Intracranial Stereotactic Radiosurgery

2nd Edition

L. Dade Lunsford, MD, FACS

Lars Leksell Professor and Distinguished Professor
Department of Neurological Surgery
Director
Center for Image Guided Neurosurgery
Director
Residency Training Program
University of Pittsburgh
Pittsburgh, Pennsylvania

Jason P. Sheehan, MD, PhD, FACS

Harrison Distinguished Professor
Vice Chair of Neurological Surgery
Professor of Radiation Oncology and Professor of Neuroscience
Department of Neurological Surgery
Director
UVA Gamma Knife Center
University of Virginia School of Medicine
Charlottesville, Virginia

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Intracranial stereotactic radiosurgery / [edited by] L. Dade
statements made in the present book. Such examination is particularly
Lunsford, Jason P. Sheehan. – 2nd edition.
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pioneers in radiosurgery, the book is a concise yet comprehensive
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Some of the product names, patents, and registered designs
current techniques are used, such as the evolution of the radiosurgery
referred to in this book are in fact registered trademarks or proprietary
modality, the sciences of radiosurgery such as physics and radiobiology,
names even though specific reference to this fact is not always made in
and the devices/technology systems used. The core of the book is the
the text. Therefore, the appearance of a name without designation as
detailed discussion of radiosurgical procedures for specific pathologies
proprietary is not to be construed as a representation by the publisher
and disorders, such as arteriovenous malformations, meningiomas,
that it is in the public domain.
pituitary adenomas, movement disorders, gliomas, ocular disorders,
and obsessive compulsive disorder. These chapters address the benefits
and limitations of radiosurgical techniques for each indication and
describe the outcomes, possible complications and their management,
and alternative treatments"–Provided by publisher.
ISBN 978-1-62623-032-3 (hardback) – ISBN 978-1-62623-033-0
(eISBN)
I. Lunsford, L. Dade, editor. II. Sheehan, Jason P., editor.
[DNLM: 1. Brain Diseases–surgery. 2. Radiosurgery–methods. 3.
Brain Diseases–radiotherapy. 4. Stereotaxic Techniques. WL 368]
RD594.15
617.4'81059–dc23
2015002877

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Contents

Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

Part I History

1 The Origins and Birth of the Leksell Gamma Knife . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Dan Leksell and L. Dade Lunsford

2 The History of Linac and Proton Beam Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Laura E. G. Warren, Brian Winey, Jay S. Loeffler, and Helen A. Shih

3 The History of CyberKnife Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Aditya Iyer, Steven D. Chang, and John R. Adler, Jr.

Part II Radiosurgical Fundamentals

4 The Radiobiology of Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

John C. Flickinger

5 The Physics of Radiosurgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

David Schlesinger, Brian Wang, and Stanley H. Benedict

6 Radiosurgical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Daniel E. Hyer, Frank J. Bova, and John Buatti

7 Critical Structures and Tolerance of the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Siavash Jabbari, Lijun Ma, Young K. Lee, Simon S. Lo, Eric L. Chang, Jimm Grimm, Lance Altenau, Daniel White,
Vikram Udani, Steven J. Goetsch, David Larson, and Arjun Sahgal

8 The Neuropathology of Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

György Szeifert, Douglas Kondziolka, Marc Levivier, José Lorenzoni, and L. Dade Lunsford

Part III Vascular Indications

9 Stereotactic Radiosurgery for Arteriovenous Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

L. Dade Lunsford, Ajay Niranjan, Hideyuki Kano, Edward A. Monaco III, and John C. Flickinger

10 Stereotactic Radiosurgery for Cavernomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Gabor Nagy and Andras A. Kemeny

11 Stereotactic Radiosurgery for Dural Arteriovenous Fistulas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

David Hung-Chi Pan, Wen-Yuh Chung, Huai-Che Yang, and Cheng-Chia Lee

v
 Contents

Part IV Benign Tumor Indications

12 Stereotactic Radiosurgery for Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

William Friedman and Frank J. Bova

13 Stereotactic Radiosurgery for Pituitary Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Cheng-Chia Lee and Jason P. Sheehan

14 Stereotactic Radiosurgery for Chordomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Dan Kunaprayoon, Ananth Charya, Jay S. Loeffler, and Helen A. Shih

15 Stereotactic Radiosurgery for Chondrosarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Hideyuki Kano, Aditya Iyer, and L. Dade Lunsford

16 Stereotactic Radiosurgery for Glomus Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Ajay Niranjan, Edward A. Monaco III, Hideyuki Kano, John C. Flickinger, and L. Dade Lunsford

17 Stereotactic Radiosurgery for Nonvestibular Schwannomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Edward A. Monaco III, Gurpreet Surinder Gandhoke, Ajay Niranjan, Hideyuki Kano, and L. Dade Lunsford

18 Stereotactic Radiosurgery for Hemangioblastomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

Hideyuki Kano and L. Dade Lunsford

19 Stereotactic Radiosurgery for Vestibular Schwannomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Jean Régis, Romain Carron, Christine Delsanti, Denis Porcheron, Jean-Marc Thomassin, Xavier Muracciole, and
Pierre-Hugues Roche

Part V Functional Indications

20 Stereotactic Radiosurgery for Trigeminal Neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Michael D. Chan and Stephen B. Tatter

21 Stereotactic Radiosurgery in Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

Patrick Pezeshkian, Antonio De Salles, and Nader Pouratian

22 Gamma Knife Radiosurgery for Obsessive–Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Nrupen Baxi, Andrew Brunswick, Eric Mazel, and Douglas Kondziolka

23 Stereotactic Radiosurgery for Hypothalamic Hamartomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Andrew G. Shetter, Heyoung L. McBride, and John F. Kerrigan

24 Stereotactic Radiosurgery for Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Mark Quigg and Nicholas M. Barbaro

Part VI Ocular Disorder and Pediatric Tumor Indications

25 Stereotactic Radiosurgery for Ocular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Roman Liscak and Gabriela Simonova

vi
 Contents

26 Stereotactic Radiosurgery for Pediatric Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

Christian C. Okoye, Ravi B. Patel, David B. Mansur, Alia Hdeib, Arjun Sahgal, Eric L. Chang, Mitchell Machtay,
John H. Suh, Andrew E. Sloan, and Simon S. Lo

Part VII Malignant Tumor Indications

27 Radiosurgery for Glial Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Jason Lee Schroeder, John H. Suh, Michael A. Vogelbaum, and Gene H. Barnett

28 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases . . . . . . . . . . 235
Sten Myrehaug, Simon S. Lo, Siavash Jabbari, Lijun Ma, Sunit Das, Aliaksandr Karotki, Eric L. Chang, and Arjun Sahgal

29 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases. . . . . . . . . . 243
Christopher L. Tinkle, Steve Braunstein, Penny K. Sneed, Igor J. Barani, and David Larson

30 Repeat Radiosurgery for Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Aditya Halthore, Ami B. Raval, Michael Schulder, and Jonathan Knisely

Part VIII Radiosurgical Horizon

31 Promising Advances in Radiosurgery: Where Are the Frontiers? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Brian D. Kavanagh

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

vii
 Foreword
The first edition of this book was published in 2009, and I
am honored to have been asked again to write the fore-
word to this second edition of Intracranial Stereotactic
Radiosurgery.
In December of 1985 there were three Gamma Knives in
the world, one each in Stockholm, Buenos Aires and Shef-
field. During Christmas of that year, a few weeks before my
father Lars suddenly passed away, I asked him how many
more Gamma Knives he thought there would be in the
world. His laconic answer was "maybe one or two more."
He was usually correct in his assessments of things but this
time, in retrospect, he could not have been more wrong!
Between 1968 and 1985 approximately 1,300 patients in
Sweden, Argentina and England underwent Gamma Knife
Surgery. In 2009, when I wrote the foreword for the first
edition of this book, the number of patients treated had
increased to around 500,000. Six years later, as this second
edition is published, the number of patients treated by
Gamma Knives will be approaching one million. An
unknown but likely very large number of additional
patients have been treated by other radiosurgery technol-
ogies, including protons, Cyberknife and other linac sys-
tems. Similarly, in 1985 there were just 117 published
papers on radiosurgery; a simple search on PubMed today
yields many thousands of peer-reviewed radiosurgery
papers.
Given this continued growth in radiosurgical procedures
and published science, it is not surprising that in a mere six
years there is so much more that has been learned that it
warrants an update of the previous excellent edition of this
work. That is what this wonderfully comprehensive tome
accomplishes with distinction.
The growing volume of knowledge is reflected not only
by the many more pages and chapters in this revised
edition, but also by the quantity of new data reported in
each section. The history of the development of the field
radiosurgery is now nicely complemented by a description
of the development of technologies other than the Gamma
Knife. The all-important and fundamental topic of the
radiobiology of radiosurgery has been updated, and chap-
ters on radiosurgery physics and critical structures and
brain tolerance have been added. The chapters on individual
clinical indications have been revisited and updated, includ-
viii
ing those on epilepsy, ocular disorders and pediatric brain
tumors.
As we live through our daily clinical routines we often
think that we have reached the outer limits of what we can
do for our patients, only to soon discover, again and again,
that there is more we can do. We now know more about the
use of radiosurgery for conditions such as OCD and hypo-
thalamic hamartomas, both of which are covered in new
chapters. And the final chapter by Brian D. Kavanagh is
thought-provoking; while I don't see charged particles
striking back in a big way in today’s increasingly cash-
strapped health care systems, I'm a firm believer in his
other three predictions.
In 1969, in my father’s stead, I travelled to a meeting in
India to talk about the first 7 or 8 patients we had treated in
Stockholm. After the talk there was uproar in the room. It
simply could not be true that you could do things in the
brain without a craniotomy! The chairman of the meeting
gently but firmly led me out of the lecture hall—maybe for
my own safety?
Now thinking back at my personal involvement with
stereotactic radiosurgery in different capacities over the
last 46 years, I cannot feel anything but astonishment at the
incredible developments we have seen and to which so
many have contributed. I'm also both humbled and proud of
the fact that so many patients have been helped by non-
invasive brain surgery—despite having been regarded as a
charlatan at that meeting in India years ago.
This volume is richly and interestingly illustrated and
truly a joy to read. The authors of all chapters have made
important contributions to the literature on intracranial
radiosurgery and, like its predecessor, this volume has been
elegantly compiled and edited by L. Dade Lunsford and
Jason P. Sheehan. We owe them both thanks for bringing
us this comprehensive update on all aspects of the field.
This is a work of reference for students, neurosurgery
residents and seasoned radiosurgery practitioners alike. It
deserves to occupy a prominent place in our bookshelves—
or even better—on our desks!
Dan Leksell, MD
Stockholm, Sweden
Preface
Since the first edition of Intracranial Stereotactic Radiosur-
gery published in 2009, substantial advancements have
been made in the field. This prompted us to begin work on
the current edition as a means of detailing contemporary
radiosurgery and the many advances that had occurred. By
its very nature, radiosurgery is minimally invasive and
relies upon sophisticated technology to aid in its delivery.
The minimally invasive nature led to a more favorable side
effect profile, and this was one of the core principles which
drove Leksell to conceive of stereotactic radiosurgery.
Technological advances in neuro-imaging, medical physics,
computer science, and engineering have lead to improve-
ments in the speed, accuracy, precision, and comfort of
radiosurgical delivery to single or multiple (10+) targets in
a single session. They have also yielded better clinical
outcomes.
Beyond technologic gains, the field has improved as a
result of an increased fund of knowledge. Knowledge in this
field has been acquired through multicenter trials coordi-
nated through national and international research groups.
Scientific dialogue and education have been fostered by
mature radiosurgical user groups. The user groups have
also created journals and held congresses for timely and
frank discussions of radiosurgical advances.
Intracranial radiosurgery continues to prove disruptive
to existing treatment paradigms (e.g. management of brain
metastasis). It has also spawned the application of its
principles to extracranial sites such as the spine. The field
of radiosurgery appears to be more vibrant than ever. The
current work provides a comprehensive assessment of
radiosurgery's past and present, and it affords a glimpse
of its bright future.
L. Dade Lunsford, MD, FACS
Pittsburgh, Pennsylvania
Jason P. Sheehan, MD, PhD, FACS
Charlottesville, Virginia
ix
 Contributors
John R. Adler, Jr., MD Steve Braunstein, MD, PhD
Dorothy and TK Chan Professor, Emeritus Assistant Professor
Department of Neurosurgery Radiation Oncology
Stanford University University of California–San Francisco
Stanford, California San Francisco, California

Lance Altenau, MD, FACS Andrew Brunswick, MD

Neurosurgical Medical Clinic Resident Physician
San Diego, California Department of Neurosurgery
New York University Langone Medical Center
Igor J. Barani, MD New York, New York
Associate Professor
Departments of Radiation Oncology and Neurological John Buatti, MD
Surgery Professor and Chair
University of California, San Francisco Department of Radiation Oncology
San Francisco, California Professor
Department of Otolaryngology, Neurosurgery
Nicholas M. Barbaro, MD University of Iowa Carver College of Medicine
Betsey Barton Professor and Chairman of Neurological Iowa City, Iowa
Surgery
Indiana University Romain Carron, MD, PhD
Goodman Campbell Brain and Spine Service de Neurochirurgie Fonctionnelle & Stéréotaxique
Indianapolis, Indiana Aix-Marseille Universite
Hôpital Universitaire La Timone
Gene H. Barnett, MD, MBA Marseille, France
Professor and Director
Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Michael D. Chan, MD
Center Assistant Professor
Department of Neurological Surgery Wake Forest School of Medicine
Cleveland Clinic Winston-Salem, North Carolina
Cleveland, Ohio
Eric L. Chang, MD
Nrupen Baxi, MD Professor and Chairman
Neuromodulation / Functional and Stereotactic Department of Radiation Oncology
Neurosurgery Fellow Keck School of Medicine of USC
New York University Langone Medical Center Los Angeles, California
New York, New York
Steven D. Chang, MD
Stanley H. Benedict, PhD Robert C. and Jeannette Powell Professor
Professor and Vice Chair of Clinical Physics Department of Neurosurgery
Department of Radiation Oncology Stanford University School of Medicine
University of California–Davis, Comprehensive Cancer Stanford, California
Center
Sacramento, California Ananth Charya, MD, MS
The Ohio State University College of Medicine
Frank J. Bova, PhD Columbus, Ohio
Principle Investigator
McNight Brain Institute Radiosurgery/Biology Laboratory Wen-Yuh Chung, MD
Albert E. and Birdie W. Einstein Professor of Computer- Department of Neurosurgery
Assisted Stereotactic Neurosurgery Neurological Institute
Department of Neurosurgery Taipei Veterans General Hospital
University of Florida National Yang-Ming University School of Medicine
Gainesville, Florida Beitou, Taipei, Taiwan

x
 Contributors

Sunit Das, MD, PhD Alia Hdeib, MD

Division of Neurosurgery Clinical Instructor
St. Michael's Hospital and Li Ka Shing Knowledge Institute Neurosurgery
Labatt Brain Tumour Research Centre, Hospital for Sick Case Western Reserve University School of Medicine
Children Cleveland, Ohio
Toronto, Ontario, Canada
Daniel E. Hyer, PhD
Christine Delsanti, MD Clinical Assistant Professor
Service de Neurochirurgie Fonctionnelle & Stéréotaxique Department of Radiation Oncology
Aix-Marseille Universite University of Iowa Hospitals and Clinics
Hôpital Universitaire La Timone Iowa City, Iowa
Marseille, France
Aditya Iyer, MD
Antonio De Salles, MD, PhD Neurosurgery Resident
Professor in Residence and Director Stanford School of Medicine
Stereotactic Surgery Program Stanford, California
Co-Director
Radiosurgery Program Siavash Jabbari, MD
Neurosurgery Department Department of Radiation Oncology
University of California–Los Angeles Sharp Healthcare
Los Angeles, California San Diego, California

John C. Flickinger, MD
Hideyuki Kano, MD, PhD
Department of Radiation Oncology
Research Associate Professor
University of Pittsburgh Medical Center
Department of Neurological Surgery
Pittsburgh, Pennsylvania
University of Pittsburgh
University of Pittsburgh Medical Center-Presbyterian
William Friedman, MD
Pittsburgh, Pennsylvania
Professor and Chairman
Department of Neurosurgery
University of Florida Aliaksandr Karotki, PhD
Gainesville, Florida Department of Medical Physics
Odette Cancer Centre
Gurpreet Surinder Gandhoke, MD, MCh Sunnybrook Health Sciences Centre
PGY-4 Resident Toronto, Ontario, Canada
Center for Image-Guided Neurosurgery
Department of Neurological Surgery Brian D. Kavanagh, MD, MPH, FASTRO
Professor and Interim Chair
University of Pittsburgh Medical Center-Presbyterian
Department of Radiation Oncology
Pittsburgh, Pennsylvania
University of Colorado Denver School of Medicine
Anschutz Medical Campus
Steven J. Goetsch, PhD, FAAPM
Director of Medical Physics Aurora, Colorado
San Diego Gamma Knife Center
La Jolla, California Andras A. Kemeny, MD, FRCS
Consultant Neurosurgeon
Jimm Grimm, PhD Thornbury Radiosurgery Centre
Bott Cancer Center BMI Thornbury Hospital
Holy Redeemer Hospital Sheffield, South Yorkshire, United Kingdom
Meadowbrook, Pennsylvania

Aditya Halthore, MD
Resident
Department of Radiation Medicine
Hofstra North Shore LIJ School of Medicine
Manhasset, New York

xi
 Contributors

John F. Kerrigan, MD Dan Leksell, MD

Director Chairman
Pediatric Epilepsy and Clinical Neurophysiology Programs Leksell Gamma Knife Society
Division of Pediatric Neurology and Comprehensive Stockholm, Sweden
Epilepsy Center
Hypothalamic Hamartoma Program Marc Levivier, MD, PhD
Barrow Neurological Institute at Phoenix Children’s Professor & Chairman
Hospital Department of Neurosurgery & Gamma Knife Center
Phoenix, Arizona Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland
Jonathan Knisely, MD
Chief, Division of Radiosurgery and Stereotactic Program, Roman Liscak, MD, PhD
Department of Radiation Medicine Associate Professor
Co-Director, Center for Stereotactic Radiosurgery and Head of the Stereotactic and Radiation Department
Stereotactic Radiation Therapy Na Homolce Hospital
Hofstra North Shore LIJ School of Medicine Prague, Czech Republic
Manhasset, New York
Simon S. Lo, MD, FACR
Associate Professor of Radiation Oncology
Douglas Kondziolka, MD, MSc, FRCSC, FACS
Director of Radiosurgery Services and Neurologic Radiation
Professor
Oncology
Department of Neurosurgery and Radiation Oncology
University Hospitals Seidman Cancer Center
Vice-Chair
Case Western Reserve University
Clinical Research (Neurosurgery)
Cleveland, Ohio
Director
Center for Advanced Radiosurgery Jay S. Loeffler, MD
New York University Langone Medical Center Professor and Chair
New York, New York Chief
Department of Radiation Oncology
Dan Kunaprayoon, MD Herman and Joan Suit Professor
Department of Radiation Oncology Department of Radiation Oncology
University of Cincinnati College of Medicine Massachusetts General Hospital
Cincinnati, Ohio Boston, Massachusetts

David Larson, MD, PhD, FACR, FASTRO José Lorenzoni, MD

Professor Departamento de Neurocirurgia
Departments of Radiation Oncology and Neurological Pontificia Universidad Católica de Chile and Centro Gamma
Surgery Knife de Santiago
University of California-San Francisco Santiago, Chile
San Francisco, California
L. Dade Lunsford, MD, FACS
Cheng-Chia Lee, MD Lars Leksell Professor and Distinguished Professor
Department of Neurosurgery Department of Neurological Surgery
Neurological Institute Director
Taipei Veterans General Hospital Center for Image Guided Neurosurgery
Beitou, Taipei, Taiwan Director
Residency Training Program
Young K. Lee, PhD, MIPEM University of Pittsburgh
Medical Physicist Pittsburgh, Pennsylvania
Department of Medical Physics, Odette Cancer Center
Assistant Professor Lijun Ma, PhD
Department of Radiation Oncology, University of Toronto Professor in Residence
Sunnybrook Health Sciences Centre Department of Radiation Oncology
Toronto, Ontario, Canada University of California, San Francisco
San Francisco, California

xii
 Contributors

Mitchell Machtay, MD Christian C. Okoye, MD

Professor and Chair
Department of Radiation Oncology
Case Western Reserve University School of Medicine
University Hospitals Seidman Cancer Center
Cleveland, Ohio
Resident Physician
Department of Radiation Oncology
University Hospitals Seidman Cancer Center
Case Comprehensive Cancer Center
Cleveland, Ohio

David B. Mansur, MD David Hung-Chi Pan, MD

Associate Professor of Radiation Oncology and Pediatrics Professor
Vice Chairman for Proton Therapy National Yang-Ming University School of Medicine
Department of Radiation Oncology Director
Case Western Reserve University School of Medicine Gamma Knife Center
University Hospitals Seidman Cancer Center Taipei Medical University Shuang-Ho Hospital
Cleveland, Ohio Department of Neurosurgery
Taipei Veterans General Hospital
Eric Mazel, MA, MALS Taipei, Taiwan
Research Assistant
New York University Langone Medical Center Ravi B. Patel, MD, PhD
New York, New York Resident Physician
Department of Radiation Oncology
Heyoung L. McBride, MD, MS University Hospitals Seidman Cancer Center
Associate Professor Case Comprehensive Cancer Center
Barrow Neurological Institute Cleveland, Ohio
University of Arizona College of Medicine-Phoenix
Patrick Pezeshkian, MD
Phoenix, Arizona
Neurosurgeon
Kaiser Permanente
Edward A. Monaco III, MD, PhD
Redwood City, California
Assistant Professor of Neurological Surgery
Center for Image Guided Neurosurgery Denis Porcheron, PhD
Department of Neurological Surgery Service de Neurochirurgie Fonctionnelle & Stéréotaxique
University of Pittsburgh Medical Center Aix-Marseille Universite
Pittsburgh, Pennsylvania Hôpital Universitaire La Timone
Marseille, France
Xavier Muracciole, MD
Service de Radiothérapie Nader Pouratian, MD, PhD
Hôpital Universitaire La Timone Assistant Professor
Marseille, France Department of Neurosurgery
University of California, Los Angeles
Sten Myrehaug, MD Los Angeles, California
Department of Radiation Oncology
Durham Regional Cancer Centre Mark Quigg, MD, MSc, FANA
Oshawa, Ontario, Canada Professor
Department of Neurology
Gabor Nagy, MD, PhD University of Virginia
Department of Functional Neurosurgery Charlottesville, Virginia
National Institute of Clinical Neurosciences
Budapest, Hungary Ami B. Raval, MD
Division of Neurosurgery
Ajay Niranjan, MD, MBA Neuroscience Associates of New York
Associate Professor Staten Island University Hospital
Director of Radiosurgery Research Richmond University Medical Center
Department of Neurological Surgery Staten Island, New York
University of Pittsburgh
Pittsburgh, Pennsylvania

xiii
 Contributors

Jean Régis, MD Andrew G. Shetter, MD

Service de Neurochirurgie Fonctionnelle & Stéréotaxique Division of Neurological Surgery
Aix-Marseille Universite Barrow Neurological Institute
Hôpital Universitaire La Timone St. Joseph’s Hospital and Medical Center
Marseille, France Phoenix, Arizona
Chairman
Pierre-Hugues Roche, MD Section of Functional and Stereotactic Neurosurgery
Department of Neurosurgery Co-Director
North hospital, APHM Gamma Knife Center
Aix-Marseille University Phoenix, Arizona
Marseille, France
Helen A. Shih, MD
Arjun Sahgal, MD Chief, CNS & Eye Services
Associate Professor of Radiation Oncology and Surgery Department of Radiation Oncology
Department of Radiation Oncology Massachusetts General Hospital
University of Toronto Associate Medical Director
Sunnybrook Health Sciences Center Francis H. Burr Proton Therapy Center
Toronto, Ontario, Canada Associate Professor of Radiation Oncology
Harvard Medical School
David Schlesinger, PhD Boston, Massachusetts
Associate Professor
Departments of Radiation Oncology and Neurological Gabriela Simonova, MD, PhD
Surgery Department of Stereotactic and Radiation Neurosurgery
University of Virginia Hospital Na Homolce
Charlottesville, Virginia Prague, Czech Republic

Jason Lee Schroeder, MD Andrew E. Sloan, MD, FAANS, FACS

Assistant Professor of Surgery Peter D. Cristal Chair of Neurosurgical Oncology
Department of Surgery Director, Brain Tumor and Neuro-Oncology Center
Division of Neurosurgery Professor & Vice-Chair for Research
University of Toledo Medical Center Department of Neurological Surgery
Toledo, Ohio University Hospitals Case Medical Center & Case
Comprehensive Cancer Center
Michael Schulder, MD, FAANS Cleveland, Ohio
Vice Chair and Residency Program Director
Department of Neurosurgery Penny K. Sneed, MD
Director Professor in Residence and Vice Chair
Brain Tumor Center Department of Radiation Oncology
Co-Director University of California, San Francisco
Center for Stereotactic Radiosurgery and Stereotactic San Francisco, California
Radiation Therapy
Hofstra North Shore LIJ School of Medicine John H. Suh, MD
Manhasset, New York Professor and Chairman
Department of Radiation Oncology
Jason P. Sheehan, MD, PhD, FACS Rose Ella Burkhardt Brain Tumor and Neuro-oncology
Harrison Distinguished Professor Center
Vice Chair of Neurological Surgery Cleveland Clinic
Professor of Radiation Oncology and Professor of Cleveland, Ohio
Neuroscience
Department of Neurological Surgery Gyorgy Szeifert, MD, PhD
Director Péterfy Traumatological Center
UVA Gamma Knife Center Department of Neurotraumatology
University of Virginia School of Medicine Semmelweis University of Budapest
Charlottesville, Virginia Budapest, Hungary

xiv
 Contributors

Stephen B. Tatter, MD, PhD Brian Wang, PhD

Professor Associate Professor and Chief of Physics
Department of Neurosurgery Department of Radiation Oncology
Comprehensive Cancer Center University of Louisville
Brain Tumor Center of Excellence Louisville, Kentucky
Medical Center Boulevard
Winston-Salem, North Carolina Laura E. G. Warren, MD, EdM
Resident Physician
Jean-Marc Thomassin, MD Harvard Radiation Oncology Program
Professor Boston, Massachusetts
ENT Department
CHU Timone Daniel White, MD
Marseilles, France Neurosurgery
Sharp Chula Vista Medical Center
Christopher L. Tinkle, MD, PhD Chula Vista, California
Resident Physician
Department of Radiation Oncology Brian Winey, PhD, DABR
University of California, San Francisco Assistant Professor
San Francisco, California Physics Division
Department of Radiation Oncology
Vikram Udani, MD Massachusetts General Hospital
Neurosurgical Medical Clinic Harvard Medical School
San Diego, California Boston, Massachusetts

Michael A. Vogelbaum, MD, PhD, FAANS, FACS Huai-Che Yang, MD

Professor of Surgery (Neurosurgery) Department of Neurosurgery
Associate Director Neurological Institute
Neurosurgical Oncology Taipei Veterans General Hospital
Rose Ella Burkhardt Brain Tumor and Neuro Oncology National Yang-Ming University School of Medicine
Center Beitou, Taipei, Taiwan
Cleveland Clinic
Cleveland, Ohio

xv
 1 The Origins and Birth of the Leksell
Part I Gamma Knife 1

History 2 The History of Linac and Proton Beam

Radiosurgery 11

3 The History of CyberKnife Radiosurgery 16

I
 The Origins and Birth of the Leksell Gamma Knife

1 The Origins and Birth of the Leksell Gamma Knife

Dan Leksell and L. Dade Lunsford

Key Points
● The background and early development of radiosurgery.
● Building a solid science foundation is a time-consuming
effort.
● The regulatory environment has historically affected
disruptive innovations.

1.1 Background
Cerebral radiosurgery is a relatively new addition to the
armamentarium of neurological surgeons, having come of
age only in the late 1980s and early 1990s. However, the his-
torical background of cerebral radiosurgery goes back much
further to the late 1930s and may not be well known by
many young neurosurgeons today. The possibility of deliver-
ing a high dose of ionizing radiation through the intact skull
to a small and deep-seated cerebral target was a discovery
with roots belonging to the early history of neurosurgery in
Europe. In 1930 Herbert Olivecrona, one of the early Euro-
pean pioneers of neurosurgery, established the first neuro-
surgical department in Scandinavia. A few years later a young
and aspiring neurosurgeon, Lars Leksell, joined the team
training in neurosurgery at the Serafimerlasarettet in Stock-
holm, which at the time was the hospital of the Karolinska
Institute (▶ Fig. 1.1).
Leksell gained firsthand experience in the difficulties fac-
ing Olivecrona and his patients, especially those with brain
tumors and vascular malformations. This experience initi-
ated a lifelong quest to develop and apply less invasive and
less traumatic interventions for these difficult brain pathol-
ogies. As Olivecrona expanded his practice for newly diag- Fig. 1.1 Pioneering Swedish neurosurgeon Herbert Olivecrona with
nosed intracranial disorders, the mortality among his colleagues during surgery at the Serafimerlasarettet, the first
patients approached 60%. Death often occurred in the oper- Scandinavian training center for neurosurgery.
ating room (OR) itself. One of the first procedures witnessed
by Lars Leksell involved a young boy with a tumor of the
posterior fossa. The boy was prone on the operating table thrashing about the way he did.” In the course of his work
and the hospital gatekeeper was acting as anesthetist (a in neurosurgery, Olivecrona developed a stoic personality,
specialty that did not yet exist in Sweden in that era). The no doubt engendered by the challenges of those early years.
gatekeeper/anesthetist sat on the floor while delivering When Leksell joined Olivecrona for training in the 1930s, he
ether into the boy’s face. Olivecrona often told how in the was welcomed by a mixture of Churchillian “blood, sweat
early years of neurosurgery, patients, nurses, and even Oli- and tears” (▶ Fig. 1.2).
vecrona himself were half asleep from the vapors of ether in Dismayed by the level of mayhem in the OR, Leksell began to
the OR. As Leksell recalled the events of this particular ope- believe that there had to be better, less traumatic ways to help
ration, the boy started moving about on the table at a crit- patients requiring neurosurgery. These early training experien-
ical surgical moment in the surgery. Olivecrona began ces became the fulcrum for a life in constant search of mini-
yelling at him to “lie still, lie still!” Moments later a vessel mally invasive ways to treat neurosurgical disorders. He was in
in the boy’s headburst and his life could not be saved. Olive- fact a neurophysiologist at heart, and worked in the laboratory
crona stood up, looked out of the window, and said to his of Ragnar Granit, who in 1967 won the Nobel Prize in Physiol-
scrub nurse: “there is Pettersson in the garden; bring him in ogy or Medicine. Together with Granit, Leksell was the first to
and prepare him for surgery in an hour.” He then left the describe the gamma motor system, which regulates muscle
OR, proceeded to kick off his rubber boots, looked at Leksell, tone. His doctoral degree in this subject was granted by the Kar-
and said about the boy: “It was mostly his own fault, olinska Institute.

2

1.2 Stereotactic Surgery as a
Method to Improve Patient
Outcomes
Almost 30 years before Leksell’s training at the Karolinska Insti-
tute, Sir Victor Horsley and Robert Clark had in 1908 published
a report describing an instrument for localizing structures in
the brain that they named a stereotactic device.1 This first use of
Fig. 1.2 Olivecrona’s operating room in Stockholm during the dawn of
Scandinavian neurosurgery.
The Origins and Birth of the Leksell Gamma Knife
stereotactic methodology was based on a three-dimensional
Cartesian coordinate system, which allowed targeting of any
point within its confines. The intention was to study cerebellar
physiology in monkeys, and it allowed Horsley to reliably deliv-
er a probe to a deep target in the animal brain. The paper was
soon forgotten and interest in stereotactic techniques did not
resurface until the 1940s, more than 10 years after Leksell’s first
experiences with Olivecrona. Although it was common in the
1930s and 1940s for trainees from the United States to travel to
Europe for additional training, it was rather rare for Europeans
to seek additional training in the United States. After the con-
clusion of the Second World War, Leksell arranged a fellowship
for training under the team of Ernst Spiegel, a neurologist, and
Henry Wycis, a neurosurgeon, who were working at Temple
University in Philadelphia. Spiegel and Wycis were the first gen-
erally recognized pioneers to apply stereotactic principles to
human patients,2 and over the years they developed several
models of their stereotactic instruments, including those
mounted to plaster casts on the head and others attached
directly to the vertex of the skull to anchor a probe holder. Lek-
sell returned to Stockholm and by 1949 had published his
article describing a prototype stereotactic guiding device using
a rectilinear coordinate system and an arc-centered principle to
deliver a probe to an intracranial target defined by radiographs
of the skull.3 During this same era, several other clinical investi-
gators designed their own stereotactic instruments. These con-
temporaries of Leksell included Jean Tallairach in Paris, Traugott
Riechert in Freiburg, and Irving Cooper in New York City. The
only instrument to use rectilinear Cartesian coordinates was
the Leksell instrument, which was used on a patient for the first
time in 1949. The design of the instrument, based on the arc-
centered principle, was intuitive and made the instrument easy
to use (▶ Fig. 1.3).
Two years later, in 1951, Leksell conceived the idea of replac-
ing the probe that was delivered surgically with his stereotactic
guiding device with multiple, narrow, cross-fired beams of ion-
izing radiation capable of traversing the intact skull. 4 In his first
report of this he outlined how this might be accomplished. By
attaching an X-ray tube to the arc of the guiding device, the
tube could be rotated in the anteroposterior (AP) direction and
also moved laterally along the arc to simulate an indefinite
number of X-ray beams, all aimed toward a common point of
beam intersection. The point of intersection was selected as the
target for surgery (▶ Fig. 1.4). Leksell anticipated that the best
Fig. 1.3 The basic principle of the arc-centered
Leksell stereotactic instrument. The intersection
of three planes (X, Y, and Z) defined the target
point for treatment, with this point being located
at the center of an arc. (a) By knowing the radius
of the arc (19 cm), the surgeon could deliver a
probe to the target point after choosing an
anatomically safe trajectory (left). (b) The first
Leksell frame (1949) is shown on the right.
3
 The Origins and Birth of the Leksell Gamma Knife
Fig. 1.4 The X-ray tube of an orthovoltage dental X-ray device was
mounted on the semicircular arc of the prototype Leksell frame. The
delivery of multiple converging beams to a common point of beam
intersection created the field of radiosurgery.
type of ionizing radiation for use with his device would be X-
rays or gamma rays. He also stated that the available orthovolt-
age energy of 200 kV was too low to sufficiently penetrate tis-
sue and protect skin. With this landmark paper, the term
“stereotactic radiosurgery” was coined. Of historical interest is
the journal editor’s initial rejection of this seminal paper with
the notation that “Everyone knows there is no such thing as
radiosurgery.”
1.3 Initial Clinical Experience
In 1953, Leksell put into practice the hypothetical suggestions
made in his 1951 report when two patients with trigeminal
neuralgia were treated with his technique of stereotactic radio-
surgery.5 The original stereotactic instrument lent itself well to
these initial applications. The target was the gasserian ganglion,
a structure whose treatment had previously required a subtem-
poral craniotomy in an era long before the introduction of the
operating microscope and safe neuroanesthesia. The first pa-
tient treated with Leksell’s technique had a gradual reduction
of pain until its complete disappearance at 5 months postoper-
atively. The second patient became pain-free after a few days,
and both patients remained pain-free at 17 years after their
surgery. The orthovoltage X-ray tube that was attached to the
arc of Leksell’s instrument was heavy and its energy was low, at
280 kV. The entire setup was awkward and took too long to
deliver the intended dose of radiation. However, the prelimi-
nary results warranted continued efforts in stereotactic radio-
surgery, and the search began for a better source of radiation.
In the mid-1950s Leksell made contact with the radiobiolo-
gist Börje Larsson, who was on the Faculty of Medicine at
Uppsala University and eventually became dean of the Gustav
Werner synchrocyclotron laboratory in Uppsala, an hour north
of Stockholm. Larsson was evaluating the effect of proton radia-
tion on cell biology.6–15 Leksell at the time was chairman of
the Department of Neurosurgery at the University of Lund, a
city in southern Sweden 700 km south of Uppsala. Despite the
distance, he soon established a very close collaboration with
Larsson. This led to Leksell’s stereotactic instrument being
4
Fig. 1.5 The cyclotron in Uppsala that generated cross-fired proton
beams guided by a version of the Leksell stereotactic methodology.
duplicated but made much sturdier so as to mate it with the
cyclotron. The set-up was such that the patient undergoing
stereotactic radiosurgery was positioned on a couch that piv-
oted around the exit point of the fixed beam of the cyclotron,
thus again simulating an indefinite number of beams intersect-
ing at the center of the stereotactic arc, which was the target to
be irradiated.11,16
A long series of animal experiments were then undertaken to
better understand the effects of single-dose radiation on the
brain, to determine the dose necessary to obtain a lesion in nor-
mal brain tissue, and to refine the methodology of stereotactic
radiosurgery. The initial confirmatory animal work was per-
formed on goats, which were allowed to roam freely on Lars-
son’s farm until they died of natural causes. Their brains were
then harvested and studied to assess the lesion created by the
radiation they had been given.
Following extended study of the effects of stereotactic radia-
tion on the brains of goats and other animals, a third patient
was treated at Uppsala in 1961 with the proton radiosurgical
technique (▶ Fig. 1.5). Nevertheless, the cyclotron used for the
treatment, although a good source of cross-fired proton radia-
tion (the proton Bragg peak effect was not used), was not prac-
tical from a clinical standpoint. The method was cumbersome
and relied on very expensive equipment that required signifi-
cant technical support and support in physics.
After Leksell succeeded Olivecrona as Professor of Neurosur-
gery at the Karolinska Institute and returned to Stockholm, his
commute to Uppsala became easier. Patients undergoing ster-
eotactic radiosurgery had their stereotactic frames applied in
Stockholm and were then driven in the back seat of Leksell’s
Daimler to Uppsala to undergo the radiosurgical procedure
itself. The search for a radiosurgical technology that could be
used in the daily routine of a hospital therefore continued. A
linear accelerator in the Department of Radiation Oncology at
Uppsala was adapted for stereotactic irradiation and a small
 The Origins and Birth of the Leksell Gamma Knife

Fig. 1.6 Lars Leksell attempted to use an early-generation linear

accelerator for stereotactic radiosurgery, but was worried about the
wobble of the beam caused by the excessive weight of the gantry.

Fig. 1.7 The design of the first Gamma Knife, based on the
series of patients with arteriovenous malformations (AVMs) specifications established in 1963. This prototype instrument used 179
were treated with this methodology (▶ Fig. 1.6). The results sources of cobalt 60, which emitted gamma rays that converged on a
target at the focal point of treatment.
were disappointing. The wobble of the gantry caused by the
very heavy head of the photon delivery device provided unac-
ceptable uncertainty in accurate dose delivery.
Leksell did not like the complexity of the linear accelerator
and its dependence on physics and engineering support to
remain operational. The search began for a device that was
extremely precise, reliable, and capable of operation by the sur-
geon without significant need for additional technical person-
nel. The device also had to be designed so that it would leave as
little room for surgeon error as possible. Knowing that sur-
geons, like everyone else, can make mistakes, Leksell often
quoted Norman Brown’s aphorism that “Fools with tools are
still fools.”
In 1963, the technical specifications for what was to become
the prototype Gamma Knife were finalized.17 Despite Leksell’s
personal interests in functional brain surgery and his plan to
use it to create radiodestructive lesions in the brain for unre-
sponsive behavioral,18 nociceptic,5,16 or movement disorders,
the first patient treated had a craniopharyngioma. The patient
Fig. 1.8 Erik-Olof Backlund explains the thermoplast Gamma Knife
was treated at the factory in Studsvik, Sweden, where the first
head-fixation system to a pioneering early patient. The thermoplast
Leksell Gamma Knife was built and loaded with 179 sources of system was used for fixation of the patient’s head because the
cobalt 60.17 In early 1968, this prototype machine was installed stereotactic frame on which the Gamma Knife was mounted could not
at the Sophiahemmet in Stockholm, one of very few private fit within the helmet used with the first Gamma Knife. The thermoplast
hospitals in Sweden because it was built under the auspices of cast of the first treated patient was given by Professor Backlund to L.
then Swedish Queen Sophia (▶ Fig. 1.7). Meticulous, cautious, Dade Lunsford when Lunsford was inaugurated as the first Lars Leksell
Professor of Neurosurgery at the University of Pittsburgh in Pennsyl-
and exceedingly slow clinical exploration ensued. This was a
vania.
hallmark of Leksell’s philosophy: Don’t treat large numbers of
patients until you have convinced yourself and your colleagues
that what you do makes a difference without undue complica-
tions. In fact, between 1968 and 1986 an average of less than secondary collimators were designed to focus the beams and
three patients per month were treated by Gamma Knife surgery contained a small slit rather than a circular opening. It was
in Stockholm. designed to create a discoid rather than oblate spheroidal radio-
The term Gamma Knife derived from its early description as surgical field, as if to “section” a target. The helmet containing
strålkniven, or “radiation knife” in Swedish; the concept was to the secondary collimators was too small to accommodate the
use the photon beam intersection as a surgical sectioning tool frame itself. As a result, after the frame had been used in deter-
within the closed skull. Since the 179 cobalt 60 sources pro- mining the target for surgery, the frame was removed from the
duced gamma rays, the new technology eventually came to be plaster or Surgiplast cast that had been applied to the patient’s
known as the “Gamma Knife.” The prototype Gamma Knife had head (▶ Fig. 1.8). Bearings were seared into the plaster at the Z
two collimators, of 3 × 5 and 3 × 7 mm, respectively. These and Y coordinates of the three-dimensional field of treatment

5
 The Origins and Birth of the Leksell Gamma Knife
with the Gamma Knife, and the patient was moved to the left or
right manually, using trunnions to reach the X coordinate of the
treatment site.
Most of the early patients treated with the Gamma Knife had
functional disorders,19 including intractable pain, trigeminal
neuralgia, and refractory obsessive–compulsive/anxiety disor-
ders for which neither medication or psychiatric treatment pro-
vided any benefit. The first reported patient to be treated for an
AVM underwent radiosurgery in 1971.20 As usual, Leksell
authorized a single patient to be treated, with an ensuing 2-
year period of observation. The necessary obliterative dose of
gamma radiation was unknown and the effect unpredictable.
Fortunately, follow-up angiography showed obliteration of the
patient’s AVM, which stimulated Ladislau Steiner to proceed
with the Gamma Knife treatment of additional cases. Imaging
for target localization consisted primarily of pneumoencepha-
lography, cisternography, and cerebral angiography. Because
this occurred in an era before computers were available, both
target localization through X-ray films and dose planning were
done manually. Dose determination was done by means of a
nomogram handcrafted by the physicist21 (▶ Fig. 1.9).
The wavy lines on the nomogram would probably not inspire
confidence today, and it is possible that patients received either
a larger or a smaller dose of radiation than intended in those
early years. This did not matter very much because at the time
nobody really knew the effective and safe dose for any of the
Fig. 1.9 (a) Manual target localization and (b) dose determinations
were performed using special nomograms developed by Lars Leksell
and medical physicists.
6
emerging indications treated with the Gamma Knife. The cross-
fired proton experiments in Uppsala had revealed that 140 Gy
were needed to produce a radiodestructive lesion in the brain.
In the early years, the photon doses that the Gamma Knife
delivered were therefore were very high, often around 200 Gy.
Today such doses are never used, and in fact, most patients do
not receive even 10% of that dose. Little was it known at the
time that the appropriate radiobiological response for many
indications of stereotactic radiosurgery could be achieved with
nonnecrotizing doses of radiation. Today some sources profess
that nonnecrotizing doses of radiation delivered in radiosurgery
can modulate brain function, much like deep brain stimulation.
In contrast to Leksell’s early experience in the ORs of Olive-
crona, the new, noninvasive Gamma Knife procedure was
undramatic. There was no blood, no sweat, and absolutely no
tears. When the patient had been positioned in the focus of the
collimator helmet of the Gamma Knife, the treatment team
called the kitchen and ordered sandwiches and Swedish beer
for lunch. At the end of the procedure, the premises did not
look like any other OR. When the frame was removed from the
patient’s head, everyone was happy. The patients were happy
because they were going home on the day of brain surgery, and
the doctors were also happy, perhaps because they had had too
much beer for lunch (▶ Fig. 1.10).
Fig. 1.10 (a) The prototype noninvasive Leksell Gamma knife OR, with
Lars Leksell at the console and surrounded by colleagues, including
Erik-Olof Backlund (far left) and Bengt Jernberg, his engineer (far right).
(b) At the end of the procedure, celebratory starköl (Swedish beer) was
routine.

While the original prototype remained at the private Sophia-
hemmet in Stockholm, Leksell arranged for the construction of
a second Gamma Knife that was installed in the basement of
the Radiumhemmet on the grounds of the Karolinska Hospital
in Stockholm. This unit entered service in 1975 and was rede-
signed to produce a more oblate spheroid field that was suit-
able for morphological and pathological targets in the brain.
Disciples of Leksell who were given special projects began addi-
tional work: Ladislau Steiner and Christer Lindquist were
assigned to treat AVMs20; George Noren to treat acoustic neuro-
mas22; Tiit Rähn to treat pituitary tumors23; and Erik-Olof Back-
lund to treat craniopharyngiomas.17,24
Seven years after the prototype Gamma Knife was installed in
Stockholm, the first computed tomography (CT) scanner in the
country was installed at the Karolinska Hospital in 1974.25 Sud-
denly, it became possible to directly visualize cerebral pathologies
and the surrounding brain without having to rely on indirect
signs of pathology such as the displacement of a ventricle or a
vessel. The Leksell frame was redesigned to make it compatible
with CT imaging, and was further modified in the 1980s to make
it compatible with magnetic resonance imaging (MRI).26
1.4 Spreading the Gospel
Leksell much preferred working in Stockholm to traveling to
meetings. This meant that his son Dan (a coauthor of this chap-
ter), long before finishing medical school, was asked to travel in
his stead to give talks all over the world. Dan Leksell spoke
about the early experiences with the radically new, noninvasive
form of neurosurgery made possible with the Gamma Knife in
Stockholm. At the time, the possibility of curing brain disease
without a craniotomy was considered incredible. Like most dis-
ruptive innovations, descriptions of the method and roles of
radiosurgery were for many years met with great skepticism if
not outright hostility. Dan Leksell usually started his talks by
showing an engraving done by the Renaissance German artist
Matthias Greuter (▶ Fig. 1.11). He then began by telling his audi-
ence that he was not going to talk about anything new, and that
what was done in Stockholm had already been done during the
Renaissance. At this, everybody smiled and laughed. But by the
time he was finished with his lecture, nobody was laughing!
Fig. 1.11 This Renaissance-era lithograph from the annals of Mathias
Greuter was often used to introduce talks about the Gamma Knife and
its roles to audiences around the world.
The Origins and Birth of the Leksell Gamma Knife
In 1979, Lars Leksell was persuaded by his friend Robert
Rand, Professor of Neurosurgery at the University of California–
Los Angeles (UCLA), to donate the prototype first Gamma Knife
to him. As the story goes, the fully loaded (but with low-
strength cobalt 60, now in its third half-life) unit was shipped
from Stockholm to Long Beach, California, in a special container
marked “radioactive.” During the long trek from Stockholm
around the world to California, the freighter carrying the unit
stopped periodically to unload cargo at various ports. The
inspecting harbormaster invariably told the captain to move on
after finding the “radiation-containing” cargo in the freighter’s
hold. The story reminded Leksell of the saga of the Flying
Dutchman, who was allowed to enter port every 7 years to look
for true love. Eventually, the freighter carrying the prototype
Gamma Knife docked in Long Beach, and shortly thereafter in
1980, the knife miraculously appeared in a vault at UCLA. It
remains unclear how many patients Rand treated using this
prototype Gamma Knife, although an early report showed its
potential in a rabbit model of ocular melanoma. 27 After some
years, the unit was unloaded and shipped back to Stockholm to
potentially rest at the Stockholm Technological Museum.
1.5 The Next Gamma Knife Units
With such abundant skepticism surrounding its efficacy, radio-
surgery did not catch on quickly as a treatment modality. Lars
Leksell was not particularly interested in the economic poten-
tial of this remarkable discovery. Three of Leksell’s trainees
eventually persuaded him to authorize the construction of two
additional Gamma Knife units. They were constructed in Swit-
zerland by an authorized agent, Scanditronix. Based on the per-
sistent intercessions of Roberto Chescotta and Hernan Bunge,
also prior students of Leksell, a third Gamma Knife was built in
1984 and shipped to Buenos Aires for installation in the Clinica
del Sol. Unit 4 was delivered to Sheffield, England, where it
entered service under the direction of David Forster
(▶ Fig. 1.12). In a remarkable prediction of the direction of the
Fig. 1.12 David Forster and Gamma Unit 4 in Sheffield, England.
7
 The Origins and Birth of the Leksell Gamma Knife

Gamma Knife technology, the initial design of these third and

fourth units required moving the patient’s positioning on the
treatment table to accurately focus the 179 beams of radiation
delivered by the instrument (rather than the surgeon manually
moving the patient’s head and treatment target into the focus
of the selected beams). Unfortunately, this radical idea foun-
dered because of insufficiently reliable table-positioning tech-
nologies in that era. Both the Buenos Aires and the Sheffield
units were subsequently reconfigured to again have the sur-
geon manually position the patient’s head at the focus of these
instruments’ radiation beams.
With the passage of time, the tireless efforts of a few pioneers
eventually brought about grudging acknowledgment of the
potential of radiosurgery. Leksell’s disciples diligently evaluated
the indications for radiosurgery to which each of these pioneers
was assigned. During the 1980s other radiosurgical pioneers Fig. 1.13 Gamma Unit 5 (the first installation to have 201 sources of
emerged: Juan Barcia Salorio in Madrid,28 Volker Sturm in Hei- cobalt 60 and a new, 18-mm secondary collimator helmet) was
installed at Presbyterian University Hospital at the University of
delberg, Federico Colombo in Vicenza, Italy,29 and Osvaldo Betti
Pittsburgh Medical Center (UPMC), and began clinical operation on
in Buenos Aires and Paris, all of whom adapted linear accelera- August 14, 1987. Since then, more than 12,600 patients have
tors to emulate the principle of the Gamma Knife. Using fractio- undergone Gamma Knife radiosurgery at UPMC, with different models
nated techniques with accelerated helium ions, John H. of the Gamma Knife.
Lawrence30 and then Jacob Fabrikant, working at the Berkeley
cyclotron, began to create pituitary lesions and to obliterate
AVMs. Raymond Kjellberg, working in the Cambridge cyclotron
the rate at which the Pittsburgh group published their data was
unit in Cambridge, Massachusetts, that had been donated to
very high, and has continued to be very high since they began
Harvard by the Navy in thanks for its collaboration in the Man-
their reporting. In relatively short order, several more installa-
hattan Project during the Second World War, used the Bragg
tions of the Gamma Knife in the United States followed its debut
peak principle of proton beam therapy to treat a large number
at Pittsburgh, and in 1990 the first Gamma Knife Center in Asia
of patients with AVMs or pituitary tumors. 31
became operational at Tokyo University under the supervision
Despite all the efforts of these early enthusiasts, it would take
of Kintomo Takakura. Other countries would subsequently fol-
almost 20 years for the development of sufficient traction to
low suit.
advance the field of radiosurgery. After studying with Lars Lek-
sell and Erik-Olof Backlund at the Karolinska institute in 1979
and for a year in 1980 and 1981, L. Dade Lunsford returned to
Pittsburgh, Pennsylvania, with a two-part plan: to establish a
1.6 A Final Perspective
dedicated OR for image-guided neurosurgery (installing the In December of 1985, a few weeks before Leksell died and when
first dedicated CT scanner)32 and to develop CT-compatible there were still only four Gamma Knives in the world, his son
technologies for radiosurgery.33 Beginning in 1982, a 5-year Dan asked him, “How many more machines do you think the
effort pushed the concept of stereotactic radiosurgery with the world might absorb or need?” His answer was “Maybe two or
Gamma Knife in the United States through many regulatory three more.” As of the time of this writing, more than 300 Gam-
hurdles, including those of the U.S. Food and Drug Administra- ma Knife centers have appeared in the world and the number
tion (FDA) and the U.S. Nuclear Regulatory Commission (NRC).27 continues to grow annually.
The greatest issue in implementing use of the knife was devis- During the first two decades after its introduction, the Gam-
ing a method for the on-site loading of the new 201-source ma Knife existed at only four treatment centers in the world,
Gamma Knife with its four focusing collimator helmets (with whereas the ensuing two decades have seen the installation of
apertures of 4, 8, 14, and 18 mm, respectively) because the NRC more than 300 of these instruments. New generations of the
would not allow moving a loaded unit across any distance. Gamma Knife have been introduced at regular intervals, each
The Pittsburgh site initiated a new explosion of interest in bringing a higher level of sophistication to stereotactic radio-
radiosurgery as a method and in the Gamma Knife as a radio- surgery. The latest generation (Perfexion; Elekta AB, Stockholm,
surgical tool (▶ Fig. 1.13). After installation of the Gamma Knife Sweden) incorporates several significant improvements, not
at Pittsburgh in 1987, the Pittsburgh team, under the leadership least of which are shorter treatment times, improved patient
of L. Dade Lunsford, began publishing not only their early clini- treatment efficiency, and vastly more sophisticated treatment
cal results with the new instrument, but also cost-effectiveness planning.
data and other information relating to its use.34 It did not take One very important contributing factor to all of this must be
long for the information from Pittsburgh to spread and kindle recognized. The rate of development of neuroimaging since Sir
international interest. Many have often wondered why the 20 Geoffrey Hounsfield was awarded the Nobel Prize for inventing
years of painstaking work done in Stockholm never by itself led CT in 197635 has been astonishing and all-important for the
to the greater acceptance of stereotactic radiosurgery. The development of radiosurgery. The subsequently developed of
answer is that independent corroboration is a key factor for the MRI has become instrumental to neurosurgeons’ daily work.26
credibility of any new technology. It should also be added that Gamma Knife radiosurgery represents the treatment-delivery

8

Fig. 1.14 The fifth-generation Leksell Gamma Knife represented the therapeutic correlate to the (a,b) early generation of computed tomography
scanners. (c,d) The most recent Gamma Knife device (the Perfexion instrument) corresponds to new imaging methods with 3-Tesla magnetic
resonance imaging.
technology that was needed to mirror the revolution in diag-
nostic imaging of the past half century (▶ Fig. 1.14). In the cur-
rent regulatory environment it is unlikely that this history
could be repeated. The way in which Lars Leksell, his collabora-
tors, and his disciples could work in the 1950s to 1970s would
not be possible today. Had the current regulatory environment
existed in that era, it is unlikely that radiosurgery would have
emerged.
A great source of pride for radiosurgery providers
throughout the world is the sheer number of patients who
have benefited from the hard work done by so many in this
field. Statistics reported by about 80% of all Gamma Knife
centers indicate that as of 2014, more than a million
patients had undergone Gamma Knife surgery, and approxi-
mately 60,000 new patients undergo such surgery every
year. Between 1968 and 1988 approximately 80 papers on
Gamma Knife surgery were published; over the next 15
years, more than 2,000 such papers were published in the
peer-reviewed literature. This development would probably
have both perplexed and amused Lars Leksell. The introduc-
tion of new methods and disruptive technologies in medi-
cine is not easy. It requires perseverance and patience. New
The Origins and Birth of the Leksell Gamma Knife
medical approaches and technologies are regarded with
appropriate skepticism and must prove their value before
being widely adopted.
References
[1] Horsley V, Clarke RH. The structure and functions of the cerebellum exam-
ined by a new method. Brain 1908; 31: 45–124
[2] Spiegel EA, Wycis HT, Freed H, et al. Stereoencephalotomy. Proc Soc Exp Biol
Med 1948; 69: 175–177
[3] Leksell L. A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand
1949; 99: 229–233
[4] Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir
Scand 1951; 102: 316–319
[5] Leksell L, Backlund EO. Stereotaxic gamma capsulotomy. In: Hitchcock ER,
Ballantine HT, Meyerson BD, eds. Modern Concepts in Psychiatric Surgery.
Amsterdam: Elsevier/North-Holland Biomedical Press;1979:213–216
[6] Andersson B, Larsson B, Leksell L, et al. Histopathology of late local radiole-
sions in the goat brain. Acta Radiol Ther Phys Biol 1970; 9: 385–394
[7] Dahlin H, Larsson B, Leksell L, Rosander K, Sarby B, Steiner L. Influence of ab-
sorbed dose and field size on the geometry of the radiation-surgical brain le-
sion. Acta Radiol Ther Phys Biol 1975; 14: 139–144
[8] Dahlin H, Sarby B. Destruction of small intracranial tumours with 60Co gam-
ma radiation. Physical and technical considerations. Acta Radiol Ther Phys Bi-
ol 1975; 14: 209–227
9
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[9] Larsson B. Blood vessel changes following local irradiation of the brain with
high-energy protons. Acta Soc Med Ups 1960; 65: 51–71
[10] Larsson B, Leksell L, Rexed B. The use of high-energy protons for cerebral sur-
gery in man. Acta Chir Scand 1963; 125: 1–7
[11] Larsson B, Leksell L, Rexed B, Sourander P, Mair W, Andersson B. The high-en-
ergy proton beam as a neurosurgical tool. Nature 1958; 182: 1222–1223
[12] Mair W, Rexed B, Sourander P. Histology of the surgical radiolesion in the hu-
man brain as produced by high-energy protons. Radiat Res Suppl 1967; 7
(Suppl): 384–389
[13] Rexed B, Main W, Sourander P, et al. Effect of high energy protons on the
brain of the rabbit. Acta Radiol 1960; 53: 289–299
[14] Sarby B. Cerebral radiation surgery with narrow gamma beams; physical ex-
periments. Acta Radiol Ther Phys Biol 1974; 13: 425–445
[15] Wennerstrand J, Ungerstedt U. Cerebral radiosurgery. II. An anatomical study
of gamma radiolesions. Acta Chir Scand 1970; 136: 133–137
[16] Leksell L. Cerebral radiosurgery. I. Gammathalanotomy in two cases of in-
tractable pain. Acta Chir Scand 1968; 134: 585–595
[17] Backlund E-O. The history and development of radiosurgery. In: Lunsford LD,
ed. Stereotactic Radiosurgery Update. Philadelphia, PA: Elsevier; 1992: 3–9
[18] Mindus P, Bergström K, Levander SE, Norén G, Hindmarsh T, Thuomas KA.
Magnetic resonance images related to clinical outcome after psychosurgical
intervention in severe anxiety disorder. J Neurol Neurosurg Psychiatry 1987;
50: 1288–1293
[19] Leksell L. Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand
1971; 137: 311–314
[20] Steiner L, Leksell L, Greitz T, Forster DM, Backlund EO. Stereotaxic radiosur-
gery for cerebral arteriovenous malformations. Report of a case. Acta Chir
Scand 1972; 138: 459–464
[21] Arndt J, Backlund EO, Sahlin H, et al. A computer controlled dose planning
system for irradiation of small volumes of the brain with a multi-cobalt unit.
Paper presented at: the Third Congress of the European Society of Radiology;
June 22–27, 1975; Edinburgh, Scotland
[22] Leksell L. A note on the treatment of acoustic tumours. Acta Chir Scand 1971;
137: 763–765
10
[23] Thorén M, Rähn T, Hall K, Backlund EO. Treatment of pituitary dependent
Cushing’s syndrome with closed stereotactic radiosurgery by means of 60Co
gamma radiation. Acta Endocrinol (Copenh) 1978; 88: 7–17
[24] Backlund EO, Rähn T, Sarby B, De Schryver A, Wennerstrand J. Closed stereo-
taxic hypophysectomy by means of 60-Co gamma radiation. Acta Radiol Ther
Phys Biol 1972; 11: 545–555
[25] Leksell L, Jernberg B. Stereotaxis and tomography. A technical note. Acta Neu-
rochir (Wien) 1980; 52: 1–7
[26] Leksell L, Leksell D, Schwebel J. Stereotaxis and nuclear magnetic resonance. J
Neurol Neurosurg Psychiatry 1985; 48: 14–18
[27] Rand RW, Khonsary A, Brown WJ, Winter J, Snow HD. Leksell stereotac-
tic radiosurgery in the treatment of eye melanoma. Neurol Res 1987; 9:
142–146
[28] Barcia-Salorio JL, Broseta J, Hernandez G, et al. Radiosurgical treatment in
huge acoustic neuromas. In: Szikla G, ed. Stereotactic Cerebral Irradiation. IN-
SERM Symposium, No. 12. Amsterdam: Elsevier/North-Holland Biomedical
Press; 1979: 245–249
[29] Colombo F, Benedetti A, Pozza F, et al. External stereotactic irradiation by lin-
ear accelerator. Neurosurgery 1985; 16: 154–160
[30] Lawrence JH, Tobias CA, Linfoot JA, Born JL, Chong CY. Heavy-particle therapy
in acromegaly and Cushing disease. JAMA 1976; 235: 2307–2310
[31] Kjellberg RN, Koehler AM, Preston WM, Sweet WH. Stereotaxic instrument
for use with the Bragg peak of a proton beam. Confin Neurol 1962; 22: 183–
189
[32] Lunsford LD, Rosenbaum AE, Perry J. Stereotactic surgery using the “thera-
peutic” CT scanner. Surg Neurol 1982; 18: 116–122
[33] Lunsford LD, Leksell L, Jernberg B. Probe holder for stereotactic surgery in the
CT scanner. A technical note. Acta Neurochir (Wien) 1983; 69: 297–304
[34] Lunsford LD, Flickinger J, Lindner G, Maitz A. Stereotactic radiosurgery of the
brain using the first United States 201 cobalt-60 source gamma knife. Neuro-
surgery 1989; 24: 151–159
[35] Hounsfield GN. Computerized transverse axial scanning (tomography). 1. De-
scription of system. Br J Radiol 1973; 46: 1016–1022

2 The History of Linac and Proton Beam Radiosurgery
Laura E. G. Warren, Brian Winey, Jay S. Loeffler, and Helen A. Shih
Key Points
● Particle-beam experiments in physics laboratories and the
development of stereotactic neurosurgical techniques in the
early 20th century provided the foundations for stereotactic
radiosurgery.
● Lars Leksell, a Swedish neurosurgeon, is widely credited with
the introduction of charged-particle radiosurgery to the in-
ternational medical community with his famous 1951 paper
on stereotactic radiosurgery of the brain.
● Linear accelerator–, as compared with cyclotron-based, ra-
diosurgery developed in the 1980s and 1990s.
● Advances in imaging for diagnosis and treatment planning,
patient-positioning technologies, and the construction of
dedicated clinical facilities have resulted in increasing utiliza-
tion of stereotactic radiosurgery and the expansion of its
clinical applications over the past two decades.
2.1 The Early Years
The Swedish physician Lars Leksell introduced the world to the
stereotactic utilization of therapeutic X-radiation in 1951.1 His
published paper entitled “The Stereotaxic Method and Radio-
surgery of the Brain” is often cited as the introduction to the
technical and practical aspects of clinical stereotactic radiosur-
gery. In subsequent years, Leksell continued to have a fruitful
collaborative relationship with Borje Larsson, a physicist and
radiobiologist in the cyclotron unit at Uppsala University in
Sweden. Leksell advocated the use of proton radiosurgery pre-
dominantly for benign brain tumors. This was motivated by his
concern that the biology of malignant neoplasms was such that
radiosurgery might prove ineffective for treating them, and that
the combination of the great incidence of benign tumors and
limited capacity of his radiosurgery unit would make the
expansion of radiosurgery to the treatment of malignant dis-
ease logistically challenging.2 Leksell understood that the inva-
sive nature of the contemporary neurosurgery of his time
resulted in high perioperative morbidity and mortality, and was
therefore enthusiastic about minimally invasive methods for
treating intracranial lesions.
Although Leksell can certainly be credited for his clinical
applications of radiosurgery, the work of other international
centers in the decades before Leksell’s work helped to provide
its foundational underpinnings. Ernest Rutherford, the 1908
Nobel laureate in chemistry, demonstrated the existence of and
named the proton in 1919.3,4 In 1932, James Chadwick discov-
ered neutrons under Rutherford’s guidance.5 Chadwick’s dis-
covery sparked considerable interest in the clinical utilization
of neutron beams. Robert Stone experimented with fast-neu-
tron radiotherapy in Berkeley, California,6 treating approxi-
mately 250 patients in this way between 1937 and 1942.
Unfortunately, his experiments demonstrated the potential for
severe late tissue injury with such therapy, and the results were
The History of Linac and Proton Beam Radiosurgery
not superior to those with X-ray therapy. Stone’s work was dis-
continued in 1942, when the cyclotron at Berkeley was reallo-
cated to other purposes.
In 1946, Robert Wilson, who had worked on the Manhattan
Project, first proposed that accelerated protons and heavier ions
could be utilized for treating human patients.7 His work intro-
duced the therapeutic concept of the Bragg peak, a distinct and
localized region of high-dose radiation that was characteristic
of proton beam irradiation. Soon thereafter, Wilson and Edward
Creutz, who had joined the Department of Physics at the Carne-
gie Institute of Technology in Pittsburgh, Pennsylvania, after
having worked on the Manhattan Project, described the meth-
odology by which they were able to produce monoenergetic
protons from a cyclotron, further raising the potential for the
clinical application of proton beam irradiation. 8 On the other
side of the United States, in Berkeley, California, Ernest Orlando
Lawrence founded the Radiation Laboratory at the University of
California, a physics laboratory centered around a newly devel-
oped cyclotron that had been built with his student Niels Edlef-
sen.9 Animal studies were soon underway, with the ultimate
goal of oncologic applications. Studies focusing on pituitary
irradiation were undertaken on the basis of prior work demon-
strating that hypophysectomy might be of benefit in the treat-
ment of various diseases, including metastatic breast cancer. 10,
11 John Lawrence, Ernest Lawrence’s brother, left Yale to join his
brother at Berkeley and was integral to these initial therapeutic
efforts.12 Cornelius A. Tobias, another prominent member of the
Radiation Laboratory at Berkeley, which later became the Don-
ner Laboratory, described the value of high-energy particles in
1958 when he stated that “[These] particles, when focused,
travel in a straight beam with little divergence and may be
directed to any portion of the body.” Moreover, noted Tobias,
“As the particles penetrate tissue, their scattering is very small
compared with electrons, and for practical purposes negligibly
small amounts of radiation fall outside the main beam.”13
After promising animal studies showing tumor regression or
the arrest of tumor growth, Lawrence treated 26 metastatic
breast cancer patients with pituitary proton irradiation using a
340-MeV proton beam from a 184-inch synchrocyclotron at the
Donner Laboratory in Berkeley, California. Lawrence and his
colleagues described decreased pituitary function and gross
microscopic damage to the pituitary gland.13,14 A good clinical
response in a few of the patients was also seen. In 1957, proton
beam experiments in the Donner Laboratory were discontinued
in favor of experiments with 910-MeV helium ions and then
with heavier ions.15
Internationally, Lars Leksell and his colleagues at the Univer-
sity of Uppsala were equally interested in destroying small,
selected regions within the central nervous system with high-
energy heavy particles.16 They utilized a 185-MeV proton beam
from a 230-cm synchrocyclotron. Animal studies showed that it
was possible to produce sharply delineated lesions in any re-
gion of choice in the central nervous system.17,18 In 1960, Lek-
sell and his colleagues performed their first stereotactic proton
beam “operation.”17 However, following these experiments,
Leksell stated that “Although the synchrocyclotron is a valuable
11
 The History of Linac and Proton Beam Radiosurgery
Fig. 2.1 Harvard University Physics Professors Jabez C. Street (left,
standing) and Kenneth Bainbridge (right, standing), with then
graduate student Dr. Roger W. Hickman (kneeling), examining the first
Harvard Cyclotron in about 1940. Construction of the cyclotron had
been completed in 1938. (Used with permission from Professor
Richard Wilson, from Wilson R. A Brief History of the Harvard
University Cyclotrons. Cambridge, MA: Harvard University Press; 2004.
Available at: http://users.physics.harvard.edu/~wilson/cyclotron/his-
tory.html. Updated June 16, 2003. Accessed May 14, 2014.)
research tool, it has proved too complicated for general neuro-
surgical application.”19 This was particularly relevant in Swe-
den, where patients had to be transported from Stockholm to
Uppsala, a distance of over 70 km, for proton beam treatment.
Given these limitations, Leksell and his collaborators in medical
physics developed the Gamma Knife, which utilizes cobalt-60
as a radioactive source and had multiple channels through
which to deliver radiation therapy.20 Between 1968 and 1982,
Leksell treated 762 patients with arteriovenous malformations
(AVMs) or benign tumors with Gamma Knife-based stereotactic
radiosurgery.20 The history of Gamma Knife radiosurgery is dis-
cussed in-depth in Chapter 1 of this book.
At Harvard University, the first cyclotron was built in 1937
(▶ Fig. 2.1). It was primarily used to produce radioactive iso-
topes for medical purposes. However, the cyclotron was sent
from Harvard (Cambridge, Massachusetts) to Los Alamos (New
Mexico) in 1943 to assist in the Manhattan Project, with the
promise that the U.S. Government would replace the unit at the
conclusion of the Second World War. In 1956 a new, 160-MeV
cyclotron was built at Harvard with funds from the U.S. Depart-
ment of Defense (▶ Fig. 2.2). This was commissioned under the
direction of Robert Wilson and was intended for research in
medical physics. However, its uses in physics research waned
over the next 5 years and clinical applications for it became of
increasing interest. Dr. Raymond Kjellberg, a pituitary neuro-
surgeon at Massachusetts General Hospital in Boston, visited
Stockholm in 1959; inspired by his visit and supported by his
departmental chief, Dr. William Sweet, Kjellberg began a pro-
gram in therapeutic stereotactic proton beam irradiation. In
1961, the neurosurgical staff at Massachusetts General treated
the first patient to undergo “small-field” irradiation, a 2-year-
old girl with an inoperable glioma of the diencephalons.
12
Fig. 2.2 Dr. Lee Davenport, a research fellow and physics professor,
and Dr. Leo Lavatelli, then a doctoral-degree candidate, in the second
Harvard University Cyclotron control room in about 1950. (Used with
permission from Professor Richard Wilson, from Wilson R. A Brief
History of the Harvard University Cyclotrons. Cambridge, MA: Harvard
University Press; 2004. Available at: http://users.physics.harvard.edu/
~wilson/cyclotron/history.html. Updated June 16, 2003. Accessed May
14, 2014.)
Unfortunately, despite significant initial tumor shrinkage, the
patient died several years later.21 Thereafter, the work at the
Harvard cyclotron was predominantly focused on pituitary
adenomas and AVMs.22,23,24
The treatment of pituitary adenoma was an early clinical
application of the Harvard cyclotron because of the ability to
localize the sella turcica, and therefore the pituitary that was
the treatment target, on plain orthogonal radiographs. A 1968
New England Journal of Medicine article describes 14 acrome-
galic patients who were followed after stereotactic radiother-
apy, of whom 9 experienced a reduction in size of their hands,
feet or facial features and 8 demonstrated a striking decrease in
their level of human growth hormone.24 Kjellberg and col-
leagues also described their experience with 75 consecutive
patients treated with proton beam therapy for AVMs.25 Lesions
were localized using pretreatment angiography and stereotactic
techniques. Patients were selected based on inoperability of
their lesions, most often because these lesions were large, cen-
trally located, or within the speech areas of the patient’s domi-
nant cerebral hemisphere. Sixty-six of these patients were
treated without complications. Kjellberg and his colleagues also
proposed dose-effect curves for radiation necrosis of the brain.
This relationship was the basis for later dosimetry in radiosur-
gery both with the linear accelerator and Gamma Knife.26,27
2.2 Fundamental Stereotactic
Principles
Although the development of instruments capable of precisely
delivering ionizing radiation was critical to the emergence of
stereotactic radiosurgery, so too was the development of ster-
eotactic methods in the neurosurgical arena. In 1908, Sir Victor
A. H. Horsley and his colleague Robert H. Clarke at University

College London developed a stereotactic device using a set of
three coordinates in an orthogonal frame of reference by which
to precisely identify the coordinates of an intracranial structure.
They initially utilized this technology to study a desired loca-
tion within the brain of a monkey. The coordinate system used
with their device was relative to bony landmarks of the skull,
including the interior orbital rim and internal auditory canal.
Horsley and Clarke then suggested potential clinical applica-
tions of their stereotactic device,28,29 but their recommenda-
tions were largely ignored by contemporary neurosurgeons.
Nearly three decades later, after modifications for the use of
intracerebral reference structures rather than landmarks on the
skull for the localization of treatment targets, Spiegel and Wycis
introduced stereoencephalotomy and destroyed selected areas
of the thalamus in the treatment of psychiatric disorders
and pain.30,31 Intraoperative radiographs allowed for localiza-
tion of intracranial structures. Soon thereafter, as described
above, Leksell and others developed closed radiosurgical meth-
ods for treating intracranial abnormalities with stereotactically
directed ionizing radiation. Critical subsequent technologic
advances included mechanical X-ray coupling.19 Target localiza-
tion improved dramatically with diagnosis based on computed
tomography (CT) and treatment planning within a stereotactic
coordinate space referenced to the treatment system. 32,33 Mag-
netic resonance imaging (MRI) was subsequently used to
increase the specificity of target localization.34
However, despite these imaging advances in the delineation
of treatment targets, techniques had to be developed for using
target information gathered in three-dimensional (3D) imaging
in conventional X-ray stereotactic space.35 This approach was
felt to be less accurate than methods based on CT/MRI imaging.
More recent developments in this field have included in-room
imaging options such as the two-dimensional (2D)/3D image
registration provided by sophisticated stereotactic treatment-
planning software and cone-beam CT devices attached to linear
accelerator (linac) based treatment systems.
Given the desire for improved accuracy of patient positioning,
techniques evolved to allow reproducible patient positioning
and treatment with stereotactic radiosurgery. The team at the
Harvard Cyclotron Laboratory developed a patient-positioning
system known as the Stereotactic Alignment for Radiosurgery
(STAR) system.36 Target-centered stereotaxis was the basis for
the system, with the stereotactic coordinates obtained directly
from CT, MRI, or angiographic imaging. As with other accelera-
tor systems used in physics research, the STAR system was
designed with a fixed-direction, horizontal beam (▶ Fig. 2.3).
Patients were rotated into different positions in a precise fash-
ion such that the beam was always aimed at the same target
within the patient’s head, allowing treatment to be fully isocen-
tric. Implantation of radiopaque fiducial markers before treat-
ment planning further improved the efficiency of the treatment
system.37
2.3 Introduction of Linear
Accelerator–Based Radiosurgery
The 1980s were a time of rapid growth in the development of
stereotactic radiosurgery. Whereas the early years of radio-
surgery predominantly focused on heavy particle-based
The History of Linac and Proton Beam Radiosurgery
Fig. 2.3 A patient undergoing treatment with the stereotacic align-
ment for radiosurgery (STAR) device at the Francis H. Burr Proton
Therapy Center at Massachusetts General Hospital in Boston. Patients
treated with the device are rotated around a fixed-beam line.
delivery, in the 1980s linac-based delivery was pioneered.
Multiple international groups contributed to the development
of linac-based stereotactic radiosurgery. Neurosurgeon Osval-
do Betti and engineer Victor Derechinsky in Buenos Aires, and
neurosurgeon Federico Colombo in Vicenza, Italy, coupled
stereotactic devices to available medical linear accelerators. 38,
39,40 On the basis of these investigators’ initial reports, Ken R.
Winston and Wendell Lutz adapted a stereotactic apparatus
and developed a special collimator to ensure positional accu-
racy for the dependable provision of linac-based radio-
surgery.41,42 This technology was the basis for modern
radiotherapy with linac-based systems. The use of linear
accelerators in radiosurgery remained controversial during
the 1990s based on the assertion by some clinicians that
Gamma Knife units had better accuracy than linac units due
to fewer moving parts. This fueled the development of linac-
based technologies for specific use in radiosurgery. In 1992,
the first commercially built linear accelerator dedicated to
radiosurgery was installed in Boston. 2,43 Researchers at the
University of Florida in Gainesville also reported their early
experiences with linac-based stereotactic radiosurgical sys-
tems.44,45 Subsequent critical developments in radiosurgery
included “frameless” technologies, which were initially devel-
oped to facilitate neurosurgical applications. 46 Fiducial
markers on the patient’s scalp were used to translate spatial
data provided by a surgical probe onto preoperative CT or
MRI scans. Several refinements were made to the initial tech-
nology for linac-based radiosurgery, 47,48 which has since has
become commonly used as a result of significant improve-
ments in patient comfort, the increased availability of
advanced in-room imaging options, and reduced need for
departmental staff resources as compared with those required
for frame-based systems.
13
 The History of Linac and Proton Beam Radiosurgery
2.4 Migration from Clinical Labo-
ratories to Hospital-Based Facilities
Early facilities for particle therapy were housed either within
national laboratories or in freestanding structures. The Lawrence
Berkeley Laboratory was an example of the former and the Har-
vard Cyclotron Laboratory of the latter. However, as the thera-
peutic utilization of particle beams assumed greater importance,
there was a need for the deliberate construction of facilities
intended to provide optimal patient care. In 1990 the first hospi-
tal-based proton facility opened at the Loma Linda Medical Cen-
ter in Loma Linda, California.49,50 All clinical treatments provided
through the Massachusetts General Hospital took place at the
Harvard Cyclotron Laboratory in Cambridge, Massachusetts,
until 2001, when a new proton beam facility was constructed
and opened at the hospital’s main campus in Boston with fund-
ing from the U.S. National Cancer Institute. Hundreds of centers
around the world are now using linear accelerators, proton
beam accelerators, or the Gamma Knife to deliver stereotactic
treatment to hundreds of thousands of patients a year.
2.5 Future Directions
As linac-based therapy expanded and more proton beam-based
treatment centers opened, stereotactic radiation expanded from
the treatment solely of intracranial lesions to that of other ana-
tomical sites, including the spine, chest, abdomen, and pelvis.
The fundamental principles of intracranial stereotactic radio-
therapy, precise anatomical localization and high dose per frac-
tion treatment, form the basis of stereotactic body radiotherapy.
The development of the CyberKnife (Accuray Inc., Sunnyvale,
CA), a linac-based system, obviated the need for rigid fixation of
the anatomical site to be treated.51,52 Intracranial applications of
radiosurgery have also significantly expanded since the original
treatments of AVMs and pituitary adenomas. In addition to the
evolution of treatment technologies and clinical applications for
stereotactic radiotherapy, the antitumor effects of single-dose
radiotherapy and accurate radiobiological modeling are active
areas of research and are becoming better understood.
In 1993, Charles B. Wilson, Professor of Neurosurgery at the
University of California, San Francisco, and founder of its Brain
Tumor Research Center, stated in the foreword to the first edi-
tion of Stereotactic Radiosurgery that “Ultimately, the results
and complications in comparable groups of patients treated
with radiosurgery must be judged against those obtained with
other therapeutic approaches.... Objective comparisons are the
ultimate yardstick of therapeutic superiority.”53 More than two
decades later, Dr. Wilson’s counsel has been followed, and peer-
reviewed data support the ever-expanding utilization of radio-
surgery. His wisdom regarding the metrics by which radiosur-
gery should be evaluated must be kept in mind as this field of
medicine continues to evolve and grow in the decades to come.
References
[1] Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir
Scand 1951; 102: 316–319
[2] Lunsford LD, Alexander E, Loeffler JS. General introduction: history of radio-
surgery. In: Alexander E, Loeffler JS, Lunsford LD, eds. Stereotactic Radiosur-
gery. New York, NY: McGraw-Hill; 1993:1–4
14
[3] Rutherford E. Collisions of alpha particles with light atoms. III. Nitrogen and
oxygen atoms. Philos Mag 1919; 37: 571–580
[4] Rutherford E. Collisions of alpha particles with light atoms. IV. An anomalous
effect in nitrogen. Philos Mag 1919; 37: 581–587
[5] Chadwick J. Possible existence of a neutron. Nature 1932; 129: 312
[6] Stone RS. Neutron therapy and specific ionization. Am J Roentgenol Radium
Ther 1948; 59: 771–785
[7] Wilson RR. Radiological use of fast protons. Radiology 1946; 47: 487–491
[8] Creutz EC, Wilson RR. Mono-energetic protons from a cyclotron. Rev Sci Ins-
trum 1946; 17: 385–388
[9] Lawrence EO, Edlefsen NE. On the production of high-speed protons. Science
1930; 72: 376–377
[10] Tobias CA, Anger HO, Lawrence JH. Radiological use of high energy deuterons
and alpha particles. Am J Roentgenol Radium Ther Nucl Med 1952; 67: 1–27
[11] Tobias CA, Van Dyke DC, Simpson ME, Anger HO, Huff RL, Koneff AA. Irradia-
tion of the pituitary of the rat with high energy deuterons. Am J Roentgenol
Radium Ther Nucl Med 1954; 72: 1–21
[12] Williams JE. Donner Laboratory: the birthplace of nuclear medicine. J Nucl
Med 1999; 40: 16N–20N, 18N, 20N
[13] Lawrence JH, Tobias CA, Born JL, et al. Pituitary irradiation with high-energy
proton beams: a preliminary report. Cancer Res 1958; 18: 121–134
[14] Lawrence JH. Proton irradiation of the pituitary. Cancer 1957; 10: 795–798
[15] Suit HD, Chu W. History of charged particle radiotherapy. In: DeLaney TF,
Kooy HM, eds. Proton and Charged Particle Radiotherapy. 1st ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2008:1–7
[16] Larsson B, Leksell L, Rexed B, Sourander P, Mair W, Andersson B. The high-en-
ergy proton beam as a neurosurgical tool. Nature 1958; 182: 1222–1223
[17] Leksell L, Larsson B, Andersson B, Rexed B, Sourander P, Mair W. Lesions in
the depth of the brain produced by a beam of high energy protons. Acta Ra-
diol 1960; 54: 251–264
[18] Larsson B, Leksell L, Rexed B, Sourander P. Effect of high energy protons on
the spinal cord. Acta Radiol 1959; 51: 52–64
[19] Leksell L. Stereotaxis and Radiosurgery: An Operative System. 1st ed. Spring-
field, IL: Charles C. Thomas; 1971
[20] Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983; 46:
797–803
[21] Kirn TF. Proton radiotherapy: some perspectives. JAMA 1988; 259: 787–788
[22] Kjellberg RN, Koehler AM, Preston WM, Sweet WH. Stereotaxic instrument
for use with the Bragg peak of a proton beam. Confin Neurol 1962; 22: 183–
189
[23] Kjellberg RN, Sweet WH, Preston WM, Koehler AM. The Bragg peak of a pro-
ton beam in intracranial therapy of tumors. Trans Am Neurol Assoc 1962; 87:
216–218
[24] Kjellberg RN, Shintani A, Frantz AG, Kliman B. Proton-beam therapy in acro-
megaly. N Engl J Med 1968; 278: 689–695
[25] Kjellberg RN, Hanamura T, Davis KR, Lyons SL, Adams RD. Bragg-peak proton-
beam therapy for arteriovenous malformations of the brain. N Engl J Med
1983; 309: 269–274
[26] Flickinger JC. An integrated logistic formula for prediction of complications
from radiosurgery. Int J Radiat Oncol Biol Phys 1989; 17: 879–885
[27] Saunders WM, Winston KR, Siddon RL, et al. Radiosurgery for arteriovenous
malformations of the brain using a standard linear accelerator: rationale and
technique. Int J Radiat Oncol Biol Phys 1988; 15: 441–447
[28] Horsley V, Clarke R. The structure and functions of the cerebellum examined
by a new moethod. Brain 1908; 31: 45–124
[29] Clarke R, Horsley V. On a method of investigating the deep ganglia and tracts
of the central nervous system (cerebelleum). BMJ 1906; 2: 1799–1800
[30] Spiegel EA, Wycis HT. Mesencephalothalamotomy for relief of intractable
pain. Am J Med 1949; 6: 504
[31] Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus for operations
on the human brain. Science 1947; 106: 349–350
[32] Bergström M, Greitz T. Stereotaxic computed tomography. AJR Am J Roent-
genol 1976; 127: 167–170
[33] Boëthius J, Bergström M, Greitz T, Ribbe T. CT localization of stereotactic sur-
gery. Appl Neurophysiol 1980; 43: 164–169
[34] Leksell L, Herner T, Leksell D, Persson B, Lindquist C. Visualisation of stereo-
tactic radiolesions by nuclear magnetic resonance. J Neurol Neurosurg Psy-
chiatry 1985; 48: 19–20
[35] De Salles AA, Asfora WT, Abe M, Kjellberg RN. Transposition of target infor-
mation from the magnetic resonance and computed tomography scan images
to conventional X-ray stereotactic space. Appl Neurophysiol 1987; 50: 23–32
[36] Chapman P, Ogilvy C, Butler W. A new stereotactic alignment system for
charged-particle radiosurgery at the Harvard Cyclotron Laboratory, Boston.

In: Alexander E, Loeffler JS, Lunsford LD, eds. Stereotactic Radiosurgery. 1st
ed. New York. NY: McGraw-Hill; 1993:105–108
[37] Gall KP, Verhey LJ, Wagner M. Computer-assisted positioning of radiotherapy
patients using implanted radiopaque fiducials. Med Phys 1993; 20: 1153–
1159
[38] Betti OO, Galmarini D, Derechinsky V. Radiosurgery with a linear accelerator.
Methodological aspects. Stereotact Funct Neurosurg 1991; 57: 87–98
[39] Colombo F, Benedetti A, Pozza F, et al. Stereotactic radiosurgery utilizing a lin-
ear accelerator. Appl Neurophysiol 1985; 48: 133–145
[40] Colombo F, Benedetti A, Pozza F, et al. External stereotactic irradiation by lin-
ear accelerator. Neurosurgery 1985; 16: 154–160
[41] Lutz W, Winston KR, Maleki N. A system for stereotactic radiosurgery with a
linear accelerator. Int J Radiat Oncol Biol Phys 1988; 14: 373–381
[42] Winston KR, Lutz W. Linear accelerator as a neurosurgical tool for stereotactic
radiosurgery. Neurosurgery 1988; 22: 454–464
[43] Kooy HM, Nedzi LA, Loeffler JS, et al. Treatment planning for stereotactic ra-
diosurgery of intra-cranial lesions. Int J Radiat Oncol Biol Phys 1991; 21:
683–693
[44] Friedman WA, Bova FJ, Spiegelmann R. Linear accelerator radiosurgery at the
University of Florida. Neurosurg Clin N Am 1992; 3: 141–166
[45] Friedman WA, Bova FJ. The University of Florida radiosurgery system. Surg
Neurol 1989; 32: 334–342
The History of Linac and Proton Beam Radiosurgery
[46] Roberts DW, Strohbehn JW, Hatch JF, Murray W, Kettenberger H. A frameless
stereotaxic integration of computerized tomographic imaging and the oper-
ating microscope. J Neurosurg 1986; 65: 545–549
[47] Kato A, Yoshimine T, Hayakawa T, et al. A frameless, armless navigational sys-
tem for computer-assisted neurosurgery. Technical note. J Neurosurg 1991;
74: 845–849
[48] Tan KK, Grzeszczuk R, Levin DN, et al. A frameless stereotactic approach to
neurosurgical planning based on retrospective patient-image registration.
Technical note. J Neurosurg 1993; 79: 296–303
[49] Slater JM, Miller DW, Archambeau JO. Development of a hospital-based pro-
ton beam treatment center. Int J Radiat Oncol Biol Phys 1988; 14: 761–775
[50] Slater JM, Archambeau JO, Miller DW, Notarus MI, Preston W, Slater JD. 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:
383–389
[51] Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL. The Cyberknife:
a frameless robotic system for radiosurgery. Stereotact Funct Neurosurg
1997; 69: 124–128
[52] Chang SD, Adler JR. Robotics and radiosurgery—the cyberknife. Stereotact
Funct Neurosurg 2001; 76: 204–208
[53] Alexander E III, Loeffler JS, Lunsford LD, eds. Stereotactic Radiosurgery. 1st ed.
New York, NY: McGraw-Hill; 1993
15
 The History of CyberKnife Radiosurgery
3 The History of CyberKnife Radiosurgery
Aditya Iyer, Steven D. Chang, and John R. Adler, Jr.
Key Points
● The CyberKnife is capable of delivering large doses of fo-
cused ionizing radiation to well-defined targets.
● It consists of a lightweight linear accelerator mounted on a
mobile industrial robotic arm.
● No rigid immobilization of the patient is required to undergo
CyberKnife treatment.
● The CyberKnife can be used for both isocentric and noniso-
centric treatment
● The CyberKnife can target lesions throughout the body.
3.1 Introduction
Over the past several decades, the CyberKnife (Accuray Inc.,
Sunnyvale, CA) has become an important tool for treating
lesions with maximal precision through the entire body.
Since its introduction into clinical use in 1994, the Cyber-
Knife, which can be used to treat lesions anywhere in the
body (in contrast to the Gamma Knife, which is used solely
for treating intracranial lesions), has been used to treat more
than 100,000 patients around the world. The technology that
underlies the CyberKnife derives from the basic principles
that motivate stereotactic radiosurgery as a field, and the his-
tory of the CyberKnife is therefore inextricably linked to the
history of image guidance, therapeutic radiation, and radio-
surgery. More specifically, the CyberKnife combines the tech-
nology of the lightweight linear accelerator (linac) with
advances in image guidance and robotics. As with all radio-
surgery, the purpose of the CyberKnife is to administer large
doses of ionizing radiation to destroy well-defined targets
within the body while minimizing damage to surrounding
structures.
3.2 Image Guidance and
Radiosurgery in the Decades
before CyberKnife
The beginnings of stereotaxis and image guidance in neurosur-
gery date back to the origin of neurosurgery as a medical field
itself. Working alongside mathematician Robert Clark, neuro-
surgeon Sir Victor Horsley developed the first tool to localize
intracranial structures in three dimensions in the early 20th
century.1 Using a rigid head frame that provided a Cartesian
coordinate system, Horsley postulated that any point within
the cranial vault could be assigned three coordinates relative to
the frame, and that clinicians could therefore reliably describe
and target intracranial structures. However, this technology
never progressed beyond animal models, and for the few deca-
des after its origin, stereotaxis remained a concept rather than
an approach integrated into clinical practice.
16
In the late 1940s, Ernest Spiegl, a neurosurgeon at Temple
University in Philadelphia, combined Horsley’s principles of
frame-based localization with plain-film radiography and cre-
ated a Cartesian atlas of the human head, naming the method
stereoencephalotomy.2 Given the high intraoperative mortality
in open cranial surgery for movement disorders at the time,
Spiegl and colleagues initially used frame-based localization to
target the extrapyramidal system.3 However, it was not until
Swedish neurosurgeon Lars Leksell, the father of modern ster-
eotactic radiosurgery, combined the principles of image guid-
ance with the nascent practice of therapeutic radiation that
radiation was successfully used to treat neurological disorders.
In 1947 Leksell developed the first arc-based stereotactic appa-
ratus for inserting electrodes and needles into desired locations
within the brain with submillimeter accuracy.4 During Leksell’s
time, medical particle accelerators (such as the linac used in the
CyberKnife, and the cyclotron) were too expensive or cumber-
some for medical purposes. Working alongside Swedish physi-
cists Kurt Liden and Börje Larsson of Uppsala University, Leksell
concluded that gamma rays were the most practical source of
therapeutic radiation at the time and proceeded to develop the
Gamma Knife, which has become the most widely used radio-
surgical device.5,6
3.3 Linear Accelerator Technology
From the 1920s until the 1950s, linacs remained within the
realm of theoretical physicists. The technology was initially
developed to accelerate charged particles through oscillating
electrical fields in vacuum-sealed tubing so that the energy
transfer upon collisions of the accelerated particles with other
particles would result in a stream of subatomic particles that
physicists could study. During the Second World War, Russell
and Sigurd Varian of Stanford University developed, in their
high-energy physics laboratories, a linear beam vacuum tube
named the klystron that generated X-rays with mega-electron
voltage and served as a high-frequency amplifier.7 Notably, X-
rays of this energy were sufficient to penetrate and ablate
biological tissue. The Varians patented this technology and
founded Varian Associates, which ultimately became Varian
Medical Systems (Palo Alto, CA). The technology was popular-
ized in 1956 after Stanford University radiologist Henry Kaplan
used this medical linac to successfully treat a 2-year-old boy
with retinoblastoma.8,9
Over the next several decades, both the multileaf collimator
and achromatic bending magnets were added to the linac,
respectively allowing the more precise contouring of X-ray
beams and energy stabilization. Additionally, with introduction
of the computed tomography (CT) scanner in the 1970s, linac
technology became more practical for targeting intracranial
lesions, as described in Chapter 2. Betti and Derechinsky 10
described one of the earliest clinical experiences with the linac,
with promising results. Lutz and Winston11 subsequently
defined the dosimetry of this method, and the modern linac
system became commercially available in the 1980s. However,
 The History of CyberKnife Radiosurgery

as in the case of the Gamma Knife, the original linac relied on

rigid immobilization of the patient to achieve submillimeter
accuracy. Patient movement, in addition to the more subtle
motion of respiration, the beating heart, and blood flow
through arteries and veins, necessitated a rigid frame screwed
into patients’ bone structures to ensure submillimeter accuracy.

3.4 The Early Years of Frameless

Radiosurgery
In 1985, while studying with Lars Leksell at the Karolinska
Institute in Sweden, the American neurosurgeon John Adler
envisioned a way to expand on Leksell’s vision of minimally
invasive neurosurgery by completely abandoning the use of a
head frame altogetherfor such surgery. Although several groups
had in the early 1990s proposed approaches to frameless radio-
surgery, none of these was clinically practical. Bova et al at the
University of Florida, Gainesville, used an infrared tracking sys-
tem that was calibrated with an external frame that was held to
Fig. 3.1 The original Neurotron 1000 designed by John Adler from U.S.
the patient’s body with a bite block.12 However, given the lim- Patent 5,207,223, entitled “Apparatus and Method for Performing
ited computing power of the time, it would often take days to Stereotaxic Surgery.”
weeks for the system to recalculate new targets to account for
patient movement.
The technological opportunities and innovations in the San
Francisco Bay Area’s burgeoning Silicon Valley facilitated the 3.5 The Modern CyberKnife
advent of the CyberKnife. In the early 1990s, while working
The modern CyberKnife consists of a compact, 120-lb, 6-MeV
at Stanford University, John Adler collaborated with Professor
linac capable of providing 6 Gy of radiation per minute. The
Tom Bradford and his graduate student at the Stanford School
linac is mounted to a robotic arm with six degrees of freedom
of Engineering to develop more efficient computer algorithms
(Kuka GmbH, Augsburg, Germany), allowing up to 1600 direc-
for accurately correlating X-ray and computed tomography
tions in which the instrument’s beam can be aimed to reach a
(CT) scans in real time.7 These algorithms would ultimately
lesion. Two orthogonally mounted X-ray generators, attached to
be used to identify and correlate the motion of set anatomical
the ceiling and the wall, respectively, are registered to X-ray
landmarks so that radiation beams could be redirected to
images that have been extracted from a CT scan done for the
remain on a treatment target despite movement. Additional-
initial planning of a patient’s treatment. Any movements of the
ly, in the 1980s, robots used in the manufacturing industry
target region in the patient’s body are corrected both by read-
were becoming increasingly portable and offering an
justing the linac and rotating the patient on a mobile treatment
expanded range of motion, making them ideal platforms for
bed.15 This provides submillimeter accuracy comparable to that
holding a mobile radiation source such as the linac. However,
of frame-based systems.16
the size and weight of the linacs of that the time made this
Given the maneuverability of its robotic arm, the CyberKnife
unfeasible.
system can be used to treat both isocentrically (in which all of
A small Silicon Valley-based company named Schonberg En-
the instrument’s beams converge at a single point) and noniso-
gineering was working on miniaturizing the linear accelerator,
centrically; the instrument’s beams are not constrained to pass
and by the late 1980s had developed an ultra-lightweight linac
through the geometric center of a target lesion, but rather
weighing less than 300 pounds. This gave way to Adler’s first
through any part of the lesion. This allows more uniform radia-
design for a frameless stereotactic radiosurgery system
tion dosage throughout the entire region of a target, as opposed
(▶ Fig. 3.1). His design included a linac mounted on a mobile
to a maximum dose of radiation at the geometric center and a
industrial robot. As patients moved either voluntarily or invol-
declining dose to the remainder of the target. Additionally,
untarily, two X-ray generators, oriented orthogonally to one
frameless radiosurgery makes fractionation and hypofractiona-
another, continuously generated plain-film images that were
tion possible both for intra- and extracranial structures because
then subjected to software processing to correlate the motion
there is no need to apply a rigid frame to the patient. Before the
of fixed, radiographically visible landmarks. The robotically
introduction of the CyberKnife, no method existed for fractio-
mounted linac would then readjust the direction of its beams
nating the treatment of extracranial targets with stereotactic
so that they remained on target. If submillimeter accuracy was
precision.
not achieved, the treatment would stop until the system could
readjust. With this idea, Adler and the Schonberg brothers were
awarded U.S. Patent 5,207,223 in 1993, and Accuray, Inc., was
founded. Originally named the Neurotron 1000,13 the initial
3.6 Extracranial Radiosurgery
CyberKnife was a 300-lb, 6-MeV linac attached to an industrial Until recently, the applications of radiosurgery were limited to
robot designed by GMF.14 the brain and upper cervical spine. However, over the past

17
 The History of CyberKnife Radiosurgery
decade, the CyberKnife has been used to treat other spinal
lesions. Traditional spine radiosurgery had relied on surgically
implanted fiducials to account for nonrigid deformation of the
spine as well as for voluntary and involuntary patient motion of
the types usually encountered in such surgery. In the early
2000s, Accuray, Inc., of Sunnyvale, California, developed a fidu-
cial-free system for CyberKnife that continuously refers to
radiopaque skeletal structures and is capable of targeting
lesions with great precision.
The CyberKnife can also be used to treat lesions anywhere in
the visceral organs of the body. Lesions in the chest, abdomen,
and pelvis move significantly more than those in the brain and
spinal cord during treatment, particularly with respiration.
Treatment begins when gold fiducial markers are inserted per-
cutaneously within the target, which the CyberKnife’s orthogo-
nal X-ray system detects. Additionally, infrared cameras track
light-emitting diodes (LEDs) attached to the patient’s skin. The
Synchrony system for the CyberKnife continuously correlates
the position of the infrared-emitting LEDs with the implanted
gold markers, and the instrument’s radiation beams are
adjusted accordingly.17
In summary, the CyberKnife allows the safe and effective
treatment of lesions throughout the body with minimal com-
plications. The technology that underlies the CyberKnife is
the culmination of more than a quarter century of advances
in image guidance, radiation therapy, robotics, and software
engineering. As radiosurgery evolves, new technologies will
emerge to allow shorter treatment times with even greater
precision and less patient discomfort. The CyberKnife repre-
sents a major step in this evolution of radiosurgical devices.
The history of the CyberKnife demonstrates that multidisci-
plinary collaboration is essential to advance the practice of
medicine, and that industry and academia can successfully
work together to better the lives of patients throughout the
world.
18
References
[1] Clarke RH, Horsley V. THE CLASSIC: on a method of investigating the deep
ganglia and tracts of the central nervous system (cerebellum). Br Med J
1906:1799–1800. Clin Orthop Relat Res 2007; 463: 3–6
[2] Spiegel EA, Wycis HT, Thur C. The stereoencephalotome (model III of our ster-
eotaxic apparatus for operations on the human brain). J Neurosurg 1951; 8:
452–453
[3] Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus for operations
on the human brain. Science 1947; 106: 349–350
[4] Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir
Scand 1951; 102: 316–319
[5] Larsson B, Lidén K, Sarby B. Irradiation of small structures through the intact
skull. Acta Radiol Ther Phys Biol 1974; 13: 512–534
[6] Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983; 46:
797–803
[7] Adler JR. Accuray, Incorporated: a neurosurgical business case study. Clin
Neurosurg 2005; 52: 87–96
[8] Ginzton EL, Mallory KB, Kaplan HS. The Stanford medical linear accelerator. I.
Design and development. Stanford Med Bull 1957; 15: 123–140
[9] Kaplan HS, Bagshaw MA. The Stanford medical linear accelerator. III. Application
to clinical problems of radiation therapy. Stanford Med Bull 1957; 15: 141–151
[10] Betti O, Derechinsky V. Multiple-beam stereotaxic irradiation] Neurochirur-
gie 1983; 29: 295–298
[11] Winston KR, Lutz W. Linear accelerator as a neurosurgical tool for stereotactic
radiosurgery. Neurosurgery 1988; 22: 454–464
[12] Bova FJ, Buatti JM, Friedman WA, Mendenhall WM, Yang CC, Liu C. The Uni-
versity of Florida frameless high-precision stereotactic radiotherapy system.
Int J Radiat Oncol Biol Phys 1997; 38: 875–882
[13] Cox RS. Positioning accuracy of the Neurotron 1000. Radiother Oncol 1995;
32 971: 301
[14] Adler JR, Cox RS. Preliminary experience with the CyberKnife: image-guided
stereotactic radiosurgery. In: Alexander III E, Kondziolka D, Loeffler JS, eds.
Radiosurgery. Basel, Switzerland:Karger; 1996:316–326
[15] Romanelli P, Adler JR Jr. Technology Insight: image-guided robotic radiosur-
gery—a new approach for noninvasive ablation of spinal lesions. Nat Clin
Pract Oncol 2008; 5: 405–414
[16] Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP. An analysis of the accu-
racy of the CyberKnife: a robotic frameless stereotactic radiosurgical system.
Neurosurgery 2003; 52: 140–146, discussion 146–147
[17] Ozhasoglu C, Saw CB, Chen H, et al. Synchrony—cyberknife respiratory com-
pensation technology. Med Dosim 2008; 33: 117–123
 4 The Radiobiology of Radiosurgery 20
Part II
5 The Physics of Radiosurgery 30
Radiosurgical Fundamentals 6 Radiosurgical Devices 42

7 Critical Structures and Tolerance of the

Central Nervous System 52

8 The Neuropathology of Radiosurgery 58

II
 The Radiobiology of Radiosurgery
4 The Radiobiology of Radiosurgery
John C. Flickinger
Key Points
● The linear-quadratic equation cannot reliably extrapolate
from data for conventional fractionated radiotherapy beyond
dose-fractions of 6–10 Gy to estimate equivalent radiation
effects for the high-dose (12–25 Gy) single-fraction radiosur-
gery. Consistently high negative values were found for alpha/
beta ratios calculated from radiosurgery responses that
conflict with values seen with conventional fractionated
radiotherapy.
● Radiation injury models need to take into account contribu-
tions from the target or tumor affecting radiation injury
reactions in the surrounding normal tissue.
● Much of the radiation response of a radiosurgical target and
surrounding tissue appears to be mediated by the
supporting vasculature.
● Areas of tumor hypoxia in heterogeneously enhancing
tumors may lead to radioresistance that can be addressed
through different approaches including fractionated
radiotherapy.
4.1 Introduction
Radiobiology is the study of tumor and normal tissue res-
ponse to ionizing radiation with the goal of isolating these
responses to promote more tumor-cell death with less nor-
mal tissue injury. In comparison with standard large-field
radiotherapy techniques (without image guidance), radiosur-
gery techniques change this balance first and foremost by
eliminating the need to irradiate a 1–2 cm margin around a
target or tumor volume to full treatment doses that allows
for positional errors in the radiation target definition and
delivery. Radiosurgery techniques also exploit the ability of
small volumes of normal organs to tolerate much higher radi-
ation doses without injury than large volumes of the same
organ. This dose-volume effect for radiation becomes highly
pronounced at very small volumes such as those treated in
radiosurgery. By using stereotactic fixation and localization
techniques, radiosurgery allows clinicians to eliminate the
need to expand radiation treatment volumes by adding mar-
gins around well-defined target/tumor volumes to correct for
the localization and targeting errors seen with conventional
radiotherapy setups. The highly conformal radiation-dose dis-
tributions delivered through multiple beams using radiosur-
gery techniques reduce the amount of normal tissue
subjected to full treatment doses within the intracranial
treatment volume and also reduce the radiation dose falloff
into surrounding normal tissue outside of the target volume.
Treatment can therefore change from multiple small dose-
fractions that a large volume of surrounding normal tissue
can tolerate to high-dose single-fraction radiation doses that
markedly smaller, thin rims of normal tissue adjacent to
radiosurgical targets can tolerate.
20
4.2 Categories of Normal Tissue
Response to Radiation
Normal tissue is typically categorized as being either early
responding or late responding in its response to radiation.
Early-responding tissues have faster-growing cells as in the case
of epithelial or mucosal layers that are continuously replaced by
fast-growing stem cells. This occurs in the oral mucosa, skin,
hair follicles, and intestinal crypts where the responses can be
mucositis, skin redness, hair loss, and diarrhea. Late-responding
or slow-growing tissues include that of the brain and spinal
cord where the late responses of concern are radiation necrosis
of brain or radiation myelopathy.
Another way to categorize the responses of organs or tissues
to radiation is based on whether they are serial or parallel
organs. Organs with a parallel structure have redundancy as the
key defense against radiation injury. Organs such as lung, kid-
ney, and liver are relatively sensitive to irradiation of the whole
organ, but can withstand very high doses to portions of the
organ (with loss of function in those high-dose regions) with-
out significant loss of overall function if the radiation dose to a
reasonable portion of the organ is kept below a certain rela-
tively low threshold. Organs with a serial structure—such as the
spinal cord or esophagus—can generally withstand higher doses
to small portions of the organ without loss of function of that
portion (or the overall organ); unfortunately, when injury to
even a small portion of that organ occurs, considerable loss of
function develops as a result.
4.3 What Is the Rationale for
Fractionation in Conventional
Radiotherapy?
Prior to the introduction of radiosurgery, almost all clinical
radiation therapy of intracranial targets was fractionated. From
the reaction of skin that received much higher doses with
external beam orthovoltage radiotherapy used before the intro-
duction of megavoltage radiotherapy sources (cobalt 60 and the
linear accelerator), it became obvious that early and late normal
tissue reactions could be limited through fractionation while
maintaining high response rates in treating malignant tumors.
The radiobiological analysis of a few cell culture lines of fast-
growing malignant tumors and clinical experience with tumor
control and complications from common fast-growing malig-
nant tumors commonly treated with fractionated radiotherapy
strongly supported this observation. These studies showed that
increased fractionation (reducing daily radiation dose-fractions
to the range of 1.8 to 2.0 Gy per fraction [/fr] and treating with
more fractions to equal or slightly higher total doses) preferen-
tially spared normal tissue from radiation injury without much
change in tumor control. With the widespread use of 1.8- to
2.0-Gy fractions, radiation oncologists became comfortable
treating all tumors with this fraction formula (both rapidly

growing malignant and slow-growing benign tumors), espe-
cially because most information about normal tissue tolerance
was garnered using these fractionation schemes.
Slow-growing benign tumors have been notoriously difficult
to study in cell cultures or animal models. Their radiobiological
responses—and particularly how these responses change with
different fractionation—are poorly defined. Prior to the advent
of radiosurgery, few radiation oncologists had more than lim-
ited experience treating with high doses of single-fraction radi-
ation. Stereotactic radiosurgery provided clinicians with the
ability to administer high single doses of radiation to intracrani-
al targets with relative safety. Radiosurgery ushered in a new
era of understanding how different approaches to radiation
treatment planning and radiobiology may be modified in the
clinic to achieve goals previously thought unreachable.
4.4 What Exactly Happens When a
Tissue Is Radiated?
When a person undergoes X-ray treatment or cobalt irradiation,
the target region is exposed to a high-energy photon beam. The
beam interacts with the tissue at the target, producing a cas-
cade of ionizing electrons that result in biochemical damage
within the cells exposed to the radiation. Both single-stranded
and double-stranded DNA breaks may occur. Depending on
how much biochemical damage occurs and how much of that
damage can be repaired by the cell, the consequences lead to
necrosis (rapid cell death), apoptosis (slow programmed cell
death), or cell survival (with or without survival of abilities such
as further mitosis, hormonal secretion, etc.). The exact biology
of these injury and repair responses is being unraveled to show
increasing complexity with potential points of modification. 1,2,3
Tumor control by radiation treatment comes not only through
radiation directly affecting tumor cells, but also through effects
on the adventitia, most notably the supporting vasculature. 4
Within the range of doses commonly used for radiosurgery, the
The Radiobiology of Radiosurgery
dominant mode of cell death in tumors seems to be mediated
through radiation effects on endothelial cells in the supporting
vasculature.4 These effects on the vasculature seem to become
pronounced with dose-fractions at 8 to 12 Gy or higher. Patho-
logical studies of tumors resected after radiosurgery also indi-
cate that vascular endothelium may be the primary target
responding to radiosurgery.5 This vasculature effect seems to
explain why single-fraction radiosurgery provides similarly
high tumor rates for very different tumors found to differ
widely by being either highly resistant or highly sensitive to
radiation whether in cell culture models or in clinical experi-
ence with conventional fractionated radiotherapy.
Optimizing the outcome of any clinical intervention (radia-
tion, drug therapy, or surgery) usually requires striking a bal-
ance between maximizing the desired outcome of the
intervention (tumor cure, vascular malformation obliteration,
etc.) while minimizing undesired sequelae of the intervention
(complications). This balance can be represented in many clini-
cal situations by a pair of dose-response curves representing
cure (tumor control or arteriovenous malformation [AVM]
obliteration) and complications (radiation injury) as shown in
(▶ Fig. 4.1). The separation between the curves has been
referred to as the therapeutic window, whereas the ratio of cure
to complication risk is referred to as the therapeutic ratio.
Radiosurgery exploits the radiobiological fact that smaller vol-
umes of normal tissue can withstand much higher doses of
radiation than larger volumes of normal tissue. Reducing the
volume of tissue irradiated to high doses reduces the complica-
tion risk for any dose given to the target, shifting the complica-
tion dose-response curve for the treatment to the right, further
away from the complication curve, thereby improving the ther-
apeutic ratio. The effect on both curves must be adequately
assessed to evaluate potential radiation dose-response modifi-
cations (such as altered fractionation; radiation protectors; or
radiosensitizing drugs, such as some chemotherapy or hypoxic
radiation sensitizers) to find if they improve the therapeutic
ratio.
Fig. 4.1 Typical sigmoid dose-response curves for
tumor control and complications and the effect
of reducing treatment volume on the complica-
tion curve.
21
 The Radiobiology of Radiosurgery

4.5 How Do We Estimate Effects one dose/fr d1 and total dose D1 to a different fractionation
scheme with dose/fr d2 and total dose D2 according to a given
of Fractionating Radiation? alpha/beta (α/β) ratio as follows:6
 
The linear-quadratic (LQ) formula is the most widely accepted Gy
Total dose D1 Gy  d 1 þ
way to represent fractionation effects in radiotherapy. 6–11 It fr 
Gy
relates the log of surviving cells after a dose-fraction of ionizing ¼ total dose D2 Gy  d 2 þ ð4:2Þ
fr
radiation as being proportional to a linear function of the dose/
fr (consisting of the dose/fr × a coefficient, alpha [α]) plus a sec-
ond quadratic function (consisting of the dose/fr2 × a second Another formula useful in the clinic is the expression for NTD 2,
coefficient, beta [β]). This LQ formula forms a power series the normalized total dose at 2-Gy/fr, which is the equivalent
modeling radiation cell killing with a combination of linear, total dose administered with daily 2-Gy fractions using a given
single-hit kinetics (which could mathematically represent dou- alpha/beta value.6 NTD2 for a given alpha/beta ratio α/β can be
ble-stranded DNA breaks leading to cell death) and quadratic, calculated for a course of radiotherapy given with a dose/fr of d
double-hit kinetics (which could mathematically represent a Gy/fr with the following equation:6,11
critical accumulation of single-stranded DNA breaks leading to h i
    d Gy
cell death). The LQ formula represents the chances of either Gy fr þ
NTD2 ¼ Total dose at d h i ð4:3Þ
tumor cure or normal tissue injury, P(cure or complication), fr 2 Gy þ fr
from a single fraction of radiation of dose, d, by the following
probabilistic double-exponential equation:

 ▶ Table 4.1 shows the 2-Gy/fr equivalent doses predicted for
Pðcure or complicationÞ ¼ EXP K
EXP d  d2
different single-fraction radiosurgery doses with the LQ formu-
ð4:1Þ
la using different alpha/beta ratios.
Equations 4.2 and 4.3 ignore the effect of overall treatment
where EXP represents the number “e” (2.7183, used in natural time, which should be negligible for central nervous system tis-
logarithms) raised exponentially to the power of the terms that sue and benign tumors in normal circumstances. A time-
follow, K represents the number of target clonogens, whereas α dependent repopulation term should be added for protracted
and β are the linear and quadratic coefficients. fractionated treatment of fast-growing malignant tumors.
This mathematical expression describes sigmoid-shaped Repopulation of malignant tumors accelerates 2 to 3 weeks
dose-response curves with the probability of cure or complica- after the start of radiotherapy. Because of clinical studies that
tions increasing with dose from 0% to a limit of 100% as the related poor tumor control from head and neck cancer radio-
dose is increased (▶ Fig. 4.1). Although used in research, this therapy with increasing overall treatment time, split-course
expression of the LQ formula is virtually never used in day-to- radiotherapy with planned 2-week breaks in the middle to alle-
day clinical radiotherapy practice. viate mucositis are no longer routinely used.
A much more useful calculation in the clinic is the formula to The ratio of the alpha coefficient divided by the beta coeffi-
equate the effect of a fractionated course of radiotherapy with cient (the alpha/beta ratio) provides a useful parameter to

Table 4.1 Calculation of radiobiologically equivalent dose (normalized total dose) for fractionated radiotherapy with 2-Gy fractions (NTD 2) from single-
fraction radiosurgery according to the linear-quadratic equation using different values of alpha/beta (and no time correction)
NTD2 (α/β = 10) equivalent NTD2 (α/β = 2) equivalent NTD2 (α/β = 1) equivalent NTD2 (α/β = 0) equivalent
dose (Gy) for early-reacting dose (Gy) for late-reacting dose (Gy) with a lower dose (Gy) for model with no
Single-fraction dose (Gy) tissue tissue (brain, etc.) value of α/β α component

4 4.7 6 6.7 8

6 8.0 12 14.0 18

8 12.0 20 24.0 32

10 16.7 30 36.7 50

12 22.0 42 52.0 72

14 28.0 56 70.0 98

16 34.7 72 90.7 128

18 42.0 90 114.0 162

20 50.0 110 140.0 200

22 58.7 132 168.7 242

24 68.0 156 200.0 288

NTD2 equivalent values of 52-72 Gy from α/β values of 1 to 0 appear to reflect observed risks of optic neuropathy for a single fraction dose of 12 Gy.

