)
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
in thorax cancers, 600
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
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
standard clinical risk target volume (CTV1), 641f
target volume definition, 628–629
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
radiation-induced toxicity of, 368–369
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
roles and responsibilities of, 10t
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
PTV in, 230
quality assurance for, 233–234
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
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
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
Target volume
assessment of, 3–4
defined, 3
localization of, 3–4
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
prognosis of, 490–491
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
radiation-induced toxicity of, 370–371
Thorax/lung cancers
in CTV, 601
diagnostic workup for, 598–599
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
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
dose prescription, 270, 273
quantitative assessment of implants, 274–276
target coverage, 276–277
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
target volume definition, 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
CT scanners for, 7
3D systems for, 8
for EBRT, 458–467
dose fractionation, 466–467
field setup, 461
target volume definition, 458–461
treatment technique, 461–466
electron beams, 288–310
basic physics and properties of, 288–296
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
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
target volume definition, 469–471
for rectal cancers, 409–412
staffing and, 8–10
ACR standards for, 9t
dosimetrists, 10
medical physicist, 9–10
roles and responsibilities of, 10t
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
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
radiotherapeutic management of, 427–428
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
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
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