22

quantify fractionation effects in target tissues and tumors. With
the alpha/beta ratio for a given organ or tumor, we can estimate
the total dose and number of fractions needed to change from
treatment with one dose per fraction to another dose per frac-
tion with the same effect on that tissue or tumor. Because dif-
ferent kinds of tumors, different organs, and even different
types of injury reactions in the same organ (e.g., skin redness
vs. late skin fibrosis) have different alpha/beta ratios, changing
to a different fractionation scheme with an equivalent effect
calculated for one organ will lead to a different effect on organs
or tumors with different alpha/beta ratios. This became appa-
rent when early radiation therapists tried switching to cheaper
and more convenient hypofractionated radiation schemes with
larger dose-fractions producing similar acute skin reactions and
found increased late complications.
Different tissues can be lumped into categories by their alpha/
beta ratios as either early-responding tissues (fast-growing with
injury responses such as mucositis or skin erythema occurring
relatively short time after radiation) or late-responding tissues
(slow-growing tissues that take a longer time after radiation
exposure for injury reactions to become apparent). Studies of
fractionation effects in radiotherapy clinics and in animal mod-
els found brain and spinal cord to be late-responding tissues, rel-
atively more sensitive to large dose-fractions, with alpha/beta
ratios around 2. Faster-growing, faster-responding tissues such
as skin erythema or mucositis reactions have alpha/beta values
in the intermediate range of 5 to 8, whereas many fast-growing
malignant tumors have alpha/beta values closer to 10.6 Smaller
radiation dose-fraction schedules cause proportionally less
injury to normal tissues (or a limited number of tumors) with a
low alpha/beta ratio (a smaller alpha or single-hit component to
radiation cell-kill kinetics) compared with malignant tumors (or
faster-responding tissues) with higher alpha/beta ratios.
Because most malignant tumors have higher alpha/beta
ratios than adjacent normal tissue, increasing fractionation for
conventional large-field radiotherapy improves the therapeutic
window most of the time. This is not the case for all tumors that
can be treated by radiation and may not hold for radiosurgery
dose distributions. First, there is a wide variation of alpha/beta
ratios found in malignant tumors. Some malignant tumors such
as melanoma or prostate cancer (or at least some strains of
them) have lower alpha/beta ratios than surrounding normal
tissues (skin or rectum/bladder), supporting the use of larger
dose-fractions for treatment.10 Second, benign tumors should
have lower alpha/beta ratios than malignant tumors. Third, and
possibly most important for radiosurgery, alpha/beta ratios for
the tumor cells themselves do not describe the radiation res-
ponse of the supporting adventitia such as the endothelial cells
within the tumor vasculature, which appear to be responsible
for most of the response with high-dose single fractions and
appear to have low alpha/beta ratios.4
4.6 What Are the Limitations of
Using the Linear-Quadratic
Formula in Radiosurgery?
The LQ formula provides a reasonably good fit to postradiation
single-cell culture survival data and is useful in the clinic for
The Radiobiology of Radiosurgery
limited extrapolations from one course of fractionated radio-
therapy to another with different-sized dose-fractions, particu-
larly within a dose-fractions range of 1 to 8 Gy. Extrapolating
from 1.8- to 2.0-Gy fractions used in conventionally fractio-
nated radiotherapy to the high single-fraction doses commonly
used in radiosurgery stretches the formula beyond limits of
accuracy.
▶ Table 4.1 takes commonly used single-fraction radiosur-
gery doses and relates predicted equivalent doses for fractio-
nated radiotherapy with 2-Gy fractions (NTD2) using alpha/beta
values of 10 for early-reacting tissues and 2 for late-reacting tis-
sue (which is the accepted value for brain tissue from large
studies of fractionated radiotherapy data). The last column pro-
vides dose-equivalent dose calculations using an alpha/beta val-
ue of zero (specifically, α = 0), making it a quadratic-exponential
formula rather than a true LQ formula. A conservative estimate
of the NTD2 equivalent for brain injury is easily calculated using
an alpha/beta value of zero because it is simply one-half the sin-
gle-fraction dose squared. Using an alpha/beta value of zero is
quite a stretch from the theoretical basis of the formula, which
presupposes some contribution with single-hit kinetics (the
alpha component) corresponding to direct double-stranded
DNA breakage. From what is known about optic nerve tolerance
(discussed in the next section), an alpha/beta ratio somewhere
between 0 and 1 seems to fit the data for optic nerve injury risk
with radiosurgery doses near 12 Gy.
4.7 What Are the Optic Nerve
Tolerance Doses for Radiosurgery?
An early analysis of optic nerve complications in the combined
Harvard University and University of Pittsburgh experience rec-
ommended 8 Gy as a safe dose limit for the optic nerves/
chiasm.12 The lowest optic chiasm dose quoted for radiation-
induced optic injury in that study was 9.7 Gy. As shown in
▶ Table 4.1, the LQ formula with values of 0 and 2 for α/β pre-
dicts that a 10 Gy single-fraction dose to the optic chiasm
should have the equivalent effect of 32 Gy or 50 Gy at 2 Gy per
fraction, respectively, for α/β = 0 or 2, respectively. Using an α/β
value of 0, the equivalent dose at 2 Gy per fraction for the 9.7-
Gy radiosurgery dose that causes optic neuropathy is only
47 Gy. From clinical experience with fractionated radiotherapy
of pituitary adenomas and other parasellar tumors, the risk of
optic neuropathy for 46 to 48 Gy at 2 Gy per fraction should be
approximately 1/300.13
Stafford et al reported a later analysis of the Mayo Clinic
experience with four cases of optic neuropathy occurring out
of 215 radiosurgery patients receiving a median optic chiasm
dose of 10 Gy.14 One case of optic injury developed after a
dose of 12.8 Gy with radiosurgery alone, where the risk
seemed to be approximately 3%. The other cases developed
after prior fractionated radiotherapy (7 Gy preceded by
58.8 Gy fractionated, 9 Gy after 45 Gy fractionated, and one
case that followed two radiosurgery procedures delivering 9
and later 12 Gy to the optic system after 50.4 Gy of fractio-
nated radiotherapy).
Leber et al from Graz, Austria, analyzed optic neuropathy
risks in 50 patients after 24- to 60-month follow-up (median 40
23
 The Radiobiology of Radiosurgery
months) post–Gamma Knife radiosurgery for benign skull base
tumors.15 They found optic neuropathy risks of 0% with < 10 Gy,
27% with 10 to 15 Gy, and 78% with > 15 Gy. No cavernous sinus
nerve injury developed with doses of 5 to 30 Gy. The optic
nerve injury risks seen in the Graz and Mayo Clinic series are
what would be expected with 2-Gy fraction equivalent values
calculated with alpha/beta ratios between 0 and 1 Gy/fr, rather
than the value of 2 Gy/fr expected from a large body of data for
fractionated radiotherapy.6
4.8 What Are the Problems
Assessing Radiobiological
Parameters from Radiosurgery
Data?
Analyzing clinical radiosurgery data to delineate dose-res-
ponse relationships and define radiobiological parameters is
full of difficulties. Radiosurgery plans typically use inhomo-
geneous dose distributions with doses prescribed to 50 to
80% isodose-treatment volumes covering from 90 to 100% of
the target volume. Absolute minimum doses within the tar-
get volume typically run 5 to 30% lower than the prescription
dose, and they are highly dependent on how accurately tar-
gets are contoured. Contours of the same tumor/target vol-
ume or critical structures can vary slightly from one clinician
to another. With the steep dose falloff at the edge of the
tumor contour in most radiosurgery plans, there can be sig-
nificant variation in absolute minimum dose with subtle dif-
ferences in tumor contouring, much more than the variation
seen for average dose, percent coverage, or other parameters.
Early treatment-planning programs for Gamma Knife radio-
surgery were not integrated with imaging and tumor-con-
touring tools. After starting with that approach, many
Gamma Knife centers such as Pittsburgh did not routinely
contour all target volumes until many years later. Single-frac-
tion radiosurgery dose-response data for AVM obliteration
and radiation injury to brain parenchyma and cranial nerves
can be used to calculate alpha/beta ratios; however, as shown
in ▶ Table 4.2, they yield values of −30 to −60 Gy/fr rather
than 2 to 3 Gy/fr, as would be expected from conventional
fractionated radiotherapy data.6,9,10
Attempts to calculate alpha/beta ratios for benign tumor
control are further limited by the difficulty defining any clear
dose response using the very small number of failures that
Table 4.2 Calculated alpha/beta ratios for different end points after ra-
diosurgery at the University of Pittsburgh
Clinical end point n α/β ratio
Facial weakness 31/218 acoustic −60.8 ± 81.4
schwannomas
Hearing loss 57/138 acoustics with −39.6 ± 9.2
hearing
In-field AVM obliteration 293/355 AVMs obliterated −49.3 ± 5.3
Post-RS imaging changes 87/307 AVMs with changes −29.7 ± 2.4
24
occur. The long-term failure rate for vestibular schwannoma
radiosurgery is in the range of 1 to 2%. Tumors that have been
previously resected have higher marginal failure rates, but
there are more difficulties with defining the true target vol-
ume because of difficulty distinguishing gross tumor from
postoperative effects and inability to define microscopic
areas of residual tumor that can lead to marginal recurrence.
Unresected and unbiopsied meningiomas defined by imaging
criteria provide more clearly defined targets for defining a
dose response without a biopsy, but they also have at least a
2% chance of misdiagnosis.16 After excluding known cases of
misdiagnosis in the Pittsburgh unbiopsied meningioma expe-
rience, it was not possible to define a significant dose res-
ponse by prescription dose. Tumor contours were lacking to
test dose-response relationships for absolute minimum dose;
any assessment would be limited by the lack of failures to
analyze (because of the 93% tumor control rate). Genetic dif-
ferences in tumors and/or host adventitia (particularly endo-
thelial cells) can lead to radiobiological heterogeneity that
flattens or blurs tumor dose responses. That could make
alpha/beta ratios more difficult or impossible to define from
the data—the same way that misdiagnosis could.
Malignant tumors, particularly brain metastases, have higher
failure rates, which should make dose responses easier to
define. The chief problem with assessing radiobiological param-
eters from dose responses for brain metastasis radiosurgery is
reliably distinguishing recurrence from radiation injury reac-
tions before patients die from advanced metastatic cancer. In
other problems such as tumor/adventitial heterogeneity, possi-
ble slight variations in tumor definitions remain.
4.9 What about Neuropathy
Models for Acoustic Schwannoma
Radiosurgery?
The LQ formula runs into problems in modeling dose-res-
ponse curves for cranial neuropathies after single-fraction
radiosurgery of acoustic schwannomas. We should be able
to calculate values of alpha, beta, and the alpha/beta ratio
from clinical data for the single-fraction dose-response
curve. Data for injury to the facial, acoustic, and auditory
nerves after acoustic schwannoma radiosurgery should
allow the calculation of alpha/beta ratios for radiation
injury to these nerves. We analyzed 218 acoustic schwanno-
ma patients who underwent radiosurgery at the University
of Pittsburgh from 1987 to 1997 with more than 2 years of
follow-up.17 Higher doses used in our early experience at
Pittsburgh resulted in higher rates of facial and trigeminal
neuropathy and poorer hearing preservation during that
time than are seen with marginal doses of 12 to 13 Gy cur-
rently in use. This analysis assumed that the dose to the
facial and auditory nerves matched the marginal doses pre-
scribed at the time of radiosurgery because these nerves
invariably lie along the capsule of the tumor. This assump-
tion is not as reliable for the trigeminal nerve so that data
will be excluded, although the findings were similar. We
found small, negative values for the beta coefficients for
facial and auditory neuropathy, with best-fitting alpha/beta

ratios in the range of −30 to −55 (▶ Fig. 4.2 and ▶ Table 4.2).
Not only does this clash with the expected value of α/β = 2
from an analysis of conventional fractionated radiotherapy
data, the negative values for beta and the alpha/beta ratios,
which mathematically describe the empirically best-fitting
dose-response curves for this data, should be disallowed by
the theoretical rationale for the LQ formula.
4.10 What about Radiobiological
Analyses of AVM Radiosurgery?
We found similar problems using the LQ formula to fit dose-
response data for AVM radiosurgery. We analyzed oblitera-
tion after Gamma Knife radiosurgery in 351 AVM patients
with 3 to 11 years of follow-up imaging after Gamma Knife
radiosurgery at Pittsburgh.18 The median marginal-dose
range was 12 to 30 Gy (median 20 Gy) to treatment volumes
that varied from 0.26 to 4.0 cc (median 5.7 cc). We docu-
mented obliteration with angiography in 193/264 (73%) AVM
The Radiobiology of Radiosurgery
patients and with magnetic resonance imaging (MR) alone in
75/87 (86%) AVM patients who had refused angiographic fol-
low-up. The overall corrected obliteration rate (assuming 96%
accuracy for MR) was 75%.
Because part of the AVM nidus may be unintentionally omit-
ted from the treatment volume due to poor visualization at
radiosurgery, it makes more sense to define a radiobiological
dose-response analysis for in-field nidus obliteration (whether
or not there was obliteration within the treatment volume).
The best-fitting values of alpha/beta ratios for in-field oblitera-
tion for empirically derived logistic regression models were α/
β = −44.4 ± 12.5 and α/β = −45.3 ± 9.8, for angiographic only and
for MR plus angiographic obliteration, respectively. We derived
similar values with standard LQ Poisson models of α/β = −48.1 ±
5.9 for angiographic obliteration only and α/β = −49.3 ± 5.3 for
MR or angiographic obliteration. ▶ Fig. 4.3 shows the dose-res-
ponse curve for in-field MRI or angiographically defined oblit-
eration. The negative alpha/beta ratio was necessary to
mathematically describe the plateau in the in-field dose-res-
ponse curve (at approximately 23 Gy).
Fig. 4.2 Linear-quadratic (Poisson) dose-response
curves for the development of auditory and facial
neuropathies according to marginal (minimum
tumor) dose. These curves and their corre-
sponding alpha/beta ratio values were obtained
from nonlinear regression analysis of 218 acous-
tic schwannoma patients who underwent radio-
surgery at the University of Pittsburgh from 1987
to 1997 with more than 2 years of follow-up.
Fig. 4.3 Standard linear-quadratic (Poisson) dose-
response curve for postradiosurgery, magnetic
resonance, or angiographic arteriovenous mal-
formation obliteration of 297 patients who
underwent Gamma Knife radiosurgery at the
University of Pittsburgh from 1987 to 1997
without embolization. Each square and associ-
ated error bar represents the percent obliteration
rate with the respective 95% confidence interval
for each marginal-dose groups at the mean
marginal-dose value for each group.
25
 The Radiobiology of Radiosurgery
We also derived an alternative maximum obliteration rate
model for the dose response of AVM obliteration using data
for overall obliteration rather than in-field obliteration as the
end point. This model added an empirically fitted maximum
obliteration rate to the dose-response function to account for
marginal misses or any unknown factor that could limit the
maximum obliteration rate from reaching 100%. Because it
required only overall obliteration data, it avoided any poten-
tial error in determining whether failures with persistent
AVM nidus were inside or outside the original radiosurgery
volume. We found a maximum obliteration rate for cases
treated without embolization of 87.9 ± 4.9% (p < 0.0001). The
additional failure rate due to embolization (i.e., probable
increased marginal miss) was 16.4 ± 7.6% (p = 0.03). This
model had less sensitivity to the alpha/beta value, so its value
could not be precisely defined aside from seeing a poor fit
with any positive values. A negative value for the alpha/beta
ratio could not be precisely defined when negative values
were allowed. The alpha/beta ratio value converged to zero
when constrained to positive values, but unlike the data for
in-field obliteration, an adequate fit was achieved at that
value.
Radiation injury reactions after AVM radiosurgery also pro-
vide excellent data to test radiobiological models. New areas of
increased signal develop on T2-weighted MR sequences in brain
adjacent to AVM in approximately 30% of patients within 2
years after radiosurgery. These postradiosurgery imaging
changes represent a radiation injury reaction involving sur-
rounding brain. These signal changes are symptomatic in a third
of the patients developing this reaction (10% of all AVM radio-
surgery patients). The chance that these changes produce
noticeable symptoms varies dramatically with location within
the brain. Because modeling the influence of location on symp-
tomatic sequelae is extremely complex,19 postradiosurgery
imaging changes (that do not seem to vary with location) repre-
sent a better end point for radiobiological analysis of parenchy-
mal brain injury.
We tested the fit of the LQ equation with data for postradio-
surgery imaging changes in 307 AVM patients with more than 2
years of follow-up after radiosurgery at Pittsburgh. We identi-
fied postradiosurgery imaging changes in 87 of these patients;
32 were symptomatic. We used marginal dose (minimum AVM
nidus dose prescribed) to represent dose. As shown in
▶ Table 4.2, the best-fitting alpha/beta value with nonlinear
regression analysis using a Poisson model (Equation 4.1) was α/
β = −29.7 ± 2.4. Although marginal dose is a simplified way to
represent the inhomogeneous dose distribution to the sur-
rounding normal tissue, we obtained a negative alpha/beta val-
ue that was consistent with those for AVM obliteration, facial,
and auditory neuropathies.
4.11 Do Radiation Injury Reactions
Come Only from Tissue Outside
the Target/Tumor?
Except for functional radiosurgery, where the target is nor-
mal tissue, it seems intuitive that radiation injury reactions
should depend only on the dose distribution of radiation
26
received by the normal tissue surrounding a radiosurgery
target volume, the same tissue that manifests that injury.
Normal tissue complication probability models calculate
chances of radiation injury from dose distribution to normal
tissue outside the target/tumor. If this is true, then there
should be no difference in complications between different
targets (AVM, benign or malignant tumor) after accounting
for the effects of dose and volume. To test this, we modeled
postradiosurgery imaging changes (symptomatic or asympto-
matic edema) that developed in 27 of 307 AVM patients and
compared them with those developing in 14 of 291 meningi-
oma patients, all of whom had 2 or more years of follow-up.
▶ Table 4.3 shows the results of the multivariate logistic
regression model comparing postradiosurgery imaging
sequelae for AVM versus meningioma while controlling for
the effects of dose (in a LQ expression with marginal dose
and marginal dose squared) and for treatment volume in the
model. The probability of postradiosurgery imaging sequelae
was significantly higher (p < 0.0001) for AVM patients by a
factor of 7.5 (95% confidence interval [CI]: 3.4–16.4). The
ratio of the regression coefficients for marginal dose and
marginal dose squared gave an alpha/beta ratio of −42.2 ±
17.2 for these postradiosurgery imaging changes for the com-
bined data set.
Reanalyzing these data using symptomatic postradiosurgery
injury as the end point gave similar results, despite the fact that
location was not incorporated into the analysis to keep it as
simple as possible. An AVM had a significantly higher (p = 0.04)
risk of symptomatic postradiosurgery sequelae by a factor of
2.58 (95% CI: 1.04–6.41). The approximate alpha/beta value cal-
culated using symptomatic postradiosurgery sequelae as an
end point was −42.0 ± 26.7.
These comparisons of postradiosurgery imaging changes and
of symptomatic sequelae in AVM versus meningioma radiosur-
gery targets demonstrate that the target tissue can have a sub-
stantial effect on the chance of developing a radiation injury
reaction and should not be ignored in radiobiological models.
The higher risk of an injury reaction in treating an AVM com-
pared with meningioma suggests that the injury reaction of the
target vasculature may affect the surrounding normal tissue
and its supporting vasculature and contribute to radiation
injury reaction outside the target.
Table 4.3 Multivariate logistic regression models comparing postradio-
surgery imaging changes (symptomatic or asymptomatic edema) in 307
AVM patients and 291 meningioma patients with 2 or more years of fol-
low-up
Variable p value Odds ratio 95% confidence
interval
AVM vs. menin- < 0.0001 7.502 3.43–16.40
gioma
Marginal dosea 0.0143 2.457 per Gy 1.197–5.043
0.9789 per Gy2
Marginal dose
squareda
0.0148 0.9624–0.9958
Volume < 0.0001 1.142 per mL 1.217–3.431
aApproximate value of α/β = −42.21 ± 17.22.

4.12 What Was Learned from the
RTOG Dose-Escalation Study for
Radiosurgery?
The Radiation Therapy Oncology Group (RTOG) Phase 1
Radiosurgery Dose-Escalation Study (95-05) was a landmark
study that provided a number of important findings. 20 One
hundred fifty-six patients who failed prior conventional
radiotherapy for either brain metastasis or primary tumors
were enrolled and treated according to a dose-escalation
protocol stratified by lesion diameter. 20 Brainstem tumors
were excluded from the study because of higher risks of
symptomatic injury expected that could have confounded
the analysis. Starting with marginal doses of 18, 15, and
12 Gy for diameters ≤ 20, 21–30, and 31–40 mm, respec-
tively, the study escalated doses in 3-Gy intervals in succes-
sive patient cohorts until unacceptable toxicity was
reached, defined as irreversible RTOG grade 3, 4, or 5 neu-
rologic toxicity within 3 months of radiosurgery in > 30% of
patients. They defined maximum tolerated dose (MTD) as
the next lowest dose level before reaching unacceptable
(> 30%) toxicity. The cohort with tumors ≤ 20 mm never
exceeded 30% grade 3 or greater toxicity despite dose esca-
lation to 24 Gy, and investigators balked at escalating to
higher doses. ▶ Fig. 4.4 shows the reported late neurologic
toxicity data at each size category fitted to logistic dose-
response curves.
4.13 Other Models
Several authors have suggested modifying the standard LQ
model because laboratory and clinical studies have shown
more of a linear dose response with doses above 6 Gy/fr due
to the quadratic component overestimating the response. 21,
22,23,24 They have suggested using alternative models such as
a mixed LQ model that switches from a LQ response at low-
dose fractions to a linear response after a break point dose
The Radiobiology of Radiosurgery
(such as 6–8 Gy). Guckenberger et al tested the fit of the
standard LQ model compared with the LQ model in a large
multicenter lung cancer radiosurgery database and found
no significant difference in the fit of the clinical data
between the two models in assessing tumor control. 25 It is
possible that any improvement in fit could have been
blurred out by heterogeneity in tumor radioresponsiveness
and heterogeneity due to variations in target definition
and treatment delivery between institutions and individual
patients.
4.14 Tumor Hypoxia
Several authors have documented poorer control after radio-
surgery of heterogeneously enhancing brain metastases com-
pared with homogeneously enhancing brain metastases.26,27
This is thought to be from tumor hypoxia occurring in areas of
poor contrast enhancement that confers relative radioresist-
ance to those areas of tumor. Radiation resistance due to
tumor hypoxia may be addressed by fractionating radiation
treatments to allow for reoxygenation of hypoxic regions after
more fully oxygenated regions are more easily killed off by the
initial fractions of radiation. Other approaches to address
radioresistance due to tumor hypoxia include surgical resec-
tion before or after radiation treatment, use of selective
hypoxic sensitizing drugs, or chemotherapy (such as mitomy-
cin C) with greater toxicity to hypoxic cells. ▶ Fig. 4.5 shows a
radiosurgery dose plan for 20 Gy to a brain metastasis with a
higher dose (30 Gy) specified to a central nonenhancing por-
tion of the tumor.
4.15 Future Developments
Different radiobiological strategies continue to be explored to
better control tumors with radiosurgery with less toxicity. All
radiobiological strategies need to be evaluated through careful
laboratory and clinical trials.
Fig. 4.4 Logistic dose-response curves fit to the
late toxicity data reported for the RTOG (Radia-
tion Therapy Oncology Group) Radiosurgery
Dose-Escalation Study. The numbers refer to the
number of tumors treated at each dose level for
each size category (filled diamonds, < 20 mm;
squares, 21–30 mm; open diamonds, 31–
40 mm). The doses where 10% late toxicity occurs
in the fitted curves are shown next to the legend.
MTD, maximum tolerated dose.
27
 The Radiobiology of Radiosurgery

Fig. 4.5 Radiosurgery treatment plan for a brain metastasis with 20 Gy prescribed to the tumor margin and 30 Gy to the central nonenhancing portion
of the tumor thought to have greater radioresistance from tumor hypoxia.

[14] Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of
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29
 The Physics of Radiosurgery
5 The Physics of Radiosurgery
David Schlesinger, Brian Wang, and Stanley H. Benedict
Key Points
● The three basic principles of stereotactic radiosurgery (SRS)
are (1) generation of high-dose gradients, (2) accurate and
precise target localization, and (3) delivery of small fields to
high doses.
● High-dose gradients are created by spreading the energy of
the treatment delivery over a large surface area.
● Accurate and precise target localization is achieved through
the use of immobilization and image-guidance techniques.
● The physics of small-field delivery poses particular challenges
for SRS and stereotactic radiotherapy (SRT) and requires
great care when measuring and modeling.
● The specialized nature of SRS/SRT requires equally specialized
quality assurance and credentialing procedures.
5.1 Introduction
The technical aspects of stereotactic radiosurgery (SRS) have
profound differences as compared with those used for tradi-
tional intracranial radiotherapy. Traditional intracranial radia-
tion involves the irradiation of large volumes of tissue,
including both normal and abnormal tissue. A large number
(often 20–30) of small doses (~ 2–3 Gy) are given, with a rest
period (usually 1–3 days) in between each treatment fraction.
The treatment relies on the differential ability of normal and
pathological tissue to repair DNA damage induced by the radia-
tion.1 In contrast, SRS relies less on differential repair and more
on differential targeting for its treatment effect. A large dose of
radiation, delivered in one to at most five fractions, is directed
towards ideally only the targeted pathological tissue. The sur-
rounding normal tissue would receive no dose, but in actuality
SRS treatments do not quite reach this idealized goal. The
resulting realized tumoricidal efficacy is likely due to both DNA
damage as well as biological effects that occur only after a
threshold dose has been absorbed.2,3
The differences in requirements between traditional radia-
tion oncology and SRS and stereotactic radiotherapy (SRT) led
to the development of specialized equipment and procedures
for the latter. In this chapter, we discuss the technical underpin-
nings of SRS/SRT, including physics, immobilization techniques,
treatment planning, image guidance, quality assurance, and
credentialing. We place special emphasis on the features that
develop as a response to the specific technical demands of ster-
eotactic radiosurgery.
5.2 Basic Physical Principles of
Stereotactic Radiosurgery
Stereotactic radiosurgery relies on three basic principles to
achieve its goal of differential targeting: (1) generation of high-
dose gradients by spreading out the radiation dose over a large
30
surface area, (2) accurate and precise target localization, and (3)
the delivery of small fields to high doses.
5.3 Generation of High-Dose
Gradients
Stereotactic radiosurgery devices, regardless of modality, all fol-
low a similar guiding principle to create the steep dose gra-
dients required by radiosurgery; they each spread the total
energy delivered to the target out over a wide surface area. In
the case of Gamma Knife radiosurgery, this is achieved through
the use of many (either 201 or 192) widely distributed beams
all collimated so they intersect at a focal spot.4 CyberKnife
radiosurgery also makes use of large numbers of widely distrib-
uted beams that intersect at the targeted tissue (although not
always a distinct focal spot).5 Linear accelerator (linac)-based
radiosurgery makes use of either a relatively large number of
non-coplanar modulated fields or a series of non-coplanar arcs
that intersect isocentrically at a point within the targeted tis-
sue.6,7 The fields themselves may be shaped using small circular
cones, or micro-multileaf collimators (MLCs)8,9—the latter of
which may be static for each field, may modulate during deliv-
ery of each field, or in the case of arcs may modulate over the
course of the arc (volume-modulated arc therapy [VMAT]).10
Because the incoming photons are widely distributed as they
enter the patient, the intensity of each individual radiation
beam is relatively low and causes minimal damage to normal
tissue distant from the focus point. However, the sum total
intensity of all of the beams at the target is quite high. The large
spatial distribution achieves a very steep gradient away from
the target.
5.4 Precise and Accurate
Localization
The ability to aim large numbers of beams or arcs at a small
point in three-dimensional (3D) space is not in itself sufficient
for radiosurgery. To be useful, that small point in space has to
coincide with the targeted tissue as accurately and precisely as
possible throughout the course of treatment. In SRS, this is
achieved through a combination of modern 3D-imaging techni-
ques to permit visualization of the target and surrounding tis-
sue, methods to define the 3D spatial relationships between the
targeted tissue and the treatment device, and methods for
immobilization to prevent the targeted tissue from moving out
of the treatment beams during the procedure.
5.5 Small Fields, High Doses
The prior principles—spreading out the energy, and precise and
accurate localization—then permit the final principle: delivering
high doses of radiation to small volumes of tissue. Radiosurgical
targets are generally quite small in the broad scope of radiation

oncology—hard limits vary, but a good rule of thumb is that tar-
gets should be less than 30 mm in largest diameter. Targets larg-
er than this treated to high doses increase the risk of adverse
treatment outcomes. Doses are also quite large, typically in the
range of 10 to 150 Gy point-dose maximum within the target—
with the largest doses of 80 to 150 Gy usually reserved for func-
tional lesioning cases.11,12
5.6 Technical Challenges for
Stereotactic Radiosurgery
Developing technical solutions that can achieve the above goals
is no small task, and much of the development of SRS/SRT has
been in refinements to help reach them.13 Accurately placing
the targeted tissue at the intersection of the beams creates chal-
lenges for imaging, localization, and immobilization. Accurately
computing dose to small fields, which depart from well-investi-
gated reference standards, creates challenges for radiation
metrology and dosimetric modeling. In the remainder of this
chapter, we describe how techniques adopted for radiosurgery
address these issues.
5.7 Immobilization Techniques
5.7.1 Frames
Radiosurgery evolved directly from the practice of stereotactic
neurosurgery, which involved the placement of an invasive
frame system over a patient’s head both to immobilize the pa-
tient and to create a coordinate system, allowing neurosurgeons
to consistently target any desired point in the brain. Radiosur-
gery replaced the neurosurgery probe with a focal point of con-
verging beams, and therefore had similar requirements for
immobilization and localization.
Several frames have been and continue to be in use in radio-
surgery, including the Leksell G-Frame,14 Gill-Thomas-Cosman
(GTC) frame,15 and the BRW frame.15,16 Although the details
vary slightly depending on the design, the basic principles of
each frame are similar. The frame defines a targeting coordinate
system that encompasses the volume of the target and sur-
rounding tissue (usually the entire head). The patient is imaged
with the frame and associated external fiducials, which create a
coordinate transformation between the native image coordi-
nate system and the frame coordinate system. The frame is rig-
idly mounted to the treatment table, which creates a fixed
transformation between the frame coordinates and the delivery
machine coordinates. The advantages of stereotactic frames are
their mechanical stability, accuracy,17 and their relative simplic-
ity. The disadvantages of stereotactic frames are that they are
mildly invasive, practically limit radiosurgery to a single-frac-
tion treatment, and create a procedural time constraint in that
treatment planning, imaging, and delivery must all occur on the
same day, as adjusting the frame after imaging for treatment
planning would alter the targeting coordinate system.
5.7.2 Masks
To overcome some of the disadvantages of invasive stereotactic
frames, thermoplastic mask systems were developed.18 In these
The Physics of Radiosurgery
systems, the back of the patient’s head is supported by an insert
and a plastic mask is stretched over the patient’s face. The plas-
tic of the mask is flexible when heated, but becomes rigid when
cooled. Mask systems have the advantage that they can be
easily removed and reapplied to a patient, making multiple
fraction treatments practical. The disadvantage of mask sys-
tems is that they are not as robust in terms of immobilization,
with patient motion routinely greater than 1 mm reported
within the mask.19 Because of their immobilization uncertainty,
mask systems are typically used only for SRT and traditional
hyperfractionated treatment schemes.
5.7.3 Relocatable Frames
Relocatable frame systems have been developed that attempt to
improve on the immobilization capability of mask systems yet
maintain the ability to reputably remove and replace the frame.
The TALON frame20 is a hybrid system that involves implanting
two titanium base screws into the patient’s skull. An adjustable
Nomogrip/TALON device is attached to the base screws and
locked into a patient-specific position. The patient can then be
removed and reattached to the TALON device.
Several systems have been developed that use dental fixation
to assist in immobilization of the head. In these systems, a den-
tal mold of the patient’s upper palate is created. The dental
applicator is then attached to a frame system.21 The patient
position within the frame system is determined either through
measurement22 or on-board imaging.23 In some systems, the
intratreatment position of the patient can be monitored using
optical tracking24 or a vacuum monitoring system.25 The uncer-
tainties of using these systems have been shown to approach
uncertainties reported with frame systems.
5.7.4 Fully Frameless
The development of on-board 3D-imaging, 6-degree-of-free-
dom robotic couches, and intradelivery imaging and position-
monitoring systems have made feasible the idea of frameless
radiosurgery: In these systems, no frame is required.
5.8 Problems Posed by Small and
Nonstandard Treatment Fields
Medical physicists have historically defined a “small field” as
any field smaller than conventional field sizes: usually smaller
than 3 cm × 3 cm.26 A slightly less subjective definition is a field
size “smaller than the lateral range of charged particles that
deposit dose at a point along the central axis.”27,28 Small fields
or very small fields can also be defined in terms change in out-
put factor (OF) as a function of change in field size or detector
position (e.g., a very small field is any field whose OF changes
by more than 1.0% given a 1.0-mm change in field size or detec-
tor position).28 Stereotactic radiosurgery tends to fall within
any of the clinically relevant definitions of small field size.
In addition, many specialized radiosurgery devices have geo-
metries that are incompatible with standardized calibration
protocols such as TG-51 and IAEA TRS-398, which are based on
broad (10 × 10 cm) reference fields and are specified to use ion
chambers to measure dose using water as a medium to achieve
31
 The Physics of Radiosurgery
a direct conversion from collected charge to absorbed dose in
water.27 For example, neither a Gamma Knife nor CyberKnife
has the ability to create a 10 cm × 10 cm reference field. It is also
not practical to create a water-filled phantom for a hemispheri-
cal Gamma Knife geometry, although attempts at this have been
made.29 For the reasons outlined above, for these devices an ion
chamber may not be the appropriate choice for conducting
measurements.
Clinical dosimetric measurements required for commission-
ing an SRS machine, modeling SRS performance, or providing
quality assurance must take into account the effects small fields
can have on different measurement devices and techniques.
Serious consequences garnering attention from prominent
news organizations have been reported in cases where this has
not been the case.30
5.9 Effects of Small and
Nonstandard Fields
When radiation fields are collimated to small sizes approaching
the size of the detector, a variety of assumptions used in relat-
ing observed readings to dose start to break down.
Below a threshold field size, the radiation source as viewed
from the perspective of the detector is partially obscured by the
collimation. This has the effect of blurring and widening the pe-
numbra of the beam and lowering the output at the position of
the detector. Measurements not taking this into account could
overestimate the field size and underestimate the output dose
rate.26
When field sizes are smaller than the range of charge par-
ticles liberated in the medium, the assumption of charged par-
ticle equilibrium (CPE) that underpin measurements with
detectors such as ionization chambers start to break down. The
average energy in the spectrum of electrons reaching the cen-
tral axis of the beam rises as compared with the spectrum with
CPE in place.31 In addition, the loss of CPE makes the presence
of the detector itself a significant source of measurement uncer-
tainty as it perturbs the particle fluence in the medium. The
conversion from collected charge to absorbed dose in the me-
dium relies on standardized protocols that are a function of
geometric setup, and beam quality. The lack of CPE increases
the uncertainty of these protocols. Lack of consideration for
small-field measurements can affect absolute output measure-
ments, as well as dose ratios such as OFs, percent depth dose/
tissue maximum ratios (PDDs/TMRs), and off-axis ratios
(OARs).26
Finally, the absorbed dose gradient near a field edge is not
correctly measured by finite-sized detectors such as ion cham-
bers due to volume averaging of signal over the volume of the
chamber. The small sizes and blurred penumbras in SRS fields
enhance this effect, and can lead to increased uncertainty when
measuring beam profiles.
The major problem for machine designs that are incompati-
ble with standard reference dosimetry protocols are that they
break the traceability those protocols maintain with national
and international standards laboratories.27 Machines that can-
not provide standard reference (i.e., 10 cm × 10 cm) fields or
cannot be measured in water are left to cobble together modifi-
cations to the standards that often vary from center to center. 32,
32
33 The emergence of high-dose-rate flattening-filter-free (FFF)
modes on recent SRS/SRT-capable linear accelerators may cre-
ate another departure from standardized protocols.34
5.10 Detectors for Stereotactic
Radiosurgery and Stereotactic
Radiotherapy
A large variety of detectors are now available to the clinical
physicist, including “Farmer”- type ion chambers, microioniza-
tion chambers, solid-state detectors, radiochromic film, gel dos-
imeters, diamond detectors, etc. It is essential for SRS/SRT that
an appropriate choice of detector be made depending on the
dosimetric task at hand (e.g., absolute dose output measure-
ments or relative dose profile measurements).
A recent addendum to the American Association of Physicists
in Medicine (AAPM) TG51 protocol34 maintains the recommen-
dation that cylindrical ionization chambers be used for refer-
ence dosimetry for treatment machines that can conform to the
field-size requirements and water-phantom requirements of
the protocol. Very small (volume < 0.05 cm3) chambers are not
recommended due to perturbations from high-Z electrodes, sig-
nificant polarity effects, and recombination behavior that can
be difficult to model.
For devices that do not conform to standard protocols, work
is ongoing within both the AAPM and International Atomic
Energy Agency (IAEA) to create a complementary protocol that
can encompass these machines while maintaining traceability
to reference standards. A recent summary of the proposed
approach defines a system of intermediate reference fields,
including a machine-specific reference (msr) field for machines
that can produce a static field, but not of standard reference
dimensions, and a plan-class-specific reference (pcsr) field for
machines that are composed of many small fields (e.g., Gamma
Knife, CyberKnife, tomotherapy, step-and-shoot intensity-
modulated radiotherapy [IMRT]). Correction factors will be
used to correct for differences between these intermediate
reference fields and standard reference fields.27
Beam profiles in the setting of SRS/SRT are best measured
using high-resolution detectors such as microionization cham-
bers, stereotactic diode detectors, diamond detectors, or radio-
chromic film. Errors due to volume-averaging effects can be
minimized using deconvolution35,36,37 or extrapolation35,38
techniques, which can separate out the detector response from
the underlying signal.
5.11 Physics Considerations for
Proton SRS/SRT
The physics of proton interaction in tissue make them a theo-
retically attractive alternative to photons in an SRS/SRT setting.
Protons have a predictable, finite depth of penetration that
depends on the energy of the protons and the density of the
material. Protons deposit minimal energy in tissue near the sur-
face and for most of the proton’s path. However, near the end of
the path there is a steep rise in ionization density, creating
what is known as a Bragg Peak. Beyond the peak, dose is

negligible. To achieve complete coverage of the tumor in the
longitudinal direction, the energy of the proton beam is modu-
lated, either with compensators or by summing pencil beams of
varying energy to “spread out” the Bragg Peak to cover the tar-
get. For typical radiosurgery geometry of many converging
beams, the use of protons would mean the beams could be
delivered to the target, where they would stop. The exit dose
from each beam would be negligible, greatly reducing the inte-
gral dose to normal tissue.39
However, in practice, achieving the benefits of protons can be
challenging. Tissue inhomogeneity can create significant range
uncertainty for protons. Any deviation in the patient’s position
relative to the simulation position accentuates this range uncer-
tainty. Range uncertainty limits the use of beam arrangements
where the distal edge of a beam abuts a critical structure
(which is often the case in SRS/SRT scenarios). Passive-scattered
proton systems have poor beam-shaping capabilities relative to
modern X-ray systems and can lead to higher integral doses.40
Scanned protons perform better, but are more sensitive to
imaging and motion uncertainties. Many currently active pro-
ton centers lack the kind of on-board 3D imaging that is avail-
able on X-ray accelerators, which contributes to these
uncertainties.41
5.12 Treatment Planning
Treatment planning for intracranial radiosurgery has its unique
features and challenges compared with conventional fractio-
nated radiotherapy and treatment to other body sites. Radiation
dose is very high, and critical structures are usually located
near the target. Therefore, a steep dose falloff from the target is
required and planning target volume (PTV) margins are small.
Despite these demanding challenges, several unique features
can make the treatment planning for intracranial radiosurgery
easier because of the location and tissue composition of the cra-
nium. First, many noncoplanar beams can be used to spread an
intermediate or low-dose bath to a larger region to avoid an
ablative dose to normal structures. Specifically, vertex beams
are often used to smear the dose in a cranial–caudal direction
while maintaining the required target dose. This cannot be
easily achieved at other body sites because of potential collision
concerns between the treatment machine and the patient or
treatment couch. Second, treatment targets are usually located
away from inhomogeneity interfaces of tissue and bone or air.
Dose distributions can be calculated accurately by simple fast
algorithms.4 In contrast, targets in lungs demand a more
sophisticated, time-consuming Monte Carlo dose-calculation
algorithm to accurately represent dose distribution. Treatment-
planning algorithms have evolved tremendously in the past
decades thanks to the advances of computational hardware.
Current calculation algorithms generate more accurate dose
distributions that have been verified by measurements. 42,43 The
largest inaccuracy from previous simple algorithms occurs at
inhomogeneity interfaces such as the target in lungs. When
comparing with the treatment outcome of historical data, the
plan needs to be recalculated with a current algorithm to accu-
rately represent the dose distribution. 44,45 Treatment planning
for intracranial radiosurgery suffers less from this issue because
of its relative homogenous tissue composition. 4
The Physics of Radiosurgery
5.12.1 Isocentric versus Nonisocentric
The isocenter is a virtual point in space where two axes cross
and around which the treatment device and couch rotate.
When treating a spherical-shaped target, one single isocenter is
generally placed at the center of the target. Gamma Knife and
other treatment machines with conical collimators use this so-
called isocentric planning technique. For an irregular-shaped
target, Gamma Knife planning places several isocenters inside
the target with associated different collimator sizes to generate
a conformal plan (▶ Fig. 5.1). This is referred as ball packing.46
For an irregular-shaped target, CyberKnife planning aims some
beams at the peripheral region of the target, not passing the
isocenter to patch dose to this area. Such planning is called an
nonisocentric technique (▶ Fig. 5.2).
5.12.2 Forward versus Inverse
In the early days of radiosurgery, the planning computer was
not powerful enough to perform optimization with multiple
iterations and forward planning was predominantly utilized for
intracranial radiosurgery. In contemporary practice, inverse
planning techniques are increasingly used with the develop-
ment of IMRT. In forward planning, treatment planners choose
various parameters such as collimator size, number and loca-
tion of isocenter, beam angle, arc angle, couch angle, and beam
weights. This technique relies on the experience of the planner,
and the developed plan may not be optimal. In inverse plan-
ning, dosimetric goals and constraints are first set by planners
for both the treatment target and normal structures. A com-
puter program then optimizes all the variable parameters to
meet these goals and constraints. For specialized CyberKnife,47
Axesse, Novalis, Edge, and tomotherapy48 devices, the number
of beam parameter combinations is enormous and most cases
can only be planned by an inverse technique. Although inverse
planning has become an important technique for intracranial
radiosurgery, a forward technique still remains a fast and effi-
cient way for many cases.
5.13 Beam Shaping and Delivery
The Gamma Knife was developed more than half a century ago,
and it is still a popular way to deliver radiosurgery treat-
ments.49,50 The Gamma Knife uses many intersecting circular
beamlets from different directions to create a spherical-shaped
high-dose region around the treatment target. It is not surpris-
ing that the initial application of a linac for radiosurgery has
used a conical collimator to shape the radiation beam by mim-
icking the Gamma Knife’s circular beamlets.51,52 Plans are gen-
erated by a forward technique, often with templates of
predefined couch and beam angles. The next development,
spearheaded by Brainlab (Munich, Germany) and Varian (Palo
Alto, CA), utilizes a MLC for a conformal arc delivery technique.
In this approach, an MLC is shaped continuously to match the
beam-eye-view shape of the target at all delivery arc angles.53,54
One advantage of the conformal arc technique over a cone-
based technique is its ability to deliver more efficiently to a
nonspherical-shaped target. A conformal arc is still a forward-
planning process that requires a manual selection of arcs and
adjustment of the weighing. In challenging cases where the
33
 The Physics of Radiosurgery
Fig. 5.1 Gamma Knife plan of a vestibular schwannoma using multiple isocenters to achieve conformality.
dose needs to be shaped to avoid nearby critical structures, an
IMRT technique is often utilized to inversely optimize beams to
generate a high dose at the target while keeping the dose to
critical structures within tolerance. An IMRT technique uses
many fixed beams to avoid irradiating ablative dose from
any single gantry angle. The next evolution of VMAT was a
34
Fig. 5.2 Cyber Knife plan of four targets with 74
nodes and 107 beams, MU 12564.
combination of inverse IMRT and arc delivery techniques. Simi-
lar to a conformal arc approach, VMAT spread a small dose to a
larger region by delivering the dose in several arcs. Unlike a
conformal arc, VMAT can inversely optimize the plan to avoid
critical structures by modulating MLC shape, gantry rotation
speed, and dose rate. Another benefit of VMAT is its ability to

Fig. 5.3 Eclipse plan of single isocenter with four arcs for two targets, MU 5029.
treat multiple targets with one isocenter and multiple non-
coplanar arcs, providing a unique efficient treatment-delivery
approach (▶ Fig. 5.3).10,55
5.14 Margins and Issues with
Margin Assumption
A PTV margin is typically added from clinical target volume
(CTV) for most radiotherapy to account for setup uncertainties.
A PTV margin is typically assumed to be zero for intracranial
radiosurgery plans.56 This is probably because historically a
frame is always used to invasively attach the skull to the treat-
ment couch for all intracranial radiosurgery treatments. Unlike
other body parts, the brain is not subject to internal motion;
thus, a lesion stays fixed in space during treatment. However,
several issues need to be considered for potential violation of
this zero PTV margin assumption. First, errors from multimo-
dality image registration can propagate to target contour uncer-
tainty. Most intracranial targets are delineated on functional
image datasets such as magnetic resonance imaging (MRI) and
then registered to a planning computed tomography (CT) data-
set. Any mismatch between the two registered image sets
would cause target contour uncertainty. Second, intrafractional
motion during radiation treatment delivery causes target
uncertainty. Frameless immobilization has become more com-
mon for intracranial radiosurgery thanks to recent advances in
image-guidance technology. Such a frameless approach utilizes
less invasive masks and offers an alternative to the traditional
The Physics of Radiosurgery
frame-based method where a localization frame is screwed into
the patient’s skull. Even though the frameless approach is more
convenient and comfortable, a patient could move up to 2 mm
inside an immobilization mask during treatment, causing addi-
tional uncertainty.57 Third, a nontrivial discrepancy remains
between the two isocenters of the treatment-delivery and the
image-guidance systems, which is on the order of a submillime-
ter.58,59 Fourth, setup localization images are registered to the
treatment-planning image set before treatment delivery to an
individual patient, and any registration mismatch is not
accounted for. Last but not the least, possible tumor cells may
lie outside of the lesion as defined by imaging contrast. This
uncertainty is arguably the margin from gross tumor volume
(GTV) to CTV,56,60 and some physicians account this indirectly
by placing the prescription isodose line several millimeters
beyond the visual tumor. All these assumptions should be char-
acterized to start an intracranial radiosurgery program and an
end-to-end test can evaluate the overall geometric uncertain-
ties by simulating the whole process with a phantom.
5.14.1 Dose Inhomogeneity and
Conformity
Dose inhomogeneity and conformity are two competing met-
rics for intracranial radiosurgery planning, similar to other
radiotherapy planning. Inhomogeneity is evaluated as the
percentage of maximum dose to the prescription dose. The
location of the maximum dose is called a hot spot and should
35
 The Physics of Radiosurgery
occur inside the treatment target. Conformity measures how
well the prescription isodose surface matches the target out-
line. A common conformity metric is defined as the product
of two ratios. One measures the amount of prescription iso-
dose spillover into normal tissue—defined as the ratio of tar-
get volume encompassed by the prescription isodose volume
to the prescription isodose volume. The other measures how
much target is not covered by the prescription isodose—
defined as the ratio of target volume encompassed by the
prescription isodose volume to the target volume. This con-
formity metric ranges from 0 to 1, with 1 being the best
case.61 As shown in ▶ Fig. 5.4, an additional 5-mm cone was
used to avoid a cold spot at the corner of this irregular-
shaped target. Because the isodose clouds overlap from the
two cones, this plan will generate a higher hot spot than a
single isocenter plan. In this case, conformity is achieved at
the sacrifice of inhomogeneity. Dose inhomogeneity and con-
formity varies greatly with the delivery approach and are a
function of the prescription isodose surface. For example,
Hazard and colleagues proposed a uniform method to choose
a prescription isodose surface to balance target coverage
and conformity for the dynamic conformal arc delivery
approach.62
5.14.2 Multimodality Imaging
Registration
A primary CT image dataset is often required for dose calcula-
tions and image guidance, but intracranial radiosurgery targets
often cannot be easily visualized on the CT dataset. Multimo-
dality imaging registration is required to map the target delin-
eation onto the primary CT dataset. Such modalities include
MRI,63 positron emission tomography (PET),64 proton magnetic
36
resonance (MR) spectroscopic imaging,65,66 and single-photon
emission computed tomography (SPECT).67 The geometric
uncertainty should be quantified and corrected for MRI distor-
tion. Inherent system distortion is caused by inhomogeneities
in the main magnetic field and nonlinearity of gradient fields.
Such system distortion increases with distance from the mag-
net center; it can be corrected by the use of phantoms. 68,69
However, patient-related distortions cannot be easily corrected,
which is mainly a concern for a high magnetic field.
5.15 Image Guidance
Traditional intracranial radiosurgery procedures utilized
invasive frames together with localization boxes to immobi-
lize patients and to align the target for treatment delivery.
The advancements in image guidance have been one of the
most valuable contributions to radiosurgery. Image guidance
has facilitated the application of noninvasive frameless
immobilization, thus enabling multiple fraction treatments
and the flexibility of separate days for simulation and treat-
ment delivery. In addition to these benefits of patient con-
venience and a less invasive procedure, image guidance has
provided direct visualization of the treatment target or skull
surrogate before or during the ablative high-dose delivery. Of
course, all of these advantages come with an additional imag-
ing dose to patients for some techniques and associated qual-
ity assurance procedures required to verify the coincidence
of the imaging and treatment isocenters. Common image-
guidance techniques include stereoscopic two-dimensional
(2D) X-ray, volumetric 3D X-ray, infrared or optical guidance,
and MR guidance. They can be used either for setup guidance
before treatment delivery or for intrafractional guidance dur-
ing treatment.
Fig. 5.4 Eclipse plan of two cones and four arcs
each, MU 4644.

5.15.1 Stereoscopic 2D X-Ray Imaging
In this technique, a set of digital reconstructed radiographs
(DRRs) are first generated from a planning CT dataset. Two pla-
nar X-ray images are then acquired at an oblique or orthogonal
angle with patients at the treatment position. Then, the X-ray
images are registered to the DRRs to calculate image-guidance
shifts. This technique includes room-mounted and gantry-
mounted imaging systems. In the room-mounted setup, kilo-
voltage (kV) X-ray tubes and digital detecting panels are
installed oppositely at the ceiling and on the floor with image
beams passing through targets obliquely. Typical commercial
systems with this technique are Novalis54 and CyberKnife.47 For
gantry-mounted systems, a kV X-ray tube and detecting panel
are installed orthogonally to the treatment beam on the gantry.
Two kV images can be acquired orthogonally at two gantry
angles for image guidance. An alternative technique is to
acquire a pairing of a kV image and a megavoltage (MV) image
from the portal imager without the need of a rotating gantry.
Gantry-mounted systems are available for most modern linac
machines.
The room-mounted setup separates the hardware compo-
nents of the image-guidance system from the treatment-deliv-
ery system. The associated advantages include a more-stable
imaging isocenter that is not subject to the changes of the gan-
try position, and shorter imaging time compared with gantry-
mounted systems. Room-mounted systems can also be used for
intrafractional guidance during treatment delivery in addition
to setup guidance prior to treatment. On the other hand, the
gantry-mounted system can image the target at any angle with-
out the concerns that gantry blocks images at certain angles.
5.15.2 Volumetric 3D X-Ray Imaging
Another popular method is to use image guidance with volu-
metric 3D cone-beam CT (CBCT), which is reconstructed from a
number of projections acquired with the gantry-mounted kV
imager. The CBCT image set is registered to the planning CT
dataset to derive the shifting and rotational corrections.70 Com-
pared with the 2D technique, volumetric 3D imaging can dis-
play the anatomy at all three view planes: axial, sagittal, and
coronal. This feature is especially attractive when treating mul-
tiple targets with a single isocenter setup. One limitation is the
use of CBCT for setup guidance for non-coplanar beams because
of potential collision between the couch and gantry. Another
major limitation of volumetric 3D technique is its inability for
intrafractional guidance because the whole process of image
acquisition and reconstruction takes approximately 1 minute,
which is too long for real-time guidance.
There is an increasing interest to plan and treat multiple
intracranial targets with one single isocenter and several
non-coplanar arcs55 due to the high efficiency of treatment
delivery. The shorter treatment time is advantageous for pa-
tient comfort and associated less variation of target position.
However, uncorrected rotational discrepancy between treat-
ment and planning positions could introduce nontrivial dosi-
metric errors. For example, a rotation discrepancy of 1
degree causes a displacement of 1.7 mm at a distance of
10 cm from the isocenter. Such displacement could shift
treatment target partially or even totally outside of treatment
The Physics of Radiosurgery
field. In this case, a robotic couch is necessary to correct set-
up rotational errors. When the required rotation is outside
the limits of the robotic couch, the immobilization and setup
image-guidance process should be repeated. During treat-
ment delivery, intrafractional guidance should monitor both
the rotational and shift changes.
5.15.3 Infrared and Optical Guidance
X-ray image-guidance techniques expose patients with addi-
tional imaging dose that is not trivial, especially when used
for intrafractional guidance. Infrared 71 and optical72,73 guid-
ance are two popular techniques to solve this issue. Infrared
technique uses ceiling-mounted cameras to detect either
reflection of passive markers or active light-emitting
markers. The markers are attached to a bite block that is
formed to the patient’s dentition. Infrared guidance techni-
ques can be used for either initial setup prior to treatment
delivery or intrafractional guidance. The major limitation is
the potential movement of markers relative to the patient
skull. In the past few years, optical guidance techniques have
emerged for intracranial radiosurgery applications. Several
groups have investigated an open mask immobilization with
a commercial AlignRT system.72,73 In this optical guidance
technique, a reference image is first generated from the skin
rendering of the planning CT dataset. Three ceiling-mounted
camera pods capture facial landmarks of the patient and then
compare them with the reference image. One major advant-
age of this optical guidance technique is the ability of moni-
toring any movement during treatment delivery without
additional imaging dose. In addition, patients are more com-
fortable and compliant under the less restrictive immobiliza-
tion masks. The optical guidance technique is typically used
as an intrafractional guidance method after setup guidance
by an X-ray–based technique. Some issues may cause local-
ization errors using the optical technique, for example, its
dependence on room lighting and region-of-interest (ROI)
selection.73 In addition, skin deformations can occur when
patients change weight or take medication, causing a shift
between the positions of treatment target and monitored
facial surface.
5.15.4 MR-Based Guidance
Magnetic resonance-based image-guidance systems are recent
exciting developments that could introduce paradigm change
for intracranial radiosurgery. Two types are explored for an
integrated MRI-linac system74,75 and MRI with radioactive sour-
ces such as the ViewRay system. The advantages of MR image
guidance include nonradiation imaging dose, fast 3D volumetric
data, and high soft-tissue contrast. They can provide both pre-
treatment and intrafractional guidance with a 3D dataset that
can be viewed in many planes. The MR-based image guidance
can provide direct target visualization, which is a major advant-
age over other image-guidance techniques that relies on skull,
skin, or markers as a surrogate. For intracranial radiosurgery
applications, MR images are already used in most cases for tar-
get delineation during treatment-planning process; therefore,
an MR-based technique provides unique same image modality
guidance.
37
 The Physics of Radiosurgery
5.16 Quality Assurance and Safety
The safety of the patient and the treatment team are critical
concerns in any radiotherapy procedure, but perhaps especially
so with SRS/SRT. Doses are high and the number of fractions is
small, meaning there is little or no room to correct for mistakes
in treatment delivery as can be done in conventional radiother-
apy. Modern treatment devices increasingly rely on complex
simulation imaging, on-board imaging, and intradelivery treat-
ment-monitoring techniques to ensure correct beam delivery.
Certain devices used for SRS (the Gamma Knife being a promi-
nent example) rely on radioactive material (RAM) as an energy
source, and thus special care and custodianship of the RAM. A
robust quality assurance, risk management, and training regime
are essential to the safe and effective operation of a radiosur-
gery program.
5.16.1 Quality Assurance Needs for SRS/
SRT
A large selection of published studies and reports are available
from national and international organizations, which outline
best practices for commissioning and quality assurance of gen-
eral aspects of beam delivery devices, in-room imaging equip-
ment,76 MLCs,77 treatment-planning systems,78 and secondary
dosimetry check software.79 The authors refer the reader to
these reports for guidance on these aspects of SRS/SRT treat-
ment delivery. The scope of a quality assurance program is also
beginning to move beyond standardized, one-size-fits-all pro-
cedures and instead is based on a formal, risk-based analysis
of the relative risks involved in a procedure using techniques
such as failure mode and effect analysis (FMEA) and fault-tree
analysis.80
The high doses delivered with SRS/SRT combined with the
sharp dose gradients create a requirement for extremely
aggressive tolerances for targeting accuracy. Even small devia-
tions from the intended target can cause significant changes in
tumor control probability. For example, Treuer et al studies a
cohort of 20 patients with an arteriovenous malformation and
20 patients with brain metastasis, looking at the effect of target
point deviations on predicted obliteration/tumor control and
normal tissue complication probability. They found that a devi-
ation of 1.3 mm decreases rates of obliteration/local control by
approximately 5% and could indicate a need for expanded treat-
ment margins.81
However, as discussed earlier, PTV margins are often not
applied in the setting of SRS/SRT.56 Also, the assumptions of a
small number of beams and a large number of fractions that
underlie common margin formulas used in traditional radio-
therapy are violated in the setting of SRS/SRT.82 Margins inher-
ently increase the volume of tissue irradiated in a treatment,
and this extra volume may by itself contribute to an increase in
complication rates.
The limited ability to compensate for beam delivery uncer-
tainty by expanding treatment volumes reinforces the goal of
minimizing beam delivery uncertainty as much as possible. The
AAPM TG-142 suggests some action levels for various parts of
the radiotherapy treatment process based on subjective obser-
vation of the authors regarding what is likely to be achievable
38
given the overall uncertainties of various aspects of the com-
plete treatment.76
5.16.2 Winston-Lutz and Hidden
Target/End-to-End Tests
The recognition early on that traditional quality assurance pro-
cedures for linear accelerators were inadequate in the setting of
SRS/SRBT led to the development of specialized procedures to
ensure accuracy of the procedure. Perhaps the most prominent
of these tests is the Winston-Lutz test, which assesses the coin-
cidence of the mechanical and radiation isocenters of the linear
accelerator.51 The classic Winston-Lutz test involves placing a
small spherical target at the presumed isocenter of the treat-
ment machine (usually using the room lasers). A suitable colli-
mator is set on the machine (often a circular collimator in the
case of SRS) and a radiographic film is placed perpendicular to
the collimator downstream of the target sphere. The film is
exposed, resulting in a radiation spot with the superimposed
shadow of the target sphere. The offset between the center of
the target shadow and the center of the field can be used to
determine the difference between mechanical and radiation
isocenter. The test is repeated at various gantry, table, and colli-
mator angles to evaluate the stability of isocenter coincidence.83
Over time, the Winston-Lutz test has been modified as tech-
nology has evolved. Methods have been developed to make use
of electronic portal imaging devices (EPIDS) to replace film as a
detector. On-board CBCT systems are used to align to the test
target to test the coincidence of the on-board imaging system
with the mechanical and radiation isocenters. Targets have
evolved as well, with purpose-built Winston-Lutz phantoms
available that are more intuitive to setup than the original
spherical target.83
A related, but critical quality assurance technique is the end-
to-end test (aka the hidden target test) that attempts to evalu-
ate the complete treatment uncertainty from simulation
through delivery, albeit on a phantom. Although the details
can take many forms, the test involves a phantom with an
embedded target, as well as an embedded detector (usually
radiochromic film or radiosensitive gel). In some cases, the tar-
get and detector are designed as separate swappable inserts in
the phantom. The phantom, with target embedded, is imaged
using regular clinical imaging protocols, and a treatment plan is
developed to treat the target to a specified dose. The phantom
is then setup on the treatment machine and the treatment is
delivered. The resulting dose distribution as captured on film or
gel is then compared with the original plan using either abso-
lute dose differences or a combined dose/distance metric such
as gamma analysis.84,85
Certain specialized SRS/SRT devices have associated special-
ized quality assurance tests. For example, the most recent ver-
sion of the Gamma Knife uses a traceable set of specialized
diode detectors to create calibration offsets for the treatment
table. A set of master diode detectors is calibrated against a pre-
cisely measured “reference” Gamma Knife. These master tools
are then used to create calibration offsets for site-specific diode
detectors that are used at clinical sites.50 Another example is
the CyberKnife, which uses an “isocrystal” to define the
mechanical room coordinate system. Images of the isocrystal

on the in-room X-ray system are used to determine the X-ray
source/detector alignments.86
5.17 Clinical Implementation of an
SRS/SRT Program
Clinical implementation of an SRS/SRT program requires careful
up-front planning of scope of indications to be treated, staff
required to implement the clinical and technical aspects of the
program, device selection, credentialing standards, and an
ongoing program of SRS/SRT-specific training.
When developing the scope of the program, important con-
siderations include the clinical and technical expertise of the
treatment team, the expected patient load on the machine (and
whether or not this load is on top of a traditional radiotherapy
load), and the availability of published national protocols or
other clinical guidelines for treating each indication. Departures
from established clinical standards should only be attempted
with oversight and approval of the institutional review board.
The SRS/SRT requires workflows and time commitments that
differ, and are in many instances greater, than what is required
for traditional radiotherapy treatments. Personnel and time
estimates should bear this in mind. A variety of sources can be
used to estimate required staffing levels. National professional
organizations such as the AAPM, American Association of Neu-
rological Surgeons/Congress of Neurological Surgeons (AANS/
CNS), and American Society for Radiation Oncology (ASTRO)
have published benchmarks that can aid in estimation.87
Choice of treatment machine should take into consideration
the overall scope of the radiation oncology and neurosurgery
programs at the institution. In many cases, the existing treat-
ment devices within the radiation oncology department will be
sufficient for SRS/SRT procedures with little or no modification.
In other cases, a specialized radiosurgery treatment device such
as a Gamma Knife or CyberKnife may make the best clinical and
financial sense. The critical issue in equipment selection is to
ensure that the system as a whole (from imaging through deliv-
ery) meets the strict requirements for accuracy and precision
for SRS/SRT.
Strict credentialing standards and a regular program of SRS/
SRT-specific training is another critical component of any radio-
surgery program. Several misadministrations in an SRS setting
can be directly traced back to a lack of proper training one or
more members of the treatment team. The American College of
Radiology (ACR) and ASTRO provide definitions and minimum
qualifications for neurosurgeons, radiation oncologists, medical
physicists, dosimetrists, and radiation therapists who are par-
ticipating in radiosurgery procedures.88 In addition, for devices
that make use of radioactive materials, the U.S. Nuclear Regula-
tory Commission and various agreement states have specific
regulatory requirements for experience, credentials, and train-
ing required for authorized users (radiation oncologists) and
authorized medical physicists performing radiosurgery.
Because of the different workflows, targeting strategies, pre-
scription doses, and specialized treatment devices used in SRS/
SRT, specific training is recommended. Up-front training prior
to clinical operation should involve vendor-specific training on
the device(s) to be used for SRS/SRT, as well as observation at
centers with extensive experience in performing SRS/SRT.
The Physics of Radiosurgery
Training should include all personnel involved in the treatment
team so that the entire scope of the procedure is covered.
Ongoing training should include a review of clinical operational
procedures, a review of recent reports of misadministrations
and medical events, reviews of any vendor-reported safety
notices, and simulations of clinical mishaps to rehearse emer-
gency response procedures.
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41
 Radiosurgical Devices

6 Radiosurgical Devices
Daniel E. Hyer, Frank J. Bova, and John Buatti

response and normal tissue complications are based on such a

Key Points prescription technique.2,3 If radiosurgery is performed with a
new device that requires the use of a margin to account for
● Two of the most important aspects of radiosurgery are a uncertainties in patient positioning, the increase in volume of
sharp dose gradient and accurate target positioning that en- irradiated tissue is likely to add a significant risk of complica-
ables treatment of a radiographically defined target without tion to what may otherwise be a safe and effective treatment.
a margin. For example, the inclusion of a 2-mm margin would increase
● The addition of a margin to account for positioning uncer- the volume of irradiated tissue by nearly 60% for a 24-mm-
tainties directly impacts the target dose that may be safely diameter target. ▶ Table 6.1 shows the volumes of typical radio-
delivered. surgery targets, and the volume increases when a 2-mm margin
● When a new system is developed, a qualified physicist should is added.
perform an end-to-end test to understand its strengths and The addition of a margin to account for positioning uncer-
weaknesses. Pretreatment tests validating all system align- tainties directly impacts the target dose that may be safely
ments should also be conducted as part of any radiosurgery delivered. Relationships between radiosurgical volume and risk
program. of complications have long been established.4 For example, if it
● Frame-based radiosurgery has been the gold standard of is safe and effective to deliver 20 Gy to a 2.4-cm-diameter tar-
radiosurgery treatment since its inception. The frame-based get, then if a 2-mm margin is used, the largest lesion that could
approach provides reliable localization when paired with the be safely treated with 20 Gy would be reduced to 2.0 cm in
appropriate delivery equipment and its treatment efficacy is diameter (see ▶ Table 6.1). This not only reduces the effective-
well established. ness of the treatment for larger target volumes, but also need-
● To overcome frame-based limitations, noninvasive, often lessly exposes normal tissue to the target dose. This would be
referred to as frameless, positioning systems have been the surgical equivalent of removing the diseased tissue and
developed. With a frameless system, immobilization and then removing another 2-mm margin of normal brain.
localization are no longer inherently linked. Although positioning uncertainties certainly limit the ability
to effectively perform radiosurgery, the importance of a sharp
dose gradient must also be remembered. Values provided in
▶ Table 6.2 show the increase in irradiated tissue if one
6.1 Introduction assumes a system with a 6-mm dose gradient is used instead of
a system with a 3-mm gradient. In this context, gradient refers
Radiosurgery was first defined by Leksell as “a single high dose
to the distance between the prescription isodose line and a line
fraction of radiation, stereotactically directed to an intracranial
that is 50% of the prescription isodose line. If we again use the
region of interest.”1 By focusing multiple beams of radiation on
previously referenced dose-volume relationship, it can be seen
the target tissue, Leksell was able to produce a sharp dose gra-
that the target diameter that could be safely treated with 20 Gy
dient outside of the selected target tissue that allowed the sur-
rounding normal tissue to be spared. This differed from other
forms of fractionated radiotherapy at the time, as it did not rely
Table 6.1 Increase in target volume with the addition of a 2-mm margin
on the differential sublethal damage repair between the target
and normal tissue, but rather on dose concentration to the tar- Volume of target (cc)
get achieved by an enhanced technical delivery paradigm and a Diameter of target (cm) No margin 2-mm margin % increase
very rapid falloff of dose in the adjacent normal tissue. It was
1 0.52 1.44 174
evident early on that for this new therapy to be effective, the
target must be readily identified (generally by imaging) and 1.2 0.90 2.14 137
accurately positioned, leading to the stereotactic approach to
1.4 1.44 3.05 113
radiation delivery. If this was not possible, the sharp dose gra-
dient would actually work against the clinician as the target tis- 1.6 2.14 4.19 95
sue could easily be missed or undertreated and normal tissue
1.8 3.05 5.58 83
could receive a very high radiation dose.
This chapter will focus on stereotactic positioning systems 2 4.19 7.24 73
and collimators necessary to successfully deliver radiosurgery.
2.2 5.58 9.20 65
Positioning devices and collimators are both important topics
to explore, as the spatial accuracy of dose delivery and sharp- 2.4 7.24 11.49 59
ness of the beam profile dictate the treatment approach more 2.6 9.20 14.14 54
so than the type or design of the radiation source. Historically,
radiosurgery dose distributions have been prescribed to the 2.8 11.49 17.16 49
boundary of the enhancing volume (i.e., without margins added 3 14.14 20.58 46
to the clinical target volume). The clinical data regarding tumor

42
 Radiosurgical Devices

would be decreased from 2.4 cm to approximately 1.8 cm when technologies can be broken down into two main categories:
moving from a 3-mm gradient to a 6-mm gradient. These two minimally invasive systems and noninvasive systems.5 Mini-
examples point out two of the most important aspects of radio- mally invasive systems include the popular frame-based sys-
surgery: sharp dose gradients and accurate target positioning tems that are attached to the patient’s skull through the use of
that enables treatment of a radiographically defined target pins, whereas noninvasive systems include devices such as
without a margin. maxillary fixation systems, thermoplastic masks, and in-room
imaging. Before discussing positioning systems in detail, a key
distinction should be made between localization, sometimes
6.2 Stereotactic Positioning referred to as alignment or positioning, and immobilization. In
Systems the simplest sense, localization refers to the ability to position
the target at a desired location, usually the isocenter of the
The term stereotactic refers to the use of a mathematically treatment device, and immobilization refers to the ability to
defined three-dimensional (3D) coordinate system to precisely hold the target in place during treatment delivery. It is impor-
locate targets inside of the brain. Various technologies tant to understand that these two aspects are not always linked,
have been developed for stereotactic localization, and these and both must be considered for radiosurgery. For example, a
thermoplastic mask may be used to immobilize a patient, but
provides little benefit for localization. Similarly, a cone-beam
Table 6.2 Increase in irradiated tissue due to gradient computed tomography (CBCT) scan at the treatment machine
may be used for localization, but provides no benefit in immo-
Volume of 50% of RX (cc)
bilization. The difference between a localization error and an
Diameter of immobilization error can be seen in ▶ Fig. 6.1.
target (cm) 3-mm gradient 6-mm gradient % increase The following sections detail devices commonly used in
1 2.14 5.58 160 radiosurgery and describe their proper use in each of these
categories.
1.2 3.05 7.24 137

1.4 4.19 9.20 120

6.3 Minimally Invasive Positioning
1.6 5.58 11.49 106
Systems
1.8 7.24 14.14 95
Minimally invasive systems, such as the Leksell,7 Brown-Rob-
2 9.20 17.16 86
erts-Wells,8 and Brainlab9 (Munich, Germany) frames, are rig-
2.2 11.49 20.58 79 idly affixed to the patient’s head during treatment. This is
accomplished through the use of pins that are tightened against
2.4 14.14 24.43 73
the patient’s skull, as shown in ▶ Fig. 6.2. By rigidly affixing a
2.6 17.16 28.73 67 frame to the patient’s skull, a geometric relationship is estab-
lished between the patient’s intracranial anatomy and the ster-
2.8 20.58 33.51 63
eotactic frame that has a known geometry. An external fiducial,
3 24.43 38.79 59 such as a localizer box, is then attached to the frame, and a
computed tomography (CT) scan is acquired. The positions of

Fig. 6.1 Images showing localization errors (left) and immobilization errors (right). With localization errors, the target moves away from the planned
position and the effect is a geometric miss. With immobilization errors, the target moves during treatment, and the effect is to blur the dose delivered
to the target.6 (Used with permission from JNSPG.)

43
 Radiosurgical Devices
Fig. 6.2 Minimally invasive head frame and localizer box.
several fiducial rods embedded in the localizer box are then
located in each slice of the CT scan, and because the geometric
relationship between each fiducial rod and the frame is well
known, a coordinate system transformation can be determined
that will convert the native CT coordinate system to a new coor-
dinate system based on the localizer’s fiducial system.10,11
Applying this coordinate system transformation to the entire
CT dataset will allow the position of any point in the image vol-
ume to be uniquely referenced to the stereotactic ring’s coordi-
nate system, which is rigidly fixed to the patient’s head. The
intracranial target can then be aligned to the treatment unit’s
isocenter using the frame and associated coordinate system—
providing the localization necessary for treatment delivery.
With the frame-based approach, the frame also serves as an
immobilization device, as it is rigidly mounted to the patient
support system and holds the patient’s head motionless during
treatment delivery.
6.3.1 Gamma Knife Frame System
The Gamma Knife is a unique system for performing stereotac-
tic radiosurgery (SRS), and it was developed around the frame-
based approach. Localization with the Gamma Knife system
44
relies solely on mechanical positioning of the patient’s head
based on the stereotactic coordinate system that is derived
from the imaging acquired for treatment planning. The latest
Gamma Knife unit, called the Perfexion (PFX), was introduced
in 2006 and performs patient positioning with an automatic
positioning system (APS).12 The APS consists of a robotic treat-
ment table that is calibrated to the stereotactic coordinate
system and can automatically position the patient at each treat-
ment isocenter. The head frame is attached to the APS through
a couch mount. The mechanical treatment range in the X/Y/Z
orientations is (160/180/220) mm. In addition to these transla-
tions, the APS can also tilt the entire coordinate system to three
different gamma angles to allow additional clearance during
treatment: 70 degrees (chin up position), 90 degrees (horizon-
tal), or 110 degrees (chin down).
The manufacturer’s specification for agreement between the
radiation focal point and the APS mechanical isocenter is
0.4 mm—the alignment of all radiation beams to a single point
in space. However, one group found the agreement to be as
small as 0.26 mm.12 Additionally, reproducibility of stereotactic
coordinates—the accuracy that an individual coordinate can be
revisited—with the APS is stated to be better than 0.05 mm. The
mechanical accuracy afforded by this system is often considered
the gold standard to which other technologies are compared.
However, this mechanical accuracy of positioning is only one
component of a multifaceted treatment process. With such a
small mechanical accuracy, the primary source of localization
errors is the imaging acquired for treatment planning. Previous
studies have shown that determining the coordinates of a high
contrast object on a CT scan can be achieved with an accuracy
of approximately ± 1 voxel.13 The scan diameter required to
accommodate a stereotactic localizer is approximately 350 mm.
With a 512 × 512 imaging matrix, this results in an in-plane pix-
el dimension of 0.67 × 0.67 mm. Therefore, the positional error
of the APS can be thought to be quantum limited, with the
quantum sink being the determination of the stereotactic coor-
dinates from the CT scan.
6.3.2 Linac Frame Systems
Two main challenges present themselves when adapting a linac
to perform radiosurgery: achieving high mechanical isocentric
accuracy and accurately localizing the patient at the treatment
machine. Several systems have been developed to overcome
these challenges; each are discussed in detail in the following
sections.
Floor Mounted
At the University of Florida, Gainesville, a floor-stand system
was developed to perform stereotactic radiosurgery with a
standard linac.13,14 This system, shown in ▶ Fig. 6.3, is
mounted to the treatment room floor and attaches to the
linac gantry via a sliding gimbal mount. The floor-stand sys-
tem links the beam isocenter to the patient rotation isocen-
ter, both of which are necessary for non-coplanar treatment
delivery. This linkage relieves the burden of isocentric accu-
racy from not only linac gantry rotation, but also the patient
support system, with the latter being a subsystem that is not
only subject to large changes in load due to varying patient

size, but also one that historically has been difficult to main-
tain due to component wear. Through the use of high-preci-
sion bearings and low-mass components, the floor stand’s
gantry arm and patient support system are capable of high-
precision rotations about the isocenter. The floor stand has
been shown to have a mechanical accuracy of 0.2 ± 0.1 mm as
determined through a Winston-Lutz test at various couch
and gantry positions. 13 This level of mechanical accuracy
rivals that of Gamma Knife systems and cannot be achieved,
even on modern linacs, without the use of the floor-stand
system.
The floor-stand system also has provisions for accurately
localizing the patient during radiosurgery. As seen in ▶ Fig. 6.3,
the patient’s head frame is attached to the patient support sys-
tem of the floor stand for treatment. The patient support sys-
tem has manual adjustments in the longitudinal, lateral, and
vertical directions along with a calibrated vernier scale. As part
of the commissioning process, the vernier scale is calibrated
such that (0,0,0) coincides with the center of the stereotactic
volume of the Brown-Roberts-Wells frame, and the translation-
al axes are aligned with that of the head ring. Similar to the
Gamma Knife system, the positioning of the patient is com-
pletely mechanical and based on the stereotactic coordinate
system derived from the planning CT. The resolution of the ver-
nier scale used to set the stereotactic coordinates has a resolu-
tion of 0.1 mm. The main uncertainties in localization and
treatment alignment when using the floor stand are based on
Radiosurgical Devices
Fig. 6.3 Floor-stand system for performing ra-
diosurgery. (a) Side view of the gantry and
gimbal in the 0 degree position; (b) top view of
the gantry and gimbal rotated through 90
degrees. The floor stand is attached to the linac
through a sliding gimbal bearing (A) and has
precision bearings for the gantry arm (B) as well
as couch rotation (C). The system produces a
mechanical accuracy of 0.2 ± 0.1 mm.13
the voxel size of the imaging modality used to determine the
desired isocenter locations, identical to the uncertainty of the
Gamma Knife.
Couch Mounted
With a couch-mounted SRS system, the patient is placed on
the standard linac treatment couch and their head is fastened
to an adapter that overhangs the end of the treatment
couch.3 The adapter typically includes mechanical adjust-
ments to allow fine positioning of the patient’s head in 6
degrees of freedom. However, unlike the floor stand and
Gamma Knife systems discussed so far, the positioning accu-
racy and rigidity of a standard treatment couch is not suffi-
cient for absolute alignment of the linac’s isocenter to a
targeted stereotactic coordinate. Instead, couch-mount sys-
tems must rely on room lasers to align the target point to the
linac’s isocenter. When room lasers are used, the stereotactic
coordinates are determined from the planning CT and then
transferred to the exterior of the localizer box through either
printouts or panels with a calibrated scale (see ▶ Fig. 6.4).
The room lasers, which are used as a link between the room
coordinates and stereotactic coordinates, are then aligned
with the markings on the localizer box using the mechanical
adjustments on the couch adapter. The use of such a system
brings the room laser systems into the quality assurance loop
for each radiosurgical procedure. For this reason, the room
45
 Radiosurgical Devices
Fig. 6.4 Localizer box with computer-generated overlays for room laser
alignment. (Image courtesy of Joseph C. T. Chen, MD, PhD.)
lasers must be accurately aligned to the treatment machine
isocenter before being used to position the patient. This can
be performed by imaging a radiopaque marker at the inter-
section of the lasers to verify alignment before patient treat-
ment. Demonstration of laser alignment prior to treatment
should be considered a necessary step with couch-mounted
systems.
Using a couch-mounted system also puts significant iso-
centric demands on the treatment machine. Isocenter wan-
der due to gantry, collimator, and couch rotations must be
minimized to ensure accurate targeting. Wander can be mini-
mized with a dedicated SRS linac that is tuned from the fac-
tory for this purpose. Values of 0.3 ± 0.1 and 0.6 ± 0.1 mm for
gantry and couch isocentricity, respectively, are reported in
the literature for a dedicated SRS linac. 15 The localization
accuracy of a couch-mount system, which relies on aligning
the room lasers to an isocenter that is not a point but rather
a distribution in space, will inherently be less accurate than
floor stand or Gamma Knife systems in which the isocenter
accuracy is on the order of 0.2 to 0.4 mm. Additionally, the
verification of isocentric alignment at patient support angles
other than 0 degree can be difficult because the lasers do not
rotate with the patient for non-coplanar beam alignment.
Visual alignment of the room lasers to markings on the local-
izer box also have inherent inaccuracies that vary between
users and could easily account for an additional 0.5 mm of
localization uncertainty.
46
Imaging Dependent
When SRS treatments with linacs first started over 30 years
ago, megavoltage (MV) portal images were the only in-room
imaging modality available. Megavoltage portal images were
unsuitable due to their poor contrast, resolution, and inabil-
ity to visualize intracranial anatomy: all of which limited
their utility and adoption for SRS localization. However,
recent developments in image-guided radiotherapy, including
the advent of gantry-mounted kilovoltage (kV) CBCT, have
led some groups to localize frame-based SRS patients with
imaging rather than the mechanical or laser-based systems
discussed thus far.
With these systems, the patient’s head frame is fastened to
an adapter on the treatment couch as described in the pre-
vious section. At this point, rather than mechanical localiza-
tion based on the stereotactic coordinate system, a CBCT is
acquired of the patient’s head. An automatic registration
between the planning CT and (treatment) CBCT can then be
performed to calculate the shift that must be applied to local-
ize the patient to the treatment isocenter. One group eval-
uated the accuracy of such a workflow by acquiring the CBCT
with the localizer box still attached to the patient’s head and
mapping the CBCT dataset to the same stereotactic coordinate
system as the planning CT.16 Using this method, the mean
image registration accuracy between the CBCT and the plan-
ning CT dataset was found to be 0.28 mm. A potential advant-
age of CBCT-based SRS is the ability to use the 3D image to
detect frame slippage by comparing the relationship between
the frame and patient anatomy in both the CBCT and planning
CT, which are taken at two different time points. Without a
CBCT, a depth helmet can be used to detect frame slippage,
but its interpretation is highly subjective and accuracy is 1 to
2 mm.5
One of the biggest sources of uncertainty with an imaging-
dependent system such as CBCT is the potential misalignment
between the treatment and imaging isocenter, which is gener-
ally held to within a tolerance of < 1 mm.17 A misalignment of
1 mm can severely limit the clinician’s ability to perform SRS
when targeting small lesions and should be carefully evaluated
on an individual system basis. The isocentric wander of the
machine should also be evaluated, as this will be another source
of uncertainty, similar to the couch-mount systems described
in the previous section. As with laser-alignment systems, a
Winston-Lutz test demonstrating coincidence between the
imaging and treatment isocenters should be part of the pre-
treatment quality assurance process. It should also be noted
that a 6-degree-of-freedom adjustment of the head is necessary
for proper patient alignment when using a CBCT system for
radiosurgery.
6.4 Noninvasive Positioning
Systems
Minimally invasive frame-based radiosurgery has been the gold
standard of radiosurgery treatment since its inception. The
frame-based approach provides reliable localization when
paired with the appropriate delivery equipment and its treat-
ment efficacy is well established. However, the use of a head

frame is associated with substantial shortcomings relating to
patient comfort and clinical workflow.
To overcome these shortcomings, several noninvasive, often
referred to as frameless, positioning systems have been devel-
oped. With a frameless system, immobilization and localization
are no longer inherently linked. Due to this decoupling, immo-
bilization and localization will be discussed separately for
frameless systems in the following sections.
6.4.1 Immobilization
Thermoplastic Mask
One of the most common immobilization devices used in radio-
therapy is a custom-made thermoplastic mask that conforms to
the patient’s outer-body contour and is affixed to the patient
table (see ▶ Fig. 6.5). A thermoplastic mask is made of a low-
melting-point plastic that is rigid at room temperature, but easy
to mold and stretch when heated. To create a mask, the patient
is first positioned on the simulation table, generally in a supine
orientation with a small head cushion to improve patient com-
fort, and the thermoplastic mask is warmed in a water bath to
approximately 150°F so that it can be stretched and fitted to the
patient’s face. The mask should be molded to incorporate as
many hard body points as possible (bridge of nose, chin, etc.).
After fitting, the mask is attached to the treatment couch and
allowed to cool in place to provide a rigid mold of the patient in
the treatment position. Many variations of masks exist, mainly
differing in extent of coverage (head or head and shoulder) and
material thickness. When properly used, intrafraction motion
as small as 0.7 mm has been reported with thermoplastic
masks, a testament to their rigidity and custom-fitted construc-
tion.18 However, interfraction differences do occur and have
been reported to be as large as 2 to 3 mm,18,19 clearly demon-
strating the need for masks to be paired with a reliable localiza-
tion device.
Bite Plate
Bite plates, also called upper jaw fixation devices, offer a method
for noninvasively immobilizing the patient’s head. Anatomically,
Radiosurgical Devices
the teeth in the upper jaw provide the structure necessary to
rigidly immobilize the patient’s head. A bite plate is made by
filling an upper dentate impression tray with a rapidly harden-
ing dental material, placing the tray in the patient’s mouth, and
waiting for the material to harden and form an impression
around the patient’s upper teeth. After hardening, the bite plate
can be removed from the patient’s mouth and connected to a
couch-mounted frame to rigidly immobilize the patient’s head.
When fitted by experienced technicians, bite plates can offer
reproducible and rigid immobilization. The reproducibility of
reseating the bite plate in the patient’s mouth has been investi-
gated and reported to be as low as 0.24 mm.20 One group has
further developed the bite plate system by attaching a vacuum
tube to the dental cast to provide added fixation by providing
suction to the hard palate.19
Elekta (Stockholm, Sweden) has commercialized a vacuum-
assisted bite plate called the Extend system, allowing the Gam-
ma Knife to be used for multifraction treatments. The system
consists of a vacuum-monitored bite plate with associated frame,
as shown in ▶ Fig. 6.6. The performance of the Extend system
was recently evaluated with a digital probe, and the mean intra-
fraction accuracy over 36 fractional treatments was found to be <
0.5 mm.6 It is expected that similar bite plate systems could
offer equivalent intrafraction accuracy. Because this system is
rigidly fixed to the APS, which is capable of reproducing coordi-
nates to within 0.05 mm, it can also be used for localization of
the patient’s head, and the mean interfraction setup difference
was found to be 0.64 mm across the same patient cohort.
Ear Canal
A unique noninvasive immobilization system that has not seen
widespread use in the United States is the Laitinen stereotactic
frame, which consists of two earplugs and a nasion held togeth-
er with a reinforced plastic and aluminum frame.21 When prop-
erly fitted, this frame provides a rigid system to immobilize the
patient’s head based on external anatomy. Reports of intrafrac-
tion motion using such a system are limited in the literature,
but one may expect accuracy similar to the bite plate systems
described in the previous section.
Fig. 6.5 Thermoplastic mask used for immobili-
zation during frameless radiosurgery. (Image
courtesy of CIVCO Medical Solutions.)
47
 Radiosurgical Devices

Fig. 6.6 Elekta extend vacuum-assisted bite plate

for immobilization. (Image courtesy of Elekta.)

6.4.2 Localization objects within the field-of-view of the two cameras.24 Objects
such as small, reflective aluminum-covered spheres are often
Multiplanar X-Ray Imaging used as they can be easily detected by light-emitting diode
(LED) cameras emitting infrared light. By establishing a rigid
X-ray imaging is becoming one of the most popular techniques
body relationship between the locations of the objects and a
for localization in radiosurgery. Several different systems exist,
reference point, such as the treatment isocenter, the optical
ranging from 2D stereoscopic imaging systems to 3D CBCT
tracking cameras can be used to effectively track the location of
systems. Cone-beam computed tomography systems can be
the target. This principle has been applied to intracranial ster-
applied to frameless radiosurgery in the same manner as
eotactic radiotherapy and SRS.25,26
frame-based radiosurgery, with the frame being replaced with
One of the most successful applications of such a system is
a frameless immobilization device. Two-dimensional stereo-
the Varian Optical Guidance Platform (Varian, Inc., Palo Alto,
scopic imaging systems are also used for radiosurgery and may
CA), which consists of a bite plate attached to an array of small
offer an advantage over CBCT systems for frameless radiosur-
reflective balls that can be tracked by ceiling-mounted cameras.
gery, as images can be quickly acquired throughout the treat-
An example of a bite plate with markers attached is shown in
ment duration at a wide range of couch and gantry angles to
▶ Fig. 6.7. Here the bite plate has been combined with a ther-
verify positioning. This is advantageous, as immobilization with
moplastic mask for immobilization. The average localization
a frameless approach may exhibit a wider range of intrafraction
error when using such a system has been reported to be
motion than with frame-based radiosurgery; therefore, imaging
0.82 mm.20 One of the biggest advantages of optical tracking is
during the treatment duration can provide desirable position
the ability to continuously monitor the position of the patient
verification.
rather than at discrete moments in time before or perhaps dur-
One 2D imaging system used for radiosurgery is the ExacTrac
ing treatment as is the case with X-ray images.
system by Brainlab. This system consists of two floor-mounted
kV X-ray units and two ceiling-mounted imaging detectors. As
with any 2D imaging system, a fixed relationship between Surface Monitoring
intracranial lesions and the cranial skeletal anatomy must be
The optical tracking systems described in the previous section
assumed due to the fact that soft-tissue anatomy cannot be
have recently been taken a step further with the introduction
readily visualized on a 2D image. However, even frame-based
of 3D surface imaging with a system of video cameras. Such
systems are subject to the same assumption of a fixed relation-
systems do not require the use of reflective spheres, but rather
ship between skeletal and intracranial anatomy. By acquiring
map and directly track the patient. One such system, marketed
two X-ray images in a stereoscopic geometry and registering
by Vision RT (London, UK) as the AlignRT system, yields sub-
these with digitally reconstructed radiographs (DRRs) calcu-
millimeter accuracy (0.75 mm) for the translational degrees of
lated from the treatment-planning system, 6D corrections can
freedom and less than 0.1 degree for each rotational axis in a
be calculated to position the patient at the treatment isocenter.
phantom study.27 The advantage of surface monitoring is that a
Such systems have a demonstrated submillimeter localization
surrogate for the patient, such as a bite plate, is not needed:
accuracy.22,23
This reduces the potential for error due to malaligned fitting or
incorrect seating. One disadvantage is that the surface motion
can be tracked only with respect to a reference image, which
Optical Tracking can be a surface contour extracted from the planning CT image
Optical tracking involves the use of stereoscopically mounted or a surface image acquired previously with AlignRT. In our
infrared cameras that effectively triangulate the location of experience, the latter provides a better reference surface, as the

48

body contour determined from the planning CT is highly
dependent on a number of factors, including the threshold used
for automatic body contour detection. When capturing a refer-
ence surface, an absolute localization device such as X-ray imag-
ing should be used first to accurately position the patient. The
reference image should include hard structures such as the
bridge of the nose in the region of interest; mobile structures
such as the eyes should be excluded. To enable surface monitor-
ing, immobilization devices such as thermoplastic masks must
be modified to have an opening around the patient’s face,
which may compromise their integrity; however, investigations
are underway to potentially perform radiosurgery with no
immobilization but by constant surface monitoring instead to
detect patient motion.28
6.5 Collimators
In recent years, SRS delivery techniques have expanded beyond
the Gamma Knife, CyberKnife, and linac-based delivery using
circular collimators to include the adaptation of linacs with
multileaf collimators. Although each of these systems offers
unique features, they are all bound by the same principle that a
large number of beam paths are required to concentrate the
dose in the target area and create a steep dose gradient. It is
important to note that as new SRS delivery techniques emerge,
clinicians must examine the impact on dose conformity com-
pared with historical SRS delivery techniques using Gamma
Knife or linac-based delivery with circular collimators. A loss in
dose conformity may force the user to adopt a treatment sched-
ule that deviates from historical radiosurgical data. Although
the use of new equipment may be appropriate in certain clinical
situations, a cautious approach is warranted.
6.6 Cones
Circular collimators, called cones, are used to collimate the pho-
ton beam near the patient and reduce the geometric penumbra,
Radiosurgical Devices
Fig. 6.7 Bite plate with optical array.
and hence the dose to normal tissue, outside of the target. The
dose gradient at the margin of the target is similar for Gamma
Knife and linac-based radiosurgery systems employing cones,
with linac cones offering superior penumbra for large cone sizes
as a result of the source geometry.29,30 The lateral dose gradient
for a small cone can be visualized in (▶ Fig. 6.8), where the lat-
eral falloff for a trigeminal neuralgia treatment is plotted for
both Gamma Knife and linac-based plans with circular cones
and a varying numbers of treatment arcs.31 In general, cone-
based radiosurgery with a non-coplanar arc set should yield a
3D dose distribution with a penumbra (80–20%) in the range of
2 to 3 mm.
Although a very sharp dose gradient can be achieved with
a circular cone, some targets do not conform well to the
resultant spherical dose distribution and require multi-iso-
center plans to improve conformity. The use of multiple iso-
centers increases the degrees of freedom for developing a
treatment plan and allows the planner to customize not only
the shape, but also the dose gradient in directions near crit-
ical structures. However, with additional isocenters, the
treatment time is also increased, amplifying concerns regard-
ing immobilization for frameless patients and comfort for
frame-based patients. For these reasons, the use of a multi-
leaf collimator (MLC) for irregularly shaped lesions has been
gaining traction.
6.7 Multileaf Collimator
Compared with cones, a MLC offers the advantage of conform-
ing to the shape of the target in the beam’s eye view rather than
being limited to only circular shapes. Traditional MLCs are
designed with ~ 40 to 50 cm of distance between the isocenter
and the collimator to allow clearance when treating larger parts
of the body but at the cost of a larger geometric penumbra,
which is a disadvantage for radiosurgery. To overcome this, sev-
eral manufacturers have created micro-MLCs, which are add-on
devices that attach to the accessory tray of the linac.32,33 Micro-
MLCs utilize leaves with widths of 2 to 3 mm projected to the
49
 Radiosurgical Devices
isocenter, compared with 5 mm at isocenter for standard MLCs.
The difference in penumbra (80–20%) for the Brainlab m3
micro-MLC compared with a standard Varian 120 leaf MLC was
demonstrated to be about 1 mm (2.5 mm compared with
3.5 mm).33
Although the MLC allows complex target shapes to be treated
with a single isocenter, several other potential issues surface in
their implementation. One issue is the ability to accurately
position the leaves. With a cone, the field size is fixed and can
be precisely machined to an extremely high tolerance. When
creating a shape with an MLC, one must rely on the accuracy of
leaf positioning, which in general is held to a tolerance of 1 mm
projected to the isocenter.17 When treating a 10-mm-diameter
lesion, a 1-mm discrepancy in leaf position results in a substan-
tial portion of the target area that could potentially be under-
dosed or normal tissue that could potentially be overdosed.
Additionally, the output factor for small fields is highly depend-
ent on field size and errors in dose computation could quickly
grow if the field size is 10 to 20% different than planned. When
an MLC is used to treat multiple targets from a single isocenter,
collimator rotational accuracy also becomes an important factor
in accurately aligning the radiation beam with the target coordi-
nate. Finally, due to the undulated shaping caused by the finite
width of each leaf, MLCs may not be suitable for target sizes less
than ~ 1 cm.
Comparing cones with MLCs, one can draw the conclusion
that small and spherical targets are likely best treated with
cone-based radiosurgery, whereas MLCs are best utilized when
treating large, irregularly shaped targets. When properly com-
missioned for clinical use, both of these devices can effectively
aid the neurosurgeon and radiation oncologist in developing
quality treatment plans.
6.8 Conclusions
Advances in technology are responsible for an array of radio-
surgical devices commercially available for performing
radiosurgery. By evaluating this equipment with the major
50
Fig. 6.8 Lateral dose falloff from Gamma Knife
and linac radiosurgery systems for a left-sided
trigeminal neuralgia treatment. Linac plans were
developed with a number of different arc sets
and Gamma Knife plans were developed with and
without some sources plugged to improve
brainstem sparing.31 (Used with permission from
IOP Publishing Ltd.)
underlying principles of radiosurgery in mind—immobiliza-
tion, localization, and dose gradients—clinicians can effec-
tively select equipment that meets the needs of their clinical
practices. When a new system is brought into the clinic, a
qualified physicist should perform an end-to-end test to
understand the strengths and weaknesses of the proposed
technique. Pretreatment tests validating all system align-
ments should also be conducted as part of any radiosurgery
program.
References
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42 Report on Stereotactic External Beam Irradiation. Report of the American
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[15] Rahimian J, Chen JC, Rao AA, Girvigian MR, Miller MJ, Greathouse HE. Geo-
metrical accuracy of the Novalis stereotactic radiosurgery system for trigemi-
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[29] Plowman PN, Doughty D. Stereotactic radiosurgery, X: clinical isodosimetry
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51
 Critical Structures and Tolerance of the Central Nervous System

7 Critical Structures and Tolerance of the Central Nervous

System
Siavash Jabbari, Lijun Ma, Young K. Lee, Simon S. Lo, Eric L. Chang, Jimm Grimm, Lance Altenau, Daniel White, Vikram Udani, Steven J. Goetsch,
David Larson, and Arjun Sahgal

estimates for both conventionally fractionated radiotherapy

Key Points
● Accumulating clinical evidence and access to volumetrically
accurate dose-calculation tools have allowed evidence-based
critical-structure dose-tolerance estimates for single-session
and single-fraction stereotactic radiosurgery (SRS). New guide-
lines have recently emerged based on dose-volume histogram
analysis (DVH) data as outlined in the recent Quantitative Anal-
ysis of Normal Tissue Effects in the Clinic (QUANTEC) report. 2,3,
4,5 In this chapter, we summarize the current knowledge of dose

stereotactic radiosurgery (SRS).
● Evidence supports the current dose limits to selected critical
organs-at-risk in the central nervous system specific to sin-
gle-fraction SRS and for normal brain tissue, brainstem, optic
pathway tissue, auditory apparatus tissue, and spinal cord.
● Options for the treatment of radiation necrosis have im-
proved substantially in the past few years.
7.1 Introduction
The concept and application of partial-volume dose tolerances
was systematically investigated by Emami et al in 1991, 1 and
recommendations emerged specific to conventionally fractio-
nated external beam radiotherapy (1.8 to 2.0 Gy per fraction).
Given the limited evidence available, the dose tolerances rec-
ommended were based mainly on expert opinion and clinical
experience. Furthermore, given that three-dimensional (3D)
treatment planning and volumetric dose-calculation tools were
not available at the time, the Emami dose-volume estimates
were limited to crude estimates of the volume effect by stipu-
lating dose limits to a 1/3 versus 2/3 versus full organ
irradiation.
In the following decades, accumulating clinical evidence and
access to volumetrically accurate dose-calculation tools have
allowed evidence-based critical-structure dose-tolerance
limits to selected critical organs-at-risk (OARs) in the central
nervous system (CNS) as they pertain to single-fraction SRS.
Dose limits for conventional fractionated radiation will only be
briefly discussed where applicable.
7.2 Dose Tolerances of CNS
Structures
7.2.1 Brain
Brain injury induced by SRS has traditionally been categorized
as “acute,” referring most commonly to reversible treatment-
induced edema occurring during or soon after completion of
therapy. “Early delayed” or “subacute” refers most commonly to
reversible treatment-induced edema occurring up to 12 weeks
after treatment. “Late” refers most commonly to radiation
necrosis (▶ Fig. 7.1), which is considered a potentially reversible
focal or diffuse process within the radiated target volume that
can develop several months to years postirradiation.6
The dose-limiting phase 1 study that guides mainstream SRS
prescription practice was conducted by the Radiation Therapy
Oncology Group (RTOG) and published in 2000. 7 These dose
limits were based on the incidence of irreversible grade 3
(severe) or any grade 4 (life-threatening) or grade 5 (fatal) RTOG
CNS toxicity. In total, acute and chronic grade 3 CNS toxicities

Fig. 7.1 a-e A 48-year-old man with a cerebellar metastases secondary to lung cancer was treated with stereotactic radiosurgery (SRS) to 18 Gy in a
single fraction. The series of axial T1 postgadolinium magnetic resonance images from left to right represent (a) the baseline image followed by
images taken every 2 months thereafter. After what looked like an excellent response, the lesion became more variegated, enhancing, and grossly
enlarged by 6 months. The last image (e) taken at 8 months post-SRS show signs and symptoms of ataxia. The patient underwent surgery, and the
surgical pathology confirmed radiation necrosis.

52
 Critical Structures and Tolerance of the Central Nervous System
(irreversible edema requiring admission for intravenous [IV]
steroids) were observed in 10% of patients, grade 4 toxicity
(radionecrosis requiring reoperations) in 10%, and grade 5 CNS
toxicity (fatality were reported) in 3%. Specific to the recom-
mended dose limits, the incidence of grade 3 to 5 acute and
chronic CNS toxicity was 10% with the recommended 24 Gy
dose for tumors ≤ 2 cm, 20% with the recommended 18 Gy dose
for tumors 2.1 to 3 cm, and 14% for tumors > 3 cm in size treated
to the recommended 15 Gy dose. Multivariate analysis demon-
strated that maximum tumor diameter and higher dose were
associated with a significantly increased risk of grade 3, 4, or 5
neurotoxicity. For tumors up to 3 cm in diameter, these doses
have been used for years with toxicity profiles that are much
lower than those in the Shaw et al study,11 and they remain the
standard protocol for SRS. For tumors > 3 cm, treatment with
single fraction SRS can at times yield serious complications, and
data are more limited. A series from Han et al reported on sin-
gle fraction SRS for large tumors (> 14 cm3) only.8,9 The mini-
mum and maximum diameters and volumes were 3 and 5.7 cm
and 14.1 and 49.6 cm3, respectively. They based the prescription
dose according to volume, with 15 to 16 Gy for tumors 14 to
25 cm3, 12 to 14 Gy for tumors 26 to 35 cm3, and 10 to 11 Gy for
tumors > 36 cm3. Fifteen of 80 patients (18.8%) developed unac-
ceptable CNS toxicities, RTOG CNS grade 3 to 5 (died from cere-
bral edema).8 This underscores the care required when
selecting patients with large brain metastases for SRS, and why
fractionated SRS is emerging as a mainstream therapy for larger
tumors.
Beyond the prescribed dose and tumor diameter, several ret-
rospective studies have been reported evaluating DVH-based
predictors of radiation necrosis.3,10,11,12 Importantly, one should
note that there is significant heterogeneity in the literature
with respect to the definition of radiation necrosis (radio-
graphic necrosis vs. symptomatic radionecrosis), the indications
treated (arteriovenous malformations, brain metastases, etc.),
and the SRS technique that confounds the generalizability of
these studies. Nevertheless, one consistent parameter found to
be predictive has been the volume of nontarget brain tissue
exposed to 10 or 12 Gy in a single fraction (V10, V12). 2,3,13,14
The data support keeping the V12 no greater than 5 to 15 cc
depending on location and eloquence of tissue irradiated
(brainstem, thalamus, and basal ganglia are considered higher
risk regions of the brain for necrosis). The QUANTEC guidelines
also note a rapid increase in toxicity when the volume of nor-
mal brain tissue exposed to > 12 Gy exceeds 5 to 10 cc, and they
caution more stringent limits for eloquent regions.3 Treatment
of radiation necrosis will be discussed at the end of the chapter.
Analogous dose-volume metrics predictive of radionecrosis
are as yet to be determined in the setting of hypofractionated
SRS, which refers to delivery of SRS over two to five fractions.
This practice is emerging in particular for larger tumors, as
radiobiologically by fractionating the dose we can still dose
escalate as opposed to dose de-escalate with single-fraction
SRS, as the tumor size increases. This is due to the protective
effects afforded by fractionation on the normal brain tissue.
One retrospective review of 5-fraction hypofractionated SRS
identified the volume of normal brain tissue exposed to 28.8 Gy
(single-fraction equivalent of 14 Gy, assuming α/β = 2 Gy for the
normal brain) as predictive of radiation necrosis, and that vol-
ume should be restricted to no more than 7 cc. This was based
on 2 of the 78 patients (2%) developing radiation necrosis
requiring surgical intervention.15 At this time, we do not have
sufficient data to make any firm DVH-based recommendations
for hypofractionated SRS, but data are emerging.
The DVH metrics to predict other well-known acute effects
(nausea, vomiting, headaches, seizures, tumor-related edema,
and mass effect symptoms) have not been established. Simi-
larly, neurocognitive toxicity in the form of memory decline has
been reported following SRS, whole-brain radiotherapy (WBRT)
plus SRS, and WBRT alone; however, the mechanism following
SRS alone is poorly understood, as the integral brain dose for a
limited number of lesions is typically subclinical as compared
with WBRT.
With respect to life-threatening acute toxicity, it is accepted
that complications can occur if the whole brain is exposed to
10 Gy in a single fraction, whereas more modest dose-fractiona-
tion regiments (4 Gy × 5, 3 Gy × 10) have been found to be
acceptable and therapeutically equivalent per randomized tri-
als.16,17 For conventionally fractionated partial brain radiother-
apy, dose limits of 60 to 72 Gy (if indicated) are acceptable per
the QUANTEC review.17
7.2.2 Brainstem
Brainstem radiation injury can be a life-threatening complica-
tion following SRS. Often, necrosis of the brainstem tissue man-
ifests clinically as focal motor, sensory, or cranial nerve deficits,
general neurological demise, and can cause death, especially if
the necrosis occurs in the medulla oblongata. Specific to single-
fraction SRS, QUANTEC recommends a maximal point dose of
12.5 Gy as safe with respect to limiting the risk of toxicity to <
5%.2,4,18,19 A recent review of the University of California San
Francisco (UCSF) experience of brainstem metastases treated
with SRS was reported by Kased et al. Forty-two patients with
brainstem metastases were treated to median dose of 16 Gy,
and the median target volume was 0.26 cc. Four of 42 patients
developed brainstem complications post-SRS.19 All four lesions
associated with complications were over 1 cc in volume, yield-
ing a freedom from complication probability of 100% for tumor
volumes < 1 cc vs. 40% for tumor volumes ≥ 1 cc at 6 months,
and 100% vs. 0%, respectively, at 1 year (p < 0.001). There was no
relationship between the risk of brainstem complications and
the prescribed dose. In addition to larger volume, multivariate
analysis suggested significantly greater complication risks with
melanoma or renal cell histology. Our current practice is 15 Gy
in a single fraction for brainstem metastases < 2 cm, with the
risk of complication weighed against tumor control.
There are clinical data that support higher doses to the edge
of the brainstem from the trigeminal neuralgia literature. 20
Dose exposure has ranged from 20 Gy to even as high as 45 Gy
in a single fraction to a very small volume of the brainstem.21
The location of exposure being on the edge of the brainstem
surface may be the factor that explains the rare incidence of
toxicity reported in SRS for trigeminal neuralgia.20 Ultimately,
typical practice is to limit the brainstem maximum point dose
to 12 to 15 Gy.10,11,14
With respect to conventionally fractionated radiotherapy, the
dose tolerance for < 5% risk of toxicity ranges between 54 to
59 Gy according to QUANTEC guidelines, depending on if a par-
tial or the complete brainstem volume is irradiated. 4
53
 Critical Structures and Tolerance of the Central Nervous System
7.2.3 Optic Pathway
Most studies and patterns of clinical practice suggest that the
maximum point dose should be 8 Gy in a single fraction to the
optic nerves and chiasm. The fear of causing blindness has
propagated this conservative threshold. QUANTEC recently rec-
ommended a maximum dose of 10 to 12 Gy to the optic nerves
and chiasm as yielding an acceptable risk of optic tissue injury,
especially in patients with limited therapeutic options and/or
prognosis.4,22,23,24
The most extensive DVH-based toxicity analysis to the optic
chiasm was reported by the Mayo Clinic. Stafford et al reported
on 215 patients (218 treatments) treated with single-fraction
SRS, and the median optic nerve point maximum dose was
10 Gy. Within this cohort, 66% had prior surgery or irradiation;
radiation-induced optic neuropathy (RON) occurred in less than
2% of cases treated with 12 Gy or less.23
The QUANTEC review of the literature specific to convention-
ally fractionated radiation supports a maximum dose limit of
54 to 55 Gy as associated with a low risk (< 2%) of RON, particu-
larly when fraction size is kept below 2 Gy.4 This is also specific
to conventional fractionation proton-based therapy. Notably,
fraction size appears to be critical in the risk of late radiation
injury to the optic apparatus, and fraction sizes of > 1.9 Gy per
day may be associated with higher rates of toxicity in the 60 to
70 Gy dose range.4,25 Importantly, patient-specific variables
have been reported to increase the risk of radiation-related
injury to the optic apparatus. For example, patients with pitui-
tary neoplasms may have an increased sensitivity to visual
pathway injury based on conventional dose-fractionation liter-
ature,26 and a dose limit of 46 to 48 Gy at 1.8 Gy per day has
been recommended by some investigators. Generally, greater
caution should be taken for patients with significant comorbid-
ities such as advanced age and diabetes mellitus, as some
reports have suggested a factor contributing to an increased
risk of radiation-induced visual injury,4,25 although this rela-
tionship requires further study and validation. Similar factors
have not been elucidated in the SRS literature.
7.2.4 Auditory Apparatus
The cochlea is generally regarded to be the relevant OAR with
respect to hearing toxicity (sensorineural hearing loss [SNHL])
following SRS. The majority of the literature arises from the SRS
vestibular schwannoma literature. This is explained by the
inherent proximity of the cochlea to the tumor, and routine
hearing assessments in these patients. However, due to the sig-
nificant heterogeneity in terms of OAR definition (cochlea vs.
volume/length of acoustic nerve vs. both), tumor size, and
tumor location (intracanalicular vs. extracanalicular), a wide
range of dose tolerances for this end point have been reported.
In a summary of the literature, we and the QUANTEC authors
conclude that lower doses to the cochlea are likely associated
with lower risk of SNHL, and marginal cochlear doses of 12 to
14 Gy are associated with an acceptable risk for this end point
and clinical setting.27,28
A large series of vestibular schwannoma patients treated
with SRS was reported by Kondziolka et al. Their series con-
sisted of 162 patients, and the mean target dose was 16 Gy.
Although cochlear dose was not reported, the authors
54
concluded that there was no change in hearing grade in 51% of
patients treated, and 61% maintained useful hearing post-SRS. 27
A small study of 15 patients with long-term assessments noted
improved sensorineural hearing preservation rates of 73% ver-
sus 20% when the marginal tumor doses were ≤ 14 Gy.29 The
relationship between the single fractional mean dose tolerance
and the marginal (maximum) dose tolerance of the cochlea,
and the relative predictive value of each, is unknown. For exam-
ple, Brown et al30 have determined a dose tolerance of 5 to 6 Gy
for the cochlea (volumetric dose), whereas other investigators
have found mean cochlear doses in the range of 3 to 4 Gy to be
predictive for hearing loss in single fraction radiosurgery. 31,32
Interestingly, Paek et el reported that patients receiving mean
brainstem cochlear nucleus doses of 6.9 Gy had improved hear-
ing outcomes as compared with those receiving 11.1 Gy. In this
study, the cochlear nucleus dose was a more predictive factor
for SHNL loss than the cochlear dose.33 At this time, there is
conflicting evidence as to the most predictive structure for
SNHL post–single-fraction SRS, and specific dose-tolerance lim-
its, but a marginal or maximum dose of < 12 to 14 Gy to the
cochlea is a reasonable objective, and if possible, a mean dose
of < 4 to 6 Gy may be optimal.
For hypofractionated treatments, one study reported a signif-
icant risk of hearing loss when the cochlea receive a dose of
8 Gy in three sessions (a single fractional dose equivalence of
5.4 Gy assuming α/β = 3 Gy for the cochlea).34 Such a dose is in
agreement with the mean single fractional cochlea dose toler-
ance of 5 to 6 Gy as reported by Brown et al.30 It is significantly
lower than the conventional mean dose tolerance of 35 to 45 Gy
(as discussed below).
The mean dose tolerance of the cochlea to conventional radi-
ation has been estimated as < 35 to 45 Gy with varying risk and
severity of SNHL as the end point.28
7.2.5 Spinal Cord
Radiation myelopathy is a rare and feared complication follow-
ing both conventionally fractionated radiation and SRS. Patients
typically develop focal motor and/or sensory deficits, bowel and
bladder deficits, and pain.35 With lateralized high-dose radia-
tion, a Brown-Séquard syndrome may develop and is character-
istic. Myokymia is one of the electromyographic (EMG) findings
that can prove radiation as the etiology. Characteristic mag-
netic resonance imaging (MRI) findings include intramedullary
T2 signal change at the treated level and focal gadolinium en-
hancement. The time course of symptom onset (typically
occurring 6 months to 3 years posttherapy) is variable and
shorter times to complication have been observed with SRS
versus conventional radiotherapy-induced radiation myelop-
athy. At this time, there are no human data to confirm varia-
bility in the sensitivity of cervical versus thoracic versus
lumbar spinal levels to radiation injury. However, the cauda
equina is generally more tolerant to radiation than the cord
itself. Prior irradiation clearly increases the risk of myelopathy,
and cumulative dose limits to the cord have been suggested.
However, the modeling of time-dependent repair between
courses is not known with enough certainty to make
recommendations.
Sahgal et al meticulously documented known radiation myel-
opathy cases following stereotactic single-fraction SRS and
 Critical Structures and Tolerance of the Central Nervous System

hypofractionated SRS. In addition, analyses were done in both limiting the spinal cord dose to ≤ 135.5 Gy cumulative biologi-
unirradiated36 and previously irradiated37 patients. The most cally effective dose, with each course limited to 98 Gy or less as
recent multi-institutional DVH-based analysis comprised nine the biological effective dose.38
known cases of radiation myelopathy in patients with no his-
tory of prior radiation, and the DVH data were compared with a
multi-institutional cohort of 66 previously unirradiated spine 7.3 Treatment of Cerebral
SRS patients. A logistical regression risk model36 was developed
and recommended maximal point doses to the thecal sac were Radiation Necrosis
reported—these are summarized in ▶ Table 7.1. Given a single
Steroid therapy, typically using dexamethasone, has been the
fraction, the authors recommended no more than 12.4 Gy as a
traditional mainstay treatment for symptomatic cerebral radia-
point maximum dose to the thecal sac or cord planning organ-
tion necrosis. Other agents include hyperbaric oxygen therapy,
at-risk volume (typically a 1.5-mm expansion on the true cord
pentoxifylline, antiplatelet medications, and anticoagulant
itself).
therapies. These treatments have shown limited efficacy in this
The separate reirradiation study consisted of 19 previously
setting. Surgical resection can be considered for severely
irradiated patients who were retreated with spine SRS, and
symptomatic patients refractory to steroid treatments. The
DVH data compared with five cases of reirradiation SRS-
humanized monoclonal anti-VEGF (vascular endothelial
induced radiation myelopathy.37 This study yielded dose limits
growth factor) antibody bevacizumab has demonstrated effi-
based on the amount of prior conventional radiation and
cacy in the treatment of symptomatic radiation necrosis. In a
recommended at least a 5- to 6-month interval between prior
retrospective review of 24 patients, 23 patients demonstrated
conventional radiation and retreatment spine SRS. The recom-
clinical and radiographic improvement with this therapy, and
mendations are summarized in ▶ Table 7.2.
an average dexamethasone dose reduction of 9.4 mg was
In the setting of no prior irradiation and conventional fractio-
achieved.39 Only one patient was reported to have an adverse
nated radiation to the full circumference of the spinal cord,
grade 3 toxicity secondary to the bevacizumab (pulmonary
doses below 50 Gy appears to be associated with a very low
embolism). A small randomized trial from the MD Anderson
(< 1%) risk of radiation-induced myelopathy. A total dose of
Cancer Center (Houston, TX) was reported. Fourteen patients
60 Gy in this setting seems to be associated with a ~ 5% risk of
were randomized to placebo versus bevacizumab and those
myelopathy; dose escalation to ~ 69 Gy precipitously increases
in the bevacizumab arm had significant clinical and radiolog-
this risk to ~ 50%.5 The risk of myelopathy with conventional
ical improvements, although with higher rates of adverse
reirradiation is not well established. Based on a literature
effects.40 The use of bevacizumab needs further study before
search that identified eight reports of reirradiation myelopathy
recommendations can be made, as its underlying effect on
and 40 individual patients as control, Nieder et al recom-
the process of radiation necrosis as opposed to the edema
mended “with due caution” a time interval of at least 6 months
alone is unknown.
(ideally more than 12–24 months) between courses, and
There is some interesting recent evidence utilizing diffusion
tensor imaging that has suggested variation in brainstem fiber
radiation sensitivity to injury with conventional irradiation. 41 It
Table 7.1 Spine SRS thecal sac maximum point volume doses for pa-
is likely that with advancing functional and fiber tract–based
tients with no prior radiation exposure36
imaging, further dose-tolerance optimization and refinement
1 Fraction 2 Fractions 3 Fractions 4 Fractions 5 Fractions can be achieved based on CNS structure subunits and individu-
12.4 Gy 17.0 Gy 20.3 Gy 23.0 Gy 25.3 Gy alized patient anatomy/physiology.41 The study and under-
standing of radiation injury and risk of radiation necrosis/
myelopathy is under rapid evolution and expansion, as at this
point little is known to guide clinical decision making and risk
Table 7.2 Spine SRS thecal sac maximum point volume doses for pa- prediction.
tients with prior radiation exposure (minimum time interval between
courses of 5 months)37
Prior conventional radiotherapy dose 1 Fraction 7.4 Summary
20 Gy in 5 fractions 9 Gy Based on the above literature review and citations, a reasonable
summary of OAR dose-tolerance parameters for intracranial
30 Gy in 10 fractions 9 Gy
single-fraction radiosurgery is provided in ▶ Table 7.3. We will
37.5 Gy in 15 fractions 9 Gy continue to gain a greater appreciation of the true dose toler-
ance to the critical organs-at-risk as the field progresses, and
40 Gy in 20 fractions *
what is needed are shared databases with dosimetric data and
45 Gy in 25 fractions * actuarial outcomes to understand the actuarial incidence of
50 Gy in 5 fractions * these toxicities. We suspect that risks are lower than expected
due to modern radiation treatment–planning systems allowing
Insufficient data with single-fraction SRS to make recommendations for accurate dose calculations and greater precision in planning
given these prior radiation doses. Refer to the original publication for
and delivery technology. This may translate to favorable tumor
detailed fractionated (2 to 5 fraction) SRS spinal cord dose limits and the
control to toxicity profiles, particularly for tumors adjacent to
rules that govern these limit.
critical organs at risk.

55
 Critical Structures and Tolerance of the Central Nervous System

Table 7.3 Reasonable organ-at-risk (OAR) dose-tolerance parameters for intracranial single fraction SRS
OAR Volume parameter Dose Clinical end point Note

Brain 5–10 cc 12 Gy Radionecrosis Tolerance and clinical sensitivity dependent on

location and eloquence

Brainstem Dmax 12.5 Gy Brainstem radionecrosis For brainstem metastasis, 15 Gy to lesions < 2 cm in
volume is practiced

Optic pathway Dmax 10–12 Gy Radiation-induced visual injury Refers to optic nerve and chiasm

Cochlea Marginal (Dmax) dose 12–14 Gy Sensorineural hearing loss Cochlear nucleus may also be important but further
Mean dose data required
< 4–6 Gy

Abbreviation: Dmax = maximum point dose to structure.

[17] Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the treat-
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57
 The Neuropathology of Radiosurgery
8 The Neuropathology of Radiosurgery
György Szeifert, Douglas Kondziolka, Marc Levivier, José Lorenzoni, and L. Dade Lunsford
Key Points
● Three main histological types of gamma radiolesions that are
acute, subacute, and chronic variants of tissue reactions have
been recognized in different neoplasms irrespective of their
ontogenetic nature.
● No significant relation has been found between the morpho-
logical characteristics of the evoked histological reaction and
the time interval elapsed after stereotactic radiosurgery. This
relative time and environment autonomy of the developed
pathological lesions with a similar histological picture in
different neoplasms suggests a vascular mechanism and/or a
genetically directed origin presumably induced by the
ionizing energy of high-dose photon irradiation.
● Endothelial damage of the vessel wall appears to be among
the earliest morphological changes following irradiation
accompanied by an increased apoptotic activity in the
surrounding brain tissue.
● These pathophysiological processes might contribute to
stromal vessel occlusion followed by necrosis of tumor
parenchyma, and could boost cellular death evoked by the
radiation effect of stereotactic radiosurgery.
8.1 Introduction
In our study to explore short- and long-term tissue reactions
evoked by single high-dose irradiation in different human brain
tumors and experimental animals following Gamma Knife
radiosurgery, histopathological investigations demonstrated
that Gamma Knife radiosurgery generates degenerative and
proliferative tissue reactions in the parenchyma, stroma, and
vessels of the irradiated target volumes. Three main histological
types of gamma radiolesions—acute, subacute, and chronic var-
iants of tissue reactions—were recognized in different neo-
plasms irrespective of their oncogenetic nature. There was no
significant relation between morphological characteristics of
the evoked histological reaction and the time interval elapsed
after Gamma Knife surgery. The relatively equivalent temporal
and histological development of the pathological lesions
regardless of the brain location or the tumor cell of origin sug-
gests a vascular mechanism and/or a genetically mediated res-
ponse resulting from high-dose photon-ionizing energy.
Experimental studies indicate that endothelial damage of blood
vessel walls appears to be among the earliest morphological
changes; this is accompanied by an increased apoptotic activity
in the surrounding brain tissue. These pathophysiological proc-
esses might contribute to stromal vessel occlusion followed by
cell death of tumor parenchyma. The vascular effect then boosts
the cellular death evoked by stereotactic radiosurgery (SRS).
8.2 Background
In 1958, Larsson et al published in Nature the results of animal
experiments that indicated “with high-energy protons a
58
sharply delimited lesion can be made at any desired site in the
central nervous system.”1 The basic histopathological lesion
(▶ Fig. 8.1) created by high-energy ionizing radiation in neural
tissue is a coagulation necrosis within the target volume, sur-
rounded by a distinct boundary between the necrosis and adja-
cent normal structures, according to the sharp radiation falloff.2
Whereas target necrosis was the goal with maximum doses
above 100 Gy, almost all human tumors are irradiated at lower,
more cytostatic doses. Early lesions appeared in the spinal cord
following irradiation with doses of 400 and 200 Gy on the third
and ninth day, respectively. They were sharply defined and had
about the same width as the beam. In the cerebral hemispheres,
the earliest alterations were observed 14 days after irradiation
with 200 Gy, and the changes between 2 and 8 weeks were sim-
ilar. A striking feature of these lesions was the paucity of cellu-
lar reaction at the periphery of necrosis: The tissue further
away from the lesion appeared undamaged. However, irradia-
tion with ~ 400 Gy produced a very different lesion. The irradi-
ated hemisphere of the animal was markedly swollen and the
midline structures were displaced. The affected region sur-
rounding the necrosis was at least the size of the necrotic area
itself. Other parts of the brain showed no pathological changes.
These were the early experimental observations after single
high-dose irradiation. This phase of postirradiation reaction
was called the necrotic stage. The next period of postradiosur-
gery changes was the resorption stage. This stage was character-
ized by the resorption of cellular debris, macrophage reaction,
and the beginning of glial scar formation around the lesion.
These changes were observed in goats between 18 and 28
months following high-dose single-session proton irradiation.
The late stage was characterized histologically by prominent
glial scar formation surrounding a cavity.1–5
Radiosurgery, a term first coined by Professor Lars Leksell, has
become a successful treatment modality in the neurosurgical
arsenal over the past four decades.6,7 Since 1967, when the first
patient with a craniopharyngioma was treated in Stockholm with
the prototype Gamma Knife, more than one million patients
worldwide have undergone Gamma Knife radiosurgery using sev-
eral different models. Patients have also been treated with other
radiosurgical technologies such as modified linear accelerators or
charged particle devices. Because the treatment indications and
the number of treated patients have been increasing exponen-
tially, it is important to evaluate the pathological processes that
result from radiosurgery. Such an analysis provides a better
understanding of the radiobiology and the pathophysiological
mechanisms that lead to beneficial therapeutic effects as well as
the undesired side effects of radiosurgery. In addition to further
technical advances in the method of dose delivery, the future of
radiosurgery rests on a better understanding of the biological
basis of radiation, which will enable treatment of new disorders.8
Now that we have amassed a great deal of clinical experience in
radiosurgery, it is time to review the pathological fundamentals
of the effect of single high-dose irradiation.2,9,10
The term radiosurgery refers to the application of ionizing
radiation energy in experimental biology or clinical medicine
for the precise and complete destruction of chosen target

Fig. 8.1 Sharply demarcated experimental gamma radiolesion (i.e., coagulation necrosis) towards surrounding brain tissue in rat brain 6 months after
160 Gy irradiation. (a) Hematoxylin and eosin (H&E), × 100. (b) Masson’s trichrome for fibrin stain, × 100. (c) A complete cavity developed 1 year after
single high-dose irradiation: H&E, × 100.
structures containing either healthy or pathological tissue,
without significant concomitant or late radiation damage to
adjacent tissues.11 Therefore, the goal of radiopathology should
be to study the short- and long-term effects of high-dose
focused irradiation on neural tissue and to examine its patho-
logical effect using histological, tissue culture, and biological–
biochemical methods. Radiopathology includes an analysis
using ultrastructural studies of the tissue, cellular, genetic, and
molecular changes in both the human body and in experimen-
tal animals. In addition, studies using cell lines and other in
vitro experiments aid our understanding of the effects of ioniz-
ing radiation delivered from radiosurgical devices. A better
understanding of radiobiological processes will enhance the
quality of radiosurgery and stimulate the development of new
applications for the benefit of patients in need.
8.3 Materials and Methods
Histopathological investigations were performed on surgically
resected brain tumor specimens from patients who had
The Neuropathology of Radiosurgery
undergone previous Leksell Gamma Knife (LGK) radiosurgery.
These patients had radiological and clinical progression that
warranted removal of the lesion via craniotomy. The tumors
studied included metastases, astrocytomas, meningiomas, ves-
tibular schwannomas, and hemangioblastomas. Radiosurgery
was performed using the LGK model C (Elekta Instruments AB,
Stockholm, Sweden). Dose planning was based on magnetic res-
onance imaging (MRI) and computed tomography (CT). Treated
volumes ranged between 266 and 25.600 mm3 (median:
4.700 mm3). Tumors received 12 to 20 Gy as marginal dose
(median: 16 Gy) at 30 to 60% isodose line (median: 50%), with
24 to 40 Gy maximal dose (median: 32 Gy).
Histopathological investigations were performed on surgical
pathology materials. Resected specimens were fixed in 10%
neutral buffered formaldehyde, processed routinely, and
embedded in paraffin. Besides routine hematoxylin and eosin
and Masson’s trichrome staining, immunohistochemical reac-
tions were carried out for glial fibrillary acidic protein (GFAP),
vimentin, S100, neurofilament, synaptophysin, EMA, pankera-
tin, CK7, CK20, CAM5.2, CD3, CD20, CD31, and CD68 (PGM1)
59
 The Neuropathology of Radiosurgery
Fig. 8.2 Steps of experimental Gamma Knife radiosurgery. (a) The rat stereotactic frame; (b) placement of the Leksell Model G base ring around the
rat; (c) the rat in the focus of the C unit gamma knife using a 4 mm isocenter. (d) A laser is used to mark the target for beam intersection.
antigens to characterize the phenotypic nature of the tumor
cells and the reactive cell population around/or infiltrating neo-
plastic tissues. Ki67 and p53 reactions were used to assess pro-
liferative activity of tumor cells. Biotin–streptavidin–peroxidase
complex methods were performed according to standard proto-
cols on 5-µm paraffin sections.
Rat experimental radiosurgery was carried out according to
standard protocols using a small animal stereotactic radiosur-
gery frame specific for Gamma Knife (▶ Fig. 8.2). Sacrificed ani-
mals were fixed via a perfusion procedure with 10% neutral
buffered formaldehyde. Removed whole-brain basal surfaces
were correlated to isodose curves (▶ Fig. 8.3a,b), then cut for
5-mm slices marking the contralateral, nonirradiated side
(▶ Fig. 8.3c,d), and processed for histology as described above.
8.4 Results
The morphological appearance of various lesions suggestive of
radiation effect in different tumors was not found to correlate
with the histopathological type of the irradiated neoplasm nor
with the time interval between radiosurgery and craniotomy.
The temporal development of radiation responses included
immediate (milliseconds to hours), early (days to weeks), and
delayed (months to years after exposure) effects. However, the
morphological and clinical appearance can be described as
acute, subacute, or chronic types. The acute reaction may
60
develop in an early or delayed manner, but chronic-type tissue
response evolves only in a delayed fashion.12
Histopathological changes attributable to radiosurgery were
observed within the tumor parenchyma, connective tissue stro-
ma, and vessels. These changes were either degenerative or
proliferative. Degenerative alterations occurred mostly in the
parenchyma of different tumors, whereas proliferative proc-
esses were realized first in the connective tissue stroma and the
blood vessels within the neoplasm. The basic histopathological
alteration attributable to the ionizing energy of high-dose radi-
ation was recognized as a well-circumscribed lesion with sharp
demarcation from adjacent tissues that corresponded to the
steep radiation falloff of the delivered dose (▶ Fig. 8.4a–c).
Regarding the histological and cellular composition of these
very high-dose gamma radiosurgical lesions, three main types
were realized. In the acute-type reaction, coagulation necrosis
constituted the center with a network of acidophilic fibrinoid
material and amorphous homogeneous tissue debris
(▶ Fig. 8.4d). No cellular reaction or scanty basophilic hyperchro-
matic apoptotic cells—characterized by nuclear fragmentation
and pyknosis intermingled with scattered polymorphonuclear
leukocytes and some dilated postcapillary venules—surrounded
this necrotic core. There was no prominent macrophage or lym-
phocytic infiltration, reactive gliosis, or scar tissue formation. A
similar histological picture of the acute-type lesion could be
observed either at an early or a delayed time interval after

Fig. 8.3 Pathological processing of irradiated rat brains. (a) The rat brain prior to fixation; (b) marking the lesion site for histology; (c) preparation of
the specimen. (d) Sections are made of the brain to process for histopathology.
radiosurgery. These parenchymal changes were accompanied
with alterations of stromal vessels around the necrotic core
characterized by endothelial destruction, fibrinoid necrosis,
undulation of the internal elastic membrane with vacuolation,
and accumulation of eosinophilic material (transudation) in the
vessel wall.
The second type of gamma radiosurgical lesion was termed
as subacute. These pathological responses were observed sev-
eral months to years after radiosurgery. The main histological
feature of these changes was an inflammatory tissue response.
The central coagulation necrotic core was surrounded by a mac-
rophage rim (▶ Fig. 8.5a). These macrophages revealed phago-
cytotic activity and mainly CD68 (PGM1), but sometimes CD31
immunohistochemical reactivity as well. The necrosis in this
targeted volume was usually circumscribed, homogeneous, and
sharply demarcated from surrounding remaining tumor tissue
as compared with other adjacent tissue changes outside of
the target volume irradiation. These changes included an irreg-
ular multifocal appearance with entrapped tumor islands
(▶ Fig. 8.5b). A granulation tissue zone extended beyond the
macrophage layer and contained abundant small vessels, capil-
laries, arterioles, and venules accompanied by inflammatory
cells, fibrocytes, and fibroblasts expressing vimentin positivity.
Postirradiation vasculopathy was also observed at the
The Neuropathology of Radiosurgery
periphery of the central necrotic region. A reactive gliotic scar
mantle formed by astrocytic elements and abundant glial fila-
ments constituted the outer border of the subacute radiosurgi-
cal response, as confirmed by GFAP immune positivity.
The third, chronic-type or “end-stage” pathological reaction,
was detected several years after radiosurgery. The central part
of the radiolesion was replaced by hypocellular scar tissue with
degenerative changes that included hyaline deposition and/or
focal calcification that was demarcated sharply from the
surrounding tumor tissue (▶ Fig. 8.6a). Scattered fibrocytes,
fibroblasts, and sporadic focal lymphocytic infiltration were
identified surrounding dense collagen bundles (▶ Fig. 8.6b).
Immunohistochemical markers for tumor antigens such as
S100 or neurofilament reactions demonstrated considerable
decrease in these areas. Advanced postirradiation vasculopathy
with subendothelial spindle-shaped cell proliferation and hya-
line degeneration resulted in subtotal or even complete luminal
obliteration of blood vessels within the high-dose volume.
Acute-type histological changes were found at 2 to 17
months (median: 11 months) after radiosurgery. The subacute-
type histological response developed at 4 to 59 months
(median: 16 months) after radiosurgery. The chronic-type tis-
sue response was observed 18 to 82 months (median: 32
months) following radiosurgery.
61
 The Neuropathology of Radiosurgery
Experimental radiosurgical responses in animals demon-
strated endothelial destruction in the irradiated vessel wall
(▶ Fig. 8.7) and enhanced apoptotic activity in the surrounding
brain tissue at an early stage (▶ Fig. 8.8). Late postirradiation
vasculopathy with narrowed channels lumina and even ische-
mic vessel occlusion occurred ~ 1 year after radiosurgery
(▶ Fig. 8.9).
8.5 Discussion
The continuous development of stereotactic radiosurgery tech-
niques and treatment of new disorders warrant further radio-
biological and pathological research to improve therapeutic
interventions and to reduce undesired side effects. The original
intention of radiosurgery was to treat functional disorders,6,7,13
but soon after its introduction arteriovenous malformations
(AVMs)14 and brain tumors15,16 in high-risk surgical regions
became major targets for the method.
62
Fig. 8.4 Acute-type tissue responses following
vestibular schwannoma radiosurgery. (a) Gam-
maPlan treatment planning of the tumor at the
time of radiosurgery. (b) Characteristic magnetic
resonance signal changes 2.5 months following
irradiation. (c) Sharply demarcated tissue necrosis
at the boundary of the irradiation (hematoxylin
and eosin [H&E], × 200). (d) Necrotic tissue debris
and scattered pyknotic, apoptotic cells in the
center of the irradiated volume, 2.5 months
following radiosurgery (H&E, × 300).
The experimental basis for brain tumor radiosurgery has
been well described and provides evidence for the effectiveness
of high-dose irradiation.17–23 Human pathological case reports
and reviews support the experimental results.24–31 Our purpose
here was to evaluate the effect of radiosurgery on experimental
animals and treated human brain tumors that required delayed
resection. These pathological data include an evaluation of vari-
ous different tumor types and a review of the histology at vari-
ous intervals after irradiation.
In human brain tumors, the morphology of the radiosurgical
lesion appeared to be similar to that found in experimental ani-
mals. Our studies confirmed that ionizing energy from high-
dose irradiation evoked either degenerative or proliferative his-
topathological changes in the investigated brain tumors. Degen-
erative changes including necrosis and apoptosis occurred in
the parenchyma of the tumor and resulted in cell destruction.
In contrast, fibrinoid and calcium deposition generally
appeared in the connective tissue stroma and blood vessel wall.
Proliferative processes such as granulation tissue formation,

Fig. 8.5 (a) Subacute-type tissue reaction. Central necrosis surrounded
by an inflammatory cell reaction consisting of mostly macrophages in a
renal cell carcinoma metastasis 7 months after Gamma Knife radio-
surgery (hematoxylin and eosin [H&E], × 300). (b) Irregular tumor
necrosis outside of the irradiated target volume (H&E, × 200).
inflammation, macrophage invasion, fibrocyte–fibroblast pro-
liferation, and scar tissue production were found in the stroma
and vasculature of tumors. Such changes appear to provide a
scavenger function that facilitates the replacement of the
destroyed neoplastic tissue (necrotic debris) with scar tissue.
Scar tissue itself consists of hyaline degenerated collagen bun-
dles and glial fibrils that have a certain propensity for contrac-
tion. This contraction of scar tissue might play a role in the
volumetric regression of the tumor as noted frequently on fol-
low-up imaging studies.
Three main histopathological responses of radiosurgery were
delineated. Acute-type gamma responses were characterized by
tissue necrotic changes that developed either early or at a
delayed time interval. Subacute-type responses demonstrated
resorptive activity either early or in a delayed manner. Chronic
responses showed evidence of attempted tissue repair, but only
at the delayed stage. These changes seem to progress consecu-
tively over time without any significant relationship between
tumor histological type or time interval after irradiation. The
only consistent observation was that chronic-type lesions were
The Neuropathology of Radiosurgery
Fig. 8.6 (a) Chronic-type infiltration with prominent lymphocytic
component in a metastatic tumor 12 months following radiosurgery
(hematoxylin and eosin [H&E], × 200). (b) End-stage lesion consisting
of hypocellular scar tissue with hyaline degeneration and dystrophic
calcification sharply demarcated towards brain tissue in a metastatic cc
15 months after radiosurgery (H&E, × 100).
noted in a delayed fashion and indicate that these changes are
end stage.
Radiosurgery destroys or inactivates the targeted neoplastic
cell proliferation either by a dose-related direct, early cytotoxic
effect (coagulation necrosis, apoptosis) or by late vascular ische-
mic changes. It has been suggested that the radiobiological
mechanism of radiosurgery on benign tumors is a combination
of both cytotoxic and vascular effects.32 The direct cellular influ-
ence may be the consequence of lysosomal membrane injury
releasing various hydrolytic enzymes with the cytoplasm,
which begins a cascade of events resulting in cellular necrosis.
In addition, indirect DNA damage leading to strand breaks
caused by the high dose of radiation delivered to the target vol-
ume by the intersection of the converging photon beams. This
high dose to a small target volume leads to cell death at the
start of the next cell cycle (apoptosis, i.e., programmed cell
death). It is for this reason that rapidly proliferating tumors
with high cellular mitotic rates, such as metastases or
63
 The Neuropathology of Radiosurgery
Fig. 8.7 Destruction of endothelial cell layer 2 months after 15 Gy irradiation (Factor-VIII immune reaction, × 200).
Fig. 8.8 Enhanced apoptotic activity in the brain tissue 2 months after 15 Gy irradiation (Caspase-3 immune reaction, × 200).
malignant gliomas, react earlier to radiosurgery than do slowly
growing benign tumors with lower proliferation rates. Nonneo-
plastic lesions that are not proliferating, such as AVMs, react
with an even more prolonged latency period. Late vascular
effects of radiosurgery likely are mediated by the progressive
vascular reaction. Radiosurgical doses used in clinical practice
usually do not affect normal high-flow brain vessels.33 However,
the abnormal pathological vessels of tumors or vascular malfor-
mations seems to have a higher sensitivity to the energy of
high-dose photon radiation delivered by radiosurgery. The dis-
crepancy in this vascular response provides a pathophysiologi-
cal basis for selective radiosurgical irradiation in both tumors
and nonneoplastic brain targets such as AVMs.34,35
To date, most histopathological studies evaluated morpholog-
ical changes in cerebral tumors that required delayed resection
after radiosurgery. However, both postoperative and or delayed
autopsy studies are relatively rare because of the high clinical
64
response rate of radiosurgery. Previous publications described
effects such as decreased tumor cell population, increased
fibrous stroma, central necrosis, macrophage rim development,
lymphocytic infiltration, vascular changes, and reactive astrocy-
tosis.25,26,36,37 Jagannathan et al concluded that radiation
necrosis and tumor radiation resistance were the most common
causes precipitating a need for surgical resection after radiosur-
gery in patients with brain metastasis.38 They have found that
survival of patients with viable tumors was significantly lower
than survivals in patients in whom only necrosis was seen.
Kano et al reported that a shorter interval from stereotactic
radiosurgery to resection was associated with a higher rate of
tumor recurrence.39 If a resection was necessary within two
months after radiosurgery, the pathology always showed viable
tumor.40
Histopathological and immunohistochemical investigations
suggest that radiosurgery evokes necrotic changes in brain

Fig. 8.9 Narrowed vessel lumina and ischemic stroke in the frontal lobe 1 year after 70 Gy irradiation (hematoxylin and eosin, × 100).
metastases and their vascular stroma accompanied by a ster-
ile inflammatory reaction.41 Three histological types of tissue
responses were observed in metastases as well. The tissue
responses disclosed a certain temporal development, but did
not have a significant correlation with the histological origin
of the tumors. The inflammatory reaction had a prominent
role in the local tumor control process. Tumors that required
craniotomy for recurrent disease in < 5 months after radiosur-
gery were found to have minimal-to-no inflammatory reac-
tions. Neoplasms that required resection > 5 months after
irradiation demonstrated a moderate-to-intense inflamma-
tory response. Immunohistochemistry revealed a predomi-
nance of CD68-positive macrophages in the subacute-type
lesions and CD3-positive T lymphocytes in the chronic-type
tissue reactions. The sparse inflammatory reactivity in less
responsive metastatic neoplasms (those requiring cranioto-
my < 5 months) raises the question of either an inherent
delay in the response of these tumors to radiosurgery or pos-
sibly an impairment of the immune system in these patients.
The pathophysiological mechanism by which radiosurgery
evokes an inflammatory response in brain metastases may
originate from the treated tumor cells or the vascular endo-
thelium. For example, ionizing radiation may damage the
blood–tumor barrier, permitting cellular elements in the
blood, especially leukocytes, to traverse the vessel wall and
infiltrate the surrounding tumor parenchyma. This theory is
supported by the histopathological observation that many of
these inflammatory cell infiltrates appeared to originate and
propagate in perivascular spaces of the tumor and surround-
ing brain tissue. It is also possible that focused irradiation
stimulates the immune system of the brain, similar to what
has been observed in other pathological conditions such as
AVMs after radiosurgery.32,34,35,42 The original concept of
immune privilege of the central nervous system already has
been modified, and a variety of studies have demonstrated
that both afferent and efferent immune pathways are present
in the normal central nervous system. 43
The Neuropathology of Radiosurgery
8.6 Conclusions
From the results of the study described here, we propose a
histopathological classification system for tissue responses
observed in patients who had brain tumors that progressed
after radiosurgery and required subsequent craniotomy. We
observed that single high-dose irradiation evoked three forms
of histological reactions: acute, subacute, and chronic types.
The specimens were composed initially of coagulation necrosis,
usually accompanied by an inflammatory response and vascular
changes followed by scar tissue formation in a variety of cere-
bral neoplasms with different histological subtypes. The time
course of these histopathological reactions suggests that the
response gradually evolves from the acute-type, to the suba-
cute-type, to the chronic-type morphologies. We also wit-
nessed postirradiation vasculopathy to varying extents in the
tumors analyzed. A more favorable tumor response to radiosur-
gery was connected with a brisker CD68-positive and CD3-pos-
itive cellular reactions; however, given the paucity of data
further studies are required.
The similar morphological appearance of radiosurgery effects
in different tumors and different patients suggests that the
evoked histopathological reaction is likely related to the biolog-
ical effect of radiosurgery. We believe that these tissue
responses represent both direct cellular effects and vascular
mechanisms induced by single high-dose irradiation. The acute
effect indicates direct cellular damage influenced by cytokines
released at the time of injury. Subacute and chronic effects
might be mediated by the inflammatory cascade triggered by
the ionizing energy of radiosurgery. Our human pathological
observations are in accordance with the results of genetic and
pharmacological studies that revealed the critical role of both
radiation-induced microvasculature and tumor cell damage,
constituting the fundamental elements of the tumor response
to radiation.44 One goal of radiobiological research in the future
could be to focus on stimulation of these pathways to enhance
efficacy and selectivity of radiosurgery. 45
65
 The Neuropathology of Radiosurgery

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T2 matching to differentiate tumor growth from radiation effects after ster-
[18] Kondziolka D, Lunsford LD, Claassen D, Pandalai S, Maitz AH, Flickinger JC. Ra-
eotactic radiosurgery. Neurosurgery 2010; 66: 486–491, discussion 491–492
diobiology of radiosurgery: Part II. The rat C6 glioma model. Neurosurgery
[40] Kano H, Kondziolka D, Zorro O, Lobato-Polo J, Flickinger JC, Lunsford LD. The
1992; 31: 280–287, discussion 287–288
results of resection after stereotactic radiosurgery for brain metastases. J
[19] Blatt DR, Friedman WA, Bova FJ, Theele DP, Mickle JP. Temporal character-
Neurosurg 2009; 111: 825–831
istics of radiosurgical lesions in an animal model. J Neurosurg 1994; 80:
[41] Szeifert GT, Salmon I, Rorive S, et al. Does gamma knife surgery stimulate cel-
1046–1055
lular immune response to metastatic brain tumors? A histopathological and
[20] Inoue HK, Kohga H, Hirato M, Nakamura M, Ohye C. Neurobiologic effects of
immunohistochemical study. J Neurosurg 2005; 102 (Suppl): 180–184
radiosurgery: histologic, immunohistochemical and electron-microscopic
[42] Szeifert GT, Salmon I, Balèriaux D, Brotchi J, Levivier M. Immunohistochemi-
studies of a rat model. Stereotact Funct Neurosurg 1994; 63: 280–285
cal analysis of a cerebral arteriovenous malformation obliterated by radiosur-
[21] Linskey ME, Martinez AJ, Kondziolka D, et al. The radiobiology of human
gery and presenting with re-bleeding. Case report. Neurol Res 2003; 25:
acoustic schwannoma xenografts after stereotactic radiosurgery evaluated in
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the subrenal capsule of athymic mice. J Neurosurg 1993; 78: 645–653
[43] Wikstrand C, Ashley DM, Bigner DD, Hale LP. Cellular immunology. Lympho-
[22] Niranjan A, Wolfe D, Tamura M, et al. Treatment of rat gliosarcoma brain tu-
cyte populations, cytokines and target-effector systems. In: Bigner D, McLen-
mors by HSV-based multigene therapy combined with radiosurgery. Mol
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Ther 2003; 8: 530–542
Nervous System. 6th ed. Vol. 1. London: Arnold; 1998:231–249
[23] Niranjan A, Moriuchi S, Lunsford LD, et al. Effective treatment of experimental
[44] Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response.
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[24] Szeifert GT, Massager N, DeVriendt D, et al. Observations of intracranial neo-
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(Suppl): 623–626

66
 9 Stereotactic Radiosurgery for
Part III Arteriovenous Malformations 68

Vascular Indications 10 Stereotactic Radiosurgery for

Cavernomas 81

11 Stereotactic Radiosurgery for Dural

Arteriovenous Fistulas 91

III
 Stereotactic Radiosurgery for Arteriovenous Malformations
9 Stereotactic Radiosurgery for Arteriovenous
Malformations
L. Dade Lunsford, Ajay Niranjan, Hideyuki Kano, Edward A. Monaco III, and John C. Flickinger
Key Points
● Radiosurgery is associated with arteriovenous malformation
obliteration rates that average 78% of patients at 3 to 5
years.
● Hemorrhage risks related to a history of prior arteriovenous
malformation hemorrhage and are significantly higher in
patients with associated aneurysms.
● Embolization prior to radiosurgery for intracranial arteriove-
nous malformations worsens eventual obliteration rates, but
is an important part the management of dural arteriovenous
fistulas.
● Adverse radiation effects are related to dose, volume, and
location of the arteriovenous malformation.
9.1 Introduction
Arteriovenous malformations (AVMs) are congenital vascular
anomalies comprised of an abnormal number of blood vessels
that are abnormally constructed. The blood vessels directly
shunt blood from arterial input to the venous system without
an intervening capillary network to dampen pressure. Both
abnormal blood vessel construction and abnormal blood flow
lead to a risk of rupture and intracranial hemorrhage. In addi-
tion, patients with lobar vascular malformations may suffer
from intractable vascular headaches or develop seizure disor-
ders. The annual incidence of AVM recognition is thought to be
approximately 10,000 patients per year in the United States.
However, the increasing reliance on magnetic resonance imag-
ing (MRI) has led to an increasing recognition of these vascular
anomalies even in patients with minimal symptoms. The deci-
sion making relative to management of an AVM must be care-
fully evaluated based on a number of risk factors. The options
for management include observation, endovascular emboliza-
tion alone or in preparation for other adjuvant management,
craniotomy and surgical removal, or stereotactic radiosurgery
(SRS).1 All treatments may be done in one or more stages.
In general, the following factors are evaluated when a patient
is seen with an AVM: The patient’s age, associated medical con-
dition, history of a prior hemorrhagic event, prior management
if any, overall volume and morphology, location of the AVM, ini-
tial presenting symptoms (headache, seizures, local neurologic
deficits), the AVM angio architecture (e.g., compact vs. diffuse
nidus), estimation of its surgical risks, presence of a proximal or
intranidal aneurysm and prior surgical experience in training.
In making a decision for management strategies, we often
employ a decision-tree algorithm as shown in ▶ Fig. 9.1.
Optimal management depends on careful consideration of
the above factors and the estimated risk of subsequent hemor-
rhage. The patient’s clinical presentation and location are
important issues as well as symptoms in each patient. Age, prior
68
bleeding event, smaller AVM size, deep venous drainage, and
high flow rates have been suggested by some as increasing the
potential for subsequent bleeding. For-larger volume AVM
(average diameter 4–5 cm), observation may be the only rea-
sonable strategy in view of the risks of even multimodality ma-
nagement.2 This may be especially true for patients who have
never bled previously. Endovascular embolization using a varie-
ty of particulate, glue, or coil methods may be used as an
adjunct prior to craniotomy and surgical removal.3,4 Endovascu-
lar management has also been used in preparation for SRS,
although its role prior to radiosurgery has declined with the
realization that embolization rarely leads to significant volu-
metric reduction. Although the flow within the AVM may
change after embolization, SRS must include the original vol-
ume. In contrast, before surgical removal, embolization may
provide major benefit, either by reducing flow, or eliminating
deep-seated feeders that would otherwise be a significant pro-
blem during AVM resection. Recanalization of embolized AVM
components over time may require repeat SRS.
Surgical removal is an important option for patients with
lobar vascular malformations of suitable size, especially at cen-
ters of excellence with extensive AVM experience. Incomplete
removal requires adjuvant management, perhaps including
radiosurgery. Spetzler and Martin, among others, defined the
relationship of AVM volume, pattern of venous drainage, and
location within critical areas of the brain as important consider-
ations that help to facilitate outcome prediction at the time of
surgical resection at centers of excellence. Outcomes after AVM
radiosurgery do not correlate with the same predictions of the
Spetzler-Martin (SM) scale when microsurgery is used.5 Out-
comes after radiosurgery may be predicted based on volume,
location, age, angioarchitecture, and dose delivered.6 Stereotac-
tic radiosurgery is an excellent management strategy for
patients with AVMs < 30 mm in average diameter (for a single
procedure). Staged procedures are used for larger vascular mal-
formations or for those that were incompletely obliterated 3
years or more after an initial procedure.
The chief benefit of radiosurgery management is risk reduc-
tion; the chief deficit of radiosurgery is the latency interval that
is required to achieve complete obliteration of the AVM.7,8 The
latency interval is generally 2 to 3 years, but in selected patients
it may be longer. Arteriovenous malformation radiosurgery has
been used for children not suitable for other management strat-
egies as well as for older patients who have significant medical
risk factors for surgical removal.
9.2 The History of Radiosurgery
Radiation to obliterate abnormal blood vessels in the brain is a
procedure that was first considered in the late 1960s. Raymond
Kjellberg, using the Harvard-affiliated proton facility in Cam-
bridge, Massachusetts, advocated proton Bragg peak stereotac-
tic radiation during the 1970s and early 1980s.9,10 More than

Fig. 9.1 Clinical algorithm for choosing management option for patients with intracranial arteriovenous malformations.
1,000 AVM patients were treated, but the dose-planning techni-
que was quite rudimentary. The technology of the Bragg peak
proton facility was designed to provide a low exit dose based on
the radiophysiological characteristics of this technology. The
doses that were actually used in this series of patients were
quite low, and do not correspond to doses that we now know
may be effective in the obliteration of an AVM. Although Kjell-
berg maintained that Bragg peak radiation stabilized AVM
blood vessel walls and reduced the subsequent risk of hemor-
rhage (in comparison with age-related survivals from a life
insurance table), only 20% of patients had complete obliteration
of their AVMs over time. Fabrikant and Steinberg, working at
the Lawrence Livermore Laboratory in Berkley, California,
began to use a helium ion beam to perform multisession AVM
irradiation in the 1980s.11
In Stockholm, Lars Leksell and Ladislau Steiner initiated work
with the first-generation Leksell Gamma Knife unit in Stock-
holm.12 The first patient was treated in March 1970, using the
original prototype 179-cobalt-60 source photon beam unit
designed by Larsson and Leksell. The target definition was
based on biplane angiography done during the procedure itself.
Patients were observed for a period in preparation for a larger
experience that began to emerge in Stockholm using the sec-
ond-generation unit built in 1975.
Stereotactic Radiosurgery for Arteriovenous Malformations
Linear accelerator (linac) technologies have been adapted for
SRS. Betti, working in France and Argentina,13 Barcia-Salorio in
Spain,14,15 and Columbo in Italy,16,17,18 were pioneers in the
application of photon radiation using newer-generation linacs.
In addition, surgeons and radiation oncologists working at the
Joint Center in Boston, Massachusetts,19 and in Gainesville, Flor-
ida,20 used modified linacs to treat a large number of vascular
malformations. Most centers continue to evaluate SRS as part of
an overall management plan, which may include embolization,
microsurgical removal, or radiosurgery alone or in combination.
We will discuss our current viewpoint relative to the role of
embolization subsequently.
9.3 The University of Pittsburgh
Experience
Our first AVM patient was treated in August 1987,21 and we
reported our initial experience with 227 patients in 1991. 22
Confirming the work of others, we noted that the 2-year success
rate in terms of complete obliteration was related to nidus vol-
ume and dose. In high-dose cases (AVM < l cc), obliteration rates
of 100% were noted, which declined to 85% for volumes of 1 to
4 cc and 58% for AVMs larger than 4 cc in volume.
69
 Stereotactic Radiosurgery for Arteriovenous Malformations

Table 9.1 Patient demographics of twenty-year radiosurgery experience Table 9.2 Brain locations and grades of 1,050 arteriovenous malforma-
at the University of Pittsburgh 1987–2010 tions (AVM)

N 1,050 AVM location (N = 906)

Patient age Temporal 17.8%

Median 36 years Frontal 18.4%

Range 3–80 years Parietal 17.6%

Gender Thalamus/basal ganglia 15.3%

Male 546 (52%) Occipital 11.5%

Female 504 (48%) Cerebellar 6.4%

Presenting symptoms Brainstem 6.3%

Hemorrhage 472 (45%) Dural 2.8%

Seizures 233 (22%) Corpus callosal 1.8%

Headache 195 (19%) Intraventricular 1%

Sensory motor deficit 84 (8%) Pineal 1%

Incidental 66 (6%) Spetzler-Martin grade

Prior management Grade I 2.2%

Embolization 210 (20%) Grade II 24.0%

Surgery 73 (7%) Grade III 43.8%

Grade IV 15%

Grade V 3%
Our subsequent 25-year experience in Pittsburgh, Pennsyl-
vania, has now increased to more than 1,400 patients who Grade VI 12%
have undergone Gamma Knife radiosurgery for their AVM
Coexistence of aneurysm 98 (9.3%)
using one or more radiosurgical procedures. We have more
recently analyzed the outcome data of 906 patients who
underwent radiosurgery between 1987 and 2004 (▶ Table 9.1,
▶ Table 9.2, ▶ Table 9.3). Our median patient age was 36 Table 9.3 Radiosurgical parameters of arteriovenous malformations
years (with a range of 3–80). Typical symptoms at presenta- treated at the University of Pittsburgh
tion included hemorrhage (46%), seizures (24%), and head- AVM radiosurgical parameters
ache (18%). Eight percent had neurologic deficits (8%). An
AVM volume
incidental AVM was detected in 4% of patients. Prior manage-
ment strategies included surgical removal or clot evaluation Median 3.4 mL
in 7%. Twenty-one percent underwent one or more interven-
Range 0.065–57.7 mL
tional procedures (embolization). The median target volume
was 3.4 cc (range .065–57.7 cc). The median margin dose was Radiosurgery dose
20 Gy (range 13–32 Gy). A single procedure was performed in Median 20 Gy
865 (95.5%) of patients, and repeat radiosurgery for incom-
Range 13–32 Gy
plete nidus obliteration after 3 years was needed in 113
(12.5%) patients. Prospective volume-staged radiosurgery Radiosurgery
was performed in 41 (4.5%) patients. Single session 1,000/1,050 (95.2%)
At a median follow-up of 3 years, complete nidus obliteration
was achieved in 78% (confirmed by angiography or MRI). In Prospective volume staged 50/1,050 (5.0%)
addition, 21% of patients achieved subtotal obliteration of the Repeat radiosurgery 130/1,050 (12.4%)
nidus. During the follow-up interval, 38 bleeds (4.1%) occurred
after the procedure. Seizure control was improved in 51% of
patients who presented with seizures. Adverse radiation effects
(AREs) resulting in neurological deficits developed in 24 A subset of (n = 217) patients with AVMs who underwent
patients (2.6%), and the detection of new T2 signal increase sur- Gamma Knife surgery at our institution was classified as SM
rounding the AVM target in 108 patients (12%). We noted long- grade I or II.23 The median target volumes was 2.3 cc (range
term complications such as delayed cyst formation or encepha- 0.1–14.1 cc). The median margin dose was 22 Gy (range 15–
lomalacia in 16 patients (1.7%). No patient in this AVM series 27 Gy). Arteriovenous malformation obliteration was confirmed
has developed a radiation-related tumor at the time of this by MRI in 148 patients and by angiography in 100 patients with
writing. a median follow-up of 64 months (range 6–247 months). The

70

actuarial rates of total obliteration determined by angiography
or MRI after one SRS procedure were 58, 87, 90, and 93% at 3, 4,
5, and 10 years, respectively. The median time to complete
MRI-determined obliteration was 30 months. Cumulative rates
of AVM hemorrhage 1, 2, 3, 5, and 10 years after SRS were 3.7,
4.2, 4.2, 5.0, and 6.1%, respectively. This corresponded to rates
of annual bleeding risk of 3.7, 0.3, and 0.2% for years 0–1, 1–5,
and 5–10, respectively, after SRS. The presence of a coexisting
aneurysm proximal to the AVM correlated with a significantly
higher hemorrhage risk. Temporary symptomatic adverse radi-
ation effects developed in five patients (2.3%) after SRS, and
two patients (1%) developed delayed cysts.
We performed SRS in 474 patients with SM grade III AVMs. 24
The AVMs were categorized by scoring the size (S), drainage
(D), and location (L): IIIa was a small AVM (S1D1L1, n = 282); IIIb
was a medium/deep AVM (S2D1L0, n = 44); and IIIc was a me-
dium/eloquent AVM (S2D0L1, n = 148). The median target vol-
ume was 3.8 mL (range 0.1–26.3 mL) and the margin dose was
20 Gy (range 13–25 Gy). Eighty-one patients (17%) underwent
prior embolization, and 58 (12%) underwent prior resection. At
a mean follow-up of 89 months, the total obliteration rates
documented by angiography or MRI for all SM grade III AVMs
increased from 48% at 3 years to 69% at 4 years, 72% at 5 years,
and 77% at 10 years. The SM grade IIIa AVMs were more likely
to obliterate than other subgroups. The cumulative rate of hem-
orrhage was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4%
at 5 years, and 9% at 10 years. The SM grade IIIb AVMs had a sig-
nificantly higher cumulative rate of hemorrhage. Symptomatic
adverse radiation effects were detected in 6%.
At the University of Pittsburgh, 135 children underwent
SRS.25 The median target volume was 2.5 cc (range 0.1–17.5 cc).
The median margin dose was 20 Gy (range 15–25 Gy). The
actuarial rates of total obliteration documented by angiography
or MRI at 71.3 months (range 6–264 months) were 45, 64, 67,
and 72% at 3, 4, 5, and 10 years, respectively. The median time
to complete angiographically documented obliteration was 48.9
months. Of 81 patients with 4 or more years of follow-up, 57
patients (70%) had total obliteration documented by angiogra-
phy. Factors associated with a higher rate of documented AVM
obliteration were smaller AVM target volume, smaller maxi-
mum diameter, and larger margin dose. The rates of AVM hem-
orrhage after SRS were 0, 1.6, 2.4, 5.5, and 10.0% at 1, 2, 3, 5,
and 10 years, respectively. The overall annual hemorrhage rate
was 1.8%. Larger-volume AVMs were associated with a signifi-
cantly higher risk of hemorrhage after SRS. Permanent neuro-
logic deficits due to adverse radiation effects developed in two
patients (1.5%) after SRS; in one patient (0.7%), delayed cyst for-
mation occurred.
Fifty-six patients with basal ganglia AVMs and 77 with thala-
mic underwent SRS.26 Of these 113 (85% of 133 patients) had a
prior hemorrhage. The median target volume was 2.7 cc (range
0.1–20.7 cc), and the median margin dose was 20 Gy (range 15–
25 Gy). Obliteration of the AVM eventually was documented on
MRI in 78 patients and on angiography in 63 patients in a
median follow-up period of 61 months (range 2–265 months).
The actuarial rates documenting total obliteration after radio-
surgery were 57, 70, 72, and 72% at 3, 4, 5, and 10 years, respec-
tively. Factors associated with a higher rate of AVM obliteration
included basal ganglia location, a smaller size, and a higher
margin dose. Fifteen (11%) of 133 patients suffered a
Stereotactic Radiosurgery for Arteriovenous Malformations
hemorrhage during the latency period and seven patients died.
The rate of post-SRS AVM hemorrhage was 4.5, 6.2, 9.0, 11.2,
and 15.4% at 1, 2, 3, 5, and 10 years, respectively. The overall
annual hemorrhage rate was 4.7%. When five patients with sev-
en hemorrhages occurring earlier than 6 months after SRS were
removed from this analysis, the annual hemorrhage rate
decreased to 2.7%. Larger-volume AVMs had a higher risk of
hemorrhage after SRS. Permanent neurologic deficits due to
AREs developed in six patients (4.5%), and in one patient a
delayed cyst developed 56 months after SRS.
Sixty-seven patients had AVMs in the brainstem.27 In this ser-
ies, 51 patients (76%) had a prior hemorrhage. The median tar-
get volume was 1.4 cc (range 0.1–13.4 cc). The median margin
dose was 20 Gy (range 14–25.6 Gy). Obliteration of the AVMs
was eventually documented in 35 patients at a median follow-
up of 73 months (range 6–269 months). The actuarial rates of
documentation of total obliteration were 41, 70, 70, and 76% at
3, 4, 5, and 10 years, respectively. Higher rates of AVM oblitera-
tion were associated only with a higher margin dose. Four
patients (6%) suffered a hemorrhage during the latency period,
and two patients died. The rate of AVM hemorrhage after SRS
was 3.0, 3.0, and 5.8% at 1, 5, and 10 years, respectively. The
overall annual hemorrhage rate was 1.9%. Permanent neuro-
logic deficits due to AREs developed in seven patients (10%)
after SRS, and a delayed cyst developed in two patients (3%).
Higher 12-Gy volumes and higher SM grades were associated
with a higher risk of symptomatic AREs.
Sixty-four patients (median age 47 years, range 8–75 years)
underwent SRS for a cerebellar AVM.28 Forty-seven patients
(73%) presented with an intracranial hemorrhage. The median
target volume was 3.85 cc (range 0.2–12.5 cc), and the median
marginal dose was 21 Gy (range 15–25 Gy). AVM obliteration
was confirmed by MRI or angiography in 40 patients at a
median follow-up of 73 months (range 4–255 months). The
actuarial rates of total obliteration were 53% at 3 years, 69% at 4
years, and 76% at 5 and 10 years. Elevated obliteration rates
were statistically higher in patients who underwent AVM SRS
without prior embolization. A smaller AVM volume was also
associated with a higher rate of obliteration. Four patients (6%)
sustained a hemorrhage during the latency period and three
died. The cumulative rates of AVM hemorrhage after SRS were
6% at 1, 5, and 10 years. This correlated with an overall annual
hemorrhage rate of 2.0% during the latency interval. One pa-
tient experienced a hemorrhage 9 years after confirmed MRI
and angiographic obliteration. A permanent neurologic deficit
due to adverse radiation effects developed in one patient (1.6%)
and temporary complications were seen in two additional
patients (3.1%).
Eighty-seven patients underwent SRS for AVMs in the region
of the sylvian fissure.29 Before undergoing SRS, 40 (46%) of
these patients had experienced hemorrhage and 36 (41%) had
had seizures. The median target volume of the AVM was 3.85 cc
(range 0.1–17.7 cc), and the median marginal dose of radiation
was 20 Gy (range 13–25 Gy). Over a median follow-up period of
64 months (range 3–275 months), AVM obliteration was con-
firmed by MRI or angiography for 43 patients. The actuarial
rates of confirmation of total obliteration were 35% at 3 years,
60% at 4 and 5 years, and 76% at 10 years. Of the 36 patients
who had experienced seizures before SRS, 19 (53%) achieved
outcomes of Engel class I after treatment. The rate of seizure
71
 Stereotactic Radiosurgery for Arteriovenous Malformations
improvement was 29% at 3 years, 36% at 5 years, 50% at 10
years, and 60% at 15 years. No seizures developed after SRS in
patients who had been seizure-free before treatment. The
actuarial rate of AVM hemorrhage after SRS was 5% at 1, 5, and
10 years. This rate equated to an annual hemorrhage rate dur-
ing the latency interval of 1%; no hemorrhages occurred after
confirmed obliteration. No permanent neurologic deficits
developed as an adverse effect of radiation; however, delayed
cyst formation occurred in three patients.
One-hundred eighty-eight patients had ventricular-region
AVMs.30 The median patient age was 32 years (range 3–80
years), the median target volume was 4.6 cc (range 0.1–22 cc),
and the median marginal dose was 20 Gy (range 13–27 Gy).
Arteriovenous malformation obliteration was confirmed by
MRI or angiography in 89 patients during a median follow-up
of 65 months (range 2–265 months). The actuarial rates of total
obliteration were 32% at 3 years, 55% at 4 years, 60% at 5 years,
and 64% at 10 years. Higher rates of AVM obliteration were
obtained in the 26 patients with intraventricular AVMs.
Twenty-five patients (13%) sustained a hemorrhage during the
initial latency interval after Gamma Knife surgery, indicating an
annual hemorrhage rate of 3.4% prior to AVM obliteration. No
patient experienced a hemorrhage after AVM obliteration was
confirmed by imaging. Permanent neurologic deficits due to
adverse radiation effects developed in seven patients (4%).
9.4 The Stereotactic Radiosurgical
Procedure
We perform intracranial radiosurgery using the Leksell Gamma
Knife (beginning with the model unit U, and proceeding on to
the B, C, 4-C, and in recent experience the Perfexion model)
(Elekta AB, Stockholm, Sweden). The patient’s clinical studies
and imaging are reviewed for suitability for SRS. As noted previ-
ously, we evaluate the bleeding history, the age of the patient,
existing comorbidities, location, and clinical symptomatology.
Patients with lobar AVMs were placed prophylactically on anti-
convulsants for a period of 2 to 4 weeks around the time of the
procedure. This has reduced the risk of a perioperative seizure
event from as high as 5% in year 1 of our 20-year experience to
a risk of less than 1% at the current time. We require that all
women within the child-bearing age have a recent negative
pregnancy test or we perform it on the day of the procedure.
Patients are evaluated preoperatively by the neurosurgeon,
the radiation oncologist, and the nursing team. On the morning
of the procedure, the patients arrive at 6:00 am and begin con-
scious sedation using oral lorazepam followed by intravenous
conscious sedation (fentanyl and midazolam) as needed. Scalp
anesthetic injection using a combination of Marcaine and Xylo-
caine is injected at the sites of pin application. At the current
time, we prefer to use titanium pins with plastic inserts to min-
imize the risk of MRI artifacts. General anesthesia may be
required for frame application in imaging in patients younger
than 12 years of age.
Neurodiagnostic imaging follows using both intravenous par-
amagnetic contrast-enhanced three-dimensional (3D) volumet-
ric MRI scan, and a whole-head T2 fast spin-echo imaging
sequence. Patients subsequently undergo biplane digital sub-
traction angiography (DSA) as the next step. In patients where
72
MRI scans are not possible (those with undetermined implants,
pacemakers, old aneurysm clips, etc.), we use contrast-
enhanced stereotactic computed tomography angiography
(CTA). The development of axial imaging as part of the imaging
paradigm is critical for AVM management. This has allowed us
to make superior 3D conformal plans much more carefully in
comparison with using two-plane angiography alone.
Imaging studies are placed in a dose-planning computer sys-
tem (Elekta Instruments, Inc., Atlanta, GA, USA), which has both
high speed and high resolution. We begin the planning using
MRI while the patient is undergoing angiography. Angiography
is used to fine tune or idealize the angiographic plan. In both
the 4-C and Perfexion models currently used, optimization of
the dose planning is achieved by confining the sharpest falloff
isodose (usually the 50%) to the edge of the 3D-defined volume.
Each slice is looked at serially to confirm excellent conformality
(conforming the edge dose to the 3D target volume). High selec-
tivity (rapid falloff of the radiation dose outside of the target) is
equally important (▶ Fig. 9.2). We also assess the patient for the
presence of proximal and intranidal aneurysms. We strive to
reduce dose to draining veins when feasible. Typical doses at
the margin of the AVM are 18 to 25 Gy and never below 16.
Maximal doses are usually 36 to 50 Gy at the margin of the
AVM. Final dose selection depends on the volume and location,
which also helps to estimate ARE risks. We also consider the
presence of preexisting neurologic conditions, the patient’s age,
and prior bleeding history. Because the dose to the surrounding
brain is a critical predictor of ARE, we must maximize confor-
mality and selectivity.
At the conclusion of the procedure, patients receive 20 to
40 mg of methylprednisolone. This coupled with anticonvul-
sants in lobar AVM patients tends to reduce the risk of periope-
rative seizures. For those patients who have previously
undergone embolization in an attempt to reduce flow or to
achieve volumetric reduction of the AVM, or for those who have
had intracranial surgery or hematoma evacuation, Gamma
Knife radiosurgery may be used as an adjuvant strategy rather
than a primary management. We often perform radiosurgery
once the patient has achieved a stable neurologic improvement,
but almost never within the first month after an ictal event
such as a bleed or embolization. For patients who have had
intracranial hemorrhages, we prefer to wait between 1 and 3
months to see if there will be a regional clot reabsorption. The
AVM nidus should not be compressed by clot at the time of the
radiosurgery. Failure of radiosurgery can be traced in some
ways to inadequate planning, inadequate recognition of the 3D
geometry of the AVM, reappearance of a component of the AVM
previously embolized, or reappearance of a component of the
AVM that was previously compressed by intracerebral
hematoma.
Follow-up imaging is recommended at regular intervals.
Whenever possible, imaging is done at our center, but if the pa-
tient lives at a distance, we recommended the images be done
at an imaging site closer to home. Communication with the
patient’s referring physician team is critical. We normally rec-
ommend MRI scans as 6 months and then annually to assess
the effect of radiosurgery. If at the end of 3 years MRI suggests
complete obliteration, then we request that a repeat DSA be
performed. If MRI clearly defines residual nidus, angiography is
delayed, and the patient is contacted to suggest the possible

need for repeat radiosurgery to achieve the final obliteration re-
sponse. In such cases, repeat stereotactic imaging may include
both repeat MRI as well as angiography.
For those patients who have large AVMs (determined by mul-
tiplying the MRI X, Y, Z dimensions of the AVM and dividing by
2, a rough approximation of an ellipsoid volume), we recom-
mend consideration of prospective staged SRS. Staged radio-
surgery, with two stages separated usually by 3 months, is
recommended for AVMs larger than 15 cm3. We also consider it
for those AVMs between 10 and 15 cm3. For those AVM volumes
10 cm3 or smaller, we normally perform single-stage radiosur-
gery. The interval between stages varies from 3 to 6 months
based on the goal of some radiobiological repair of surrounding
brain during the observation interval. However, we do not want
to wait too long, as the goal of protection from bleeding cannot
Stereotactic Radiosurgery for Arteriovenous Malformations
Fig. 9.2 (a) Anteroposterior and lateral carotid
artery angiograms documenting the left frontal
arteriovenous malformation with a volume of 4.7
cc at the time of the initial stereotactic radio-
surgery (SRS). The margin dose was 22 Gy. (b)
Anteroposterior and lateral carotid artery angio-
grams, 4 years after initial SRS, showing a residual
nidus with a volume of 2 cc in the SRS field. This
residual nidus was treated by the second SRS with
a margin dose of 20 Gy. (c) Anteroposterior and
lateral carotid artery angiograms, 4 years after
the second SRS, showing the absence of nidus.
begin until the radiosurgical procedure has been completed for
all volumetric components of the AVM.
9.5 Current Outcomes of AVM
Stereotactic Radiosurgery
In the absence of treatment, the overall risk of a spontaneous
bleed from a brain AVM appears to range from 1 to 5% per year
depending upon various risk factors.31 In the Finnish popula-
tion-based 24-year study, hemorrhage was a relatively constant
lifetime risk with an annual death risk of approximately 1% and
approximately a 4% risk of bleed per year.31 Recent work
reported from the cooperative trial in Canada suggested that an
annual bleed rate may be as high as 5% (C. Wallace, personal
73
 Stereotactic Radiosurgery for Arteriovenous Malformations

communication). We performed an individualized analysis of
the hemorrhage risk of AVM patients before radiosurgery. 32 Our
findings demonstrated an overall crude annual hemorrhage
rate of 2.4% per year.
There were several factors associated with hemorrhage risk,
the primary one being a prior hemorrhage (an identification of
a single draining vein on angiography), and the detection of a
diffuse AVM nidus on angiography. Pollock et al constructed an
estimation of bleed risks related on these significant factors
(▶ Table 9.4 and ▶ Table 9.5).32 For low-risk AVMs (no prior
hemorrhage and no other risk factors, diffuse nidus or single
draining vein), the annual risk rate was approximately 1% per
year. In contrast, the risk of a second hemorrhage for patients
with additional risk factors ranged from 2.0 to 3.7% for AVMs
with a compact nidus up to 8.94% for those with high-risk fea-
tures of the angioarchitecture (one draining vein or diffuse
morphology).
In talking with families, we often use a rule of thumb to esti-
mate the lifetime bleeding risk related to a patient’s age. The
age at which the risk of a bleed is greater than the risk of mor-
bidity from radiosurgery may well depend upon the location
and size of the AVM. A simple lifetime analysis risk rate sug-
gests that a patient’s age subtracted from 105 will give the total
cumulative risk of that patient having a bleeding event.33,34
Table 9.4 Estimate annual risk of initial and second hemorrhages in arte-
riovenous malformation (AVM) patients with an arteriovenous malforma-
tion (AVM)32
AVM characteristics Estimated risk of intracranial hemorrhage
1st bleed 2nd bleed
Low-risk AVM (well-
defined nidus and > 1 1.00% 3.70%
draining vein)
High-risk AVM (diffuse
nidus or only one 2.20% 8.90%
draining vein)
Clearly, for a child the risk is very large, whereas for a senior
citizen the remaining lifetime risk of a bleed for a patient who
has never bled before may be reasonably low.
9.6 Bleeding Risks after AVM
Stereotactic Radiosurgery
We have also analyzed the bleeding rate during the observation
interval (latency interval) after radiosurgery and before com-
plete AVM obliteration.35 For this study, we evaluated 312
patients with clinical angiographic outcomes followed for an
average of 4 years. Twenty-one patients suffered AVM bleeds at
a median of 8 months after radiosurgery. The overall total risk
of postradiosurgery hemorrhage per patient was 7.4%, after
exclusion of additional bleeding risk factors such as untreated
aneurysms. The actual hemorrhage rate from a patent AVM
before complete obliteration was 4.8% per year during the first
2 years after radiosurgery, and 5% per year for the third to fifth
years after radiosurgery, if the AVM continued to be unobliter-
ated. Our data have not provided strong evidence to date that
there is a protective benefit of radiosurgery that gradually
emerges during the observation years, even before complete
obliteration has occurred. In contrast, studies from the Univer-
sity of Tokyo experience reported by Maruyama and col-
leagues36 as well as reinterpretation of the outcome data from
the Karolinska experience37of Steiner have suggested that there
may be some protective benefit to AVMs even before complete
obliteration of their nidus occurs.
Our recent analysis showed that at our institution, 33
patients (8%) sustained an additional hemorrhage after SRS. 38
The overall annual hemorrhage rate until obliteration after SRS
was 1.3%. The presence of a patent aneurysm was significantly
associated with an increased rehemorrhage risk after SRS
(annual hemorrhage rate, 6.4%) compared with patients with a
clipped or embolized aneurysm (annual hemorrhage rate, 0.8%;
p = 0.033). Patients who have a proximal unsecured aneurysm
have an increased risk of postradiosurgical hemorrhage. If the

Table 9.5 Estimated lifetime risk of hemorrhage according to history of prior hemorrhage and whether any high-risk morphological risk features
(increased risk diffuse morphology or one draining vein) are absent or present 32,34
Patient age at Lifetime risk of
Expected survival (y)
diagnosis (y) intracranial bleed

Low-hemorrhage-risk AVMs High-hemorrhage-risk AVMs

No prior bleed Prior bleed No prior bleed Prior bleed

15 77 46 90.5 75.1 99.7

25 67 40.4 86.1 68.9 99.2

35 78 34.8 80.4 61.9 98.2

45 79 28.7 72.4 53.4 95.9

55 80 22 61.2 43 90.4

65 83 16.4 49.5 33.2 81.5

75 86 10.4 34.1 21.9 64.3

85 91 5.8 20.3 12.6 43

Abbreviation: AVM, arteriovenous malformation.

74

aneurysm is immediately proximal to the AVM, it will likely
close as the AVM obliterates. We have not found that intranidal
aneurysms increase the risk of bleeding during the latency
interval. For those patients with aneurysms in more than one
arterial branch proximal to their AVM, we believe that the
aneurysm requires a different management algorithm that
should be determined based on those characteristics that guide
whether surgery or endovascular is best management. Such
aneurysms generally do not go away at the time that the AVM is
obliterated.
To date, in our experience no patient has suffered a hemor-
rhage after definitive high-resolution angiography has con-
firmed complete obliteration of their AVM. We have a single
patient with more than 50 aneurysm clips who has undergone
multiple surgical procedures. The AVM was thought to be obli-
terated after radiosurgery, but the patient suffered a subse-
quent hemorrhage. A new AVM was identified on follow-up
angiography (neither CT nor MRI scan was feasible in this pa-
tient). The possibility of recanalization of previously treated
AVM requiring additional treatment and monitoring is impor-
tant. For this reason, even in those patients who have angio-
graphic complete closure of their AVM, we recommend MRI
scans at 2-year intervals to assess the overall brain response to
detect late AREs or delayed cyst development.
Although the studies of both Karlsson et al and Maruyama et
al36,37provide some evidence of an overall reduction in bleeding
rates during the latency interval, this hypothesis remains
largely unproven at the present time. In addition, both ours as
well as other outcome studies have shown that even with com-
plete obliteration, the hemorrhage rate is not zero. For patients
who have defined angiographic obliteration, we may safely esti-
mate that the lifetime risk of a bleed in such patients is now less
than 1%.
9.7 Obliteration of an
Arteriovenous Malformation after
Stereotactic Radiosurgery
Of the 996 patients with AVMs in our series, 407 patients had
sustained an hemorrhage.38 The overall rate of total obliteration
defined by angiography or MRI was 56, 77, 80, and 82% at 3, 4,
5, and 10 years, respectively. Furthermore, we believe that there
is approximately a 95% accuracy that MRI-detected obliteration
will be confirmed by follow-up angiography.39 There are some
patients who are unwilling to undergo repeat angiography even
though this remains the gold standard for detection of res-
ponse. Even the presence of an early draining vein, without dis-
cernible nidus, is a sign of satisfactory response. To our
knowledge, no patient has subsequently bled when only an
early draining vein is seen. Follow-up angiography afterwards
at 6 months to 1 year in such cases invariably shows loss of the
early draining vein as well.
Failure of obliteration is multifactorial, and as noted earlier
may be related to dose, volume, inadequate recognition of the
3D geometry, recanalization of the previously embolized com-
ponent, or a clot-compressed AVM that was subtotally treated.
In our studies designed to detect the reasons for marginal fail-
ure, we noted that such persistence of out-of-field residual AVM
Stereotactic Radiosurgery for Arteriovenous Malformations
was seen in 18% of previously embolized patients, but only 5%
of nonembolized patients. We have also noted that the success-
ful obliteration for the same-volume AVMs may be slightly low-
er in women and is higher in children; however, it occurs more
completely and at a faster rate in children than in adults.
9.8 Adverse Effects of
Radiosurgery
Early adverse effects are relatively rare and include headache
from the frame application, nausea from conscious sedation
medications, and the relatively small risk of developing seizures
in patients with subcortical lobar AVMs.39,40,41,42 It is for this
reason that prophylactic anticonvulsants are used in these
patients, but not in patients with deep-seated AVMs. Late AREs
of radiosurgery are relatively rare. We evaluated data from 85
AVM patients who developed symptomatic complications after
Gamma Knife radiosurgery and compared this with 337
patients who had no complications and were evaluated as part
of another multi-institutional study.43 Thirty-five of 85 patients
were classified as having permanent symptomatic sequelae. We
constructed various models to study the effects of AVM location
and the volume of tissue receiving 12 Gy or more (the 12-Gy
volume) with the risk of developing permanent postradiosur-
gery AREs. The locations of AVMs in increasing order of risk
were frontal, temporal, interventricular, parietal, cerebellar, cor-
pus callosum, occipital, medulla, thalamus, basal ganglia, and
pons and midbrain. We were able to construct statistical mod-
els predicting the risk of permanent radiation sequelae with a
12-Gy volume. Such data are very important for subsequent
planning of additional patients relative to a risk:benefit analy-
sis. This database, though useful, was constructed with a rela-
tively small number of complications considering the large
number of patients and the relatively large number of variables.
It is likely that the risk prediction for some brainstem locations
is significantly overestimated. Certainly, the risk of complica-
tions is expected to be high for large-volume AVMs in critical
locations of the brain. It is for this reason that for larger-volume
AVMs, 15 cc or more, we clearly recommend staging with the
goal to increase the obliteration rate while maintaining safety.
We generally divide the AVM into two volumes of approxi-
mately equal proportion. At the time of the first procedure
(which is done with angiography and MRI), we devise a plan for
the entire AVM and then gradually subtract isocenters from the
plan until we develop a 50% volume that corresponds to the ini-
tial stage. The second-stage volume is then done to reproduce
the original plan at an interval of 3 to 6 months. This strategy
promotes the brain’s ability to repair normal tissue and to pre-
vent adverse radiation effects.
Other complications of AVM radiosurgery are relatively rare.
Such complications have taken many years to fully understand
or even develop. These risks include the risk of hemorrhage
despite obliteration (1% lifetime), the risk of temporary or per-
manent radiation injury, the risk of late cyst formation at the
site of the obliterated nidus, and the long-term risk for radia-
tion-induced tumor. Cyst formation after AVM radiosurgery
was first reported by Japanese investigators who had sent
patients to receive Gamma Knife radiosurgery in Sweden in the
early years of radiosurgery.44 Cyst formation has also been
75
 Stereotactic Radiosurgery for Arteriovenous Malformations
reported in other long-term follow-up studies.45,47 In our 20-
year experience, we have detected 16 patients (1.7%) with
delayed cyst formation. We also observed that patients who
developed delayed cyst formation were more likely to have had
prior bleeds. This raises the intriguing possibility that residual
iron deposition in the brain tissue may serve as a radiation sen-
sitizer that could potentiate the effects of radiosurgery on a
long-term basis. Such cysts have been managed with observa-
tion, simple drainage, cyst shunting, or surgical fenestration.
Patients with perioperative T2 signal change without additional
neurologic problems do not require additional treatment.
In our experience of more than 14,000 Gamma Knife proce-
dures, we have not identified a patient who fits the Cahan
requirements for a radiation-related tumor.46 Recently, Sheehan
and Steiner reported two patients who have had radiosurgery
for their AVM and developed delayed meningiomas.48 As a rela-
tively common tumor in older patients, it is not clear from a
population basis that this represents a significant increased risk
compared with the natural history of meningioma develop-
ment. There are, however, two additional cases of a glioblasto-
ma reported after AVM radiosurgery.49,50 With more than half a
million patients having undergone Gamma Knife radiosurgery
over the last 40 years, the denominator (number treated) is rel-
atively known, but the numerator (the incidence of radiation-
related tumors) remains largely an estimate. We provide an
estimate to patients that the gross risk of developing a radia-
tion-related tumor is approximately 4 in 50,000, a 1 in 12,500
risk. We do, nonetheless, warn our patients that the risk of a
radiation-related tumor may be as high as 1 in 1,000, although
neither our personal experience nor data published from Shef-
field, England, can confirm this incidence.51
9.9 Repeat Radiosurgery
For those patients who have a residual nidus identified by
imaging 3 or more years after radiosurgery, we recommend
repeat radiosurgery. For such patients, we are occasionally able
to increase the dose slightly to the residual smaller-volume
AVMs. We evaluated the outcomes and risks of repeat SRS for
incompletely obliterated cerebral AVMs.52 During a 20-year
period, repeat SRS was performed in 105 patients who had
incompletely obliterated AVMs at a median of 40.9 months after
initial SRS (range 27.5–139 months). The median AVM target
volume was 2.3 cm3 (range 0.1–18.2 cm3) at the time of the sec-
ond procedure. The median margin dose at repeat SRS was
18 Gy. The actuarial rate of total obliteration by angiography or
MRI after repeat SRS was 35, 68, 77, and 80% at 3, 4, 5, and 10
years, respectively. The median time to complete angiographic
or MRI obliteration after repeat SRS was 39 months. Factors
associated with a higher rate of AVM obliteration were smaller
residual AVM target volume and a volume reduction of 50% or
more after the initial procedure. Seventeen patients (16%) had
hemorrhage after repeat SRS and six patients died. The cumula-
tive actuarial rates of new AVM hemorrhage after repeat SRS
were 1.9, 8.1, 10.1, 10.1, and 22.4% at 1, 2, 3, 5, and 10 years,
respectively, which translate to annual hemorrhage rates of
4.05 and 1.79% of patients developing new postrepeat-SRS
hemorrhages per year for years 0–2 and 2–10 following repeat
SRS. Factors associated with a higher risk of hemorrhage after
76
repeat SRS were a greater number of prior hemorrhages, larger
AVM target volume at initial SRS, larger target volume at repeat
SRS, initial AVM volume reduction less than 50%, and a higher
Pollock-Flickinger score. Symptomatic adverse radiation effects
developed in 5 patients (4.8%) after initial SRS and in 10
patients (9.5%) after repeat SRS. Prior embolization and a higher
SM grade were significantly associated with higher rates of
adverse radiation effects after repeat SRS. Delayed cyst forma-
tion occurred in five patients (4.8%) at a median of 108 months
after repeat SRS (range 47–184 months). In this group, the per-
manent neurologic injury was slightly higher than would be
expected with those patients who had no prior radiation
injury.53 However, it should be recalled that most patients had
relatively larger AVMs to begin with, and received relatively
lower radiation margin doses. If we are unable to give in a sin-
gle procedure more than 16 Gy or more, we believe that staged
radiosurgery must be considered to try to increase the chances
of the obliteration rate. We know that the successful oblitera-
tion response declines rapidly below a 15-Gy edge dose.
9.10 The Management of Large
Arteriovenous Malformations
Large AVMs pose a major challenge both for surgical resection
embolization and radiosurgery. Multimodality management is
probably going to be critical for such AVMs that have any hope
of treatment. Embolization of an AVM has been performed
using a variety of agents over the course of time, including glue,
coils, silk threads, polyvinyl alcohol, and more recently Onyx
(ev3, Plymouth, MN). Prior studies have shown the recanaliza-
tion rates of 14 to 15% of patients who had prior AVM emboliza-
tion. Because we cannot use a single-staged radiosurgical
procedure for such large-volume AVMs, we have recommended
a staged prospective approach. Although fractionated radio-
therapy (2–4 Gy per fraction to a total dose of 50 Gy) has virtu-
ally no significant benefit54 in terms of AVM obliteration while
having significant long-term side-effect risks, radiosurgery div-
ided into two sessions seems to have an acceptable risk predic-
tion. Kjellberg using stereotactic Bragg peak radiotherapy
achieved obliteration rates of < 20%, although he postulated that
such radiation stabilized blood vessel walls reduced the risk of a
subsequent bleed.10 Most of the AVMs treated by this technique
had large-volume AVMs. In a group of 48 patients treated by
Pan et al,55 an obliteration rate of only 25% was noted after 14
months in a single radiosurgical strategy when relatively larger
doses were given to the edge (16.5–17.7 Gy). Approximately
37% had moderate and 12% had severe adverse radiation effects
when the AVM volume was larger than 10 cc. We noted the
rather narrow window between dose response and complica-
tion, and the low chance of receiving a total obliteration with
low dose. We switched to prospective volume staging
(▶ Fig. 9.3) as an option to manage larger AVMs unsuitable for
primary single-session radiosurgery. At our institution, 47
patients with large AVMs underwent SRS using two or more
stages. Eighteen patients (38%) had a prior hemorrhage and 21
patients (45%) underwent prior embolization. 56 The median
interval between the first-stage SRS and the second-stage SRS
was 4.9 months (range 2.8–13.8 months). The median target
volume was 11.5 cc (range 4.0–26 cc) in the first-stage SRS and

9.5 cc in the second-stage SRS. The median margin dose was
16 Gy (range 13–18 Gy) for both stages. In 17 patients, AVM
obliteration was confirmed after two to four SRS procedures at
a median follow-up of 87 months (range 0.4–209 months). Five
patients had near-total obliteration (volume reduction > 75%,
but residual AVM). The actuarial rates of total obliteration after
two-stage SRS were 7, 20, 28, and 36% at 3, 4, 5, and 10 years,
respectively. The 5-year total obliteration rate after the initial
staged volumetric SRS with a margin dose of 17 Gy or more was
62% (p = 0.001). Sixteen patients underwent additional SRS at a
median interval of 61 months (range 33–113 months) after the
initial two-stage SRS. The overall rates of total obliteration after
staged and repeat SRS were 18, 45, and 56% at 5, 7, and 10
years, respectively. Ten patients sustained hemorrhage after
staged SRS, and five of these patients died. Three of 16 patients
who underwent repeat SRS sustained hemorrhage after the
procedure and died. Based on Kaplan-Meier analysis (excluding
the second hemorrhage in the patient who had two hemor-
rhages), the cumulative rates of AVM hemorrhage after SRS
were 4.3, 8.6, 13.5, and 36.0% at 1, 2, 5, and 10 years, respec-
tively. This corresponded to annual hemorrhage risks of 4.3, 2.3,
and 5.6% for years 0–1, 1–5, and 5–10 after SRS. Multiple hem-
orrhages before SRS correlated with a significantly higher risk
of hemorrhage after SRS. Symptomatic adverse radiation effects
were detected in 13% of patients, but no patient died as a result
of an adverse radiation effect. Delayed cyst formation did not
occur in any patient after SRS.
9.11 The Role of Preradiosurgical
Embolization
Embolization has a major benefit in preparation for craniotomy
and microsurgical removal.57 Its primary benefit is reducing the
flow through the AVM, or removal of deep-seated feeders that
may be problematic for subsequent surgical removal. We used
embolization early in our experience for larger-volume AVMs. 58
The goal was to decrease the volume of the AVM to make it
Stereotactic Radiosurgery for Arteriovenous Malformations
Fig. 9.3 The graph showing higher percentage of
arteriovenous malformation obliteration rates
with higher margin doses. MR, magnetic reso-
nance.
more effective for radiosurgery. However, embolization can
only be effective if it permanently reduces the nidus volume.
Reduction in flow from an AVM does not provide improvement
in radiosurgical outcome data. Our analysis suggests that radio-
surgical embolization had a negative effect on AVM obliteration
rates.59 We analyzed the long-term benefits and risks of SRS for
patients with AVMs who underwent prior embolization. 60 At
our institution, 120 patients underwent embolization followed
by SRS. In this series, 64 patients (53%) had at least one prior
hemorrhage. The median number of embolizations varied from
one to five. The median target volume was 6.6 cc (range 0.2–
26.3). The median margin dose was 18 Gy (range 13.5–25.0 Gy).
After embolization, 25 patients (21%) developed symptomatic
neurologic deficits. The overall rates of total obliteration docu-
mented by either angiography or MRI were 35, 53, 55, and 59%
at 3, 4, 5, and 10 years, respectively. Factors associated with a
higher rate of AVM obliteration were smaller target volume,
smaller maximum diameter, higher margin dose, timing of
embolization during the most recent 10-year period (1997–
2006), and lower Pollock-Flickinger score. Nine patients (8%)
had a hemorrhage during the latency period, and seven patients
died of hemorrhage. The actuarial rates of AVM hemorrhage
after SRS were 0.8, 3.5, 5.4, 7.7, and 7.7% at 1, 2, 3, 5, and 10
years, respectively. The overall annual hemorrhage rate was
2.7%. Factors associated with a higher risk of hemorrhage after
SRS were a larger target volume and a larger number of prior
hemorrhages. Permanent neurologic deficits due to AREs devel-
oped in three patients (2.5%) after SRS, and one patient had
delayed cyst formation 210 months after SRS. No patient died
of AREs. A larger 12-Gy volume was associated with higher risk
of symptomatic AREs. Using a case-control–matched approach,
the authors found that patients who underwent embolization
prior to SRS had a lower rate of total obliteration (p = 0.028)
than patients who had not undergone embolization (▶ Fig. 9.4).
Others have reported that up to 30% of patients who had AVM
embolization subsequently had an increase in the nidus volume
when an angiogram was performed at the time of radiosurgical
targeting.61 Twelve percent of embolized AVMs showed
77
 Stereotactic Radiosurgery for Arteriovenous Malformations
Fig. 9.4 Radiosurgery dose plans of staged radiosurgery for large-volume arteriovenous malformation (AVM). The medial part of nidus was selected
for stage I treatment. A margin dose of 16 Gy was prescribed to this target (yellow line). The nidus volume for stage II radiosurgery (outlined in blue)
was also defined at the time of first radiosurgery. Dose plan of second-stage radiosurgery showing complete coverage of the remaining AVM nidus.
recanalization within a year.62 Unlike surgery that removes an
AVM nidus within a few weeks of embolization, radiosurgery
takes several years to be fully effective. This latency interval,
unfortunately, allows sufficient time for embolized AVM com-
ponents to recanalize, remodel, or even recruit new feeding
blood vessels. In a report using both embolization and radiosur-
gery, permanent neurologic deficits ranged from 5 to 12% of
patients with a mortality rate of 1.5 to 2.7% of patients. 61,62,63
Complete obliteration rates varied from 47 to 55%.61,62,63 In a
study of 47 patients who had radiosurgery and embolization in
comparison with 47 matched patients who were treated with
radiosurgery alone, nidus obliteration was achieved in 47% of
the embolization group, but in 70% of the radiosurgery group. 64
Experience using adhesive agents such as Onyx is still in its
early stages; therefore, whether radiosurgery will have a signif-
icant improvement in patients who have previously undergone
liquid adhesive embolization is yet to be defined.
9.12 Treatment of Dural
Arteriovenous Malformations
In contrast to the experience with intracranial AVMs, dural
vascular malformations or dural arteriovenous fistulas
(DAVFs) (▶ Fig. 9.5) may indeed benefit from embolization
78
and radiosurgery.65 The timing of the individual procedures
is critical. In general, we prefer to do radiosurgery first in a
newly diagnosed patient, at a time when the entire connec-
tion of the fistula can be defined. Most of these lesions
occur in the region of the transverse or sigmoid sinus, and
may be associated with pulsatile tinnitus. 66 Others may
occur in the cavernous sinus and are associated with diplo-
pia, impaired vision, or exophthalmos. Lesions of the superi-
or sagittal sinus may cause papilledema, vision loss, and
hydrocephalus. Those lesions that have cortical venous
drainage are prone to have intracranial hemorrhages, pro-
gressive deficits, or seizures. Because such patients have an
overall intracranial hemorrhage rate of approximately 2%
per year, management of these lesions may be very impor-
tant. 66 We generally recommend early radiosurgery fol-
lowed the same day by embolization. Patients have their
frame placed and undergo MRI, followed by initial angiogra-
phy, and are transferred for Gamma Knife radiosurgery with
a femoral sheath catheter left in position. After completion
of the radiosurgical component of the procedure, they are
transferred back to the interventional radiology suite where
they undergo embolization. The combination of radiosur-
gery and embolization provides both early symptom relief
of the DAVF and long-term relief of the condition as fistula
closure by radiosurgery.

Fig. 9.5 (a) Axial T1-weighted contrast-enhanced magnetic resonance images showing the transverse sinus dural arteriovenous fistula (AVF). (b)
Digital subtraction lateral carotid artery angiogram showing the radiosurgery dose plan covering the transverse sinus dural AVF. (c) Digital subtraction
anteroposterior carotid artery angiogram showing the radiosurgery dose plan covering the transverse sinus dural AVF.
9.13 Future Directions
Radiosurgery of an AVM is a well-established management
strategy for AVMs at the present time. With more than 25
years of experience using the Gamma Knife technique, and
with thousands of patients worldwide who have undergone
this procedure, we understand the overall success rate, the
complication rate, and the various alternative strategies. We
believe that at the present time, embolization has an impor-
tant role prior to microsurgery, an important role after
radiosurgery for the management of DAVFs, and a relatively
limited role in the prospective management of AVMs within
the brain. Although outcome studies continue to be looked
at both in Canada and in the United States, we suspect that
most patients with an intracranial AVM require strong con-
sideration for intervention, providing that the management
strategy has an acceptable risk to the patient. It seems
unlikely that higher doses will be feasible. Today the ability
to conform dose and to restrict dose (selectivity) seem to be
maximized with the current imaging techniques as well as
radiation delivery systems, including the new Perfexion
Gamma Knife (Elekta AB). We may be able to increase the
chance of obliteration by developing specific radiation sen-
sitizers delivered by microcatheters immediately before
radiosurgery. To date, brain-protection technologies or
drugs have been disappointing. The greatest remaining
issue for AVM radiosurgery is the risk of a latency interval
hemorrhage, so efforts to reduce the latency interval would
be important. The recognition of late long-term side effects
including the possible risk of radiation-related tumors or
late cyst development continues to be evaluated. Within the
context of a disease that has a 1% annual mortality left
untreated, the current data have shown that SRS is a safe
and effective management strategy that can be applied to
both lobar as well as deep-seated AVMs. Many AVM patients
were never treatable by any technique prior to the develop-
ment of radiosurgery.
Disclaimer: Dr. Lunsford is a stockholder and consultant with
Elekta AB, Stockholm, Sweden.
Stereotactic Radiosurgery for Arteriovenous Malformations
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bleeding after stereotactic radiosurgery for hemorrhagic arteriovenous mal-
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10 Stereotactic Radiosurgery for Cavernomas
Gabor Nagy and Andras A. Kemeny
Key Points
● The natural history of cerebral cavernomas is varied accord-
ing to their anatomical location. Many are silent and the risk
of persisting disability after one bleed is low for hemispheric
lesions, whereas those found in the thalamus, basal ganglia,
and brainstem typically behave more aggressively with in-
creased rebleed risk resulting in higher cumulative morbidity
following subsequent hemorrhages. However, despite our
increasing knowledge on natural history, currently we are
unable to predict future behavior of an individual lesion at
presentation.
● At present, there is no high-quality evidence to define the
relative roles of microsurgery, stereotactic radiosurgery, and
wait-and-watch policy in the management of detected
cerebral cavernomas. Although their indications are partly
overlapping, their role in the management of cerebral caver-
nomas is rather complementary.
● Stereotactic radiosurgery using current protocols appears to
be an effective treatment alternative for deep-seated cere-
bral cavernomas with multiple hemorrhages—reducing pre-
treatment annual rebleed rates from about 30% to near zero
within 2 years after treatment. It is also effective for cerebral
cavernomas causing therapy-resistant epilepsy, especially if
applied early—within 3 years after presentation. In modern
stereotactic radiosurgical series radiation only induces a low
rate of mild morbidity.
● We recommend early stereotactic radiosurgery soon after
presentation in neurologically intact or minimally disabled
patients harboring deep-seated cerebral cavernomas. In our
opinion, waiting for the cumulative morbidity of the natural
history to justify an otherwise low-risk intervention does not
serve the patient well.
10.1 Introduction
Owing to earlier and more reliable radiological detection, as well
as to our better understanding of their natural history, manage-
ment strategy of cerebral cavernomas (CCMs; also known as
cavernous malformations, cavernous angiomas, or cavernous
hemangiomas) has significantly changed during the last two
decades.1,2 However, due to the lack of high-quality evidence,
their optimal management is still debated. Consensus seems to
exist in the treatment of hemispheric (superficial) CCMs: micro-
surgery for symptomatic and observation for incidental lesions.
Deep and eloquent lesions in the brainstem, thalamus, and basal
ganglia, especially those after one or no hemorrhage, pose a
dilemma because they seem to behave more aggressively if
untreated, whereas any intervention would carry a higher risk.3
Stereotactic radiosurgery (SRS) was introduced for the treat-
ment of CCMs based on the assumption that their pathological
vessels would respond similarly to arteriovenous malforma-
tions (AVMs), which are known to undergo thrombo-
Stereotactic Radiosurgery for Cavernomas
obliteration after SRS.4 Since then, increasing worldwide clinical
experience together with documented histopathological cases
seem to support the initial intuition: SRS is recommended as a
treatment option for surgically inaccessible CCM with repeated
hemorrhages.5 Moreover, a more proactive attitude, recom-
mending SRS early soon after the first presentation, has
recently been proposed by some large centers to avoid the step-
wise neurologic deterioration caused by repeated hemorrhages
of deep-seated lesions in light of the safety of modern radiosur-
gical techniques.6,7
However, the skepticism about the effectiveness and safety of
SRS that dominated views among neurovascular experts even
10 years ago8 still exists.9,10 Admittedly, there is no reliable
radiological measure (“end point”) currently available to dem-
onstrate cure; thus, the proponents’ argument is based only on
observational statistics, whereas as in all interventions, even
SRS carries the risk of morbidity. On the other hand, one is also
aware of the disadvantages of microsurgery, from surgical com-
plications to persisting risk of bleed after surgery. 11,12 Therefore,
should SRS be considered a viable alternative for microsurgery
for symptomatic cases in terms of efficacy and for wait-and-
watch policy in a neurologically intact patient in terms of
safety? By reviewing SRS literature recently, we concluded that
the quality of published articles was disappointingly heteroge-
nous and recommended standard data collection and treatment
criteria based on our current knowledge on natural history and
modern SRS techniques.7 In this chapter, after a brief summary
of natural history, we critically review the literature of CCM SRS
based on our standard criteria addressing the issues frequently
raised by critics of SRS and arguing for the safety and effective-
ness of modern CCM SRS.
10.2 Natural History of
Cavernomas
Cerebral cavernomas with distinct pathological and magnetic
resonance imaging (MRI) characteristics (▶ Table 10.1) com-
pose a large proportion of the previously described angiograph-
ically occult vascular malformations (AOVMs) (▶ Fig. 10.1).13,14,
15 Their estimated prevalence is 0.15 to 0.9%16,17,18; 76% of them
are located supratentorially, 8% in the basal ganglia/thalamus,
and 18% in the brainstem. Multiple CCMs are found in 19% of
the patients,19 more frequently in familiar forms constituting at
least 6% of all cases.20 A contemporary population-based pro-
spective study detected approximately 6 cases/million/year in
Scotland.21 Forty-seven to 60% of the cases are asymptomatic at
detection, and only 9.3% of the lesions initially found inciden-
tally or presented with seizures go on to cause hemorrhage or
focal neurologic deficit within 5 years, but the risk of a second
event increases to 42.4%.22 When patients become sympto-
matic, typically in their 30 s, 37% present with seizures, 36%
with hemorrhage, 23% with headaches, and 22% with focal neu-
rologic deficits.19 Twenty-one to 33% of CCMs is associated with
developmental venous anomalies (DVAs) in adults20,23 that are
81
 Stereotactic Radiosurgery for Cavernomas

Table 10.1 MRI appearance of CCMs according to time of bleed and classification
MRI appearance Pathological characteristics

Hyperacute (< 24 h) T1: Iso- or hyperintense

T2: Iso- or hyperintense center, hypointense periphery,
hyperintense rim

Acute (1–3 d) T1: Iso- or hypointense

T2: Hypointense

Subacute—Type I Subacute bleed, surrounded by a rim of hemosiderin-

Early (3–7 d) T1: Hyperintense stained macrophages and gliosis
T2: Hypointense
Late (7–14 d) T1: Hyperintense
T2: Hyperintense

Chronic (> 14 d) or unbled

Type II T1: Reticulated mixed signal Loculated areas of bleed and thrombosis of different age,
T2: Reticulated mixed signal, surrounded by hypointense surrounded by gliotic and hemosiderin-stained brain, may
rim be areas of calcification in larger lesions
GE: Reticular core, with hypointense magnifying rim
Type III T1: Iso- or hypointense Resolved hemorrhage, surrounded by hemosiderin-stained
T2: Hypointense with hypointense rim magnifying lesion size gliotic brain
GE: Hypointense, magnifying greater than T2
T1: Not or poorly visible May be telangiectasia
Type IV T2: Not or poorly visible
GE: Punctate hypointense

Abbreviations: CCMs, cerebral cavernomas; MRI, magnetic resonance imaging.

thought to promote CCM formation20 and to increase the risk of observational studies, with only few exceptions.31,33 Prospective
hemorrhage (▶ Fig. 10.1).24 studies estimated rebleed rate between 4.5 and 22.9%/y.32,34 The
cumulative incidence of rebleed was found 56% after 5 years and
72% after 10 years.35 Moreover, even lesions that presented with
10.2.1 Definition of Clinical nonhemorrhagic symptoms have been found to have higher risk
Hemorrhage of bleeding than incidental lesions (2.18 and 0.33%/y, respec-
tively).23 Several studies suggest that increased rebleed risk is
The key factor influencing CCM management is the definition of
time limited and decreases a few years after the first hemor-
clinical hemorrhage, as the first clinical bleed seems to have
rhage (“temporal clustering”).23,35,36 However, even if this were
major impact on later behavior of the lesion.25 This definition is
the case, risk of rebleeding seems to be increased for at least 5
far from obvious. Not all clinical events (acute neurologic deteri-
years after the initial bleed.37,38 Brainstem and thalamic/basal
oration) are associated with evidence of concurrent hemor-
ganglia CCM are generally observed to have higher initial and
rhage,26 whereas hemosiderin ring is almost always present
rebleed rates (2.3 to 6.8 and 21 to 60%, respectively).11,39 It is not
even in clinically silent cases. The latter is explained by ultra-
clear, however, whether deep-seated CCM are more prone to
structural studies that suggest a compromised blood–brain bar-
bleeding, or whether any bleed is more likely to be symptomatic
rier at the site of a CCM that may lead to a chronic erythrocyte
due to higher functional density of deep eloquent structures.
leak into the surrounding brain and consequently to deposition
For therapeutic decision making, it is fundamental to note
of hemosiderin even in the absence of clinically significant hem-
the difference between first and repeated hemorrhages and
orrhage.27 In our opinion, the most comprehensive and clinically
also the distinct behavior of superficial and deep-seated lesions.
useful definition is described by Al-Shahi Salman et al: A hem-
Moreover, it is also possible that there are even more distinct
orrhage is a clinical event with acute or subacute onset symp-
subpopulations, some lesions behaving aggressively with a high
toms with radiological, pathological, surgical, or cerebrospinal
risk of rebleeding temporarily or for a much longer period after
fluid evidence of recent extra- or intralesional hemorrhage,
a first hemorrhage, whereas others are more quiescent. If this is
whereas the mere existence of a hemosiderin ring or the sole
the case, the proportion of more unstable lesions is unknown
increase in diameter are not considered as hemorrhage.15
and currently we are unable to predict from a first bleed which
pattern of behavior a CCM would follow.
10.2.2 Risk of Hemorrhage
Despite evidence of de novo CCM formation,14,28 retrospective
studies assuming lesion presence since birth gave similar esti-
10.2.3 Morbidity of Hemorrhage
mates for first-ever hemorrhage rates as prospective studies, 0.1 Morbidity of superficial hemispheric CCM after a bleed usually
to 2.7%/lesion/y16,17,29,30,31 and 0.25 to 3.1%/person/y.16,23,26,29,30, manifests in epilepsy and only rarely in focal neurologic deficit,40,
31,32 A first, bleed may destabilize a CCM and increase the risk of 41 whereas deep eloquent lesions have a higher rate of permanent

further bleeding, which is supported by the majority of focal neurologic morbidity and mortality.34,40,41,42 A single bleed

82

from a deep eloquent CCM leads to persisting neurologic deficit
in up to 40 to 60%, with a substantial risk of mortality,29,34,38,43
and the chance for permanent disability cumulatively increases
with each subsequent bleeding episode.38,42
10.3 Treatment Options for
Cavernomas
Three management options can be considered for a CCM:
microsurgical removal, SRS, and observation. Surgery for symp-
tomatic superficial hemispheric CCM is usually safe and effec-
tive,44 whereas incidental hemispheric lesions can be observed
Stereotactic Radiosurgery for Cavernomas
Fig. 10.1 (a) T1- and (b) T2-weighted axial
magnetic resonance images (MRIs) of a dorsal
ponto-mesencephalic cerebral cavernoma (CCM)
with evidence of recent hematoma and associ-
ated developmental venous anomalies (DVAs)
(arrow). T1-weighted (c) coronal and (d) sagittal
MRIs of the same DVA (arrow). (e) Anteroposte-
rior and (f) lateral views of the same DVA during
late venous phase of digital substraction angiog-
raphy. Angiographically occult CCM is not visible
(black dotted circle).
due to the low chance of causing persisting morbidity. For
deep-seated lesions, surgical removal is generally recom-
mended only in limited circumstances in experienced hands.
Lesions should either reach the pial or ependymal surface or
should be approachable through a noneloquent surgical corri-
dor, and also have a history of repeated hemorrhages with pro-
gressive neurologic deficit or cause significant mass effect. 36,45,
46,47 Surgery also has an adjuvant role in managing obstructive
hydrocephalus caused by growing or hemorrhagic CCM located
to highly eloquent regions when the symptoms arise from
raised intracranial pressure rather than from focal neurologic
deficit (▶ Fig. 10.2). Recent meta-analyses performed on surgi-
cal series for brainstem or thalamus/basal ganglia CCM found
83
 Stereotactic Radiosurgery for Cavernomas
10 to 14% persisting morbidity and 1.5 to 1.9% mortality, with
an 89 to 91% resection rate. Importantly, the rebleed rate never
goes to zero even after microsurgical removal due to the pro-
portion of residual lesions. Sixty-two percent of partially
resected lesions rebled with an annual rate of 0.5 to 2.0% and
with 6% mortality.11,12 Thus, though an effective salvage treat-
ment, surgical removal as a prophylactic measure in patients
harboring deep-seated CCM with no or minimal neurologic def-
icit is rarely considered.48,49 Thus, the question for these lesions
is whether to observe or treat them with SRS.7,10 Currently,
there is no consensus for the role of these three modalities in
CCM management. It is important to note that despite the over-
lap between indications,2,3 the three are not competitive but
complement each other, and a decision should be made on an
individual basis taking into account not only CCM location and
behavior, but the age and medical condition of the patient.
Moreover, the final treatment decision is also influenced by
neurosurgeon’s experience and the preference of the fully
informed patient.
10.3.1 Radiosurgery for Cavernomas
Rationale for Cavernoma Radiosurgery
It is well documented that radiation induces hyalinization and
thickening of the wall of the endothelium-lined pathological
vessels of an AVM.50 The idea to use SRS for an AOVM was ini-
tially based on the assumption that the majority of these lesions
were partially thrombosed AVM; therefore, the vessels would
be further obliterated by high-dose focused radiation, as
observed in the pathological vessels of a true AVM. 51 Despite
later histopathological studies finding most AOVM to be CCM,13
early clinical studies found that these lesions had responded in
a similar timescale to a true AVM, with reduction of rebleed
rate within a 2-year latency period after treatment.4 Moreover,
histological studies of surgically resected previously irradiated
CCM showed similar radiation-induced vasculopathy as seen in
AVM: fibrinoid necrosis, endothelial destruction, hyalinization,
marked fibrosis, and scar tissue formation.52,53,54 Most but not
all vessels were obliterated; there were also signs of neovascu-
larization similar to a subtotally obliterated AVM.54 Of note,
these specimens came from lesions that remained symptomatic
after radiation, and those rendered silent by the treatment may
84
Fig. 10.2 Computed tomography scan of the
same patient as in ▶ Fig. 10.1. (a) 2.5 weeks after
presentation demonstrating occlusive hydroce-
phalus. (b) Due to symptoms of raised intra-
cranial pressure, a third ventriculostomy was
performed resulting in improved clinical and
radiological states. Of note, at this stage micro-
surgical removal of cerebral cavernoma was not
necessary, as the primary problem was occlusive
hydrocephalus and not progressive focal neuro-
logic deficits due to brainstem compression. In
case of growing or clinical progression, micro-
surgery is the treatment of choice. However, in
case of hematoma resolution, stereotactic radio-
surgery is a good alternative for microsurgery in
this otherwise clinically intact patient.
actually show complete response, were they removed for analy-
sis. Alternatively, the scarring of the wall of such a low-pressure
lesion may sufficiently stabilize it to prevent a rebleed even
without full obliteration.
The Effect of Radiosurgery on Hemorrhage Rate
The primary aim of SRS is to reduce the risk of future hemor-
rhage and consequential neurologic deterioration. Indeed, this
is reported by the majority of SRS studies comparing pre- and
posttreatment bleed rates beyond a latency of 2 to 3 years. 7 The
first report of a large clinical series using a modern SRS techni-
que with sufficient follow-up time was published in 1995. 4 It
was found that the rebleed rate fell from 32%/patient/y pre-
treatment to 8.8%/patient/y within the first 2 years after treat-
ment and to 1.1%/patient/y thereafter. Recent updates from this
group including more patients and longer follow-up time 55 and
other contemporary SRS series focusing on deep eloquent
lesions,38,56,57,58,59,60 and studies analyzing mixed population of
lobar and deep CCM, confirmed this finding.41,61,62
The Effect of Radiosurgery on Epilepsy
Although for patients with intractable epilepsy from a CCM,
surgical resection of hemispheric CCM is the treatment of
choice, as it is associated with low morbidity and high effective-
ness.44 However, several conditions may warrant treatment
alternatives, including eloquent location lesions, the patient’s
medical condition, or the patient’s preference. For these cases,
SRS may be a real alternative. A retrospective multicenter study
demonstrated that 53% of the patients suffering from long-last-
ing epilepsy refractory to medical therapy became seizure-free
(Engel classes IA and B) within a mean of 4 months after SRS;
20% showed significant (class II) and only 26% little or no
improvement (classes III and IV).63 Patients with CCM located in
the mesial temporal lobe did worse than those treated in other
locations. More recent studies found similar results: 39 to 54%
of the patients became seizure-free (class I), and 14 to 20.5%
improved significantly (class II).62,64 A meta-analysis found that
31% of the patients became seizure-free and 35% improved sig-
nificantly after SRS.65 In the first instance, this seems inferior to
surgical series, as class I response was achieved in 69% of the
surgical cases refractory to previous medical therapy. 66

However, considering preintervention seizure duration, SRS
seems to be as effective as surgery if applied early after seizure
onset. Although 90% of the patients treated with SRS improved
with short history of epilepsy (≤ 3 years) and only 38.5% with
longer lasting epileptic disease,64 81% improved with ≤ 1-year
history and 70% with longer duration of epilepsy in the surgical
group.66
Critical Considerations in Cavernoma
Radiosurgery
Unlike for an AVM, there is currently no radiological measure
for CCM cure after SRS, which certainly keeps skepticism alive.
These lesions are angiographically occult, and MRI generally
fails to demonstrate a definite change in the appearance of the
lesion after SRS. Although only a few of the irradiated CCM
enlarge41,56,67,68 and the proportion of true growth is somewhat
higher in an untreated population,14,28 CCMs after SRS appear
heterogenous on MRI. Approximately half of the lesions
shrank,55,67 but postradiosurgery shrinkage may in part be due
to resolution of intralesional hematomas. Thus, it is impossible
to tell from an individual lesion whether it is secured from fur-
ther bleed or not.
Due to the lack of an exact measure for cure, a prospective
randomized controlled trial to clarify the conflicting issues sur-
rounding SRS may appear attractive. However, it is unlikely to
realize such a trial in the near future for numerous reasons, par-
ticularly due to the widely different immediate impact of the
three options that would limit enrollment. We have therefore
recently suggested a prospective international data collection
including all detected cases regardless of subsequent choice of
management modality.7 Until such data arrive to answer critical
voices addressing both effectiveness and safety of CCM SRS, it is
crucial to define standard data collection and modern SRS treat-
ment protocol.
Although most of the published literature demonstrated a
reduction in the rebleed rate of CCM with multiple hemor-
rhages after a 2-year latency period following SRS, this is not a
universal finding: A temporary increase in rebleed rate was also
reported,38,67,69 as well as reduction of rebleed rate after a
latency period longer than 2 years.53 We have alluded to the dif-
ficulties interpreting hemorrhagic events, particularly when
attempts are made to account for prediagnosis clinical events;
these exceptions may reflect the varied interpretation of what
counts as a hemorrhage and may well be due to different pa-
tient selection. The key for proper interpretation of CCM SRS is
the understanding of their natural history—to distinguish
between the risk of first and repeated hemorrhages, and to take
the anatomical position into account because lobar CCMs have
a much lower annual incidence both of bleed and rebleed than
deep eloquent lesions. Analyzing mainly55 or exclusively38,57,58,
70 results of SRS for deep eloquent CCM that had bled at least
twice prior to treatment (i.e., proven to behave more aggres-
sively), we find consequently a sharp decrease in the annual
rebleed rate from 30.5 to 32.5% to 0 to 2.4% within 2 years after
SRS. When confining analysis exclusively to SRS for CCM that
had bled no more than once prior to treatment, during the first
2 years after SRS a higher rate of hemorrhage may be found
when compared with first ever hemorrhage rate.38 However,
this is still much lower than the rebleed rate of untreated
Stereotactic Radiosurgery for Cavernomas
lesions expected in a mixed population of CCM with more
aggressive and benign nature. Importantly, the rate of further
bleed after the 2-year latency period is minimal even in this
population. Recent debate on the effect of SRS on CCM hemor-
rhage rate is centered on whether the decrease of the rebleed
rate within 2 years can really be attributed to the radiobiologi-
cal effect of the treatment or whether it simply reflects natural
history, as several observational studies raised the idea that
hemorrhages may occur in clusters.23,35,36 The contrary argu-
ment is supported by the observations that lesions with long
pretreatment history of repeated hemorrhages seem to main-
tain a high rate of hemorrhagic events for many years.37,38
Another supporting argument is that the time course of reduc-
tion in rebleed rates after SRS parallels the time course of histo-
logical changes known to develop after irradiation. Thus,
coincidence of the marked fall in rebleed rate within 2 years
after SRS with the natural history seems unlikely. As current
radiosurgical literature lacks untreated control group, 1 this
debate will be speculative until such data arrive.
Early studies, often cited by critics of SRS, reported high radi-
ation-associated complication rates. However, those studies
were from an era with poor delineation of the target with com-
puted tomography (CT) or less conformal MRI, and with the use
of higher-dose protocols.53,60,69,71 Clearly, these studies repre-
sent the early experimental phase of the collective learning
curve of CCM SRS. Contemporary treatment protocols, particu-
larly those using a gamma radiation–based instrument, include
prescription dose less than 20 Gy (typically 12–15 Gy), highly
conformal MRI-based treatment planning, and without evi-
dence of recent bleed (type II or III,14 at least 3 months after last
hemorrhage) (▶ Fig. 10.3). The lesion is defined strictly within
the hemosiderin ring that is speculated to be a radiosensi-
tizer72; an associated DVA is preserved similarly to microsur-
gery,43 as irradiating a DVA is associated with a high rate of
complication.73 Modern studies applying such treatment proto-
cols have reported low rates of adverse radiation effects result-
ing in only low rate of mild persisting morbidity, and mortality
related to the treated lesion was minimal.7
Utilization of SRS for this condition is expanding. Since the
introduction of modern CCM SRS in 1995, we treated 314
lesions in 285 patients at the National Centre for Stereotactic
Radiosurgery in Sheffield until 2012. Of these, 191 lesions were
deep seated. Reflecting our aim to move toward earlier treat-
ment, numbers increased from an annual 3 to 4 treatments
before 2000 up to an average of 12 between 2000 until 2011,
and to 26 in 2012.7 When publishing our data in 2010, we had
treated 46% of deep-seated CCM presenting in our catchment
area with SRS, but estimated to treat only 10 to 30% of newly
diagnosed such lesions in the UK. We concluded that the geo-
graphical difference represented a reluctance to refer these
lesions for SRS, owing to the perceived conflicting evidence on
its safety and effectiveness.38 The fact that the number of
treated deep-seated CCM almost doubled since 2010 suggests
that the argument for early SRS treatment is winning at least in
the clinical practice in the UK.
Critical Review of Radiosurgical Literature
We have recently suggested standard data collection criteria to
the radiosurgical community, as the lack of quality evidence
85
 Stereotactic Radiosurgery for Cavernomas
makes it currently impossible to lay down a universal indication
algorithm for SRS in the management of CCM.7 Moreover, the
disappointingly heterogenous quality of literature on CCM SRS
with distinct measures of natural history, posttreatment bleed
rates, and morbidity provides ammunition for the critics who
often cite early experimental and low-quality contemporary
studies with predilection to support their negative view.2,9,10
Improved data collection with standardized reporting and
treatment criteria seems to be the most realistic way to obtain
a better view on safety and effectiveness until high-level evi-
dence becomes available.
First, the definition of clinical hemorrhage should be standar-
dized in all future studies published in the CCM field, 15 leading
to a clear distinction between hemorrhagic and nonhemorrha-
gic clinical events, helping their separate documentation. 38 Ret-
rospective annual first bleed rate for treated lesions (lesion/y)
86
Fig. 10.3 (a) T1-weighted and (b) T2-weighted
axial, coronal, and sagittal, as well as (c) treat-
ment planning on proton density-weighted
magnetic resonance images (MRIs) of a type II14
right thalamic cerebral cavernoma (CCM) at the
time of stereotactic radiosurgery. (d) Treatment
planning T2-weighted MRI of a type II CCM
located in the left midbrain tegmentum. Red line:
lesion definition. Yellow line: 50% (prescription)
isodose line. Green line: 30% isodose line.
should be reported separately to annual rebleed rate until treat-
ment. Hemorrhage rates should be calculated separately within
2 years posttreatment and thereafter. In our view, it is crucial to
offer separate analysis for superficial and deep-seated lesions,
and similarly for lesions with 0, 1, or multiple bleeds due to
their disparate natural history. Although causal relationship
with SRS is not proven for all cases, all lasting neurologic deteri-
oration unrelated to a posttreatment hemorrhage should be
considered as an adverse radiation effect to determine the max-
imal potential morbidity of SRS. Due to delayed protection that
is specific to this treatment modality, morbidity related to post-
treatment hemorrhage should also be recorded accurately.
With contemporary treatment protocol, a gamma radiation–
based instrument appears to be the most precise SRS treatment
due to the highest conformity achieved with multiple isocen-
ters. The largest experience has been accumulated worldwide
 Stereotactic Radiosurgery for Cavernomas

with Gamma Knife SRS over the last decades, but a Rotating
Gamma System also seems to be effective.41
A few systemic reviews dealing with CCM SRS have been pub-
lished; none of them meet the above criteria because they typi-
cally pooled studies of heterogenous quality. Surgical reviews
usually refer to early reports, thus supporting a negative view.8,
11,39 Similar to all therapeutic interventions, SRS also had its
technical evolution, and using early experimental studies as
arguments against SRS is similar to quoting poor surgical results
from a premicroscopic era as arguments against surgery. A
recent systemic review applying criteria of modern evidence-
based medicine found only one study comparing SRS with sur-
gery and one comparing SRS with observation.1 However, both
studies represented early attempts, with poor definition of natu-
ral history, selection criteria, and follow-up. A detailed extensive
meta-analysis pooled all available SRS studies published until
2009 without distinction on natural history, anatomical location,
and SRS technique.65 As large, modern SRS series has been pub-
lished since then: This study unavoidably underestimates its
effectiveness with overestimation of its morbidity. The other
study specifically focused on SRS of brainstem CCMs, analyzing
five series.74 Of these, only three would meet strict methodical
criteria of data analysis based on our current knowledge of
natural history and of modern CCM SRS techniques.57,58,70
▶ Table 10.2 summarizes data from the most relevant contem-
porary SRS series using our recently suggested criteria, focusing

Table 10.2 Summary of CCM series using modern gamma radiation–based stereotactic radiosurgery
Study Patients/lesions Deep Superficial Pre- Pre-TRT Post- Post- Permanent Post-TRT Mortality Treatment
(N) (n) (n) TRT 1st rebleed TRT TRT ARE bleed re- related to years
bleed (/y) bleed bleed (%) lated mor- treated
(/y) until 2 after 2 bidity (%) CCM (%)
y (/y) y (/y)

Kida & Ha- 152 87 65 N/A 31.8a 8b <5 N/A N/A 2 1991–2001
segawa,
200461†

Liu et al, 125 63 49 N/A 29.2 10.3 3.3 3.2 9.6 0 1993–2002
200562‡

Kida, 84 84 0 N/A N/A 7.1 1.8 N/A N/A 2.4 N/A

200956†

Wang et al, 96 13 83 N/A N/A 4.2 < 2.1 5.2 N/A 0 1995–2005
201064

Lunsford et 103 93 10 N/A 32.5 10.8 1.06 1 N/A 1 1988–2005

al, 201055††

Monaco et 68 68 0 N/A 32.38 8.2 1.37 1.5 N/A 2.9 1988–2005

al, 201070††

Nagy et al, 113/118 118 0 2.2c 30.5 5.1 1.3 7.3 7.3 0 1995–2008
201038 2.9 15 2.4

Lee et al, 49/50 50 0 N/A 31.3 3.3 1.74 4.1 N/A 0 1993–2010
201257‡

Jay et al, 16 16 0 N/A N/A 3.72 3.59 0 0 6.25 1998–2009

201275

Park & 20 20 0 N/A 39.5 8.2 0 5 0 0 2005–2010

Hwang,
201358

Liscák et al, 112 50 62 N/A N/A 3.2 0.5 0.9 3.6 2.7 1992–2000
201367

Frischer et 38 38 0 N/A 7.2 2.63 0.6 7.9 N/A N/A 1987–2011

al, 201359

Fedorcsák et 45/51 14 37 2d 21.7 7.1 0 7 7 0 2008–2012

al, 201441 0.3 0 0 0 0 0 0

Abbreviations: ARE, adverse radiation effect; CCM, cerebral cavernoma; N/A, not applicable.
Source: Data from 38,41,55–59,61,62,64,67,70,75
Note: Latest reports from each group are listed only. (All except one group used Leksell Gamma Knife; the one exception 41 used GammaART-6000).
†, ‡, †† Data from the same groups analyzing either both deep-seated and superficial, or brainstem lesions only.
aDuring 5 years prior to radiosurgery.
bFirst year after treatment.
cFirst line: “low-risk” group, second line: “high-risk” group.
dFirst line: deep-seated, second line: superficial.

87
 Stereotactic Radiosurgery for Cavernomas

mainly on the effect of hemorrhage rate of SRS and on its
safety.7 Only studies using a modern SRS technique and provid-
ing useful information with at least one of the relevant outcome
parameters were considered.38,41,55–59,61,62,64,67,70,75 Of note, stud-
ies specifically focusing on the effect of SRS on epilepsy are not
listed. We must also acknowledge that all of these are retrospec-
tive observational studies that lack a control group.
Hemorrhage
For pragmatic reasons, the minimal definition of clinical hem-
orrhage is a new clinical event associated with imaging evi-
dence of hemorrhage.38,41,55,57,58,70 However, over half of the
listed studies fail to define what they consider as hemorrhage.
Moreover, the lack of distinction between deep-seated and
superficial CCMs55,61,62,64,67 and the lack of distinction between
first and repeated bleed67 make it hard to obtain a proper view
on the real effect of SRS on hemorrhage rate. On this basis of
strict definition, the annual rebleed rate falls from 30.5 to 39.5%
pretreatment to 3.3. to 15% within the first 2 years after SRS,
and to 0 to 2.4% thereafter in deep-seated lesions with multiple
hemorrhages (n = 179).38,57,58,70 Only one study analyzed sepa-
rately those deep-seated lesions after a single or no bleed prior
to SRS and found that annual bleed rate from the pretreatment
2.2% stabilized at 1.3% after a 2-year period of temporary
increase to 5.1% (n = 77).38 As discussed earlier, this result pre-
sumably reflects the proportion of more aggressive lesions
treated before a second bleed and the delayed response to SRS.
Morbidity after Radiosurgery
The rate and severity of morbidity in untreated cases are both
significantly associated with hemorrhage, exacerbated by
repeated hemorrhage, and are seen more readily when CCMs
are in deep eloquent locations. As the beneficial effect of SRS is
expected only after a latency period and the risk of hemorrhage
never seems to reach zero, posttreatment hemorrhage may also
add to persisting morbidity. In those studies where this was
mentioned, 0 to 9.6% of patients suffered persisting neurologic
deficit due to hemorrhage after SRS (n = 442)38,41,58,62,67,75 and
all mortality (1.2%, n = 747) related to treated CCM also came
from hemorrhage.38,41,58,61,62,64,67,70,75 Once suffering from a
bleed, the likelihood of permanent deficit seems to be the same
with posttreatment hemorrhages as with pretreatment hemor-
rhages, suggesting that the benefit of SRS is not to reduce the
severity but the frequency of bleeds.38

Fig. 10.4 Proposed algorithm for the management of cerebral cavernomas. CCM, cerebral cavernoma; MRI, magnetic resonance imaging. *Surgery is
first option in most cases, but stereotactic radiosurgery is a valid alternative. **Both modalities appear to be effective, but currently there is no
evidence to demonstrate superiority of either. (From Nagy G, Kemeny AA. Stereotactic radiosurgery of intracranial cavernous malformations.
Neurosurg Clin N Am. 2013;24:584. Used with permission.)

88

Adverse radiation effects may be temporary, as perilesional
edema causing either temporary neurologic deficits or remain-
ing clinically silent is typically seen within 12 months after SRS.
Persisting adverse radiation effects typically present later, and
using modern treatment protocols (see above) their rates are
low (0 to 7.9%, n = 324), resulting in only mild morbidity even in
deep-seated lesions.38,41,57,58,59,70,75 Persisting morbidity for
hemispheric lesions is negligible.
10.4 Summary
Stereotactic radiosurgery for CCM is one of the most vibrant
fields of contemporary SRS, which has gained wide acceptance
during the last two decades. This may be in large part due to
better imaging, the evolution of radiosurgical techniques, and
our better understanding of the natural history despite their
heterogenous and unpredictable nature. Stereotactic radiosur-
gery for this indication evolved from experimental attempts
treating aggressive inoperable lesions to becoming an attractive
treatment modality, especially for deep-seated lesions soon
after first presentation to prevent further clinical deteriora-
tion.6,7 Undoubtedly, particularly during the last few years, it
has been considered to complement microsurgery and wait-
and-watch policy (▶ Fig. 10.4).7
We acknowledge that SRS in the management of CCM
remains controversial due to the lack of high-level evidence,
although dissenting voices are increasingly in the minority.
There is now sufficient positive experience supporting the use
of SRS for CCMs located in the brainstem, thalamus, basal gan-
glia, or internal capsule, once they become symptomatic. Fur-
thermore, due to the recognized cumulative morbidity of
repeated hemorrhages on one hand and the low risk of radia-
tion induced adverse effects on the other, we advocate an early
intervention 3 to 6 months after the first bleed (once the pa-
tient has recovered and hematoma resolved). It has been said
that “controversy is the child of ignorance.” The CCM contro-
versy may remain the subject of debate until after further rigor-
ous studies are conducted.
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clinical disability in patients with cavernous malformations of the brain. Neu-
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[41] Fedorcsák I, Nagy G, Dobai JG, Mezey G, Bognár L. [Radiosurgery of intracere-
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brainstem: experience with 100 patients. J Neurosurg 1999; 90: 50–58
[44] Lekovic GP, Porter RW, Spetzler RF. Supratentorial and infratentorial caver-
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[46] Dukatz T, Sarnthein J, Sitter H, et al. Quality of life after brainstem cavernoma
surgery in 71 patients. Neurosurgery 2011; 69: 689–695
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malformations. Acta Neurochir (Wien) 2013; 155: 2079–2083
[50] Szeifert GT, Levivier M, Lorenzoni J, Nyáry I, Major O, Kemeny AA. Morpho-
logical observations in brain arteriovenous malformations after gamma knife
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radiosurgery of angiographically occult vascular malformations: indications
and preliminary experience. Neurosurgery 1990; 27: 892–900
[52] Gewirtz RJ, Steinberg GK, Crowley R, Levy RP. Pathological changes in surgi-
cally resected angiographically occult vascular malformations after radiation.
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[53] Karlsson B, Kihlström L, Lindquist C, Ericson K, Steiner L. Radiosurgery for
cavernous malformations. J Neurosurg 1998; 88: 293–297
[54] Nyáry I, Major O, Hanzély Z, Szeifert GT. Histopathological findings in a surgi-
cally resected thalamic cavernous hemangioma 1 year after 40-Gy irradiation.
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[55] Lunsford LD, Khan AA, Niranjan A, Kano H, Flickinger JC, Kondziolka D. Ster-
eotactic radiosurgery for symptomatic solitary cerebral cavernous malforma-
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[56] Kida Y. Radiosurgery for cavernous malformations in basal ganglia, thalamus
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role of Gamma Knife surgery. J Neurosurg 2012; 117 (Suppl): 164–169
[58] Park SH, Hwang SK. Gamma knife radiosurgery for symptomatic brainstem
intra-axial cavernous malformations. World Neurosurg 2013; 80: e261–e266
[59] Frischer JM, Gatterbauer B, Holzer S, et al. Microsurgery and radiosurgery for
brainstem cavernomas: effective and complementary treatment options.
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graphically occult vascular malformations. Neurosurg Focus 2009; 26: E16
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1229–1236, discussion 1236–1238
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surgery and the risk of haemorrhage from cavernous malformations. Br J
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[72] St George EJ, Perks J, Plowman PN. Stereotactic radiosurgery XIV: the role of
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diosurgery for intracranial cavernous malformations: a sustainable hypothe-
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[73] Lindquist C, Guo WY, Karlsson B, Steiner L. Radiosurgery for venous angio-
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[75] Jay SM, Chandran H, Blackburn TP. Gamma knife stereotactic radiosurgery for
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370

11 Stereotactic Radiosurgery for Dural Arteriovenous
Fistulas
David Hung-Chi Pan, Wen-Yuh Chung, Huai-Che Yang, and Cheng-Chia Lee
Key Points
● A dural arteriovenous fistula is considered an acquired dis-
ease. Dural arteriovenous fistulas with anterograde cortical
venous drainage have been clinically regarded as benign,
whereas dural arteriovenous fistulas with retrograde cortical
venous drainage are considered aggressive in behavior.
● For dural arteriovenous fistulas without retrograde cortical
venous drainage or dural arteriovenous fistulas with benign
symptoms, radiosurgery may be indicated as an initial treat-
ment. An obliteration rate of more than 70% is expected for
cavernous sinus dural arteriovenous fistulas, and 60% for the
non–cavernous sinus dural arteriovenous fistulas. Few com-
plications are reported.
● For aggressive dural arteriovenous fistulas with extensive ve-
nous reflux, immediate risks of hemorrhage, progressive
neurologic deficits, or severe venous hypertension, initial
treatment with endovascular procedure including emboliza-
tion and angioplasty or with surgery is suggested.
11.1 Introduction
Intracranial dural arteriovenous fistulas (DAVFs) are abnormal
arteriovenous communications within the dura, in which me-
ningeal arteries shunt blood directly into the dural sinus or lep-
tomeningeal veins.1,2 The incidence of DAVFs has been
estimated at 5 to 20% of all intracranial vascular malforma-
tions.3,4,5,6 Dural arteriovenous fistulas constitute only 6% of
supratentorial vascular malformations, whereas they are 35% of
infratentorial malformations.7 The mean age of presentation for
a DAVF is 50 to 60 years of age with no sex preference, although
there is a wide range seen.8,9 Unlike the more common intra-
cerebral or parenchymal arteriovenous malformations (AVMs),
DAVFs are thought to be acquired due to inflammation, throm-
bosis, or trauma of the dural sinus. However, the exact etiology
and underlying disease are difficult to trace in many cases and
the DAVFs are considered idiopathic.10,11 Dural arteriovenous
fistulas most commonly occur in the regions of the cavernous
sinus, transverse/sigmoid sinuses, tentorium/ orcula, or cerebral
convexities with drainage to the superior sagittal sinus. 1,12,13,14
A thorough understanding of DVAF morphology requires a
detailed cerebral angiographic investigation. Drainage of the
venous flow from a DAVF can be antegrade or retrograde
through a dural sinus, through a cortical vein, or both. The pat-
tern of the venous drainage is not necessarily static though.
Gradual alternation in the venous flow from antegrade to retro-
grade and delayed recruitment of arterial feeders into the nidus
(sump effect) have been observed in some patients. 3,9,13 This is
hypothesized to occur as a result of progressive sinus hyperten-
sion with redirection of the blood flow into cortical veins. 2,12,15
The gradual venous hypertension and reflux of the cortical
Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
veins may eventually predispose to the risks of cerebral hemor-
rhage and/or other neurologic deficits.1
Not all DAVFs demonstrate such a progressive clinical course
though. Although not frequently seen, some DAVFs can regress
and thrombose gradually resulting in a spontaneous cure.16,17
The factors predisposing to DAVF progression or involution
have not been clearly clarified.
11.2 Angioarchitecture and
Classifications of Dural
Arteriovenous Fistulas
There are many different classifications of DAVFs. The most
popular classifications are the Borden-Shucart and Cognard
classifications.12,15 Both systems classify the DAVFs based on
their angiographic venous drainage pattern. However, owing to
the unique clinical characteristics of DAVFs involving the caver-
nous sinus (CS), Barrow’s classification, which describe the
feeding arteries to the CS DAVFs, is also commonly used to clas-
sify this particular type of DAVFs.18
The Borden-Shucart system distinguishes DAVFs depending
on the site of drainage and the presence of cortical venous
drainage.15 Tape I DAVFs drain directly into the sinus or menin-
geal veins with antegrade flow, whereas type II DAVFs have ret-
rograde flow through the sinus into the subarachnoid veins.
Type III DAVFs directly drain into the subarachnoid veins in a
retrograde fashion.
The system of Cognard similarly separates DAVFs depending
on the site of drainage and the presence of cortical venous
drainage, but also considers the direction of flow through the
draining vein as well as the presence of cortical venous ecta-
sia.12 Cognard type I DAVFs have solely antegrade sinus drain-
age, similar to the Borden-Shucart system. Cognard type II
DAVFs demonstrate retrograde drainage and are subdivided
depending on whether drainage is through the sinus (IIa), corti-
cal vein (IIb), or both (IIa + b). Cognard type III DAVFs drain
directly into cortical veins similar to Borden-Shucart, but Cog-
nard gives lesions with venous ectasia a separate designation of
type IV. Dural arteriovenous fistulas that drain into spinal peri-
medullary veins are designated type V by Cognard. Cognard et
al present their series of 258 patients and demonstrate a strong
correlation between DAVF type and rate of aggressive clinical
symptoms and risk of hemorrhage.
According to Barrow’s classification,18 CS DAVFs are classified
into direct (type A) and indirect (types B–D) types. Direct CS
DAVFs are high-flow shunts between the cavernous portion of
the internal carotid artery and the CS, usually caused by a trau-
matic laceration of the internal carotid artery or rupture of an
intracavernous carotid aneurysm. Indirect CS DAVFs are dural
fistulas between the CS and meningeal branches of the internal
carotid artery (type B), the external carotid artery (type C), or
both (type D).
91
 Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
11.3 Clinical Manifestations
The clinical presentation of a DAVF is dependent on its location
and pattern of the venous drainage. The most common loca-
tions are the CS followed by transverse-sigmoid sinus (TSS) that
together account for about 80% of the cases.5 Patients with CS
DAVFs often have ocular manifestations (exophthalmos, chemo-
sis, visual impairment, and diplopia). The duration of clinical
symptoms prior to diagnosis of a CS DAVFs is about 4 months at
median. In the TSS DAVFs, pulsatile tinnitus and throbbing
headache were the most common symptoms.5
Similar to other cerebral arteriovenous malformations,
DAVFs can hemorrhage, with an estimated annual risk of
approximately 1.8%.19 van Dijk et al in 2002 reported that
persistence of the cortical venous reflux in DAVFs yields an
annual hemorrhage rate of 8.1% and a mortality rate of
10.4%.20 Duffau et al reported a high risk of early rebleeding
(35% within 2 weeks) after the first episode of hemorrhage,
with graver consequence from the second bleed. 21 Söderman
et al in 2008 evaluated hemorrhage rate in their 85 cases of
DAVFs with retrograde cortical venous drainage. They found
a lower hemorrhage rate compared with those of the other
previous reports. In their patients already presenting with an
intracranial hemorrhage, the annual risk for the recurrent
hemorrhage was 7.4%, whereas in those patients not present-
ing with a hemorrhage, the bleeding rate was approximately
1.5% per year.22 Pan et al in 20135 reported a Gamma Knife
radiosurgery (GKRS) series of 321 DAVF patients, 7 of the 206
CS DAVF patients (3.4%) experienced a hemorrhage, and 16 of
the 115 noncavernous sinus (NCS) DAVF patients (13.9%) had
a hemorrhagic event prior to diagnosis. The report also dem-
onstrated that arteriovenous shunts involving the anterior
skull base, tentorium, or sphenoparietal sinus harbored a
higher risk of hemorrhage (▶ Table 11.1).5
Table 11.1 Incidence of intracerebral hemorrhage (ICH) and nonhemorrhagic neurologic deficit (NHND) before GKRS in 321 patients with DAVFs
Number ICH
Cavernous sinus 206 7 3.4
Transverse-sigmoidal 72 8 11.1
sinus
Petrosal sinus 9 1
Superior sagittal sinus 8 0
Tentorium 9 2
Frontal base (anterior 6 3
fossa)
Sphenoparietal 4 2
Vein of Galen 2 0
Jugular foramen 2 0
Clivus 2 0
Foramen magnum 1 0
Total 321 23
Abbreviations: DAVFs, dural arteriovenous fistulas; GKRS, Gamma Knife radiosurgery; NHND, nonhemorrhagic neurologic deficits: hemiparesis,
hemiparesthesia, cerebellar sign, dementia, mental confusion.
92
Because a DAVF is considered an acquired disease, two poten-
tial inciting factors for DAVF formation were found: 13.4% of the
patients had history of head trauma and 6% had prior head and
neck surgeries.5 Dural arteriovenous fistulas with anterograde
cortical venous drainage have been clinically regarded as
benign, whereas DAVFs with retrograde cortical venous drain-
age (CVD) are considered aggressive in behavior.9,20,23 In 1990,
Awad et al reported a meta-analysis of 377 DAVFs and defined
100 aggressive cases as those with hemorrhages or progressive
focal neurologic deficits; the other 277 DAVFs were defined as
benign cases.1 They concluded that no location of the DAVFs
was immune from the aggressive neurologic behavior. The fac-
tors that predict aggressive neurologic presentation included
leptomeningeal venous drainage, variceal or aneurysmal
venous dilation, and galenic drainage of the DAVFs.
Beyond hemorrhagic episodes, some patients suffered persis-
tent or slowly progressive neurologic deficits, including symp-
toms of hemiparesis, hemiparesthesia, cerebellar sign,
dementia, and mental confusion. From the authors’ experience
in analysis of 321 DAVF patients, the incidence of nonhemor-
rhagic neurologic deficits is 4.4% (9 of 206 cases) in CS DAVFs
and 37.4% (43 of 115 cases) in NCS DAVFs.
The relationship between duration of clinical symptoms and
angiographic types of DAVF was also analyzed. In 115 patients
with NCS DAVFs, the average duration of symptoms before diag-
nosis in Borden type I (Cognard type I and type IIa) patients
(n = 63) was 19.2 months (range 3–168 months). For Borden
type II (Cognard type IIb and type IIa + b) patients (n = 35), the
average duration of symptoms was 39.1 months (range 2–180
months). For Borden type III (Cognard type III, type IV, and type
V) patients (n = 17), the average duration of symptoms was 23.7
months (range 1–144 months). This longer duration of symp-
toms seen with higher-grade DAVFs (p < 0.0001 between Bor-
den type I and type II/III, independent t test) suggests that
% NHND %
9 4.4
27 37.5
11.1 4 44.4
— 3 37.5
22.2 4 44.4
50.0 3 50
50.0 0 —
— 1 50.0
— 0 —
— 0 —
— 1 100.0
7.2 52 16.2

DAVFs with retrograde flow may be present for longer time pri-
or to the diagnosis.
11.4 Treatment Options
The recommended therapeutic intervention for a DAVF is
dependent on the anticipated natural history and hemodynam-
ic change of the lesion. For lesions with antegrade sinus drain-
age (Borden type I) and benign clinical manifestations,
intervention is usually palliative or observational unless the
patient’s symptoms are intolerable.6,9 For patients with throb-
bing headache, pulsatile tinnitus, ophthalmologic deterioration,
progressive neurologic deficits, increased intracranial pressure,
or elevated risk of hemorrhage, therapeutic intervention is rec-
ommended.12,15,24,25
Advances in the field of interventional neuroradiology have
increased treatment options for patients with DAVFs. Oblitera-
tion of the fistula can be attempted through a transarterial or
transvenous route. Transarterial embolization alone rarely leads
to a complete obliteration of the DAVF because there are usually
numerous arterial feeders to the nidus. The purpose of a trans-
arterial approach is mainly for reduction of arterial feeders and
the palliative symptomatic relief.24 For curative treatment, addi-
tional treatment through a retrograde transvenous approach
may be necessary. In transvenous embolization, superselective
disconnection of the refluxing vein is preferred over sacrifice of
the dural sinus, although this sometimes becomes necessary to
achieve a cure.24 Endovascular therapy can also be combined
with surgery or radiosurgery when it is not feasible to com-
pletely obliterate a DAVF alone.
An open surgical approach is indicated for DAVFs with
aggressive features that are not amenable to comprehensive
endovascular treatment. Typically, lesions involving the anteri-
or cranial fossa or tentorial incisura are often associated with
hemorrhage; thus, surgical intervention is indicated. Surgical
strategies include ligation of the fistula at the junction with the
drainage vein, interruption of arterial feeders, coagulation and/
or excision of the fistula in the dura, and resection of the
involved sinus.17,26,27 Recent studies have suggested that dis-
connection of the draining vein alone without resection of the
sinus is equally efficacious as resection of the fistula. The former
can avoid risks of venous hypertension associated with the
sinus removal, particularly where the sinus is patent. 28,29,30,31
Reported morbidity and mortality of surgical intervention has
ranged from 0 to 13%.32
Stereotactic radiosurgery has long been used for treatment of
intraparenchymal AVMs; treatment of DAVFs would be a natu-
ral extension of this. In 1993, Chandler and Friedman first
reported a case in which a DAVF located in the anterior fossa
was successfully treated with radiosurgery.33 Since then, radio-
surgical treatment has been delivered for DAVFs in various loca-
tions, including the CS, TSS, superior sagittal sinus, tentorium,
and other locations.34–42 Guo et al35 and Pollock et al40 have
separately reported an approximately 80% obliteration rate for
CS DAVFs treated by Gamma Knife alone or combined with
embolization. Söderman et al in 2006 reported on 49 patients
with 52 DAVFs, with a 68% obliteration rate and another 24%
with flow regression at 2 years.6 More recently, Yang et al in
2010 reported a series of 40 DAVF patients treated at the
Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
University of Pittsburgh (UPMC). They found an 83% obliteration
rate for patients who had up-front radiosurgery with emboliza-
tion, and a 67% obliteration rate in patients who underwent
radiosurgery alone.43 At the University of Virginia, Cifarelli et al
in 2010 reported a 65% obliteration rate in a series of 55 DAVF
patients.44 Radiosurgery is often combined with endovascular
therapy to provide immediate relief of symptoms and possibly
reduction of the hemorrhage risk.8,14,34,36,37,45,46 In some reports,
DAVF obliteration rates using radiosurgery alone are comparable
to those using the combined method, as the rates of sympto-
matic improvement.35,37,39 Complications directly related to the
radiosurgical procedure are notcommonly found.
11.5 Radiosurgical Technique and
Planning
11.5.1 Principle
Stereotactic radiosurgery is characterized by a steep dose falloff
of radiation to the target margin; therefore, it relatively spares
the radiation exposure to surrounding normal tissues. Its applica-
tion has been improved by many neurosurgeons, neuroradio-
logists, radiation oncologists, and physicists to advance the
treatment of intracranial vascular or neoplastic lesions. Although
stereotactic radiosurgery (SRS) facilities change over the ensuing
decades, the basic concepts have not changed: the radiobiological
effects of radiosurgery on vascular lesions is due to endothelial
damage, undulation of internal elastic membrane, proliferative
vasculopathy with narrowing the lumen, subendothelial cell pro-
liferation, and finally, complete lumen obliteration.47
11.5.2 Stereotactic Frame Placement
Patients undergo stereotactic frame placement (Leksell frame,
type G; Elekta Instruments AB, Stockholm, Sweden) supple-
mented by local anesthesia with conscious sedation as needed.
Prior to the frame placement, the scalp is prepared with Beta-
dine and alcohol, and the areas of the pin placements are infil-
trated with a long-acting local anesthetics. For the CS DAVF, the
target is usually central of the skull, and the axis of frame place-
ment is in the midline without lateralization. On the other
hand, the frame is usually lateralized to the side of the lesion
when a DAVF is located in the region of the lateral sinus.
11.5.3 Radiographic Images
After the frame fixation, all patients undergo thin-sliced stereo-
tactic magnetic resonance imaging (MRI) with and without
intravenous contrast administration. Precontrast MRI sequen-
ces include fast spin-echo (FSE) axial and coronal T2-weighted
(3-mm sections) images, contrast-enhanced three-dimensional
volumetric MRI, and time-of-flight MR angiography (MRA; 1.5-
mm sections). All patients subsequently undergo biplane X-ray
angiography as the next examination. For patients who cannot
tolerate an MRI (e.g., those with undetermined implants, pace-
makers, or old aneurysm clips), computed tomography (CT)
may be an alternative option. However, the image resolution of
CT will be less distinctive, especially when the patient had
undergone prior surgery or embolization.
93
 Stereotactic Radiosurgery for Dural Arteriovenous Fistulas

11.5.4 Treatment Planning and Dose
Prescription
Target localization of the DAVF is performed by integrating
imaging data from a stereotactic noncontrast MRI, a thin-cut
axial view time-of-flight MRA, and a cerebral X-ray angiogram.
Our treatment goal is to occlude the fistulous shunts com-
pletely. Proper delineation of the treatment target to include all
abnormal arteriovenous shunts on the dural sinus wall is cru-
cial for a successful treatment. The target volume is defined
along the involved dural sinus wall where the true AVF occurs.2,
3,39,47,48,49 The remote arterial feeders and drainage veins distal
to the sinus are excluded from the treatment volume, as they
are not considered a part of the true nidus.
Usually, the prescribed margin dose for DAVF radiosurgery is
around 18 to 20 Gy (range 15–25 Gy). The target coverage is
within a 50 to 70% isodose line. For the treatment of CS DAVFs,
we preferred to use a large (14- or 18-mm type C and 16-mm
Perfexion Gamma Knife [Elekta Instruments AB]) collimator to
cover the margin of the CS. In our center’s CS DAVF series, the
average number of isocenters was 3 (range 1–14). For the NCS
DAVFs, a greater number of isocenters (several large and many
8-mm small shots) were used to cover the treatment volume,
with a mean number of isocenters of 13 (range 1–27). Care is
taken to protect the adjacent critical structures such as the
optic nerve and brainstem to receive radiation doses less than 8
to 9 Gy.
11.6 Follow-up Program
After GKRS, both a clinical neurologic examination and radio-
graphic imaging study (MRI with MRA) are performed at
Table 11.2 Clinical outcome after GKRS in 264 patients with DAVFs
available for neurologic and imaging follow-ups
Outcome CS NCS
Complete improvement 109 (70%) 64 (59%)
Partial improvement 47 (30%) 40 (37%)
Stationary (no change) — 2 (2%)
Progression — 1 (1%)
Death — 1 (1%)
Total 156 108
Abbreviations: CS, cavernous sinus; DAVFs, dural arteriovenous fistulas;
GKRS, Gamma Knife radiosurgery; NCS, noncavernous sinus.
6-month intervals. Cerebral X-ray angiography is usually per-
formed between 1 to 3 years after GKRS, if complete regres-
sion of the lesion has been shown on the MRI. For CS DAVFs,
a noninvasive color Doppler ultrasonography (CDU) exam-
ined through eyeballs is performed every 3 months to evalu-
ate flow direction and velocity in the superior ophthalmic
vein (SOV). Frequently, normalization of the CDU is associ-
ated with concomitant findings of complete obliteration of
DAVF on the MRI and cerebral angiography.50
Patient outcomes after radiosurgery are grouped into four
categories: (1) complete improvement, indicating complete
symptomatic relief with complete obliteration of the DAVF on
cerebral angiogram and/or MRA; (2) partial improvement, indi-
cating partial resolution of clinical symptoms with > 50% regres-
sion of the DAVF nidus on MRA; (3) stationary, indicating no
change of the DAVF nidus on the follow-up MRA; (4) progres-
sion, indicating enlargement or aggressive change of the DAVF
nidus on MRA.
11.6.1 Treatment Results of DAVF
Radiosurgery
In our series at the Taipei Veterans General Hospital, post-GKRS
follow-up studies were available in 156 (76%) of 206 patients
with CS DAVFs and 108 (94%) of 115 patients with NCS DAVFs.
The median follow-up period for the CS group was 20.8 months
(range 1–149 months); for the NCS group it was 28 months
(range 2–141 months).
▶ Table 11.2 summarizes the clinical outcomes in our 264
DAVF patients with follow-ups. For the CS DAVFs, 109 of the
156 patients (70%) showed complete improvement and 47
(30%) were partially improved. No lesions were stationary or
progressed after radiosurgery. For the NCS DAVFs, 64 of the 108
(59%) showed complete improvement, 40 (37%) were partially
improved, 2 (2%) were stationary, 1 (1%) showed progression,
and 1(1%) patient died.
To evaluate the response to GKRS in DAVFs with different
venous drainage patterns, we further analyzed treatment
results of the 108 patients with NCS DAVFs based on the Borden
classification (▶ Table 11.3). The results show that radiosurgery
was effective in treating Borden type I lesions, with a 72% com-
plete obliteration rate; another 28% had partial improvement.
However, for Borden type II and III lesions, a lower cure rate
was observed. Of the 48 Borden type II and III patients, com-
plete obliteration was observed in 21 (44%) patients, with
another 48% showing partial improvement, 4% stationary, and
2% progression. There was one late mortality (2%) in the group
of type II–III DAVF patients.

Table 11.3 Clinical outcome after GKRS in 108 patients with NCS DAVFs stratified by Borden classification
Borden type Complete improvement Partial improvement Stationary Progression Death Total

I 43 17 0 0 0 60

II 12 18 1 1 0 32

III 9 5 1 0 1 16

Total 64 40 2 1 1 108

Abbreviations: GKRS, Gamma Knife radiosurgery; NCS DAVFs, noncavernous sinus dural arteriovenous fistulas.

94

Table 11.4 Time span between treatment and image-proven oblitera-
tion in dural arteriovenous fistula radiosurgery
CS NCS
n Median time n Median time
(mo) (mo)
MRI/MRA 100 21.4 (5.1– 70 31.1 (4.7–
149.5) 140.1)
Angiography 51 24.2 (4.2– 52 32.8 (7.3–
100.7) 143.7)
Abbreviations: CS, cavernous sinus; MRA, magnetic resonance angiog-
raphy; MRI, magnetic resonance imaging; NCS, noncavernous sinus.
The time span between radiosurgery and image-proven obliter-
ation is listed in ▶ Table 11.4. For patients with CS DAVFs, the
median obliteration time is 21.4 months in MRI/MRA, and 24.2
months in cerebral angiography. For patients with NCS DAVFs, the
median obliteration time is 31.1 months in MRI/MRA, and 32.8
months in cerebral angiography. Several reports including ours
have noted that the time span between radiosurgery and DAVF
obliteration in some cases can be as short as within 6 months.6,35,
51,52,53 Because the fistulous vessels of DAVFs that lie along the
sinus wall are usually small, DAVFs seem to respond more
promptly to radiosurgery compared with intracerebral AVMs.39
In our patients, one case died due to a new intracerebral
hemorrhage 59 months after the treatment. This is the only
mortality in our series. Postradiosurgical hemorrhage due to an
uncontrollable venous hypertension was found in another pa-
tient with an extensive, aggressive DAVF (Borden type II) involv-
ing the TSS. This patient recovered from the hemorrhage and
improved after further combined treatment with endovascular
embolization and repeated radiosurgery (▶ Fig. 11.1). In this
series, 98% (260 of 264 patients) had a stable or improved clin-
ical condition after radiosurgery. For the assessment of adverse
reactions to radiation on MRI, there was only one patient who
developed radiation-induced brain edema 6 months after radio-
surgery. The edema subsided gradually after steroid treatment.
For some DAVFs with extensive involvement of dural sinuses
and cortical veins, repeated radiosurgery might be necessary
for the complete obliteration of the DAVFs. In our series, 5 CS
DAVFs and 14 NCS DAVFs had required repeated radiosurgery 1
to 3 years after the first treatment. The method and dose selec-
tion during second radiosurgery were similar to the first
treatment.
In the literature, cumulative reports have proven the efficacy
of GKRS in treating DAVFs. Shin reported on two patients with
tentorial DAVFs treated with greater than 20 Gy to the fistula,
with complete obliteration obtained in both patients at 27 and
29 months.41 Söderman reported on 49 patients with 52 DAVFs,
showing a 68% obliteration rate and another 24% with flow
regression at 2 years.6 O’Leary achieved a 77% complete obliter-
ation rate with improvement in another 15% of patients.45 In
Brown et al’s series, of the 50 patients with angiographic fol-
low-up at the Mayo Clinic (Rochester, MN), 68% demonstrated
complete obliteration, with another 14% showing near-total
obliteration.8 In Koebbe’s UPMC series published in 2005, all 18
Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
patients had complete or near-complete resolution of their pre-
senting symptoms. Of the eight patients with angiographic fol-
low-up, all demonstrated complete obliteration. 14 In the UPMC
series published in 2010, at a median follow-up of 45 months
(range 23–116 months), 28 patients (harboring 32 DAVFs) had
obliteration confirmed by imaging. They found a 83% oblitera-
tion rate in patients who had up-front SRS with embolization
and a 67% obliteration rate in patients who only had SRS. Caver-
nous carotid fistulas were associated with higher rates of occlu-
sion (p = 0.012) and symptom improvement (p = 0.010) than
were TSS-related fistulas.43 In the series of 55 patients treated
at the University of Virginia, the compete obliteration rate of
DAVF was 65%.44 Although some of the patients in these pub-
lications had been treated with surgical resection or endovas-
cular embolization prior to radiosurgery, they were referred
for radiosurgery for further management of the residual
DAVFs. From these studies, we can estimate an overall success
rate of complete obliteration associated with radiosurgery of
DAVFs at 65 to 77%, with a greater number of patients gain-
ing symptomatic relief from the radiosurgical treatment.
11.7 Complications
The potential complications after radiosurgery include persis-
tent venous hypertension, intracranial hemorrhage, cranial
nerve dysfunction, sinus stenosis with thrombus formation, late
cystic expanding hematoma, and focal radiation-induced brain
edema.
For a DAVF with retrograde cortical venous drainage, the risk
of intracranial hemorrhage after radiosurgery continues until
such venous reflux has ceased, which is equivalent to the clo-
sure of the AVF. Although the hemorrhage risk after radiosur-
gery in the latency period before DAVF obliteration is low,
Söderman et al showed a 2.5% annual hemorrhage rate after
GKRS,6 and our data showed a 0.6% hemorrhage rate.5
In CS DAVFs, the normalization of the reverse pulsatile flow
in SOV is usually observed at 3 to 9 months after GKRS,50 indi-
cating a gradual change of the velocity and direction of the
venous flow. After the treatment, thrombosis of the SOV may
be sometimes observed by MRI in patients with temporary
worsening of symptoms and signs before the onset of clinical
improvement.54 Lau et al reported such a case of concurrent
thrombus formation in the SOV and anterior cavernous sinus 1
month after radiosurgery. Barcia-Salorio et al also reported that
2 of their 25 patients had experienced a temporary worsening
of symptoms as the shunt occluded.51
In our series, there was one patient complicated with a late
hemorrhagic cyst formation in the region of the DAVF, similar
to those seen after intracranial AVM radiosurgery.55 The case is
the first DAVF patient with such a late complication of SRS
reported in the literature. The patient underwent craniotomy
to resect the chronic hemorrhagic cyst 6.5 years after the
radiosurgery.
Other radiation-related complications are rare. Until now,
there is no report of temporal lobe radiation necrosis, hypo-
thalamic–pituitary axis dysfunction, or radiation-induced sec-
ondary brain tumor for DAVF patients treated with SRS.
95
 Stereotactic Radiosurgery for Dural Arteriovenous Fistulas

Fig. 11.1 Common carotid angiogram in (a) lateral and (b) anteroposterior views shows a Cognard type IIa + b dural arteriovenous fistula (DAVF)
involving transverse-sigmoid sinus in a 64-year-old man presented with conscious change at admission. The patient underwent Gamma Knife
radiosurgery (GKRS) initially with a peripheral dose of 16 Gy and maximum dose of 29 Gy (mean 21.5 Gy) to the DAVF nidus. Radiation volume was
35.3 mL. (c) One week after GKRS, a right temporal lobe hematoma due to remote venous congestion of the patient was noted in computed
tomography. The patient was further treated with endovascular embolization immediately. Two years after the combined treatment, the residual
DAVF showing in (d) lateral and (e) anteroposterior common carotid angiogram was further treated by the repeated GKRS. Follow-up angiogram (f,g)
several years later showed almost complete obliteration of the DAVF. The patient’s neurologic status significantly improved.

approximately 1.5% annual hemorrhage rate among the

11.8 Special Considerations and
Debates
11.8.1 Natural History of DAVF
The underlying etiology and natural course of DAVF are not yet
very well understood, and the magnitude of the risk varies con-
siderably between studies.19,20,21,22 Söderman et al reported an
85-patient series with 25-year follow-up that demonstrated
patients without previous hemorrhage, and 7.4% among those
with previous hemorrhage.22 However, the selection bias,
including sensitivity of current image modalities, compliance of
patients’ follow-up, and presence of asymptomatic patients, still
existed. We do know the presence of cortical venous reflux
entails a higher risk of intracranial hemorrhage, but it is not
clear whether the duration of the disease process has any
impact on the risk.

96

Several studies had noted that the period between radiosur-
gery and DAVF obliteration in some cases could be short, as
compared with results of AVM radiosurgery.6,35,51,56,57 Different
opinions might exist that to what extent obliteration after
radiosurgery could be attributed to the treatment, or the nature
course of the disease, especially when there were several case
reports showing spontaneous DAVF obliteration. 53,58,59,60 Never-
theless, a fast closure of the fistulas will shorten the period that
the patient suffers from throbbing headache, tinnitus, or oph-
thalmologic symptoms. In addition, for the cases with cortical
venous reflux, multimodal treatment including radiosurgery
and endovascular procedure may reduce the exposed time at
risk of intracerebral hemorrhage or disease progression.
11.8.2 Selection of Treatment Methods
for DAVFs
The management for a DAVF should be individualized, taking
into consideration the clinical presentation of the patient, the
anticipated natural history of the lesion based on location and
angioarchitecture of the DAVFs, and the benefit and inherent
risk of the treatment modality. It is generally agreed that DAVFs
presenting with hemorrhage, progressive neurologic deficits, or
increased intracranial pressure require prompt treatment
by endovascular embolization, surgery, or a combination of
these procedures, to provide immediate relief of the venous
congestion.
For Borden type II–III lesions with a single or few CVDs, or
DAVFs with an isolated dural sinus and CVDs, complete obliter-
ation of the lesion may be achieved effectively by surgery or
endovascular intervention.61,62,63 However, when DAVFs involve
dural sinuses with multiple complex feeders and CVDs, surgical
and endovascular treatment can be technically challenging.
Lucus et al in 1997 reported a meta-analysis and concluded that
even with combined therapy of surgery and embolization, over
30% of DAVFs involving TSS will demonstrate residual filling or
persistent symptoms.64 The current application of SRS can pro-
vide an additional therapeutic method to improve the treat-
ment result.
When a treatment is indicated for Borden type I DAVFs, the
therapeutic benefit should outweigh the risks of the treatment.
Evidence had shown that injury or increased pressure in the
dural sinus could trigger the development of DAVFs or cause
neurologic deficits secondary to venous hypertension.2 Thus,
sacrificing a functioning dural sinus in Borden type I DAVFs by
transvenous intervention or surgery may not be justified. Fur-
thermore, it is difficult to achieve a complete obliteration of
Borden type I DAVFs by transarterial embolization alone due to
the frequently complex and torturous course of the arterial sup-
ply.24 Studies had shown that local ischemia caused by incom-
plete closure of the DAVFs after endovascular and/or surgical
intervention can increase expression of various vascular growth
factors, which can recruit new collaterals resulting in recanali-
zaton of the DAVFs.65,66,67,68 Thus, the use of endovascular inter-
vention or surgery as a first-line treatment for Borden type I
DAVFs with the intention of palliation rather than cure should
carefully balance the risks and benefits of the procedure. Our
study and others have shown that DAVFs with benign venous
drainage can be safely treated using radiosurgery with a high
Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
angiographic complete obliteration rate with preservation of
functioning dural sinuses.22,35,42,46
Currently, our strategy of treatment for DAVF patients is as
follows:
● For Borden type I (Cognard types I, IIa) DAVFs with persistent
benign symptoms (headache, pulsatile tinnitus, or eye symp-
toms): Radiosurgery may be indicated as an initial treatment.
● For Borden type II/III (Cognard types IIa + b, IIb, III) DAVFs
with retrograde CVD:
a) Symptomatic CVD25 (with hemorrhage, increased intracra-
nial pressure, or progressive neurologic deficits): Surgery
or endovascular procedures are indicated for the initial
treatment.
b) Asymptomatic CVD25 (with only headache, pulsatile tinni-
tus, or eye symptoms, but without hemorrhage or in-
creased intracranial pressure): Endovascular procedure
may be the first- line management. Alternatively, radiosur-
gery can be considered as an initial treatment for patients
who are elderly, medically frail, or harboring complex
DAVFs.
In 2010, UPMC published their treatment experience of DAVF
and suggested a potential treatment and follow-up algorithm
for patients with DAVF, as shown in ▶ Fig. 11.2. For DAVFs with
good vascular access, SRS followed or preceded by embolization
has the best early and later obliteration rates. For patients with
poor vascular access for embolization, SRS alone is usually an
effective option with low complication rates. They recommend
that all patients have annual MRI follow-up after SRS. Angiogra-
phy remains the standard to access treatment responses in all
patients with aggressive DAVFs. However, for patients with less
aggressive DAVFs and symptomatic improvement, MRI/MRA
may be a sufficient method to access outcomes.43
11.8.3 The Role of Sinus Recanalization
in Treating DAVFs
Two hypotheses have been proposed for the initial pathophysi-
ology of DAVFs. One is physiological arteriovenous shunts are
open due to an increment of the sinus and venous pressure.2
The other one is angiogenesis when venous hypertension
induced by an obstruction of the venous outflow may reduce
cerebral perfusion and lead to hypoxia with de novo formation
of DAVFs.67 Based on these theories, a correction of the venous
hypertension in the sinus should reduce cerebral venous edema
and reverse vicious cycle of creating DAVFs. Using endovascular
balloon angioplasty or stent implantation inside the sinus may
correct such venous hypertension.
This is especially important when facing the patients with
complicated DAVFs, such as multiple sinuses stenosis, single
venous drainage, or DAVFs involving superior sagittal sinus
with venous hypertension. Sinus occlusion by embolization or
resection sometimes carries the risk of further damaging the
venous drainage and cause disastrous results. Any therapeutic
intervention of DAVFs in these conditions should be performed
carefully after recognizing that the fistulous portion of the sinus
does not have a drainage function.
In these difficult conditions, recanalization of the sinus could
be the only way to restore venous outflow and correct venous
97
 Stereotactic Radiosurgery for Dural Arteriovenous Fistulas
hypertension. Recently, we began to use balloon inflation or
stent placement combined with GKRS to treat some DAVFs with
partially obstructed sinuses. The idea of angioplasty is also pro-
posed in some reports.69–74 In 2000, Murphy et al reported a
case of TSS DAVF treated with transluminal angioplasty and
stent placement in a partially thrombosed fistulous sinus. 73
Other authors subsequently described that stent placement for
DAVFs is a promising technique and should be considered a
first-line treatment.70,71
In our experience, the use of balloon dilation or stent im-
plantation did improve the direction and flow of venous
return, and might facilitate DAVF obliteration if subsequent
GKRS was performed. However, the study on the efficacy and
safety of the angioplasty combined with GKRS is still ongoing
and needs more case population for consolidating the clinical
result.
11.9 Summary
Stereotactic radiosurgery using the Gamma Knife is a safe and
effective alternative treatment for DAVFs. This method provides
a minimally invasive therapeutic modality for patients who
harbor less aggressive DAVFs, but who suffer from intolerable
98
Fig. 11.2 Potential treatment algorithm for ma-
nagement of dural arteriovenous fistula. DAVFs,
dural arteriovenous fistulas; MRI, magnetic reso-
nance imaging; SRS, stereotactic radiosurgery.
(Adapted from Yang et al.43)
headache, pulsatile tinnitus, or ocular symptoms. For aggressive
DAVFs with extensive CVD, immediate risks of hemorrhage,
progressive neurologic deficits, or severe venous hypertension,
initial treatment with endovascular procedure including embo-
lization and angioplasty or with surgery is suggested. In such
cases, radiosurgery may serve as a secondary treatment for fur-
ther management of the residual fistulas. The latent period for
the effects of radiation to occur and the longer time for cure
compared with surgery and endovascular therapy remains a
major drawback for radiosurgery. However, the gradual obliter-
ation of a DAVF after radiosurgery can avoid immediate risk
of aggravated venous hypertension or infarction, which some-
times complicates endovascular embolization and surgery. It
is believed that using a multidisciplinary approach to DAVF
management yields better results.
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kyo) 2003; 43: 477–482, discussion 482–483
[58] Luciani A, Houdart E, Mounayer C, Saint Maurice JP, Merland JJ. Spontaneous
closure of dural arteriovenous fistulas: report of three cases and review of
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[59] Pritz MB, Pribram HF. Spontaneous closure of a high-risk dural arteriovenous
malformation of the transverse sinus. Surg Neurol 1991; 36: 226–228
[60] Saito A, Furuno Y, Nishimura S, Kamiyama H, Nishijima M. Spontaneous clo-
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[61] Heros RC. Gamma knife surgery for dural arteriovenous fistulas. J Neurosurg
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[62] Jiang C, Lv X, Li Y, Zhang J, Wu Z. Endovascular treatment of high-risk tentori-
al dural arteriovenous fistulas: clinical outcomes. Neuroradiology 2009; 51:
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 12 Stereotactic Radiosurgery for
Part IV Meningiomas 102

Benign Tumor Indications 13 Stereotactic Radiosurgery for Pituitary

Adenomas 107

14 Stereotactic Radiosurgery for

Chordomas 120

15 Stereotactic Radiosurgery for

Chondrosarcomas 128

16 Stereotactic Radiosurgery for Glomus

Tumors 132

17 Stereotactic Radiosurgery for

Nonvestibular Schwannomas 137

18 Stereotactic Radiosurgery for

Hemangioblastomas 146

19 Stereotactic Radiosurgery for Vestibular

Schwannomas 150

IV
 Stereotactic Radiosurgery for Meningiomas
12 Stereotactic Radiosurgery for Meningiomas
William Friedman and Frank J. Bova
Key Points
● Although resection is the gold standard for meningioma
treatment, some common meningioma locations (e.g., cav-
ernous sinus or petroclival region) are not readily amenable
to a complete resection because of location and the proxim-
ity of vital neural and vascular structures.
● Local tumor control rates for benign (i.e., World Health
Organization [WHO] grade I meningiomas) are high, but
long-term control for atypical and malignant meningiomas is
less favorable.
● Stereotactic radiosurgery for meningiomas conveys a long-
term morbidity rate of 10% or less.
12.1 Introduction
Stereotactic radiosurgery (SRS) is a minimally invasive
treatment modality that delivers a large, single dose of radi-
ation to a specific intracranial target while sparing sur-
rounding tissue. Unlike conventional fractionated
radiotherapy, SRS does not maximally exploit the higher
radiosensitivity of brain lesions relative to normal brain
(therapeutic ratio). Its selective destruction is dependent
mainly on sharply focused high-dose radiation and a steep
dose gradient away from the defined target. The biological
effect is irreparable cellular damage (probably via DNA
strand breaks) and delayed vascular occlusion within the
high-dose target volume. Because a therapeutic ratio is not
required, traditionally radioresistant lesions can be treated.
However, because destructive doses are used, any normal
structure included in the target volume is subject to
damage.
The basis for SRS was conceived over 60 years ago by Lars
Leksell.1 He proposed the technique of focusing multiple beams
of external radiation on a stereotactically defined intracranial
target. The averaging of these intersecting beams results in very
high doses of radiation to the target volume, but innocuously
low doses to nontarget tissues along the path of any given
beam. His team’s implementation of this concept culminated in
the development of the Gamma Knife.
An alternate radiosurgical solution using a linear accelera-
tor (linac) was first described in 1984 by Betti and Derechin-
sky.2 Colombo et al described such a system in 1985, 3 and
linacs have subsequently been modified in various ways to
achieve the precision and accuracy required for radiosurgical
applications.4–7 In 1986, a team composed of neurosurgeons,
radiation physicists, and computer programmers began
development of the University of Florida linac-based radio-
surgery system.8 This system has been used to treat over
3,800 patients at the University of Florida since May 1988,
and is in use at multiple sites worldwide. Many other com-
mercial versions of radiosurgical systems are currently
available.
102
12.2 Radiosurgery Technique
Although the details of radiosurgical treatment techniques dif-
fer somewhat from system to system, the basic paradigm is
quite similar everywhere. Below is a brief description of a typi-
cal radiosurgical treatment at the University of Florida.
Almost all radiosurgical procedures in adults are performed
on an outpatient basis. The patient reports to the neurosurgical
clinic the day before treatment for a detailed history and physi-
cal, as well as an in-depth review of the treatment options. If
radiosurgery is deemed appropriate, the patient is sent to the
radiology department for a volumetric magnetic resonance
imaging (MRI) scan. A radiosurgical plan can be generated, in
advance, using this MRI study. The next morning, the patient
arrives at 7:00 am. A stereotactic head ring is applied under
local anesthesia. No skin shaving or preparation is required.
Subsequently, stereotactic computed tomography (CT) scanning
is performed. One-millimeter slices are obtained throughout
the entire head. The patient is then transported to an outpa-
tient holding area where he and his family have breakfast and
relax until the treatment-planning process is complete.
The stereotactic CT scan and the nonstereotactic volumetric
MRI scan are transferred via Ethernet to the treatment-plan-
ning computer. The CT images are quickly processed so that
each pixel has an anteroposterior, lateral, and vertical stereotac-
tic coordinate, all related to the head ring previously applied to
the patient’s head. Using image fusion software, the nonstereo-
tactic MRI is fused, pixel for pixel, with the stereotactic CT. The
preplan performed the day before is, likewise, fused to the ster-
eotactic CT. Final dosimetry then begins and continues until the
neurosurgeon, radiation therapist, and radiation physicist are
satisfied that an optimal dose plan has been developed. A varie-
ty of options are available for optimizing the dosimetry. The
fundamental goal is to deliver a radiation field that is precisely
conformal to the lesion shape, while delivering a minimal dose
of radiation to all surrounding neural structures.
With linac systems, the target dose distribution can be tail-
ored by varying collimator sizes, eliminating undesirable arcs,
manipulating arc angles, using multiple isocenters, and differ-
entially weighting the isocenters.9 In our center, multiple iso-
centers are used to achieve highly conformal dose distributions,
exactly analogous to the Gamma Knife technique. Some linac
systems use an alternative approach that relies upon a com-
puter-driven multileaf collimator to generate nonspherical
beam shapes which are conformal to the beam’s eye view of the
tumor. The multileaf collimator can be adjusted statically or
dynamically as the linac rotates. Intensity modulation can be
used to achieve dose distributions that are close to those seen
with multiple isocenters and treatment time can be reduced.
When dose planning is complete, the patient then is attached
to the radiosurgical machine. It takes approximately 10 minutes
to treat each isocenter. For meningiomas, we almost always use
a peripheral dose of 12.5 Gy at the 70% isodose line. The head
ring is removed, and after a short observation period, the pa-
tient is discharged. Patients with benign meningiomas undergo
MRI follow-up yearly for 5 years, then every 3 years. Patients

with atypical or malignant meningiomas need more frequent
follow-up.
12.3 Meningiomas
Meningiomas are the most common benign primary brain
tumor, with an incidence of approximately 7/100,000 in the
general population. Surgery has long been thought to be the
treatment of choice for symptomatic lesions and is often cura-
tive. Many meningiomas, however, occur in locations where
attempted surgical cure may be associated with morbidity or
mortality, such as the cavernous sinus or petroclival region.10,11
In addition, many of these tumors occur in the elderly, where
the risks of general anesthesia and surgery are known to be
increased. Hence, there is interest in alternative treatments,
including radiotherapy and radiosurgery, either as a primary or
adjuvant approach.
Simpson, in a classic paper, described the relationship
between completeness of surgical resection and tumor recur-
rence.12 A grade I resection, which is complete tumor remov-
al with excision of the tumor’s dural attachment and
involved bone, has a 10% recurrence rate. A grade II resection,
complete resection of the tumor and coagulation of its dural
attachment, has up to a 20% recurrence rate. Grade III resec-
tion is complete tumor removal without dural resection or
coagulation. Grade IV resection is subtotal and grade V resec-
tion is simple decompression. Recurrence rates in the grade
IV and V groups basically reflect the natural history of the
tumor, with high rates of recurrence over time. Unfortu-
nately, some common meningioma locations, such as the cav-
ernous sinus or petroclival region, are not readily amenable
to a complete dural resection or coagulation strategy because
of location and the proximity of vital neural and vascular
structures. In addition, relatively high complication rates
have been described for meningioma surgery in some loca-
tions and in the elderly.
Pollock and colleagues13 analyzed 198 patients with men-
ingiomas < 35 mm in diameter, treated with either surgical
resection or Gamma Knife radiosurgery. Tumor recurrence
was more frequent in the surgical resection group (12% vs.
2%). No statistically significant difference was detected in the
3- and 7-year actuarial progression-free survival rate
between patients with Simpson grade 1 resections and those
who underwent radiosurgery. Progression-free survival rates
with radiosurgery were superior to Simpson grade 2, 3, and 4
resections. Complications were much lower in the radiosur-
gery group.
Meningiomas have many ideal characteristics for radio-
surgery: They are easily visualized on MRI. They are gener-
ally distinct and separate from surrounding brain. It appears
that radiation provides tumor control which is at least
equivalent to surgery. And as discussed above, these tumors
are frequently in locations where complete surgical resec-
tion is impossible or risky. Below, we review the major ser-
ies in the literature on radiosurgery for meningiomas. We
look at the largest overall series, then at some specific
reports categorized by meningioma location. We conclude
with a short review of the relatively small linac radiosur-
gery experience.
Stereotactic Radiosurgery for Meningiomas
12.3.1 Major Series
The first significant report on radiosurgery for meningiomas
was published by Kondziolka et al in 1991.14 They described 50
patients treated with the new University of Pittsburgh Gamma
Knife unit. Two-year actuarial tumor control was 96%. Three
patients had experienced radiation-induced neurologic deficit
(6%). As of 2008, over 64,000 patients with meningiomas had
been treated with Gamma Knife units and many more with
linac systems. The originally reported numbers on tumor con-
trol and complications have held up fairly well.15
In 2005, Malik et al16 reported on 309 meningiomas treated
with the Sheffield Gamma Knife unit. Five-year actuarial control
was 87% for benign meningiomas, 49% for atypical tumors, and
0% for malignant tumors. Complications occurred in 3% of the
patients.
In 2008, Kondziolka et al17 updated the Pittsburgh experi-
ence: 972 patients with 1,045 meningiomas had been treated.
The overall control rates for benign meningiomas were 93 and
97% for those with previous histological confirmation. Fifty-
three patients followed for 10 years had a control rate of 91%.
Overall morbidity was 8%. Atypical tumor control was 50% and
malignant tumor control was 17%.
In 2012, Pollock et al18,19 provided updates on the Mayo Clinic
(Rochester, MN) Gamma Knife experience: 416 patients had
been treated. The 5- and 10-year local controls rates were 96%
and 89%; 11% of patients experienced a radiation-induced com-
plication. The median peripheral dose was 16 Gy. Risk factors
for complications included higher tumor volume and parasagit-
tal/falx/convexity location.
In 2012, Santacroce et al20 reported a retrospective observa-
tional analysis of 4,565 consecutive patients harboring 5,300
benign meningiomas treated at 15 Gamma Knife centers in
Europe. Median tumor dose was 14 Gy. Only tumors with > 2-
year follow-up were included in the analysis. Five- and 10-year
actuarial control rates were 95 and 89%, respectively. Perma-
nent morbidity was seen in 7% of patients.
12.3.2 Location-Specific Series
Ding et al21 reported on 65 patients with 90 benign parasagittal
or falcine meningiomas (▶ Fig. 12.1). The median prescription
dose was 15 Gy. Actuarial tumor control was 85% at 3 years and
70% at 5 years. Morbidity was 8.2%. The authors felt that these
control rates and complications rates compared favorably with
surgery for tumors in this location.
Flannery et al22 reported on 168 petroclival meningiomas
and cerebellopontine angle meningiomas (▶ Fig. 12.2). The
median dose was 13 Gy. Five- and 10-year tumor control rates
were 91 and 86%, respectively. Morbidity was 8%. Salvage ther-
apy included surgery4 and repeat radiosurgery.8
Zenonos et al23 reported on 24 patients with foramen mag-
num meningiomas. The median tumor dose was 13 Gy. At a
median follow-up of 47 months, all tumors were controlled. No
patient suffered a radiation-induced complication. The authors
present a management paradigm calling for radiosurgery of
small, minimally symptomatic tumors or for residual tumor
after far lateral surgical approaches.
Kondziolka and colleagues24 reported on 125 patients with
convexity meningiomas. The mean marginal dose was 14.2 Gy.
103
 Stereotactic Radiosurgery for Meningiomas

Fig. 12.1 (a) Axial enhanced computed tomography radiosurgical image. One isocenter was used, elongated axially by arc elimination, for this 4.1-cc
tumor; 15 Gy was delivered to the 80% isodose line. (b) Axial enhanced magnetic resonance image 12 years later shows tumor shrinkage.

Fig. 12.2 (a) Axial enhanced radiosurgical magnetic resonance image (MRI); 11 isocenters were used to treat this 10.6-cc tumor; 12.5 Gy was
delivered to the 70% isodose line (shown in red). (b) Axial enhanced MRI image 8 years later shows tumor shrinkage.

Actuarial tumor control at 3 and 5 years was 95 and 86%. Over-
all morbidity was 9.6%. The authors felt that radiosurgery for
this location was most valuable for patients with tumors in crit-
ical locations or in poor medical condition.
A number of authors have reported on radiosurgery for
cavernous sinus meningiomas (▶ Fig. 12.3), a location almost
universally recognized as inappropriate for surgery. In 2002,
Lee et al25 reported on 159 such patients. Actuarial tumor
control was 93% at 5 and 10 years. Morbidity was 9%. Kimball
et al26 reported on 55 patients treated at University of Flori-
da. Actuarial tumor control was 100% at 5 years and 98% at
10 years. Sixty-five percent of patients had improvement in
their presenting cranial neuropathies and one patient was
made worse. Spiegelmann et al27 reported on 102 patients

104

treated in Tel Aviv. Gross tumor control was 98%. Complica-
tions were seen in five patients. Pollock et al 28 reported on
115 patients treated with the Mayo Clinic Gamma Knife.
Tumor control was 99% at 5 years and 93% at 10 years; 12% of
patients had complications. Williams et al 29 reported on 138
“parasellar” meningiomas treated in Charlottesville, Virginia.
Tumor control was 95% at 5 years and 69% at 10 years; 10% of
patients experienced complications.
12.4 Linear Accelerator
Radiosurgery
Although at least an order of magnitude smaller than the
published Gamma Knife experience, multiple linac radiosur-
gical series have been published. 30–35 Hakim et al were the
only ones of this early group to report actuarial statistics. 36 A
total of 127 with 155 meningiomas were treated. Actuarial
tumor control for patients with benign tumors was 89.3% at
5 years. Six patients (4.7%) had permanent radiation-induced
complications.
The University of Florida report on linac radiosurgery treat-
ment of meningiomas is one of the largest published. 37,38 Two
hundred ten patients were treated from May 1989 through
December 2001. All patients had follow-up for a minimum of 2
years and no patients were lost to follow-up. Actuarial local
control for benign tumors was 100% at 1 and 2 years, and 96%
at 5 years. Actuarial local control for atypical tumors was 100%
at 1 year, 92% at 2 years, and 77% at 5 years. Actual control for
malignant tumors was 100% at 1 and 2 years, but only 19% at 5
years. Permanent radiation-induced complications occurred in
3.8%, all of which involved malignant tumors. These tumor con-
trol and treatment morbidity rates compare well with all other
published series.
Kimball et al26 reported on the University of Florida experi-
ence with cavernous sinus meningiomas. Fifty-five patients
were treated. Actuarial tumor control was 100% at 5 years and
98% at 10 years. Sixty-five percent of patients reported
improvement in their cranial nerve dysfunction, only one pa-
tient was worse. Spiegelmann et al27 reported on their experi-
ence with 117 cavernous sinus meningiomas. Tumor control
was 98%; 37% of patients had improved cranial neuropathies;
five patients were worse.
Stereotactic Radiosurgery for Meningiomas
Fig. 12.3 (a) Axial enhanced radiosurgical treat-
ment magnetic resonance image (MRI). Five
isocenters were used to treat this 8.8-cc tumor;
12.5 Gy was delivered to the 70% isodose line
(shown in red). (b) Axial MRI 12-years later shows
tumor shrinkage.
As of April 2014, the University of Florida experience with
meningiomas included 619 patients.
12.5 Summary
An extensive literature, involving thousands of patients, consis-
tently demonstrates excellent long-term tumor control after
radiosurgery for benign meningiomas. Morbidity is generally in
the range of 10% long term. It is frequently minor (i.e., cranial
neuropathy, seizure, headache). It compares especially well to
surgical morbidity for tumor locations known to be high risk for
surgery (cavernous sinus, petroclival, parasagittal, foramen
magnum).
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327

13 Stereotactic Radiosurgery for Pituitary Adenomas
Cheng-Chia Lee and Jason P. Sheehan
Key Points
● Stereotactic radiosurgery offers a high rate of tumor control
for functioning and nonfunctioning pituitary adenomas.
● A higher margin dose is required to achieve endocrine remis-
sion in functioning adenomas.
● The rate of endocrine remission after radiosurgery appears
faster than that achieved with fractionated radiotherapy.
● The most frequent complication following radiosurgery of a
pituitary adenoma is hypopituitarism. However, radiation-in-
duced hypopituitarism occurs in only a minority of patients.
13.1 Introduction
Pituitary adenomas represent one of the most common types of
intracranial tumors.1,2 They are quite common among the gen-
eral population and constitute 10 to 20% of all intracranial
tumors.3 They are classified by size, with microadenomas < 1 cm
in size and macroadenomas at least 1 cm in size, and by hormo-
nal secretory status, with hormone hypersecretion from func-
tioning lesions and absence of abnormal hormonal production
comprising nonfunctioning lesions. Although their macroscopic
appearance and anatomical location are relatively homogene-
ous, pituitary tumors have the potential to generate a wide
variety of clinical sequelae. Nonfunctioning pituitary adenomas
enlarge progressively in the pituitary fossa and often extend
beyond the sellar turcica. The enlargement of the tumor may
cause mass effects, including visual field deficits resulting from
optic apparatus compression, and hypopituitarism resulting
from compression of the normal pituitary gland. For function-
ing pituitary adenomas, prolactinomas result in amenorrhea–
galactorrhea syndrome; growth hormone (GH)-secreting
adenomas cause acromegaly in adult and gigantism in child;
adrenocorticotropic hormone (ACTH)-secreting adenomas
cause Cushing syndrome.
Treatment options for pituitary tumors include medical ther-
apy, microscopic or endoscopic surgical resection, radiosurgery,
radiotherapy, or observation depending on the biochemical
profile and clinical status of the patient. Stereotactive radiosur-
gery (SRS) is used to treat a number of so-called benign intra-
cranial tumors, and pituitary adenomas represent one such
example. Radiosurgery is most commonly as adjunctive treat-
ments following incomplete surgical resection leaving residual
tumor, tumor recurrence, or failure of medical therapy. In this
chapter, we present the principal and method of the radiosur-
gery for pituitary tumors, including nonfunctioning adenomas,
ACTH-secreting adenomas, GH-secreting adenomas, and prolac-
tinomas. Although postradiosurgery radiographic tumor control
for nonfunctioning adenomas is excellent, typically around 90%,
the rates of biochemical remission for functioning adenomas
are lower than the tumor control rates. The highest endocrine
remission rates are achieved in patients with Cushing disease
and the lowest in those with prolactinomas; rates range from
Stereotactic Radiosurgery for Pituitary Adenomas
30 to 80%. Because of the rare but well-documented occurrence
of late recurrence following endocrine remission, long-term
and rigorous clinical and radiographic follow-up is necessary
for all pituitary adenoma patients treated with radiosurgery.
13.2 History
Radiotherapy for pituitary disorders had been introduced in
1909 for acromegaly.4,5,6 The initial procedure described by
Griming would deliver (from the oral cavity) 200 roentgens to
the sella over a period of 1 month with sessions of 1 hour twice
per week. On the other hand, Beclere had excellent idea to
rotate the patient so that “the hypophysis was treated by cross-
fire through four to five different areas on the frontotemporal
region.”4 However, radiation was elapsed for nearly 30 years
until the 1950s, when several authors published their systemic
study on radiotherapy of pituitary adenomas,7,8,9 and concluded
that radiotherapy to pituitary fossa tumors is most effective at
dosage levels of about 4,000 roentgen. With the advancement
of modern radiological facilities, radiotherapy plays an impor-
tant role in treating residual or recurrent pituitary adenomas.
The Gamma Knife was subsequently employed by Leksell to
treat the first pituitary adenoma patient in 1968. Initially con-
ceived by Lars Leksell in 1951, SRS delivers a single high, con-
centrated dose of radiation to the target. According to Leksell’s
series in 1980, 95 patients with Cushing disease and Nelson
syndrome have been treated by gamma radiation.10,11 Small
and spatially well-defined volumes of tissue in the pituitary
gland can be selectively destroyed. With the smallest collimator,
a kind of intracellular “microradiosurgery” is possible. In a
review of 37 patients with an observation time of more than
one year, complete remission was obtained in 29 cases. This is a
promising result. Since then, radiosurgical devices and techni-
ques have developed significantly with thousands of pituitary
adenomas treated in the interim.
Around the time of Leksell’s development of the Gamma
Knife, innovative work in the field of radiosurgery using heavy
particles from cyclotrons was conducted by Raymond Kjellberg
and Jacob Fabrikant. Later, in 1983 at a hospital in Buenos Aires,
Betti and Derechinsky developed the concept of a modified lin-
ear accelerator (linac) for SRS.12,13 Their system relied upon a
10-MV linac, and it utilized a chair for the patient which was
based upon the Talairach stereotactic frame.14 Other innovative
developments in linac-based SRS devices followed shortly
thereafter from Winston and Lutz in Boston, Massachusetts,
Hartman and Sturm in Heidelberg, Germany, Barcia-Salorio in
Valencia, Spain, Colombo in Vincenza, Italy, and Podgorsak in
Montreal, Canada.12–18
13.3 Patient Selection and Pre-SRS
Evaluation
Initial diagnosis of pituitary adenomas was based on the combi-
nation of clinical features of different types of pituitary
107
 Stereotactic Radiosurgery for Pituitary Adenomas
adenomas, and biochemical assessment according to recom-
mended endocrine guidelines. All patients suspected of harbor-
ing a pituitary tumor should undergo a complete endocrine
evaluation, neuroimaging study, and ophthalmic examination
before SRS. Endocrine studies should be done through each fac-
et of the hypothalamic–pituitary–end organ axis, including GH,
insulin-like growth factor-1 (IGF-1), ACTH, serum cortisol, pro-
lactin, T4 or free T4, thyroxin-stimulating hormone (TSH), lutei-
nizing hormone (LH), follicle-stimulating hormone (FSH), and
testosterone (men) levels. Imaging studies consisted of mag-
netic resonance imaging (MRI) with and without contrast using
thin slices, and volume acquisition through the region of the
sella turcica. The ophthalmologic evaluation included visual
acuity and visual field testing.
If a patient has a neurologic deficit attributable to an adeno-
ma, surgery is the initial treatment of choice for all tumors
except a prolactinoma. Transsphenoidal surgery (endoscopic or
microscopic) allows for the most rapid relief of mass effect and
reduction in excessive hormone levels in patients with Cushing
disease and acromegaly. Prior surgical resection also facilitates
subsequent radiosurgery; radiosurgeons can always prescribe a
higher dose with safe margin, which are especially important
for hormone remission of functioning adenomas.
13.4 Principles of Stereotactic
Radiosurgery
The use of a single high dose of ionizing beams to treat intra-
cranial disorders was a creative concept. Radiosurgery is
characterized by a steep dose falloff, thereby relatively spar-
ing radiation exposure to surrounding normal tissues. Its
application has changed the direction of many fields such as
neurosurgery and radiation oncology. Significant contribu-
tions have been made by numerous neurosurgeons, radiation
oncologists, and physicists to advance the field of SRS. How-
ever, despite all the changes in SRS over the ensuing decades,
the fundamental concepts have not changed: The radiobio-
logical effects of radiosurgery is due to a vascular effect or a
cytotoxic effect.19
From its inception, radiosurgery has been a multidiscipli-
nary discipline. The definition sanctioned by the American
Association of Neurological Surgeons, Congress of Neurologi-
cal Surgeons, and American Society for Radiation Oncology
calls for delivery of radiosurgery by a team consisting of a
neurosurgeon, radiation oncologist, and medical physicist. 20
Similarly, the American College of Radiology recommended a
similar multidisciplinary approach to ensure quality of care
and went so far as to specify specific responsibilities during
the SRS process for the individual members of the multidisci-
plinary team.21
13.5 Radiosurgical Technique and
Planning
13.5.1 Stereotactic Frame Replacement
Patients underwent stereotactic frame placement (Leksell
frame; Elekta Instruments AB, Stockholm, Sweden)
108
supplemented by local anesthesia and conscious sedation as
needed.22 Prior to frame placement, the scalp is prepared
with alcohol, and the areas of the pin placements are infil-
trated with a long-acting local anesthetics. The use the angle
of the optic apparatus as the axis of frame is usually helpful.
This angle approximates a line joining the lateral canthus and
the top of the pinna, and it makes identification of the optic
nerves, chasm, and tracts easier by having an image that
demonstrates the entire optic apparatus in a single MRI
slice.23
13.5.2 Radiographic Images
Afterward, all patients underwent thin-sliced stereotactic MRI
with and without intravenous contrast administration. Imaging
studies were also obtained for all patients using standard pitui-
tary MRI sequences at the University of Virginia (Charlottesville,
VA). Precontrast sequences included coronal and sagittal T1-
weighted (1-mm sections), fast spin-echo (FSE) axial. and coro-
nal T2-weighted (1-mm sections) images. The postcontrast
sequences included coronal T1-weighted (1-mm sections), sag-
ittal FSE T1-weighted (1-mm sections), and coronal spoiled gra-
dient echo (SPGR) T1-weighted images. Since 2010, dynamic
MRI sequences were utilized as part of radiosurgical planning
sequencing.24,25,26
For patients who cannot tolerate an MRI, computed tomogra-
phy (CT) may be an alternative option. However, the accuracy
would be less and the lesions are usually blurred, especially if
the patient underwent prior surgical resection. Positron emis-
sion tomography (PET) imaging may also be of value for detect-
ing hypersecretory adenomas; such images can be overlaid on
stereotactic tomographic images (e.g., MRI or CT). 27
13.5.3 Treatment Planning
Regardless of the radiosurgical modality used, SRS requires
clear and accurate imaging of that target. Advances in radio-
graphic imaging over the past 20 years have increased the effi-
cacy and safety of radiosurgical treatment of pituitary lesions.
The current treatment planning for a pituitary adenoma is usu-
ally performed using computer-based software. The target vol-
ume and the surrounding structures are contoured. A dose plan
can be rendered to deliver an ideal dose to the target and a safe
dose to adjacent critical structures. Conformality, dose uniform-
ity, and gradient index should be assessed and adjusted made
to optimize the dose plan.
When treating a tumor near the optic apparatus, the adjust-
ment of the frame angle may be appropriate (▶ Fig. 13.1).
13.5.4 Dose Selection
In general, single-session radiosurgical margin doses vary
from 12 to 18 Gy for nonfunctioning adenomas, and from 15
to 30 Gy for functioning adenomas. 28–33 Care should be taken
to avoid high doses or “hot spots” to critical neurovascular
structures such as the cranial nerves (CNs) or carotid artery
within the cavernous sinus region. Radiosurgery can be
hypofractionated in two to five sessions to deliver a more
optimal dose plan tailored to the constraints of a particular
case.

Fig. 13.1 Case illustrating the dosing plan of a pituitary adenoma. A prescription dose of 20 Gy (inner green isodose line) was delivered to the margin
of the adenoma and lower isodose lines are shown in yellow and the outer green lines. Evaluation of the dose-volume histogram for radiation exposure
to the optic apparatus (in blue) should be performed. In this case, the chiasm received a maximal dose of 5.9 Gy, and right optic nerve a maximum
dose of 6.3 Gy.
13.5.5 Dose Limitations to Critical
Structures
Visual deterioration following SRS is rare and can be avoided if
the dose to the optic apparatus is restricted to ≤ 8 Gy, although
reports of 10 to 12 Gy have been described by some groups. 34
Transitionally, a distance of 3 mm or more between the rostral
extent of the adenoma and the optic apparatus is desirable. The
absolute distance between the optic apparatus is not the limit-
ing factor, but rather defines how steeply the radiation gradient
must be constructed so that a tolerable dose is delivered to the
optic apparatus while still delivering an effective dose to the
adenoma. If an acceptable gradient cannot be constructed, then
alternative treatment should be considered. Modern radiosur-
gical devices may allow a distance of as little as 1 to 2 mm. 35,36,
37 Ultimately, the tolerable absolute dose permitted likely varies
from patient to patient; it is affected by factors such as previous
damage to the optic apparatus by pituitary adenoma compres-
sion, ischemic changes, type and timing of previous interven-
tions (e.g., fractionated radiotherapy and surgery), the patient’s
age, and the presence or absence of other comorbidities.(e.g.,
diabetes or hypertension).29,38
The majority of CNs in the cavernous sinus appear to be more
resistant to radiation effects than the optic nerve, but reports of
cranial neuropathy, particularly after repeat radiosurgery, are
well documented.29 Although the tolerable limit to the caver-
nous sinus nerve is unknown, reports have detailed effective
Stereotactic Radiosurgery for Pituitary Adenomas
radiosurgical doses of between 19 and 30 Gy to this region with
a low risk of appreciable side effects.36,39,40,41,42 Injury to the
cavernous segment of the carotid artery is rare after SRS, with
only one isolated case report.43 In cases where the tumor
appears to extend into the cavernous sinus, shielding can be
used to lower radiation doses to critical structures.
There does appear to be a direct correlation between the
effect on adenoma volume and the endocrine remission rate
following radiosurgery.30,32,36 Fortunately, because most pitui-
tary adenomas are small enough to be well suited for SRS, dose-
volume considerations are not usually a limiting factor. Because
the systemic effects of functioning adenomas can be so devas-
tating, it seems intuitive to deliver a reasonably high dose
(≥ 20 Gy to the margin) to allow rapid hormonal normalization
and control of tumor growth. For improved rates of hormonal
normalization in functioning adenomas, margin dose of 25 or
30 Gy may even be chosen. However, it is not known to what
degree a higher margin dose (e.g., 20 vs. 30 Gy) will result in
delayed hypopituitarism. In cases of functioning adenomas
with radiologically identifiable targets in the cavernous sinus,
radiosurgical plans can be devised with higher range treatment
doses while shielding much of the normal stalk, gland, and
optic apparatus. Nonfunctioning pituitary adenomas appear to
require a lower radiosurgery treatment dose than functioning
adenomas.33,43 The lowest effective dose for a nonfunctioning
tumor is not unknown, but many centers deliver 12 to 15 Gy to
the margin.
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 Stereotactic Radiosurgery for Pituitary Adenomas

13.6 Outcomes of Radiosurgery
for Nonfunctioning Pituitary
Adenomas
Because the endocrine presentation is silent, the primary radio-
surgical goal for nonfunctioning adenomas is radiological
tumor control. Stereotactic radiosurgery resulted in tumor con-
trol rates of 83 to 100% with a median 46-month follow-up, and
new-onset hypopituitarism following radiosurgery was
observed in 0 to 40% with a median of 9%. ▶ Table 13.1 lists the
major radiosurgical series for nonfunctioning adenoma patients
since 2002. In our experience at the University of Virginia with
140 nonfunctioning pituitary adenomas patients, we have
reported an approximately 90% tumor control and delayed
hypopituitarism in 30% of patients.44 New or worsening CN def-
icits were observed in 14% of patients. In a recent multicenter
trial evaluating the role of SRS for 512 patients with nonfunc-
tioning pituitary adenomas (median follow-up of 36 months;
range 1–223 months), an overall tumor control rate of 93% was
reported.33 Favorable outcomes of tumor control and neuro-
logic preservation were more commonly seen in patients older
than 50 years, those with a tumor volume < 5 cc, and those
without prior fractionated radiotherapy.33
13.7 Outcomes of Radiosurgery
for Functioning Pituitary
Adenomas
Unlike nonfunctioning adenomas, the primary radiosurgical
goal for functioning adenomas is both endocrine remission and
radiological tumor control. Radiological tumor control usually
accompanies endocrine remission, but some adenomas exhibit

Table 13.1 Major radiosurgery series for nonfunctioning pituitary adenomas

Study N Mean or median FU (mo) Mean or median margin Tumor control (%)
dose (Gy)

Feigl et al, 200276 61 55 15 94

Sheehan et al, 200231 42 31 16 98

Wowra et al, 2002 77 30 58 16 93

Petrovich et al, 200378 52 34 15 100

Losa et al, 200479 54 41 17 96

Muacevic et al, 200480 51 22 17 95

Kajiwara et al, 200581 14 32 13 93

Picozzi et al, 200582 51 41 17 97

Iwai et al, 200583 28 36 12 93

Mingione et al, 200684 100 46 19 92

Voges et al, 200685 37 57 13 100

Liscák et al, 200786 140 60 20 100

Pollock et al, 200826 62 64 16 97

Hoybye et al, 200987 23 78 20 100

Kobayashi et al, 200988 71 50 NA 97

Castro et al, 201089 14 42 13 100

Hayashi et al, 201090 43 36 18 100

Gopalan et al, 201191 48 95 18 83

Iwata et al, 201192 100 33 21 Gy/3 fr, 25 Gy/5 fr 98

Park et al, 201124 125 62 13 90

El-Shehaby et al, 201293 21 44 12 85

Runge et al, 201294 65 83 13 98

Starke et al, 201244 140 50 18 90

Wilson et al, 201295 51 50 14 100

Sheehan et al, 201333 512 36 16 93

Abbreviations: fr, fraction; FU, follow-up; Gy: gray; NA, not available.

110
 Stereotactic Radiosurgery for Pituitary Adenomas

tumor control yet fail to achieve endocrine remission. Radiosur-
gery plays an important role in the treatment of persistent
Cushing disease, acromegaly, and part of prolactinomas refrac-
tory to surgical and/or medical management.
For Cushing disease, endocrine remission is typically defined
as a normal 24-hour urine free cortisol (UFC) and serum corti-
sol. Most radiosurgical series for Cushing disease demonstrate
endocrine remission in the majority of patients after radiosur-
gery; the mean remission rate across major series is 51%. The
mean time interval after radiosurgery to endocrine remission
in successfully treated cases is 12 months.29 ▶ Table 13.2 details
recent major radiosurgical series for Cushing disease. Higher
radiosurgical doses typically are required to attain endocrine
remission in Cushing disease compared with those used to con-
trol the growth of nonfunctioning adenomas. Delayed endo-
crine recurrence after radiosurgery-induced remission can
occur. For example, in a radiosurgical series of 90 patients with
Cushing disease with a mean follow up of 45 months, recur-
rence of Cushing disease occurred in 10 patients at a mean time
of 27 months after initial remission.29 An illustrative case with
Cushing disease is shown in ▶ Fig. 13.2.
For acromegaly, endocrine remission varied widely (range 0–
82%) across series, but the mean remission rate for acromegalic
patients after radiosurgery was 44.7%. Endocrine remission for
acromegaly was typically defined as a normalization of IGF-1 or
nadir serum GH < 2.5 µg/dL. Some radiosurgical series use the

Table 13.2 Major radiosurgical series for Cushing disease

Study N Mean or median FU (mo) Mean or median margin Endocrine remission (%)
dose (Gy)

Izawa et al, 200096 12 26 24 17

Sheehan et al, 200030 43 39 20 63

Shin et al, 200097 6 88 32 50

Hoybye et al, 200198 18 17 NA 44

Feigl et al, 200276 4 55 15 60

Kobayashi et al, 200299 20 64 29 23

Laws et al, 2002100 40 NA 20 74

Pollock et al, 200263 9 42 20 78

Choi et al, 2003101 7 43 29 56

Petrovich et al, 200378 4 34 15 NA

Witt et al, 200337 8 24 24 0

Wong et al, 2003102 5 38 NA 100

Devin et al, 2004103 35 42 15 49

Kajiwara et al, 200581 2 39 26 50

Voges et al, 200685 17 59 16 53

Castinetti et al, 2007104 40 55 30 43

Jagannathan et al, 200729 90 45 23 54

Petit et al, 2008105 33 62 20 52

Pollock et al, 2008106 8 73 20 87

Tinnel et al, 200862 12 37 25 50

Castinetti et al, 2009107 18 94 28 50

Kobayashi et al, 200988 30 64 29 35

Wan et al, 2009108 68 67 23 28

Hayashi et al, 201090 13 36 25 38

Sheehan et al, 201132 82 31 24 54

Wein et al, 2012109 17 23 18 59

Grant et al, 2013110 15 40 35 73

Sheehan et al, 201370 96 48 22 70

Abbreviations: FU, follow-up; NA, not available.

111
 Stereotactic Radiosurgery for Pituitary Adenomas

Fig. 13.2 A 34-year-old woman with Cushing disease underwent two transsphenoidal surgeries before radiosurgery. The sella was empty, and there
was no visible tumor on magnetic resonance imaging. Persistent high serum cortisol (40 µg/dL) and urine free cortisol (UFC; 324 µg/24 h) levels were
noted. The patient underwent whole-sellar stereotactic radiosurgery (SRS) with a margin dose of 25 Gy. Endocrine remission was achieved 22 months
after whole-sellar SRS. The serum cortisol and UFC were gradually decreased, and suppressive medications were halted. However, the patient
eventually developed partial hypopituitarism at 56 months after SRS. TSS, transsphenoidal surgery; GKS, Gamma Knife radiosurgery.

results of an oral glucose tolerance test (OGTT) to define endo-
crine remission for acromegaly. ▶ Table 13.3 provides an over-
view of recent major radiosurgical series for acromegalic
patients. From prognostic factor analysis, patients with a func-
tioning adenoma volume of < 3 cc at the time of radiosurgery
have been noted to have significantly higher chance of endo-
crine remission following radiosurgery.32 Thus, maximum safe
surgical resection prior to radiosurgery increases the chance of
endocrine remission. At the University of Virginia, the median
time to endocrine remission after radiosurgery for acromegaly
was 24 months, and this was longer than for comparable Cush-
ing disease patients.32,45 Although drawn from retrospective
studies, there appears to be compelling evidence to temporarily
halt pituitary suppressive medications around the time of
radiosurgery for patients with acromegaly; this approach por-
tends a greater rate of endocrine remission after SRS. 46
▶ Fig. 13.3 illustrates an acromegaly case who underwent SRS
and achieved successful remission within 27 months.
For prolactinoma treated with a margin dose of 13 to
30 Gy, the remission rate varied from 0 to 84%. 38,47–52 Patients
who were treated with a higher radiation radiosurgical dose
had a significantly higher remission rate. 37,38,49,50 In a cohort
of prolactinoma patients, Witt reported there was no remis-
sion with a margin dose under 19 Gy. 37 Pan et al reported a
52% remission rate and a higher margin dose of 30 Gy in a
retrospective study of 128 patients in whom Gamma Knife
radiosurgery (GKRS) was used as an up-front treatment for
prolactinomas.53 Although some reports demonstrated an
acceptable outcome with a large sample size, SRS used as the
primary treatment is not typical in most medical centers. 53
Because prolactinomas usually respond well to medical ther-
apy, SRS is reserved for patients who have medicaly refrac-
tory prolactinomas. Thus, prolactinoma patients typically
undergoing SRS demonstrate a more aggressive adenoma
phenotype. At the University of Virginia, only 26% of patients
with medically refractory prolactinomas achieved normaliza-
tion of prolactin at a mean of 24.5 months after SRS; those
off antisecretory medication at the time of SRS were more
likely to achieve endocrine remission.38 These results are also
consistent with the study of Landolt et al. 48
13.8 Complications
The side effects of ionizing radiation are classified as acute
(within days), early delayed (within weeks), and late delayed
(within months to years) toxicity.
13.8.1 Acute Radiation Injury
Acute toxicity of SRS is rare compared with conventional
radiotherapy. Some acute radiation injuries such as skin
changes and hair loss were rarely present in a current clinical
setting.

112
 Stereotactic Radiosurgery for Pituitary Adenomas

Table 13.3 Major radiosurgical series for acromegaly

Study N Mean or median FU Mean or median Endocrine remission
(mo) margin dose (Gy) (%)

Izawa et al, 200096 29 26 24 41

Shin et al, 200097 6 43 34 67

Zhang et al, 200052 68 34 31 37

Fukuoka et al, 2001111 9 42 20 50

Ikeda et al, 2001112 17 56 25 82

Feigl et al, 200276 9 55 15 60

Pollock et al, 200263 26 42 20 42

Attanasio et al, 2003113 30 46 20 23

Choi et al, 2003101 9 43 29 50

Muramatsu et al, 2003114 4 30 28 50

Petrovich et al, 200378 5 34 15 NA

Witt et al, 200337 4 24 24 25

Castinetti et al, 2005115 82 50 25 17

Gutt et al, 200554 44 23 18 48

Kajiwara et al, 200581 2 54 14 0

Koybayashi et al, 2005116 67 63 19 5

Jezkova et al, 2006117 96 54 35 50

Voges et al, 200685 64 54 17 38

Pollock et al, 2007118 46 63 20 50

Roberts et al, 2007119 9 25 21 44

Vik-Mo et al, 2007120 61 66 27 17

Jagannathan et al, 200828 95 57 22 53

Losa et al, 2008121 83 69 22 60

Pollock et al, 2008106 27 47 20 67

Tinnel et al, 200862 9 35 25 44

Castinetti et al, 2009107 43 102 24 42

Ronchi et al, 2009122 35 120 20 46

Wan et al, 2009108 103 67 21 37

Hayashi et al, 201090 25 36 25 40

Iwai et al, 2010123 26 84 20 38

Poon et al, 2010124 40 74 20–35 75

Franzin et al, 2012125 103 71 23 61

Liu et al, 201249 40 72 21 48

Grant et al, 2013110 13 40 35 61

Lee et al, 2014126 136 62 25 67

Abbreviations: FU, follow-up; NA, not available.

113
 Stereotactic Radiosurgery for Pituitary Adenomas
Fig. 13.3 Stereotactic radiosurgery was performed for a 39-year-old man with residual adenoma after surgical resection. Although the patient failed
to discontinue the long-acting octreotide once, endocrine remission was achieved 23 months after SRS. He developed new hormone deficiencies,
including hypogonadism at 25 months, hypothyroidism at 41 months, and hypoadrenalism at 44 months after SRS. m, months; TSS, transsphenoidal
surgery; GKS, Gamma Knife radiosurgery.
13.8.2 Early Delayed Radiation Injury
The early delayed radiation injuries include hypopituitarism
and hypothalamic dysfunction, radiation necrosis, new-onset
visual deterioration, or other CN dysfunctions. Complications
resulting from SRS vary depending on tumor size, the extension
of tumor, and radiation doses.
Hypopituitarism and Hypothalamic
Dysfunction
Hypothalamic–pituitary dysfunction is the most common
intermediate-to-late complication of SRS of pituitary adeno-
mas. Approximately 30 to 50% of patients develop a new hor-
mone deficiency within 5 to 10 years after radiosurgery. 28,29,
32,33,54 Using SRS for pituitary adenoma at the University of
Virginia, 30% patients developed a delayed onset of hypopi-
tuitarism within 3 years. The thyroid function was affected
most, then gonadotrophic hormone, ACTH, and growth hor-
mone.55 There appeared to be two potent and independent
variables, margin dose to the tumor and suprasellar exten-
sion,55 which were predictive of the risk of developing a hor-
mone deficiency. Although an ideal radiosurgical dose plan
has a steep gradient index that minimizes the dose to normal
pituitary tissue and therefore reduces the risk of treatment-
induced hypopituitarism, a true safe dose below which the
114
patient is not afflicted with hypopituitarism does not practi-
cally exist. Furthermore, an optimal radiosurgical dose to
the target lesion should not be compromised for the sake of
avoiding hypopituitarism. The clinical consequences of mac-
roscopic tumor progression, recurrence, or persistent hor-
mone hypersecretion far outweigh those of radiosurgery-
induced hypopituitarism, which can readily be managed with
medical therapy by neuroendocrinologists.
On the other hand, very few patients have new-onset diabe-
tes insipidus after SRS, and the incidence of diabetes insipidus
after radiosurgery is generally related to changes in the tumor
complex that mechanically impact the pituitary. Other hypo-
thalamic dysfunctions, including poor control of body tempera-
ture, and changes in sleep and appetite, are exceedingly rare
event after SRS.
Cranial Neuropathy Including Optic Neuritis
The second most common radiosurgery-related complica-
tion following treatment of pituitary adenomas is cranial
neuropathies. Multiple CNs, including II, III, IV, V, and VI, by
virtue of their location in the parasellar and suprasellar
regions are at risk of inadvertent injury from radiosurgical
treatment. Most radiosurgery series report neurologic defi-
cit rates of < 5%, with optic neuropathy as the most common
owing to its high sensitivity to radiation-induced damage. 33

In a recent study of 217 pituitary adenoma patients who
underwent radiosurgery, 9 patients (4%) developed new or
worsened CN dysfunction. Of those patients with radiosur-
gery-induced cranial neuropathies, six (67%) experienced
complete resolution over a median follow-up of 32 months.
As such, the radiosurgical maximum dose to the optic appa-
ratus should be kept below the limit threshold of 8 to 12 Gy
to minimize the risk of optic nerve damage. Careful dose
planning with contouring of critical structures and shielding
of the same can often achieve a solution that delivers an
optimal dose to the target and a typically safe dose to the
critical structures.
Radiation Necrosis
Radiation necrosis rarely occurs in the SRS for pituitary adeno-
ma. Neurologic deterioration due to radiation necrosis is often
delayed, occurring several months to several years after ioniz-
ing radiation to the sellar region. For patients with pituitary
adenoma, radiation necrosis can occur in the tumors that
extends to cavernous sinus; temporal lobe necrosis has also
been described in very few cases.28
13.8.3 Late Delayed Radiation Effects
In the era of conventional radiotherapy, late delayed radia-
tion complications included radiation-induced secondary
brain tumors, and cerebrovascular disturbance in the treat-
ment of sellar tumors. 56,57,58,59 In the current clinical set-
ting, the risk of a radiation-induced secondary tumor is
quite low when radiosurgery is used in the treatment of
sellar tumors. This may be due to the longer latency period;
however, radiobiologically, it is possible that the sharp dose
falloff achieved with SRS results in very few cells at risk for
malignant transformation as compared with broader-field
radiotherapy approaches. 60 This hypothesis is supported by
a long-term follow-up study by Rowe and colleagues, 61 in
which only one new primary intracranial tumor was
reported among 4,877 patients treated by SRS. Fortunately,
there are currently no reported cases in the literature of
radiation-induced neoplasm following radiosurgery for
pituitary tumors. As for cerebrovascular complications, we
found only one case report of a patient who had a cerebral
infarction with internal carotid artery occlusion after SRS
for a pituitary tumor. 43
13.9 Prognosis
Late biochemical recurrence of secretory pituitary adenomas is
fortunately rare after successful radiosurgery-induced endo-
crine remission. However, in some radiosurgical series, late
recurrence rates of up to 20% have been reported. Several Cush-
ing disease radiosurgery series have described late biochemical
recurrence.29,62 The overall incidence of late biochemical
recurrence is relatively low.29,63 Ultimately, the existence and
potential for biochemical recurrence despite successful endo-
crine remission underscores the importance of long-term
endocrine follow-up after radiosurgery for functioning pitui-
tary adenomas.
Stereotactic Radiosurgery for Pituitary Adenomas
13.10 Special Considerations and
Debates in the Management of
Pituitary Adenomas
13.10.1 Comparison of External Beam
Radiation Therapy versus Radiosurgery
As a result of the reported higher complications rates as well
as the longer and lower success rates particularly for endo-
crine remission of functioning adenomas after EBRT, the cur-
rent role of adjuvant, postsurgical management of recurrent
or residual pituitary adenomas has largely shifted away from
external beam radiotherapy (EBRT) to radiosurgery. Radiosur-
gery provides certain advantages over EBRT, including
increased convenience for the patient due to the relative ease
of single-session radiosurgery treatment compared with
EBRT and a better ability to spare normal pituitary and neu-
ral structures due to steeper gradient indices. Additionally,
late-responding tissue, such as pituitary adenoma cells, have
a greater radiobiological response than early-responding tis-
sue to higher radiation doses in fewer fractions—of which
radiosurgery represents the most extreme end of the spec-
trum, as it is usually delivered in one session. Furthermore,
the rate of endocrine remission following radiosurgery is
unequivocally more rapid than after EBRT. 64 The faster endo-
crine remission achieved with radiosurgery as compared with
EBRT can yield substantial benefits to patients with function-
ing adenomas.
Just as with radiosurgery, the most frequently encountered
complication following EBRT is delayed hypopituitarism,
although the reported rates, ranging from 50 to 100%
depending on the duration and quality of endocrine follow-
up, are significantly higher than in the radiosurgery litera-
ture.65 In most EBRT series, the rates of optic neuropathy are
comparable to those found in radiosurgery series. However,
at a total radiation dose of 65 Gy, the 5-year risk of visual def-
icits after EBRT is up to 50% with reports of optic neuropathy
at doses as low as 46 Gy in 1.8-Gy fractions. 66 More severe
complications, which occur at a reportedly higher frequency
following EBRT than radiosurgery, include a 10-year risk of
radiation-induced neoplasia of 2.7% and a 5-year stroke risk
of 4%, presumably from radiation-induced carotid stenosis or
occlusion.57 It is important to note that EBRT, which was
developed prior to radiosurgery, has been used to treat pitui-
tary adenoma patients for a longer period; this has resulted
in more extended follow-up intervals in the EBRT literature
than in the radiosurgery literature. However, the radiosurgi-
cal literature has become quite mature as of late, and the
severe complications associated with ischemic stroke and
radiation-induced neoplasia well documented with EBRT do
not seem to be observed with radiosurgery. Nevertheless,
these severe complications are at least theoretically possible
with radiosurgery, too.
Although radiosurgery has displaced EBRT as the preferred
adjuvant treatment modality for pituitary adenoma patients,
there remain cases in which EBRT is favored. For large pitui-
tary adenomas, typically > 3 cm in diameter, tumors with
irregular anatomy, including diffuse local infiltration and
115
 Stereotactic Radiosurgery for Pituitary Adenomas
suprasellar or brainstem extension, and lesions in very close
proximity to neural structures highly sensitive to radiation
(e.g., the optic apparatus), EBRT may represent a safer treat-
ment option than radiosurgery. External beam radiotherapy
provides reasonable tumor control, with rates exceeding 90%
in most series for nonfunctioning adenomas, but a lower and
later rate of endocrine remission for functioning lesions, with
a differential response based on the adenoma subtype. 59,67
External beam radiotherapy may also be used for patients
with pituitary carcinoma.
13.10.2 Role of Up-front Radiosurgery
As a general principle, the use of radiosurgery in the ma-
nagement of pituitary adenomas should be reserved for
recurrent or residual lesions and for patients with function-
ing adenomas who remain symptomatic from persistent
hormone hypersecretion despite surgical intervention. The
literature does not support the routine use of up-front
radiosurgery for pituitary adenomas, especially for func-
tioning adenomas. However, radiosurgery may be used as
an up-front treatment in rare and unusual circumstances. In
a multicenter study that enrolled patients from the Univer-
sity of Virginia, the University of Pittsburgh, and Taipei Vet-
eran General Hospital,68 41 patients with nonfunctioning
adenoma underwent GKRS as primary management due to
advanced age, multiple comorbidities, and psychiatric disor-
ders. The overall tumor control rate was 92.7%, and the
actuarial tumor control rate was 94 and 85% at 5 and 10
years postradiosurgery, respectively. Radiosurgery could
also be considered as an up-front treatment in a patient
with an adenoma that residues largely in the cavernous
sinus and for whom resection is unlikely to produce sub-
stantial reduction in the overall tumor volume.
13.10.3 Various Histological Entities of
Nonfunctioning Adenomas versus the
Efficacy of SRS
Silent corticotroph pituitary adenoma represents a rare entity
of nonfunctioning adenoma. Prior studies suggest that it may
appear more aggressive with a high recurrent rate. At the Uni-
versity of Virginia, 27 consecutive patients (16% of a whole ser-
ies of nonfunctioning adenoma) with silent corticotroph
pituitary adenoma were identified based upon a histopatholog-
ical analysis. The actuarial progression-free survival was 97, 95,
and 89% in the nonfunctioning group and 84, 52, and 52% in the
silent corticotroph pituitary adenoma group at 3, 5, and 8 years,
respectively.69 Hence, silent corticotroph pituitary adenoma
represents an aggressive entity with a higher recurrence rate
after SRS. In view of the increased risk of recurrence or progres-
sion, prescribing higher than the dose generally used for non-
functioning adenomas (13–18 Gy) may be reasonable. This
provides a critical implication that an increased margin dose
may be used to treat patients bearing silent ACTH adenoma in
the future clinical practice. However, a multicenter study or
clinical trial may be of paramount importance to confirm this
finding.
116
13.10.4 The Radioresistant Effects of
Antisecreting Medications
The negative effect of somatostatin analogs on the results of
SRS for acromegaly was first reported in 2000. 48,63 Landolt
and colleagues detailed the influence of octreotide on the
results of SRS in 31 patients. They found that patients
treated with octreotide at the time of SRS achieved a nor-
mal level of growth hormone and IGF-1 after a significantly
longer interval than patients who did not receive the
drug.48 Pollock et al also reported similar results in 2002. 63
The similar condition also occurred in the patients with
prolactinomas: The remission rate was in patients receiving
an antisecretory medication at the time of radiosurgery. 53
As a result of these studies, we discontinued antisecreting
medications for 6 weeks before SRS, and resumed them 2 to
6 weeks after SRS. Similar findings of deleterious effects
from ketoconazole after SRS for patients with Cushing dis-
ease have been found. 70 Larger, randomized clinical trials
are still necessary to confirm the negative relationship
between hormone-suppressive medications and outcome of
radiosurgery.
13.10.5 Whole-Sellar Stereotactic
Radiosurgery of MRI-Indeterminate
Functioning Adenomas
Although being the best neuroimaging study for defining pitui-
tary adenomas, MRI has been reported to fail to detect between
36 and 64% of patients with ACTH-secreting pituitary
adenomas.71
The patients frequently have residual tumor with micro-
scopic infiltration of the venous sinuses or adjacent dura and
are neither readily evident on neuroimaging studies nor sur-
gically accessible. As a result, recurrence rates for Cushing
disease have been reported to range from 5 to 27% with a
mean follow-up period ranging from 6.7 to 9.6 years. 72,73,74,75
Based on the considerations above, total and partial hypo-
physectomies appear to be a reasonable approach for
selected patients. At the University of Virginia, we delivered
radiosurgery to the entire sella for symptomatic patients with
a medically refractory, invasive, or imaging-negative func-
tioning pituitary adenomas. Adopting a similar rationale of
hypophysectomy, whole-sellar SRS attempts to treat recur-
rent or persistent diseases by delivering focused high-dose
radiation to the entire sellar and parasellar contents because
microscopic invasion can neither be localized on imaging
studies nor identified by surgeons intraoperatively. Endocrine
remission of 54, 78, and 87% was achieved within 2, 4, and 6
years after SRS, respectively. We observed hypopituitarism in
42.2% of the patients, with 3.1% eventually developing panhy-
popituitarism during the follow-up period. Compared with
the morbidities of persistent hypersecretion from functioning
adenomas, patients with postradiosurgery hypopituitarism
can be readily and fully treated with hormonal replacement.
Therefore, whole-sellar SRS could be an effective treatment
for functioning adenoma patients without a discrete adeno-
ma on MRI.

13.11 Conclusions
Radiosurgery plays an important role in the contemporary ma-
nagement of patients with a pituitary adenoma. Stereotactic
radiosurgery is typically used in patients with substantial resid-
ual tumor or recurrence after surgical resection of nonfunction-
ing adenomas. Stereotactic radiosurgery is also employed for
patients with functioning adenomas that fail to achieve endo-
crine remission after prior resection. Neurologic function after
radiosurgery is usually preserved or at times improved, even
when the treated adenoma extends into the cavernous sinus.
Delayed postradiosurgical hypopituitarism is the most common
complication, but is manageable with appropriate hormone
replacement. Life-long neuroimaging and endocrine follow-up
is recommended for patients with pituitary adenoma treated
with radiosurgery.
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with low toxicity. Neuro-oncol 2011; 13: 916–922
[93] El-Shehaby AM, Reda WA, Tawadros SR, Abdel Karim KM. Low-dose Gamma
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[94] Runge MJ, Maarouf M, Hunsche S, et al. LINAC-radiosurgery for nonsecreting
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[95] Wilson PJ, De-Loyde KJ, Williams JR, Smee RI. A single centre’s experience of
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[96] Izawa M, Hayashi M, Nakaya K, et al. Gamma knife radiosurgery for pituitary
adenomas. J Neurosurg 2000; 93 (Suppl 3): 19–22
[97] Shin M, Kurita H, Sasaki T, et al. Stereotactic radiosurgery for pituitary adeno-
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[98] Höybye C, Grenbäck E, Rähn T, Degerblad M, Thorén M, Hulting AL. Adreno-
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after treatment with stereotactic radiosurgery. Neurosurgery 2001; 49: 284–
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[99] Kobayashi T, Kida Y, Mori Y. Gamma knife radiosurgery in the treatment of
Cushing disease: long-term results. J Neurosurg 2002; 97 (Suppl): 422–428
[100] Laws ER, Reitmeyer M, Thapar K, Vance ML. Cushing’s disease resulting from
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48: 294–299
[101] Choi JY, Chang JH, Chang JW, Ha Y, Park YG, Chung SS. Radiological and hor-
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[102] Wong GK, Leung CH, Chiu KW, et al. LINAC radiosurgery in recurrent Cush-
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[103] Devin JK, Allen GS, Cmelak AJ, Duggan DM, Blevins LS. The efficacy of linear
accelerator radiosurgery in the management of patients with Cushing’s dis-
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[104] Castinetti F, Nagai M, Dufour H, et al. Gamma knife radiosurgery is a success-
ful adjunctive treatment in Cushing’s disease. Eur J Endocrinol 2007; 156:
91–98
[105] Petit JH, Biller BM, Yock TI, et al. Proton stereotactic radiotherapy for persis-
tent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab
2008; 93: 393–399
[106] Pollock BE, Brown PD, Nippoldt TB, Young WF Jr. Pituitary tumor type affects
the chance of biochemical remission after radiosurgery of hormone-secreting
pituitary adenomas. Neurosurgery 2008; 62: 1271–1276, discussion 1276–
1278
[107] Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radio-
surgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94:
3400–3407
[108] Wan H, Chihiro O, Yuan S. MASEP gamma knife radiosurgery for secretory pi-
tuitary adenomas: experience in 347 consecutive cases. J Exp Clin Cancer Res
2009; 28: 36
[109] Wein L, Dally M, Bach LA. Stereotactic radiosurgery for treatment of Cushing
disease: an Australian experience. Intern Med J 2012; 42: 1153–1156
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[111] Fukuoka S, Ito T, Takanashi M, Hojo A, Nakamura H. Gamma knife radiosur-
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[115] Castinetti F, Taieb D, Kuhn JM, et al. Outcome of gamma knife radiosurgery in
82 patients with acromegaly: correlation with initial hypersecretion. J Clin
Endocrinol Metab 2005; 90: 4483–4488
[116] Kobayashi T, Mori Y, Uchiyama Y, Kida Y, Fujitani S. Long-term results of gam-
ma knife surgery for growth hormone-producing pituitary adenoma: is the
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[117] Jezková J, Marek J, Hána V, et al. Gamma knife radiosurgery for acromegaly—
long-term experience. Clin Endocrinol (Oxf) 2006; 64: 588–595
[118] Pollock BE, Jacob JT, Brown PD, Nippoldt TB. Radiosurgery of growth hor-
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[119] Roberts BK, Ouyang DL, Lad SP, et al. Efficacy and safety of CyberKnife radio-
surgery for acromegaly. Pituitary 2007; 10: 19–25
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[122] Ronchi CL, Attanasio R, Verrua E, et al. Efficacy and tolerability of gamma
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(Oxf) 2009; 71: 846–852
[123] Iwai Y, Yamanaka K, Yoshimura M, Kawasaki I, Yamagami K, Yoshioka K. Gam-
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Knife surgery for acromegaly. J Neurosurg 2010; 113 (Suppl): 149–152
[125] Franzin A, Spatola G, Losa M, Picozzi P, Mortini P. Results of gamma knife ra-
diosurgery in acromegaly. Int J Endocrinol 2012; 2012: 342034
[126] Lee CC, Vance ML, Xu Z, et al. Stereotactic radiosurgery for acromegaly. J Clin
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119
 Stereotactic Radiosurgery for Chordomas
14 Stereotactic Radiosurgery for Chordomas
Dan Kunaprayoon, Ananth Charya, Jay S. Loeffler, and Helen A. Shih
Key Points
● Chordomas are rare, indolent, but locally aggressive tumors
of the skull base and spine with a propensity for recurrence.
● Stereotactic radiosurgery allows for increased relative biolog-
ical effectiveness compared with conventionally fractionated
radiotherapy, which can be particularly meaningful for a
disease requiring a high fractionated dose for response.
● Stereotactic radiosurgery for chordomas has been used in
different settings, most prominently in the management of
patients with recurrent or residual disease.
● The wide range of local control rates reported reflects the
variability of patient populations and treatment settings.
● High margin dose and smaller tumor volumes are associated
with improved local control.
● Dosimetric advantages of stereotactic radiosurgery allow for
favorable trade-offs between tumor control and adverse radi-
ation events.
14.1 Introduction
Chordomas are rare, indolent, but locally aggressive tumors of
the skull base and spine that arise from the embryological rem-
nants of the notochord with dural epithelial–mesenchymal ori-
gin.1 These tumors are often not clinically evident until late
stages due to invasion and local destruction of nearby tissues.
Indistinct margins, local invasiveness, high tumor burden, and
proximity to critical bony, vascular, and neural structures create
significant challenges in the clinical management of these neo-
plasms.2 Chordomas may occur anywhere along the spine and
skull base, but most commonly arise from the spheno-occipital
or sacrococcygeal regions. The distribution between cranial,
mobile spine, and sacral regions is approximately even, with
frequencies of 30.0, 29.2, and 32.8%, respectively.3 With skull
base presentations, chordomas frequently cause destruction of
the clivus with subsequent invasion of the posterior fossa and
compression of the brainstem or the nasopharynx. 4 Cranial
chordomas may present with cranial neuropathies, headache,
endocrinopathy, or hemorrhage.5 Although considered to be of
low metastatic potential, late-stage diagnosis of chordomas
increases the likelihood of distant metastases.1 Five percent of
chordomas metastasize, with likely sites including the brain,
bones, lung, and skin at the time of initial diagnosis.2
14.2 Epidemiology
Recent population-based studies using data from the Surveil-
lance, Epidemiology, and End Results (SEER) program of the
National Cancer Institute (NCI) estimated that chordomas
account for 1 to 4% of primary bone malignancies. Chordomas
are rare malignancies with an incidence rate of 0.089 per
100,000.3 Incidence rates are higher in men as compared with
women (0.10 per 100,000 vs. 0.06 per 100,000). Prevalence of
120
chordomas was higher in whites (91.2%) as compared with
blacks (2.2%) and other races/ethnicities (6.5%). Furthermore,
the annual incidence rate of chordomas in whites was four-fold
greater than blacks. The average age of diagnosis for chordomas
is typically in the sixth decade, with a worse prognosis associ-
ated with diagnosis at 70 years or greater. Chordomas have a
lower incidence in ages < 40, with < 5% of cases occurring in chil-
dren or adolescents.3 Survival analysis of 594 patients with cra-
nial chordomas within the SEER database demonstrated 3-, 5-,
and 10-year relative survival rates of 80.9, 73.5, and 58.7%,
respectively.6 Both males and females had similar 5-year (71.9%
vs. 75.4%) and 10-year (57.8% vs. 59.3%) survival probabilities.
Individuals older than 50 years and less than 10 years at diag-
nosis face worse prognosis as compared with individuals of
ages 11 to 49 years.
14.3 Pathogenesis
Chordomas arise from the remnants of the notochord that con-
tinue to reside within the vertebrae and axial skeleton after
involution of the embryonic notochord. Human embryo and
fetus studies in addition to cell-differentiation-tracking experi-
ments indicate these notochordal remnants preferentially
locate to anatomical sites that correspond to the typical loca-
tions of chordoma lesions.2 Moreover, molecular phenotyping
experiments demonstrate similar morphology between noto-
chordal nest cells and those obtained from chordomas.
The notochordal hypothesis is further supported by the dem-
onstration of transcription factor T (brachyury) gene duplica-
tion in individuals with familial chordoma.7 Brachyury is
expressed in normal, undifferentiated embryonic notochord in
the axial skeleton and is known to be overexpressed in cases of
sporadic chordoma as well. Individuals with familial chordoma
possess unique duplications, which consist solely of the bra-
chyury gene, within the 6q27 chromosomal regions as demon-
strated by high-resolution-array comparative genomic
hybridization.8
14.4 Histopathology and
Radiographic Features
First recognized by Virchow in 1857, chordomas display charac-
teristic vacuolated physaliferous cells and display variable levels
of histological atypia. However, the association between histo-
pathological features and biological activity remains to be eluci-
dated.2 Chordomas can classically be categorized into three
different histological variants as follows: (1) classical, which
exhibit lobulated masses comprising of groups of cells sepa-
rated by fibrous septa with pathognomonic vacuolated cyto-
plasm; (2) chondroid, which display characteristics of both
chordoma and chondrosarcoma; and (3) dedifferentiated. Tradi-
tionally, chordomas are recognized by positive immunohisto-
chemical staining for cytokeratin markers such as S-100 and
epithelial membrane antigen (MUC-1). Staining for brachyury

may provide a more sensitive and specific biomarker for detect-
ing combined with traditional assays for cytokeratin staining.2
Radiographically, chordomas typically appear as midline
lesions with destructive bony involvement. On magnetic reso-
nance imaging (MRI) and computed tomography (CT), these
lesions appear as soft-tissue masses.9 Specifically, on MRI, these
tumors display as isointense or hypointense to the surrounding
musculature, which is indicative of calcification and bony inva-
sion on T1-weighted images.2 On T2-weighted images, chordo-
mas display high signal, inhomogeneous texture. With
gadolinium, patchy to dense enhancement can be seen.9 Chor-
domas have decreased uptake of radioisotope on bone scan as
compared with other bone malignancies.
14.5 Treatment Options
14.5.1 Surgery
Surgical management is the traditional initial management of
choice for skull base chordomas. A variety of broad surgical
approaches are employed, which are dependent on tumor loca-
tion and surgical preference.10 These include transsphenoidal,
transmaxillary, transnasal, high anterior cervical retropharyng-
eal, and transoral approaches, as well as minimally invasive
endoscopic methods.2 An aggressive surgical approach achiev-
ing maximal radical resection must be balanced with reducing
operative morbidity and preserving critical neuroanatomical
structures, such as the brainstem, cranial nerves, pituitary, and
cavernous sinus. In light of the above, surgical approaches may
be directed at ameliorating brainstem and optic nerve tumor
compression and reducing tumor volume to set the stage for
future radiotherapy.11 Even when gross total resection is
achieved, local tumor recurrence rates can be high. In a series of
74 patients who underwent surgical resection for skull base
chordomas, gross total resection was achieved in 53 patients.
Among these patients, the 10-year recurrence-free survival was
31%.10 Furthermore, in patients who underwent surgical resec-
tion without subsequent adjuvant radiotherapy, local recur-
rence may be as high as 70%.1 In light of the above, the
paradigmatic management strategy for skull base chordomas
typically involves both maximal resection and adjuvant radio-
therapy. Exceptions are small lesions that can be gross totally
resected, with unlikely residual microscopic disease. These
patients can be curatively managed with surgery alone.
14.5.2 Conventional Radiation Therapy
En bloc resection is achievable in a low percentage of patients
with skull base chordomas, and as a result, adjuvant radiother-
apy reduces the local recurrence compared with surgery alone.
Postoperative irradiation is limited by adjacent anatomical
structures; the tolerance dose of the brainstem and cranial
nerves is lower than the effective treatment dose necessary for
local tumor control. Chordomas are ineffectively treated with
radiation doses < 60 Gy.1 Patient series employing conventional
radiotherapy with doses between 40 and 60 Gy demonstrate
local control rates nearing 50%.2,12 Others have advocated for
doses approaching 80 Gy.13 Technological advances in photon
radiotherapy allow for greater targeting accuracy with highly
conformal techniques to allow for steep dose reductions at the
Stereotactic Radiosurgery for Chordomas
tumor margins.14 External beam radiotherapy with convention-
al fractionation involves daily treatments, five times per week,
over approximately 7 to 8 weeks to deliver an effective cumula-
tive radiation dose. External beam radiotherapy for skull base
chordomas employs both image-guided intensity-modulated
radiotherapy and conventional fractionated stereotactic radio-
therapy to minimize radiation dose to nearby structures while
optimizing target conformality.15 Despite the advancements in
delivery with better conformality indices, photons still have a
relatively high exit dose (beyond the tumor target), resulting in
significant normal-tissue collateral irradiation.
14.5.3 Charged Particle Therapy
Proton and carbon radiotherapy permits higher radiation doses
to tumors with less exposure to surrounding critical structures
due to their physical beam characteristics.16–20 Due to their
mass and charge, accelerated particles have a characteristic
beam profile such that the integral dose in normal tissue is less
both proximally and distally to tumor targets in addition to
achieving a concentration of dose within the target.16,17 These
facilities are complex and expensive to maintain. There are a
limited number of treatment centers that constrain this as a
resource for patient care.
14.5.4 Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS) allows for several advantages
compared with conventional radiotherapy. The use of high dose
per fraction is associated with an increased relative biological
effectiveness (RBE), especially important in the treatment of
chordomas, which are slow growing and have traditionally
been viewed as relatively radioresistant tumors.5 Stereotactic
radiosurgery can be delivered as a single fraction or few frac-
tions (typically 2–5 sessions). Although there are no long-term
prospective data guiding the use of fractionated stereotactic
radiotherapy versus single-fraction radiosurgery, tumor vol-
ume, target conformality, setup uncertainty, and dose gradient
are taken into account during planning to determine number of
fractions for treatment. Stereotactic radiosurgery offers a clear
practical and logistical advantage over several weeks of treat-
ment courses of conventional photon or particle therapies.
Several factors should be considered when undergoing SRS
planning. High-resolution thin-slice MRI with long TR (repeti-
tion time) and contrast offers better target definition. This is
especially important in the case of recurrence or prior failed
radiotherapy. However, MRI alone does not define calcification,
cortical bone, or destructive edges well, and should be comple-
mented by high-resolution CT with attention to bone and soft-
tissue windows that may decrease out-of-field tumor recur-
rence.21 To avoid geographic misses, some groups suggest liber-
al inclusion of the whole bony clivus and consideration of a
boost dose.13 Beam-blocking techniques and conformal plan-
ning with multiple isocenters with automatic positioning sys-
tems should be employed to decrease risks of complications,
especially when the target volume is located close to critical
structures such as the brainstem or optic nerves.
Stereotactic radiosurgery can be delivered with different
techniques. These include Gamma Knife (GK), CyberKnife (CK),
and linear accelerator (linac)-based treatments. The majority of
121
 Stereotactic Radiosurgery for Chordomas
the reported series utilizes GK, which uses a hemispheric array
of cobalt-60 sources delivering photon radiation converging on
a focal point. Patients are immobilized with a fixed frame to
achieve positioning accuracy < 0.5 mm. Dose is typically pre-
scribed to the 50% isodose line, maximizing dose at the center
of the target and minimizing dose at the target edge with a
sharp dose falloff.14
The CK consists of a robotic, image-guided stereotactic sys-
tem with a linac mounted on a fully articulated robotic arm
capable of 6 degrees of freedom without external frame–based
fixation.22 As a result, an advantage of the CK system is the
capacity to treat tumors with complex shapes or difficult loca-
tions that are otherwise challenging to treat using frame-based
systems. Similar to other treatment modalities, radiation dose
to the tumor margin is planned based on volume, location, and
a history of prior radiotherapy.23 The treatment-planning sys-
tem of the CK affords the flexibility to select either isocentric-
or nonisocentric-based methods. However, nonisocentric radia-
tion delivery characteristically results in greater homogeneity
in coverage and steeper dose falloff outside the target mar-
gins.22 Thus, nearby critical structures can be delineated and
spared based on dose-weighted contouring of the tumor vol-
ume. Moreover, the CK affords the ability to deliver fractionated
radiosurgical regimens, which further reduces the radiation risk
to critical structures adjacent to the lesion.
Linac SRS employs photons generated from a traditional linac
produced by accelerating electrons onto a metal target. Treat-
ment can be planned using dynamic conformal arcs or with
multiple beams with the goal of producing a highly conformal
dose gradient delivering differential dose to target and normal
tissues. This can be achieved with beam modulation, multiple
isocenters, and micro-multileaf collimation. Compared with GK,
linac SRS is more homogeneous, but may be less conformal
when irradiating irregularly shaped targets.24 Protons are also
being developed for delivery of SRS, although this is still in an
early stage and there are a limited number of facilities with
proton therapy compared with the wider availability of photon
SRS.
There is a wide range of local control rates reported
(▶ Table 14.1).13,21,25–30 Reported overall survival at 5 years is
generally higher than local control, consistent with local failure
as the common site of disease progression more commonly
than systemic disease. Few studies report long-term outcomes
of at least 10 years. A series from Japan treating 37 patients
with chordomas and chondrosarcomas of the skull base
reported 5- and 10-year actuarial local control of 76 and 67%,
and overall survival of 80 and 53%.25
A number of factors determine treatment outcomes such as
tumor size or volume at time of irradiation. Patients presenting
with large tumor volume are especially challenging because
the most effective first-line therapy, surgery, is unlikely to
completely resect disease, even with aggressive skull base
approaches. Pamir et al reported a series of 26 skull base chor-
domas patients treated with surgery and radiation, with seven
patients receiving GK radiosurgery. Data from this study
describe inevitable tumor progression after surgery in tumors
with initial volumes ≥ 20 cc.31 Based on this observation, their
treatment algorithm recommends immediate adjuvant radio-
surgery for residual tumors ≤ 30 cc. In the study by Hasegawa et
al, only tumor volume was significant for long-term control on
122
both univariate and multivariate analyses, corresponding to 5-
and 10-year long-term control rates of 87 and 76% in tumors <
20 cc and 51 and 51% in tumors ≥ 20 cc.25 This corroborates ear-
lier experience with proton therapy associating tumor volume <
25 cc with long-term control.32
Other reports portray weaker association between tumor
volume and long-term control. The North American Gamma
Knife Consortium aggregated outcomes of 71 patients from six
academic medical centers who underwent GKSRS for intracra-
nial chordomas. They reported 5-year long-term control rates
of 82% for volumes < 7 cc and 57% for volumes ≥ 7 cc that was
significant on univariate but not multivariate analysis. 28 Koga et
al evaluated 14 patients with skull base chordomas or chondro-
sarcomas undergoing GK and also did not find tumor volume a
significant factor for long-term control on univariate or multi-
variate analysis.33 Martin et al did not find any of their factors,
including tumor volume, to reach statistical significance on
multivariate analysis in their series of 28 patients with chordo-
mas or chondrosarcomas undergoing GK as primary or adjuvant
treatment.34 Nonetheless, smaller residual tumor volumes may
be indicative of more complete up-front resection. They are also
potentially better candidates for repeat radiosurgery with fewer
side effects depending on degree of overlap.27
Although dose and volume are thought to be the main
parameters, other factors have been found to be associated with
tumor control and survival. Younger age was reported as a
favorable predictor for both survival and tumor control on uni-
variate and multivariate analysis, which has not been seen in
other studies.13,25,28,29,33,34 Gender has not been shown to be an
associated risk factor.13,25,28,34 Presentation and timing of treat-
ment were also examined, and they found that < 2 cranial nerve
deficits were associated with survival but not tumor control on
multivariate analysis. Symptom duration before SRS or interval
from diagnosis to SRS was not associated with longer tumor
control.
Perhaps the most obvious variable in disease control outcome
is radiation dose delivered. The composite findings of several
studies suggest a margin dose ≥ 15 Gy is required for long-term
control.13,25,28,35 Hasegawa et al reported that a margin dose ≥
15 Gy and maximum dose ≥ 30 Gy approached statistical signifi-
cance on univariate analysis, but not on multivariate analysis. 25
In another series of 25 chordoma patients treated at the Mayo
Clinic, a subset analysis demonstrated a 4-year actuarial control
rate of 50% for patients treated to < 15 Gy and 100% for patients
treated to ≥ 15 Gy.13 Koga et al found dose of treatment to be
the only factor on multivariate analysis to affect long-term con-
trol, requiring doses > 16 Gy.33 Kondziolka et al demonstrated
no progression of small tumors < 30 cc when treated to a mar-
gin dose > 20 Gy.35 Reports from smaller series have not found
margin dose to be a significant factor for tumor control. 26,34
However, prescribed doses or tumor volume alone can
obscure the clinical picture. For example, patients with prior
radiotherapy were prescribed significantly lower doses and also
had larger tumor volumes than patients without prior radio-
therapy, complicating the interpretation of these results.28
Prior treatment with either surgery or radiotherapy may be
associated with long-term tumor control and survival. Kano
et al found that not having prior radiotherapy was associated
with improved patient survival, but not tumor control on mul-
tivariate analysis.28 Other series have not found prior resection,
 Table 14.1 Studies and patient characteristics in published chordoma series treated with SRS
Study N Disease location Setting Interval SRS Median/mean Median/mean Normalization 5-y LC 5-y PFS 5-y OS Notes
between technique tumor volume margin dose
Dx and SRS (cm3) (Gy)
(mo)

9 clival Includes chondrosar-

Cho et al, 10 sphenopetroclival Adjuvant, comas. Only 6 patients
30 — GK 4.57 17 (15–20) 50–70% — 40% 80%
200830 2 petrous bone salvage with chordomas
9 not reported receiving SRS

10 clivus
Dassoulas et Adjuvant,
15 2 sphenopetroclival — GK 5.8 15.3 — 42.6% — — —
al, 200926 definitive
3 cavernous sinus

Hasegawa et Adjuvant, Includes

37 Skull base — GK 19.7 14 (9–20) — 72% 42% 80%
al, 200725 definitive chondrosarcomas.

Hauptman et 2 clivus 5 patients received

15 Adjuvant — Linac 12.3 15.5 90% — — —
al, 201136 3 cavernous sinus SRS

6 clivus
1 of upper clivus,
Henderson et cavernous sinus, or- Adjuvant, Includes extracranial
18 — CK 128 35 in 5 fractions 75% (60–84%) 59.1% — 74.3%
al, 200922 bits definitive chordomas
11 vertebral or sa-
cral

Adjuvant,
Ito et al,
19 19 clivus definitive, — GK 3.3 17.8 — — 47.9% — —
201027
salvage

10 clivus
2 clivus/sella 55% overall,
Jiang et al, Adjuvant, Includes extracranial
20 1 of cavernous sinus, 1–192 CK 16.1 32.5 (18–50) — 46% intracra- — 52.5%
201223 salvage chordomas
parasellar, and clival nial
7 vertebral or sacral

49 clivus
11 sphenopetroclival Adjuvant,
Kano et al, 14.6 (0.5– 28% underwent prior
71 1 craniocervical definitive, GK 7.1 15 — — — 80%
201128 297) RT
junction salvage
10 cavernous sinus

Koga et al, Includes

14 Skull base Adjuvant 8–96 GK 12.4 18 — — 43% —
201033 chondrosarcomas.

Krishnan et al, Adjuvant, Includes

34 — — GK 14.4 15 — 32% 67% —
200513 salvage chondrosarcomas.

Liu et al, Adjuvant, Includes

31 Skull base — GK 11.4 12.7 44% (35–60%) 21.4% — 75.8%
200821 salvage chondrosarcomas.
Stereotactic Radiosurgery for Chordomas

123
 Stereotactic Radiosurgery for Chordomas

number of prior resections, or prior radiotherapy to be associ-

includes those who did

Abbreviations: CK, CyberKnife; Dx, diagnosis; GK, Gamma Knife; LC, local control; OS, overall survival; PFS, progression-free survival; Rx, prescription; linac, linear accelerator; SRS, stereotactic radiosurgery; RT,
ated with tumor control.13,34 A series from China found extent

Includes extracranial

Reported outcomes
of resection to correlate with progression-free survival (PFS)

Seven patients
not receive RT
and overall survival (OS), but not recurrence.29 They reported

received SRS
chordomas
dismal 5- and 8-year PFS of 45 and 18%, and OS of 71 and 46%. 29
These long-term results are consistent with the natural history
Notes

of the disease, with patients exhibiting multiply recurrent and

late failures.31
The limited data suggest mixed findings with regard to possi-
5-y OS

62.9%

70.9%
ble significance of histology with outcomes. Ouyang et al

—
reported PFS rates by chordoma subtype, reporting 3-year PFS
of 86, 100, and 40% for classic chordoma, chondroid type, and
5-y PFS

dedifferentiated type, respectively.29 The difference between

45%
—

—
classic and chondroid subtypes was statistically significant. Ito
et al found MIB-1 labeling index to correlate with progression-
free period on simple regression with an optimum cutoff point
of 3.44%, the only factor found to significantly affect recur-
5-y LC

62.9%

rence.27 Other studies have not found histopathology to be a

—
—

significant factor.25,33
A few SRS series characterized their failures as in-field versus
Normalization

out-of-field. Liu et al reported with mean imaging follow-up of

28 months overall tumor progression in 9 of 31 patients (29%),
57.1%

with the majority (78%) occurring out-of-field.21 Krishnan et al

50%

showed a more even split between in-field (43%) and out-of-

field (57%), with an overall rate of 7 of 25 (28%) patients with
Median/mean
margin dose

evidence of progression on MRI at a median follow-up of 4.5

years.13 Hasegawa et al reported a higher proportion of in-field
failures (9/16, 56%) versus out-of-field failures (44%), as well as
16.5

16.2
(Gy)

a higher overall failure rate of 43% at a mean follow-up of 59

months.25
tumor volume
Median/mean

The tumor size and median tumor margin dose among these
series are variable, with tumor sizes ranging from 11.4 to 19.7
< 3 cm
(cm3)

cc and margin dose from 12.7 to 15 Gy. Despite variable follow-

12.4
9.8

up and patient populations, the reported data suggest an asso-

ciation between tumor size and in-field failure, with larger
tumors associated with a higher proportion of in-field failures.
technique

The association with margin dose is less clear.

These outcomes underscore the importance of dose and vol-
SRS

GK

GK

GK

ume parameters on local control and raise questions regarding

Dx and SRS

the mechanisms of in-field versus out-of-field failures. Sug-

between
Interval

gested hypotheses for in-field failures include insufficient dose

0–133
(mo)

or inherent biological resistance, whereas geographic misses

—

are thought to relate to out-of-field failures.13

Plan heterogeneity is postulated to have a role in out-of-field
Definitive,

definitive,
Adjuvant,

Adjuvant,

failures.25 Use of multiple isocenters in treatment planning to

salvage

salvage

salvage
Setting

provide an aggregate dose necessitates overlap of high-dose

spheres and ultimately nonuniform target dose. This is common
in Gamma Knife radiosurgery, which is typically prescribed
such that the 50% isodose line encompasses the target. Gamma
12 middle cranial
Disease location

3 craniocervical
5 multiple sites

Knife radiosurgery results in a heterogeneous dose distribution

with a decreasing dose gradient from the target center to the
Skull base

Skull base
21 sellar
36 clivus

margins, which may lead to an increasing risk of tumor recur-

fossa

rence outside the treatment volume due to underdosing at the

margin. This can be magnified in cases where the dose at the
Table 14.1 continued

margin is reduced to spare nearby critical structures.

28

77

26

radiation therapy.
N

Chordoma growth patterns, surgery, and postoperative imag-

Ouyang et al,

ing may also affect the rate of out-of-field failures.23,25,33 Chor-

Martin et al,

Pamir et al,

domas are invasive and destructive of both bone and adjacent

200734

201329

200431
Study

soft tissue, leading to indistinct margins even with combined

use of CT and MRI for treatment planning. Postoperative

124

changes and specific surgical approach, which may entail
extraction of tumor piecemeal, can contribute to greater uncer-
tainty of the target volume. For patients with out-of-field fail-
ures, repeat radiosurgery remains an option for further
control.25,26
Patients treated with other SRS modalities, including Cyber-
Knife and linac, exhibit outcomes within the reported range of
Gamma Knife series. Henderson et al reported a series of 18
patients who underwent CyberKnife radiosurgery (CKRS) for
either clival or extracranial chordomas. Unlike other series,
Henderson et al delivered treatment in five fractions. Overall
quality-of-life measures of patients improved and remained
stable.22 Jiang et al presented a series of 20 patients receiving
CKSRS as either primary adjuvant therapy or for tumor
recurrence (▶ Table 14.1). Within this study, postoperative
clinical improvement was achieved despite a larger volume
than many of the other series.23 Hauptman et al reported
their linac experience treating 15 patients with skull base
chordomas and chondrosarcomas.36 Thirteen of these
patients had chordoma, and five of them were treated with
SRS. Three patients remained stable, one recurred, and one
was lost to follow-up. No differences in radiation dosage or
volume were noted between those with control and the pa-
tient that failed.
When SRS is used in the recurrent adjuvant or salvage set-
ting, outcomes are suboptimal compared with its use in the pri-
mary adjuvant setting. Jiang and colleagues reported that only
29% of patients treated for recurrence had stable or improved
outcomes in the recurrent setting compared with 82% in the
primary adjuvant setting.23 Nevertheless, repeat SRS can offer
improved local control. Dassoulas et al reported that 5-year
actuarial tumor control after one Gamma Knife radiosurgery
(GKRS) was 43% and increased slightly to 50% when including
patients who underwent repeat GKRS, albeit this was among a
small series of 15 patients.26 Stereotactic radiosurgery in com-
bination with fractionated radiotherapy may increase the risk
of adverse events; the timing of SRS should be carefully consid-
ered as well.33
14.6 Complications
Given the often challenging location and relative radioresist-
ance of skull base chordomas, injury secondary to radiation is a
significant risk. The likelihood of radiation-related complica-
tions in the management of these tumors can be influenced by
characteristics of treatment plans, including dose, duration of
treatment, fractionation, type of radiation delivered, and the
ability to conform the dose to tumor contours. Although several
series demonstrate adverse radiation events associated with
conventional radiotherapy, including endocrinopathies, cranial
nerve deficits, and temporal lobe toxicity, the association with
single-fraction radiosurgery and radiation-related complica-
tions has been poorly characterized.36 Fractionated radiation,
particularly with more conformal techniques such as the use of
proton therapy, may lower the risk of radiation-related compli-
cations in adjacent critical structures due to reduced tumor exit
dose, but, in general, SRS is also associated with low morbidity
due to its high dose conformality.26,28 An alternative to decrease
radiation injury risks of single-fraction radiosurgery is
Stereotactic Radiosurgery for Chordomas
hypofractionated radiosurgery over two or more fractions.21 A
number of studies detail instances of adverse radiation events
in chordoma patients treated with SRS (▶ Table 14.2).
In a series of 25 patients with skull base chordomas treated
with SRS, 34% experienced adverse radiation events, with the
most common complication being cranial nerve dysfunction. 13
Per Hauptman et al, one patient who underwent SRS experi-
enced lower cranial nerve dysfunction after receiving 7.78 Gy to
21.11% of the brainstem at the 50% isodose line, which was sig-
nificantly greater brainstem exposure as compared with other
patients within the series.36 To minimize brainstem complica-
tions, it is recommended that exposure dose should be held to
less than 12 Gy. Cranial nerve deficits resulting from tumor exit
radiation dose may include, but is not limited to, ocular paraly-
sis, diplopia, dysarthria, and dysphagia.13,21,33
As with conventional radiotherapy, endocrinopathy has been
reported as a potential complication of SRS as well. Krishnan et
al reported anterior pituitary dysfunction in 10% of patients. 13
In addition, in a series of 31 patients, Liu et al reported one pa-
tient treated with GK who experienced pituitary dysfunction
18 months after radiosurgery.21 However, in a series of 15
patients with skull base chordomas treated with either linac
stereotactic radiotherapy or SRS, no patients treated with SRS
displayed endocrinopathy, whereas patients who underwent
fractionated radiotherapy experienced pituitary endocrinopa-
thies at cumulative doses > 30 Gy.36
Radiation-induced brain necrosis and temporal lobe toxicity
has been observed in both photon and proton-based radiother-
apy. In 62 patients with skull base tumors treated with proton
irradiation from 1998 to 2005, 7 patients demonstrated tempo-
ral lobe damage, ranging from asymptomatic grade 1 to symp-
tomatic grade 3 toxicity, associated with a fractionated relative
biological effective dose > 60 Gy.37,38 In patients treated with
SRS, temporal lobe toxicity has been demonstrated to be a
rarely encountered complication except in the case of reirradia-
tion. Hauptman et al described one patient who developed
temporal lobe radiation-related changes after reirradiation for
recurrent chordoma, including feelings of déjà vu and general-
ized anxiety. These symptoms subsequently resolved and may
be attributed to recurrent radiation treatments.36 Krishnan et al
reported that 17% of patients receiving SRS experienced radi-
ation-induced brain necrosis and temporal lobe toxicity. 13 Of
note, all of these patients had received external beam radio-
therapy prior to radiosurgery. For patients previously with-
out irradiation, radiosurgery alone may reduce the risk of
complications.
Reirradiation due to recurrent chordoma can increase the
likelihood of adverse radiation events, although the association
between repeat radiation and treatment-related complications
is not well documented. Fractionated photon or proton-based
radiotherapy for skull base chordomas prior to future single-
fraction SRS confounds analysis of potential radiation-associ-
ated complications. For example, the high percentage of adverse
radiation events in patients who underwent CKRS as reported
by Krishnan et al can be mitigated by the fact that no patients
who underwent SRS alone experienced treatment complica-
tions.13 In patients who underwent CKRS alone, Jiang et al
reported no postradiosurgery radiation-induced complications
in patients with clival chordomas.23 With respect to repeat SRS,
in a series of 37 patients with skull base chordomas treated
125
 Stereotactic Radiosurgery for Chordomas

Table 14.2 Complication rates in published chordoma series treated with SRS
Study Improved symptoms (%) Overall complication rate (%) Complications

Hasegawa et al, 200725 44.8 3 Facial numbness

Pituitary dysfunction, lower cranial nerve palsies,

Hauptman et al, 201136 — 13.3
transient temporal lobe radiation injury

Henderson et al, 200922 — 50 Diplopia, lower cranial nerve palsies

PBRT-induced visual deterioration and gait dis-

Jiang et al, 201223 30.7 15 turbance, leg weakness, no SRS-related complica-
tions

Kano et al, 201128 — 9 CN V–VII neuropathy, anterior pituitary dysfunction

Koga et al, 201033 — 10 Diplopia

Diplopia, ocular neuromyotonia, hearing loss, dys-

Krishnan et al, 200513 — 34.5 arthria, dysphagia, radiation necrosis, anterior
pituitary dysfunction

Liu et al, 200821 75 13 Pituitary dysfunction, ocular paralysis

Martin et al, 200734 — 5.5 Dizziness, nausea

Abbreviations: CN, cranial nerve; PBRT, proton beam radiotherapy; SRS, stereotactic radiosurgery.

with multiple GK treatments, reportedly no patients experi-
enced complications.25 However, Henderson et al reported
three patients who had previously received conventional radio-
therapy and/or GK who developed diplopia and lower nerve
cranial palsies after CKRS.22
14.7 Summary
Although maximum safe resection remains the primary treat-
ment, SRS has an important role in the multimodality manage-
ment of chordomas. It has been shown to be a safe and effective
treatment option for patients with residual or recurrent dis-
ease, and in some cases as definitive treatment for patients with
small-volume tumors. There is a wide range of outcomes,
including local control, overall survival, and complication rates,
reflecting the variability of patient populations and treatment
settings. Retrospective studies have examined the association of
a number of prognostic factors, with high margin dose and
smaller tumor volume as most consistently associated with
improved patient outcomes. Delivery of an appropriately high
margin dose can be challenging given anatomical constraints
and dose-limiting critical structures. However, dosimetric
advantages of SRS allow for favorable trade-offs between tumor
control and adverse radiation events. Stereotactic radiosurgery
may be considered as primary adjuvant therapy for residual
small-volume chordomas.
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127
 Stereotactic Radiosurgery for Chondrosarcomas
15 Stereotactic Radiosurgery for Chondrosarcomas
Hideyuki Kano, Aditya Iyer, and L. Dade Lunsford
Key Points
● Chondrosarcomas of the skull base are relatively slow grow-
ing, locally invasive tumors that usually do not metastasize
until very late in their natural history.
● Stereotactic radiosurgery for skull base chondrosarcomas is
an important adjuvant option for these rare tumors, as part
of a team approach that includes initial surgical removal of
symptomatic larger tumors.
● Stereotactic radiosurgery is associated with a high rate of lo-
cal tumor control and a low risk of neurologic complications.
15.1 Introduction
Chondrosarcoma is an osteocartilaginous tumor that is usually
dural based.1 Cranial chondrosarcomas originate from primitive
mesenchymal cells within the cartilaginous matrix of the skull
base.2 The typical sites of origin are synchondroses of the clivus,
the sphenoid-ethmoid region, the parasellar area, and the tem-
poral-occipital junction.3,4 The differential diagnosis of chon-
drosarcoma includes chordoma, chondromyxoid fibroma,
plasmacytoma, nasopharyngeal carcinoma, and other meta-
static tumors.5 The ability to distinguish chondrosarcomas from
chordomas by imaging alone is often difficult but important
because the prognosis is generally considered better for chon-
drosarcomas.6,7 Chordomas have a tendency to cause brainstem
compression because they arise from the clivus, but chondro-
sarcomas tend to affect the lower cranial nerves, as they
frequently originate from the occipitotemporal bone synchond-
rosis.8 The most common presenting symptom is diplopia sec-
ondary to an abducens nerve palsy, closely followed by
headache.9 Chondrosarcomas are relatively slow growing,
locally invasive tumors that usually do not metastasize until
very late in the natural history.10 The main subtypes of chon-
drosarcomas include a conventional/classic type that consti-
tutes 80% of cases and clear cell, mesenchymal, and
dedifferentiated variants that constitute the remaining 20%. 11
The conventional/classic type is further divided into World
Health Organization (WHO) grade I to III tumors based on the
degree of cellularity and atypia. The mesenchymal type exhibits
the most aggressive growth behavior and poorest prognosis.12
15.2 Surgical Resection for
Chondrosarcomas
Maximal safe microsurgical resection is considered the first-
line management for intracranial chondrosarcomas to confirm
the histological analysis and pursue the first-line option of
maximal safe resection.13,14 The ability to obtain a gross total
resection has improved as microsurgical skull base access tech-
niques have matured. However, chondrosarcomas are rarely
completely resectable and additional management options
128
must be considered for residual tumors.14,15 Crockard et al
reported a 93% 5-year survival rate for 17 patients who under-
went surgery alone.16 Wanebo et al17 reported that 23 patients
with chondrosarcoma of the skull base underwent 43 surgical
resections with a mean follow-up of 97 months. Ten patients
underwent adjuvant radiotherapy (RT). The 5- and 10-year
overall survival rates were 93 and 71%, respectively. Bloch et al
found a recurrence rate of 44% in patients who underwent sur-
gical resection alone, compared with 9% in patients who had
surgery followed by RT.12 A recent review of the literature
described the management of 560 patients with intracranial
chondrosarcomas; the 5-year mortality was 11.5% and the
median survival was only 24 months. There was also no associ-
ation between the rate of recurrence and the histological grade
of the tumor.12
15.3 Radiotherapy for
Chondrosarcomas
Reports of the use of fractionated proton beam RT have
increased in the past decade. Over the past 30 years, depend-
able dose constraints for normal tissues at the skull base for
protons were studied, and doses have been escalated to
improve biological response while maintaining a reasonable
toxicity profile.18,19,20,21 Most proton facilities rely on the use of
the Bragg peak effect, which facilitates energy deposition at the
target with a sharp exit dose falloff medially, thereby reducing
the potential for brainstem injury. Although most studies are
small patient series, the reported tumor progression-free sur-
vival (PFS) at 5 years after surgical resection with or without
proton RT varies from 85 to 95%.22,23,24 Advances in photon-
based radiotherapy (PBRT) such as intensity-modulated radio-
therapy (IMRT) have facilitated improved dose conformality to
a defined target volume and increased sparing of adjacent nor-
mal tissue. Combs et al25 reported on a series of patients who
received IMRT with dose ranging from 66 to 76 Gy. They noted a
5-year PFS and survival of 100% without cranial nerve deficit or
brainstem damage.
15.4 Stereotactic Radiosurgery for
Chondrosarcomas
Stereotactic radiosurgery (SRS) has been used as a minimally
invasive primary, adjuvant, or salvage option for chondrosarco-
mas. Stereotactic radiosurgery has been shown to result in less
toxicity to surrounding structures and have fewer complica-
tions than fractionated RT in the management of chondrosarco-
mas. Relatively little data exist to define the use of SRS in the
multimodality management of chondrosarcomas (▶ Table 15.1).
The tumor margin after surgical resection is often unclear on
magnetic resonance imaging (MRI) because of bone destruction
and surrounding tissue infiltration. In such cases, the coregis-
tration of MR and computed tomography (CT) images during
dose planning is useful. Koga et al reported the results of four

Table 15.1 Studies and patient characteristics in published series of chondrosarcoma treated with stereotactic radiosurgery
Study N Radiation Median age Median
margin dose
Krishnan et al, 4 SRS 45 15 Gy
200527
Hasegawa et al, 7 SRS 47 14 Gy
200728
Cho et al, 200831 11 SRS ± RT 38 12.7 ± 58.2 Gy 3.7 cc
Koga et al, 201026 4 SRS 43 15.6 Gy
Iyer et al, 201229 22 SRS ± RT 42 15 Gy
Abbreviations: NA, not applicable; RT, fractionated radiotherapy; SRS, stereotactic radiosurgery.
patients who had surgical resection followed by SRS at a
median follow-up of 99 months.26 Three of the four patients
(margin doses: 15, 16, 20 Gy) had no change in tumor size dur-
ing follow-up. One patient, who received a lower tumor margin
dose of 12 Gy, had tumor recurrence 100 months after SRS.
Krishnan et al27 reported 25 patients with chordomas and four
patients with chondrosarcomas who were treated by SRS. All
four patients with chondrosarcomas had tumor control at 5
years. No prognostic factors were identified in these early stud-
ies. Hasegawa et al28 reported 30 patients with chordomas and
seven patients with chondrosarcomas who underwent SRS. The
actuarial 5-year PFS rate in patients with low-grade chondro-
sarcomas was 80%. A tumor volume of > 20 mL significantly
improved PFS. Iyer et al studied 22 patients who underwent
Gamma Knife SRS for residual or recurrent intracranial chon-
drosarcomas.29 The overall patient survival after SRS was 95,
70, and 56% at 1, 5, and 10 years, respectively. Factors associated
with longer survival after SRS included a shorter interval (< 6
months) between diagnosis and SRS, age > 40 years, and either
a single or no prior resection. Treated tumor control rates were
91% at 1 year, 72% at 5 years, and 54% at 10 years. Factors asso-
ciated with longer PFS after SRS included patient age > 40 years
and no prior RT. Jiang et al30 reported 16 intracranial and spinal
chondrosarcoma patients who underwent CyberKnife SRS at
the median follow-up of 33 months. The mean tumor volume
was 35.1 cc. The margin dose varied from 22 Gy with a single
fraction to 30 Gy with five fractions. The overall patient survival
was 81% at 1 year, 67% at 3 years, and 55% at 5 years. The tumor
control was 80% in primary, 50% in recurrent, and 0% in meta-
static tumor. Adverse radiation effects were seen in one patient.
15.5 Report of the North Amer-
ican Gamma Knife Consortium
Seven participating centers of the North American Gamma
Knife Consortium (NAGKC) identified 46 patients who under-
went Gamma Knife SRS for skull base chondrosarcomas. Thirty-
six patients had prior surgical resections and six had prior frac-
tionated RT. The median target volume was 7.8 cc (0.9–41 cc)
and the median margin dose was 15 Gy (10.5–20 Gy). At a
median follow-up of 66 months after SRS, eight patients had
Stereotactic Radiosurgery for Chondrosarcomas
Tumor Local control Survival Median fol-
volume low-up (mo)
14.4 cc 5 y: 100 NA 58
19.7 cc 5 y: 76% 5 y: 90% 59
10 y: 67% 10 y: 53%
5 y: 89% 5 y: 100% 56
10 y: 80% 10 y: 100%
NA 5 y: 100% NA 65
8.0 cc 5 y: 72% 5 y: 70% 60
10 y: 54% 10 y: 56%
died. The overall survival after SRS was 89% at 3 years, 86% at 5
years, and 76% at 10 years. The overall survival after SRS in
patients without prior RT (N = 41) was 94% at 3 years, 91% at 5
years, and 80% at 10 years (▶ Fig. 15.1). In the group of patients
without prior RT, larger tumor volume (continuous data) was
significantly associated with worse overall survival (p = 0.049,
hazard ratio [HR] = 1.07, 95% confidence interval [CI] = 1.00–
1.14). In the group of patients without prior RT, the 5-year
overall survival was 100% when the tumor volume was < 5 cc
compared with 84% for patients whose tumor volumes ≥ 5 cc
(p = 0.049). Local tumor progression occurred in 10 patients.
The PFS after SRS was 88% at 3 years, 85% at 5 years, and 70% at
10 years. Prior RT was significantly associated with shorter PFS.
The PFS in patients without prior RT was 92% at 3 years, 88% at
5 years, and 81% at 10 years (▶ Fig. 15.1). In patients without
prior RT, larger tumor volume (continuous: p = 0.035, HR =
1.074, 95% CI = 1.005–1.147; ≥ 5 cc: p = 0.043) was significantly
associated with shorter PFS. The PFS in patients without prior
RT and with tumor volume < 5 cc was 100% at 10 years, whereas
the PFS in patients without prior RT and with tumor volume ≥ 5
cc was 87% at 3 years, 81% at 5 years, and 69% at 10 years. The
PFS in patients with residual tumor and no prior RT (N = 33)
was 94% at 3 years, 90% at 5 years, and 82% at 10 years after
SRS. The PFS in patients with recurrent tumor and no prior RT
(N = 8) was 86% at 3, 5, and 10 years after SRS. Recurrent tumors
were not associated with PFS (p = 0.977). Eight patients required
a salvage surgical resection and three patients (7%) developed
adverse radiation effects. Twenty-two (56%) of 39 patients who
had cranial nerve deficits before SRS improved. Clinical
improvement after SRS was noted in patients with abducens
paralysis (61%), oculomotor paralysis (50%), lower cranial dys-
function (50%), optic neuropathy (43%), facial neuropathy (38%),
trochlear paralysis (33%), trigeminal neuropathy (15%), and
hearing loss (10%).
15.6 Summary
Stereotactic radiosurgery provides a reasonable benefit-to-risk
profile for patients with residual or newly diagnosed small-vol-
ume skull base chrondrosarcomas. The ability to achieve tumor
control of chondrosarcomas is likely enhanced by earlier recog-
nition and the application of multimodal treatment in
129
 Stereotactic Radiosurgery for Chondrosarcomas

Fig. 15.1 (a) A T1-weighted contrast-enhanced axial magnetic resonance image (MRI) of a 32-year-old woman shows a chondrosarcoma at the time of
stereotactic radiosurgery (SRS). She underwent surgical resection followed by SRS for a residual tumor. Tumor volume was 1.2 cc and margin dose was
14 Gy. (b) An axial computed tomography image (CT) of the same patient at the time of SRS. (c) A T1-weighted contrast-enhanced reconstructed
coronal MRI. (d) A reconstructed coronal CT. (e) A T1-weighted contrast-enhanced reconstructed sagittal MRI. (f) A reconstructed sagittal CT.

appropriate patients. Maximal safe resection should be the pri-
mary initial management of chondrosarcomas. Stereotactic
radiosurgery is a potent treatment option for small- to me-
dium-sized chondrosarcomas and is associated with improve-
ment of cranial nerve function in selected cases, especially
patients who present with diplopia related to an abducens
palsy. The improvement of neuroimaging and radiosurgical
techniques has likely led to earlier detection of residual or
recurrent chondrosarcomas following resection and facilitated
improvements in radiosurgical delivery.
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ity chondromas: two case reports. Br J Neurosurg 2005; 19: 241–243
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ginous tumors at the skull base. Cancer 1973; 32: 410–420
[3] 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
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head and neck. Yonsei Med J 2005; 46: 228–232
[5] Neff B, Sataloff RT, Storey L, Hawkshaw M, Spiegel JR. Chondrosarcoma of the
skull base. Laryngoscope 2002; 112: 134–139
[6] Goel A. Chordoma and chondrosarcoma: relationship to the internal carotid
artery. Acta Neurochir (Wien) 1995; 133: 30–35
[7] Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base.
Strahlenther Onkol 1999; 175 (Suppl 2): 57–63
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ings in chordoma and chondrosarcoma of the skull base. Am J Ophthalmol
1993; 115: 97–104
[9] Bloch OG, Jian BJ, Yang I, et al. Cranial chondrosarcoma and recurrence. Skull
Base 2010; 20: 149–156
[10] Gay E, Sekhar LN, Rubinstein E, et al. Chordomas and chondrosarcomas of the
cranial base: results and follow-up of 60 patients. Neurosurgery 1995; 36:
887–896, discussion 896–897
[11] Amichetti M, Amelio D, Cianchetti M, Enrici RM, Minniti G. A systematic re-
view of proton therapy in the treatment of chondrosarcoma of the skull base.
Neurosurg Rev 2010; 33: 155–165
[12] Bloch OG, Jian BJ, Yang I, et al. A systematic review of intracranial chondrosar-
coma and survival. J Clin Neurosci 2009; 16: 1547–1551
[13] Lanzino G, Dumont AS, Lopes MB, Laws ER Jr. Skull base chordomas: over-
view of disease, management options, and outcome. Neurosurg Focus 2001;
10: E12
[14] Sekhar LN, Pranatartiharan R, Chanda A, Wright DC. Chordomas and chon-
drosarcomas of the skull base: results and complications of surgical manage-
ment. Neurosurg Focus 2001; 10: E2
[15] Sen CN, Sekhar LN. The subtemporal and preauricular infratemporal ap-
proach to intradural structures ventral to the brain stem. J Neurosurg 1990;
73: 345–354
[16] Crockard HA, Cheeseman A, Steel T, et al. A multidisciplinary team approach
to skull base chondrosarcomas. J Neurosurg 2001; 95: 184–189
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nial base chondrosarcomas. Neurosurgery 2006; 58: 249–255, discussion
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[18] Austin-Seymour M, Munzenrider J, Goitein M, et al. Fractionated proton radi-
ation therapy of chordoma and low-grade chondrosarcoma of the base of the
skull. J Neurosurg 1989; 70: 13–17
[19] Debus J, Hug EB, Liebsch NJ, et al. Brainstem tolerance to conformal radiother-
apy of skull base tumors. Int J Radiat Oncol Biol Phys 1997; 39: 967–975
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ma and chondrosarcoma of the skull base. Skull Base 2011; 21: 201–206
[21] Hug EB, Slater JD. Proton radiation therapy for chordomas and chondrosarco-
mas of the skull base. Neurosurg Clin N Am 2000; 11: 627–638
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ing surgery and high-dose photon and proton irradiation in 96 patients af-
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131
 Stereotactic Radiosurgery for Glomus Tumors
16 Stereotactic Radiosurgery for Glomus Tumors
Ajay Niranjan, Edward A. Monaco III, Hideyuki Kano, John C. Flickinger, and L. Dade Lunsford
Key Points
● Stereotactic radiosurgery is a minimally invasive option for
management of glomus tumors.
● It can be used as a primary management or as an adjunct
treatment for recurrent or residual glomus jugulare tumors
after surgical resection.
● It is associated with a high rate of local tumor control and a
low risk of neurologic complications for glomus tumors.
16.1 Introduction
Glomus jugulare tumors are benign, but locally invasive tumors
that arise from the paraganglionic chemoreceptors and may
occur in intracranial and extracranial locations. There are two
types of paragangliomas: sympathetic and parasympathetic.
Most head and neck paragangliomas are derived from parasym-
pathetic paraganglionic tissue that travels along the glossophar-
yngeal and vagus nerves. Head and neck glomus tumors
include carotid body tumors, jugulotympanic tumors, and glo-
mus vagale. Histologically, these are benign tumors with rare
malignant forms. Paragangliomas contain two cell types: the
chief cells and the supporting sustentacular cells. The chief cells
belong to the diffuse neuroendocrine system (DNES) and con-
tain neurosecretory granules. Physiologically, these are chemo-
receptors sensitive to changes in serum pH, pCO2, and pO2.
These tumors typically occur in older patients, but can be
found in young adults, especially in those with familial inheri-
tance. Glomus tumors are highly vascular; they are usually soli-
tary. Generally, symptoms are caused by local invasion of
adjacent structures or the effect of the tumor mass. The symp-
toms of these tumors include tinnitus, hearing loss, disequili-
brium, otalgia, dysphagia, hoarseness, and shoulder drooping
related to progressive cranial symptoms as the tumors pro-
gresses. In rare cases, these tumors may produce the hormone
norepinephrine, which may cause headaches, anxiety, hyper-
tension, and tachycardia. Because of the highly vascular nature
and relatively inaccessible anatomical location of glomus jugu-
lare tumors, surgical resection is often challenging. The ideal
treatment for patients with a glomus tumor remains controver-
sial. Treatment options include surgical resection, endovascular
embolization, fractionated radiation therapy, and stereotactic
radiosurgery (SRS), alone or in combination. Skull base tumors
may extend intra- as well as extracranially, as is typical in the
glomus jugulare variant. When located entirely in the middle
ear, glomus tympanicum tumors can be seen via otoscopic
examination.
Stereotactic radiosurgery has become an integral part of con-
ventional and advanced skull base surgery. Despite the advan-
ces in skull base techniques, the goal of total resection of such
tumors is often problematic and associated with significant
risk to critical structures of the skull base, including those with-
in the jugular bulb. Aggressive resection of such tumors
132
sometimes results in severe adverse neurologic events, ranging
from deficits in hearing, facial weakness, and symptoms of
vagal and glossopharyngeal dysfunction. Stereotactic radiosur-
gery is a primary option for these patients: It minimizes the
risks of open surgical techniques, preserves existing cranial
nerve (CN) function in most patients, and achieves tumor
growth arrest. Adjuvant Gamma Knife stereotactic radiosurgery
(GKSRS) is used for larger tumors after their initial partial
resection, providing long-term tumor growth control of a sig-
nificantly reduced tumor volume.
16.2 University of Pittsburgh
Experience
Between 1987 and 2010, 20 patients (9 men and 13 women)
with glomus tumors underwent GKSRS at our institution.
Median patient age was 54 years (32–88 years). Seven patients
had SRS for residual tumor after prior resection, whereas
13 had SRS as the primary management. Histological confirma-
tion was available for 8 patients; 12 were diagnosed based on
imaging characteristics. The tumors were categorized as Glass-
cock-Jackson grade 1 (n = 5), grade 2 (n = 2), grade 3 (n = 5), and
grade 4 (n = 8). The tumors were also categorized as Fisch stage
A (n = 1), stage B (n = 2), stage C (n = 4), and stage D (n = 13).
16.2.1 Stereotactic Imaging
Radiosurgery was performed using the GK (models U, B, C, 4C,
or Perfexion; Elekta Instruments AB, Stockholm, Sweden). Gam-
ma Knife SRS is a single-day outpatient surgical procedure. It
begins with rigid fixation of an imaging- (computed tomogra-
phy [CT], magnetic resonance imaging [MRI]) compatible Lek-
sell stereotactic frame (model G; Elekta Instruments) to the
patient’s head. Local anesthetic scalp infiltration (5% Marcaine
and 1% Xylocaine) is supplemented by mild intravenous seda-
tion with fentanyl and midazolam. A three-dimensional (3D)
volume acquisition MRI using a gradient pulse sequence (div-
ided into 1- or 1.5-mm-thick 28–36 axial slices) was performed
to cover the entire lesion and surrounding critical structures.
Stereotactic images were transferred via a fiberoptic Ethernet
to the GammaPlan (Elekta Instruments) dose-planning com-
puter where images are first checked for any distortion or inac-
curacy. Planning was performed on thin-slice axial MRI with
coronal and sagittal reconstructions. Computed tomography is
also valuable when bony involvement is defined in advance.
Using newer-generation dose-planning systems, both MRI and
CT data can be fused to best define the tumor margins and rela-
tionship to skull base bony structures (▶ Fig. 16.1).
16.2.2 Dose Planning
Dose planning is one of the most critical aspects of radiosur-
gery. A 3D conformal radiosurgery plan is necessary to limit the
radiation dose to adjacent critical structures (selectivity).
 Stereotactic Radiosurgery for Glomus Tumors

Fig. 16.1 (a) A 67-year-old man presented with 8-month history of pulsatile tinnitus and headache. Magnetic resonance imaging (MRI) showed a
vascular mass in the region of left jugular foramen. He underwent Gamma Knife radiosurgery as primary management of this tumor. At radiosurgery
the target volume was 3.5 cc. A conformal radiosurgery dose plan was designed using T1-weighted contrast-enhanced MRI, T2-weighted MRI,
computed tomography (CT), and angiography. A margin dose of 18 Gy was prescribed to 50% isodose line. (b) One-year follow-up MRI shows
regressed tumor.

Highlights of GK meningioma radiosurgery planning include 16.2.3 Dose Prescription

accurate 3D delineation of tumor volume, use of multiple iso-
centers, beam weighting, and use of beam-blocking patterns,
when appropriate, to achieve selectivity. Precise 3D conformal-
ity between planned isodose volume and tumor volumes is
needed to avoid radiation-related complications. This degree of
conformality can be achieved through complex multi-isocenter
planning. Glomus tumor dose planning at our center was typi-
cally performed using a combination of small-diameter (4- and
8-mm) collimators. For large tumors, 14-, 16- (Perfexion mod-
el), or 18-mm collimators may be used. The median target vol-
ume in this cohort was 12.5 cc (1.1–26.7 cc). An average of 10
isocenters (3–14) was used to yield conformal and selective
radiosurgery.
After optimizing the plan, a maximum dose within the target
and minimal dose at the target edge was determined. The treat-
ment isodose, maximum dose, and dose to the margin were
jointly decided by a multidisciplinary team including a neuro-
surgeon, a radiation oncologist, and a medical physicist, after
considering the goal of radiosurgery in an individual patient
and the estimated tolerance of the surrounding structures. A
mean margin dose of 13 Gy (12–18 Gy) was prescribed to the
tumor margins. For the last decade, we have prescribed a mar-
gin dose of 12–15 Gy to the edge of a glomus tumor, depending
on volume, anatomical location, and CN function. This radiosur-
gical dose is associated with both a low complication rate and a

133
 Stereotactic Radiosurgery for Glomus Tumors
high rate of tumor control. After prescribing the margin dose,
the falloff to surrounding critical structures (selectivity) was
assessed so that adjacent critical structures received a tolerance
dose. Dose delivery was accomplished in a single session by
positioning the head serially for each subsequent isocenter until
a fully conformal radiosurgical dose was delivered.
16.2.4 Postoperative Care and
Evaluations
Patients received an intravenous dose of 40 mg of methylpredni-
solone at the conclusion of the radiosurgical procedure. The
stereotactic frame was removed and patients were observed for
1 to 2 hours prior to discharge. After radiosurgery, all patients
were evaluated with serial gadolinium-enhanced MRI scans and
clinical examination. Studies were generally requested following
a schedule of 6 months, 12 months, and 2, 4, 8, and 16 years.
16.2.5 Results
At a median follow-up of 29.5 months (range 6–112 months),
17 patients were alive and 3 had died from unrelated causes.
Overall survival was 85%. Imaging follow-up was available in 17
patients. Tumors were stable or regressed in 88.25% of patients.
Five patients reported improvement in tinnitus, and one noted
worsening.
16.2.6 Discussion
Glomus jugulare tumors are indolent, locally destructive lesions
arising from the paraganglionic tissue surrounding the jugular
bulb. Current treatment options for glomus jugulare tumors
include surgical resection, endovascular embolization, convention-
ally fractionated external beam radiation therapy, SRS, or a combi-
nation of these modalities. Surgery preceded by embolization is
often considered a mainstay of treatment, especially in young
patients. Postoperative cranial neuropathies are common and can
serve to limit functional capacity after surgery. This postoperative
morbidity has led to an increase in the use of fractionated radio-
therapy for the treatment of glomus jugulare tumors, especially in
elderly patients or those with very large tumors.
The goal of surgery is complete tumor removal, whereas the
goal of conventionally fractionated external beam radiation
therapy and SRS is long-term tumor control. Both complete
tumor resection and long-term tumor control should prevent
tumor growth and regional extension that could lead to pro-
gressive symptoms, neurologic deficits, and ultimately death.
Irrespective of the mode or outcome of treatment, few patients
die of residual or recurrent tumor, unless there is intracranial
extension.1 Therefore, glomus jugulare treatment should focus
primarily on decreasing morbidity rather than on prolonging
survival.
16.3 Role of Fractionated Radia-
tion Therapy
Fractionated radiation therapy has been used to treat residual
tumor after resection.2 A meta-analysis of published reports on
134
the management of glomus tumor using fractionated radiation
therapy suggested a high tumor control rate, with minimal
morbidity and mortality.3 In a later study, Mukherji et al
reported a tumor control rate of 70% or higher using fractio-
nated radiation therapy.4 The rate of complications is relatively
low (0–10%), and complications include osteonecrosis of the
temporal bone, mastoiditis, and alopecia. Traditional external
beam radiation, however, is limited by the relative imprecision
of radiation delivery and needs a prolonged treatment course
often requiring several weeks. Advances in delivery of fractio-
nated radiation therapy using intensity-modulated or image-
guided techniques likely will further improve tumor control
rates and reduce adverse radiation effects.
16.4 Clinical Outcomes of
Radiosurgery for Glomus Jugulare
Tumors
Several single-institution small retrospective studies reporting
the use of SRS for glomus tumors have established the role of
radiosurgery in the management of this rare tumor
(▶ Table 16.1). Liscák et al reported 52 patients with glomus
jugulare tumors treated by GKSRS.5 Twenty-four patients had
prior surgical resection, 14 had prior embolization, and 5 had
prior fractionated radiation therapy (RT). The median tumor
volume was 5.7 cc (range 0.5–27 cc) and median margin dose
was 16.5 Gy (range 10–30 Gy). All patients had tumor control
after a median of 24 months. The neurologic symptom control
rate was 96%. Sheehan et al reported results for glomus tumor
radiosurgery from their institution.6 Eight patients were treated
using 15 Gy margin dose. At a median follow-up of 28 months,
all seven patients with radiological follow-up showed tumor
growth control. In a recent analysis from the University of Vir-
ginia, a margin dose of 13 Gy or greater appeared to confer a
higher rate of tumor control with minimal morbidity in a series
of 15 patients with glomus tumors.7
Although the majority of published radiosurgical series for
glomus tumor cases have been from GK centers, sporadic
reports of linear accelerator (linac) radiosurgery have also been
published (▶ Table 16.1). In a 2009 report on a series of 34
patients with large (defined as > 15 cm3) skull base tumors,
including some patients harboring glomus tumors, Tuniz et al 8
demonstrated local tumor control in all patients and 21% clini-
cal improvement after multisession CyberKnife treatment. In
another series of nine patients (eight with glomus jugulare
tumors), CyberKnife treatment achieved local tumor control in
all patients.9
16.5 Meta-analysis
Ivan et al reported a meta-analysis of tumor control and mor-
bidity for patients with glomus jugulare tumors. 10 They iden-
tified 869 patients with from 46 publications. Patients who
underwent gross total resection alone had a tumor control
rate of 86% at a mean follow-up of 88 months. Patients who
underwent subtotal resection followed by SRS had a tumor
control rate of 71% at a mean follow-up of 96 months.
Patients who underwent SRS alone had a tumor control rate
 Stereotactic Radiosurgery for Glomus Tumors

Table 16.1 Published series of glomus jugulare tumor radiosurgery

Study N Radiosurgery device Median margin Tumor volume (cc) Local control (%) Median follow-up
dose (Gy) (mo)

Liscák et al, 19995 66 GK 16.5 5.7 100 24

Pollock et al,
42 GK 14.9 19.7 97 44
200413

Gerosa et al,
20 GK 17.5 7 100 51
200614

Foote et al, 200215 25 GK 15 10.4 100 35

Maarouf et al,
12 Linac 15 NR 100 48
200316

Saringer et al,
13 GK 12 9 100 50
200117

Eustacchio et al,
19 GK 14 5.22 94.7 86
200218

Jordan et al, 200019 8 GK 16.3 9.81 100 35

Verma et al, 200620 17 GK 15 6.95 76 48

Wegner et al,
18 CyberKnife 20 (3 fractions) — 100 22.5
201021

Genc et al, 201014 18 SRS 15.6 5.5 94 53

Sheehan et al,
134 GK 15 5.5 92.7 50.5
201212

Abbreviations: GK, Gamma Knife; Linac, linear accelerator; SRS, stereotactic radiosurgery.

of 95% at a mean follow-up of 71 months. Patients who
underwent gross total resection suffered worse rates of CN
deficits involving CNs IX–XI than those who underwent SRS
alone.
Guss et al reported a meta-analysis in patients with glomus
jugulare tumors who underwent SRS.11 They identified 335
patients from 19 studies. Across all studies, 97% of patients
achieved tumor control, and 95% of patients achieved clinical
control. These meta-analyses of glomus tumor cases revealed
that radiosurgery is associated with a high local tumor control
rate > 95%. In a comparison of gross total resection, subtotal
resection, subtotal resection plus radiosurgery, and radiosur-
gery alone, radiosurgery alone had the lowest rate of CN IX–XII
deficits and the lowest rate of tumor progression.
microsurgical resection. The absence of trigeminal nerve dys-
function at the time of radiosurgery and higher number of
isocenters were significantly associated with progression-free
survival. Trigeminal nerve dysfunction in patients with glo-
mus tumors likely suggests a larger volume. Pulsatile tinnitus
improved in 49% of patients who reported it at presentation.
New or progressive CN deficits were noted in 15% of patients;
improvement in preexisting CN deficits was observed in 11%
of patients. Twenty-five percent of patients with new or
worsened CN deficits demonstrated tumor progression on
follow-up neuroimaging studies. The development of a new
or worsening CN deficit was a good predictor of delayed
tumor growth. No patient died as a result of tumor
progression.

16.6 Multi-institutional Studies 16.7 Patient Selection and

Sheehan et al performed a multicenter retrospective analysis
under the auspices of the North American Gamma Knife Con-
sortium (NAGKC). These authors reported results of 134
GKSRS procedures performed for 132 patients with a median
follow-up of 50.5 months.12 Prior resection was performed in
51 patients and prior RT was performed in 6 patients. The
median tumor volume was 5.5 cc (range 0.6–58.6 cc). The
median margin dose was 15 Gy (range 10–18 Gy). In this ser-
ies, tumor control was achieved in 93% of patients. The 5-year
tumor control rate was 88% after SRS. The majority of the
patients in this series had Fisch type C and D glomus tumors.
Such tumors are typically considered more challenging for
Radiosurgery Considerations
Several factors are considered in determining whether radio-
surgery is the optimal initial treatment. These include the
patient’s age, presenting signs and symptoms, associated
comorbidities, tumor size and invasiveness, as well as growth
rate. Patients with small- to moderate-volume size (volume < 15
cc) and typical imaging features are considered good candidates
for up-front radiosurgery. Modern radiosurgery systems such
as Leksell Gamma Knife Perfexion can treat intra- as well as
extracranial tumor components in a single session. Most of
these tumors are slow-growing neoplasms that respond well to

135
 Stereotactic Radiosurgery for Glomus Tumors
radiosurgery. Current recommended radiosurgical doses (12–
15 Gy), are associated with a high rate of local tumor control for
patients with glomus tumors. In addition, a dose plan that con-
forms to the shape of tumor and respects dose constraints of
adjacent neural and vascular structures at risk is necessary.
After radiosurgery, it is important for patients with glomus
tumors to undergo serial long-term neuroimaging clinical
evaluations.
16.8 Summary
Glomus jugulare tumors are rare, highly vascular tumors that
arise from the paraganglionic structures of the glossopharyng-
eal and vagal nerves. Because of the highly vascular nature and
surgically formidable anatomical location of glomus tumors,
curative resection often proves challenging. Treatment options
include surgical resection, endovascular embolization, fractio-
nated radiation therapy, and SRS, alone or in combination.
Although radiation therapy confers a reasonable rate of tumor
control, radiosurgery appears to offer at least a comparable rate,
but without the risks inherent with fractionated approaches.
Stereotactic radiosurgery can be used as an up-front treatment
or as an adjuvant therapy for patients with recurrent or residual
glomus jugulare tumor after surgical resection. Stereotactic
radiosurgery is associated with a high rate of local tumor con-
trol and a low risk of neurologic complications for patients with
glomus jugulare tumor.
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136
[5] Liscák R, Vladyka V, Wowra B, et al. Gamma Knife radiosurgery of the glomus
jugulare tumour—early multicentre experience. Acta Neurochir (Wien) 1999;
141: 1141–1146
[6] Sheehan J, Kondziolka D, Flickinger J, Lunsford LD. Gamma knife surgery for
glomus jugulare tumors: an intermediate report on efficacy and safety. J Neu-
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[7] Chen PG, Nguyen JH, Payne SC, Sheehan JP, Hashisaki GT. Treatment of glo-
mus jugulare tumors with gamma knife radiosurgery. Laryngoscope 2010;
120: 1856–1862
[8] Tuniz F, Soltys SG, Choi CY, et al. Multisession cyberknife stereotactic radio-
surgery of large, benign cranial base tumors: preliminary study. Neurosur-
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[9] Bianchi LC, Marchetti M, Brait L, et al. Paragangliomas of head and neck: a
treatment option with CyberKnife radiosurgery. Neurol Sci 2009; 30:
479–485
[10] Ivan ME, Sughrue ME, Clark AJ, et al. A meta-analysis of tumor control rates
and treatment-related morbidity for patients with glomus jugulare tumors. J
Neurosurg 2011; 114: 1299–1305
[11] Guss ZD, Batra S, Limb CJ, et al. Radiosurgery of glomus jugulare tumors: a
meta-analysis. Int J Radiat Oncol Biol Phys 2011; 81: e497–e502
[12] Sheehan JP, Tanaka S, Link MJ, et al. Gamma Knife surgery for the manage-
ment of glomus tumors: a multicenter study. J Neurosurg 2012; 117:
246–254
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mors. Neurosurg Focus 2004; 17: E10
[14] Gerosa M, Visca A, Rizzo P, Foroni R, Nicolato A, Bricolo A. Glomus jugulare
tumors: the option of gamma knife radiosurgery. Neurosurgery 2006; 59:
561–569, discussion 561–569
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and complications after stereotactic radiosurgery. Head Neck 2002; 24: 332–
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[16] Maarouf M, Voges J, Landwehr P, et al. Stereotactic linear accelerater-based
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radiosurgery in the treatment of glomus jugulare tumors. Minim Invasive
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[18] Eustacchio S, Trummer M, Unger F, Schröttner O, Sutter B, Pendl G. The role of
Gamma Knife radiosurgery in the management of glomus jugular tumours.
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[20] Varma A, Nathoo N, Neyman G, et al. Gamma knife radiosurgery for glomus
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 Stereotactic Radiosurgery for Nonvestibular Schwannomas

17 Stereotactic Radiosurgery for Nonvestibular

Schwannomas
Edward A. Monaco III, Gurpreet Surinder Gandhoke, Ajay Niranjan, Hideyuki Kano, and L. Dade Lunsford

most affected.2 It is believed that the growth patterns and bio-

Key Points
● Nonvestibular schwannomas are relatively rare intracranial
tumors that can arise from any cranial nerve and are thought
to show similar growth patterns and biological behavior as
vestibular schwannomas.
● In a fashion similar to that for vestibular schwannomas, treat-
ment of nonvestibular schwannomas has evolved with the
advent of modern microsurgical skull base approaches and
stereotactic radiosurgery.
● The results after stereotactic radiosurgery for nonvestibular
schwannomas compare favorably with those after surgery,
while avoiding surgically related complications.
● The paradigm shift in management of skull base tumors
extends to nonvestibular schwannoma treatment, with ster-
eotactic radiosurgery becoming the dominant modality and
surgical resection being reserved for large tumors or those
causing symptoms from mass effect.
17.1 Introduction
Cranial nerve (CN) schwannomas are typically benign tumors
arising from the Schwann cells making up the nerve’s myelin
sheath. Cranial nerve VIII is the most frequent site of origin for
these tumors. However, they can arise from any of the other
CNs, with the trigeminal nerve being the second-most common
site of origin (▶ Fig. 17.1). In a series of 62 patients with nonves-
tibular cranial nerve schwannomas (NVCNS), Safavi-Abbasi et al
reported that 76% of these tumors originated from either the
trigeminal nerve or the jugular foramen.1 In patients with type
2 neurofibromatosis, the oculomotor and trigeminal nerves are
logical behavior of CN schwannomas are similar regardless of
the nerve of origin.3,4,5,6 Nedzelski and Tator coined the terms
“nonacoustic neuroma” and “nonvestibular schwannoma” in
1982 in a review of eight cases involving patients harboring
such tumors.7 Nonvestibular cranial nerve schwannomas
account for less than 10% of intracranial schwannomas and less
than 0.5% of all intracranial neoplasms.5,8 Symptoms from these
tumors are typically referable to dysfunction of the nerve from
which the tumor arises, but can also be related to mass effect
on surrounding structures or even nonspecific such as head-
aches. The most common presenting complaint of patients
found to have trigeminal schwannomas is facial sensory dis-
turbance or pain.9
Prior to the advent or stereotactic radiosurgery (SRS), sur-
gical resection was the mainstay of treatment of NVCNS.
Complete resection of NVCNS, like that for vestibular
schwannomas, can be curative. Advancements in microsur-
gical techniques have contributed to improved outcomes for
patients harboring such tumors, but the morbidity associ-
ated with surgical resection is not trivial, especially for
tumors arising from the lower CNs. 10,11,12 Stereotactic radio-
surgery has an established role in adjuvant and primary
management of skull base tumors and has the benefit of
avoiding surgery-related morbidity. 3,5,8,13–18 The first pub-
lished radiosurgical series was reported by Pollock et al in
1993, and the work described the results of Gamma Knife
(GK) SRS in a small number of patients with trigeminal or
jugular foramen schwannomas. 16 Regardless of the treat-
ment modality, the goals of management for these tumors
should include excellent tumor control, improvement or
preservation of neurologic function, and limitation of treat-
ment-related morbidity.

Fig. 17.1 (a) Axial, (b) sagittal, and (c) coronal contrasted T1-weighted magnetic resonance images of a 19-year-old woman who presented with
complaints of headache, nausea, and vomiting. Physical examination identified hypoesthesia of the right face. Imaging revealed a large dumbbell-
shaped tumor involving Meckel’s cave and the posterior fossa consistent with a trigeminal schwannoma. The patient went on to receive multimodality
therapy including surgical resection, followed by stereotactic radiosurgery. Pathology revealed a benign schwannoma.

137
 Stereotactic Radiosurgery for Nonvestibular Schwannomas
17.2 Treatment Options
17.2.1 Microsurgery
The rationale for surgical resection of NVCNS is that it can be
curative. Resection is valuable in instances where there is diag-
nostic uncertainty, mass effect from the tumor with associated
symptoms, or when the tumor has a large cystic component
that may be unresponsive to radiosurgery. Resection can also
be undertaken in patients who show tumor progression after
radiosurgery. For patients with larger tumors in whom the risk
of complete tumor removal without significant morbidity is
judged to be high, a staged approach where surgical resection is
combined with another treatment modality, such as radiosur-
gery, can be undertaken.1
The published experience with microneurosurgery for
NVCNS is meaningfully smaller than that for vestibular schwan-
nomas, in line with the epidemiology of these tumors. The most
data involve patients harboring trigeminal schwannomas. Sur-
gical resection of all types of skull base lesions has evolved dra-
matically over the last several decades, owing to the
development of modern skull base approaches. The same is true
for NVCNS. Prior to modern techniques, total resection of
NVCNS occurred, at best, only 50% of the time.19 Contrast those
results with those of Samii et al.20 In a 27-patient retrospective
series involving trigeminal schwannomas, the tumor recur-
rence rate was only 7.4%, with recurrent tumors having
involved the cavernous sinus. Details are scant in this study
about the effects of surgery on patients’ symptoms. Day and
Fukushima, in their report on 37 patients, achieved gross total
resection in 73% of patients with trigeminal schwannomas. 21
Symptomatically, the number of patients with facial pain was
reduced from 13 to 2 after surgery. Hypesthesia was rela-
tively unaffected by surgery in this cohort, as 29 of 32
patients had persistent hypesthesia after surgery. Sharma et
al reported a total tumor excision rate for trigeminal schwan-
nomas of 76% with a mean follow-up period of over 5 years. 22
Zhang et al surgically treated 42 patients harboring trigemi-
nal schwannomas and observed an 81% total resection rate
when the tumor did not involve the cavernous sinus, and
only a 40% rate when it did. 23 Fukaya et al reported a retro-
spective surgical series of 57 patients with trigeminal
schwannomas.9 This study is notable, as it included patients
treated by conventional approaches and those who under-
went skull base approaches. In this cohort, only 38% of the
patients treated before 1990 with conventional approaches
achieved complete tumor removal. Using skull base
approaches, 90% of the patients treated after 1990 had com-
plete tumor removal. During the mean follow-up period of
4.9 years, these authors reported no tumor recurrences.
Wanibuchi et al describe their larger surgical experience in
105 patients with trigeminal schwannomas. 24 Total removal
was achieved in 75.2% of patients. The most common preope-
rative symptom in this series was facial hypesthesia, which
was only improved in 15.9% of patients. Facial pain, the sec-
ond-most common presenting symptoms in the cohort, sub-
sided in 91.7% of patients. Trigeminal motor dysfunction
improved in only one of three patients. Diplopia related to
abducens nerve dysfunction resolved in 13 of 18 patients, but
only in 1 of 3 patients with oculomotor nerve dysfunction.
138
Headache, the third-most common presenting symptom,
resolved in 93.3% of affected patients postoperatively.
Microsurgical resection of NVCNS utilizing the operative
microscope and modern skull base approaches has greatly
improved the effectiveness of surgery. When performed by
experienced surgeons, in carefully selected patients, micro-
surgery can be curative and result in meaningful improve-
ment in symptoms. It is not surprising that all evidence is
class 3, given the extremely limited numbers of patients pos-
sessing these tumors. Results of microsurgical management
of schwannomas arising from the other CNs must be extrapo-
lated. ▶ Table 17.1 shows results of select recent surgical
series for NVCNS.
17.2.2 Stereotactic Radiosurgery
Stereotactic radiosurgery has become an established primary
and adjuvant treatment modality for skull base neoplasms
(▶ Fig. 17.2). Stereotactic radiosurgery has been reported to
achieve tumor control for NVCNS at rates similar to those of the
best surgical series.8 One of the earliest series on SRS manage-
ment of NVCNS was by Pollock et al.16 In this series, six patients
with trigeminal schwannomas and five with jugular foramen
schwannomas underwent GKSRS. Doses ranged from 12 to
20 Gy. The tumor control rate for the trigeminal tumors was
100% at a median follow-up of 21 months and 75% for the jugu-
lar foramen tumors at a mean follow-up of 10 months. Two
patients showed improvement in CN symptoms. This early
experience paralleled results for vestibular schwannomas; since
then, numerous publications have appeared in the literature
describing the results of SRS for NVCNS.
Kano et al reported on 33 consecutive patients with trigemi-
nal schwannomas treated by GK.14 A third of patients had pre-
viously undergone microsurgical resection. A median margin
dose of 15 Gy was administered to a median target volume of
4.2 cc. The rates of progression-free survival in this cohort at 1,
5, and 10 years after SRS were 97.0, 82.0, and 82.0%, respec-
tively (▶ Fig. 17.3). Over 90% of patients had stable or improved
neurologic signs and symptoms following SRS. Factors associ-
ated with improved tumor control included smaller tumor size
and root or ganglion-type tumors. Not unexpectedly, patients
who had primary SRS management also had improved out-
comes when compared with patients who had previously
undergone craniotomy. Hasegawa et al administered a mean
dose of 14.2 Gy to a mean tumor volume of 10 cc in 42 patients
harboring trigeminal schwannomas.25 Actuarial 5- and 10-year
tumor control rates were both 84.0%. Forty percent of patients
showed improvement in clinical symptoms. Larger tumors in
this series were more likely to progress despite SRS treatment.
Pan et al evaluated 56 patients treated with GK for trigeminal
schwannomas, 42 of whom had primary SRS management. 4
The mean target volume was 8.7 cc and a mean tumor margin
dose of 13.3 Gy was utilized. After a mean follow-up period of
68 months, the tumor growth control rate was 93.0%. Neuro-
logic deficits improved in 44.6% of patients. Phi et al reviewed a
cohort of 22 consecutive patients with trigeminal schwanno-
mas.26 Having administered a mean marginal dose of 13.3 Gy to
a median volume of 4.1 cc, they observed tumor growth control
in 95% of patients after a median follow-up of 46 months.
Two thirds of patients presenting with facial pain showed
 Stereotactic Radiosurgery for Nonvestibular Schwannomas

Table 17.1 Recent selected microsurgical series

Study N Cranial Tumor Follow-up Tumor Improvement in Complications (%) Tumor recur- Mortality
nerve volume (mo) control clinical signs and rence rate (%) (%)
(cc) rate (%) symptoms (%)

Sedney et al, 81 JF NR NR 91 NR New cranial neuro- 8.9 0

201342 GTR, 54 pathy, 4.5
NTR, 23 Worsened cranial
STR, 1 neuropathy, 22.6
CSF leak, 4.5
ICH, 3

McRackan et al, 53 VII 27.9 NR 100 NR HB IV or worse, 51.8 0 0

201243 GTR, 45
STR, 8

Fukaya et al, 57 V NR 58.8 98 NR New cranial neuro- 0 0

20109 GTR, 43 pathy, 58.5
NTR, 3 CSF leak, 4.2
PR, 1

Safavi-Abbasi et 43 V, 24 14.8 44.5 97 Improved KPS New cranial neuro- 3.2 0

al, 20101 JF, 7 pathy, 18.4
VII and XII, CSF leak, 15.8
3 each Hydrocephalus, 2.6
IV and X, 2 Meningitis, 2.6
each
III and VI,
1 each

Fukuda et al, 15 JF NR 84.3 70 NR IX, X deficit, 40 60 0

200946 NTR, 10
STR, 5

Bulsara et al, 53 JF NR 100.8 94.3 NR Worsened IX/X neu- 5.7 0

200839 CTR, 48 ropathy, 30.0
Other, 4 CSF leak, 5.7

McMonagle et 33 VII NR NR NR NR VII nerve sacrificed, 9.1 0

al, 200844 CTR, 21 63
STR, 4 CSF leak, 2.8
Other, XII deficit, 2.8
11 Headache, 2.8
Intractable vertigo,
2.8

Sanna et al, 22 JF 36.6 NR 100 NR Lower cranial nerve 0 0

200641 CTR, 21 deficit, 50
STR, 1 CSF leak, 13.5
Meningitis, 4.5

Abbreviations: CTR, complete tumor removal; GTR, gross total resection; HB, House-Brackman; ICH, intracranial hemorrhage; JF, jugular foramen; KPS,
Karnofsky Performance Score; NTR, near-total resection; NR, not reported; PR, partial resection; STR, subtotal resection.

meaningful improvement in this symptom. A third of patients
with facial hypesthesia also improved.
Results after SRS for jugular foramen tumors have been nota-
bly similar (▶ Fig. 17.4). Martin et al reported the results of GK
treatment for 35 tumors in 34 patients.27 The median margin
tumor dose was 14 Gy to a median tumor volume of 4.2 cc. The
reported actuarial tumor control rates were 97 ± 2.7% at 5 years
and 94 ± 5.9% at 10 years. Over 48% of tumors showed radio-
graphic reduction in size, although a small number of patients
(four) experienced a brief period of slight tumor expansion with
associated loss of central contrast enhancement. All four of
these patients eventually demonstrated tumor regression.
Improvement in CN function occurred for 20% of affected
nerves, whereas 77% remained stable. No new cranial
neuropathies were observed in preoperatively intact nerves.
Peker et al retrospectively identified 17 patients who had been
treated with GKSRS for jugular foramen schwannomas.28 They
administered a mean marginal dose of 13 Gy to a mean tumor
volume of 5.9 cc. After a mean follow-up period of 64 months,
they observed a tumor control rate of 100%. Neurologic symp-
toms improved in 35.3% of patients and no patients died during
follow-up. Zhang et al treated 27 patients with jugular foramen
tumors using the GK.29 Nearly 45% of these patients had under-
gone previous microsurgery. The mean tumor volume was 13.5
cc and the mean margin dose was 14.6 Gy. Ninety-six percent of
patients who were followed over a mean of 38.6 months
showed shrinkage or stability of their tumors. Neurologic
improvement was noted in 64% of patients.

139
 Stereotactic Radiosurgery for Nonvestibular Schwannomas

Fig. 17.2 GammaPlan (Elekta Instruments AB, Stockholm, Sweden) poster shows a conformal radiosurgery dose plan for a 20-year-old woman with
residual trigeminal schwannoma left after a two-stage surgical resection. Axial, sagittal, and coronal contrast-enhanced magnetic resonance images
were used for planning. A margin dose of 12.5 Gy was prescribed to the 50% isodose line.

Fig. 17.3 Axial contrast-enhanced magnetic res-

onance images of a young woman treated by
stereotactic radiosurgery for residual trigeminal
schwannoma after surgery, at the time of (a) her
Gamma Knife procedure in 2009, and (b) 4 years
later at follow-up. In response to radiosurgery,
the residual area of tumor has decreased in size.

Data on schwannomas arising from the remaining CNs are three hypoglossal schwannomas, two abducens tumors, and
quite limited (▶ Fig. 17.5). For example, in a series combining one each from the facial nerve, trochlear nerve, oculomotor
all types of NVCNS, Elsharkawy et al included treatment of nerve, and glossopharyngeal nerve.30 Two- and 5-year

140

actuarial progression-free survival rates were 91 and 78% for
the entire cohort, which constituted 69% trigeminal schwan-
nomas. The results were not stratified on the basis of tumor
location. Not surprisingly, higher maximum tumor dose was
significantly associated with better tumor control. Safavi-
Abbasi et al reviewed a combined series of microsurgical and
radiosurgical patients with NVCNS from multiple nerves. 1 In
this series of 62 tumors, only 24.2% of tumors arose from
areas other than the trigeminal nerve or jugular foramen.
Only four tumors outside of the trigeminal nerve and jugular
foramen were treated by radiosurgery. There are limited
reports on facial schwannomas treated by radiosurgery. Litre
et al reported a series of 11 patients with facial schwanno-
mas treated with GK.31 In 10 of the 11 patients, tumors
shrank or remained stable during a median follow-up of 39
months. Two patients had resolution of hemifacial spasm
after treatment, four had improvement in facial nerve func-
tion, and one patient had improvement in vestibular and
hearing function. Kida et al reported on 14 patients who
received SRS for facial schwannomas. 13 The mean tumor vol-
ume was 5.5 cc and the mean tumor margin dose was
12.9 Gy. The tumor control rate after a mean follow-up of
31.4 months was 100%. Facial nerve function improved in five
of the cases. Finally, Madhok et al reported results in six
patients with facial schwannomas. 32 Tumor control after a
median follow-up of 61.5 months was 100% and facial nerve
function was preserved at preradiosurgery status in all
patients.
Stereotactic Radiosurgery for Nonvestibular Schwannomas
Fig. 17.4 Axial contrast-enhanced magnetic res-
onance images of a 54-year-old woman who
initially presented with hoarseness and hearing
loss. She initially underwent a craniotomy that
resulted in an incomplete resection of a jugular
foramen schwannoma. The tumor rapidly grew
during subsequent surveillance and she was
referred for a Gamma Knife procedure. (a) A
stereotactic image obtained on the day of
radiosurgery showing the residual tumor. (b) Four
years later the tumor has responded to radio-
surgery with a dramatic decrease in size.
Fig. 17.5 Axial contrast-enhanced magnetic res-
onance images of a 51-year-old woman who
presented with vertical diplopia. The patient
initially elected for observation, and the tumor
grew over the course of several years. She elected
to undergo a Gamma Knife procedure. (a) A
stereotactic image obtained on the day of
radiosurgery revealing a tumor at the edge of the
tentorium on the left side consistent with a
trochlear schwannoma. (b) At follow-up 4 years
later, the tumor has meaningfully reduced in size
in response to radiosurgery.
Taken together, the abundance of evidence suggests that SRS
is an effective primary and adjunctive treatment for NVCNS.
The largest experiences are with trigeminal and jugular fora-
men tumors, but it is likely that the results can be extrapolated
to tumor arising from other nerves. A meaningful proportion of
patients show improvement in their symptoms following SRS.
As expected, features such as smaller tumor volume and higher
marginal doses are associated with improved tumor control. All
available evidence is class 3. ▶ Table 17.2 provides an overview
of selected recent studies in which SRS was used to treat
NVCNS.
17.2.3 Fractionated Radiotherapy
Although the rates of new cranial neuropathy after single-ses-
sion SRS compare very favorably with those observed after
open resection, some have argued that conventional fractio-
nated radiotherapy or fractionated SRS, by sparing normal tis-
sues and allowing for repair of sublethal damage between
fractions, may improve upon this risk to benefit ratio. Wallner
et al in an early report identified eight patients treated with
conventional fractionated therapy to NVCNS with doses of 45 to
54 Gy.33 Half of these patients failed this conventional therapy.
These authors could make no firm conclusions on the utility of
fractionated therapy in this setting. Zabel et al performed frac-
tionated stereotactic radiotherapy using a median dose of
57.6 Gy, with 1.8 Gy per fraction in 13 patients with NVCNS. 34
Local control was 100% after a median follow-up of 33 months.
141
 Stereotactic Radiosurgery for Nonvestibular Schwannomas

Table 17.2 Overview of recent selected radiosurgical series

Study N Cranial Tumor Follow- up Tumor Improvement in Complications (%) Marginal Mortality
nerve volume (mo) control clinical signs and dose (Gy) (%)
(cc) rate (%) symptoms (%)

Elsharkawy et al, 36 III, 1 2.9 54 91, 78 (2, 64 Facial paresthesia, 2 13.5 0

201230 IV, 1 5 y) Slurred speech,
V, 25 tongue deviation,
VI, 2 and drooling, 1
VII, 6
IX, 1
XII, 3
JF, 2

Peker et al, 17 JF 5.9 64 100 35 Transient hoarse- 13 0

201228 ness, 5.9

Yianni et al, 74 V 5.3 48.2 93, 79 (5, 14.9 Facial paresthesia 16.4 0
201247 10 y) and numbness, 8.6
Diplopia, 1.3

Kimball et al, 49 III, 2 5.3 37 97, 83 (1, 39 Facial palsy, 2 12.5 0

201148 V, 25 5 y) Anesthesia dolorosa,
VII, 2 2
XII, 1 Facial numbness, 4.1
JF, 18 Diplopia, 2
RS, 1

Kano et al, 33 V 4.2 72 82 33.3 Facial pain, 3 15 0

200914 (5, 10 y) Facial sensory loss, 3

Hasegawa et al, 37 V 10.3 54 84 40 Facial numbness, 8.1 14.2 0

200725 (5, 10 y) Facial pain, 8.1
Corneal ulcer, 2.7

Kida et al, 200713 14 VII 5.5 31.4 100 42 HB III facial palsy, 7.1 12.9 0

Martin et al, 34 JF 4.2 83 97, 94 (5, 20 Worsened lower CN 14 0

200727 10 y) function, 2

Litre et al, 200731 11 VII 0.9 39 91 38 None 13 0

Abbreviations: CN, cranial nerve; HB, House-Brackman; JF, jugular foramen.

Four patients experienced improvement in their presenting
symptoms. Showalter et al compared 39 patients harboring
NVCNS treated by either single-session SRS or multisession
stereotactic radiotherapy.35 The single-session group was
treated to a median marginal dose of 12 Gy, whereas the frac-
tionated cohort received a median dose of 50.4 Gy in 1.8- to
2.0-Gy fractions. They observed no statistically significant dif-
ference in tumor control or CN function. Nishioka et al
reviewed their experience with NVCNS and fractionated stereo-
tactic radiotherapy.36 Almost 60% of patients were treated pri-
marily. Doses ranged from 40 to 54 Gy in 20 to 26 fractions.
Sixteen of 17 patients experienced stable or regressed tumors
over the median follow-up of 59.5 months. Forty-seven percent
of patients had improvement in their presenting symptoms. No
patient experienced worsened or new CN deficits. Choi et al
report treating 42 NVCNS located adjacent to the optic appara-
tus, brainstem, and other CNs with multi- and single-session
linear accelerator (linac)-based SRS (one to three sessions). 37
Although the patients treated with single-session SRS had two
new cranial neuropathies compared with none in the multises-
sion cohort, this difference was not statistically different. Tumor
control was equivalent.
No prospective randomized trials comparing single versus
multisession SRS or fractionated stereotactic radiotherapy for
NVCNS have been conducted, nor are they likely to be con-
ducted. To date, there does not appear to be a meaningful
improvement in the risk-to-benefit ratio by performing fractio-
nated SRS or stereotactic radiotherapy. The inconvenience of a
protracted treatment course, sometimes requiring 25 to 30 dai-
ly radiation sessions, and the limited repeatability of conven-
tional techniques makes a fractionated treatment option less
preferred to single-session approaches.
17.3 Complications
17.3.1 Microsurgery
Not only has the efficacy of microsurgery improved with the
advent of modern skull base techniques, so has the safety. One-
year mortality following attempted surgical resection of NVCNS
prior to the advent of modern microsurgery and skull base
approaches was 41% as reported by Schisano and Olivecrona in
1956.38 In a selected group of patients, Samii et al reduced this

142
 Stereotactic Radiosurgery for Nonvestibular Schwannomas

number to 0% with the use of modern techniques to resect tri- Hydrocephalus,1,21 quadriparesis, sinus thrombosis requiring
geminal schwannomas.20 In the hands of very experienced skull anticoagulation,20,42 meningitis,1 and intracranial hemorrhage42
base surgeons and for selected patients, greatly improved rates have also been reported.
of mortality have become the norm.1,9,21,24
Cranial neuropathy is one of the primary complications
related to microsurgical resection of NVCNS. Day and Fukushi- 17.3.2 Stereotactic Radiosurgery
ma, in their report on trigeminal schwannomas, observed a
Stereotactic radiosurgery is a minimally invasive approach that
recurrence rate of 3%, and the development of new trigeminal
eliminates certain surgical complications such as CSF leaks and
deficits in 11 patients.21 Specifically, one patient developed
sinus thromboses. However, SRS is not without complications.
new facial pain, six developed facial hypesthesia, another five
Minor transient complications such as headache and nausea
facial anesthesia, and 20 experienced new trigeminal motor
have been reported in NVCNS treatment. 1 But as with microsur-
deficits. In the trigeminal schwannoma series by Samii et al,
gery, the most common concern following SRS is the develop-
75% of patients had new or worsened trigeminal, facial, or coch-
ment of new or worsened cranial neuropathy. Kano et al found
lear nerve function postoperatively.20 Wanibuchi et al surgically
that 2 of 33 patients treated with GK for trigeminal schwanno-
treated 105 patients and observed worsened or new facial hyp-
mas developed new trigeminal deficits, although both patients
esthesia in 42.1% and new facial pain in 2.5% of patients. 24 Trige-
also demonstrated tumor progression.14 Adverse radiation
minal motor weakness was observed in 3.9% of patients. One
effects (AREs) in the form of increased peritumoral T2 signal
patient suffered worsened oculomotor diplopia. Fukaya et al
change were only noted in 6.1% of patients, but these were
noted an 18.8% rate in transient and a 58.5% rate of permanent
asymptomatic. Pan et al noted a 9% rate of slightly worsened CN
cranial nerve palsies after microsurgery for trigeminal
symptoms after GKSRS for trigeminal tumors. 4 Hasegawa et al
schwannomas.9
observed a 14% rate of new or worsened symptoms with SRS to
Neurologic deficits involving the lower CNs are of particular
trigeminal schwannomas, including facial numbness, facial
concern because they can lead to breathing difficulty, aspiration
pain, corneal ulcer, and abducent palsy.25 Sheehan et al
pneumonias, and dysphagia, all of which can be life threatening.
reported that 12% of patients suffered worsening facial pain
Bulsara et al observed no new lower CN deficits in 53 patients
after trigeminal tumor treatment and ultimately required surgi-
after microsurgical resection of jugular foramen tumors, but
cal resection (n = 2) or repeat SRS (n = 1).45 No patients devel-
did report frequent worsening.39 For example, there was a 26%
oped symptoms related to adverse radiation effects. In the
rate of permanent glossopharyngeal and vagal dysfunction
report by Phi et al, 27% of patients experienced new or wors-
postoperatively. Samii et al observed a nearly 40% rate of CN
ened cranial neuropathies after treatment of trigeminal
dysfunction following resection.40 Sanna et al reported a 95%
schwannomas.26 However, only half of the cranial neuropathies
rate of CN morbidity in 23 resected patients.41 Specifically, they
were permanent. Interestingly, loss of central contrast enhance-
noted that 50% of patients suffered worsened CN IX and X func-
ment, tumor expansion, and tumor location in the cavernous
tion postoperatively. Sedney et al reported that a more conser-
sinus were factors significantly related to the development of
vative surgical approach with subtotal resection decreased, but
these cranial neuropathies.
did not eliminate, postoperative CN IX and X deficits. 42 Using
Martin et al reported on their results treating jugular fora-
the more conservative surgical approach, the number of perma-
men tumors using GKSRS and noted only one patient (2%)
nently lower CN deficits decreased nearly sevenfold, a finding
experienced CN dysfunction.27 In the 17 patients treated for
that was statistically significant. Despite this, gastrostomy tube
jugular foramen tumors by Peker et al, only one (5.8%) devel-
placement was required in 5 of 28 patients.
oped increased hoarseness in the setting of slight tumor expan-
Facial nerve dysfunction can be extremely disabling and can
sion with loss of central contrast enhancement. 28 Hasegawa et
meaningfully diminish a patient’s quality of life. There is nota-
al reported on the treatment of jugular foramen schwannomas
ble facial nerve morbidity with resection of facial nerve
with SRS in a series where no patient developed lower CN defi-
schwannomas. McRackan et al sacrificed the facial nerve in 36
cits after SRS.15
of 53 patients at the time of microsurgical resection. 43 At one
In the treatment of facial nerve schwannomas, Kida et al
year, only seven patients possessed House-Brackmann (HB)
reported that one of 14 patients treated developed persistent
grade 1 function. The rate of HB grade 4 function was 14.3%
facial palsy of HB grade 218, whereas Litre et al did not observe
preoperatively and 51.8% postoperatively. McMonagle et al also
new or worsened CN deficit in their 11 treated patients. 31 Mad-
reported requiring 21 facial reconstructions after resection in
hok et al also did not detect new cranial neuropathies or
33 patients with facial schwannomas.44 Fifty-five percent of
changes in hearing after SRS for facial schwannomas.32 These
patients had total removal of their tumors with loss of the facial
series, though small, confirm the experience with vestibular
nerve. Only one patient had complete resection with preserva-
schwannomas in that facial nerve injury is meaningfully less
tion of the nerve. Notably, they report that facial outcomes were
common with SRS than with microsurgical resection.
better in patients in whom “no removal, decompression or sub-
total removal was undertaken.” Thus, these authors concluded
that surgical intervention for schwannomas should occur after
facial nerve function deteriorates to at least a HB grade 4.
17.4 Summary
Other noteworthy complications have been observed follow- Nonvestibular cranial nerve schwannomas are rare skull base
ing microsurgery. Spinal fluid leaks occur at variable rates. lesions and can arise from any of the CNs. They most frequently
Samii et al noted cerebrospinal fluid (CSF) leaks in 16.7% arise from the trigeminal nerve and the jugular foramen. Evolu-
of patients after trigeminal schwannoma resection.20 tion in the management of NVCNS has paralleled that of the

143
 Stereotactic Radiosurgery for Nonvestibular Schwannomas
much more common vestibular schwannoma. Surgical resec-
tion has long been a primary treatment option. However, only
after the advent of modern skull base techniques have the mor-
bidity and mortality been reduced to reasonable levels.
Stereotactic radiosurgery has become an established primary
and adjuvant treatment modality for skull base neoplasms,
including NVCNS. Radiosurgery avoids most surgically related
complications. The rates of new or worsened cranial neuropa-
thy after SRS compare favorably with the results of microsur-
gery. Direct comparisons of surgery and SRS are difficult
because surgery is often reserved for larger symptomatic
lesions, and SRS cohorts include a meaningful number of post-
surgical recurrences. It is not clear that the theoretical benefits
of fractionated approaches have been established in the current
literature to convincingly justify its use versus single-session
SRS. There will not be a one-size-fits-all therapy for NVCNS.
Instead, therapy needs to be individualized. Large tumors or
tumors causing symptoms from mass effect are candidates for
surgical resection. Smaller tumors and tumors in patients con-
sidered a high risk for surgery can be addressed safely by SRS.
▶ Fig. 17.6 shows a treatment algorithm that can be applied to
patients harboring NVCNS.
References
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gery for trigeminal schwannomas. J Neurosurg 2005; 102 (Suppl): 220–224
[5] Pollock BE, Foote RL, Stafford SL. Stereotactic radiosurgery: the preferred ma-
nagement for patients with nonvestibular schwannomas? Int J Radiat Oncol
Biol Phys 2002; 52: 1002–1007
[6] Sun S, Liu A, Wang C, Luo B, Wang M. Clinical analysis of Gamma Knife sur-
gery for trigeminal schwannomas. J Neurosurg 2006; 105 (Suppl): 144–148
[7] Nedzelski J, Tator C. Other cerebellopontine angle (non-acoustic neuroma) tu-
mors. J Otolaryngol 1982; 11: 248–252
144
Fig. 17.6 A simplified algorithm for the ma-
nagement of nonvestibular schwannomas is
shown. At the time of initial diagnosis, an
asymptomatic lesion could either be observed or
treated by stereotactic radiosurgery (SRS). In
younger individuals there is a meaningful like-
lihood of growth; thus, SRS may be elected. If
during observation a tumor grows, SRS is the
preferred approach, especially in the setting of a
continued lack of symptoms. For symptomatic
tumors without mass effect, our group recom-
mends SRS due to its minimal invasiveness,
safety, and efficacy. It is the primary treatment
modality in individuals who are not candidates for
surgery. In individuals with tumors producing
symptomatic mass effect, microsurgery is the
preferred approach. In the event of residual
tumor or tumor recurrence after microsurgery,
SRS is the recommended treatment.
[8] Mabanta SR, Buatti JM, Friedman WA, Meeks SL, Mendenhall WM, Bova FJ.
Linear accelerator radiosurgery for nonacoustic schwannomas. Int J Radiat
Oncol Biol Phys 1999; 43: 545–548
[9] Fukaya R, Yoshida K, Ohira T, Kawase T. Trigeminal schwannomas: experience
with 57 cases and a review of the literature. Neurosurg Rev 2010; 34: 159–
171
[10] Goldenberg RA, Gardner G. Tumors of the jugular foramen: surgical preserva-
tion of neural function. Otolaryngol Head Neck Surg 1991; 104: 129
[11] Ojemann RG. Skull-base surgery: a perspective. J Neurosurg 1992; 76: 569–
570
[12] Netterville JL, Civantos FJ. Rehabilitation of cranial nerve deficits after neuro-
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[15] Hasegawa T. Stereotactic radiosurgery for nonvestibular schwannomas. Neu-
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rosurgery 1998; 42: 233–240, discussion 240–241
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experience with 68 cases. J Clin Neurosci 2008; 15: 738–743
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of gamma knife surgery in 37 cases. J Neurosurg 2007; 106: 18–23
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schwannoma: is it possible to preserve cranial nerve function? J Neurosurg
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[28] Peker S, Sengöz M, Kılıç T, Pamir MN. Gamma knife radiosurgery for jugular
foramen schwannomas. Neurosurg Rev 2012; 35: 549–553, discussion 553
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for jugular foramen schwannomas. J Neurosurg 2002; 97 (Suppl): 456–458
[30] Elsharkawy M, Xu Z, Schlesinger D, Sheehan JP. Gamma Knife surgery for
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[31] Litre CF, Gourg GP, Tamura M, et al. Gamma knife surgery for facial nerve
schwannomas. Neurosurgery 2007; 60: 853–859, discussion 853–859
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for facial schwannomas. Neurosurgery 2009; 64: 1102–1105, discussion 1105
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rosurgery 2011; 68: 1200–1208, discussion 1208
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145
 Stereotactic Radiosurgery for Hemangioblastomas
18 Stereotactic Radiosurgery for Hemangioblastomas
Hideyuki Kano and L. Dade Lunsford
Key Points
● Hemangioblastomas of the brain present as sporadic lesions
or as manifestations of von Hippel-Lindau disease.
● Surgical resection is the usual treatment of choice for most
symptomatic hemangioblastomas, but vascularity or critical
location often makes complete resection impossible.
● Stereotactic radiosurgery is an important tool in selected
patients with hemangioblastomas; it is associated with a
satisfactory tumor control rate as well as relatively low risk of
adverse radiation effects.
18.1 Introduction
Hemangioblastomas are rare, highly vascular, but often well-
circumscribed tumors with cystic components of the central
nervous system (CNS) and are most often detected in the poste-
rior fossa.1,2 Hemangioblastomas of the brain present both as
sporadic lesions or as manifestations of von Hippel-Lindau
(VHL) disease.3,4,5 In approximately 75 to 80% of patients, the
hemangioblastoma is a sporadic, single lesion involving the cer-
ebellum, brainstem, or upper cervical spinal cord. 6 Approxi-
mately 20 to 25% of hemangioblastomas are associated with
VHL disease.6 Although they occur throughout the cerebrospi-
nal axis, multifocal hemangioblastomas associated with VHL
disease predominate in the posterior fossa.3,7
18.2 Von Hippel-Lindau Disease
Von Hippel-Lindau (VHL) disease is an autosomal dominant
neoplasia syndrome resulting from a germline mutation of the
VHL tumor suppressor gene located on chromosome 3. 8
Patients with VHL disease are predisposed to develop CNS and
visceral lesions including renal cell carcinoma, pancreatic neu-
roendocrine tumors, and pheochromocytomas.9 Hemangioblas-
tomas in the CNS are a major cause of morbidity and mortality.
Ammerman et al10 reported the long-term natural history of
VHL-associated hemangioblastomas. Hemangioblastomas tend
to exhibit a saltatory growth pattern characterized by periods
of growth over an average of 13 ± 15 months followed by peri-
ods of dormancy for an average of 25 ± 19 months. Despite
measurable growth in almost all hemangioblastomas (97% of
patients), only 41% of patients became symptomatic. Forty-five
percent of the hemangioblastomas that eventually produced
symptoms were present at the time of the initial magnetic reso-
nance imaging (MRI) study.
18.3 Surgical Resection of
Hemangioblastomas
Management of hemangioblastomas frequently requires weigh-
ing the benefits and potential complications of therapeutic
146
interventions against the slowly progressive natural history of
the disease. Surgical resection is the usual treatment of choice
for most symptomatic hemangioblastomas.11 However, vascular-
ity or critical location often makes complete resection impossi-
ble. In patients with multiple hemangioblastomas, complete
resection of all tumors is not feasible. Furthermore, cystic lesions
tend to have a more favorable surgical outcome compared with
the more vascular solid lesions. Wang et al12 reported 39
hemangioblastoma patients who underwent radical surgical
resection. Postoperatively, 11 patients deteriorated after surgery
and two patients died. Jagannathan et al13 reported 80 heman-
gioblastoma patients (who underwent 126 surgical resections
for 164 cerebellar hemangioblastomas) and noted no tumor
recurrences at an average of 5 years after surgery. In contrast,
subtotal resection is associated with a high risk of tumor recur-
rence. Conway et al3 reported 40 hemangioblastoma patients
who underwent partial resection and noted progression in 8
patients (20%) and additional morbidity in 6 patients (15%).
18.4 Fractionated Radiation
Therapy
Conventional radiation therapy (RT) has been used for residual,
recurrent, or inaccessible tumors.11,14 Smalley et al14 treated 27
hemangioblastoma patients with fractionated RT after incom-
plete surgical removal. The recurrence-free survival rates at 5,
10, and 15 years were 76, 52, and 42%, respectively. Local con-
trol was significantly better in patients receiving ≥ 50 Gy com-
pared to those treated with lower doses (57% vs. 33%).
Radiation therapy may be administered following resection. In
contrast, the progression-free survival after SRS for all heman-
gioblastomas was 89.9 and 85.9% at 5 and 10 years, respec-
tively.15 These data suggest that local control rate after SRS may
be enhanced compared to RT. However, no prospective trial has
been performed.
18.5 Stereotactic Radiosurgery
During the past 25 years stereotactic radiosurgery (SRS) has
been used as a minimally invasive primary, adjuvant, or salvage
option for hemangioblastomas (▶ Table 18.1).1,5–24 Although
surgical resection and radiation therapy both have a role in the
treatment of hemangioblastomas, the role of SRS has not been
well defined. Stereotactic radiosurgery is applied most com-
monly for residual tumors that were not completely removed
or for patients with deep-seated tumors that are considered to
have excessive risks for microsurgery (▶ Fig. 18.1 and
▶ Fig. 18.2). Patrice et al21 reported an 86% actuarial rate of
tumor control at 2 years after SRS. Niemela et al25 reported 11
hemangioblastoma cases and showed a reduction in the treated
volume in 6 tumors at a median 30 months after SRS. Chang et
al17 reported that in 13 patients (with 29 hemangioblastomas)
who underwent linear accelerator (linac) radiosurgery, a higher
dose improved results.
 Stereotactic Radiosurgery for Hemangioblastomas

Table 18.1 Summary of studies of stereotactic radiosurgery for hemangioblastomas

Study No. of patients/ Mean follow-up Mean tumor vol- Mean margin dose 5-y OAS 5-y PFS
tumors (mo) ume or diameter (Gy)

Patrice et al, 199621 22/38 24.5 0.97 cc 15.5 88% 86%

(2 y) (2 y)

Niemela et al, 10/11 43 13.5 mm 20 67.5% 100%

199625

Chang et al, 199817 13/29 43 1.6 cc 23.2 92.3% (overall) 96.6%

(overall)

Pan et al, 199819 13/20 29 20 mm 18.4 92.3% (overall) 69.2%

(overall)

Wang et al, 200524 35/93 66 13 mm 17.2 69.0% 82.9%

(overall) (overall)

Tago et al, 200523 13/38 36 0.23 cc 20 80.8% 96.2%

Kano et al, 200815 32/74 61.4 0.72 cc 16 94.4% 89.9%

Moss et al, 20097 31/94 69 1.8 cc 23.4 NA 82%

Sayer et al, 201122 14/26 55.4 1.65 cc 18 NA 74%

Abbreviations: NA, not available; OAS, overall survival; PFS, progression-free survival.

Fig. 18.1 (a) A T1-weighted contrast-enhanced

axial magnetic resonance image (MRI) of a 50-
year-old male shows a sporadic cystic heman-
gioblastoma before surgical resection. (b) A T1-
weighted contrast-enhanced axial MRI shows
residual tumor after surgical resection. (c) A T1-
weighted contrast-enhanced axial MRI shows
tumor recurrence at the time of stereotactic
radiosurgery (SRS). Tumor volume was 3.4 cc and
margin dose was 18 Gy. (d) A T1-weighted
contrast-enhanced axial MRI shows tumor re-
gression 10 years after SRS.

Wang et al24 reported 35 patients with 93 hemangioblasto-
mas treated with Gamma Knife SRS (GKSRS). The 5-year pro-
gression-free survival was 71% and the actuarial survival rate
was 83%. Matsunaga et al18 reported 22 patients with 67
hemangioblastomas treated with GKSRS. The progression-free
survival after SRS was 88% at 5 years and 78% at 10 years. Sayer
et al22 reported a 5-year PFS of 74% in 14 patients with 26
hemangioblastomas. Tago et al23 reported actuarial 5- and 10-
year control rates of 96.2%. Kano et al15 reported that tumor
volume played a role in progression-free survival. Margin doses
of ≥ 15, 16, and 18 Gy in patients with VHL-related hemangio-
blastoma were associated with improved progression-free

147
 Stereotactic Radiosurgery for Hemangioblastomas
survival. Moss et al7 indicated that cessation of cyst fluid pro-
duction typically took over 1 year in their series of patients, and
in four patients, associated mass effects necessitated drainage
of the associated cyst or resection of the tumor nodule. They
concluded that SRS is effective in treating only the mural nod-
ule of hemangioblastomas, as opposed to an associated cystic
component; it is not the ideal treatment for quickly reducing
associated mass effect symptoms. However, in patients with
surgically inaccessible tumors, radiosurgery can be a useful
alternative, as tumor control usually leads to ultimate resolu-
tion of the cystic component as well. Sayer et al26 treated 14
patients with 26 hemangioblastomas by GKSRS. In their analy-
sis, tumor progression was more common in sporadic patients,
women, and in patients with larger tumors. In patients with
multiple hemangioblastomas as compared with those with only
a solitary hemangioblastoma, the radiosurgically treated lesion
was 7.9 times more likely to progress after SRS.
18.6 Multicenter Retrospective
Trial
Six participating centers of the North American Gamma Knife
Consortium and 13 Japanese GK centers identified 186 patients
with 517 hemangioblastomas who underwent SRS.27 Eighty
patients had 335 hemangioblastomas associated with VHL disease
and 106 patients had 182 sporadic hemangioblastomas. The
median tumor volume was 0.2 cc (median diameter: 7 mm) in
VHL patients and 0.7 cc (median diameter: 11 mm) in sporadic
hemangioblastoma patients. The median margin dose was 18 Gy
148
Fig. 18.2 A T1-weighted contrast-enhanced axial
magnetic resonance image of a 40-year-old
woman shows cystic and solid von Hippel-Lindau
disease–related hemangioblastomas in multiple
locations at the time of stereotactic radiosurgery
(SRS). She underwent prior surgical resections 16
and 2 years before SRS.
in VHL patients and 15 Gy in patients with sporadic hemangio-
blastomas. At a median of 5 years (0.5–18 years), 20 patients had
died from intracranial disease progression and 9 patients had died
from other causes. The overall survival was 94% at 3 years, 90% at
5 years, and 74% at 10 years. Factors associated with longer sur-
vival included younger age, no neurologic symptoms, fewer
tumors, and higher Karnofsky Performance Status. Thirty of 80
(38%) VHL patients developed new tumors and 15 (14%) of 106
sporadic hemangioblastoma patients had recurrences of residual
tumor from the original tumor. The 5-year rate of developing a
new tumor was 39% for VHL patients and a recurrence of residual
tumor from the original tumor was 21% for sporadic hemangio-
blastoma patients. Factors associated with a reduced risk of devel-
oping a new tumor or recurrence of residual tumor included
younger age, fewer tumors, and sporadic rather than VHL-associ-
ated hemangioblastomas. The progression-free survival of treated
tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years.
Factors associated with an improved progression-free survival
included VHL-associated hemangioblastoma, solid tumor, smaller
tumor volume, and higher marginal dose. Twelve patients (6%)
developed adverse radiation effects (AREs) after SRS and one pa-
tient died due to AREs.
18.7 Summary
Stereotactic radiosurgery is an important tool in selected
patients with hemangioblastomas: It is associated with a satis-
factory tumor control rate as well as relatively low risk of
adverse radiation effects. Stereotactic radiosurgery can be

applied for growing residual tumors, for patients with progres-
sive deep-seated tumors who are high risk for microsurgery, for
VHL patients who develop new tumors, and for recurrences of
residual tumor from the original tumor in sporadic hemangio-
blastoma patients who progress under serial observation.
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149
 Stereotactic Radiosurgery for Vestibular Schwannomas
19 Stereotactic Radiosurgery for Vestibular Schwannomas
Jean Régis, Romain Carron, Christine Delsanti, Denis Porcheron, Jean-Marc Thomassin, Xavier Muracciole, and Pierre-Hugues Roche
Key Points
● The superior safety efficacy of stereotactic radiosurgery over
microsurgery in small- to middle-sized vestibular schwanno-
mas is demonstrated in five comparative studies. Normal
motor facial nerve function and serviceable hearing are more
likely to be preserved with radiosurgery as compared with
microsurgery.
● In very large Koos stage IV schwannomas, a combined
approach with a deliberate subtotal removal with functional
monitoring of the facial nerve followed by radiosurgery of
the remnant dramatically reduces the risk of facial palsy as
compared with radical removal.
● Hypofractionation of radiosurgery (stereotactic radiotherapy
or multisession radiosurgery) has failed until now to
demonstrate any advantage over single-dose, high-precision
radiosurgery.
19.1 Introduction
Acoustic neuromas are usually benign tumors of the cerebello-
pontine angle (CPA) arising from the Schwann cells of the
sheath of the vestibular nerve. At the beginning of the 20th cen-
tury, pioneers such as Cushing, based on crude preoperative
work-up (X-ray of the internal auditory canal, audiometry, and
vestibulometry), removed huge tumors in patients presenting
with neurologic symptoms.1 Surgery was performed through a
suboccipital approach with the only goal to save the life of the
patient. Surgery performed through a suboccipital approach
was at that time attempted as a life-saving procedure and lim-
ited concern was given to other neurologic function (e.g., crani-
al nerve [CN] VII or VIII preservation). Surgery was usually
incomplete, the mortality was high, and facial nerve function
and hearing were systematically sacrified. 1
Following the advent of ventriculography with Dandy in the
1920s, the preoperative diagnosis was improved and further
refined by angiography and cisternography. Complete removal
became a realistic goal.2 In the 1960s, tumors were more fre-
quently detected at an earlier stage with only otologic symp-
toms. Otologists and neurosurgeons then developed new
surgical approaches such as the translabyrinthine and the
suprapetrous approaches.3 Technical advances—especially the
introduction of the operative microscope—allowed operation
on these smaller tumors with the aim to preserve anatomically
and sometimes even functionally the motor function of the
facial nerve.
In the 1970s and 1980s, with the advent of computed tomog-
raphy (CT) and magnetic resonance imaging (MRI), even early
diagnosis of smaller tumors became commonplace. In 1968,
Leksell proposed the introduction of Gamma Knife radiosurgery
(GKRS) for the management of vestibular schwannomas (VSs).4
In 1968, the first cases of VSs were treated using the Gamma
Knife. The procedure was based on crude localization derived
150
from pneumoencephalography, rudimentary head fixation, and
very-high-dose prescription.5 Over time, the pioneers under-
stood that the therapeutic goal of long-term tumor control was
achievable by using a lower regimen of dose while sparing the
motor facial nerve, and without compromising hearing and tri-
geminal nerve sensory function.6 This preliminary experience
stressed the need for 2 years of follow-up for proper assessment
of the clinical outcome, and at least 3 years for the evaluation of
tumor control.
Over the last three decades, microsurgery (MS) and stereo-
tactic radiosurgery (SRS) have become well-established ma-
nagement options for VSs. The evolution in the management of
VSs can be separated into three periods: the microsurgical pio-
neers period; the demonstration of SRS as a first-line therapy
for small- and medium-sized VSs; and at present, a period of
SRS maturity based on a large worldwide accrual of patients.
The tumor size is classified according to Koos et al,7 the extent
of the tumor in the bottom of the internal auditory canal
according to Ohata et al,8 the functionality of hearing according
to Gardner and Robertson,9 and the facial motor nerve function
according to House.10 To date, five comparative studies (two
level II and three level III) published in peer-review journals
have demonstrated improved hearing preservation rate, a bet-
ter motor facial function, and a similar long-term tumor control
when SRS is performed as compared with MS for tumors of the
same size.11–15 Additionally, the direct and indirect costs are
much lower with SRS.15,16
Given the long life expectancy of these patients and the
severe potential disability related to the functional risks inher-
ent to the management of these tumors, VSs should be man-
aged by an experienced multidisciplinary team that is able to
integrate all micro- and radiosurgical approaches to provide the
highest level of care and the highest probability of functional
preservation to ensure good quality of life.
19.2 Therapeutic Options and/or
Surgical Technique(s)
The main therapeutic options for VSs are a “wait-and-see”
strategy,17 radiosurgery, SRS (2–10 fractions), and microsurgical
resection (either through a retrosigmoid translabyrinthine or
suprapetrous approach).
19.2.1 Simple Follow-ups Based on
Clinical Interviews and Serial MRI Scans
Simple follow-ups (i.e., observation) based on clinical inter-
views and serial MRI scans have been advocated for some
time.18 For several years, this has been the standard in our
group for small intracanalicular VSs. Under conditions of suffi-
ciently long periods between follow-ups, combined with strict
criterion for defining growth, the vast majority of the modern
observational series demonstrates that the subtotality of
tumors will grow and that the majority of patients, whose

hearing was still functional at the commencement of the wait-
and-see strategy, will progressively lose their hearing over the
course of a few years.17,19,20
Upon their very comprehensive review of the literature (34
series), Sughrue and colleagues17 found that 982 patients, who
had follow-ups over a period of 26 and 52 months, had a mean
growth of VSs of 2.9 mm/y. Fifty percent of the patients lost
their hearing, despite the short duration of the maximum fol-
low-up relative to their life expectancy. The authors concluded
that the speed of the tumor’s growth is a much more reliable
predictor of hearing loss than the initial size of the VS. Bakkouri
et al21 published a series detailing 325 patients in which they
emphasized the difficulties faced in maintaining rigorous pa-
tient follow-up of conservatively managed patients. In fact, they
report a tracking loss of 24% of the 325 patients. This loss
occurred despite their efforts to retain and maintain contact
and follow-ups. We have also recently done a comparison of
this wait-and-see attitude with an early proactive radiosurgical
management strategy.20 We found (p = 0.0009) that at 3 years,
patients who were operated on by Gamma Knife had a 73.3%
chance of preserving hearing as opposed to 35% with the mere
wait-and-see strategy.20 Hence, radiosurgery is the preferred
treatment option for these patients to maintain their residual
serviceable hearing.
In another study, we placed our focus on patients who had
several years of serial pure tonal audiogram before radiosur-
gery.22 Among 72 consecutive patients, we observed an annual
hearing loss of 3.72 dB/y before radiosurgery, 4.06 dB/y the first
year after GKRS, and 1.24 dB/y in the following years. This
study22 supports the findings from the previous study, and it
suggests a marginal additional risk of hearing loss correspond-
ing to radiosurgical toxicity (difference not significant).23 We
have successfully demonstrated that in younger patients the
probability of preserving functional hearing is high.24 Our find-
ings have subsequently been confirmed by Lobato-Polo et al, 25
who provides additional support in favor of earlier proactive
radiosurgical management of these patients.
19.2.2 Radiosurgery
Radiosurgery in the management of VSs is hereafter analyzed
based on a review of our own prospective cohort as well as cur-
rent literature resources. Of 13,341 GK procedures performed
by the staff at the Stereotactic & Functional Neurosurgery
Department of Timone University Hospital (Marseilles, France),
3,717 patients had VSs, 2,991 of whom were operated on
between July 14, 1992, and June 1, 2011. All 2,991 patients have
been prospectively evaluated; 2,336 patients were nonneurofi-
bromatosis type II (NF2; 164 treatments) with follow-ups lon-
ger than 3 years.
In 7% of these patients, the VSs were previously resected.
According to the Koos’ classification system, the VSs were of
stage I in 17.6%; stage II in 51.8%; stage III in 27%; and stage IV
in 3.6%. The mean tumor volume was 2.63 cc. In 46% of patients,
hearing was still serviceable at the time of the radiosurgery
according to the Garner-Robertson scale, although it was sub-
normal in 20.9% of the patients. Long-term tumor control was
achieved in 97.5% of the patients. A transient facial palsy was
observed in 0.5% of the cases. The rate of trigeminal injury was
0.5%. Serviceable hearing was preserved after 3 years in 78% of
Stereotactic Radiosurgery for Vestibular Schwannomas
patients. This rate reached 95% of patients who had no prior
history of sudden hearing loss. Other predictors of functional
hearing preservation were age (specifically younger), small size
of the tumor, and a dose to the modiolus of the cochlea < 4 Gy.
We observed no radioinduced tumor. Only large Koos stage IV
VSs were contraindicated for up-front radiosurgery. For
patients harboring large-sized Koos stage IV VSs, we used a
combined approach of deliberate partial microsurgical removal
followed by radiosurgery of the residue. This cohort is unique
because of the size of its population and length of the follow-
up; it demonstrates the efficacy of radiosurgery as well as its
safety with regard to its high rate of hearing preservation.
At our center, patients were preoperatively evaluated and
prospectively followed up with a clinical evaluation comprising
the following: pure tone audiometry (PTA) and speech discrim-
ination score (SDS), vestibulometry, the Schirmer test, and seri-
al MRI scans (at 6 months and 1, 2, 3, 5, 7, 10, and 15 years).
One hundred forty-eight patients with NF2 harbored VSs. A fol-
low-up of more than 3 years is available for 2,336 patients (NF2
excluded). The mean age at the time of radiosurgery is 66.3
years. The Koos stage was stage I in 17.6% of patients, stage II in
51.8% of patents, stage III in 27% patients, and stage IV in 3.6% of
patients. Initial symptoms were as follows: hypoacousia in
49.5% of patients, tinnitus in 19.4%, vertigo in 13.2%, and 5.1%
experienced instability. A past history of sudden hearing loss
was reported in 21.5% of patients. It is important to note that
microsurgical resection of the VS had been performed prior to
radiosurgery in 7% of these cases. The day before intervention,
in 87% of cases patients reported hypoacousia, 65% reported
tinnitus, 52% reported imbalance, 31% reported veritgo, 8.2%
reported facial palsy, 7.5% reported a hemifacial spasm, 5.3%
reported trigeminal neuralgia, and 4.8% of the patients
reported hypoesthesia. Our methodology has been previously
described.26
Defining the limits of the tumor is first done on the stereotac-
tic three-dimensional T1-weighted gadolinium-enhanced MRI
sequence (magnetization prepared rapid acquisition gradient
echo [MP-RAGE] Siemens or comparable sequences). The
absence of distortion between the MRI and stereotactic CT is
systematically checked with scrutiny and a shift of the dose
plan is performed consequently if and when necessary. The lim-
its of the internal auditory canal, vestibule, semicircular canals,
and cochlea are defined on CT. Dose planning corresponding to
the cisternal portion of the tumor, adjacent cochlear and facial
nerves, respectively, is corrected according to high-resolution
T2-weighted (constructive interference in steady state [CISS]
Siemens) with and without contrast. The dose to the margin is
12 Gy (Gardner-Robertson ≥ 3) and 11 Gy if hearing is still serv-
iceable.9 Our dose-selection policy has not changed since 1992
for VS, which confers a very good homogeneity to our series.
Patients were treated using a Gamma Knife model B, 4, or 4C, or
Perfexion. Additionally, between 2005 and 2010 an extensive
search and cross-referencing exercise was conducted on
PubMed, which produced 213 articles. Of these, 55 reported on
a series of more than 30 patients, providing us with safety effi-
cacy data. A second filtering enabled us to rule out any dupli-
cated series and general review papers (15 articles). The
majority are retrospective studies. However, three studies were
prospective, reporting on 69, 78, and 111 patients, respec-
tively.27,28,29
151
 Stereotactic Radiosurgery for Vestibular Schwannomas
19.2.3 The Prospective Cohort of
Timone Hospital
The prospective cohort of Timone Hospital demonstrates tumor
control in 97.5% of the patients (▶ Fig. 19.1) in the last of neuro-
imaging (MRI) follow-ups. With 2.5% of patients, as a result of a
continuous growth of the schwannoma at the 3-year mark, we
have consequently been led to propose new radiosurgery in 20
patients or a resection in 39 patients. The MRI follow-ups during
the first year revealed an average of 20% in schwannoma growth
rate, followed thereafter by stabilization at 3 years after radio-
surgery. In these patients with transient enlargement, a
decrease in tumor volume was observed after the third year fol-
lowing SRS. At 7 years, the volume corresponded to 60% of the
volume at the time of radiosurgery (−40% decrease). The rate of
transient facial palsy was < 0.5%. This rate was 3% during the first
period corresponding to our learning curve (with the first 100
patients). The rate was subsequently reduced to 1.4% during the
period preceding the introduction of the dose-planning com-
puter workstations (involving 212 patients), and dropped fur-
ther to 0.5% after the introduction of the workstations, and their
integration in anatomical imaging (360 patients). Since the
introduction of robotic radiosurgery (2,319 patients), this transi-
ent facial palsy rate has virtually disappeared in unilateral VS.30
19.3 Radiosurgery Main Series of
Literature
The main series of radiosurgery literature and their results are
summarized in ▶ Table 19.1. These series are very heterogene-
ous in terms of devices, size of tumors, prescribed doses, inclu-
sion or exclusion of NF2 patients, the rate of patients who had
been operated on previously, methods of measurement, defini-
tion of tumor control, and overall duration of follow-up time,
from when the patient is released postsurgery to the final out-
patient visit.
Fig. 19.1 Example of result of radiosurgery in a unilateral vestibular schwannoma patient with deafness at the time of radiosurgery. The long-term
magnetic resonance imaging follow-up demonstrates favorable efficacy with a dramatic regression of the lesion at 10 years.
152
The results of the 15 series of GKRS are fairly homogene-
ous.24,27,28,29,31–40 Only one linear accelerator (linac) series has
been found. In this linac series, hearing was not evaluated. 41 In
the GKRS series, tumor control between 3 and 10 years of fol-
low-up varied from 92 to 98% (97.5% for our series) and the
tumor control rate was 90% in the one linac-based series. Trige-
minal injury rates ranged from 0 to 9% (0.5% in our series and
with the one linac series exhibiting a rate of 3.6%).
The rate of facial palsy varied between 0 and 7% (0.5% in our
series and 4.4% with the linac series). The rate of serviceable
hearing preservation ranged from 56.6 to 78.6% (63% in our ser-
ies). Whether other linac-based radiosurgery devices (adapted
linac, Novalis Radiosurgery [Brainlab, Munich, Germany], or
CyberKnife) actually allow or not to reach the same level of
results published in the GKRS literature is still a matter of con-
troversy. A recent interesting paper from Gevaert et al working
with a Novalis compares VS dose planing from Novalis with
those of a CyberKnife and a Gamma Knife. These authors con-
clude that “only GK Perfexion is complying with all SRS con-
straints of high conformity while minimizing low-dose spread”
and that “non-isocentric beams (CyberKnife) or intensity-
modulated radiotherapy (IMRT) beams (Novalis-Tx-DMLC-
IMRT) are spreading more low dose than multiple isocenters
(Gamma Knife).”
19.3.1 Stereotactic Radiotherapy
Stereotactic radiotherapy (SRT) was reported in seven series
(▶ Table 19.1), and the experience was very heterogeneous in
terms of technique.42–48 Maire et al report treating much larger
tumors than the others.45 The Chang series was hypofractio-
nated (three fractions, 18–21 Gy).43 The others were hyperfrac-
tionated from 25 to 32 fractions, delivering 45 to 57.6 Gy by
fractions of 1.8 to 2 Gy. In Andrews et al’s series, the follow-up
was short, which makes it difficult to draw substantial conclu-
sions.48 In the remaining series, tumor control varied from 93
to 98%. The rate of injury of the trigeminal nerve varied
 Stereotactic Radiosurgery for Vestibular Schwannomas

Table 19.1 Radiosurgery and stereotactic radiotherapy for vestibular schwannomas: Analysis of the literature from 2005 to 2010 (MEDLINE) and com-
parison with our own series
Study Population Volume Technique Dose Follow-up (mo) Tumor control CN CN VII CN VIII Cancer
(cm3) (Gy) Lost to follow- (%) V (%) (%) (%)
up (%) (Audio)

Chung et al, 195 4.1 (0.04– GK 13 (11–18.2) 31 (1–110) 10 y: 96.8% 1.1 1.5 60% 0
2005 R31 39% 23.1) 2 lost

Lunsford et 829 2.5 GK 13 (10–20) NR 10 y: 98% 3.1 <1 78.6% 0

al, 2005 R33 20% > 10 y 252 pa-
tients

Wowra et al, 111 1.6 (0.08– GK 13 (10–16) 7 y (5–9.6) 6 y: 95% 2.7 2.7 NR 0
2005 R28 33.3% 8.7)

Van Eck et al, 78 2.28 (0.1– GK 13–65% 22 97.4% 3.8 1.2 69.2% 0
2005 P27 NR 11.7)

Hasegawa et 317 5.6 (0.2– GK 13.2 (10–18) 93 94.4% (10 y: 2 2? 67.5% 0

al, 2005 R32 22.7% 36.7) 29 lost 92%)
GR 1–2:
30.6%

Hempel et al, 123 1.6 (0.1– GK 13 (10–14.5) 98 (63–129) NR 5.8 0 NR 0

2006 R66 NR 9.9)

Liu et al, 74 10.8 GK 12.3 (12–14) 68.3 (30–122) 5 & 10 y: 7 5 72.3% 0

2006 R35 25.6% (0.11– 95.9%
27.8)

Hudgins et 159 3.3 cm3 GK 14 (8 at 20) 12 y 96.4% 0 0 NR 0

al, NR
2006 R34

Chopra et al, 216 1.3 (0.08– GK 13 (12–13) 68 (max: 143) 10 y: 98.3% 3.7 0 56.6% 0
2007 R36 0% 37.5)

Niranjan et 96 0.112 mm3 GK 13 (10–18) 28 (12–144) 99% 0 0 63.3% 0

al, NR (0.1–0.5)
2008 R37 Koos I

Régis et al, 184 NR GK 12 7 y (3–13) 98% 0.6 0.7 3 y: 60% 0

2008 P38 0% GR 1 and 2

Timmer et al, 69 2.28 GK 11 (9.3–12.5) 14 (3–56) NR 9 7 75% 0

2009 P29 NR (0.02– 16 lost
10.2)

Kano et al, 77 0.75 GK 12,5 (12–13) 20 mo (6–40) 97.4% NR 0 1 y: 0

2009 R40 0% (0.07–7,7) 89.3%
GR 1: 46 2 y:
GR 2: 31 66.8%

Tamura et al, 74 1.35 (0.06 GK 12 (9–13) 55.6 (3–11 y) 93% NR 0 3 y: 0

2009 P24 0% à 4.6) 78.4%
GR 1

Franzin et al, 50 0.73 GK 13 (12–16) 36 (6–96) 96% NR 0 68% 0

2009 R39 0% (0.03–6.6)
GR 1 or 2

Régis et al, 2087 2.63 GK 12.3 Minimum 3 y 97.5% 0.5 0.5 63% 0
2010 P20 7% GR 1 and 2:
46%

Friedman et 390 NR Linac 12.5 (10– 40 5 y: 90% 3.6 4.4 NR 0

al, 20% SRS 22.5) 42 lost
2006 R41

Combs et al, 106 3.9 (2.7– SRT 57.6 Gy 32 fr 48.5 (3–172) 3 y: 94.3% 4.7 2.3 NR 0
2005 R44 16% 30.7) Linac 1.8 Gy 6 wk 5 y: 93% (25%)
94%

153
 Stereotactic Radiosurgery for Vestibular Schwannomas

Table 19.1 continued

Study Population Volume Technique Dose Follow-up (mo) Tumor control CN CN VII CN VIII Cancer
(cm3) (Gy) Lost to follow- (%) V (%) (%) (%)
up (%) (Audio)

Chan et al, 70 2.,4 (0.05– SRT 54 Gy 30 fr 45 3 y: 100% 4 13 NRa 0

2005 R42 21% 21.1) Linac 1.8 Gy 6 wk 5 y: 98%

Chang et al, 61 Diameter SRT 18–21 Gy, 3 fr 48 (36–62) 98.4% 0 3.3 74.3% 0
2005 R43 13% mean: Linac 6–7 Gy 3 d 14 dB
18.5 mm Cyber Knife loss
(5–32)

Koh et al, 60 4.9 (0.3– SRT 50 Gy 25 fr 5 31.9 (6.1– 5 y: 96.2% 1.6 1.6 NRa 1,7
2007 R46 NR 49) Linac wk 107.4) (33%)
X-Knife 77.3%

Andrews et 89 1.6 SRT 48.5 fr of 1.8 14.7 97.8% ? 0? 2.2 ? 73.3% ? 0?

al, Linac (50.4/46.8)
2009 R48

Thomas et al, 34 1.1 (0.3– SRT 45 in 25 fr of 2 36.5 (12–85) 95.7% 0 6 56% 0

2007 P47 9.6) Linac

Maire et al, 45 NR RT 50.4 in fr of 80 (4–227) 95% (2 dead) 0 0 NR 2,2

2006 R45 Linac 1.8

Abbreviations: (Audio), % of patients with audiometry before and after; CN, cranial nerve; dB, decibels; dcd, patient dead because of tumor growth;
dose, marginal dose; fr, fraction; GK, Gamma Knife; Linac, linear accelerator; GR, Gardner and Robertson Scale; NR, not reported; P, prospective; pt,
patients; R, retrospective; RT, radiotherapy; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; ?, no sufficient follow-up for a serious
evaluation.
aNo audiometry before and after (telephone evaluation).

between 0 and 4.7%; with motor facial nerve impairment, the
range was 0 to 13%. In three instances of these SRT series, there
was no systematic objective evaluation based on pre- and post-
operative PTA and SDS enabling the evaluation of the rate of
serviceable hearing preservation.42,44,46 For Combs et al, PTA
was performed in only 25% of the patients44 and for Koh et al
only 33%.46 In Chan et al, the evaluation of serviceable hearing
preservation was based on results from telephone interviews
conducted on the patients.42 Maire et al provides no informa-
tion regarding hearing outcome.45 Series 2 only gives an objec-
tive assessment on functional hearing, where it was preserved
in 56 and 74.3% of the patients.43,47 Chan’s results show the
average loss in conversational frequencies (PTA) is of 15 dB as
opposed to 10 dB in our series of GKRS.42 The rate of functional
hearing preservation therefore does not appear to be superior
in the fractionated series. However, carcinogenesis is reported
in two of these fractionated series, with an incidence of 1.7 and
2.2% in Koh et al and Maire et al.45,46
Microsurgical resection in small- or middle-sized VS is nowa-
days less relevant in terms of efficacy. There appears to be little
benefit (from the perspective of the patient) to favor MS over
SRS.49 However, in Koos stage III with a very cystic tumor pre-
sentation and no remaining functional hearing, resection can
be proposed based on the argument that cystic tumors have
been described to present substantial volume increase after
radiosurgery. Some teams put forth the argument that patients
with disabling imbalance may be more likely to improve with a
resection associated with vestibular neurotomy. In our experi-
ence, the probability of improvement of vestibular symptoms is
not higher after MS as compared with SRS.
19.3.2 Large Koos IV Management
Microsurgical resection is systematically discussed in large Koos
stage IV VS. We have stopped advocating radical resection for
VS patients. Our team systematically proposes a combined
approach.65 The first step is a cautious deliberate partial remov-
al under neuromonitoring followed some months after by SRS
of the residual tumor. This evolution has led our team to per-
form fewer translabyrinthine approaches, which had been our
preferred approach for radical removal. Presently, we favor ret-
rosigmoid approaches.
19.4 Complications and Concerns
If there is ever a condition in which the efficacy of radiosurgery
compares favorably with microsurgical resection, it is definitely
with small- to middle-sized VSs (Koos stages I–III) in young
patients. All five of the existing comparative studies have given
consistent results and demonstrated a much lower rate of facial
motor nerve impairment and a much higher rate of serviceable
hearing preservation with GKRS as compared with microsurgi-
cal resection.11–15
The linac-based series is limited, but the Friedman series
reports similar results, at least in terms of CN V and CN VII inju-
ries.41 A series that would allow a proper evaluation of the qual-
ity of hearing outcome following linac-based radiosurgery is
still lacking. Several centers using linacs have stated their fail-
ure to obtain satisfactory safety results from single doses. The
use of hypofractionation or hyperfractionation was attempted
to improve their results.

154

A rare series of SRT with a rigorous methodology (i.e., more
than 3 years follow-up, minimum number of patients, pre- and
postoperative PTA and SDS) show rates of CN V and CN VII pres-
ervation and rate of functional hearing preservation that are
fairly comparable to those of GKRS.42–48 We have found no ser-
ies, relying on audiometric criteria to show the capacity of SRT
to provide patients with rates of functional hearing preserva-
tion, comparable to those achievable with GKRS. Severe acute
sudden hearing losses following SRT have been reported.50
Big tumors, Koos stage IV, with a significant mass effect on
the brainstem, require microsurgical decompression. However,
the radical removal of these very big tumors, even in the best
hands, can be associated with a major risk of facial palsy to the
extent of 50 to 60%. There are various degrees of severity, but
permanent cases are not uncommon. In our experience, in just
55% of the patients involved, the radical removal of large Koos
stage IV lesions is compatible with the long-term preservation
of normal facial motor nerve functions (House-Brackman grade
1 or 2). Thus, 7 years ago we gave up this approach and
switched to a combined approach as standard management for
big Koos stage IV cases. The first step of this combined approach
is the deliberate, partial removal of the tumor under neuromo-
nitoring of the motor facial nerve.
The retrosigmoid approach is used in the majority of cases.
The second step is carried out 3 to 6 months following the MS
procedure, with radiosurgery being used to treat the remnants.
This paradigm shift from radical removal to the combined
approach has increased our preservation rate of the motor
facial function, from 55% to 85%. Functional hearing, however, is
rarely retained.
Stage IV tumors of a reasonable size (generally in patients
with small posterior fossa)51 with a modest mass effect on the
brainstem can benefit from cautious radiosurgery, especially
when the patient’s hearing is still functional.52 The classical
phenomenon of transient increase of VS after radiosurgery53,54
might bring about a degradation of the patient’s neurologic
condition, thus making a resection mandatory.53 However, in
our experience with 95 patients who had moderate Koos stage
IV at the time of radiosurgery, after years of follow-up, none
presented such a complication. The tumor control rate statistics
remained at 95%, and the functional hearing preservation rate
was at 65%. No patients had facial palsy.
Young age is undoubtedly related to better clinical results,
especially in terms of hearing preservation.24,25 Preserving neu-
rologic function and particularly motor facial function is of
utmost importance in young patients with a long life expect-
ancy, making radiosurgery the preferred surgical method for
this population group (▶ Fig. 19.2).
However, the risk of malignancy must be factored and dis-
cussed whenever younger patients are being treated with ioniz-
ing radiation therapy. The most recent literature available to us,
directly pertaining to this issue, covers studies set to exception-
ally high standards.55,56 All these studies have been performed
using evidence-based methodology. The consensus is that there
is no appreciable evidence of an increased risk of carcinogenesis
in patients who have received radiosurgery.
This means that if this risk actually exists, then it must be
very low, and should be weighed against the risk of periopera-
tive mortality from MS—statistics hover around 1 to 2%. These
studies clearly demonstrate that the risk of neoplasia should
Stereotactic Radiosurgery for Vestibular Schwannomas
not deter a patient from the benefits gained as well as the dra-
matic reduction of risk from radiosurgery as compared with
MS. Using the UK Registry of Causes of Death, Rowe et al com-
piled a comparison of the risks of those having had radiosur-
gery with those with no history of radiosurgery. 55 In their
findings, they clearly demonstrate the absence of increased
incidences of cancer in patients who had received radiosur-
gery.55 According to Cahan et al, the criteria for carcinogenesis
can be discussed only if the nature of the tumor is different to
the nature of the treated tumor.57
The malignant evolution of benign schwannomas, which is
extremely rare, is a different phenomenon to carcinogenesis
proper (i.e., radio-induced tumors). Within the literature, seven
cases of VSs, which were regarded as benign at the time of the
first surgery, were found to be malignant at the point of second
surgery. A key fact is that all of these patients had had a surgical
resection, but only five patients had radiosurgical exposure. 58,
59,60 Comey et al put forward the hypothesis “that the tumours
initially regarded as benign, may already contain a minority of
malignant components, which have subsequently taken over
the majority of the tumour, and led to the recurrence and
malignant behaviour.” This explanation is for patients receiving
several stand-alone MS procedures and in rare cases may
be valid for patients receiving several MS procedures and
radiosurgery.61
Statistics on the occurrence of facial palsy following radiosur-
gery show that in all the modern series of high-precision sin-
gle-dose radiosurgeries, risks of facial palsy are less than 1%.
This is far lower than that of the most favorable results from
MS, when performed in the very best hands.11–15
Communicating hydrocephalus can classically be observed in
patients with a vestibular schwannoma. Hydrocephalus is par-
ticularly seen in older patients and in those with larger tumors.
Roche et al62,63 have nicely demonstrated that there is no
increased risk of developing any radiological and clinical signs
of hydrocephalus through radiosurgery.
In cases of failure, if the lesion size is still compatible with
radiosurgery, a second radiosurgery is proposed. This, in our
experience, has a high probability of success.64 However, in
these cases the risk of functional hearing loss is higher than in
the first round of radiosurgery. When the tumor is too large for
a second radiosurgery procedure, we always propose subtotal
resection followed by repeat radiosurgery. We no longer pro-
pose the radical removal of a VS due to the significantly higher
rate of facial palsy.65
19.5 Summary
Our series of 2,336 patients who underwent GKRS and were
subsequently followed up and monitored for more than 3
years demonstrates a high rate of tumor control and the rarity
of toxicity with 0.5% trigeminal nerve injury and 0.5% facial
palsy. Serviceable hearing preservation stands at 65% after 3
years, but is highly dependent on the initial quality of hearing,
past history of hearing loss, age, and dose to the cochlea. In
favorable cases, the rate of hearing preservation can be as high
as 90%. These results, when compared with the natural history
of these tumors, favor a protective effect of radiosurgery on
hearing.
155
 Stereotactic Radiosurgery for Vestibular Schwannomas
Fig. 19.2 Example of Gamma Knife (GK) radiosurgery in a young patient presenting with Koos class I vestibular schwannoma and normal hearing. At
more than 3 years after radiosurgery, the patient has retained serviceable hearing. This case illustrates the benefit of a proactive radiosurgical
approach in young patients with small lesions and high-quality hearing.
With more than 20 years’ experience in the field of clinical
experiments in fractionated radiotherapy in acoustics, advan-
tages over high-precision single-dose radiosurgery remain
ambiguous.
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 20 Stereotactic Radiosurgery for Trigeminal
Part V Neuralgia 160

Functional Indications 21 Stereotactic Radiosurgery in Movement

Disorders 168

22 Gamma Knife Radiosurgery for

Obsessive–Compulsive Disorder 177

23 Stereotactic Radiosurgery for

Hypothalamic Hamartomas 182

24 Stereotactic Radiosurgery for Epilepsy 193

V
 Stereotactic Radiosurgery for Trigeminal Neuralgia

20 Stereotactic Radiosurgery for Trigeminal Neuralgia

Michael D. Chan and Stephen B. Tatter

Table 20.1 Burchiel classification scheme for facial pain

Key Points Burchiel pain type Clinical history

● Microvascular decompression is the surgical treatment Type I trigeminal neuralgia > 50% episodic pain
of choice for younger patients in good health with trige- Type II trigeminal neuralgia < 50% episodic pain
minal neuralgia because of the greater durability of pain
Trigeminal neuropathic pain Caused by unintentional trauma (e.
relief.
g., tooth extraction)
● Radiosurgery represents an excellent minimally invasive al-
ternative to microvascular decompression for patients who Trigeminal deafferentation pain Caused by intentional trauma (e.g.,
are older or have significant medical comorbidities. rhizotomy)
● A median pain response rate of 85% with a median durability Symptomatic trigeminal neuralgia Multiple sclerosis
of pain relief of 5 years can be expected from patients with
trigeminal neuralgia who undergo radiosurgery. Postherpetic neuralgia Herpes zoster outbreak in trigemi-
nal distribution
● A single isocenter delivering 70 to 90 Gy to the 100% isodose
line without any collimation or plugging would be considered Atypical facial pain Somatoform pain
a standard radiosurgical technique.
● Radiosurgery may be safely repeated at least once if neces-
sary for recurrent trigeminal neuralgia pain. Table 20.2 Barrow Neurologic Institute (BNI) Pain Intensity Scale
Pain score Degree of pain

BNI I Complete pain relief without

20.1 Introduction medications

BNI II Some pain, but not requiring

Trigeminal neuralgia is a severe paroxysmal facial pain
medications
located within the trigeminal distribution on the face. Also
known as tic douloureux, this condition has been described BNI III Some pain, but adequately con-
as a “suicide disease” because of the severity of the pain. The trolled with medications
age-adjusted incidence of trigeminal neuralgia has been BNI IV Some pain, but inadequately con-
reported to be greater in women (5.9 per 100,000) than men trolled with medications
(3.4 per 100,000).1
BNI V Continued severe pain or no pain
relief

20.2 Classification of Trigeminal

Neuralgia
There are several facial pain etiologies that can closely
resemble trigeminal neuralgia. As such, it is vital to obtain a
detailed clinical history as well as imaging to rule out etiol-
ogies such as tumors or multiple sclerosis (MS). Classifica-
tion of facial pain based on clinical presentation can help to
properly select patients for the appropriate interventions.
The most commonly accepted modern classification scheme
for facial pain is the Burchiel classification, 2 which is sum-
marized in ▶ Table 20.1. Classical idiopathic trigeminal neu-
ralgia is known as type I trigeminal neuralgia in the
Burchiel classification. It is defined as pain that is episodic
at least 50% of the time. It can be located within any of the
three divisions of the trigeminal nerve and is commonly
described as sharp, stabbing, or electrical shock-like in qual-
ity. The intensity of pain has been described using the Bar-
row Neurologic Institute (BNI) pain scale. This scale is
commonly used in the scientific literature to describe pain
before and after an intervention, and to compare results
between multiple series. The BNI scale is summarized in
▶ Table 20.2.
20.3 Pathophysiology of
Trigeminal Neuralgia
The pathophysiology of idiopathic trigeminal neuralgia has
been explained by what has become known as the vascular
hypothesis. This hypothesis explains the episodic pain syndro-
me of trigeminal neuralgia by the compression of the trigeminal
nerve by a blood vessel,3 with the most common offending ves-
sel being the superior cerebellar artery. It is also thought that
the brain settles within the cranial vault with age, and thus cre-
ates a greater likelihood for such an interaction between a
blood vessel and the trigeminal nerve in the more elderly
population.
Other etiologies that can produce pain syndromes similar to
idiopathic trigeminal neuralgia include MS, tumors of the skull
base (e.g., meningioma, acoustic neuroma, metastatic disease),
Charcot-Marie-Tooth disease, lyme disease, herpes zoster, trau-
matic nerve injury, and somatoform pain disorders. The impor-
tance of the various etiologies of facial pain with regard to the
use of stereotactic radiosurgery (SRS) is the fact that radiosurgi-
cal management has a high rate of response for type I pain, but
an inferior response rate for some of the other etiologies. The

160

risk of SRS-related toxicity, though low, is another reason to dif-
ferentiate between the various causes of facial pain. Patients
with herpetic neuralgia and neuropathic pain from traumatic
nerve injury are less likely to respond to radiosurgery.
20.4 Treatment Options
The major treatment options for trigeminal neuralgia include
antiepileptic medications, microvascular decompression (MVD)
surgery, percutaneous rhizotomy, and SRS. The proper treat-
ment option for each patient is generally dependent on such
factors as the patient’s age, patient preference, type of facial
pain, medical comorbidities, severity of pain, and previous
treatments that have either succeeded or failed. A proposed
management algorithm is depicted in ▶ Fig. 20.1.
20.4.1 Medical Management
The first-line therapeutic option for newly diagnosed trigeminal
neuralgia is medical management. In general, antiepileptics are
the most common type of medication used for trigeminal neu-
ralgia, although tricyclic antidepressants, benzodiazepines, and
narcotics can also lead to pain relief in selected cases. The single
most effective medication for trigeminal neuralgia is carbama-
zepine (Tegretol; Novartis International AG, Basel, Switzerland).
Other medications that have reported responses include pheny-
toin (Dilantin; Pfizer, New York, NY), baclofen (Gablofen; CNS
Pharmaceutics, St. Paul, MN), oxcarbazepine (Trileptal; Novartis
International), gabapentin (Neurontin; Pfizer), and lamotrigine
(Lamictal; GlaxoSmithKline plc, Brentford, London, UK).
Patients who have an initial response to medical management
can undergo a trial of withdrawal of medications over time as
Stereotactic Radiosurgery for Trigeminal Neuralgia
the pain may remain in remission. It is common, however, for
patients to become refractory to medical management over
time, and these patients will commonly require surgical or
ablative management. Furthermore, some of the antiepileptics
will commonly have associated toxicities such as sedation, cog-
nitive changes, and ataxia, which if intolerable, may lead to the
need for surgery or radiosurgery. Carbamazepine, in particular,
can have a high rate of such toxicities. Oxcarbazepine and gaba-
pentin may have lower rates of toxicity. Tricyclic antidepres-
sants such as amitriptyline (Elavil; AstraZeneca, London, UK)
are often used in patients with advanced age when there is a
concern for intolerable toxicity.
Microvascular Decompression
Microvascular decompression is a surgical technique involving
a craniotomy and decompression of the trigeminal nerve from
the offending blood vessel. Intraoperative insertion of an inert
implant (generally Teflon) allows for prevention of recurrent
vascular compression. The chief advantage of MVD is the fact
that the pain relief is durable and likely curative. In general, 70%
of patients treated with MVD continue to be pain-free 10 to 20
years after the operation.4 Operative morbidity and mortality is
generally quite low, but may rise after the age of 70, the age
that noninvasive alternatives may have a greater therapeutic
ratio.5 An endoscopic microvascular decompression technique
has also been described.6
A prospective study conducted at the Mayo Clinic has looked
at the cost-effectiveness of SRS versus MVD as a definitive treat-
ment option for trigeminal neuralgia. In this study, MVD
appeared to have a higher cost in the near term, but for patients
with longer life expectancies, it appeared to be the more cost-
effective treatment option.7
Fig. 20.1 Management algorithm for trigeminal
neuralgia. IV, intravenous.
161
 Stereotactic Radiosurgery for Trigeminal Neuralgia

Stereotactic Radiosurgery
Stereotactic radiosurgery represents a noninvasive treatment
option for trigeminal neuralgia, with its main advantage being
its noninvasiveness and low morbidity rate. The great majority
of the data that exist for radiosurgical management of trigemi-
nal neuralgia involves the use of the Gamma Knife, although
there is an emerging literature for linear accelerator (linac)
approaches. The major disadvantage of SRS is the limited dura-
bility of its pain response. Most series have shown that the
median duration of radiosurgical response to be on the order of
5 years. Although SRS can be repeated, for younger patients
even a second application of SRS may not remain effective
throughout their life span. Because of issues with normal tissue
tolerance, patients are generally limited to two radiosurgical
applications over a lifetime. Elderly patients and those with sur-
gical contraindications such as severe cerebro- or cardiovascu-
lar disease or bleeding diatheses may also be best treated with a
radiosurgical approach.
Percutaneous Rhizotomy
Percutaneous ablative techniques have also had success in the
treatment of trigeminal neuralgia. These techniques include
radiofrequency rhizotomy, glycerol rhizotomy, and balloon rhi-
zotomy. The chief advantages of percutaneous ablative techni-
ques are that pain relief is immediate and that they often do not
require general anesthesia. Comparisons of the percutaneous
procedures have suggested that they likely have very similar re-
sponse rates and durability of response. However, the likelihood
of persistent hypesthesia or anesthesia dolorosa may be higher
than what is seen with MVD or a radiosurgical approach.8 The
durability of response for percutaneous techniques is limited
and similar to results with SRS. Patients with need for immedi-
ate pain relief, but who are not candidates for MVD, may be best
treated with percutaneous rhizotomy.
chapter, the following radiosurgical outcomes will refer specifi-
cally to Gamma Knife results, with the exception of the section
specifically dedicated to linac approaches.
20.5.1 Quality-of-Life and Pain
Outcomes
Successful responses to SRS are generally measured by several
end points: pain relief, ability to come off of medications, and
improvement of quality of life. A prospective quality-of-life
study performed by a group from Marseille, France, found
improvement in all quality-of-life parameters and that 58 of 83
(70%) responders were able to come off of medications after
SRS.9
Several large retrospective series have also been reported in
the scientific literature for trigeminal neuralgia after definitive
SRS. The results of the largest series of patients undergoing
Gamma Knife radiosurgery (GKRS) for the treatment of trigemi-
nal neuralgia are summarized in ▶ Table 20.3. The series that
have been reported have shown quite similar results regarding
pain response. In a series from Wake Forest, North Carolina,
Marshall et al reported a cohort of over 400 patients with trige-
minal neuralgia and reported an 86% initial response to pain
within 3 months.10
Among the greater concerns for treatment with SRS is the
increasing possibility of pain relapse with increasing time after
treatment. Riesenburger et al reported that pain relapse after
SRS is a time-dependent phenomenon. Marshall et al reported
a median durability of 4.9 years for patients with type I trigemi-
nal neuralgia.10 Lucas et al have recently reported that the ini-
tial successful response and ability to discontinue medications
was the dominant factor predicting durable pain relief after
SRS.11 Other series have found prior surgical intervention to
lead to decreased response duration after SRS.12

20.5.2 Factors that Affect Response

20.5 Radiosurgery Outcomes Several factors have been identified that affect the likelihood of
As the great majority of the data for radiosurgical outcomes treatment success for SRS in the treatment of trigeminal neural-
have come using the Gamma Knife unit, for the purpose of this gia. The development of postradiosurgical numbness has been

Table 20.3 Selected large series of Gamma Knife radiosurgery for trigeminal neuralgia
Institution N Median dose (Gy) Response rate Any toxicity

Pittsburgh13 503 80 89% 11%

Marseille40 497 85 91% 14%

Wake Forest10 448 90 86% 44%

Columbia24 293 75 76% 5%

Beaumont41 149 80 92% 25%

UVA42 136 80 90% 19%

Mayo43 117 90 85% 37%

Maryland12 112 75 81% 6%a

Brussels26 109 90 82% 38%

Spokane44 108 86 82% 19%

aSeries reported bothersome numbness only.

162

identified as a major factor that predicts treatment success in
multiple series.13 Prior surgery for trigeminal neuralgia,14 and
particularly radiofrequency ablation of the nerve,10 appears to
decrease the likelihood of treatment response. Régis et al
showed a sequential decrease in response with every previous
procedure performed.9 Having evidence based on magnetic res-
onance imaging (MRI) of contact between a blood vessel and
the trigeminal nerve appears to predict better response after
SRS.15 The dose rate of the Gamma Knife sources16 does not
appear to affect the response rate.
20.5.3 Radiosurgical Complications
Trigeminal nerve dysfunction is the major possible toxicity in
patients who have received SRS for trigeminal neuralgia. The
mechanism for such radiosurgical toxicity is damage to the sen-
sory fibers within the trigeminal nerve. There have been several
series that have reported higher rates of numbness in patients
who have received higher doses and those who have a greater
length of nerve treated. There has also been an association
between patients who experience postradiosurgical numbness
and the durability of radiosurgical treatment response.11 Other
series have suggested that excellent pain relief responses can be
achieved in the absence of trigeminal nerve dysfunction. 17
Recent data from the University of Pittsburgh (Pittsburgh, PA)
suggest that patients receiving gabapentin may have a lesser
risk of GKRS-induced numbness.18 More severe toxicities that
occur following SRS include corneal anesthesia and anesthesia
dolorosa. The likelihood of more severe toxicity is rare, with
anesthesia dolorosa rates reported to be less than 1%.10
20.6 Radiosurgical Targeting and
Treatment Planning
20.6.1 Prescription Dose
Doses delivered for SRS generally range between 70 and 90 Gy
prescribed to the isocenter. There has been one series in which
patients were treated in the repeat setting in which pain
responses were seen at doses as low as 45 Gy prescribed to the
isocenter.19 Pollock et al reported results from the Mayo Clinic
(Rochester, MN) in which patients were treated with either 70
or 90 Gy. Patients in the 90 Gy cohort experienced a greater
degree of pain relief, but also had a greater degree of numb-
ness.20 The mechanism of pain relief is believed to be focal axo-
nal degeneration of the trigeminal nerve that affects pain fibers
Stereotactic Radiosurgery for Trigeminal Neuralgia
proportionately more than sensory fibers.21 At higher doses,
necrosis is seen more commonly and may contribute to the res-
ponse to SRS; 90 Gy appears to be the upper limit of the accept-
able dose.10,20,22
20.6.2 Isocenter Location
The technical goal of trigeminal neuralgia SRS is to place a
radiosurgical 4-mm isocenter onto the trigeminal nerve as it
runs through the prepontine cistern. A sample radiosurgical
plan is demonstrated in ▶ Fig. 20.2. The rationale for placing the
isocenter within the prepontine cistern is that the nerve can be
well visualized on MRI in this area, and that the nerve is also
surrounded by cerebrospinal fluid, allowing for the precise tar-
geting and sharp dose falloff (i.e., penumbra) beyond the nerve,
minimizing the risk of damage to surrounding structures such
as the brainstem and temporal lobe.
There are several hypotheses on the target of radiation effect
when trigeminal neuralgia is treated with SRS. The putative tar-
get of radiation damage is important because of the implica-
tions it has on the ideal isocenter location. Kondziolka et al
have published that the dorsal root entry zone is more radio-
sensitive than more distal portions of the nerve because of the
transition between more radiosensitive oligodendrocytes and
more resistant Schwann cells.23 This was supported by data
from Columbia University (New York, NY), which demonstrated
improved pain outcomes in patients with greater volumes of
brainstem receiving a dose of 15 Gy.24 A strategy for targeting
the dorsal root entry zone places the isocenter such that the
50% isodose line is tangential to the brainstem. However, data
from multiple other series support equivalent pain relief while
targeting a more distal portion of the nerve such as the pars
triangularis.
Modern targeting strategies include targeting the pars trian-
gularis and using the 20% isodose line to determine isocenter
location. The rationale for targeting the pars triangularis is that
it is a relatively distal portion of the nerve, but allows targeting
of the entire nerve circumference before it diverges into multi-
ple branches. Other series have placed the 20% isodose line such
that it is tangential to the brainstem surface. The rationale for
this approach is to constrain the brainstem surface to < 20 Gy, as
this dose has been implicated in treatment-related numbness.
With this approach, the majority of the high-dose region is
within the pars triangularis.
Several series have compared the two isocenter locations. A
study from Wake Forest assessed dose delivered to the
Fig. 20.2 Targeting for trigeminal neuralgia ra-
diosurgery in the up-front and repeat settings. (a)
A Gamma Knife plan in which the target is the
pars triangularis; the 20% isodose line is tangen-
tial to the brainstem. (b) A plan after which the
patient’s pain recurred several years later. The
target is now more proximal so as to avoid
isocenter overlap from the previous plan; the 50%
isodose line is tangential to the brainstem.
163
 Stereotactic Radiosurgery for Trigeminal Neuralgia
brainstem surface and root entry zone and found that although
a higher dose to the brainstem did not predict a greater pain re-
sponse, patients with shorter nerves did have increased treat-
ment efficacy. The authors concluded that a “target” structure
of radiation damage did exist. A recent series of 99 patients
from the University of Virginia (Charlottesville, VA) compared
cohorts receiving 80 Gy in which patients with a proximal iso-
center (50% isodose line entering brainstem) experienced great-
er durability of pain relief than those with a distal isocenter
(20% isodose line tangential to the brainstem).10
Optimal isocenter location remains controversial. Both the
Wake Forest and University of Virginia data also demonstrate
that greater doses to the brainstem led to greater degree of
posttreatment numbness.
20.6.3 Use of Dose Modulation
Several studies have been published on the use of channel
blocking or multiple isocenters as a means of blocking dose
from the brainstem and delivering dose to a greater length of
nerve.
A randomized prospective study of 87 patients was con-
ducted by the University of Pittsburgh in which patients were
randomized to one versus two isocenters.25 The rationale for
such a study was to determine whether increased length of
nerve treated resulted in any difference in either efficacy or tox-
icity of radiosurgical treatment. Although there was no change
detected in efficacy, the incidence of complications correlated
with the nerve length irradiated—greater with two versus one
isocenter.
Another controversy regarding targeting and delivery of SRS
for trigeminal neuralgia involves the question of collimator
plugging. “Plugging” blocks a portion of the collimator to shape
the beam to incorporate a greater length of nerve and to
decrease the amount of brainstem exposure. A study from Brus-
sels, Belgium, showed that the addition of plugging, although
modestly improved the response to Gamma Knife, caused a
greater degree of bothersome numbness.26 The authors con-
cluded that plugging should be avoided.
20.6.4 Effect of Dose Rate
Multiple retrospective analyses have investigated if the dose
rate of the cobalt sources affected the efficacy of treatment. It
has been hypothesized that lower dose rates may have wors-
ened pain responses because of the possibility of tissue repair
within the nerve.27 However, a series from the University of
Pittsburgh recently demonstrated no differences in efficacy
over the span of a 2 half-life decay of cobalt-60 sources.28
20.7 Special Populations
20.7.1 Type II Trigeminal Neuralgia
Several reports have demonstrated a decreased response rate
and durability of response in patients with type II trigeminal
neuralgia when treated with surgical or radiosurgical modal-
ities. Tyler-Kabara et al showed that in series of 2,264 patients
with trigeminal neuralgia, those with type II pain had a greater
164
risk of relapsing over time as compared with patients with type
I pain.29 There have been much more limited series assessing
the outcomes of patients with non-type I trigeminal neuralgia
after SRS. This has been a difficult population to assess because
of the heterogeneity of the population in general, and the non-
standardized classification systems used by various institutions.
Dhople et al published a series of 35 patients with atypical tri-
geminal neuralgia from the University of Maryland.12 In this
series, the authors included patients with type II pain (continu-
ous) as well as patients with burning as opposed to lancinating
pain. There was a trend toward longer time before pain relief as
well as shorter duration of pain relief in patients with atypical
trigeminal neuralgia in this series.
A series from Wake Forest University compared outcomes of
patients with type I and type II trigeminal neuralgia. 10 In this
series, there were 61 patients with type II trigeminal neuralgia
and 32 patients with atypical facial pain. Patients with type II
trigeminal neuralgia and atypical facial pain both had decreased
initial response rates after SRS as well as a decreased durability
of pain relief. Median durability of pain relief was 4.9 years for
type I, 1.7 years for type II, and 0.7 years for atypical facial pain.
20.7.2 Multiple Sclerosis–Related
Trigeminal Neuralgia
Multiple sclerosis–related, also called symptomatic, trigeminal
neuralgia constitutes approximately 1% of patients with trige-
minal neuralgia-like symptoms. Symptoms may manifest as epi-
sodic or continuous pain, and it does not appear that the nature
of pain affects the success rate of the treatment. 30 The most
important distinction in this population with regard to thera-
peutic options is the difference in pathophysiology of the pain.
Multiple sclerosis–related trigeminal neuralgia is due to a
demyelinating process within the trigeminal neuronal pathway,
which can commonly be detected on MRI. As such, microvascu-
lar decompression is not considered an adequate treatment op-
tion, as it does not address the pathophysiology of the disease.
Medical management is considered to be first-line therapy, as it
is for idiopathic trigeminal neuralgia. Surgical options such as
glycerol rhizotomy and SRS have also been reported. Because of
the relative rarity of symptomatic trigeminal neuralgia, avail-
able published evidence is limited to small, single-institution
retrospective series.30,31 In the largest of such, a study from the
University of Pittsburgh, 37 patients were treated with GKRS
using a dose range between 70 and 90 Gy.32 The authors
reported that 36 of 37 patients reported BNI I–IIIb pain at some
point in their course with 23 patients experiencing a BNI I pain
score. Five percent of patients experienced a new-onset pares-
thesia in this series.
20.7.3 Bilateral Trigeminal Neuralgia
Bilateral trigeminal neuralgia is a complicated clinical entity
that represents approximately 2% of patients with trigeminal
neuralgia. The etiology of bilateral trigeminal neuralgia is com-
monly related to either Charcot-Marie-Tooth disease or MS.33 It
has been shown that patients with bilateral trigeminal neural-
gia are less likely to have blood vessel compression on MRI, 15
 Stereotactic Radiosurgery for Trigeminal Neuralgia

and thus likely that a proportion of these patients have pain
that is not caused by vascular compression. The clinical com-
plexity of the bilateral pain is related to the possibility of bilat-
eral trigeminal nerve dysfunction that can result from an
ablative treatment. Such dysfunction can lead to significant tox-
icity such as dysarthria and dysphagia resulting from damage to
the motor pathways of the trigeminal nerve. The efficacy of
MVD is controversial given the difference in pathophysiology of
the patients with bilateral pain. Stereotactic radiosurgery for
bilateral trigeminal neuralgia has been reported in an eight-pa-
tient series from Tufts Medical Center in Boston, Massachusetts,
without significant toxicity.34 However, long-term efficacy
remains to be reported. One approach to avoid bilateral trige-
minal nerve dysfunction has been to treat the more sympto-
matic side first, then follow the patient for 6 to 12 months to
assess for efficacy and toxicity before deciding on the manage-
ment of the other side.
neuralgia as opposed to a consequence of previous SRS such as
deafferentation pain. Furthermore, a common practice is to
select patients who had a prior response to SRS.36
It is common to prescribe a slightly lower dose at the second
radiosurgical application. Doses as high as 90 Gy3and as low as
45 Gy19 prescribed to the 100% isodose line have been shown to
yield pain responses with the second radiosurgical treatment. 19
Because the cumulative numbers in the literature are small, it is
unclear as to whether the likelihood of significant toxicity is
any worse than after the first radiosurgery.
With regards to the isocenter location in the setting of repeat
radiosurgery, data exist for placement of the isocenter in the
exact same position, or in a different position to avoid over-
lap.35 One common strategy has been to place the first isocenter
distally at the first radiosurgical treatment, with the later iso-
center being placed more proximally where the change from
oligodendrocytes to Schwann cells may make the region more
radiosensitive.

20.8 Specific Clinical Scenarios

20.8.2 Use of Computed Tomography
20.8.1 Repeat Radiosurgery Alone for Treatment Planning
Because the median durability of pain relief after SRS is on There exists a population of patients with trigeminal neural-
the order of 5 years, some patients receiving primary SRS will gia who are candidates for radiosurgical management, but
have a recurrence of trigeminal neuralgia pain at some point have contraindications to MRI such as pacemaker placement,
in their lifetime. In this scenario, a second application of SRS a ferromagnetic implant, or shrapnel exposure. In such
is a reasonable treatment option. Several institutions have patients, computed tomography (CT)-based treatment plan-
now reported on the efficacy of repeat SRS and found that ning with or without cisternography has been reported in
the response rate and durability of a second response are which the targeting of the nerve is done based on anatomical
similar to what is seen with the first application. 35 Select landmarks such as the trigeminal impression on the temporal
results of repeat radiosurgical series are presented in bone.37,38 Further follow-up is likely necessary to ensure that
▶ Table 20.4. this population does not have a higher rate of late toxicity or
Patient selection is an important issue in patients who are late pain recurrence.
considered for a second radiosurgical procedure. A detailed
history is necessary to rule out the possibility that the pain the
patient is experiencing is truly a recurrence of trigeminal 20.8.3 Linear Accelerator–Based
Approaches
Table 20.4 Repeat radiosurgery series for relapsed trigeminal neuralgia Linear accelerator–based approaches for trigeminal neuralgia
Institution N Median re- Response Any toxicity are utilized less than GKSRS for several reasons: difficulty in
treatment rate accurately characterizing the output factor for a 4-mm collima-
dose (Gy) tor, the instability associated with a linac gantry, and the fact
that inaccuracies are cumulative. The potential magnitude of
Pittsburgh36 119 70 87% 21%
error (i.e., inaccuracy) estimated for linac treatment of trigemi-
Columbia45 45 40 62% 13% nal neuralgia is thought to be as great as 30%. For sufficient
treatment of trigeminal neuralgia on a linear accelerator using a
Wake For- 37 84 84% 57%
est35 4-mm collimator, a root mean square value of all errors likely
needs to be < 1 mm.39
Tangdu Hos- 34 71 97% 12% The largest series of linac-based SRS comes from the Univer-
pital (China)
46
sity of California, Los Angeles. In this series of 179 patients, the
authors demonstrated a response rate and durability of treat-
Tufts19 27 45 86% 29% ment similar to that which is seen with Gamma Knife series.22
The authors used a median dose of 90 Gy (range 70–90 Gy) with
Medical Uni- 22 74 100% 74%
versity of the 30% isodose line tangential to the pons.
Graz (Aus-
tria)47
20.9 Summary
Mayo48 19 76 95% 21%
Stereotactic radiosurgery represents a safe and effective nonin-
Maryland49 18 70 78% 11%
vasive treatment option for trigeminal neuralgia. The major

165
 Stereotactic Radiosurgery for Trigeminal Neuralgia

limitation of SRS lies in its limited durability as compared with
MVD. Patients older than 70 years, with multiple sclerosis, or
with significant medical comorbidities represent populations
that may be well suited for SRS. Patients are generally best
managed by a multidisciplinary team to determine which treat-
ment option is optimal for each patient.
[21] Kondziolka D, Lacomis D, Niranjan A, et al. Histological effects of trigeminal
nerve radiosurgery in a primate model: implications for trigeminal neuralgia
radiosurgery. Neurosurgery 2000; 46: 971–976, discussion 976–977
[22] Smith ZA, Gorgulho AA, Bezrukiy N, et al. Dedicated linear accelerator radio-
surgery for trigeminal neuralgia: a single-center experience in 179 patients
with varied dose prescriptions and treatment plans. Int J Radiat Oncol Biol
Phys 2011; 81: 225–231
[23] Kondziolka D, Lunsford LD, Flickinger JC, et al. Stereotactic radiosurgery for
trigeminal neuralgia: a multiinstitutional study using the gamma unit. J Neu-

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knife surgery for idiopathic trigeminal neuralgia performed using a far-anterior
[40] Tuleasca C, Carron R, Resseguier N, Donnet A, Roussel P, Gaudart J, Levivier M,
cisternal target and a high dose of radiation. J Neurosurg 2004; 100: 597–605
Régis J. Patterns of pain-free response in 497 cases of classic trigeminal neu-
[18] Flickinger JC Jr, Kim H, Kano H, et al. Do carbamazepine, gabapentin, or other
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83: e501–e506
Maitz AH, Grills IS. Trigeminal neuralgia pain relief after gamma knife stereo-
[19] Dvorak T, Finn A, Price LL, et al. Retreatment of trigeminal neuralgia with
tactic radiosurgery. Clin Neurol Neurosurg 2014; 117: 107–111
Gamma Knife radiosurgery: is there an appropriate cumulative dose? Clinical
[42] Sheehan J, Pan HC, Stroila M, Steiner L. Gamma knife surgery for trigeminal
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167
 Stereotactic Radiosurgery in Movement Disorders
21 Stereotactic Radiosurgery in Movement Disorders
Patrick Pezeshkian, Antonio De Salles, and Nader Pouratian
Key Points
1. Radiosurgical thalamotomy
● Stereotactic radiosurgery thalamotomy targets the
nucleus ventralis intermedius and is currently based on
anatomical magnetic resonance imaging alone and meas-
urements relative to anterior and posterior commissures
(indirect targeting). We prefer a maximum dose of 140 Gy
delivered with one 4-mm isocenter.
● The efficacy of stereotactic radiosurgery thalamotomy for
controlling tremor is similar to that reported for radiofre-
quency thalamotomy and deep brain stimulation, with 85
to 90% of patients showing significant improvements in
tremor in short-term follow-up studies.
● Complications may arise from lesions that develop larger
than expected or from misplaced lesions. These include
involvement of the internal capsule or ventral posterior
thalamic nucleus with associated deficits of weakness or
paralysis, dysphasia, or sensory loss. Four to five percent
may experience side effects, but gradually recover over
several months.
2. Radiosurgical pallidotomy
● Stereotactic radiosurgery pallidotomy uses indirect target-
ing of the globus pallidus internus with the isocenter
being placed such that 50% isodose line of a 4-mm colli-
mator is within the globus pallidus internus and superior
to the optic tract. We prefer a radiosurgical dose of
140 Gy for creating a brain lesion with a 4-mm collimator.
● The most consistent effect of pallidal ablation is relief of
contralateral levodopa-induced dyskinesias. However, the
amount of improvement in contralateral bradykinesia,
rigidity, and tremor varies among many studies.
● Complications include visual field deficit, speech, and
swallowing difficulties, worsening of gait, and numbness
in the contralateral hemibody.
3. Radiosurgical subthalamotomy
● Stereotactic radiosurgery subthalamotomy is rarely per-
formed. To our knowledge, the only report in the litera-
ture is a case report of a radiosurgical lesioning of the
subthalamic nucleus with a single 120 Gy 4-mm shot
using indirect targeting.
● Outcomes are difficult to ascertain due to the rarity of
the procedure; however, the radiofrequency subthala-
motomy literature, albeit small, points to 45 to 60%
improvement in Unified Parkinson’s Disease Rating
Scale motor scores in the “off” period in the 16- to 24-
month follow-up.
● Given the paucity of stereotactic radiosurgery subthala-
motomies, the main complication associated with subtha-
lamotomies, virtually all of which are reports of radiofre-
quency subthalamotomies, is contralateral hemiballism,
which tends to resolve spontaneously within several
months.
168
21.1 Introduction
Despite initially being innovated for the purpose of treating
functional disorders such as Parkinson disease (PD) and psychi-
atric disease, stereotactic radiosurgery (SRS) is now mostly
used to treat brain tumors and vascular lesions. Lesional techni-
ques, such as radiosurgery, have been progressively supplanted
by technologies such as deep brain stimulation (DBS), which
provide a reversible and modulatable treatment. Still there is
considerable interest in the role of lesioning surgery, which
when performed effectively obviates the need for hardware im-
plantation and long-term maintenance, thereby significantly
reducing health care costs. Stereotactic radiosurgery in particu-
lar is a very attractive treatment modality because it provides a
precise and noninvasive means of lesioning the brain to achieve
functional improvement. However, given the irreversible nature
of the lesion and given the lack of precise and reliable means of
neurophysiological testing and confirming the physiological
target, SRS is generally reserved as an option for patients who
are not suitable for open neurosurgical procedures.
Advances in neuroimaging, computerized dosimetry, treat-
ment-planning software systems, and the promising results of
SRS in other brain diseases have reinvigorated interest in the
application of this technique in the treatment of movement dis-
orders since the 1990s. The role of lesioning in the treatment of
movement disorders is well documented in the radiofrequency
(RF) ablation literature, lending promise to the application of
SRS for the treatment of movement disorders.1–8 However, the
transition from RF lesions to noninvasive SRS lesions required
addressing additional questions, such as those related to dosing.
Initially, the safety and effectiveness of the dose used for func-
tional radiosurgery was not known. Previous reports indicated
that doses of 180 to 200 Gy were capable of and necessary for
creating a focal lesion in the brain, but were associated with
potential complications such as uncontrolled lesion size and
perilesional edema.9,10 These initial high doses are now
reduced, with a tendency toward fewer complications. Collima-
tor size and number of isocenters have also been a matter
of concern because the use of multiple isocenters and large-size
collimators have been related to increased complication
rates.11–15
In this chapter, we present a broad review of the usefulness
of SRS for the treatment of movement disorders—its indica-
tions, techniques, applications, and complications.
21.2 Definition, Patient Selection,
and Indications
Stereotactic radiosurgery has been applied for the treatment of
such movement disorders as PD, essential tremor (ET), and dys-
tonia. Before proceeding with a discussion of treatment and
outcomes, a brief definition of PD, ET, and dystonia is presented,
including patient selection criteria for neurosurgical interven-
tion and indications for intervention.

Parkinson disease is a progressive neurodegenerative disor-
der resulting in motor symptoms that are related to the death
of dopaminergic cells in the substantia nigra (SN). Early in the
course of the disease, motor symptoms dominate and include
resting tremor, rigidity, axial and appendicular bradykinesia,
and difficulty with walking and gait. Later, cognitive and behav-
ioral problems may arise, with dementia commonly occurring
in the advanced stages of the disease, whereas depression is the
most common psychiatric symptom. Other symptoms include
sensory, sleep, and emotional problems. The Unified Parkin-
son’s Disease Rating Scale (UPDRS) is a scale that was developed
as an effort to incorporate elements from existing scales to pro-
vide a comprehensive, but efficient and flexible means to mon-
itor PD-related disability and impairment. The UPDRS itself has
four components, largely derived from preexisting scales that
were reviewed and modified by a consortium of movement-
disorder specialists. These include Part I, Mentation, Behavior
and Mood; Part II, Activities of Daily Living; Part III, Motor; and
Part IV, Complications. The UPDRS scores are generally assessed
both off- and on-medication states. As patients with PD are
evaluated by a response to levodopa, PD patients should have at
least a 30% decrease in UPDRS III scores in response to
levodopa.
Essential tremor is the most common movement disorder,
typically resulting in tremor of the arms, hands, or fingers, but
sometimes involving the head or other body parts during vol-
untary movements such as eating and writing. Essential tremor
generally presents as a rhythmic tremor (4–12 Hz) that occurs
only when the affected muscle is exerting effort. Essential trem-
or is distinguished from PD by the postural and kinetic charac-
teristics of the tremor rather than the rest tremor associated
with PD. Moreover, PD is marked by bradykinesia and rigidity,
whereas patients with ET do not have such motor symptoms.
Some individuals may have both conditions. The patient’s trem-
or is evaluated with a standardized Tremor Rating Scale. The
scale describes the distribution and severity of the tremor at
rest, with maintenance of a sustained posture and with action.
Because of the fluctuating nature of tremor severity and the
effects of antitremor drugs, repeated assessments that take into
account whether the patient is on or off drugs are most
informative.
Dystonia is a neurologic movement disorder, in which sus-
tained muscle contractions cause twisting and repetitive move-
ments or abnormal postures. The disorder may be hereditary or
caused by other factors such as birth-related or other physical
trauma, infection, poisoning (e.g., lead poisoning), or reaction
to pharmaceutical drugs, particularly neuroleptics.
Patients are selected for SRS for the management of move-
ment disorders in the same manner as for procedures such as
RF thalamotomy, pallidotomy, or DBS. Patients should be
assessed in a multidisciplinary movement disorder clinic to
confirm the underlying diagnosis, in particular to exclude “Par-
kinson’s plus” syndromes such as multisystem atrophy, pro-
gressive supranuclear palsy, and striatonigral degeneration. It is
important to ensure that adequate pharmacological response
has been documented and adequate treatment has been pro-
vided before any intervention is considered. Quantifying symp-
tom severity with the standard scoring systems, such as the
UPDRS and Tremor Rating Scale, is important to define severity
of the disease and guide surgical timing. Neuropsychological
Stereotactic Radiosurgery in Movement Disorders
testing should also be performed because surgical interven-
tion, as well as radiosurgical intervention, is generally not
considered appropriate for patients with significant demen-
tia.1,2,4,5,15–22
Because neurophysiology-guided RF stereotactic surgery or
DBS offer advantages over SRS and the permanent neurologic
complication rate of SRS is worse than that of DBS (see discus-
sion below), SRS is reserved for a small subset of patients who
have medical conditions that make them unacceptable candi-
dates for invasive stereotactic neurosurgical intervention, or
require therapy but absolutely refuse invasive surgery under
any circumstances. These include elderly patients, patients suf-
fering from severe cardiac or pulmonary comorbidities, and
those who are anticoagulant dependent. In some cases, some
patients may prefer SRS to avoid an invasive surgical proce-
dure.15,17,19,20,21,23,24 Furthermore, invasive stereotactic surgery,
including both RF ablation and DBS, is associated with certain
morbidities and possible mortality. These procedures carry an
inherent risk of intracerebral hemorrhage (1–2%), infection (4–
5%), seizures, brain displacement, tension pneumocephalus,
and direct injury from probe placement, among others.8,24,25,26
Stereotactic radiosurgery is a less invasive procedure that does
not involve opening of the cranium or incisions; therefore,
there is no risk of hemorrhage or meningitis from postoperative
infection. The postoperative patient care is also simpler;
patients can return earlier to their regular activities with a
reduction in hospitalization time. The disadvantages of SRS
include irreversibility of the procedure because it is an ablative
procedure and often limited to unilateral application, variability
in efficacy, and complications based on treatment technique
such as dosage of radiation used, number of isocenters used,
and collimator size. Furthermore, the exclusive reliance on ana-
tomical targeting due to the impossibility of confirming the le-
sion site intraoperatively with electrophysiologic testing makes
target determination less certain. Moreover, a mean delay of 6
months for clinical improvement may be expected after SRS.15,
17,18,19,20,21,24
21.3 Radiosurgical Thalamotomy
Stereotactic radiosurgery thalamotomy targeting the nucleus
ventralis intermedius (VIM) has been performed by several
authors in the treatment of tremor in patients with tremor-
dominant PD, ET, and tremor related to multiple sclerosis, trau-
ma, or other causes. The reported results and complications
with SRS thalamotomy are comparable to those achieved using
other methods.15,17,19,21,23,27,28,29
21.3.1 Technique and Targeting
Currently targeting is based on anatomical magnetic resonance
imaging (MRI) alone and measurements relative to the anterior
(AC) and posterior (PC) commissures—“indirect targeting.” Con-
sequently, every effort must be made to eliminate or correct
sources of MRI distortion when calculating the stereotactic tar-
get coordinates. The current technique for targeting the VIM
thalamus is similar to conventional stereotactic procedures. In
our institution, a frameless approach using the Novalis linear
accelerator (linac) system (Brainlab, Munich, Germany) is used.
169
 Stereotactic Radiosurgery in Movement Disorders
High-resolution MR images are obtained with a 3.0-T scanner.
Contrast-enhanced images are acquired, including through the
basal ganglia, midbrain, third ventricle, and AC and PC (1-mm
isotropic resolution). Axial fast inversion recovery sequences
are performed for optimal gray–white differentiation and iden-
tification of the internal capsule (0.9-mm in-plane resolution).
High-resolution noncontrast 1-mm-cut head computed tomog-
raphy (CT; reconstructed to 0.6-mm cuts) is obtained preproce-
durally and coregistered onto the high-resolution MRI
sequences. The VIM contralateral to the predominant tremor
extremity is targeted in the following way: anteroposterior
coordinate being one-quarter the AC distance plus 1 mm anteri-
or to PC (1-mm anterior displacement is intended to reduce the
risk of adversely affecting the ventral posterolateral [VPL] sen-
sory nucleus of the thalamus); lateral coordinate being one-half
the third ventricle width plus 11 mm and superiorinferior coor-
dinate being 2.5 mm superior to the AC–PC line. A simulated
target is placed in the inferior lateral corner of the thalamus
such that 50% of the isodose line (4-mm collimator) is coinci-
dent with the inferior lateral border of the thalamus and 20%
isodose line of the 4-mm collimator is placed medial to the
internal capsule. The maximum dose of 140 Gy is delivered with
one 4-mm isocenter. The anteromedial displacement from the
actual target is done to avoid possible damage to the internal
capsule and the sensory nucleus of the thalamus (▶ Fig. 21.1).
The knowledge that the high-signal zone surrounding a tha-
lamic lesion is functionally almost intact has led to some
authors changing the placement of the lesion at the real target
instead of shifting away to avoid capsular and sensory nucleus
involvement.30 A more conservative approach has been recom-
mended by some authors using 130 Gy and preventing the 10
to 15% isodose line from extending into capsular and sensory
nucleus.30 Another important point is the concept that each
170
thalamic nucleus is represented more constantly by the per-
centage of thalamic length than by the distance from the PC.
Therefore, the regular coordinates for thalamotomy can be
adjusted for the VIM nucleus to be at a length of 45% from the
anterior tip of the thalamus in the horizontal plane.31 Recent
developments in MRI diffusion tensor and colored fractional
anisotropy techniques make possible the visualization of the
thalamic nuclei, including definition of the VIM, promising
improvement on targeting of thalamic sites.32
21.3.2 Outcomes
There are several case series of SRS thalamotomies in the litera-
ture for patients with PD or ET, documenting the success of this
technique for the treatment of tremor (▶ Table 21.1). The larg-
est series of SRS thalamotomy for ET 33 presented the results of
161 patients, who underwent a total of 203 thalamotomies
(119 unilateral and 42 bilateral). The vast majority of the
patients were treated with 140 Gy, varying from 140 to 150 Gy,
using a single isocenter and 4-mm collimation. A statistically
significant decrease in tremor scores for both writing and draw-
ing was observed after a mean postoperative follow-up dura-
tion of 56 ± 31 months. Overall, 81% of patients showed
improvements in drawing and 77% showed improvement in
writing scores. There were 14 patients who suffered neurologic
side effects that were temporary (6 patients) or permanent (8
patients), which accounted for 6.9% of the 203 treatments. As in
other series in the literature, there was a correlation between
lesion volume and complications. The mean lesion volume for
the 157 procedures in which no complications was identified as
188 ± 224 mm3, and for the 14 procedures for which complica-
tions were identified, the mean lesion volume was 871 ±
742 mm3 (p < 0.001).
Fig. 21.1 Screenshot of planning magnetic reso-
nance imaging showing ventralis intermedius
(VIM) target in the left thalamus. A dose of
140 Gy using a 4-mm collimator to a single
isocenter was delivered.
 Stereotactic Radiosurgery in Movement Disorders

Table 21.1 Literature review of radiosurgery thalamotomy for movement disorders

Study Pathology N Lesions FU Good (%) Mild Failed Complications Excellent
(mo) (%) (%)

Young et al, ET 51 51 26 (NR) 47 (92.1) — — 4 (7.8) 1 (1.9)

2000

Kondziolka et al, ET 27a 27 36 (4– 18 (66.6) 6 (22.2) — 3 (11.1) 2 (7.4)

2008 96)

Young et al, ET 161 203 56 ± 31 2 (14.2) 81 NR NR 14 (6.9)

2010

Elaimi, 2010 ET 1 1 72 1 (100) 1b — — —

Pan et al, PD 6 6 4.5 (2–9) 3 (50) 3 (50) — — 1 (16.6)

1996

Duma et al, PD 34 38 28 (6– 3 (50) 11 (29) 4 (10.5) 4 (10.5) No

1998 58)

Young et al, PD 102 102 47 (11– 78 (76.5) 12 (11.8) — 12 (11.8) 2 (1.9)

2000 93)

Ohye et al, PD and ET 30a 30 30 (24– 24 (80) — — 6 (20) No

2002 96)

Duma et al, PD and ET 42 46 30 (6– 25 (54) 13 (28) 4 (8.6) 4 (8.6) 1 (2.3)

2007 90)

Ohye et al, PD and ET 85 NR c 80 NR 4 (4.7) NR —

2009

Lim et al, PD and ET 14a 14 19.2 (7– Serious NR NR NR 3 (21.4)

2010 30) 1 (6)

Abbreviations: ET, essential tremor; FU, median and range of follow-up; NR, not reported; PD, Parkinson disease.
aPatients available for follow-up, and excellent and good.
bTransient.
cOver a 17-year interval (median follow-up and range not reported).

In addition to ET, thalamotomies have been used to treat
tremor dominant PD. Duma et al11 reported a series of 42
patients submitted to 46 thalamotomies for the treatment of PD
and ET with 6 to 90 months of follow-up (median 30 months).
No change in tremor was observed in 4 (8.6%) patients, mild
improvement in 4 (8.6%), good improvement (> 50%) in 13
(28%), excellent improvement in 13 (28%), and complete elimi-
nation was observed in 12 (26%) patients. The median time of
improvement onset was 2 months (range 1 week–8 months).
Independent neurologist evaluation scores of patients’ response
to treatment were obtained at regular clinical follow-up inter-
vals. Complications were observed in one (2.3%) patient who
was submitted to bilateral lesions and suffered a mild acute
dysarthria 1 week after treatment. Young et al34 reported the
results of 102 PD patients who underwent SRS thalamotomy
for the treatment of tremor. After a median follow-up of 47
months (range 11–93 months), 78 (76.5%) were completely
tremor-free contralateral to the treated side, 12 (11.8%) were
nearly free, and 12 (11.8%) had failed the treatment. Blinded
assessments of UPDRS tremor scores showed statistically signif-
icant improvements in overall tremor, action tremor, and trem-
or at rest. Although thalamotomies are not as effective as other
targets for other symptoms of PD, the authors reported
improvement in rigidity that was a statistically significant
improvement and was maintained at 4-year follow-up
evaluation. The physiological mechanism of such improvement
in rigidity and bradykinesia remains unexplained, but may be
attributable to the open-label design of the study. In the whole
group, one transient (0.66%) and two permanent complications
(1.3%) were reported. In all three of these patients, the side
effects were due to lesions that became larger than expected
rather than due to targeting errors.
21.3.3 Timing of Therapeutic Efficacy
and Complications
Some authors recommend that at least 1 year elapse before a
contralateral lesion is performed and further recommend that
an MRI scan be obtained immediately before a second, contrala-
teral lesion to confirm that the first lesion is of usual size, and
that there are no surrounding signal changes indicating an
excess radiation reaction. Dose, volume, and time are the key
components that determine the nature of functional ablation. 12,
35,37 In general, the MRI of a typical post-SRS thalamotomy pa-
tient demonstrates a well-demarcated, peripherally enhancing
lesion 4 to 5 mm in diameter, surrounding a hypoattenuating
central region (▶ Fig. 21.2).
Complications may arise from lesions that develop larger
than expected or from misplaced lesions. In the case of

171
 Stereotactic Radiosurgery in Movement Disorders
Fig. 21.2 (a) T1-weighted axial magnetic resonance (MR) image with gadolinium contrast demonstrating a noncontrast-enhancing hypointense area
in the left ventralis intermediate nucleus of the thalamus 7 months after SRS thalamotomy. (b) T2-weighted axial MR image demonstrating a
hyperintense area in the left VIM. (c) Fluid-attenuated inversion recovery (FLAIR) image of the same lesion demonstrating no significant perilesional
edema.
thalamotomies, such lesions may involve the internal capsule
or ventral posterior thalamic nucleus with associated deficits of
weakness or paralysis, dysphasia, or sensory loss. Approxi-
mately 4 to 5% of patients experience side effects after SRS tha-
lamotomy, but usually there is gradual recovery over several
months.
Benefits and complications from SRS have been documented
to occur between 1 and 12 months after the procedure.38,39,40
The time needed for the radiation to damage the targeted tissue
accounts for the delay in onset of benefits and complications.
The lesional effect can be accelerated by increasing the dose of
radiation; however, the optimal dose of radiation has not been
clearly established and with increased doses, higher rates of
complications have been anticipated. The peak central doses
may range from 120 to 200 Gy.
In one study, a comparison was conducted between a sub-
group of patients in whom “low-dose” lesions (mean 120 Gy)
and those in whom “high-dose” lesions were made (mean
160 Gy) for purposes of obtaining dose-response information. 17
Better tremor reduction in the high-dose group (78% mean
improvement) than in the low-dose group (56% mean improve-
ment) (p = 0.04) was reported and there were no neurologic
complications. However, Okun et al41 reported a higher rate of
complications in a series of eight patients—seven of whom were
treated with a maximum dose of 200 Gy. These included death
secondary to dysphagia, and aspiration pneumonia, hemiplegia,
visual field deficits, aphasia, and pseudobulbar laughter. Most
neurosurgeons perform radiosurgical lesioning for functional
disorders at lower doses (e.g., 140 Gy).
21.3.4 Summary
Although the efficacy of SRS thalamotomy for controlling trem-
or is similar to that reported for RF thalamotomy and DBS
172
because of the lack of neurophysiological confirmation of the
target and the sometimes unpredictable growth of the radio-
surgical lesion, the neurologic complication rate of SRS thala-
motomy may be greater than that of open procedures.13,17,33,42
Eighty-five to 90% of patients showed significant improvements
in tremor in short-term follow-up studies. These results have
changed the use of the open lesioning technique in favor of SRS
thalamotomy in some centers.13,15,17,24 Lesioning of the thala-
mus is an alternative treatment for tremor and SRS ablation
may be effective when properly performed. It should be
reserved for use in patients with severe disabling tremor who
cannot tolerate open surgical procedures and should be per-
formed by neurosurgeons who have experience in DBS or RF
thalamic procedures because targeting of the thalamus without
neurophysiological mapping can be very challenging.
21.4 Radiosurgical Pallidotomy
Unilateral or bilateral pallidotomy may be accomplished with
SRS, but is currently rarely used due to the superior effective-
ness of globus pallidus internus (GPi) and subthalamic DBS in
treating the full spectrum of PD symptoms (▶ Table 21.2). The
goals of pallidotomy include relief of contralateral levodopa-
induced dyskinesias as well as improvement in contralateral
bradykinesia, rigidity, and tremor.
21.4.1 Technique
For SRS pallidotomy, an axial image is selected that demon-
strates both AC and PC, and a coronal image is viewed at a point
2 to 3 mm anterior to the midcommissural point. The GPi and
the underlying optic tract are visualized and the isocenter is
placed such that 50% isodose line of a 4-mm collimator is with-
in the GPi and superior to the optic tract. It is crucial to define
 Stereotactic Radiosurgery in Movement Disorders

Table 21.2 Literature review of radiosurgery pallidotomy for movement disorders

Study N Lesions Dose (Gy) FU Excellent Good Fair Poor Complications
(mo) (%) (%) (%) (%) (%)

Rand et al, 8 8 140–165 NR 2 (25) 4 (50) — 2 (25) No

1993

Friedman et al, 4 4 180 12 — 1 (25) — 3 (75) 1 (25)

1996

Bonnen et al, 1 1 140 NR — — 1 (100) — 1 (100)

1997

Young et al, 29 34 120–140 20.6 (6– 65.5–86.6a — — 1 (3.4)

1998 48)

Duma et al, 18 160 (90– 8 (6–40) — 6 (33) 3 (17) 9 (50) 9 (50)

2007 165)

Abbreviations: FU, median and range of follow-up; NR, not reported.

aExcellent and good, depending on the symptom—bradykinesia or dyskinesia.

that target in both the axial and coronal planes to properly
determine the vertical coordinate in relation to the optic tract.
Furthermore, the 50% isodose line should be as far away from
the optic tract as possible, within a location that includes the
GPi completely within the 50% line, and limiting the dose to the
optic tract to 8 Gy at most. At our institution, we prefer a radio-
surgical dose of 140 Gy for creating a brain lesion with a 4-mm
collimator. With these parameters, a lesion of about 6 mm in
diameter (113-mm volume) will usually develop 3 to 9 months
after the procedure. Larger radiosurgical doses will produce
lesions more rapidly, but the volume of the lesion may vary
more, producing larger lesions that are associated with higher
complication rates. Conversely, smaller doses may fail to pro-
duce any definable lesion, therefore leading to no therapeutic
effect.
21.4.2 Outcomes
The most consistent effect of pallidal ablation is relief of con-
tralateral levodopa-induced dyskinesias. However, the amount
of improvement in contralateral bradykinesia, rigidity, and
tremor varies among many studies.43
Stereotactic radiosurgery pallidotomy was first reported by
Rand in 1993,4 who used the technique in eight patients with
doses between 140 and 165 Gy. Significant improvement in
contralateral rigidity, bradykinesia, and dyskinesias was
observed in four (25%) patients. Positive results without a major
impact in quality of life were observed in two (25%) patients
and there was no change in the course of the disease in the oth-
er two (25%) patients. Four cases of PD were described by Fried-
man et al,18 who underwent unilateral pallidotomy using a 4-
mm collimator and a dose of 180 Gy. No significant improve-
ment occurred during the follow-up interval of 18 months; one
patient developed a stroke due to radiation vasculopathy with
severe radiation changes in the blood vessels adjacent to the
radiosurgical lesion.
Young et al44 reported a comparative study of 51 patients
with PD who underwent pallidotomies. The patients were div-
ided into two groups: 29 were treated with radiosurgery
(applied dose ranged between 120 and 140 Gy with a 4-mm
collimator) and submitted to 34 lesions; 22 were treated with
RF and submitted to 25 lesions. The median follow-up was 20.6
months (range 6–48 months), and the evaluations of motor
performance and postoperative assessments were obtained by
blinded observers. Improvement in dyskinesias was observed in
86.6% versus 83.3% in the SRS and RF groups, and in bradykine-
sia and rigidity in 65.5% versus 63.6%, respectively. One patient
in the radiosurgery group (3.4%) presented with contralateral
homonymous hemianopsia secondary to a lesion larger than
expected (volume 950 mm3) at 9 months postoperatively. Two
other patients developed larger lesions (520 mm3 and 700 mm3,
respectively), but they were not associated with any clinical
side effects.
According to the authors, the results were equally as good as
those obtained in the RF pallidotomies when electrophysiologi-
cal localization was used.
21.4.3 Complications
As mentioned for thalamotomies, the drawbacks of radiosurgi-
cal pallidotomy concern the latency between the procedure and
the clinical benefit (2–3 months minimum) and the possibility
that the lesion produced by radiosurgery will continue to
enlarge on a delayed basis and involve adjacent normal struc-
tures. A review of the literature reveals only a few studies that
document the benefit of SRS pallidotomy in a blinded and
unbiased manner, with many more reports of complications
after SRS pallidotomy. One such report by Duma et al 11 is a ser-
ies of 18 patients with PD who underwent SRS pallidotomy. Fif-
teen patients were treated using a single 4-mm collimator and
three were treated using two 4-mm collimators with a median
maximum prescription dose of 160 Gy (range 90–165 Gy). Over
a median average follow-up of 8 months (range 6–40 months),
only six (33%) patients showed transient improvement in
rigidity and dyskinesia. Three (17%) patients were unchanged
and nine (50%) were worsened by the treatment. Of the six
patients with improvement, two exhibited visual field deficits.
Overall, four (22%) patients had visual field deficit, three (16%)

173
 Stereotactic Radiosurgery in Movement Disorders
had speech or swallowing difficulties, three (16%) had worsen-
ing of their gait, and one (5%) patient had numbness in the
contralateral hemibody. Nine patients (50%) had one or
more complications related to the treatment, which were unre-
sponsive to steroid treatment and considered to be permanent.
The explanation of the high complication rate in this series was
related to the variability and unpredictability of the lesion size
when the GPi served as the target.
The differences in outcome comparing VIM and GPi led the
authors to conclude that there might be a difference in sensitiv-
ity to radiation between these two nuclei, probably represent-
ing anatomical susceptibility to very small venous or arterial
infarctions in the area of the GPi, caused by the tapering end-
artery distribution of the lenticulostriate supply. 12,45
Homonymous hemianopsia after SRS pallidotomy is a serious
deficit and is seen in 4 to 6% of patients. According to the litera-
ture, these visual field deficits are permanent and not com-
pletely unexpected in view of the proximity of the optic tract to
the GPi, which may receive as much as 15 to 25 Gy, which is
well beyond the usual 8-Gy-maximum radiation dose usually
accepted for the optic apparatus. Other complications such as
weakness or paralysis and dysphagia can occur due to involve-
ment of the internal capsule by the lesion.
21.4.4 Summary
The number of centers that have been performing radiosurgery
pallidotomies compared with those performing thalamotomies
reflects the lack of reliability of the procedure and that other
therapeutic options are superior to SRS targeting the GPi. The
relatively high incidence of visual field deficits after SRS pallid-
otomy has caused many centers to limit its use to very rare
cases in which DBS or RF pallidotomy cannot be used and the
patient is significantly disabled by PD.
21.5 Subthalamotomy
The subthalamic nucleus (STN) is considered one of the major
targets and DBS as the main option for the surgical treatment of
the broad spectrum of symptoms in patients with idiopathic
PD. Benabid et al were the first group to demonstrate the effi-
cacy of STN DBS in the treatment of PD in the mid-1990s. 46
Despite the overwhelming preference of practitioners
towards DBS of the STN for treatment of PD symptoms, subtha-
lamotomy in the form of RF ablation is a seldom performed pro-
cedure; therefore, case reports are limited to mainly centers
outside of the United States that have reported on the benefits
of therapeutic RF subthalamotomy in patients with PD.47,48
These include a Cuban series of 18 patients who underwent
bilateral RF subthalamotomies and exhibited a 58% improve-
ment in UPDRS motor scores in the “off” period after average
follow-up of 16 months. Likewise, the Bristol series of 50 unilat-
eral RF subthalamotomies in 39 patients demonstrated 46%
improvement in the motor UPDRS score in 24 months.
Stereotactic radiosurgery subthalamotomy as treatment for
idiopathic PD is even more rarely performed. The only report of
radiosurgery subthalamotomy in the literature described the
case of an elderly patient previously submitted to a RF pallidot-
omy who underwent a contralateral radiosurgery lesion of the
174
STN with a single 120-Gy 4-mm shot. After 3.5 years of follow-
up, the STN lesion was stable and well placed and the patient
experienced reduction in dyskinesias and improvement in
tremor and rigidity.49
21.5.1 Complications
Given the paucity of SRS subthalamotomies, the main complica-
tion associated with subthalamotomies, virtually all of which
are reports of RF subthalamotomies being contralateral hemi-
ballism. As shown in the Cuban report, three patients devel-
oped severe generalized chorea, dysarthria, and balance
instability that lasted 6 months before spontaneously resolving.
Similarly, in the Bristol report, one patient developed postope-
rative hemiballisms on the side contralateral to the STN lesion,
lasting for 3 months before spontaneously resolving.
21.5.2 Summary
In contrast to SRS thalamotomy, which is an alternative to DBS
for the treatment of tremors associated with ET or PD, in
patients in whom surgical procedures are contraindicated, SRS
pallidotomy and subthalamotomy currently play only a limited
role in the treatment of patients with movement disorders. This
is mainly owing to the high efficacy, relatively low complication
rates, the possibility of reversibility, and fine adjustment of sti-
mulation parameters associated with DBS of basal ganglia tar-
gets in the surgical treatment of patients with movement
disorders.
21.6 Conclusions
Advances in stereotactic techniques associated with improve-
ments in MRI targeting, planning software, and a better knowl-
edge of SRS parameters have brought the technique to a
precision capable of performing focal and precise lesions in the
basal ganglia for the treatment of movement disorders,
although competing lesioning technologies are appearing in the
market, as MRI-guided focused ultrasound50 and MRI-guided
laser ablation,51 which may prove more effective and safer than
SRS.
Using modern functional SRS parameters, SRS thalamotomy
is a useful procedure for patients who are not suitable for an
open surgical procedure and understand the potential risk of
neurologic complications. Complications appear to be mostly
related to the variability of lesion volumes using the same
radiosurgical parameters rather than to the stereotactic target
precision. The factors related to this unpredictable thalamic
reaction to high single-dose radiation are still unknown.
The results of radiosurgery pallidotomy are not homogene-
ous in the literature. Many reports disclosed an unacceptably
high complication rate. Although just a few centers reported
their results, the majority of them were not satisfactory, leading
them to abandon the procedure. Moreover, further studies are
necessary to establish the role of SRS targeting the STN because
its small size and complex anatomical relationships make this
target less suitable for the procedure.
In conclusion, although the advent of DBS, with its possibility
of reversibility and fine adjustments of stimulating parameters,

has supplanted lesioning as the first alternative in movement
disorder surgery, SRS might still be the only treatment option
for selected patients. The development of alternative techniques
of targeting with the visualization of the nuclei51,52 and novel
lesioning techniques such as MRI-guided focused ultrasound
may bring better efficacy and safety to pallidotomy and subtha-
lamotomy. This in turn may bring a better understanding of tar-
geting these structures, with SRS defining further the
population of movement disorder patients who may benefit
from this technique.
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 Gamma Knife Radiosurgery for Obsessive–Compulsive Disorder
22 Gamma Knife Radiosurgery for Obsessive–Compulsive
Disorder
Nrupen Baxi, Andrew Brunswick, Eric Mazel, and Douglas Kondziolka
Key Points
● Obsessive–compulsive disorder has a lifetime prevalence of
approximately 2.3% in the general population, with treat-
ment refractory obsessive–compulsive disorder causing
significant disability.
● Neurosurgical interventions for refractory obsessive–compul-
sive disorder date to the 1950s and include target brain
lesioning with either radiofrequency or radiation energy, or
electrical brain stimulation. These interventions are designed
to disrupt circuits connecting the frontal lobe, striatum, and
thalamus that are believed to be overactive in patients with
severe obsessive–compulsive disorder.
Radiosurgery and electrical stimulation each have distinctive
●
qualities.
● For radiosurgical planning, we prefer two 4-mm isocenters in
the inferior part of the anterior limb of the internal capsule
at the midputaminal point, separated in the superoinferior
plane to mimic the current spread of an electrode.
● Of the 27 patients described in the literature who have
undergone radiosurgery for obsessive–compulsive disorder,
20 (74%) have had at least a 25% reduction and 13 (48%)
have had at least a 50% reduction in Yale-Brown Obsessive-
Compulsive Scale score.
22.1 Introduction
Obsessive-compulsive disorder (OCD) is a chronic, disabling
psychiatric disorder characterized by obsessions and/or com-
pulsions that can significantly affect quality of life for afflicted
patients. Obsessions are defined as recurrent, unwanted
thoughts, urges, or images; compulsions are repetitive behav-
iors or mental actions a patient must perform in response to a
compulsion.1 Symptoms can leave patients overwhelmed by
anxiety and unable to effectively function in society. Approxi-
mately 25 to 33% of patients with the disorder will contemplate
suicide.1,2 The mainstay of treatment has been and remains
medical. First-line therapy includes pharmacotherapy with se-
rotonin reuptake inhibitors (SSRIs) along with cognitive–behav-
ioral psychotherapy. Additional pharmacological agents include
tricyclic antidepressants, low-dose antipsychotics, and benzo-
diazepines. The estimated lifetime prevalence of OCD in the
United States is 2.3%, with a slightly higher predominance of
males in childhood and a higher predominance of women in
adulthood.3 The mean age of presentation is 19.5 years, with
25% of cases having an onset before age 14.1 There is also a high
incidence of comorbid conditions that accompany OCD, includ-
ing tic disorder, anxiety disorder, posttraumatic stress disorder
(PTSD), bipolar disorder, and major depressive disorder.1
Neurosurgery has been considered for a select subset of
patients who have severe, medically refractory OCD. Types of
intervention include target brain lesioning or electrical brain
stimulation. Lesioning can be performed using radiofrequency
or radiation energy. Multiple small studies have shown that
Gamma Knife radiosurgery (GKRS) may have the potential to
provide significant benefits to some within this subset of
patients. As is the case for all of our therapies, multiple ques-
tions remain to be answered. In this chapter, we review the
anatomy and pathophysiology of OCD as it pertains to surgical
target selection, compare GKRS to deep brain stimulation (DBS)
as surgical modalities, review major studies of GKRS for OCD to
date, and propose further avenues of research.
22.2 Anatomy, Pathophysiology,
and Surgical Target Selection
The neuroanatomy and neurobiology of OCD continue to be elu-
cidated, but remain controversial.4 Researchers have made use
of brain volumetric studies as well as functional studies such as
positron emission tomography (PET), functional magnetic reso-
nance imaging (fMRI), and single-photon emission computed
tomography (SPECT) to identify relevant anatomical struc-
tures.5–10 Functional imaging studies have consistently shown
abnormal activity in several key regions of the brain, including
the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC),
and caudate head. Activity within these circuits is heightened
during symptom provocation and normalizes with treatment,
although some argue that this may correlate with rather than
cause symptoms.11,12 These areas are believed to be linked
together by a series of parallel circuits termed corticostriatal/
thalamocortical (CSTC) circuits, which bring output from multi-
ple cortical areas including the OFC through the striatum, into
the thalamus, and then return this input to the cortex, forming
a loop.13
To further complicate matters, some have made light of the
fact that “refractory OCD” does not respond to traditional treat-
ments based on historical models of the disease. One hypothe-
sis is that refractory OCD is actually a separate disease requiring
different neuroanatomic and neurobiologic considerations. 14
Because DBS and GKRS have traditionally been used exclusively
for this subclass of OCD, one must wonder about the legitimacy
of using traditional models in the surgical treatment of this
disease.
Surgical interventions in OCD aim to interrupt the hyperac-
tivity of CSTC circuits. This can be accomplished by lesioning
either key regions in the brain or by lesioning pathways that
form the circuits connecting these regions. Because these path-
ways are diffuse, multiple targets have been proposed and
attempted. Major targets of interest have included the anterior
limb of the internal capsule (ALIC), ACC, subcaudate tracts, and
the inferior thalamic peduncle (ITP).
The most common lesioning target for the treatment of OCD,
the anterior internal capsule, was discovered somewhat fortui-
tously. Varied initial success with leucotomies and other larger
177
 Gamma Knife Radiosurgery for Obsessive–Compulsive Disorder
destructive procedures in the treatment of psychiatric disorders
led researchers Meyer and Beck to carefully analyze postmor-
tem brain specimens for predictors of success. They speculated
that a lesion in front of the anterior horn would sever connec-
tions to the frontal lobes.15,16 This lesion would interrupt fiber
tracts connecting the OFC to the caudate and thalamic nuclei,
thus disrupting circuitry vital to the pathophysiology of OCD.
Talairach was the first to perform this anterior capsulotomy in
hopes of treating refractory schizophrenia. Leksell was able to
modify this technique to utilize his stereotactic system and a
radiofrequency thermal source for lesioning. Both noted poor
results in treating schizophrenia, but satisfactory results in
nearly half the patients with anxiety or obsessional neuroses.15,
16 Leksell also performed a gamma capsulotomy where the
anterior capsule was lesioned using 100 Gy of stereotactically
delivered gamma radiation.16
22.3 Gamma Knife Radiosurgery:
Outcomes and Technical
Considerations
The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was
developed in 1989 to allow researchers to measure the severity
of OCD.17,18 A separate score is generated for both obsessions
and compulsions. Interrater variability is low, enabling its use
by different members of a research team. The scale has been
validated, with reduction in the total score correlating with
improvement in OCD symptoms. Modern research studies
including clinical drug trials and trials assessing neurosurgical
procedures have used the Y-BOCS to quantify outcomes.17,18
The total score is assessed using a 10-item questionnaire, with a
maximum possible score of 40 points. The groups are then clas-
sified in quintiles by severity, with a total score of 0–7 repre-
senting subclinical OCD, 8–15 mild OCD, 16–23 moderate OCD,
24–31 severe OCD, and 32–40 extreme OCD.18
Several early series of GKRS for OCD have been published.
Mindus et al published a series of 10 early patients with a 70%
response rate.15,19 Lopes et al first performed a randomized
clinical trial with five patients in which he reported a 60% res-
ponse rate of at least a 35% reduction in Y-BOCS score utilizing
two isocenters on each side. Lesioning remained the mainstay
neurosurgical approach for refractory OCD until the develop-
ment of DBS. Lopes et al performed a clinical trial after the ini-
tial reports of DBS in 2009, with three out of five patients
meeting response criteria at 48 months.20 Slavin et al discussed
four patients with marginal responses in 2009 at a neurosurgi-
cal meeting in Marseille, France, in 2009.21 Gouvea et al pub-
lished a report of one patient who underwent a sham
radiosurgical procedure in Brazil followed by therapeutic radio-
surgery 1 year later. She experienced no changes in her Y-BOCS
score after the sham procedure but had a dramatic benefit after
the second procedure.22 Kondziolka et al published a series of
three patients in 2011 with up to 5.5-year follow-up with sig-
nificant reductions in Y-BOCS scores for all patients, which cor-
related with improved clinical outcomes. No adverse events
were seen in this small series. They utilized two 4-mm isocen-
ters on each side and limited the maximum dose to 140 to
150 Gy instead of the 180 to 200 Gy seen in previous studies. 23
178
Sheehan et al has published the latest series of five patients
treated with a single isocenter with 140 to 160 Gy. In their ser-
ies, 80% of the patients had a major reduction in their Y-BOCS
scores.24
Patient selection for surgical OCD procedures varies slightly
among studies, but common criteria are listed in ▶ Table 22.1.
Generally, patients have a confirmed diagnosis of OCD without
significant other comorbid conditions. They also have Y-BOCS
values in the moderate, severe, or extreme range. Preprocedural
magnetic resonance imaging (MRI) is performed to evaluate for
any structural pathology. One or two isocenters are chosen in
the inferior part of the anterior limb of the internal capsule at
the midputaminal point. We prefer two 4-mm isocenters sepa-
rated in the superoinferior plane, mimicking the current spread
of an electrode, as seen in ▶ Fig. 22.1. The patient undergoes
placement of a stereotactic head frame on the day of the proce-
dure and is given a maximum dose of 140 to 180 Gy to the tar-
get. The permanent lesion within the internal capsule may take
2 to 4 months to fully form as tissue necrosis occurs. Patients
may have clinical improvements in their symptoms within 2 to
3 months postprocedure.23
Adverse events from radiosurgical lesioning procedures have
been described in older series. Mindus et al reported symptoms
of frontal lobe dysfunction including apathy and disinhibition,
which were attributed to the high radiation doses used. 15 They
advocated for lower doses to limit these effects. They also pro-
posed proactively monitoring patients for personality changes,
impulsiveness, and cognitive changes associated with possible
decreased frontal lobe processing.15 Rück et al described one
patient with right-sided radiation necrosis and another with
malignant edema that was maximal at 1 year postprocedure.
This latter patient also developed apathy and executive prob-
lems secondary to the edema. He and a third patient also devel-
oped urinary incontinence that was persistent.25 Rück et al also
noticed an average weight gain of 11 kg in long-term follow-up.
One patient became sexually disinhibited and was subsequently
convicted of rape.25 Frontal lobe symptoms were noticed in
about 50% of patients overall. The majority of recent studies
have not found significant adverse events; however, their sam-
ple sizes remain small. One group (unpublished) noted that
some patients developed cystic changes around some lesions,
which can be seen after any brain lesioning procedure.
Table 22.1 Criteria often used for patient selection
Inclusions Exclusions
DSM criteria met for OCD Age < 20 y or > 55 y
Duration of symptoms > 5 y Axis I, II, or III complicating diag-
nosis
Y-BOCS score > 26 Unable to provide informed con-
sent
Deemed refractory to available
medical and cognitive–behavioral
treatments by OCD specialists
Patient provides their own consent
Abbreviations: DSM, Diagnostic and Statistical Manual of Mental
Disorders, 5th ed.; OCD, obsessive–compulsive disorder; Y-BOCS, Yale-
Brown Obsessive-Compulsive Scale.
 Gamma Knife Radiosurgery for Obsessive–Compulsive Disorder
Results from the various GKRS studies have been pooled and
listed in ▶ Table 22.2. Of the 27 patients who have undergone
the procedure in the literature, 20 (74%) of them have had at
least a 25% reduction and 13 (48%) have had at least a 50%
reduction in Y-BOCS score. With the mean score of 32.5, a 25%
reduction may drop patients into a less severe quintile on the
Y-BOCS. On average, there was a 45% reduction (15 points) in
Y-BOCS scores postprocedure. In many patients, severe to
extreme OCD lessened to moderate, more manageable OCD.
22.4 Stereotactic Radiosurgery
and Deep Brain Stimulation
Interruption of circuits thought to be involved in OCD can be
accomplished with both GKRS and DBS. Unfortunately, there
are no long-term studies comparing the two techniques. Each
has its own distinct qualities; the choice may ultimately come
down to patient preference. We believe that from safety and
compliance standpoints for OCD patients, GKRS is superior to
DBS.
Gamma Knife radiosurgery creates a permanent lesion in the
target of interest. The effect usually takes 2 to 4 months to
become apparent, the time for tissue necrosis to occur.
Although the lesion is nonreversible and nonadjustable, there is
no risk of hardware failure and there is no need for surgeries to
change hardware. Gamma Knife radiosurgery for OCD has risks,
including the low risks of brain edema and cyst formation, as
well as adverse events such as apathy, disinhibition, and decline
in executive function that have been seen in some series.20,25
Unlike GKRS, DBS creates an immediate, reversible, and
adjustable interruption in the target of interest. Deep brain sti-
mulation requires an immediate procedure with significant risk
Fig. 22.1 Coronal magnetic resonance imaging
(T1 and T2) for radiosurgical planning in obses-
sive–compulsive disorder showing targeting of
inferior aspect of the anterior limb of the internal
capsule.
up-front—three patients in OCD trials using DBS suffered intra-
cranial hemorrhage, although only one had permanent defi-
cits.26,27,28 Deep brain stimulation also carries the risk of sudden
failure, which can be unpredictable, and which can lead to the
return of symptoms. Deep brain stimulation requires further
invasive procedures for hardware changes, and there have been
significant problems associated with battery failure.29 There
have been multiple reports of infections related to DBS hard-
ware.27,28,30,31 There have also been multiple reports of reversi-
ble stimulation-induced side effects such as hypomania,
agitation, anxiety, forgetfulness, and word-finding difficulties. 27,
28,30,32,33 Deep brain stimulation is also more expensive,
requires the use of complex devices that require specialized
programming, and is contraindicated in patients with excoria-
tion disorder or OCD with skin picking as a symptom due to
wound-healing risks.34
22.5 Conclusion
Obsessive–compulsive disorder is a severely disabling psychiat-
ric illness that affects millions of people worldwide. Treatment
of the condition can be challenging when symptoms are refrac-
tory to medical and cognitive–behavioral therapy. Lesioning
procedures for OCD first developed in the 1950s showed mod-
erate success. With the introduction of SRS, lesioning could be
performed as an outpatient procedure and with less surgical
risk with similar rates of success. Neurosurgical treatment has
been expanded with the advent of DBS, which provides a rever-
sible treatment modality. However, renewed interest in GKRS
has resurfaced as the risks of DBS have been better understood.
Several small series have shown GKRS to be effective in refrac-
tory OCD without the risk associated with deep brain electrode
179
 Gamma Knife Radiosurgery for Obsessive–Compulsive Disorder

Table 22.2 Meta-analysis of radiosurgical lesioning patients to symptom dimensions and comorbid conditions. J Clin Psychiatry 2011; 72:
17–26, quiz 119–120
Study N Pre Y- Last Y- Follow-Up Gy [3] Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-
BOCS BOCS (mo) compulsive disorder in the National Comorbidity Survey Replication. Mol
Psychiatry 2010; 15: 53–63
Lopes et al, 200920 1 30 10 48 180
[4] Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated cor-
2 32 10 48 180 tico-striatal pathways. Trends Cogn Sci 2012; 16: 43–51
[5] Abelson JL, Curtis GC, Sagher O, et al. Deep brain stimulation for refractory
3 33 22 48 180 obsessive-compulsive disorder. Biol Psychiatry 2005; 57: 510–516
[6] Jenike MA, Breiter HC, Baer L, et al. Cerebral structural abnormalities in ob-
4 34 21 48 180 sessive-compulsive disorder. A quantitative morphometric magnetic reso-
nance imaging study. Arch Gen Psychiatry 1996; 53: 625–632
5 32 40 48 180
[7] Le Jeune F, Vérin M, N’Diaye K, et al. French Stimulation dans le trouble obses-
sionnel compulsif (STOC) study group. Decrease of prefrontal metabolism
Rück et al, 200825 1 28 24 156 200
after subthalamic stimulation in obsessive-compulsive disorder: a positron
2 36 5 144 200 emission tomography study. Biol Psychiatry 2010; 68: 1016–1022
[8] Robinson D, Wu H, Munne RA, et al. Reduced caudate nucleus volume in ob-
3 38 28 84 180 sessive-compulsive disorder. Arch Gen Psychiatry 1995; 52: 393–398
[9] Saxena S, Brody AL, Maidment KM, et al. Localized orbitofrontal and sub-
4 35 1 180 200 cortical metabolic changes and predictors of response to paroxetine treat-
ment in obsessive-compulsive disorder. Neuropsychopharmacology 1999;
5 27 15 180 200
21: 683–693
6 33 1 144 200 [10] Szeszko PR, MacMillan S, McMeniman M, et al. Brain structural abnormalities
in psychotropic drug-naive pediatric patients with obsessive-compulsive dis-
7 39 35 12 180 order. Am J Psychiatry 2004; 161: 1049–1056
[11] Rauch SL, Jenike MA. Neurobiological models of obsessive-compulsive disor-
8 30 9 96 180 der. Psychosomatics 1993; 34: 20–32
[12] Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of ob-
Kondziolka et al23 1 34 24 55 140
sessive-compulsive disorder. Psychiatr Clin North Am 2000; 23: 563–586
[13] Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive
2 39 8 42 140
disorder: a necessary link between phenomenology, neuropsychology, im-
3 39 18 28 150 agery and physiology. Prog Neurobiol 2004; 72: 195–221
[14] Atmaca M. Review of structural neuroimaging in patients with refractory ob-
4 22 8 14 140 sessive-compulsive disorder. Neurosci Bull 2011; 27: 215–220
[15] Mindus P, Rasmussen SA, Lindquist C. Neurosurgical treatment for refractory
5 35 30 22 140 obsessive-compulsive disorder: implications for understanding frontal lobe
function. J Neuropsychiatry Clin Neurosci 1994; 6: 467–477
Slavin et al, 200921 1 34 21 8 180
[16] Lévêque M, Carron R, Régis J. Radiosurgery for the treatment of psychiatric
2 22 15 8 180 disorders: a review. World Neurosurg 2013; 80: e1–e9
[17] Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Com-
3 27 27 8 180 pulsive Scale. II. Validity. Arch Gen Psychiatry 1989; 46: 1012–1016
[18] Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Com-
4 37 30 8 180 pulsive Scale: I. Development, use, and reliability. Arch Gen Psychiatry 1989;
46: 1006–1011
Sheehan et al, 1 31 12 15 140 [19] Mindus , Jenike MA. Neurosurgical treatment of malignant obsessive compul-
201324 sive disorder. Psychiatr Clin North Am 1992; 15: 921–938
[20] Lopes AC, Greenberg BD, Norén G, et al. Treatment of resistant obsessive-
2 34 13 6 140
compulsive disorder with ventral capsular/ventral striatal gamma capsuloto-
3 33 31 24 140 my: a pilot prospective study. J Neuropsychiatry Clin Neurosci 2009; 21:
381–392
4 32 13 33 160 [21] Slavin KJL, Mcgrath P, Bangera N, D’Agostino A. Radiosurgical capsulotomy for
refractory obsessive-compulsive disorder: structural and functional consider-
5 31 12 33 160 ations. Paper presented at: Joint Annual Meeting EANS-SFNC; March 27–31,
2009; Marseille, France
Abbreviation: Y-BOCS, Yale-Brown Obsessive-Compulsive Scale.
[22] Gouvea F, Lopes A, Greenberg B, et al. Response to sham and active gamma
ventral capsulotomy in otherwise intractable obsessive-compulsive disorder.
Stereotact Funct Neurosurg 2010; 88: 177–182
[23] Kondziolka D, Flickinger JC, Hudak R. Results following gamma knife radio-
placement or relapsing symptoms with device failure or mal- surgical anterior capsulotomies for obsessive compulsive disorder. Neurosur-
gery 2011; 68: 28–32, discussion 23–3
function. Gamma Knife radiosurgery remains an important
[24] Sheehan JP, Patterson G, Schlesinger D, Xu Z. knife surgery anterior capsulot-
treatment option for refractory OCD and may be preferred in omy for severe and refractory obsessive-compulsive disorder. J Neurosurg
patients with excoriation disorders or medical comorbidities. 2013; 119: 1112–1118
[25] Rück C, Karlsson A, Steele JD, et al. Capsulotomy for obsessive-compulsive dis-
order: long-term follow-up of 25 patients. Arch Gen Psychiatry 2008; 65:

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Psychiatric Association; 2013
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guel EC. Suicidality in obsessive-compulsive disorder: prevalence and relation
[26]
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Blomstedt P, Sjöberg RL, Hansson M, Bodlund O, Hariz MI. Deep brain stimu-
lation in the treatment of obsessive-compulsive disorder. World Neurosurg
2013; 80: e245–e253
[27] Greenberg BD, Gabriels LA, Malone DA Jr, et al. Deep brain stimulation of the
ventral internal capsule/ventral striatum for obsessive-compulsive disorder:
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[28] Mallet L, Polosan M, Jaafari N, et al. STOC Study Group. Subthalamic nucleus
stimulation in severe obsessive-compulsive disorder. N Engl J Med 2008;
359: 2121–2134
[29] Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes in deep
brain stimulation for highly resistant obsessive-compulsive disorder. Neuro-
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[30] Denys D, Mantione M, Figee M, et al. Deep brain stimulation of the nucleus
accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen
Psychiatry 2010; 67: 1061–1068
[31] Plewnia C, Schober F, Rilk A, et al. Sustained improvement of obsessive-com-
pulsive disorder by deep brain stimulation in a woman with residual schizo-
phrenia. Int J Neuropsychopharmacol 2008; 11: 1181–1183
[32] Huff W, Lenartz D, Schormann M, et al. Unilateral deep brain stimulation of
the nucleus accumbens in patients with treatment-resistant obsessive-com-
pulsive disorder: outcomes after one year. Clin Neurol Neurosurg 2010; 112:
137–143
[33] Jiménez-Ponce F, Velasco-Campos F, Castro-Farfán G, et al. Preliminary study
in patients with obsessive-compulsive disorder treated with electrical stimu-
lation in the inferior thalamic peduncle. Neurosurgery 2009; 65 (Suppl):
203–209, discussion 209
[34] Kondziolka D, Hudak R. Management of obsessive-compulsive disorder-re-
lated skin picking with gamma knife radiosurgical anterior capsulotomies: a
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181
 Stereotactic Radiosurgery for Hypothalamic Hamartomas
23 Stereotactic Radiosurgery for Hypothalamic
Hamartomas
Andrew G. Shetter, Heyoung L. McBride, and John F. Kerrigan
Key Points
● Hypothalamic hamartomas are rare, nonneoplastic lesions
that may produce intractable gelastic and generalized seiz-
ures, cognitive and behavioral deterioration, and precocious
puberty.
● Stereotactic radiosurgery results in seizure control rates of
50 to 60% with a very low incidence of complications com-
pared with more invasive surgical alternatives.
● The principle disadvantage of radiosurgery is the long la-
tency interval before a full therapeutic effect is achieved,
which may be as long as 2 to 3 years.
● A radiation dose of > 17 Gy to the margin of the hamartoma
seems to be necessary for optimal results while limiting the
dose to the optic apparatus to < 10 Gy.
● A multidisciplinary team approach is mandatory to deter-
mine the best treatment option for any given individual
based on lesion size, topological location, and a full assess-
ment of the patient’s overall neurologic, behavioral, and cog-
nitive status.
23.1 Introduction
Hypothalamic hamartomas (HHs) are rare congenital lesions
that form on the tuber cinereum and inferior hypothalamus.
The most common presenting symptoms are medically intract-
able gelastic seizures, developmental delays, precocious pub-
erty, and behavioral disturbances. Their true incidence is
unknown, but the prevalence of epilepsy associated with HHs
has been estimated to be 1 in 200,000 children and adoles-
cents.1 As true hamartomas, they represent an aberrant devel-
opment of normal tissues. They are nonneoplastic with no
potential for growth after birth beyond that seen in normal
brain development. Hypothalamic hamartomas are usually
sporadic in nature and their exact embryological cause is uncer-
tain. Approximately 5% of patients with HHs have genetic
syndromes such as Pallister-Hall syndrome, Bardat-Biedl syn-
drome, Waardenburg syndrome, and oral–facial–digital syndro-
me. Approximately 15% of sporadic HH patients have somatic
(tumor only) mutations within GLI3, the gene that is also
responsible for Pallister-Hall syndrome.2 Despite their rarity,
HHs frequently give rise to an important epilepsy syndrome
that can have devastating consequences, is usually refractory to
drug therapy, and may be cured by surgical treatment including
radiosurgery.3
23.2 Histology and Physiology
Coons et al characterized the histopathological findings in 57
surgically resected HHs.4 All lesions were composed of histo-
logically normal small and large neurons, astrocytes, and
182
oligodendrocytes. The more numerous small neurons were
arranged in nodular clusters of varying size and density, inter-
mingled with and surrounded by the less numerous larger neu-
rons. Wu and colleagues have shown that the small neurons are
γ-Aminobutyric acid (GABA) ergic, and exhibit spontaneous
pacemaker-like firing.5 Large HH neurons, which are excitatory
projection-type neurons, have the functionally immature prop-
erty of depolarizing and firing in response to GABA ligands. 6,7
Depth electrode recordings by Munari et al first demonstrated
that the ictal discharges resulting in gelastic seizures arise from
the hamartoma itself.8 This observation has been duplicated by
other investigators and confirms the intrinsic epileptogenicity
of HHs. Based on these and other studies, Fenoglio et al have
proposed a model whereby the small spontaneously firing
GABAergic neurons synchronize the output of the normally qui-
escent larger pyramidal neurons.9 These in turn likely project to
extrahypothalamic sites such as the thalamus and hippocampus
to produce clinically apparent seizures (▶ Fig. 23.1).
23.3 Magnetic Resonance Imaging
Findings
Hypothalamic hamartomas are well visualized on high-resolu-
tion, thin-slice magnetic resonance images (MRIs), particularly
sagittal and coronal T2 fast spin-echo (FSE) images. Computed
tomography (CT) may demonstrate larger lesions, but is not ad-
equate to exclude small hamartomas. When compared with
normal gray matter, HHs are usually hyperintense on T2-
weighted images, and hypointense or isointense on T1 stud-
ies.10 In the absence of prior treatment, they rarely enhance in
response to the administration of intravenous gadolinium con-
trast, and any sign of enhancement should raise suspicion of an
alternative diagnosis.
23.4 Classification
Based on MRI findings, classification schemes for HHs have
been proposed by several authors. A comparison of these differ-
ent approaches is nicely summarized in an article by Mittal et
al.11 Arita et al distinguished intrahypothalamic hamartomas
that have a complete or partial base of attachment within the
third ventricle from parahypothalamic hamartomas, which are
attached only to the floor of the third ventricle.12 The most fre-
quently cited classification system is that of Delalande and Foh-
len (▶ Fig. 23.2).13 Under this classification, type I lesions are
those that arise below the third ventricle with a horizontal
plane of attachment to the hypothalamus. The attachment may
sometimes be narrow (pedunculated) or in other instances
broader (sessile). Type II lesions are completely within the third
ventricle and have a vertical plane of attachment to the hypo-
thalamus, usually clearly lateralized to either the right or left
side. Type III lesions occur above and below the floor of the
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

Fig. 23.1 Representation of cellular model for intrinsic epileptogenesis of hypothalamic hamartoma tissue. (a) The photomicrograph shows a cluster
of small neurons with hematoxylin and eosin staining. A single small neuron is indicated by the arrow, with loose nuclear material and dense nucleolus.
(b) The diagram represents a cluster of small neurons and two adjacent large neurons. Small neurons have intrinsic pacemaker-like firing and express
GABA as their main neurotransmitter. Large neurons, which are likely excitatory projection-type cells, have the functionally immature property of
depolarizing and firing in response to GABA. The network relationships between these cells are only partially understood. (Used with permission from
Barrow Neurological Institute.)

third ventricle and have both vertical and horizontal attach-
ments to the hypothalamus. Type IV hamartomas are “giant”
with broad attachments to the hypothalamus and mammillary
bodies, and frequently extend into the interpeduncular cistern.
Régis et al have advocated a somewhat different classification
scheme, which they feel helps to predict the most appropriate
surgical strategy (▶ Fig. 23.3).14 Régis type I lesions are located
inside the hypothalamus with a small projection into the third
ventricle. Type II lesions are predominately within the third
ventricle and have a vertical attachment to the wall of the third
ventricle. Type III abnormalities are located in the floor of the
third ventricle with close proximity to the mammillary bodies
and the columns of the fornix. Type IV lesions are located in the
interpeduncular cistern with a small sessile attachment to the
hypothalamus. Type V lesions are pedunculated, and connect to
the inferior hypothalamus by a thin stalk. Type VI abnormalities
are giant lesions that extend both above and below the floor of
the third ventricle. Hypothalamic hamartoma lesions that com-
bine features from types I to VI are classified as “Mixed” within
the Régis classification system.
23.5 Natural History
Gelastic seizures are the hallmark of epilepsy produced by HHs.
Trousseau in 1887 first recognized the possible epileptic nature
of compulsive bursts of laughter.15 Gascon and Lombroso
defined gelastic seizure as “stereotypic recurrence of ictal
laughter, inadapted to context, associated with other signs
compatible with seizure and with ictal/interictal EEG
abnormalities.”16 They are typically brief, lasting seconds, but
may occur repeatedly throughout the day. Gelastic seizures
usually begin during infancy or childhood, although they may
not be recognized as such until later in life. Some patients have
clinical events that more closely resemble crying than laughing;
these events have been termed dacrystic seizures. Over time, a
majority of patients develop other seizure types, including com-
plex partial seizures, generalized tonic-clonic seizures, tonic
seizures, and drop attacks. In older individuals, these alternate
seizure types may predominate, and gelastic seizures may
become less frequent or stop all together. These observations
have given rise to the concept of secondary epileptogenesis, in
which the presence of one seizure focus causes the emergence
of an independent seizure focus from a distant and previously
normal brain region.17 Secondary epileptogenesis may be rever-
sible when the original focus in the HH is excised or discon-
nected, or it may become permanent over time. This concept
may explain why some HH patients with an apparently com-
plete surgical resection of their lesion continue to have seiz-
ures.18 The success rate of HH treatment for controlling seizures
has an inverse correlation with patient age and lifetime dura-
tion of epilepsy at the time of surgery.19,20
A majority of patients with intrahypothalamic HHs demon-
strate significant cognitive impairment. Prigatano et al per-
formed neuropsychological assessments on 49 patients with
intractable seizures who were undergoing a presurgical evalua-
tion and who varied in age from 5 to 55 years.21 Of the total
group, 35% had no significant deficits and were functioning at a
normal or near-normal intellectual level, 18% had deficits in

183
 Stereotactic Radiosurgery for Hypothalamic Hamartomas
certain test subscores but were considered to be within the nor-
mal range of overall intelligence, and 47% were intellectually
disabled. Despite the prevalence of cognitive and developmen-
tal delays, not all patients were affected, and there was a con-
tinuous spectrum varying from severe retardation to those with
normal or above-average intelligence.
Many patients with HHs and intractable seizures also exhibit
behavioral and emotional difficulties. These include affective
disorders, emotional lability, rage attacks, temper tantrums,
and destructive or aggressive behavior directed against them-
selves or others.22 This can be a source of extreme frustration
for parents and other family members. As with cognitive func-
tion, there is a wide range in the degree to which behavioral
and mood issues manifest themselves in any given patient.
Some infants and young children who present with gelastic
seizures will develop worsening seizures and progressive intel-
lectual and behavioral deteriorations as they mature. This
downhill course has been termed epileptic encephalopathy. Both
secondary epileptogenesis and epileptic encephalopathy are
strong reasons to consider early surgical intervention in HH
patients with intractable seizures before irreversible changes
occur.18
Central precocious puberty may be present in as many as 40
to 50% of patients with HHs.3 Pedunculated hamartomas
184
Fig. 23.2 Hypothalamic hamartoma classification
system as proposed by Delalande and Fohlen.
Type I lesions have a horizontal base of attach-
ment below the plane of the floor of the third
ventricle. Type II lesions have a vertical base of
attachment above the floor of the third ventricle.
Type III lesions are typically larger, with attach-
ment both above and below the floor of the third
ventricle (or the normal position of the floor, if it
can no longer be visualized). Type IV lesions are
characterized as “giant” lesions, although the size
boundary between III and IV remains undefined.
Types III and IV often have bilateral attachment to
the hypothalamus. (Used with permission from
the Barrow Neurological Institute.)
connected to the inferior aspect of the hypothalamus (parahy-
pothalamic lesions of Arita et al and type V lesions of Régis
et al)12,14 usually have precocious puberty as their only clinical
manifestation, and are rarely associated with epilepsy, cognitive
impairment, or behavioral abnormalities. They can be treated
medically with gonadotropin-releasing hormone agonists and
usually do not require surgery. Parvizi et al analyzed MRIs in
100 patients with gelastic seizures23; Chan et al reviewed scans
in seven patients with precocious puberty.24 These two studies
indicate that patients whose lesions are attached to the anterior
region of the hypothalamus exhibit precocious puberty, where-
as those whose lesions are attached only to the posterior hypo-
thalamus near the mammillary bodies have epilepsy alone.
Patients with large hamartomas with anterior and posterior
hypothalamic attachment often have both epilepsy and preco-
cious puberty.
23.6 Surgical Treatment
Because seizures resulting from HHs are almost always refrac-
tory to medical therapy and may over time lead to secondary
epileptogenesis and epileptic encephalopathy, surgery is war-
ranted in all but the mildest forms of this disorder. This is true
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

Fig. 23.3 Hypothalamic hamartoma classification system proposed by Régis. Type I lesions are located inside the hypothalamus with a small projection
into the third ventricle. Type II lesions are predominately within the third ventricle and have a vertical attachment to the wall of the third ventricle. Type
III abnormalities are located in the floor of the third ventricle with close proximity to the mammillary bodies and the columns of the fornix. Type IV
lesions are located below the floor of the third ventricle with a broad attachment to the hypothalamus. Type V lesions are pedunculated, and connect
to the inferior hypothalamus by a thin stalk. Type VI abnormalities are giant lesions that extend both above and below the floor of the third ventricle.
Hypothalamic hamartoma lesions that combine features from types I to VI are classified as “Mixed” within the Régis system. (Used with permission
from the Barrow Neurological Institute.)

185
 Stereotactic Radiosurgery for Hypothalamic Hamartomas
despite the significant risks of surgical intervention. There are
no randomized studies evaluating the various surgical
approaches that have been utilized, and given the rarity of HHs,
evidence of this type is unlikely to be available in the foresee-
able future.3 Comparing uncontrolled surgical series with one
another is made difficult by the often significant differences in
lesion size, anatomical location, patient age, and preoperative
neurologic status. For these reasons, dogmatic statements
about the “best” surgical option for HHs are not appropriate. In
general, open surgical approaches for lesions within the third
ventricle are done from above, through the third ventricle.
Hamartomas attached to the floor of the hypothalamus can be
accessed from below using pterional, orbitozygomatic, or sub-
frontal approaches. Larger lesions that have planes of attach-
ment both within and below the third ventricle may require
combined approaches from above and below. When feasible,
complete surgical resection is the optimal strategy, but good
seizure control can also be achieved by disconnecting the lesion
from the hypothalamus, even though a portion of the hamarto-
ma remains in place. Stereotactic approaches, including radio-
surgery, are usually confined to abnormalities less than 2 to
3 cm in maximum diameter.
23.6.1 Open Surgical Procedures
Rosenfeld and his colleagues in Melbourne pioneered the use of
a transcallosal anterior interforniceal approach for intrahypo-
thalamic hamartomas.25 Their experience involved 29 patients
ranging in age from 4 to 23 years, who were followed for a min-
imum of 12 months. A complete or near-complete resection
was obtained in 62%, and a 75 to 95% resection was achieved in
an additional 24%. All patients exhibited both gelastic and other
seizure types preoperatively, and 52% became seizure-free after
surgery. Another 24% had a greater than 90% reduction in seiz-
ure frequency. Due to the surgical dissection and retraction
required to visualize the third ventricle, the transcallosal
approach may potentially injure the columns of the fornix and
therefore cause short-term memory impairment. In the Rose-
nfeld series, 14% of patients had permanent short-term memo-
ry deficits, and nearly 50% had temporary impairments. Other
significant complications included hypernatremia secondary to
syndrome of inappropriate antidiuretic hormone secretion
(SIADH), which was transient in all cases, and hyperphagia with
weight gain, which was permanent in 17%.
Ng et al reported on 26 patients who underwent transcallosal
interforniceal HH resections at Barrow Neurological Institute
(Phoenix, AZ), with findings similar to those of the Rosenfeld
group.19 Complete seizure control was achieved in 54% of their
patients, and an additional 35% had at least 90% fewer seizures.
Persistent short-term memory disturbances were seen in 8% of
their patients, and transient deficits in 58%. Other permanent
complications included diabetes insipidus, hypothyroidism,
hemianopsia, and communicating hydrocephalus (occurring in
one patient each).
Fohlen et al were among the first to advocate a transventricu-
lar endoscopic approach to HHs, either to resect them com-
pletely or to disconnect their hypothalamic attachment. 26 Ng et
al have reported the largest series using this technique.27 Forty-
two patients were treated and 37 were available for long-term
follow-up; the age range for this cohort was 8 months to 55
186
years. A complete lesion resection was obtained in 12 patients.
Seizures were reduced by more than 90% in 70% of patients,
and 49% of patients were seizure-free. Postoperative MRIs
showed small thalamic infarcts in 11 patients, although only 2
were symptomatic with transient hemiparesis. The incidence of
permanent short-term memory impairment was 8%.
Pterional or orbitozygomatic approaches to intrahypothala-
mic hamartomas result in poor seizure control rates,28 but they
may be helpful for lesions with an inferior or horizontal plane
of attachment to the hypothalamus (Delalande type I). Abla et
al reported their results in 10 such patients, 2 of whom had
combined orbitozygomatic and transventricular procedures for
hamartomas both above and below the floor of the third ven-
tricle.29 Complete seizure control was achieved in four patients
(40%) and seizure frequency decreased by more than 50% in an
additional four patients (40%). Residual complications included
diabetes insipidus, visual deficit, and hemiparesis in one patient
each.
Many investigators have noted a higher rate of complications
and a lower degree of seizure control in older patients com-
pared with pediatric patients undergoing open surgical resec-
tion. For example, Drees et al examined 40 patients 18 years of
age or older who underwent endoscopic, transcallosal, orbito-
zygomatic, or Gamma Knife stereotactic radiosurgery (GKSRS)
of their lesions.30 There were two postoperative deaths, and
one patient suffered a permanent hemianopia. Persistent hor-
monal deficits were seen in 34% of patients, and 59% experi-
enced a postoperative weight gain that averaged 12.7 kg. Only
29% of the total group became seizure-free, and 55% had a
greater than 90% seizure improvement. Of the four patients
who elected radiosurgical treatment, two became seizure-free
and none experienced a permanent complication.
23.6.2 Stereotactic Procedures
A variety of stereotactic procedures for treating HHs have been
developed in the hope that these less invasive techniques might
offer a lower risk alternative to open surgical resection.
Schulze-Bonhage et al treated 24 patients with gelastic epi-
lepsy by stereotactically implanting a single radioactive seed
into hamartomas with a mean volume of 1.2 cc, a procedure
they called interstitial radiosurgery.20 At a mean follow-up of 24
months, 46% of patients were seizure-free or had > 90%
decrease in the seizure frequency. More than half of their
patients (54%) underwent a second seed implant from 1 to 2.4
years after the initial treatment. Permanent complications
included memory decline in two patients and weight gain of
more than 5 kg in four patients.
Kameyama et al treated 24 patients with HHs and gelastic or
mixed epilepsy by stereotactically inserting radiofrequency
(RF) thermocoagulation probes into the lesions.31 The electro-
des had an uninsulated tip 2 mm in length and were heated to a
temperature of 74°C for 60 seconds. Multiple tracks (mean 3.8,
range 1–8) and multiple lesions along the same track were used
in most instances. Complete seizure freedom was achieved in
76% of their patients, and no long-term complications were
noted. These outcomes are superior to any reported for open
surgical procedures. They are particularly noteworthy because
of the size of the treated hamartomas (mean diameter 15.3 mm,
range 8–30 mm), and the apparent absence of any permanent

hemorrhagic complications despite the large number of elec-
trode tracts employed. No other investigators have duplicated
this very favorable experience in a similar number of patients.
Recently, there has been considerable interest in the use of
stereotactic laser ablation (also called laser interstitial thermal
therapy) to treat HHs. For this procedure, a thin diode laser
catheter is inserted into the hamartoma using MRI and stereo-
tactic techniques. Laser energy deposited into the surrounding
tissues heats the tissues locally and results in necrosis by ther-
mocoagulation. The extent of the thermal injury zone can be
viewed in near real time using MRI thermography, and a feed-
back loop can monitor temperatures in adjacent structures such
as the optic chiasm or mamillary bodies to shut off the laser if
predetermined temperatures are exceeded. Laser stereotactic
ablation has the potential to be less invasive and have a lower
risk than open surgery, be more precise than RF thermal abla-
tion, and produce a more rapid therapeutic response than SRS.
Curry and his colleagues have accumulated the largest expe-
rience using stereotactic laser ablation for HHs, although a
number of other centers are also actively investigating this
technique.32 They have reported 14 patients with medically
intractable gelastic epilepsy treated with stereotactic laser abla-
tion.31 Seizure freedom was achieved in 86% with a mean fol-
low-up of 9 months. A single patient sustained an
asymptomatic subarachnoid hemorrhage, but no permanent
neurologic or endocrine deficits were seen. Despite these prom-
ising initial results, not enough patients have been treated to
date to assess the true complication rate of this procedure, and
the published follow-up intervals are still too short to deter-
mine the incidence of long-term seizure control.
Stereotactic Radiosurgery
Hypothalamic hamartomas are appealing targets for SRS
because of their small size; their distinct borders, which can be
precisely imaged on MRIs; and their deep-seated locations,
which make open surgical approaches difficult. In 1998, Arita et
al were the first to describe the successful Gamma Knife radio-
surgical treatment of gelastic epilepsy in a 25-year-old man
with a small hamartoma.33 Their patient was seizure-free at a
21-month follow-up interval and sustained no new neurologic
or endocrine deficits. Interestingly, an MRI 12 months post-
treatment showed complete disappearance of the lesion—
something that has not been reported in subsequent series.
The acknowledged leaders in this field are Jean Régis and
his coworkers in Marseille, France. They have reported 60
patients with HHs treated with a 201-source cobalt-60 Gam-
ma Knife unit.14,34 Twenty-seven patients were available for
detailed prospective analysis with a minimum of 3-year fol-
low-up. In this group, median age at the time of treatment
was 17.25 years (range 3–50 years), and the median maxi-
mum lesion diameter was 11.7 mm (range 7.2–25 mm). The
median radiation dose delivered to the margins of the hamar-
tomas was 17 Gy (range 13–26 Gy), usually prescribed to the
50% isodose line. Beam-blocking strategies were used to mini-
mize dose to the optic pathways, mammillary bodies, and for-
nices. The median maximum doses to the optic chiasm, optic
tract, and mammillary bodies were 3.7 Gy (range 3–12.2 Gy),
6.4 Gy (range 3–12.2 Gy), and 18.6 Gy (range 0.9– 2.2 Gy),
respectively.
Stereotactic Radiosurgery for Hypothalamic Hamartomas
Complete seizure control was obtained in 37% of their
patients, and 22% had only rare nondisabling seizures. Nearly
all patients exhibited improvement in behavior, school per-
formance, and quality of life (QoL) as determined by parental or
patient reports and the subjective observations of the treating
group. Postoperative MRIs showed that the lesions were
unchanged in the majority of patients, with two patients show-
ing a slight decrease in the size of their lesion. Repeat radiosur-
gery was performed in nine patients who did not experience
complete seizure abatement after 3 years, although no details
were given about the radiation doses utilized for these second
procedures.
The main drawback of SRS noted in this and all other series is
the long latency period between treatment and the final effect.
Régis et al described a typical five-stage response pattern
occurring over a minimum of 2 years.14,34 In the first phase,
patients experienced an immediate mild improvement in
behavior, and seizure frequency and severity. By an average of 2
to 6 months posttreatment, seizures had returned to their pre-
operative state, although they were sometimes briefer in dura-
tion. During the third phase, seizures suddenly increased in
frequency. This period lasted several days up to 1 month, and
was followed by a fourth phase in which seizures gradually
diminished. The fifth phase was considered a consolidation
period leading to complete seizure freedom. Although there
were individual variations in these patterns, patients or their
parents need to be aware that seizures may increase in fre-
quency before they eventually subside, and that 2 to 3 years
may be required to see the full effects of radiosurgical
treatment.
The Marseille group emphasized the use of their topologi-
cal classification system to determine which patients were
best treated with GKSRS versus surgical options. They felt
that type I and type II lesions were the optimal candidates
for radiosurgery because of its superior safety profile com-
pared with endoscopic or interforniceal transcallosal resec-
tion. They also preferred radiosurgery for small- to medium-
size type III abnormalities unless seizures were rapidly pro-
gressive. Type IV and type V (rarely epileptogenic) hamarto-
mas could be treated with either GKSRS, or pterional or
orbitozygomatic disconnections, depending on the size of the
lesions and the severity of the seizures. They did not recom-
mend radiosurgery as a primary treatment for type VI
lesions, but they did advocate it as a second procedure after
surgical resection if some hamartoma remained and seizures
persisted.
Several other centers have reported their experience using
the Gamma Knife for HHs in smaller series of patients, with
results that generally parallel those of Régis et al (▶ Table 23.1).
Abla et al described 19 patients treated at the Barrow Neurolog-
ical Institute from 2003 to 2010.35 Ten patients were available
for long-term follow-up (mean 43 months, range 18–81
months) sufficient to permit an assessment of their outcomes.
The mean age in this group was 15.1 years (range 5.7–29.3
years), and the mean lesion volume was 695 mm3 (range 169—
3000 mm3). The median margin dose prescribed to the 50% iso-
dose line was 18 Gy (range 16–20 Gy). Six patients became free
of seizures, although two of these patients underwent endo-
scopic resections 14.5 and 32 months after their GKSRS. Tele-
phone interviews or patient surveys documented improvement
187
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

Table 23.1 Hypothalamic hamartoma treatment with Gamma Knife radiosurgery

Study N Age (y) Margin dose Lesion volume Follow-Up Outcome Side effects
(Gy) (mm3) (mo)

Régis et al, 200614 27a 17.25 17 646.7 > 36 37% Seizure-free; 11% transient poikilother-
(Median) (Median) (Median) 22% rare seizure; mia
improved behavior
60%

Abla et al, 201029 10b 15.1 18 695 43 60% Seizure-free 1 Patient transient poikilo-
(Mean) (Mean) (Mean) (Mean) thermia; 2 patients tempo-
rary weight gain

Barajas et al, 200538 3 3, 12, 15 12.5, 14, 15 530, 591, 1800 30–50 All improved, none None
seizure-free

Mathieu et al, 200637 4 5–29 17.5 370 22 2/4 Rare seizures None
(Mean) (Mean) (Median)

Mathieu et al, 201036 9 12–57 14–20 300–1800 6–56 4/9 Seizure-free; None
(Range) 1/9 rare seizure;
improved verbal
memory and QoL

Abbreviation: QoL, quality of life.

aSixty patients were followed prospectively; 27 with > 3-year follow-up data.
bTwenty-six patients treated; 10 with adequate follow-up data.

in overall QoL in nine patients, and improvement of behavioral
symptoms in five patients.
Mathieu et al treated six patients with small HHs (with a vol-
ume of 0.3 to 1.0 cc) using margin doses of 14 to 20 Gy. 36 Four
of these became seizure-free, and an additional patient had
seizures only rarely after treatment. They also treated three
larger lesions (Régis type IV or VI) by targeting their area of
attachment to the hypothalamus in an attempt to produce a
radiosurgical disconnection. None of these patients had worth-
while seizure reduction, and they did not recommend this
strategy for future use.
The University of Pittsburgh (Pittsburgh, PA) group37 treated
four patients with HHs varying from 0.20 to 0.55 cc in volume
with margin doses of 16 to 20 Gy. No individuals became com-
pletely seizure-free, but two exhibited rare persistent seizures
following radiosurgery.
Barajas et al reported their results in three HH patients using
lower margin radiation doses (12.5, 14, and 15 Gy) than other
centers.38 All patients had cessation of their tonic–clonic seiz-
ures; gelastic seizures persisted, although at a reduced rate.
A small number of HH patients have received SRS using lin-
ear accelerator (linac)-based devices rather than the Gamma
Knife. Selch et al treated three patients using 15 to 18 Gy mar-
gin doses prescribed to the 90 to 95% isodose line.39 With fol-
low-ups of 9 to 17 months, two patients were free of seizures
and the third had only rare seizures. Papayannis et al treated
four patients with doses of 12 to 18 Gy, none of whom had
any worthwhile seizure reduction.40 There is insufficient infor-
mation at present to judge whether linac-based radiosurgery
can produce comparable results to those documented for
GKSRS.
23.6.3 Radiosurgical Complications
The outstanding advantage of GKSRS for HHs is its very low
complication rate relative to open surgical resection. In the five
Gamma Knife series referred to above, there were no instances
of death, visual deficits, cognitive or short-term memory
decline, endocrine dysfunction, permanent weight gain, or
paresis. All of these complications have been described to some
degree in surgical series using endoscopic, transcallosal, and
pterional approaches. Transient morbidity has been seen in a
few patients undergoing radiosurgical treatment and has
included poikilothermia (four patients) and hyperphagia with
weight gain (two patients). The absence of permanent short-
term memory loss following GKSRS is a particularly important
consideration in older patients or those functioning at a normal
level preoperatively.
A single institution using stereotactic RF thermocoagulation
has also reported no long-term cognitive or endocrine deficits
using their technique.31 Complication rates following stereotac-
tic laser ablation have been low as well, but experience with
this procedure is still preliminary.32
Visual loss as a side effect of GKSRS for HHs has not been
reported to date, but this is a potential concern because of the
often close proximity of these lesions to the optic chiasm and
optic tracts and the known radiosensitivity of the optic path-
ways. In patients who have not had prior external beam radia-
tion therapy, the risk of radiation-induced optic neuropathy
following SRS is 0 to 2% if dose to the optic apparatus is 10 Gy or
less, and still low at a dose of 12 Gy or less.41 These limits need
to be respected when treating HHs, even if to do so may result
in slight under treatment of the lesion itself.
The possibility that ionizing radiation may induce secondary
benign or malignant tumors is always a concern when treating
children or young adults with an anticipated life span of many
decades. There are radiobiological reasons to believe the inci-
dence of secondary oncogenesis will be much lower using
single-session SRS than that reported for conventional fractio-
nated radiotherapy.42 Lunsford has estimated the risk of devel-
oping a secondary tumor after radiosurgery at < 1 in 20,000
treated patients.43 Despite the unlikelihood of such an event,

188
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

patients or their parents need to be informed of this possible
complication.
23.6.4 Gamma Knife Radiosurgical
Techniques
With minor modifications, Gamma Knife radiosurgical tech-
niques for treating HHs are identical to those for other small
lesions in vital locations (e.g., vestibular schwannomas). The
procedure may need to be performed under general anes-
thesia in younger patients at the discretion of their parents
and treating physicians. We have found it helpful to angle
the stereotactic frame forward from back to front in an
attempt to place the entire extent of the optic pathways and
the hamartoma in the same imaging plane. Coronal and
axial MRIs are obtained using 1-mm-thick T1 SPGR (spoiled
gradient echo) and 2-mm-thick T2 FSE sequences. The optic
pathways and the hamartoma are outlined, and small colli-
mator shots (usually 4 mm) are employed to conform the
50% isodose line as closely as possible to the margins of the
lesion. We believe the Leksell Gamma Knife Perfexion unit
(Elekta Instruments AB, Stockholm, Sweden) has significant
advantages over earlier Gamma Knife models because it
facilitates the use of multiple treatment isocenters and
allows composite shots that enable custom blocking
patterns.
Although successful seizure control has been reported
with lower doses, most centers have advocated a HH mar-
gin dose of 18 Gy or higher if at all possible. There is still
some uncertainty about the optimal treatment dose for
these lesions that represents the best compromise between
safety and efficacy. However, maximal dose to the optic
pathways should be kept below 10 Gy. We also try to mini-
mize radiation to the mamillary bodies and fornices,
although the radiation tolerance of these structures is not
well understood.
Examples of typical treatment plans for two HHs treated at
our institution are shown in ▶ Fig. 23.4 and ▶ Fig. 23.5.
23.6.5 Mechanism of Action
The radiobiology and pathophysiology of the treatment effect
on HHs treated by GKSRS is not well understood. The neuropa-
thology of surgically resected HH tissue in patients with a pre-
vious history of GKSRS was compared with surgically resected
tissue from a cohort of patients with no history of radiosur-
gery.44 Tissue necrosis was not observed. When examined with
thick-section stereology, the total nucleated cell density in
GKSRS-treated HH tissue was significantly lower than in
untreated tissue. Total neuron density was lower in a GKSRS-
dose-dependent fashion in a manner that approached signifi-
cance (p = 0.06). Gamma Knife stereotactic radiosurgery-treated

Fig. 23.4 A 39-year-old woman with gelastic seizures since early childhood was undiagnosed until age 21 when she experienced a generalized seizure.
Her generalized seizures were controlled by medications, but she continued to experience multiple daily gelastic seizures. Lesion volume was
297 mm3. She was treated using a margin dose of 18 Gy to the 50% isodose line via six isocenters using 4-mm collimators and custom beam blocking.
The lesion was classified as a Delalande type II. (Used with permission from the Barrow Neurological Institute.)

189
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

Fig. 23.5 A 10-year-old boy with daily gelastic seizures since age 5 and rare generalized seizures. His precocious puberty was treated with Lupron
(AbbVie, Inc., North Chicago, IL). He exhibited behavioral difficulties and possible cognitive decline. Lesion volume was 431 mm 3. He was treated using
a margin dose of 18 Gy to the 50% isodose line via 10 isocenters using 4-mm collimators and custom beam blocking. The lesion was classified as a
Delalande type III. (Used with permission from the Barrow Neurological Institute.)

tissue exhibited significant increases in reactive gliosis, endo-
thelial thickening, and microglial activation. These results sug-
gest that nonnecrotizing doses of GKSRS act in part by
mediating cell death, rather than by playing a purely neuromo-
dulatory role, and that they therefore contribute to the
decreased excitation in the neuronal network that is responsi-
ble for seizures in HH tissue.
23.7 Summary
Gamma Knife stereotactic radiosurgery is an effective and safe
treatment modality for patients with HH associated with
intractable epilepsy. It should be part of the treatment arma-
mentarium of any center that claims expertise in treating this
disorder.
Hypothalamic hamartomas result in diverse clinical symp-
toms and a complicated natural history that includes disability
and deterioration in most patients with concomitant epilepsy.
These patients are best managed by a multidisciplinary team
experienced in managing this rare and clinically significant
condition.
The treatment algorithm that guides clinical decision mak-
ing at our institute is shown in ▶ Fig. 23.6. The clinical feature
most favorable to selecting GKSRS is clinical stability of the
patient in terms of seizure type and frequency. This is a
highly individualized determination that must take into
account not just the absolute number of seizures, but also the
severity of the type of seizure and the impact of the seizure
activity on the patient’s and family’s QoL. When the patient’s
seizures are well tolerated and the patient is otherwise stable
with respect to cognitive function and behavior, then the
delay in efficacy is acceptable and a treatment decision favor-
ing GKSRS is appropriate to take advantage of its superior
safety profile. From our perspective, treatment decisions can
and should be revisited if clinical conditions deteriorate,
favoring the use of one of the surgical therapies with imme-
diate efficacy (surgical resection/disconnection or lesion
destruction by stereotactic thermoablation) even if GKSRS
was previously performed. Régis et al have advocated a sec-
ond Gamma Knife treatment after 3 years in patients who
improve following an initial procedure, but are not com-
pletely seizure-free. There are no reports from other centers
utilizing this strategy; to date we have preferred to consider
alternative approaches if the first Gamma Knife treatment is
unsuccessful.
We believe that GKSRS is an attractive treatment modality
for those patients who have undergone surgical resection, but
have residual HH tissue. This situation is not uncommon, as the
surgical margin between normal hypothalamus and HH tissue
is not always obvious, even under direct visualization with
assistance from intraoperative neuronavigation systems: The
surgeon should err on the side of conservative (rather than
overly aggressive) resection to minimize injury to normal
hypothalamus.

190
 Stereotactic Radiosurgery for Hypothalamic Hamartomas

Fig. 23.6 Treatment algorithm for hypothalamic hamartoma. This algorithm is based upon the surgical anatomy of the hypothalamic hamartoma as
classified by the system proposed by Delalande and Fohlen (types I through IV). 13 This approach is utilized at our institution (Barrow Neurological
Institute, Phoenix, AZ) as a guide to treatment decision making. The algorithm was developed on the basis of expert opinion and the available
literature as discussed in this chapter. Controlled, randomized treatment trials do not exist. Decision making should always be individualized to the
clinical circumstances of each patient and the experience of the local institution. Ideally, patients should be evaluated and treated at hypothalamic
hamartoma referral centers with established multidisciplinary programs. Hypothalamic hamartoma type is based on the Delalande classification.
(Used with permission from the Barrow Neurological Institute.)

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[40] Papayannis CE, Consalvo D, Seifer G, Kauffman MA, Silva W, Kochen S. Clinical
spectrum and difficulties in management of hypothalamic hamartoma in a
developing country. Acta Neurol Scand 2008; 118: 313–319
[41] Leavitt JA, Stafford SL, Link MJ, Pollock BE. Long-term evaluation of radiation-
induced optic neuropathy after single-fraction stereotactic radiosurgery. Int J
Radiat Oncol Biol Phys 2013; 87: 524–527
[42] Rowe J, Grainger A, Walton L, Silcocks P, Radatz M, Kemeny A. Risk of malig-
nancy after gamma knife stereotactic radiosurgery. Neurosurgery 2007; 60:
60–65, discussion 65–66
[43] Lunsford L.D. In discussion of: Rowe J, Grainger A, Walton L, Silcocks P, Radatz
M. Risk of malignancy after Gamma Knife stereotactic radiosurgery. Neuro-
surgery 2007; 60:60–66
[44] Kerrigan JF, Parsons A, Rice SG, et al. Hypothalamic hamartomas: neuropa-
thological features with and without prior gamma knife radiosurgery. Stereo-
tact Funct Neurosurg 2013; 91: 45–55

24 Stereotactic Radiosurgery for Epilepsy
Mark Quigg and Nicholas M. Barbaro
Key Points
● The anticonvulsant effect of stereotactic radiation has both
modulatory, nondestructive components and destructive, le-
sional components; in successful radiosurgery, focal ischemia
and neuronal destruction of the epileptic target
predominate.
● Treatment of space-occupying lesions that have epilepsy as a
symptom—tumors or arteriovenous malformations—with
Gamma Knife radiosurgery results in high rates of seizure
remission along with treatment of the lesion.
● Gamma Knife radiosurgery appears to be a reasonable option
for minimally invasive surgery for the gelastic seizures associ-
ated with hypothalamic hamartoma.
● Gamma Knife radiosurgery for the syndrome of mesial tem-
poral lobe epilepsy is safe, and in some studies has been
shown to have efficacy similar to that of open surgery,
although worse outcomes have been associated with differ-
ences in dose or patient selection.
24.1 Introduction
In association with epilepsy, stereotactic radiosurgery (SRS) is
most often used in the treatment of epileptic lesions such as
tumors or vascular malformations; epilepsy in these cases is
often one of several presenting symptoms and frequently
improves as a benefit of the treatment of the lesion. Recently,
the use of SRS has expanded into the treatment of physiological
lesions such as seen in mesial temporal lobe epilepsy or pre-
viously inoperable epileptic lesions such as hypothalamic
hamartomas. In this chapter, we outline the radiosurgical
management of epilepsy.
24.2 Experimental Models and
Mechanisms of Radiation
A coherent mechanism has not been demonstrated that
accounts for the anticonvulsant—and occasionally, proconvul-
sant—effects of SRS. Fundamental to SRS is the stripping of elec-
trons called ionization, resulting in the alteration of chemical
bonds or the production of free radicals.1,2 Susceptibility to ion-
ization is proportional to DNA synthesis. Neurons, therefore,
are relatively radioresistant; actively proliferating cells, such as
capillary cells, are radiosensitive. Ionizing radiation also dam-
ages glial cells such as oligodendroglia that produce myelin and
astrocytes.3 Furthermore, although animal models of epilepsy,
usually rats, are helpful in evaluating mechanisms, rat brains
are remarkably radioresistant, and “scaling up” directly to
humans to predict dose is not straightforward.
Hypotheses of the pro- and anticonvulsant effects of SRS fall
into two basic camps: neuromodulation and tissue necrosis.
Studies with rat models of limbic epilepsy emphasize that an
Stereotactic Radiosurgery for Epilepsy
anticonvulsant effect may arise from a nondestructive, neuro-
modulatory effect. For example, a dose-dependent reduction in
seizures was shown in kainic-acid-treated epileptic rats4,5,6 and
in electrical-stimulation epileptic rats7 despite the lack of gross
neuronal injury. Cognitive functions were spared; for example,
water maze performance was unimpaired after treatment.5,6
Experiments with kindled animals demonstrate that SRS may
alter seizure threshold through mechanisms of plasticity and
repair.8 For example, if brain irradiation is introduced before,
during, and after a kindling protocol, seizure thresholds are
worsened before kindling, unaffected at midkindling, and
reduced at the final stage of kindling. Thus, kindled epileptic
tissue may lack plasticity and the ability to recover from irradi-
ation, whereas the recovery process in normal tissue may ren-
der circuits hyperexcitable.
Neuromodulatory effects, however, may not be entirely bene-
ficial. Sometimes proconvulsant effects are observed, as out-
lined in the above animal experiments in which kindled
seizures worsened in animals treated before kindling compared
with those treated after kindling.8 This point is emphasized by
results of low-dose human protocols—designed to emulate non-
destructive doses in animal models—that demonstrated transi-
ent exacerbations in auras or sometimes complex partial
seizures.8,9 Other studies have explored, in a preliminary fash-
ion, if differential susceptibility to irradiation or ischemia
among different neuronal populations—excitatory versus inhib-
itory populations—within epileptogenic circuits occurs.9
Although neurons are resistant to radionecrosis, mitotically
active structures—vasculature and glia—are not. The other main
hypothesis, therefore, is that neuronal destruction results from
ischemia caused by radiation vasculitis. Accordingly, the major
pathological findings following focal radiation consist of endo-
thelial damage.10 Rat brains treated with SRS at 75 Gy and
examined 3 months later have, through the method of vascular
casting, a markedly decreased vascular density.11 Electron
microscopy demonstrates thickening of the vascular basement
membrane. These vascular changes precede development of
necrosis within the radiosurgical target.
Treatment of human mesial temporal lobe epilepsy demon-
strates that radionecrosis in the surgical target corresponds
with successful treatment of seizures. Magnetic resonance
imaging (MRI) and mass spectroscopy12 data from the U.S. Mul-
ticenter Pilot Study show that the volume of contrast enhance-
ment and T2 hyperintensity seen on MRI obtained 12 months
after SRS correlate strongly with outcome. No patients with T2-
weighted volumes of edema less than 200 mL at 12 months
went on to experience seizure remission between 24 and 36
months.12 Furthermore, magnetic resonance spectroscopy
(MRS) within the target showed evidence of frank ischemia;
one year after SRS, lactate (evidence of anaerobic metabolism)
appeared; choline, creatine, and N-acetylaspartate (NAA) levels
(evidence of normal neuronal activity) were largely absent. 12
Similar findings of decreased markers of neuronal activity were
observed with MRS greater than 1 year after SRS in a trial of six
patients (without seizure responses results reported).13
193
 Stereotactic Radiosurgery for Epilepsy
Histopathology of epileptic targets in humans is difficult to
interpret because tissue is obtained from failed rather than suc-
cessful SRS in the course of a “rescue” open surgery. For exam-
ple, patients who underwent open surgery after failed SRS
demonstrated hippocampal sclerosis and “radiational changes”
in operative samples14 or changes thought to be confined to
“normal” hippocampal sclerosis.15
In the U.S. Multicenter Pilot Study, one patient who under-
went temporal lobectomy for steroid-dependent symptoms
(and who was seizure-free for ~ 3 months before open surgery)
was found to have hippocampal sclerosis as well as evidence of
chronic infarcts with prominent hyalinization, thickening, and
closure of small vessels. Similar findings—necrosis with evi-
dence of vascular damage—were seen in four patients who had
anterior temporal lobectomy (ATL) between 18 and 22 months
after SRS.16 Therefore, limited data from human histopathology
show a range of findings from no changes to ischemic changes
after failed SRS.
In summary, the two mechanisms discussed above, neuro-
modulation and neuronal destruction, may not be mutually
exclusive. We will see below that SRS of mesial temporal lobe
epilepsy helps to define a therapeutic window of treatment
dose bounded by ineffectiveness, paradoxical exacerbation, or
delayed remission at the lower doses and by effective tissue
destruction at higher doses.
24.3 Treatment of Lesional
Epilepsy
In other chapters of this book, the details of SRS for mass lesions
are reviewed; in this chapter, we briefly discuss the anticonvul-
sant effects of SRS for these lesions.
24.3.1 Epileptogenic Tumors
Given the variety of types, pathology, and locations of central
nervous system (CNS) tumors, the studies on effects of SRS on
tumor-associated epilepsy are few. However, Schröttner et al
concentrated on the dose absorbed by tissue in tumor penumb-
ra, dividing patients into two groups according to the volume of
tissue outside the tumor that had received 10 Gy or more.17
Outcome was retrospectively ranked at mean duration of
approximately 2 years into excellent (Engel class I–II) or not.
High-volume patients achieved a 66% improvement rate com-
pared with 42% for the low-volume group. Because all patients
achieved tumor control with SRS (thus removing tumor res-
ponse as a confounder), the differing rates of seizure improve-
ment suggest that higher SRS volumes delivered to tumor
penumbra are important in modifying tumor-associated
epilepsy.
24.3.2 Arteriovenous Malformations
The potential efficacy of SRS in the treatment of symptomatic
localization-related epilepsies is most evident in the treatment
of arteriovenous malformations (AVMs), with an across-study
mean seizure remission rate of 70%.18–22 Representative is the
large series accumulated by Steiner et al who reported that
seizures remit after SRS in 69% of patients with AVM and
194
epilepsy.19 A later study22 described dose-volume effects on
epileptogenic AVMs opposite to that reported for epileptogenic
tumors in that seizure remission is better with smaller AVMs 22;
the amount of radiation to the margin had no clear effect. Nei-
ther study found a relationship between obliteration of the
AVM and seizure remission.19,22
24.3.3 Cavernous Malformations
The enthusiasm for the use of SRS for cavernous malforma-
tions (CMs) remains mixed. The across-study proportion of
seizure remission reported in retrospective case series is
50%.23 Remission is associated with higher doses. Represent-
ing the extremes in efficacy, Shih et al 24 reported mean mar-
ginal doses of 13 Gy and central doses of 21 Gy for a
remission rate of 25%, whereas Kim et al 25 used a mean mar-
ginal dose of 15 Gy and central dose of 26 Gy for a remission
rate of 70%. The volume or marginal dose applied to the brain
surrounding the CMs, thought important in epileptogenic
tumors17 and AVMs,19 has not been systematically studied
with respect to seizure control. Retrospective studies of open
resection suggest that removal of the hemosiderin-stained
tissue surrounding CM is associated with better outcome 26;
therefore, variable outcomes following SRS may also stem
from inconsistent inclusion of this potentially epileptogenic
region in the treatment volume.
Unfortunately, excess morbidity in terms of radiation toxicity
with higher doses and posttreatment hemorrhage with lower
doses remains a concern. For example, the early Swedish expe-
rience determined that SRS did not appreciably alter the natural
course of CMs while exposing patients to radiation-induced
complications that exceeded by 7 times those expected for the
same dose for an AVM.27 A case of a patient treated with SRS for
bilateral CMs and intractable epilepsy reported delayed (> 2-
year postoperative) radiation necrosis and intractable edema
requiring craniotomy and hyperbaric oxygen treatments.28 A
recent retrospective comparison concluded that open resection
resulted in better seizure control and hemorrhage avoidance
than SRS.24 This study, as well as comparisons with the approx-
imately 70 to 80% seizure remission rate seen after open sur-
gery for a CM,29,30 suggests that any benefits of noninvasive SRS
over open surgery for a CM must be weighed against risks of
less efficacy and possibly increased toxicities.
24.3.4 Hypothalamic Hamartomas
Hypothalamic hamartomas (HHs) are an important cause of an
epileptic encephalopathy marked by medically intractable
gelastic and other seizures usually accompanied by behavioral
and cognitive decline. Although HHs are difficult to excise with
the use of standard surgical techniques, SRS has an advantage
of noninvasive access. Series of SRS treatment of HHs33–38 dem-
onstrate a seizure remission rate of 27% across studies.
Although this rate appears low, seizure remission alone under-
estimates the benefits seen with respect to reduced morbidity
and need for less custodial care required in these cases of severe
epilepsy. Behavioral outcomes have not been rigorously quanti-
fied, but most reports cited above note that the majority of
patients undergo anecdotal improvement in behavior, sleep
quality, and learning.

A European, multicenter, prospective trial of SRS for HHs has
enrolled 60 patients, 27 of whom exceeded 3-year follow-up.31
This study emphasizes the evolution of seizure changes during
the postoperative period that track the development of the
radiosurgical lesion. Within the first 2 months, a slight improve-
ment in seizure rate typically occurs. Seizures transiently wor-
sen in frequency before reduction and remission occur.
Behavioral improvements, along with electroencephalographic
(EEG) normalization, tend to occur in a more linear fashion.
Morbidity is low, with no ill effects except for one instance of
poikilothermia noted among the above reports. Some reports
emphasize the importance of the marginal dose of radiation31 as
noted in tumors and AVMs. Patients treated with doses exceed-
ing 17 Gy to the margin of HH had greater rates of seizure
remission than those receiving less than 13 Gy.32
More recent studies compared, in nonrandomized and retro-
spective fashions, open surgical treatment for HHs. For exam-
ple, Shim et al treated 14 patients: 1 with standard surgery, 4
with SRS, and endoscopic disconnection in 11. 33 Of the 11
patients who underwent endoscopic disconnection, 6 were
seizure-free immediately after surgery. None of the four
patients who underwent SRS experienced remission. Outcome
may have been limited by the morphology of the lesions; the
authors note that they were unable to target a sessile base for
“disconnection.”
Stereotactic radiosurgery may be one of several nontradition-
al surgical approaches that can improve what is otherwise a
devastating epileptic encephalopathy. Consideration of higher
marginal doses and the morphology of the HH lesion may pro-
vide guidance in further trials.
24.4 Treatment of Physiological
Epilepsies
24.4.1 Mesial Temporal Lobe Epilepsy
Mesial temporal lobe epilepsy (MTLE) consists of atrophy, glio-
sis, and selective neuronal loss within the hippocampus and
associated limbic system. Mesial temporal lobe epilepsy is the
most frequent cause of medically intractable epilepsy in adults
(although more recent data suggest that the prevalence may be
dropping, at least among those available to the larger, estab-
lished epilepsy surgery centers34). Stereotactic radiosurgery
may have several potential benefits that drive its consideration
despite the well-established efficacy of open surgery for
MTLE.35 First, open surgery has a small, but real risk of surgical
complications such as bleeding, infection, stroke, and postope-
rative pain. Second, open surgery is expensive. The average cost
per patient for open microsurgery is nearly 50% more than that
for SRS for treatment of similar disorders36; admittedly, relative
costs of open versus SRS have not been studied. Third, some of
the adverse events of open surgery involve changes in neuro-
psychological testing. Fourth, some patients as well as physi-
cians hold persistent biases against open surgery despite
proven efficacy; noninvasive techniques may broaden the
acceptance of epilepsy surgery.
The first surgical series employing SRS in a systematic fashion
in the treatment of physiological focal epilepsy (as opposed to
epilepsy resulting from mass lesions) was reported by Talairach
Stereotactic Radiosurgery for Epilepsy
et al37 who treated 44 patients between 1959 and 1973 with the
use of yttrium 90, yielding a 75% rate of seizure remission over a
mean follow-up duration of 5.7 years.37 Unfortunately, initial
attempts in Sweden with Gamma Knife38 and elsewhere with the
use of fractionated radiotherapy and other radiosurgical techni-
ques39 were not encouraging. Many of these patients, however,
were treated before uniform definitions of MTLE existed.
24.4.2 Outcomes: Seizure Remission
Régis et al resurrected the Gamma Knife technique for treat-
ment of MTLE in 1995,40 and then conducted a subsequent trial
of seven MTLE patients.41 In this series, a target comprising the
parahippocampal gyrus, head and anterior body of the hippo-
campus, and amygdala, comprising approximately 6.5 mL 50%
isodose volume, was treated with 25 Gy. Since this publication,
nine studies of 83 patients report a wide range of efficacies of
seizure remission ranging from 0 to 86%14,15,16,47–52 with an
across-study average of 51%. In comparison, the rate of seizure
remission in the prospective, randomized trial of open surgery
for MTLE was 58%.35
Stereotactic radiosurgery studies fall into two groups. The first
comprise a variety of single-center case reports and case series.14,
15,16,42,43 With one exception,43 these series used doses smaller
than 25 Gy, and rates of seizure remission were low or nil.
The second group consists of two larger, prospective, multi-
center trials, one European44 and one American.45 The Euro-
pean trial demonstrated a 2-year postoperative seizure
remission rate of 62% with the use of a treatment protocol iden-
tical to the group’s earlier studies.
Barbaro et al in the U.S. Multicenter Pilot Study45 randomized
30 patients to a high (24 Gy, n = 13) or low (20 Gy, n = 17) dose
delivered to the target as specified by Régis et al44 with the
added specification that 50% isodose volumes were restricted
to 5.5 to 7.0 mL attained with two to six isodoses. Ten patients
in each group were seizure-free at 36-month follow-up, result-
ing in a remission rate of 77% in the high-dose and 59% in
the low-dose group, for an overall remission rate of 67%
(▶ Fig. 24.1).
Fig. 24.1 Distribution of seizure outcome as defined by Engel’s criteria
between months 24 and 36 of the National Institutes of Health-
sponsored, multicenter pilot study of stereotactic radiosurgery for
unilateral mesial temporal lobe epilepsy divided by dose.45 The overall
rate of seizure remission (Engel class IB or better) at 36 months was
76.9% for the high-dose and 58.8% for the low-dose group (p = 0.12 by
Fisher’s exact test).
195
 Stereotactic Radiosurgery for Epilepsy
Vojtěch et al published a retrospective analysis of 14 patients
with markedly different results.46 Initial doses were identical to
that reported by Régis et al; in fact, six of the patients overlap
with the European multicenter trial.44 Doses decreased with
accumulated experience; of the 14 patients in the report, the
last 6 were treated with 18 Gy because of clinically significant
“prominent radiosurgical responses” associated with 25 Gy.
None of the 14 patients were seizure-free after 39 months.
A recent report on longer term follow-up (≥ 5 years, mean fol-
low-up of ~ 8 years) of 15 patients shows that seizure remission
remains durable with 60% of patients experiencing either seiz-
ure remission or nondisabling auras.47 Because long-term fol-
low-up was not conducted with intent-to-treat criteria, the
results may be susceptible to sampling bias.
24.4.3 Treatment Protocols
The variability in seizure remission rates underscores the diffi-
culties in the determination of basic parameters of anatomical
target, dose, and target volume. The anatomical targets in SRS
of MTLE are the least variable factor, with all studies14,15,47,48,49,
50 specifying that the 50% isodose volume contains regions
thought most important in generation of mesial seizures: the
amygdala, the head and anterior body of the hippocampus, and
the parahippocampal gyrus.
Dose and target volume are more variable. Comparison of the
above studies suggests that low-dose protocols (≤ 20 Gy)14,15,42
are less successful than higher-dose protocols (> 20 Gy). 47,50,51
As noted above, in patients randomized by dose (high = 24 Gy,
low = 20 Gy), Barbaro et al noted that the high-dose group expe-
rienced a higher rate of seizure remission, experienced a short-
er latency to seizure remission, and experienced fewer auras
during development of the radiosurgical lesion (▶ Fig. 24.2).45
Variability in seizure remission among the above trials also
emphasizes the importance of patient selection. Stereotactic
radiosurgery is, in effect, a “superselective” amygdalohippo-
campectomy involving the destruction of the minimum volume
Fig. 24.2 Distribution of continuous duration of seizure remission
(defined as Engel class IB or better) from the final outcome point of 36
months postoperatively in the National Institutes of Health–sponsored
multicenter pilot study.45 Patients who dropped out early because of
“escape” temporal lobectomy or because of loss of follow-up are
counted as a duration of zero months. p value = 0.05 from two-sample
t test. Bar, average.
196
and anatomy important in the pathophysiology of MTLE.
Patients with epilepsies that may differ from the stereotypic
unilateral MTLE lesion may not be suitable for SRS. For example,
most patients in the long-term French cohort who failed SRS
also had evidence for extension of the “epileptic zone” beyond
mesial structures.47 One reason that was offered to explain poor
outcomes of the experience of Vojtěch et al was that the pri-
mary epileptic injury in some patients could be considered
symptomatic “MTLE plus.”46 Patients with evidence of involve-
ment outside of the SRS target or with symptomatic etiologies
may not experience seizure remission with the highly selective
technique of SRS.
24.4.4 Morbidities
Morbidities in the multicenter protocols do not exceed those of
open surgery and fall in line with those seen commonly after
SRS.44 Both trials outlined the typical postoperative course and
development of the radiosurgical lesion, and in many respects,
it follows the polyphasic course described after SRS of a HH. 31
Most clinical or neuroimaging changes occur between 9 and 15
months. Nearly all patients experience exacerbations in auras
before seizures decrease or remit (▶ Fig. 24.3). The most dra-
matic drop in seizure rate occurs between 12 and 18 months,
coinciding with the development and resolution of maximal
MRI changes.12
Other morbidities reported by the two multicenter studies
include visual field deficits. Superior quadrant field defects
are an expected morbidity after standard temporal lobec-
tomy, with rates of visual field defects between 52 to 100%. 48
Quantified visual fields were measured in the U.S. Multicen-
ter Study48 at 24 months after SRS. No patients reported vis-
ual changes. Fifteen (62.5%) of 24 patients had postoperative
visual field changes, all homonymous superior quadranta-
nopsias. No changes were consistent with injury to the optic
nerve or chiasm. Consistent with above findings that found
seizure remission correlating with dose, patients with seizure
remission had a higher rate of visual field defects. In the
European study, one patient had a hemianopia (indicating
direct involvement of the optic tract) and another had mixed
deficits.44
Other morbidities consisted of headache, nausea, vomiting,
and depression. Headache requires special comment, as it coin-
cides in some patients with postoperative edema. Steroids, in
response to headache, visual field changes, or MRI changes,
were used in 62% of patients.45
One potential problem of SRS compared with open surgery is
that the latency between SRS and remission may expose
patients to continued seizures. Two deaths occurred during the
latency period in a case series of five patients treated with low-
er-dose radiation.14 Given the known risk of death from uncon-
trolled seizures (SUDEP), and the possible proconvulsive effects
of lower radiation doses, it is possible that radiosurgery con-
tributed to the death in these cases. Pathological evaluation of
tissue obtained in these cases only showed evidence of MTS.
Allowing enough time for maturation of the radiosurgical lesion
may have allowed some patients treated with lower doses to
demonstrate remission, given that animal models treated with
lower doses demonstrated improvements at a slower rate than
those treated with higher doses.6,49 Future trials of SRS may

need to consider anticonvulsant prophylaxis during the latency
period.
24.4.5 Secondary Outcomes/
Neurocognition
Some studies reported secondary outcome measures such as
cognition. In fact, SRS of MTLE may serve as an interesting mod-
el of the effects of focal radiation on cognition, especially
because controversies over the cognitive sequelae of focal or
fractionated radiation therapy are often engendered by the con-
founding effects of tumors or other CNS lesions.50 Epileptic rats
demonstrated no cognitive effects attributable to SRS. 6
So far, four studies in the treatment of MTLE have reported
neurocognitive outcomes. Two single-center series reported
mixed results. Srikijvilaikul et al reported no group mean
changes at 6-month follow-up, although some individuals
showed decline in at least one cognitive domain.14 McDonald et
al reported on 27-month follow-up in three patients who
underwent dominant hemisphere low-dose SRS treatment. 51
No long-term consistent changes in neurocognitive parameters
were found, although each patient showed decline in a measure
of verbal memory. They concluded that neurocognitive changes
following SRS appeared similar to those of temporal lobectomy.
The European prospective trial reported no mean neurocog-
nitive changes over a 2-year follow-up.44
Detailed evaluation of neurocognitive outcomes were pro-
vided from the U.S. Multicenter Trial.52 Mean scores of tests of
language and verbal memory at 24 and 36 months after SRS did
not differ from preoperative baselines. Specifically, significant
verbal memory impairment was seen in 25% of dominant-
surgery patients and in 7% of nondominant patients. In fact, sig-
nificant improvement was seen in 16% of dominant and 7% of
nondominant patients. In comparison, rates of significant
impairment following dominant hemisphere temporal lobec-
tomy range from 10 to 60%.53–57 Furthermore, mood remained
stable, and quality-of-life scores improved in those patients
who experienced seizure remission.
In summary, seizure remission rates following SRS vary, but
the larger, multicenter trials with higher-dose protocols
showed remission rates similar to the gold standard of open
surgery. Favorable neurocognitive outcomes compared with
Stereotactic Radiosurgery for Epilepsy
Fig. 24.3 Mean ± standard error of the number of
auras per seizure diary interval in patients of the
National Institutes of Health–sponsored multi-
center pilot study.45 As seen in earlier studies, the
onset of auras frequently preceded frank changes
on magnetic resonance imaging and coincided
with the diminishment of complex partial seiz-
ures.
open surgery suggest that the highly selective radiosurgical le-
sion may provide some benefit. The ROSE Trial (Radiosurgery or
Open Surgery for Epilepsy), a prospective randomized trial of
standard open surgery versus SRS, is currently underway. The
ROSE Trial may provide further evidence regarding the effects
of SRS on neuropsychological functioning and whether cogni-
tive abilities may be less adversely affected by SRS relative to
traditional open surgery.
Stereotactic radiosurgery for MTLE appears to have promise.
Higher-dose protocols appear to have better results. Patient
selection and relative benefits compared with open surgery
have yet to be clearly demarcated.
24.5 Other Nonlesional Epilepsies
24.5.1 Neocortical Foci
There are no published reports on the use of SRS for nonstruc-
tural lesion neocortical foci. Régis has presented a small series
of cases where radiosurgery was delivered to perisylvian
regions including the insular cortex following localization of
the seizure focus with stereo-EEG recordings (J. Régis, personal
communication). Because localization of seizure foci in nonle-
sional neocortical epilepsies usually requires invasive techni-
ques, the noninvasive nature of SRS loses some advantage. One
may speculate that if noninvasive localization and brain map-
ping were rigorous enough to supplant invasive methods, then
SRS may have a future role.
24.5.2 Corpus Callosotomy
Transection of the corpus callosum may decrease the severity
and number of primary generalized or rapidly propagating sec-
ondarily generalized seizures in patients who are not otherwise
good surgical candidates. Small case series report that improve-
ment in seizures following SRS resection of the corpus callosum
was comparable to that reported after open callosotomy with
lack of notable complications.58,59 The future role of SRS in cor-
pus callosotomy may be more difficult to determine because
more epileptologists are currently opting for vagal nerve stimu-
lation in patients who might otherwise qualify for corpus
callosotomy.
197
 Stereotactic Radiosurgery for Epilepsy
24.6 Summary
Stereotactic radiosurgery offers an alternative to open surgery
in selected patients with epilepsy caused by mass lesions such
as tumors or AVMs with the choice of technique guided by the
location and type of the lesion rather than any epilepsy-specific
properties of the lesion. Stereotactic radiosurgery for the seiz-
ures arising from CMs appears to have a less than enthusiastic
endorsement given some studies’ findings of excessive rebleed-
ing and lower seizure-free rates than with open surgery. Stereo-
tactic radiosurgery for HHs, in contrast, appears promising
given the combination of inaccessibility to traditional surgery,
severe morbidity of gelastic epilepsy, and good safety profile.
Finally, recent trials suggest that certain protocols of SRS for
MTLE may offer a noninvasive alternative to open surgery while
yielding similar rates of seizure remission. Other possible situa-
tions merit consideration of SRS; one authority proposes that
SRS may be useful in cases of (1) epilepsy of temporal lobe ori-
gin in those who have medical contraindications to open sur-
gery, (2) temporal lobe epilepsy after failed open resection, and
(3) extratemporal epilepsy that can be noninvasively localized,
especially following a failed open surgery.60 Further work is
needed to clarify risks and benefits of SRS for these less com-
mon but important clinical situations.
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199
 25 Stereotactic Radiosurgery for Ocular
Part VI Disorders 202

Ocular Disorder and Pediatric 26 Stereotactic Radiosurgery for Pediatric

Brain Tumors 210
Tumor Indications

VI
 Stereotactic Radiosurgery for Ocular Disorders
25 Stereotactic Radiosurgery for Ocular Disorders
Roman Liscak and Gabriela Simonova
Key Points
● The eye bulb has to be reliably immobilized before the
radiosurgery.
● Build-up over the eye bulb is necessary for precise dose
calculations.
● Uveal melanoma is the most frequent indication for ophthal-
mic radiosurgery, which has a high rate of preserving of the
eye bulb.
25.1 Introduction
Due to its underlying radiobiological principles, radiosurgery is
generally used to treat small-volume lesions, and volumes of
ocular disorders usually fall within the volume constraints of
radiosurgery. The first radiosurgical experience with ophthal-
mologic indications involved the treatment of patients suffering
from uveal melanomas.1–8 However, it appears that the poten-
tial of radiosurgery to provide effective treatment for ophthal-
mologic indications is broader.
Radiosurgery of ocular disorders necessitates a close coopera-
tion with ophthalmologists. This multidisciplinary approach is
critical for patient selection, follow-up, and treatment.
25.2 Technical Issues Specific to
Stereotactic Radiosurgery for
Ocular Disorders
The Leksell Gamma Knife (GK; Elekta Instruments AB, Stock-
holm, Sweden) was originally designed to treat deep brain
202
targets, and stereotactic coordinates are derived from the posi-
tion of the coordinate head frame, which is rigidly fixed to the
skull. Proper eye fixation or an eye motion-monitoring system
is required because the eye can move during the treatment pro-
cedure. Very eccentric target volume location can also cause
some inaccuracies in the treatment-planning calculations,
including relative dose distribution and absolute dose calcula-
tions. Finally, there may be some technical inconveniences in
treating patients due to limitations in the range of the coordi-
nate system in this eccentric target location. Despite these diffi-
culties, radiosurgery is an attractive alternative treatment for
ophthalmic lesions mainly because of its accurate and precise
delivery of high conformal doses to the treatment target.
25.3 Eye Fixation
Several different eye immobilization systems and techniques
have been described in the literature.1,9–16 Tokuuye et al
described a mask fixation technique with a plastic mold gently
pressed down over the orbit to restrict ocular movements.15
Zehetmayer et al reported on a suction immobilization techni-
que for radiosurgery of intracranial malignancies using the
GK.16 Langmann et al used a fixation method of the globe by
means of a retrobulbar anesthetic block for eye treatments
using the GK.1 In the Prague (Czech Republic) center, the
treated eye was fixed under a retrobulbar local anesthesia by
suturing two rectus eye muscles to the stereotactic frame; this
procedure was done by an ophthalmologist. To ensure adequate
dose build-up and homogeneous propagation of radiation
between the tissues and the air, a partial tarsorrhaphy was per-
formed, and a plastic cover filled with tissue-equivalent gel was
used (▶ Fig. 25.1). This simultaneously acted as protection for
the cornea. This eye fixation technique showed very good
Fig. 25.1 Fixation of the eye. (a) Retrobulbar local
anesthesia; (b) Suturing two rectus eye muscles;
(c) Plastic cover filled with tissue-equivalent gel;
(d) Build-up with fixation of rectus eye muscles to
the stereotactic frame.

stability and rigidity in time. Having the patient in a prone ver-
sus supine position had no effect on stereotactic target and eye-
structure localization.12,13
Active eye immobilization techniques, where the patient con-
trols the eye position, for example, by fixating on a light source,
have been described for proton/helium ion beam therapy and
also for linear accelerator (linac)-based stereotactic radiother-
apy of malignant tumors.9,11 For proton/helium ion beam ther-
apy, a surgical intervention is performed to position tantalum
clips at the border of the visible tumor under diaphanoscopical
control. These clips are used during treatment planning to
define the target volume and to verify the position of the tumor
during treatment delivery by using X-rays.10 Petersch et al
described a noninvasive eye fixation system for the application
of linac-based stereotactic radiotherapy in the treatment of
uveal melanoma.14 The computer-controlled eye-monitoring
system is based on the patient’s fixation on a point of light.
When the eye position exceeds the preset geometrical limits to
that point of light, the system automatically initiates a cessation
of the radiation beam until the eye is repositioned to the proper
alignment.
25.4 Dosimetry and Treatment
Planning
Due to very eccentric target volume location, some inaccuracies
in the treatment-planning calculations, including relative dose
distributions and absolute dose calculations (calculation of
treatment time or monitor units), can be expected. This issue is
even more prominent for surface structures of the eye (e.g., eye
lens, eyelid, and cornea) than for target volumes itself.
Petersch et al reported excellent agreement between actual
measurements and the treatment-planning system calculations
for uveal melanomas at a depth of 15 to 20 mm.14 However, at
small depths (< 10 mm), the treatment-planning system cannot
model the influence of absorption in the eye motion-monitor-
ing device accurately if the beam passed perpendicularly
through it. Consequently, as a means of reducing dosimetric
errors, avoidance of frontal beams during radiosurgery to ocu-
lar lesions has been suggested.
Detailed dosimetric measurements were also performed at
the Prague Na Homolce Hospital. In this case, treatment-plan-
ning system calculations of target volume relative dose distri-
butions and absolute dose calculations in different depths were
compared with experimental measurements. 13 Various treat-
ment plans for different ophthalmic indications (e.g., uveal mel-
anoma, glaucoma, and retinoblastoma) calculated for the GK
were evaluated. Absolute doses measured by pinpoint ion
chamber at depths of 10 mm and deeper showed relatively
good agreement with the treatment-planning system calcu-
lated data. Absolute doses delivered during head phantom irra-
diation were systematically lower than calculated ones, usually
within 5% or even within 3%. Absolute doses measured by pin-
point ion chamber at depths < 10 mm showed a relatively large
deviation compared with the treatment-planning system’s cal-
culated data. In this situation, absolute doses delivered during
phantom irradiation were systematically lower by 15 to 20%. To
improve on inaccuracies in absolute dose calculations in surface
structures, proper tissue-equivalent built-up material attached
Stereotactic Radiosurgery for Ocular Disorders
to the treated eye was recommended (▶ Fig. 25.1). Such materi-
al should reduce discrepancies between the planned and the
delivered radiation dosimetry. Relative dose distributions
measured by polymer gel dosimetry in the region of the target
volumes were in good agreement with the Leksell GammaPlan
(Elekta AB), and measurements demonstrated that calculation
errors should not exceed more than 10% even at surface struc-
tures when built-up material is used.
Because of the marginal position of the eye, an extreme gam-
ma angle has to be used to avoid collision of the skull with the
collimator helmet of the GK model B or C. Patients usually do
not tolerate excessive backward bending of the head in a supine
position. Therefore, the prone position was used in most cases.
The problems of collisions and coordinate limits have been
overcome by the enlarged space of the collimator helmet in the
latest model of the Leksell Gamma Knife Perfexion (Elekta AB),
and patients are treated now comfortably in the supine position
without any difficulty.
25.5 Specific Disorders
25.5.1 Uveal Melanoma
Natural History and Clinical Presentation
Uveal melanoma represents the most common primary malig-
nant tumor of the eye in adults. There is a peak incidence
between 55 and 70 years of age, with a prevalence of six or sev-
en cases per million people per year. The incidence is rare in
patients younger than 20 years of age. Approximately 50% of
patients with diagnosed melanomas of the choroid or ciliary
body will die from this tumor within 15 years.17,18
Uveal melanomas are neoplasms arising from the uveal tract
that includes the iris, ciliary body, and choroid. The uveal tract
is a vascular structure with no lymphatic drainage. Lymphatic
node involvement (preauricular, submandibular, and cervical
nodes) can be diagnosed on rare occasions when subconjuncti-
val extension of the primary tumor has also been observed. The
major routes of extension are local growth and hematogenous
spread. The common sites of hematologic dissemination are the
liver, lung, and brain.
Wide variations in the grading of malignancy can be
observed, from relatively benign types with several years of
survival without dissemination, to other tumors with fast mul-
tiorgan dissemination, which can lead to the patient’s death
within a few months. Tumor growth is also influenced by the
potential cell-doubling time, which varies widely from 60 to
350 days (median ~ 70 days).19 A longer doubling time as com-
pared with a significant proportion of other tumors can explain
the relatively long survival of these patients and also the rela-
tively slow tumor response after irradiation.
The correct diagnosis for a majority of patients with uveal
melanoma can be made by taking a history and performing a
complete ocular examination. The ophthalmologic examination
includes external ocular examination, indirect ophthalmoscopy,
fluorescein angiography, and ultrasonography, which plays a
basic role at the time of diagnosis. The ophthalmologic exami-
nation also plays a role in follow-up and can be used to obtain
precise measurement of the tumor base and height. The height
of the tumor in particular represents one of the most important
203
 Stereotactic Radiosurgery for Ocular Disorders
Table 25.1 Toxicity scoring system (RTOG/EORTC LENT SOMA)
Grade 1 Grade 2
Cornea Increased tearing on Noninfectious keratitis
examination
Iris Rubeosis only Rubeosis; increased intraocular
pressure
Optic nerve Afferent pupillary defect with ≤ ¼ Pallor with asymptomatic
normal-appearing nerve visual field defect
Lens Asymmetric lenticular opac- Moderate lenticular changes
ities; no visual loss with mild-moderate visual loss
Retina Microaneurysms, nonfoveal Cotton wool spots
exudates, minor vessel attenu-
ation, and extrafoveal pigment
changes
Sclera Loss of episcleral vessels ≤ 50% Scleral thinning
Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; LENT SOMA, late effects of normal tissues, subjective, objective,
management, and analytic; RTOG, Radiation Therapy Oncology Group.
factors influencing the treatment decision, and it is used during
follow-up to evaluate the tumor’s response.
Results of Radiosurgery, Stereotactic
Radiotherapy, and Proton Beam Radiotherapy
The first experiments with radiosurgery for the treatment of
uveal melanomas were conducted using the rabbit eye melano-
ma model. The reported tumor lethal dose ranged from 60 to
90 Gy applied in a single session.5 Several authors reported the
results of Gamma Knife stereotactic radiosurgery (GKSRS) in
uveal melanomas, and some observed relatively high radiation-
related toxicity.1,2,3,4,6,7,20–25 The minimum effective dose for
long-lasting local tumor control (10–15 years), as well as the
tolerance doses for critical ocular structures, is not yet well
defined. Toktas et al24 reported 35 patients treated using GK
with standardized dose 30 Gy on 50% isodose curve for all
patients; the 3-year local tumor control rate was 83%. The most
frequent complication was retinal detachment (17%). Schirmer
et al26 used lower doses (< 25 Gy marginal dose), but the mini-
mum follow-up was relatively short (median 20.9 months) and
the patients series was relatively small (14 patients).
Our own experience represents a group of 126 patients with
uveal melanoma treated using the GK over a period of 8 years.
The LENT SOMA (Late Effects Normal Tissues, subjective, objec-
tive, management, and analytic) scoring system27 was used to
measure the radiation side effects (▶ Table 25.1). The tumor
marginal dose for radiosurgery ranged from 35 to 45 Gy, with a
median dose of 41 Gy. Tumor regression was defined as a
decrease in tumor height registered by ultrasonography scans
and by control magnetic resonance imaging (MRI). The tumor
regression was achieved in 70% of patients (▶ Fig. 25.2). The
maximum local effect has been recorded within 24 months
after radiosurgery. Patients with tumor growth progression or
without any response 30 months after treatment were candi-
dates for retreatment by radiosurgery, and patients with a
204
Grade 3 Grade 4
Infectious keratitis; corneal ulcer Panophthalmitis; corneal scar;
ulceration leading to perforation
of globe/loss of globe
Neovascular glaucoma; ability to Neovascular glaucoma without
count fingers 1 m ability to count fingers 1 m;
complete blindness
> Pallor or central scotoma Profound optic atrophy; com-
plete blindness
Moderate lenticular changes Severe lenticular changes
with severe visual loss
Massive macular Opaque vitreous hemorrhage;
exudation; focal retinal detach- complete retinal detachment;
ment blindness
> 50% Scleral thinning Scleral or periosteal graft re-
quired due to perforation
tumor height > 10 mm or extrascleral growth were indicated for
enucleation (5% in our series).
The most extensively published charged particle center is the
Paul Scherrer Institute in Switzerland.28 In their group of 2,258
patients, 5- and 10-year local tumor control rates were 96 and
95%, respectively. Five- and 10-year survival rates were 82 and
62%, respectively. Seven percent of patients underwent enuclea-
tion after proton therapy. Preservation of the eye 5 and 10 years
after the treatment was 89 and 85%, respectively. Dendale et al29
reported a large series of 1,406 patients treated by proton beam
therapy (four daily fractions); the 5-year local tumor control rate
was 96%. The 5-year enucleation for complications rate was
7.7%. Caujolle et al30,31 reported a local recurrence rate of 6.1% at
5 years from series of 1,102 patients after proton beam therapy.
Stereotactic irradiation using linac with applied doses of 45
to 70 Gy delivered usually in three fractions is also an effective
method, with tumor height reduction achievement in 97% of
cases, secondary enucleation performance in 13%, and the inci-
dence of secondary glaucoma in 20%, also including iris or
chamber angle neovascularization.8,9,32,33 Kunaprayoon23 irradi-
ated patients with a single fraction dose 14 to 20 Gy with the
following late complications: 13% patients had neovasculariza-
tion, 22% patients had vitreous hemorrhage, 28% radiation ret-
inopathy, and 19% optic papillopathy.
Complications from Radiosurgery
The most common late toxicity complications for all types of
irradiation are retinopathy, cataract, secondary glaucoma, and
optic neuropathy. The most common cause of the toxicity-
related enucleation is secondary neovascular glaucoma. Secon-
dary glaucoma is typically a late complication, and its incidence
increases with longer follow-up. Although the risk of enuclea-
tion from this reason is approximately 6% for at 2-year
follow-up after radiosurgery, it increases to 19% with at 8-year
follow-up.25,34,35 Secondary glaucoma often accompanies uveal

Fig. 25.2 (a) A 51-year-old man with uveal melanoma, 44 Gy at 50% isodose. (b) Seven years after Gamma Knife treatment—complete regression of
the melanoma with preserved vision of the eye.
melanoma before the treatment. The question remains of how
much of the treatment itself contributes to its development or
accentuation. Differentiation of the natural development of this
complication from accentuation of secondary glaucoma caused
by radiosurgery is not possible at present.
Eyes with secondary enucleations presented an initial tumor
height > 9 mm. The second frequent reason for enucleation was
the origin of the tumor in the region of the ciliary body. 22 In a
prospective study of helium ion therapy, the incidence of secon-
dary glaucoma was 29% after a mean observation period of 53
months. Incidence of rubeosis iridis in 34% of patients has been
observed using proton beam therapy after a median follow-up
of 36 months.36 A major predictive factor for the development
of rubeosis iridis and later neovascular glaucoma was a large
tumor size unsuitable for brachytherapy. The enucleation
rate was 19%: 3% for local failure and 16% because of
complications.35
An analysis of late toxicity of 126 patients of our series
recorded severe grade 3–4 retinopathy in 15% of treated
patients, radiation-related late toxicity grade 3–4 in the lens
was observed in 26%, optic neuropathy in 9%, and secondary
glaucoma in 18% of cases. Eleven percent of patients were
enucleated for worsening glaucoma during the first 2 years
after radiosurgery. The median time to occurrence of secondary
neovascular glaucoma was 18 months, so a higher incidence of
enucleation during a longer follow-up cannot be excluded. The
worsening of useful vision caused by radiation-related toxicity
during 3 years after radiosurgery was observed in 34% of
patients and was due to tumor progression in 3%, optic nerve
neuropathy in 8%, retinopathy in 9%, and neovascular glaucoma
in 14%.
Significantly lower toxicity in the optic nerve was observed
when the maximum dose to that structure was < 10 Gy (inci-
dence of late toxicity grade 3–4 in 2.4%), in the cornea when
the maximum dose did not exceed 10 Gy (incidence of late tox-
icity grade 3–4 in 3%), in the lens when the maximum dose did
not exceed 7 Gy (incidence of late toxicity grade 3–4 in 7.7%),
Stereotactic Radiosurgery for Ocular Disorders
and in the iris when the maximum dose did not exceed 15 Gy
(incidence of late toxicity grade 3–4 in 4.6%).
Prognostic Factors
The prognosis of patients with uveal melanoma is determined
by tumor size, cell type, tumor location (poor results for ciliary
body tumors), and the extent of the disease.7,10,28,35,36 The most
important prognostic factor is the presence or absence of organ
dissemination at the time of uveal melanoma diagnosis. Some
authors maintain that dissemination from uveal melanomas
starts when the tumor is > 7 mm in diameter, and growth from
a 7 to 10 mm diameter increases the risk of metastatic disease
to approximately 16%. This fact was supported by clinical obser-
vations.19 Five-year survival rates of patients with small tumors
(heights < 8 mm) and with no detected metastatic disease out-
side the eye are > 80%. For larger tumors (> 10 mm in height)
with metastases outside the eye, the 5-year survival rate ranges
from 10 to 30%. There still exists a knowledge gap regarding
growth of melanomas in situ and the documentation of the
time intervals between the diagnosis of primary tumor and the
appearance of the other organ dissemination.
The best prognosis in our group of patients was for patients
with age younger than 50 years, with a preequatorial location
of the tumor; tumor height not exceeding 5 mm; gross tumor
volume not larger than 0.5 cm3; and no other organ dissemina-
tion existed.7
Treatment Decision
Rationale criteria for selecting a treatment modality in our cur-
rent practice are the following. Small tumors (< 10 mm in
height) localized preequatorially can be successfully treated
using brachytherapy. Tumors localized equatorially or posterior
to the equator and not higher than 10 mm can be irradiated
using the GK. Tumors > 10 mm in height, especially melanomas
of the ciliary body, progression of growth after irradiation,
205
 Stereotactic Radiosurgery for Ocular Disorders
tumors combined with neovascular glaucoma, and vitreous
hemorrhage are candidates for enucleation.
25.6 Glaucoma
Glaucoma is a chronic, slowly progressive, usually bilateral neu-
ropathy of the optic nerve. Untreated glaucoma eventually
leads to complete loss of vision. About 10% of patients with
glaucoma become unilaterally or bilaterally blind.37 We cur-
rently understand the pathophysiology of glaucoma to be a pro-
gressive loss of ganglion cells resulting in visual field damage
related to the intraocular pressure (IOP).38 Although many clini-
cians now feel that there are several factors involved in the
pathogenesis of glaucoma, the only rigorously proven treat-
ment method is the lowering of IOP. This could be achieved in
two ways: by increasing the chamber-liquid drainage or by
decreasing its production. The conventional antiglaucoma
treatment—local and systemic pharmacotherapy, laser and cry-
otherapy, and incisional surgery—takes effect in this way. Pro-
duction of intraocular liquid can be decreased by affecting the
site of its origin, which is the ciliary body. Irradiation of the cil-
iary body using the GK is one such process. The intention of
radiosurgery is not complete destruction of the ciliary body, but
reduction of intraocular liquid production through action on its
vessels. It thereby achieves a decrease of IOP.
In secondary glaucoma, the goal of the radiosurgical treat-
ment is determined by the stage of the disease. When vision
has been totally or partially lost, the main aims are to abolish
the elevated IOP and to eliminate severe pain. In the early stages
of the disease, when conventional therapy has insufficient
effect and visual acuity is still preserved, the treatment has the
more difficult task of preventing any further progress of the
pathogenic mechanisms.
Because there was no previous experience in the radiosurgi-
cal treatment of glaucoma to refer to, we started to evaluate an
effective and safe irradiation of the corpus ciliare as the source
of intraocular aqueous humor.39,40 Gamma Knife stereotactic
radiosurgery (SRS) of the ciliary body led to a significant allevi-
ation of pain and reduction of IOP in advanced glaucoma. It was
effective in secondary glaucoma, especially in terms of neovas-
cularization. The latency of the treatment effect was relatively
Fig. 25.3 A plan to irradiate the ciliary body using four 8-mm collimators (50% isodose displayed) in the eye bulb with aphakia; therefore, the lens is
not visible on magnetic resonance imaging.
206
short. Four isocenters using the 8-mm collimator were dis-
placed in a cruciform manner ▶ Fig. 25.3. We delivered 20 Gy at
50% isodose, but for patients with some preserved vision, the
dose was lowered to 15 Gy at 50% isodose. The patients were
ophthalmologically followed in regular 3-month intervals dur-
ing the first year after the irradiation, then twice yearly to
assess the irradiation influence on pain, IOP, and neovasculari-
zation. In a nonrandomized prospective study, a total of 107
eyes in 103 patients were irradiated in this way. All the patients
had a long history of the disease and had exhausted all tradi-
tional forms of therapy. Because of advanced painful glaucoma
and progressive clinical symptoms, we have focused on follow-
ing the decrease in pain and the effect on IOP, as well as simpli-
fying pharmacotherapy after the radiosurgery. Positive effect
was recorded in all patients in at least one of the following
parameters. Intraocular pressure decreased usually within 12
weeks after the radiosurgery to the painless level in 52% of
cases; residual elevation of IOP remained in 45% of cases. Pain,
which was present in all patients before the treatment,
regressed within 1 to 8 weeks after the treatment. Patients
were completely pain-free in 66% of cases, and partial relief of
pain was recorded in 29% of cases. During the follow-up, which
was at least 2 years, there was no further deterioration of the
vision (if preserved before the treatment), and there were no
significant signs of postirradiation eye-bulb irritation, retinitis,
or changes in the anterior segment of the eye. In case of neovas-
cularization, at least partial regression was observed in all
affected eyes, usually 4 to 5 months after the radiosurgery.
Pharmacotherapy was reduced in 39% of patients within 2 to 3
months after the radiosurgery. Enucleation was performed in
eight blind eyes: in five of them the radiosurgery was not suffi-
ciently effective, in two eyes the reason was cosmetic, and in
one eye there was a trauma during the follow-up.
Treatment complications were not significant: short-term
postoperative lacrimation in 61% of patients caused by mechan-
ical irritation after the eye fixation, postirradiation cataracts in
two patients, and noninfectious keratitis in another two
patients.
Patients with primary open-angle glaucoma suffer less pain
or no pain, their IOP is less elevated, and their disease is mainly
expressed by defects in their visual field as a manifestation of

the optic neuropathy. A prospective 5-year clinical study to halt
progressive optic neuropathy in the early stages of glaucoma
had been concluded in our department, but the effects of radio-
surgery on patients with primary glaucoma does not seem to
be permanent and the results of GKSRS did not meet all our
expectations with recurrences in the majority of treated
patients.
25.7 Age-Related Macular
Degeneration
Age-related macular degeneration (ARMD) is the most common
cause of legal blindness in patients 50 years or older. The two
main forms are nonexudative and exudative. Exudative ARMD
forms abnormal blood vessels called choroidal neovascular
membranes (CNVMs), which develop under the retina, leak flu-
id and blood, and ultimately cause a blinding disciform scar in
and under the retina.
Age-related macular degeneration is a degenerative process
with a proliferative component, and irradiation can play an
antiproliferative role. Choroidal neovascular membranes, which
are composed of endothelial cells and proliferate more rapidly
than the endothelial cells of the retina, may be more sensitive
than the retinal vasculature. Consequently, radiation therapy
has been suggested as a treatment for subfoveal CNVMs. Many
pilot studies for exudative ARMD show stabilization or regres-
sion of CNVMs with different kinds of radiation therapy.41–50
Initial results from patients treated with radiosurgery for
ARMD show that the GK is able to affect tissues beneath the ret-
ina without damaging the overlying retinal structures. Haas et
al47 in their pilot study investigated the effect of single-fraction
(10 Gy at the 90% isodose). Gamma Knife SRS in patients with
subfoveal CNVMs due to ARMD. Ten patients were followed for
12 months. Fluorescein angiography and indocyanine green
chorioangiography demonstrated a regression of the neovascu-
lar complex in one patient and stabilization in three patients.
Enlargement of the CNVM was found in six patients and was
associated with a decrease of visual acuity in four patients. Hen-
derson et al50 followed seven patients with ARMD after GKSRS
using a marginal dose of 12 Gy. With a median patient follow-
up of 2 years, they observed stabilization of disease in five
patients; improvement of vision was recorded in one, and
impairment also in one patient.
We have constructed a prospective, nonrandomized study in
a group of 30 patients. A dose of 30 Gy in the center and a dose
of 15 Gy to the periphery of CNVM at 50% isodose were applied
in all 30 patients. Gamma Knife therapy in the studied group of
patients was safe. No severe radiation-related side effects, such
as optic neuropathy, cataract formation or keratitis, were
observed over a 2-year follow-up.
Stabilization and regression of the choroidal neovasculariza-
tion (CNV) process was closely related to a reduction of activity,
subretinal fluid, and to a decrease of leakage. We have observed
that the most prominent initial response to the treatment can
be expected in active (serous and/or hemorrhagic activity of
the membrane) well-defined membranes with a size < 10 mm
(volume of irradiated tissue under 300 mm3). The type of the
membrane also seems to be important, with a major effect in
predominantly occult forms. On the other hand, the degree of
Stereotactic Radiosurgery for Ocular Disorders
serous detachment of the retina surrounding the process does
not have any influence on the initial effect. Even where massive
serous retinal detachment in the macular region has occurred,
we have found the retina to be completely reattached after
radiosurgery. However, GK treatment can stabilize the activity
of CNVM, and in a majority of our patients, it can also stabilize
and increase visual functions (or subjective evaluation of these
functions) for a few months. In nearly half of all patients the
recurrence of neovascularization was observed over a period of
18 to 24 months after radiosurgery and the recurrence of neo-
vascularization was observed after 3 years in three quarters of
the patients. Overall results of radiosurgery in this studied
group of patients have not reached all expectations and the
effect in the majority of patients was temporary.
25.7.1 Rare Ocular Disorders Treated by
Radiosurgery
Retinoblastoma
Retinoblastoma represents the most common primary malig-
nant tumor of the eye in young children (in the first 2 years of
life). The treatment strategy depends on clinical staging (dis-
ease confined to the retina, disease confined to the globe, extra-
ocular extension, and presentation of distant metastases) and
includes tumor resection, enucleation, chemotherapy, and
external beam radiotherapy.
Our experience covers treatment of four children who were
admitted for stereotactic irradiation using the GK and had vitre-
ous seeding of malignant cells. All patients were pretreated by
the International Society of Pediatric Oncology protocol and
relapsed after standard treatment. The only remaining possi-
bility was enucleation. The whole vitreous body was irradi-
ated using the GK in a single session, with a collimator
diameter of 14 mm. To avoid growth retardation of the irradi-
ated eye and bony structures, the minimal dose delivered to
the eye globe did not exceed 15 Gy in all these patients. For
this reason, and also bearing in mind the risk of complications
of previous treatment, the applied doses were relatively low.
Local progression was observed in three out of four patients,
and three patients were enucleated a median 2 months after
radiosurgery.
Orbital and Uveal Metastases of Carcinomas
Metastatic lesions in every location of the eye and the orbit
have been described, and autopsy studies estimate the inci-
dence of these metastases to be 4 to 12% in all types of cancer
patients.51 Radiosurgery may extend treatment options for
uveal metastases because of its specific advantages: the possi-
bility of applying a high radiation dose and evidence of its spar-
ing effect on the surrounding critical structures. The
recommended minimal doses are similar to those for brain
metastases, ranging from 20 to 30 Gy—depending on the tumor
volume, location, and histology.
25.8 Other Ocular Disorders
We have recorded positive experience with treatment of ocular
hemangioblastomas (▶ Fig. 25.4). Four patients with von
207
 Stereotactic Radiosurgery for Ocular Disorders
Fig. 25.4 (a) A 16-year-old patient with hemangioblastoma and bulous elevation of retina (hemangioblastoma is covered by a 70% isodose
representing 15 Gy): 1 = lens, 2 = corpus vitreum, 3 = bulous retinal detachment, 4 = tumor, 5 = build-up filled with gel. (b) Four years after the
treatment the tumor and the retinal detachment have completely regressed.
Hippel-Lindau disease suffering from retinal or choroidal
hemangioblastomas were treated using GKSRS. Radiosurgery
had a stable effect, with follow-up exceeding 6 years in all
patients, even when several lesions in other organs progressed
and had to be surgically treated. Regression of the lesion vol-
ume by 50% or more was observed.
We irradiated the ciliary ganglion in a 32-year-old woman
suffering from severe vegetative orbital pain after a longer his-
tory of penetrating bulbar injury, three previous operations for
amotio retinae, and a cyclocryocoagulation for secondary glau-
coma. The affected eye was blind. The pain disappeared within
a week. Two and a half years after treatment, the patient was
still pain-free after several years of previous continual suffering.
A positive treatment result was observed in a case of spinocel-
lular carcinoma of the lacrimal saccus.
Radiosurgery proved to be effective in the treatment of
exophthalmos refractory to conservative treatment. Irradiation
of intraorbital muscles or inflammatory intraorbital tissue led
to a regression of exophthalmos within 3 months of the
treatment.
25.9 Summary
Radiosurgery of ocular tumors and other eye or orbital lesions
represents a reasonable therapeutic option. If successful, it can
help to preserve the eye globe and visual function. Further clin-
ical studies using radiosurgery in ocular disease are necessary
to optimize effective doses and to analyze factors influencing
the length of survival, with a careful evaluation of the side
effects, as well as to improve local treatment effects while
decreasing radiation-related complications.
208
25.10 Acknowledgments
We thank our colleagues from the Department of Ophthalmol-
ogy, first medical faculty, Charles University and the Central
Military Hospital, Prague: J. Pašta, MD, PhD; J. Vladyková, MD,
DSc; J. Ernest, MD, PhD; P. Němec, MD; and L Nováček, MD, for
their care for our patients.
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 Stereotactic Radiosurgery for Pediatric Brain Tumors

26 Stereotactic Radiosurgery for Pediatric Brain Tumors

Christian C. Okoye, Ravi B. Patel, David B. Mansur, Alia Hdeib, Arjun Sahgal, Eric L. Chang, Mitchell Machtay, John H. Suh, Andrew E. Sloan, and
Simon S. Lo

26.2 Technical Issues Specific to

Key Points
Stereotactic Radiosurgery in
● Stereotactic radiosurgery is an emerging technology in the
treatment of pediatric brain tumors, particularly given the fa- Pediatric Patients
vorable dose-volume characteristics relative to external beam Unless a frameless radiosurgical system is used, rigid fixation is
radiation therapy. typically required in single-fraction SRS, thus allowing the mar-
● There are several technical issues specific to stereotactic ra- gin around the target volume to be minimized during treat-
diosurgery in pediatric patients that must be accounted for, ment planning. As opposed to adults, where rigid fixation of
particularly with regards to head frame placement, anesthe- the skull is readily achievable, younger children have thin
sia/sedation, and associated treatment times. skulls, which may not be completely fused. An alternative to
● The role of stereotactic radiosurgery in many pediatric insertion of pins into the outer skull table is the fabrication of a
brain tumors is poorly defined, as the literature consists al- cast or Aquaplast with piers where the pins can be inserted2
most exclusively of single-institution retrospective experi- (▶ Fig. 26.1). Due to their small body size, pediatric patients
ences. may also require body casts for additional neck support.
● The frequency and severity of normal tissue toxicities and Gamma Knife stereotactic radiosurgery (GKSRS) is typically a
complications of treatment are incompletely characterized, single-day procedure, consisting of image acquisition, complex
and caution should be exercised when utilizing these ap- treatment planning, and treatment delivery. Depending on a
proaches outside of the clinical trial setting. variety of treatment-related and logistical factors, including the
complexity of the planning, the treatment-planning system
used, hospital layout, and patient transportation, the time
required can vary significantly. In particular, the treatment time
26.1 Introduction can be prolonged in circumstances where older cobalt sources
are used within a GK unit or multiple small shots (isocenters)
Primary brain tumors constitute 20% of all pediatric cancers
are utilized.
and are the most common solid tumors in childhood.1,2 Sur-
Conscious sedation and/or general anesthesia may be
gical resection is usually the mainstay of treatment, and
required for younger children and those who are unable to
maximal safe resection is the goal in most cases. However,
withstand being immobile for the whole radiosurgical
conventional fractionated radiation therapy is often indicated
for high-grade or incompletely resected or unresectable
tumors.
Stereotactic radiosurgery (SRS) refers to a strategically
delivered high dose of radiation to a target volume using
megavoltage photons generated by a linear accelerator
(linac), gamma rays from a Gamma Knife (GK; Elekta Instru-
ments AB, Stockholm, Sweden) unit, or protons generated by
a cyclotron or synchrotron unit, 1,2 typically performed in one,
but up to five, session(s). Stereotactic radiosurgery has been
used extensively to treat intracranial tumors in adults and
has become one of the standard treatments for certain
tumors. In contrast, there are relatively limited data on the
use of SRS in the treatment of pediatric brain tumors. In this
population, there is an added emphasis on limiting the mor-
bidity of radiation-induced damage to the brain, which in
some patients may lead to neurocognitive, neurologic, and
neuroendocrine dysfunction. As a result of its favorable dosi-
metric characteristics, SRS represents a very attractive treat-
ment modality for some pediatric patients with brain
tumors. Through this modality, the dose and volume of nor-
mal brain irradiated can be reduced, and subsequently the Fig. 26.1 An Aquaplast was fabricated with piers where the pins can be
toxicities that are critically dependent on these two factors inserted for fixation. (From Witt TC, Lo SS, Timmerman RD. Successful
can minimized. The physics and radiobiology of SRS are cov- treatment of a skull base malignant rhabdoid tumor with surgery,
ered in other chapters of this book. In this chapter, we focus chemotherapy and Gamma Knife-based stereotactic radiosurgery in a
on the clinical applications and results of single-fraction SRS young child. Stereotact Funct Neurosurg. 2007;85:310–313. Used with
permission from Karger AG, Basel.)
in the treatment of pediatric brain tumors.

210

procedure.3 To ensure the delivery of high-quality treatment,
patients need to remain still and cooperative during head frame
placement, acquisition of computed tomography (CT) or mag-
netic resonance images (MRIs), and treatment delivery.1,2 Thus,
prolonged anesthesia of those children undergoing SRS can be
expected. When treatment planning is performed, the neuro-
surgeon and radiation oncologist must strike a balance between
the time required in treatment planning and delivery against
the extraconformality achieved with more complex planning.
During treatment delivery, to avoid unnecessary radiation
exposure to support staff in the treatment area, patients are
usually monitored by the anesthesiologist in the control area. A
new model of GK, the Perfexion (Elekta AB), allows for short-
ened treatment and planning times by automating treatment
delivery and adding inverse treatment-planning functionality,
features that may be beneficial for pediatric patients receiving
SRS.
A frameless robotically controlled radiosurgical system such
as CyberKnife (Accuray, Inc., Sunnyvale, CA) can potentially
solve some of the problems associated with frame-based radio-
surgical systems. Other linear accelerator– (linac-)based sys-
tems allow for frameless stereotactic delivery too. In particular,
given the image acquisition, treatment planning, and treatment
delivery that occur during separate sessions, the time required
for the patient to be sedated may be substantially reduced, and
conscious sedation methods may be explored. The feasibility,
safety, and efficacy of the use of this system in the treatment of
brain tumors in pediatric patients, including very young chil-
dren, have been demonstrated.4
26.3 Treatment Options for
Specific Tumors
26.3.1 Ependymomas
Ependymomas account for 5 to 10% of all pediatric brain
tumors.5 Histologically, ependymomas are well-delineated,
moderately cellular gliomas that have a sharp demarcation
from the surrounding brain parenchyma. Because of this char-
acteristic, they are very well suited for SRS, where the pre-
scribed isodose conforms highly to the target volume, and there
is a rapid falloff of the radiation dose beyond the target volume.
Although not specifically categorized by Larson et al, based on
their characteristics, ependymomas can be regarded as class IV
targets (tumor composed of early-responding tissue with no
intermingling normal brain tissue).6
The most important factor that determines survival for
patients with ependymomas is the extent of surgical resec-
tion,5,7,8 and the presence of gross disease predicts a poor prog-
nosis. The use of SRS in pediatric ependymoma is mainly in
three settings, namely, as a boost after external beam radiation
therapy (EBRT), as a salvage treatment of recurrent disease, and
less commonly, as the sole treatment.
26.3.2 Boost Therapy
In pediatric patients with ependymomas treated in the primary
setting, a radiation dose response has been demonstrated. 8,9
This is particularly relevant in patients with high-risk,
Stereotactic Radiosurgery for Pediatric Brain Tumors
incompletely resected tumors. In the Pediatric Oncology Group
(POG) 9132 study, where radiation dose escalation to 69.6 Gy
was achieved through hyperfractionation, the 19 patients who
underwent subtotal resection had superior survival outcomes
compared with historic controls from the previous POG 8532
trial.5 Given SRS can deliver a single focused high dose of radia-
tion to a target volume, it has been used as a boost therapy after
EBRT for these high-risk patients.
Investigators from St. Jude Children’s Research Hospital
(Memphis, TN) reported their early experience with this
approach. Five pediatric patients with residual enhancing epen-
dymoma measuring < 3 cm received a boost with linac-based
SRS after EBRT to doses of 50.4 to 55.8 Gy. 10 The SRS dose was
10 Gy (range 9–15 Gy) prescribed to the 80% isodose line, deliv-
ered within the first 30 days after completing EBRT. With a
median follow-up time of 24 months, 80% survived with no evi-
dence of tumor progression, whereas complete responses were
achieved in three patients (60%). Radionecrosis occurred in one
(20%) of the five patients. In a pediatric SRS series from Harvard
University (Boston, MA), 3 of the 28 patients with ependymoma
treated with SRS received it as a boost therapy after EBRT. 11
Two (67%) of the three patients survived without evidence of
disease progression at 30 and 62 months after radiosurgery. In
a series of nine patients treated with SRS for ependymoma from
Washington University (St. Louis, MO), three were treated with
SRS as a boost therapy after EBRT to doses of 45.0 to 53.6 Gy. 12
With follow-up times ranging from 56 to 91 months, the
relapse-free survival rate was 100%. Two (67%) of the three
patients developed complications (seizures in one patient and
facial nerve palsy in the other) after SRS. In the series from Indi-
ana University (Indianapolis, IN), two pediatric patients were
treated with SRS as boost therapy after EBRT to doses of 54.0 to
55.8 Gy.13 Both patients remained progression-free at 40 and 65
months, respectively. One of the two patients developed radio-
necrosis, which was controlled with hyperbaric oxygen and ste-
roid therapy.
In summary, the combination of EBRT and boost with SRS is
associated with excellent local control of gross residual disease
in ependymoma, and may result in long-term progression-free
survival (PFS). Late radiation complications may occur, particu-
larly radionecrosis in the setting of dose escalation. Currently,
there are no prospective data supporting this approach, and a
prior POG phase II trial involving the use of SRS as a boost ther-
apy for pediatric patients with high-risk ependymoma was
closed, secondary to poor accrual. Future trials testing this
approach may be worthwhile to accurately delineate the risks
and benefits.
26.3.3 Salvage Therapy for Recurrent
Disease
The recommended treatment for patients with recurrent epen-
dymoma after prior surgery and postoperative EBRT is salvage
surgical resection. However, a complete resection may not be
safely achievable in some cases. Although chemotherapy may
also be tried, tumor responses are typically suboptimal. Stereo-
tactic radiosurgery provides an additional salvage option par-
ticularly suited for patients with recurrent ependymoma in
whom complete resection is not feasible.
211
 Stereotactic Radiosurgery for Pediatric Brain Tumors
In an early series from the University of Pittsburgh (Pitts-
burgh, PA), seven pediatric patients with recurrent ependymo-
ma (grade not specified) were treated with GKSRS. The
reported recurrence rate was 100%, and the time to progression
was 6 months.14 In a subsequent study from the same institu-
tion, 21 pediatric patients with recurrent or progressive epen-
dymoma (12 patients) or anaplastic ependymoma (9 patients)
were treated with GKSRS, to a median dose of 15 Gy (range 9–
22 Gy).15 At a median follow-up of 27.6 months, local control
was achieved in 72% of treated tumors, although distant intra-
cranial relapse occurred in 10 out of 21 patients (47%), and the
3-year distant failure rate after SRS was 80.3%. Ipsilateral facial
paresis developed in a single patient (4.8%) after a marginal
dose of 12 Gy and subsequently resolved after a short course of
steroids. Hodgson et al from Harvard University reported that
among 28 pediatric patients treated with SRS for ependymoma
(3 treated with SRS as boost therapy after EBRT and the remain-
ing treated for recurrent disease), the median PFS was 8.5
months, and the 3-year local control was only 29%.11 Out of the
25 patients treated for recurrent disease, only 3 remained dis-
ease-free. In a series from the Mayo Clinic (Rochester, MN), 26
212
adult and pediatric patients with 49 lesions were treated with
GKSRS.16 Nineteen patients (73%) had received prior cranial
external beam radiotherapy to a median dose of 54 Gy, and a
single patient developed an intracranial lesion after presenting
with a spinal ependymoma. The median prescribed dose was
18 Gy (range 12–24 Gy). After a median follow-up of 3.1 years,
the 3-year local control for all lesions treated was 72%, whereas
38 and 27% of patients developed marginal and distant failures,
respectively. Pathologically confirmed radiation necrosis was
seen in two patients (7.7%). In the Indiana University series, five
patients (two children) with 10 recurrent ependymomas were
treated with GKSRS.13 Out of the five patients who received SRS
as salvage treatment, three (60%) were alive, two (40%) were
alive without recurrence, two (40%) developed distant failure,
and three (60%) had in-field control. The 3-year in-field control
for the 10 recurrent tumors was 62.5%. ▶ Fig. 26.2 shows a case
example of SRS for treatment of resected recurrent anaplastic
ependymoma.
In summary, children presenting with recurrent ependymo-
mas not amenable to complete surgical resection have very few
effective treatment options. Local tumor progression is
Fig. 26.2 A 2-year-old child exhibited a localized
posterior fossa anaplastic ependymoma. The
patient underwent gross total resection and
postoperative radiotherapy to the operative bed
with a dose of 54 Gy in 30 fractions. He
developed recurrence in the posterior fossa (a)
and lumbar spine region and underwent gross
total resection of tumor in the posterior fossa (b)
and lumbar spine. To avoid pin insertions
associated with Gamma Knife–based stereotactic
radiosurgery in this very young child, CyberKnife
was used instead to deliver stereotactic radio-
surgery to the tumor bed and a dose of 12 Gy in
one fraction prescribed at 80% (c). There was no
evidence of disease after 18 months.
 Stereotactic Radiosurgery for Pediatric Brain Tumors

uniformly fatal, and currently available chemotherapy has been
used with limited success. Stereotactic radiosurgery provides a
minimally invasive, localized treatment modality, with the lim-
ited available data suggesting that some patients may achieve
objective responses and prolonged local control. However, mar-
ginal and distant central nervous system (CNS) relapses remain
significant issues; thus, more effective chemotherapy treat-
ments need to be developed.
26.3.4 Stereotactic Radiosurgery as the
Sole Postoperative Treatment
Stereotactic radiosurgery is seldom used as the sole, postopera-
tive intervention for gross disease in ependymoma because
most patients usually undergo EBRT. Rare exceptions are lim-
ited to patients in whom the morbidity of EBRT has been
deemed excessive; there is a scarcity of data in the literature on
this approach. In a series from Indiana University, a 16-month-
old child who had partial response to chemotherapy alone for a
subtotally resected cerebellopontine angle ependymoma
received SRS as the sole radiotherapeutic treatment, with the
goal of delaying EBRT. The ependymoma progressed after 13
months, and salvage treatment with further chemotherapy and
conformal radiation therapy was given.13
Given the lack of robust data from the literature documenting
its efficacy and safety in the up-front, postoperative setting, SRS
should not be offered in this fashion outside of a clinical trial
setting. ▶ Table 26.1 summarizes the treatment outcomes of
selected series.
26.4 Low-Grade Astrocytomas
World Health Organization (WHO) grade I and II astrocytomas
are collectively known as low-grade astrocytomas, which occur
in both adult and pediatric patients. Pilocytic astrocytomas
(WHO grade I) represent the most indolent subtype of low-
grade astrocytomas, with 10-year survival rates of over 95% in
the pediatric population.17 Diffuse astrocytomas (WHO grade II)
carry a slightly worse prognosis in the pediatric population,
with 10-year survival rates of approximately 80%.17 The main-
stay of treatment is maximal safe surgical resection, if achiev-
able. If a complete resection is not achieved, chemotherapy is
often given in young children to delay the need for immediate
postoperative radiation therapy due to concerns of collateral
damage it may cause to the developing brain. However, if gross
total resection or subtotal resection can be achieved, observa-
tion may be appropriate. In the recurrent setting, treatment
options may be more limited.
As described by Larson et al, low-grade astrocytomas or glio-
mas are classified as category III targets, which are defined as
early-responding targets intermingled with late-responding
normal brain parenchyma.6 It is more common to have normal
brain parenchyma intermingled with the target tissue in WHO
grade II astrocytomas than those which are WHO grade I. Based
on these characteristics, low-grade astrocytomas are not
regarded as ideal targets for SRS given the large amount of nor-
mal brain tissue that would need to be treated to encompass
the entirety of known disease.6 Stereotactic radiosurgery has
been used in the treatment of low-grade astrocytoma in chil-
dren in select clinical scenarios, but the data on its safety and
efficacy remain limited.
In one of the largest experiences with SRS in pediatric low-
grade astrocytomas, investigators from the University of Pitts-
burgh described 37 patients (25 pediatric patients) with recur-
rent or unresectable pilocytic astrocytoma treated with SRS. 18
Eighteen patients had brainstem tumors. The prescribed dose
was 15 Gy. At a median follow-up of 28 months, 10 had com-
plete response, 8 had partial response, 7 had stable findings,
and 12 had delayed tumor progression on imaging studies,
resulting in a crude survival rate of 89%. There was no treat-
ment-related mortality. The researchers also reported their

Table 26.1 Summary of treatment outcomes of stereotactic radiosurgery for ependymoma in children
Study N Histology Marginal dose (Gy) Setting of treatment Local control (%)

Aggarwal et al10 5 Ependymoma 10 Boost 80

Grabb et al14 7 Ependymoma 11–20a Salvage 0

(grade not specified)

Kano et al15 21 (32 lesions) Ependymoma (12 pa- 15 Salvage 72%

tients), Anaplastic
ependymoma (9 pa-
tients)

Hodgson et al11 28 Ependymoma 12.5 Salvage and boost 29b

3 Not specified Boost 67

Stafford et al73 12 (adults and chil- Ependymoma 18 Salvage 68

dren)

Lo et al13 5 (2 children) Ependymomac 12–20 Salvage 60d

2 12–14 Boost 100

aDose range for the whole group of 25 children (including those with other histologies).
bLocal control for all 29 patients.
cOne patient had anaplastic ependymoma.
dLocal control for all five patients.

213
 Stereotactic Radiosurgery for Pediatric Brain Tumors
treatment outcomes of SRS for WHO grade II fibrillary astrocy-
toma.19 Twelve patients (four children) with progressive disease
were treated with SRS to a median dose of 16 Gy and a volume
ranging from 1.2 to 45.1 mL. Four of the 12 patients had tumors
in the brainstem. At a median follow-up of 52 months, all
patients were alive. Five patients had tumor shrinkage (one
complete and four partial responses), three had stable findings,
and four had delayed progression. The crude freedom from pro-
gression (FFP) rate was 67%.
Investigators from Taiwan also reported on their experience
with 21 adult and pediatric patients (25 lesions) treated with
GKSRS for low-grade gliomas, predominantly as salvage treat-
ment (72%), but also as primary treatment (19%) or boost after
EBRT (9%).20 The median peripheral tumor dose was 14.5 Gy
(range 8–18 Gy). After a median follow up of 67 months, the
10-year PFS was 65% and complete remission rate was 17%,
with all treatment failures occurring within the radiation field.
Acute radiation effects (AREs) were graded as mild to moderate
in 40% of patients, with most demonstrating minimal to no clin-
ical symptoms. Similar findings were demonstrated in a cohort
of 24 pediatric patients treated with GKSRS for low-grade glio-
mas at the University of Virginia.21 The cohort consisted pri-
marily of 19 patients (79%) with biopsy-proven low-grade
gliomas, whereas 1 patient (4%) had a WHO grade III lesion and
4 patients (17%) did not undergo biopsies for presumed brain-
stem gliomas. Lesions were treated to a median dose of 15 Gy
(range 4–20 Gy), with a mean treatment tumor volume of
2.4 cm3. At a median radiographic follow-up of 74 months, com-
plete tumor responses were seen in five patients (21%). At last
follow-up, the PFS rate was 83%, with higher progression rates
seen in larger tumors. Increased edema after GK without tumor
progression was seen in four patients (12.5%), although no
patients experienced radiographic radiation necrosis.
Investigators from Japan reported on another large cohort of
51 adult and pediatric patients with low-grade astrocytomas,
Table 26.2 Summary of treatment outcomes of stereotactic radiosurgery for low-grade astrocytomas in children
Study N Histology
Eder et al34 12 Not specified
Hadjipanayis et al18 25 JPA
Hadjipanayis et al19 12 (4 children) Well-circumscribed
WHO grade II astrocy-
toma
Kida et al22 51 (adult and children) WHO grade I astrocy-
toma WHO grade II
astrocytoma
Barcia et al23 16 Low-grade glioma
Boëthius et al24 16 JPA
Wang et al20 21 WHO grade I and II
astrocytoma
Weintraub et al21 24 Who grade I/II astrocy- 15
toma (80%)
Abbreviations: JPA, juvenile pilocytic astrocytoma; WHO, World Health Organization.
aLocal control of 37 patients, including 12 adults.
bLocal control for all 12 patients.
cLocal control of 19 patients, including 3 adults.
214
who were treated with GKSRS.22 Out of the 51 patients, 12 had
WHO grade I astrocytomas around the optic pathway or hypo-
thalamus, whereas the remaining patients had WHO grade II
astrocytomas. The mean age for patients with grade I astrocyto-
mas was 9.8 years. The mean prescribed doses for grade I and II
tumors were 12.5 and 15.7 Gy, respectively, with respective
tumor diameters of 2.54 and 2.37 cm. With a median follow-up
period of 27.6 months, the response rates for grade I and II
astrocytomas were 50.0 and 46.2%, respectively.22 The corre-
sponding tumor control rates were 91.7 and 87.2%, respec-
tively.22 There was a significantly better response among
patients 10 years of age or older with grade I tumors and those
with a follow-up period of more than 24 months. Radiation-
induced edema occurred in 18 (35.3%) patients, cyst formation
or enlargement in 5 (9.8%), and transient tumor enlargement in
3 (5.9%).22
In a study from Spain, Barcia et al reported the treatment
results of 16 patients with low-grade gliomas treated with SRS,
6 of whom had prior conventional radiation therapy.23 The
mean dose given was 21.7 Gy. Complete response and partial
response or stabilization were observed in 50 and 31% of the
tumors treated, respectively.23 Three patients with tumors
located in the brainstem died of tumor progression. Swedish
investigators also reported favorable treatment outcomes in 19
patients (16 children) treated with SRS for pilocytic astrocyto-
ma.24 The median tumor volume and the median prescribed
dose were 2.2 mL and 10 Gy, respectively. Out of the 19 patients
treated, the tumor shrinkage rate was 85% and 95% achieved
tumor control at a median follow-up of 4.7 years.24 Increased
contrast enhancement and edema attributable to SRS were
observed in 25% of the patients.24 ▶ Table 26.2 summarizes the
treatment outcomes of selected series.
In summary, despite the notion that low-grade astrocytomas
are not ideal targets for SRS, data from various series have dem-
onstrated good local control and acceptable toxicity profile.
Marginal dose (Gy) Setting of treatment Local control (%)
10–18 Primary or adjuvant 77
15 Primary or salvage 89a
16 Primary or salvage 67b
12.5 Not specified 91.7
15.7 87.2
21.7 Primary or boost 81
10 Adjuvant 94c
14.5 Primary, boost, or sal- 65
vage
Primary or salvage 83

Fig. 26.3 A 5-year-old patient with a WHO grade I (pilocytic)
astrocytoma in the posterior fossa treated with Gamma Knife
radiosurgery to a prescribed marginal dose of 12 Gy.
▶ Fig. 26.3 shows the treatment plan of a WHO grade I astrocy-
toma treated with SRS. It appears that SRS is especially useful in
cases where there is a prior history of EBRT and complete surgi-
cal resection is not possible. Moreover SRS has shown promise
in the primary setting when the tumor location precludes com-
plete resection. However, for these same reasons, practitioners
should be cautious regarding possible toxicity given the lack of
prospective data, and strict adherence to the available data on
normal tissue tolerance for SRS should be observed. Currently,
there are not enough data to support the routine use of SRS in
children with newly diagnosed low-grade astrocytoma; this is
best tested in a clinical trial setting.
26.5 High-Grade Gliomas
High-grade gliomas constitute 15% of primary brain tumors in
children, and usually carry a dismal prognosis despite the
improvement in treatments in the past two decades.2 They
have a propensity to spread microscopically beyond the extent
of tumor demonstrated on diagnostic imaging, but the main
pattern of failure is still within 2 cm of the original tumor. 25 In
adults, prospective trials and studies have been done using
hyperfractionation or addition of a boost with brachytherapy. 26,
27 Because of its favorable dosimetric characteristics, SRS has
also been used as a boost therapy for dose escalation in adults
with high-grade gliomas,28 as well as in the recurrent setting
after prior EBRT. Given the similar poor prognosis in children,
SRS has been used in children with high-grade gliomas as pri-
mary or adjuvant treatment, boost therapy, and salvage treat-
ment for recurrent disease. However, data regarding the use of
SRS in these settings are very limited. In a series from Harvard
University, 18 patients with glioblastoma multiforme or ana-
plastic astrocytoma received SRS.11 Out of the 18 patients
treated, only 4 of them, all of whom received SRS as boost ther-
apy, survived, with progression after 50 to 119 months.11 The
Stereotactic Radiosurgery for Pediatric Brain Tumors
overall median survival time was 12 months after SRS. Other
series showed similar dismal outcomes. In a study from the
University of California, San Francisco, 11 children with high-
grade gliomas were treated with SRS. Out of the 14 tumors
treated, only 5 (36%) were controlled.29 In the study from the
University of Pittsburgh, 12 children with malignant glial
tumors (malignant astrocytoma or ependymoma) were treated
with GKSRS. Ten of the children had prior EBRT. Five of them
were alive 12 to 72 months after SRS, with three remaining dis-
ease-free.14 The remaining seven children died of their disease,
with a median survival of 6 months.
Based on the very limited data available, it is very difficult to
draw any meaningful conclusions regarding the role of SRS in
the management of high-grade gliomas in children, as the diag-
nosis portends a uniformly poor prognosis. Attempts have been
made by the Children’s Cancer Study Group (CCG) and the POG
to conduct prospective trials to test the use of SRS in recurrent
pediatric brain tumors, but they were closed because of poor
accrual. If data are extrapolated from adult literature, there
does not seem to be enough evidence to support the routine
use of SRS as the sole treatment or as boost therapy after EBRT
in children with high-grade gliomas. Radiation Therapy Oncol-
ogy Group (RTOG) has conducted a phase III randomized trial
(RTOG 9305) comparing no boost and SRS boost after EBRT and
carmustine (BCNU) chemotherapy for adult patients with glio-
blastoma multiforme, but has not resulted in any improvement
in survival outcomes.28 However, SRS may have a role in the
recurrent setting when there is a history of prior EBRT, when
the patient is not responding to chemotherapy, or when com-
plete surgical resection is not achievable. An evidence-based
review by the American Society for Therapeutic Radiology and
Oncology (ASTRO) arrived at the same conclusions.30
26.6 Medulloblastomas
Medulloblastomas constitute 15 to 20% of all childhood primary
brain tumors.9 Secondary to the high propensity for spinal axis
dissemination, craniospinal irradiation followed by a posterior
fossa boost with or without chemotherapy after maximal safe
resection of the tumor is the standard therapy. Like other
malignant brain tumors, a radiation dose response has been
demonstrated in medulloblastomas.9 Stereotactic radiosurgery
can potentially be used as boost therapy to escalate the radia-
tion dose to residual disease after EBRT. It can also be used as
salvage therapy for children who develop recurrence after radi-
ation therapy.
There are very scarce data on the use of SRS for the treatment
of children with medulloblastomas. Two series came from Har-
vard University. In the earlier series, 11 children with recurrent
and 3 children with newly diagnosed medulloblastomas were
treated with SRS to a median dose of 12 Gy as salvage treatment
and as boost therapy, respectively.31 The three patients who
received SRS as boost therapy were alive without evidence of
recurrence at a median follow-up interval of 27 months.31 Out
of the 11 children with recurrent disease, 6 developed distant
failure and eventually died of their disease, but none of the 11
patients failed locally. Their median survival time was 10
months.31 In their subsequent study with more patients
included and longer follow-up interval, Hodgson et al reported
215
 Stereotactic Radiosurgery for Pediatric Brain Tumors
a median progression-free survival time of 11 months. The 3-
year local control rate was 57%.11 Again, the main pattern of
failure was distant. In a smaller study by Woo et al, the reported
local control rate of the four patients (two children) treated
with SRS as boost therapy after craniospinal and posterior fossa
irradiation was 100%.32 The prescribed dose ranged from 4.5 to
10.0 Gy. Finally, investigators from the United Kingdom
reported on their experience with three patients treated for
isolated intracranial relapses (one to three lesions) of medullo-
blastoma.33 At median prescribed doses of 15 to 25 Gy and fol-
low-up of between 2.5 and 4 years after SRS, two patients
demonstrated complete responses, whereas the third demon-
strated stable disease. No patients have developed out of field
failures.
Based on the very limited data available, it is very difficult to
draw meaningful conclusions regarding the role of SRS in this
disease. Given our knowledge that the amount of residual
tumor after surgical resection affects disease control, using SRS
as boost therapy appears to be a sound approach for radiation
dose escalation to residual tumor. However, at present, there is
insufficient evidence to support this treatment approach as
routine practice in children with residual medulloblastoma
after surgical resection, and these high-risk patients should
continue to be enrolled on available clinical trials. In the recur-
rent setting, in which treatment options are usually much more
limited, SRS can provide a noninvasive option for ablative local
therapy. Based on the limited data from the literature, SRS may
provide reasonable local control for recurrent medulloblasto-
ma. However, it does not address the risk of distant failure,
which is addressed with chemotherapy.
26.7 Meningiomas
Meningiomas are rare in children and account for 1 to 3% of all
childhood intracranial tumors.9 The standard treatment is com-
plete surgical extirpation. If a gross total resection is achieved
and the pathology confirms a WHO grade I tumor, no further
treatment is required. However, complete resection of meningi-
omas in difficult locations, such as the skull base, is not always
achievable even with modern microsurgical techniques.
In adults, SRS has become one of the standard treatments for
meningiomas. There are abundant data in the literature docu-
menting the efficacy and safety of SRS in the treatment of men-
ingiomas in adults; this is discussed elsewhere in this book.
216
Radiobiologically, meningiomas are category II targets (tumor
composed of late-responding tissue with no intermingling nor-
mal brain tissue) and have a sharp demarcation from normal
brain parenchyma.6 Although these characteristics lend them-
selves well to SRS, the data on the use of SRS for the treatment
of children with meningiomas are very limited.
Eder et al reported the treatment results of two pediatric
patients treated with GKSRS for skull base meningiomas. Tumor
shrinkage after treatment was demonstrated in both patients. 34
Im et al reported tumor control at 2.5 years in a 15-year-old pa-
tient who underwent GKSRS after subtotal resection for a men-
ingioma.35 Other reports included both adult and pediatric
patients, and the results were collectively reported. In a series
of 121 adult and pediatric patients treated with GKSRS, DiBiase
et al reported a crude local control rate of 91.7%. 36
Data from the large body of experience in adults and limited
data in children suggest that SRS is a safe and efficacious treat-
ment for meningiomas. It appears that similarly favorable out-
comes in adults can be reproduced in children, although
caution should be exercised in its routine practice given results
of a recent meta-analysis of pediatric meningiomas failing to
demonstrate any significant relapse-free survival benefit with
up-front radiation therapy (almost exclusively EBRT).37 The typ-
ical prescribed dose for meningiomas in adults is 12 to 18 Gy,
and similar guidelines should apply to children. ▶ Fig. 26.4
shows the treatment plan of a prepontine meningioma treated
with SRS.
26.8 Vestibular Schwannomas
Vestibular schwannomas (VSs) are typically slow-growing
benign tumors that usually occur in adults. In children, VSs are
usually associated with neurofibromatosis type II (NF2).9 Treat-
ment options include observation, surgery, SRS, and fractio-
nated radiation therapy. Vestibular schwannomas are regarded
as category II targets, and they have very sharp margins of
demarcation from the surrounding normal tissue.6 These char-
acteristics render them excellent targets for SRS.
Stereotactic radiosurgery has emerged as one of the standard
treatments for VSs. There is a large body of experience in the
use of SRS in adults, but the data on its use in pediatric patients
are scarce.38,39 In the earlier adult series where the prescribed
marginal dose was 16 to 20 Gy, there was a substantial inci-
dence of hearing loss and cranial nerve deficits.39,40 These
Fig. 26.4 A 16-year-old patient with a prepontine
meningioma treated with Gamma Knife radio-
surgery to a prescribed marginal dose of 12 Gy.

results have prompted dose reduction to minimize those risks.
Utilization of reduced doses of 12 to 13 Gy in modern series has
resulted in a much higher rate of preservation of serviceable
hearing and also a lower incidence of trigeminal and facial
nerve injury from SRS.38,39
In a series from the University of Pittsburgh, 62 adult and
pediatric patients with 74 VSs were treated with GKSRS for VS
associated with NF2. Patients with bilateral VSs were treated
with staged SRS. The median marginal dose was 14 Gy. Thirty-
two tumors were associated with complete deafness, whereas
the remaining tumors were associated with some hearing func-
tion (26 of them associated with serviceable hearing). The local
control rates were 85, 85, and 81%, respectively, at 5, 10, and 15
years.41 The rates of preservation of serviceable hearing were
73, 59, and 48% at 1, 2, and 5 years, respectively, if MRI-based
image-guided treatment planning and a prescribed dose of < 14
Gy were used.41 Other studies including both adults and chil-
dren treated with SRS for VS associated with NF2 showed simi-
larly favorable tumor control rates, but worse hearing
preservation rates.42,43 ▶ Table 26.3 summarizes the treatment
outcomes of selected series.
In children, VS is usually associated with NF2, and special
considerations have to be taken in treatment recommenda-
tions. Preservation of serviceable hearing is of particular impor-
tance in children because hearing deficits can result in speech
and learning problems. Compared with sporadic VS, a higher
risk of treatment-related complications is observed in NF2-
associated VS.41 Furthermore, patients with the latter may
develop multiple CNS tumors, and it has been postulated that
radiation might predispose NF2 patients who have loss of one
allele of a tumor suppressor gene to late secondary malignant
transformation. Therefore, the goals of therapy are shifted
toward improving the therapeutic ratio and minimizing treat-
ment-related morbidity rather than complete tumor ablation at
all costs. In those with asymptomatic NF2-associated VSs, close
observation may also be the most reasonable option. Treatment
should be pursued, however, when there is progressive hearing
loss or evidence of progressive tumor growth in symptomatic
lesions. Stereotactic radiosurgery provides a minimally invasive,
effective method to control those tumors. Although malignant
Table 26.3 Summary of treatment outcomes of stereotactic radiosurgery for vestibular schwannoma associated with neurofibromatosis type II in chil-
dren
Study Age range (y) No. of patients/ Dose (Gy)
tumors
Kida et al42 7–71 20/20 13 (10–15)
Rowe et al43 11–59 96/122 Mostly 10–16, with 79
30 tumors receiv-
ing 17.5–25.0
Phi et al74 13–55 30/36 8–14
Meijer et al75 11–70 7/7 10–12
Sharma et al76 10–56 30/54 10–15
Mathieu et al41 11–79 60/72a 14 (11–20)
Abbreviation: CN, cranial nerve.
aTwo patients were lost to follow-up.
Stereotactic Radiosurgery for Pediatric Brain Tumors
transformation of NF2-associated VS has always been a concern
after SRS,44 there is no conclusive evidence in the literature sug-
gesting that the rates are higher in those with NF2 when com-
pared with the very low rate reported in sporadic VSs.41 In
those refractory to other treatment, systemic therapy may be
beneficial.45
26.9 Craniopharyngiomas
Craniopharyngiomas are benign brain tumors that commonly
occur in children. They are commonly characterized as being
purely solid, purely cystic, or mixed solid and cystic. If feasible,
maximal safe resection is the gold standard treatment. How-
ever, complete surgical resection is not always achievable, and
radiation therapy is often offered in the postoperative or sal-
vage settings to improve local control.2 Occasionally, primary
EBRT or intralesional brachytherapy is offered.
Similar to other extra-axial benign tumors in childhood, cra-
niopharyngiomas have sharp margins of demarcation from the
surrounding structures2 and based on the description by Larson
et al should be regarded as category II targets.6 These character-
istics lend themselves well to SRS, allowing for a rapid falloff of
radiation dose beyond the target volume and potentially lead-
ing to reduced toxicity. However, the typically close proximity
of the optic apparatus and hypothalamus with the tumor may
not allow for the differential dose delivery to the target and at
risk tissue, thus posing a challenge in the use of SRS for
treatment.9
There is a moderate amount of data from the literature on
the use of SRS for craniopharyngiomas in adults and children.
In a study from Sweden, the treatment outcomes of 21 patients
(11 children) with 22 craniopharyngiomas were reported. The
prescribed dose ranged from 3 to 25 Gy, and mean tumor vol-
ume was 7.8 mL. Some patients who had craniopharyngiomas
with a cystic component received SRS for the solid component
and intralesional brachytherapy for the cystic component. With
a mean follow-up time of 7.5 years (range 0.5–29.0 years), 5
tumors shrank in size, 3 were unchanged, and 14 enlarged.46
Eleven (85%) of 13 tumors that received a dose < 6 Gy to the
Tumor control (%) Hearing preserva- Complications (%)
tion (%)
100 33.3 CN VII: 20%
40 CN VII: 8%
CN V: 2%
66 33 CN VII: 5.6%
CN V: 2.8%
100 54 CN VII: 0%
67.3 67 CN VII: 3.1%
88 53 CN VII: 8%
CN V: 4%
217
 Stereotactic Radiosurgery for Pediatric Brain Tumors
margin enlarged compared with only 3 (33%) of 9 tumors that
received > 6 Gy.46 Nine (82%) of 11 tumors in children ultimately
enlarged after SRS, compared with 5 (50%) of 10 in adults. Eight
patients developed visual deterioration, which was attributed
to tumor enlargement in all but one case.46 Four patients devel-
oped pituitary deficiencies. In a study from Taiwan, Chung et al
treated 31 patients (9 children younger than 16 years) who had
craniopharyngioma with SRS. Ten tumors were purely cystic, 5
purely solid, and 16 mixed cystic and solid. Two patients had
EBRT. Although the tumor marginal doses ranged from 9.5 to
16.0 Gy (mean 12.2 Gy), the dose delivered to the optic appara-
tus was limited to 8 Gy (range 7.2–12.5 Gy). Three patients
underwent stereotactic aspiration to decompress the cystic
component before SRS. The mean target volume was 8.94 mL.
The tumor response and tumor control rates were 64.6 and
87.2%, respectively, and the complete response rate was
32.7%.47 Tumors that were purely cystic or solid had better local
control than tumors with mixed components, and smaller
tumors had better tumor control than larger ones. Three
patients developed cystic enlargement of their tumor that com-
pressed the adjacent structures at 5, 8, and 17 months after
SRS, respectively.47 They all required further intervention for
decompression.47
In an analysis from the University of Virginia (Charlottesville,
VA), Xu et al reviewed their experience with 37 patients (17
children) undergoing 39 GKSRS procedures for patients with
craniopharyngioma.48 Although a few patients underwent SRS
as primary treatment (4 patients were clinically diagnosed and
2 patents received biopsies only), an additional 28 patents
underwent previous surgery, and 2 underwent prior cyst aspi-
ration. Only the solid portions of tumor were targeted with
GKSRS, with a median tumor volume of 1.6 cm3 (range 0.1–
18.6 cm3) and prescribed to a median marginal dose of 14.5 Gy
(range 6–25 Gy). Cystic portions of tumor received either aspi-
ration or phosphorus-32 treatment. At a median follow-up of
50 months, the 5 year in-field PFS rate was 67.0%. In a multi-
variate analysis, factors relating to longer PFS included absence
of visual field defects at the time of SRS, tumor volume ≤ 1.6
cm3, and marginal dose > 14.5 Gy. Mokry et al from Austria
reported on 23 patients (11 children < 15 years) who had cra-
niopharyngiomas treated with SRS. Ten patients underwent
cyst aspiration and intracystic instillation of bleomycin prior to
SRS. The mean dose was 10.8 Gy (range 8–15 Gy). Tumor control
was 56%.49 Five patients with multicystic residual or recurrent
tumors developed tumor progression.
Another study by Amendola et al reported on the outcomes
of 14 patients (12 children) who had craniopharyngiomas
treated with GKSRS. The mean dose was 14 Gy, whereas the
maximum doses to the optic apparatus and brainstem were
limited to 8 and 14 Gy, respectively. One patient had prior EBRT.
A PFS rate of 100% was achieved at follow-up times ranging
from 6 to 86 months.50 In the series from the University of Pitts-
burgh, 46 patients (15 patients < 14 years old) received GKSRS
for craniopharyngiomas, of whom 3 patients were treated in
the primary setting and 43 patients were treated for recurrent/
residual disease.51 The median marginal dose was 13.0 Gy
(range 9.0–20.0 Gy), the median tumor volume was 1.0 cm 3,
and the median follow-up was 32 months. Tumor control varied
according to tumor type and SRS coverage. In solid and cystic
tumor types, the 5-year tumor control with complete coverage
218
was 77.5 and 100%, respectively. In patients with mixed tumors,
the 5-year control rate for complete tumor coverage and solid
component coverage only was 64.3 and 51.9%, respectively. In
patients with normal visual function before SRS, two patients
(8%) had worsening vision, whereas in patients with visual defi-
cits before SRS, two patients (11%) and five patients (26%) had
improvements and worsening of their visual function, respec-
tively. All three patients with normal baseline endocrine func-
tion prior to SRS did not develop any endocrine abnormalities
afterwards, whereas two patients with anterior hypopituitar-
ism (13%) showed changes in their function after SRS (one
improved, one worsened). The 28 patients with panhypopitui-
tarism prior to treatment remained so after treatment.
In a report from Pakistan, 35 patients (17 children) were
treated with SRS for craniopharyngiomas after one of several
previous treatments, including 11 patients receiving microsur-
gical procedures, 12 patients receiving cyst fenestration/aspira-
tion, and 2 patients receiving EBRT.52 A mean lesion volume of
12 cm3 (range 1–33.3 cm3) was treated to a mean prescription
dose of 11.5 Gy (range 8–14 Gy). At a mean follow–up of 22
months, the tumor response rate (complete or partial response)
and control rate after GKSRS were 77.1 and 88.5%, respectively.
Subsequent surgical intervention was required in several
patients, including four patients undergoing stereotactic cyst
aspiration, two requiring ventriculoperitoneal shunting, and
two requiring Ommaya reservoir placement. Among those pre-
senting with visual impairment, seven patients (50%) had
improvement in symptoms, whereas one patient (7%) had wor-
sening acuity despite decreased tumor size.
The largest body of experience on SRS for craniopharyngioma
to date was reported by a group in Japan. Kobayashi et al
reported the treatment outcomes of 107 patients (38 patients <
15 years) who had craniopharyngiomas treated with GKSRS.
Among those patients, 13 had prior external beam radiother-
apy. Ninety-eight patients had follow-up information. The
tumor diameter and volume were 1.88 cm and 3.5 mL, respec-
tively. The prescribed dose was 11.5 Gy. With a median follow-
up of 65.5 months, the tumor control rate was 79.6%, with a
complete response rate of 19.4%.53 The 5- and 10-year survival
rates were 94.1 and 91%, respectively.53 The progression-free
survival rates were 60.8 and 53.8%, respectively.53 Among the
91 patients with evaluable information on neurologic and
endocrinologic symptoms, symptomatic deterioration occurred
in 16.5% of the patients.53
In an analysis limited to cystic lesions, Park et al retrospec-
tively reviewed outcomes of 27 pediatric and adult patients
with craniopharyngioma treated with GKSRS, of whom 14
patients had undergone previous subtotal resection and 13
patients undergone neuroendoscopic aspiration.54 Baseline
characteristics showed similar preintervention tumor size
(p = 0.962) and mean tumor volume at the time of SRS
(p = 0.896). At a median follow up of 32 months, a higher num-
ber of patients recurred in the neuroendoscopic group when
compared with the subtotal resection group (54% vs. 14%,
p = 0.046), although several hormone levels, including growth
hormone (p = 0.001), follicle-stimulating hormone (p = 0.025),
and adrenocorticotropic hormone (p = 0.011), were reduced 1
year postoperatively in the subtotal resection group.
▶ Table 26.4 summarizes the treatment outcomes of selected
series.
 Stereotactic Radiosurgery for Pediatric Brain Tumors

Table 26.4 Summary of treatment outcomes of stereotactic radiosurgery for craniopharyngioma in children
Study N Dose (Gy) Other treatment received Local control (%)

Ulfarsson et al46 21 (11 children) 3–25 Intralesional brachytherapy in < 6 Gy: 15%a 6 Gy: 67%
some patients with cystic Children: 18%
component

Chung et al47 31 (9 children < 16 y) 9.5–16.0 3 children had stereotactic 87.2

aspiration (CR: 32.7)

Mokry49 23 (11 children < 15 y) 8–15 10 patients with cystic com- 56

ponent received cystic aspira-
tion and intracystic bleomycin

Amendola et al50 14 (12 children) 14 1 patient had prior EBRT 100%

Niranjan et al51 46 with 51 tumors (15 12.5–20.0 3 patients had only biopsy; 43 Solid component: 91.6%
patients < 13 y) patients had residual/recurrent Solid and cystic: 68%
tumor after surgery; 2 patients
had prior EBRT; 11 patients
had prior cyst aspiration and
phosphorus-32 administration

Xu et al48 37 (17 children) 6–25 28 patients had prior surgery; 5 y: 67.0

3 patients had biopsies only;
2 had up-front stereotactic
cyst aspiration; and 4 patients
underwent GKSRS as primary
treatment

Saleem et al52 35 patients (17 children) 8.0–14.0 2 patients had fractionated 88.5
EBRT; 11 patients had micro-
surgical resection; 12 patients
cyst fenestration/aspiration

Eder et al34 7 children 8.0–12.0 4 patients had prior resection; 86

3 patients had cystic drainage
with intracystic bleomycin

Kobayashi et al53 107 (38 children < 15 y)a 11.5 13 had prior EBRT 79.6

Abbreviations: CR, complete response; EBRT, external beam radiation therapy; Gamma Knife stereotactic radiosurgery.
aOnly98 patients had follow-up.

Data in the literature show reasonable local control with the
use of SRS for craniopharyngiomas as salvage therapy in the
setting of recurrent disease; however, there may also be a role
for SRS as primary treatment or as an adjunctive treatment to
surgery, either alone or in combination with intralesional bra-
chytherapy (for cystic lesions or components).46–54 The close
proximity of the optic apparatus to craniopharyngiomas in
many cases can create technical challenges in treatment plan-
ning, as the treatment dose may be limited in the region of
tumor very close to or abutting the optic apparatus. 2 Typically,
the dose constraint for the optic apparatus is set at 8 Gy, based
on a seminal study by Tishler et al from Harvard University.55
However, a separate analysis by Stafford et al from the Mayo
Clinic showed that optic neuropathy may not be observed even
with a maximum point dose of 10 to 12 Gy to the optic appara-
tus.56 The risk of optic neuropathy was 1.7% for patients receiv-
ing < 8 Gy, 1.8% for patients receiving between 8 and 10 Gy, and
6.9% for patients receiving > 12 Gy.56 This dataset suggests that
the marginal dose can be safely increased to 10 to 12 Gy even
when the tumor is abutting the optic apparatus, although these
constraints may also be volume dependent. In a recent update
from Mayo Clinic with mean clinical and radiographic follow-
up times of 83 and 123 months, respectively, it was confirmed
that the risk of radiation-induced optic neuropathy was very
low if the maximum dose to the anterior visual pathway was
limited to ≤ 12 Gy in one fraction.57 Data in the literature sug-
gest that 12 Gy might be an adequate dose to achieve local
control of craniopharyngioma46,47,50,53; thus, highly conformal
plans may be able to minimize the risk of optic neuropathy
while maximizing tumor control. For GKSRS, this can be
achieved using smaller shots and plugging/blank sectors. For
CyberKnife and other linac-based systems, a dose constraint
should be set on the optic apparatus when using inverse plan-
ning. Another treatment-related factor that may lead to mor-
bidity includes cystic enlargement of craniopharyngiomas
after SRS. This can result in compression of the optic appara-
tus, leading to rapid visual deterioration.47 This possibility has
to be kept in mind when a child develops visual deterioration
after SRS.
26.10 Pituitary Adenomas
Pituitary adenomas are a heterogeneous group of tumors aris-
ing from the pituitary, and are relatively rare in children.2 As in
adults, they are classified as either secretory or nonsecretory.
Maximal safe resection is the mainstay of treatment, especially
when the tumor is encroaching on the optic pathway. However,

219
 Stereotactic Radiosurgery for Pediatric Brain Tumors
complete surgical resection may not always be achieved, and in
cases of secretory pituitary adenomas, persistent hypersecre-
tion may still occur despite complete surgical resection. In these
situations, postoperative radiation therapy may be offered for
tumor or endocrine control.
There is a fair amount of literature on the use of SRS for pitui-
tary adenomas in adults.58 However, data on the use of SRS for
pituitary adenoma in children are much more limited. In a
study from the Karolinska Institute in Sweden, Thorén et al
reported excellent outcomes in eight children with Cushing dis-
ease treated with GKSRS. The observation time ranged from
2.60 to 6.75 years. Among the eight patients treated, seven
showed complete endocrine remission.59 All patients exhibited
deficiencies of growth hormones after SRS.59 In a study from
Japan, Kobayashi et al also reported excellent results in terms of
endocrine response in two children with Cushing disease
treated with GKSRS.60 Castinetti et al from France reported the
results of 40 patients (4 patients ≤ 18 years) with Cushing dis-
ease treated with GKSRS after surgery. Out of the four children
treated, two achieved normalization of their cortisol levels at
an average of 12 months.61 The median dose given was 25 Gy at
the 50% isodose line. Both pediatric patients who did not
achieve an endocrine cure were on ketoconazole at the time of
SRS.61 In the study from Harvard University, 18 patients (includ-
ing adults and children) with pituitary adenomas were treated
with linac-based SRS. The prescribed dose ranged from 10 Gy at
the 85% isodose line to 15 Gy at the 65% isodose line. Although
the tumor control rate was 100%, the rate of normalization of
hormonal activity was only 33%.62 The 3-year freedom from
CNS adverse effects rate was 72.2%.62 In the largest published
series to date, Sheehan et al reviewed the University of Virginia
experience of 418 pediatric and adult patients undergoing
GKSRS for pituitary adenoma with either persistent functioning
or radiological evidence of growth.63 Typical tumor doses
ranged from12 to 18 Gy for nonfunctioning adenomas, and 18
to 30 Gy for functioning adenomas (overall range 9–30 Gy). At a
median follow-up of 31 months, 90.7% of lesions demonstrated
radiographic control. Marginal dose significantly correlated
with improved control (p = 0.02), whereas cessation of antise-
cretory medications was not. Endocrine remission rates in
patients with acromegaly, Cushing disease, prolactinoma, and
Nelson syndrome were 53, 54, 26, and 20%, respectively. New
hormonal deficiencies were seen in 24.4% of all patients, and
factors found to significantly correlate with such deficiencies
were suppressive medications at the time of GK (p < 0.001), pri-
or craniotomy (p = 0.027), and larger tumor volumes (p = 0.007).
Limited data in the literature on children suggest that the
treatment outcomes with SRS are similar to those in adults. 59–63
Typically, the tumor control rates are uniformly excellent,
whereas the endocrine control rates are lower. The adverse
effect of antisecretory medications on endocrine normalization
is also demonstrated in children.61 One major challenge in the
use of SRS in the treatment of pituitary adenomas is the prox-
imity of the target volume to the optic pathway.9 Unlike SRS for
craniopharyngiomas, a much higher prescribed dose to the tar-
get volume is needed in secretory pituitary adenomas for endo-
crine cure.58 As in adults, if SRS is used in children with
secretory pituitary adenomas, a dose of at least 25 to 30 Gy is
required if the dose to the optic apparatus permits. For nonse-
cretory tumors, a lower dose (15–20 Gy) is required. Given the
220
dose to the optic apparatus is typically limited to 8 Gy, a suffi-
cient distance between the optic apparatus and the pituitary
tumor is needed to avoid injury to the optic apparatus.
In these situations, several options are available to providers.
Dosimetrically, different maneuvers can be used to avoid the
optic apparatus, such as plugging and adjustment of the gamma
angle (to align with the long axis of the optic apparatus).58 If
the tumor is far enough (3–5 mm) from the optic pathway, SRS
may be offered, either as definitive treatment or as an salvage
treatment after subtotal resection.2 Alternatively, other modal-
ities of treatment may be more appropriate. If there is concern
for tumor-related mass effect, transsphenoidal resection should
be offered because significant shrinkage of the tumor after SRS
is not expected. External beam radiation therapy can also be
safely offered when optic pathway encroachment is an issue,
given the wider therapeutic window and lower probability of
complications provided by fractionation.2 However, it is not
always preferable, as some data suggest SRS may produce a
quicker normalization of hypersecretion from secretory pitui-
tary adenomas.2,58
26.11 Pineal Tumors
Pineal tumors represent a wide spectrum of histologies and are
relatively rare. Common histologies include germ cell and pine-
al parenchymal tumors.2 Primitive neuroectodermal tumor
(PNET) can also occur in the pineal gland.2 Specific treatment
depends highly on histology, but is dependent on the complex
anatomy and adjacent organs at risk. The pineal gland is located
immediately adjacent to the tectal plate of the midbrain, where
the superior colliculi are located. Larger pineal tumors can also
involve the interstitial nuclei of Cajal, which control downward
gaze. Overall, the data in the literature on the use of SRS for
pineal tumors are limited.
In an early series from France, 11 patients (adult and chil-
dren) with pineal tumors of various histologies, including pine-
ocytoma, tectal astrocytoma, germinoma, pineoblastoma, and
meningioma, were treated with SRS. The marginal doses ranged
from 12 to 20 Gy. None of the 11 patients received EBRT. At a
median follow-up of 12.3 months (range 2–34 months), all
tumors responded to SRS.64 No significant complications were
observed. In another series from France, 13 patients (5 children)
were treated with GKSRS for pineal parenchymal tumors.
Among the five children treated, three had pineocytomas and
two had pineoblastomas. None of them received EBRT. The cen-
tral doses ranged from 24 to 40 Gy. Out of the five pediatric
patients treated, one with pineocytoma was lost to follow-up.
Both patients with pineoblastoma had either complete res-
ponse or 90% partial response, but one developed brain meta-
stasis at 23 months, and one died at 10 months.65 For the
remaining two patients with pineocytoma, one achieved a com-
plete response at 72 months and one a partial response after
SRS at 12 months.65
In the study from the University of Pittsburgh, Hasegawa et al
reported the results of 16 patients (adults and children) with
pineal parenchymal tumors treated with GKSRS as the primary
or an adjuvant treatment after surgery. There were six patients
in the pediatric age group. Three of them had pineocytoma, two
had pineoblastoma, and one had mixed pineal parenchymal

tumor. The prescribed dose ranged from 14 to 16 Gy. The two
patients with pineoblastoma also received craniospinal irradia-
tion. The local control was 100% for the 14 patients with imag-
ing follow-up.66 Both pediatric patients with pineoblastoma
died 18 and 47 months after SRS, whereas the other four pedia-
tric patients survived.66 Complications were not observed in
the six pediatric patients. In another study from the University
of Pittsburgh, four patients (aged 9, 18, 18, and 21 years) with
pineal nongerminomatous germ cell tumors were treated with
GKSRS. All patients received chemotherapy and fractionated
radiotherapy, and SRS was used as a boost. The marginal dose
for the SRS boost ranged from 12 to 16 Gy. At a mean follow-up
time of 25 months, local control was obtained in three of the
four patients treated.67
In a study from Japan, Kobayashi et al reported the outcomes
of 30 patients (both adult and pediatric) with pineal and related
tumors treated with GKSRS. Out of the 30 patients treated in
this study, 19 received previous radiotherapy. There were 21
pineal tumors, including 4 germinomas, 7 malignant germ cell
tumors, 2 syncytiotrophoblastic giant cell tumors, 3 pineocyto-
mas, and 2 pineoblastomas. Pineal tumors were treated to a
mean dose of 15.7 Gy, whereas pineocytomas and pineoblasto-
mas were treated to a mean dose of 16.6 Gy. The complete res-
ponse rate was 26.7%, and the overall response rate was
73.3%.68 The local control in germinomas and pineocytomas
was 100%, whereas pineoblastomas and malignant germ cell
tumors responded poorly to SRS.68 In another series from Japan,
three patients with pineal germinomas were treated with
GKSRS to a dose of 10 to 12 Gy, followed by whole ventricular
irradiation of 24 Gy. All patients had solitary pineal tumors
measuring < 3 cm. Complete response was obtained in all three
patients.69
Amendola et al from the Miami Neuroscience Center in Flori-
da reported their outcomes of 20 patients (14 patients in the
pediatric age group) with pineal tumors of various histologies,
including 13 germ cell tumors, 2 pineoblastomas, 2 low-grade
gliomas, 1 primitive neuroectodermal tumor, 1 teratoma, and 1
pineocytoma, treated with SRS. The median dose was 11 Gy
(range 8–20 Gy), and the mean target volume was 3.1 mL. Five
patients underwent chemotherapy, and four received adjuvant
EBRT. Seventeen (85%) patients were alive after treatment, with
a median follow-up of 30.4 months.70 Lekovic et al from the
Barrow Neurological Institute (Phoenix, AZ) reported their
experience with 17 patients (2 pediatric patients) with pineal
tumors treated with GKSRS. One of the pediatric patients had
malignant teratoma, which was treated with a dose of 13 Gy,
with a partial response at 15 months; the other had a nonger-
minomatous germ cell tumor, which was treated with a dose of
15 Gy, with a complete response maintained at 73 months. 71
Both patients survived without complications.71
Yianni et al reported on outcomes of 44 consecutive pediatric
and adult patients undergoing 50 radiosurgical procedures for a
variety of pineal lesions, including 11 pineal parenchymal
tumors, 6 astrocytomas, 3 ependymomas, 2 papillary endothe-
lial tumors, 2 germ cell tumors, and 20 patients without a prior
histological diagnosis.72 Lesions were treated to a marginal dose
of 18.0 Gy (range 10–30 Gy), with a mean tumor volume of
2.7 cm3. At a mean follow-up of 62.5 months, the 1-, 5-, 10-,
and 20- PFS after SRS was 93, 77, 67, and 67%, respectively.
Some variability in tumor control was noted by histological
Stereotactic Radiosurgery for Pediatric Brain Tumors
subtype, with the 5-year PFS for pineal parenchymal tumors,
astrocytomas, ependymomas, and those without histological
diagnosis being 54, 100, 67, and 81%, respectively. Worse out-
comes were seen among those with higher initial tumor grades
(p = 0.04), previous radiotherapy (p = 0.002), and radiological
evidence of necrosis (p = 0.03). Transient diplopia was noted in
one patient (2.2%), which resolved within 1 year.
The variety of tumor histologies and lack of good outcome
data in both the adult and pediatric literature on the use of SRS
for the treatment of pineal tumors renders it very difficult to
draw any meaningful conclusions regarding its role in these
tumors. The most important factor in determining the treat-
ment strategy is histology, which governs the biological behav-
ior. Tumors such as germ cell tumors and pineoblastomas have
a high propensity for neural axis dissemination and require
more than local treatment of the primary tumor alone.2 Based
on the limited literature available and the knowledge of the
patterns of failure for germ cell tumors and pineoblastomas, it
is probably appropriate to consider SRS as a boost therapy in
some cases. Stereotactic radiosurgery can also be used as a sal-
vage therapy for recurrent germ cell tumors and pineoblasto-
mas. For pineocytomas, which have a low propensity for neural
axis dissemination, SRS appears to be an appropriate treatment
modality for selected patients.
In situations where SRS may be considered, highly conformal
treatment plans are desirable to minimize the risk of damage to
surrounding critical structures. This may be achieved by using
smaller shots if the GK is used or by using an intensity-modu-
lated radiosurgical system with micro-multileaf collimation if a
linac-based system is used. There are no well-defined guide-
lines regarding the dosing for SRS for pineal tumors, but 12 to
16 Gy appears to be a reasonable dose range based on the lim-
ited data in the literature.
26.12 Complications
Specific complications of treatment are outlined above, as they
relate to each individual disease process. Long-term risks of
radiation-induced neoplasia are also a concern in pediatric
patients who have many years at risk for this rare, but late-term
side effect.
Overall, SRS remains an attractive modality in the treatment
of pediatric intracranial tumors, with its ability to give high
doses of radiation to focal areas and spare significant dose to
the surrounding normal brain. Given the limited body of litera-
ture, however, it remains unknown whether dose-volume con-
straints of normal tissues can be extrapolated from the adult
experience. In the absence of clear data, caution should be exer-
cised in utilizing these techniques outside of the clinical trial
setting.
26.13 Summary
The dosimetric characteristics, namely, high conformality and
rapid dose falloff, of SRS render it an attractive treatment for
pediatric patients with brain tumors in various settings.
Although treatment outcomes from prospective trials are lack-
ing in the literature, experience with the use of SRS for pediatric
brain tumors accumulated at various major radiosurgical
221
 Stereotactic Radiosurgery for Pediatric Brain Tumors
centers across the globe have provided valuable data that can
guide neurosurgeons and radiation oncologists in their treat-
ment decisions. With the accumulation of more data and longer
follow-up, it is hoped that more information will be available
with which to make even better management decisions. Pro-
spective trials testing the role of SRS in pediatric brain tumors
are desperately needed and given the rarity of these pediatric
brain tumors, those trials should be conducted in a cooperative
group, multi-institutional, or consortium setting.
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223
 27 Radiosurgery for Glial Tumors 226
Part VII
28 Stereotactic Radiosurgery for the
Malignant Tumor Indications Management of One to Four Brain
Metastases 235

29 Stereotactic Radiosurgery for the

Management of Five or More Brain
Metastases 243

30 Repeat Radiosurgery for Brain

Metastases 251

VII
 Radiosurgery for Glial Tumors
27 Radiosurgery for Glial Tumors
Jason Lee Schroeder, John H. Suh, Michael A. Vogelbaum, and Gene H. Barnett
Key Points
● Glial tumors remain a vexing problem with relatively limited
advances in treatment that have translated into increased
survival over the past several decades.
● RTOG 93–05, the only prospective, randomized trial investi-
gating the addition of radiosurgery to conventional therapy
reported no survival advantage from adding an up-front ra-
diosurgical boost to conventional therapy for the initial treat-
ment of glioblastoma.
● Despite the results of RTOG 93–05, a variety of investigators
have continued to explore and report on the potential role of
stereotactic radiosurgery in treating glial tumors—particu-
larly for specific subsets of patients or when other treatment
options have been exhausted.
27.1 Introduction
Although the physical properties of metastases are often con-
sidered ideal for treatment with stereotactic radiosurgery (SRS)
—typically small size at presentation, relatively spherical shape,
and histological and radiographic delineation from normal sur-
rounding brain tissue,1,2,3,4 the properties of gliomas are nearly
the complete opposite4 and often may not be considered to
appropriately fit within the constraints of common criteria for
treatment with stereotactic radiosurgery: well-circumscribed
lesions, < 4 cm in size, without subependymal spread, and not
adjacent to the optic chiasm or brainstem.5 Depending on the
histological subtype and grade of glial tumor, treatment meth-
ods traditionally consist of surgical resection or debulking, radi-
ation therapy, and/or chemotherapy.
The Brain Tumor Study Group (BTSG) scientifically estab-
lished the role of radiotherapy for high-grade gliomas; BTSG
6901 was a randomized trial that showed superior survival for
malignant glioma of 14 weeks with supportive care alone ver-
sus 36 weeks with radiotherapy.6 The same group later showed
the superiority of radiotherapy over chemotherapy in the Brain
Tumor Cooperative Group (BTCG) 7201 study where survival
after radiation (with or without chemotherapy) was superior to
chemotherapy alone.7 In fact, with few exceptions (molecular
profiling particularly for anaplastic oligodendroglioma 8 and a
paradigm change in the primary chemotherapeutic agent for
glioblastoma9 [GBM]), the prognosis for treatment of gliomas
has not markedly improved over the past several decades.6,7,8,9
With limited improvement in the prognosis for gliomas,
interest emerged in potentially utilizing “more” radiation—in
the form of radiosurgery or fractionated stereotactic radiother-
apy—in an effort to improve outcomes for these patients.
Enticed by results of focal reirradiation for recurrent disease
and concerns about higher dosage of conventional radiotherapy
on normal brain toxicity, more regional approaches utilizing
radiation “boosts” have been applied to newly diagnosed
tumors. Initially, these were delivered via brachytherapy
implants using temporary or permanent radioactive sources.10,
226
11,12,13Although patient survival appeared to improve in the
earlier phase II trials, no survival advantage was borne out in
two subsequent North American phase III trials of brachyther-
apy boosts, suggesting that much of the apparent benefit seen
in the phase II trials was due to selection bias that chose more
favorable patients in the brachytherapy groups compared with
the control groups.10,12,14
As the evaluation and debate regarding the use of brachy-
therapy boosts initially for recurrent disease and then subse-
quently for up-front treatment of malignant gliomas has run its
course, a new era opened to the parallel debate regarding radio-
surgical boosts for the same groups of patients. Data initially
collected in retrospective studies on patients with recurrent
gliomas were used to help support interest in using radiosur-
gery in the up-front setting for malignant glioma. Over approx-
imately two decades, a variety of level III to level I evidence has
been generated (retrospective and prospective studies of treat-
ment for both recurrent and newly diagnosed disease) that
authors have used to support or refute the advancement of
using radiosurgery in the treatment of malignant glioma. How-
ever, over that time only one prospective randomized trial eval-
uating the use of radiosurgery boost in the up-front setting for
malignant glioma has been completed, and as for brachyther-
apy, the reported outcome does not show a survival benefit for
the addition of a targeted boost to conventional radiation ther-
apy and chemotherapy.15 Critics and defenders of this study
abound and variations on methodology have given rise to new
reports of SRS efficacy for newly diagnosed as well as recur-
rent/progressive malignant glioma, albeit at lower levels of evi-
dence. As a result, the relative degree of excitement for or
disappointment in the potential role of radiosurgery in the
treatment of malignant gliomas has swayed depending on the
specific articles used to support or refute one’s individual posi-
tion. In this chapter, we review the potential role of radiosur-
gery in both low-grade and high-grade glioma treatment.
27.2 Treatment Options
27.2.1 Pilocytic Astrocytoma and Optic
Nerve Tumors
Pilocytic astrocytoma (PA) is a tumor of childhood and adoles-
cence that often has the capacity for surgical cure, assuming the
anatomical location is favorable. Unfortunately, these tumors
also occur in surgically untreatable areas (optic nerves and
chiasm) or in regions where complete resection is not feasible.
Pilocytic astrocytomas can also behave more aggressively and
may defy surgical cure due to early recurrence or metastasis
within the central nervous system (CNS). Consequently, radio-
surgery may be an appealing option for at least some of these
tumors in an effort to provide durable local control while also
trying to minimize long-term morbidity from repeat attempts
at surgical resection or potential radiation toxicity in children.
There remain relatively few focused reports on the successful
use of radiosurgery to treat these lesions.

Proust et al reported a case of a deep hemispheric PA that
was treated with 21 Gy to the 70% isodose line (IDL) using sin-
gle-session radiosurgery.16 Subsequent enlargement of the
tumor cyst regressed after applying intracavitary treatment
with rhenium. The reported outcome at 3-years posttreatment
was tumor stability in an asymptomatic patient. Around the
same time, Somaza et al reported their experience treating nine
pediatric patients with growing, deep-seated pilocytic astrocy-
tomas.17 This group of patients represented diverse presenta-
tions, including two patients with new diagnosis via biopsy
versus prior incomplete resections (seven patients) and failed
fractionated radiotherapy (two patients). After radiosurgery, all
tumors had growth arrest and five showed definite regression.
There were no treatment toxicities reported and long-term
results (favorable or unfavorable) were not addressed.
Lim and Leem reported two cases, one pediatric (PA) and one
adult (fibrillary astrocytoma), of optic pathway gliomas treated
with single-fraction radiosurgery (12 Gy to the 40% IDL and
14.4 Gy to the 40% IDL, respectively).18 Follow-up imaging for
each case showed a decrease in tumor size and both patients
had improvement of vision. ▶ Fig. 27.1 shows a similar case
treated by our team of a 41-month-old boy with biopsy-proven
pilocytic astrocytoma of the optic nerve and chiasm. Radiosur-
gery was completed (12 Gy to the 48% IDL) and subsequent
imaging showed initial tumor shrinkage. The patient did not
experience any improvement in his preoperative blindness and
ultimately experienced leptomeningeal dissemination (at 4.5
years posttreatment) and expired 7.5 years after treatment.
More recently, Liang et al reported on two cases of optic path-
way glioma treated with single-session radiosurgery.19 Both
tumors were confirmed to be PA, one of the optic chiasm
(treated with 11 Gy to the 50% IDL) and the other of the right
optic nerve (treated with 15 Gy to the 50% IDL). The authors
Fig. 27.1 (a) A 41-month-old boy with biopsy-proven pilocytic astrocytoma of the optic nerve and chiasm. The tumor was treated with stereotactic
radiosurgery using 12 Gy to the 48% isodose line. (b) At 8-month posttreatment, there was reduction in the tumor size.
Radiosurgery for Glial Tumors
report complete response with near disappearance of the
tumors at last radiographic follow-up. Neither patient was
reported to develop any endocrine dysfunction from treatment,
but vision outcome was not reported.
Newer, larger series have also been reported and include
some limited to pediatric pilocytic astrocytoma,20 whereas
others include multiple low-grade histologies21 or both pedia-
tric and adult patients with PA.22 Kano et al reported on out-
comes in 50 pediatric patients with pilocytic astrocytoma
treated at a single institution.20 Patient presentations were var-
ied, including prior failures of fractionated radiation therapy
with or without chemotherapy. At a median follow-up of 55.5
months, the progression-free survival (PFS) for the entire
cohort ranged between 91.7% (at 1 year) and 70.8% (at 5 years).
Weintraub et al reported a histologically mixed series (with
variable presentations, i.e., unresectable as well as residual or
recurrent tumors) that included 15 pilocytic astrocytomas. 21
The authors concluded that radiosurgery can provide good clin-
ical control of residual or recurrent pediatric gliomas, while
cautioning that worse outcomes were associated with larger
tumor volumes at the time of treatment. The most recent of
these series, reported by Hallemeier et al, consists of recurrent
or unresectable PAs in both children and adults.22 Compared
with the Kano series, the median age and median target volume
in this series are both higher. Although the median treatment
dose was similar in these two series (14.5 Gy in Kano et al vs.
15 Gy in Hallemeier et al), the reported PFS in the Hallemeier
series is lower at 65% (1 year) and 17% (5 year), possibly reflect-
ing important differences in the patient populations and/or
tumor characteristics between the two studies.
Stereotactic radiosurgery for gliomas within the optic appa-
ratus risks worsening of vision from the treatment itself, partic-
ularly when the optic nerve receives more than 8 Gy in a single
227
 Radiosurgery for Glial Tumors
session. Trying to reduce this risk, Debus et al used fractionated
stereotactic radiotherapy (FSRT) delivering 1.8 Gy daily for a
total of 54 Gy to treat 10 patients with optic nerve gliomas. 23
Nine of the 10 tumors showed response to treatment, with
three complete remissions associated with vision improvement.
This series was later updated by Combs et al and reported PFS
of 92% (at 3 years) and 72% (at 5 years).24
Taken together, these reports suggest that radiosurgery or
multifraction SRS may be an effective treatment for inoperable
or recurrent PAs, even when those tumors are situated in func-
tionally critical areas. Surgical resection probably remains the
treatment of choice for accessible lesions.
27.2.2 Low-Grade Gliomas
Fibrillary low-grade astrocytomas tend to be genetically unsta-
ble tumors that typically evolve into more malignant forms over
time. Extent of resection has been cited as a favorable survival
factor for these lesions; however, this assertion remains contro-
versial as tumor cells likely exist beyond the radiographic boun-
daries of these lesions. Despite significant improvements in the
results of surgery due to surgical navigation,25 awake cranioto-
my,26 and resection control through the use of intraoperative
magnetic resonance imaging (iMRI),27 complete resection of
these tumors may be limited by poor surgical access or by loca-
tion of the lesions within a functionally critical area of the
brain. Some of these inoperable lesions may lend themselves to
radiosurgical treatment.
Plowman reported radiographic control of two discrete and
spherical low-grade gliomas treated with radiosurgery at 2-
and 5-year posttreatment.28 The tumor observed over a longer
period of time showed slow regression during the later stages
of imaging follow-up. Barcia et al presented 16 cases of deeply
seated low-grade glioma treated with radiosurgery.29 The mean
dose delivered was 22 Gy; 13 of 16 lesions showed regression, 8
with complete response. Six of the 16 cases had previously been
Fig. 27.2 (a) A 34-year-old woman with biopsy-proven WHO grade II astrocytoma of the right thalamus. The 6-mm lesion was treated with SRS using
18 Gy to the 77% isodose line. (b) At 6-month posttreatment, the tumor developed postcontrast enhancement on magnetic resonance imaging and
the patient required steroids to treat peritumoral edema. (c) At 4-year poststereotactic radiosurgery the tumor remained stable in size, but continued
to show contrast enhancement.
228
treated with conventional radiotherapy. Three cases were
brainstem gliomas, none of which responded to the treatment
and the three patients succumbed to their disease.
In contrast, Kihlström et al reported on successful radiosurgi-
cal treatment for low-grade glial tumors within the tectum. 30
Of seven total cases, six tumors responded to treatment by
showing either regression or growth arrest. Doses administered
ranged from 14 to 35 Gy. The authors concluded that treatment
was safe and effective if the treatment dose did not exceed
14 Gy (due to development of radiation necrosis, edema, and
permanent deficits in the two cases that used doses between
30 and 35 Gy).
Park et al reported on a series of 25 patients treated for either
newly diagnosed or progressive low-grade astrocytomas.31 Six-
teen of these patients were treated for newly diagnosed tumors,
and those treated for progression had been previously treated
with surgery, radiation therapy, or a combination of both. Their
reported PFS for the entire cohort was 91.3% at 1 year, but sub-
sequently decreased to 54.1% at 5 years and 37.1% at 10 years.
Factors associated with better response were smaller tumor tar-
get volumes, higher margin treating dose, and absence of con-
trast enhancement on the pretreatment imaging studies.
A few cases of low-grade, nonenhancing tumors developing
contrast enhancement several months after SRS treatment have
been seen at our institution. ▶ Fig. 27.2 provides an illustrative
case in which a 34-year-old woman was diagnosed with World
Health Organization (WHO) grade II astrocytoma of the right
thalamus by stereotactic biopsy. The 6-mm tumor was treated
with radiosurgery using 18 Gy to the 77% IDL. At 6-month post-
treatment, the patient developed headaches and her follow-up
imaging showed avid enhancement of the lesion with peritu-
moral edema. A subsequent fluorodeoxyglucose (FDG) positron
emission tomography (PET) scan documented lesion hypome-
tabolism despite the development of contrast enhancement.
Ultimately, the patient required a cerebrospinal fluid (CSF)
diversion procedure to treat hydrocephalus. The patient’s

follow-up imaging continued to show enhancement for years;
her overall survival (OS) was 12 years from the time of
radiosurgery.
27.2.3 High-Grade Gliomas
High-grade astrocytomas (WHO grades III and IV) constitute
the most common primary intra-axial brain tumors in adults.
As described in the introduction, the value of radiotherapy as a
component of management for these lesions was originally
established in the late 1970s. Further efforts to enhance tumor
control and to minimize radiation-induced toxicity by deliver-
ing a boost to the tumor and its immediate surroundings rest
on the observation that tumor recurrence or failure most com-
monly occurs locally—with greater than 80% of tumors recur-
ring within 2 cm of the enhancing edge of the primary lesion
and half recurring within 1 cm.32,33 Consequently, whole-brain
radiotherapy does not provide superior survival or local control
over partial field treatment of these lesions.
Foundational studies in radiotherapy have shown that, up to
a point, higher doses of radiation provide an increase in survival
compared with lower doses.34,35 As a result, standard radiother-
apy of these tumors, as defined by the Radiation Therapy Oncol-
ogy Group (RTOG), uses the “shrinking field” method of
treating the region of edema (defined on T2-weighted MRI)
plus 2 cm with 4600 centigray (cGy) in 23 fractions of 200 cGy
each, and a cone-down field, determined by the region of en-
hancement (or resection bed) on postcontrast T1-weighted MRI
plus 2 cm, treated with an additional 1400 cGy in 7 fractions of
200 cGy each.
Building on these practices, the notion that even higher
“boosts” of radiation limited to the tumor and its immediate
surroundings evolved. The development of image-guided
stereotactic techniques allowed for precise targeting of struc-
tures that could be visualized on neuroimaging studies,
including computed tomography (CT), MRI, and PET. The
premise then being that adding focal stereotactic radiation
treatment—via brachytherapy (temporary or permanent) 10–14
or radiosurgery—would allow for escalation of radiation dose
to the target while maintaining a sharp dose falloff that
would spare the adjacent normal brain tissue. Sheehan
astutely points out that reasonable arguments can be made
both for and against using radiosurgery in the treatment of
high-grade gliomas.36 On one hand, the majority of treatment
failures from standard therapy occur within 2 cm of the origi-
nal lesion,32,33 supporting the potential role of additional
“local” therapy; however, on the other hand, malignant glio-
mas are highly infiltrative lesions with tumor cells beyond
the apparent radiographic lesion borders, making it appear
illogical to expect lasting success from the use of a precise,
focal treatment.36
Radiosurgery for Recurrent Malignant Glioma
A number of prospective and retrospective series have been
reported regarding the potential efficacy of radiosurgery in the
setting of recurrent glioma. However, to date there are no
randomized trials comparing radiosurgery in this group of
patients with alternative therapies, including surgery, chemo-
therapy, reirradiation (fractionated), or best supportive care.5
Radiosurgery for Glial Tumors
In 1995, Hall et al reported on the results of SRS in 35
patients with malignant glioma—75% GBM—that had failed con-
ventional treatment.37 The actuarial survival was 8 months
from radiosurgery, with the vast majority of patients (85%)
dying from local failure. Nearly a third of these patients
required reoperation after radiosurgery, with the rate of
radionecrosis found to be 14%. The authors concluded that
SRS was a useful treatment, with lower morbidity than bra-
chytherapy, for recurrent malignant glioma. Similarly, median
OS was 9 months after SRS in a group of 62 patients with
recurrent GBM treated by van Kampen et al, with half the
patients showing improved quality of life (neurologic find-
ings, frequency of seizure, and steroid dose) at 4.5 months
after radiosurgery.38 Our institution reported a median PFS of
4.7 months in 22 patients with recurrent GBMs (median vol-
ume of 9.9 cm3) when treated with 15 Gy delivered to the
(median) 60% IDL.39
Larson et al reported a mixed series of 189 patients harboring
primary and recurrent gliomas, including tumors of all histolog-
ical grades and found that survival correlated strongly with five
patient or tumor factors: lower pathological grade, younger age,
better performance status, smaller tumor volume, and unifocal
tumor.40 Chamberlain et al reported another series of 20
patients with mixed glioma histologies, although all were
treated with radiosurgery at the time of recurrence.41 Despite
using a median treatment dose of 17 Gy, seven patients devel-
oped early radiation complications (one of whom died) and an
eighth patient developed a late radiation complication. The
authors rated the efficacy of this treatment strategy as “mod-
est” and the toxicity as “acceptable.” In an effort to define
acceptable doses for radiosurgical treatments, the RTOG con-
ducted a phase I/II dose-escalation trial of SRS (RTOG 90–05) in
patients with recurrent malignant gliomas and metastases. 4
Maximum treatment doses were derived based on acceptable
levels of toxicity (▶ Table 27.1). Higher toxicity was found in
maximum tumor diameters ≥ 21 mm and those treated with lin-
ear accelerators (linacs) compared with the Gamma Knife (GK).
Additionally, SRS treatment using a linac versus GK had 2.84
times greater risk for local progression. This has not been corro-
borated by other studies.42,43
Radiosurgery for recurrent malignant glioma has been com-
pared with both alternative therapies and additional therapies,
but never in a randomized trial. Shrieve et al retrospectively
compared the efficacy and toxicity of radiosurgery with brachy-
therapy for treatment of recurrent malignant gliomas. 44
Although survival after SRS was nearly as good as for iodine-
125 (I-125) brachytherapy, the rate of reoperation was substan-
tially less. In 2002, Larson et al reported results from a phase II
Table 27.1 Maximum radiosurgical treatment dose for acceptable toxic-
ity in recurrent malignant tumors
Maximum dimension ≤ 20 mm 21–30 mm 31–40 mm
Treatment dose 2400 cGy 1800 cGy 1500 cGy
Source: Results of RTOG 90–05. (Reprinted from Shaw E, Scott C,
Souhami L, et al. Single dose radiosurgical treatment of recurrent
previously irradiated primary brain tumors and brain metastases: final
report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys.
2000;47:291–298 with permission from Elsevier.)
229
 Radiosurgery for Glial Tumors
study of radiosurgery with marimastat in the treatment of
recurrent malignant glioma.45 The reported PFS after treatment
was 15 weeks for GBM with a corresponding median OS of 38
weeks, which was not improved compared with historical con-
trols. Skeie et al reported a retrospective series of GBM patients
treated for disease recurrence with either GKSRS or reopera-
tion.46 The authors reported longer median survival after
retreatment in patients who received SRS compared with re-
operation only and a lower rate of complications associated
with SRS compared with reoperation. Skeie et al conclude that
SRS may be an appropriate alternative to reoperation for
patients with small-volume GBM recurrence, while also
acknowledging the potential weaknesses of their retrospective
study—possible selection bias and nonuniform treatment
modalities among the treatment groups over time.
Fractionation of a stereotactically guided radiotherapy treat-
ment may reduce normal tissue toxicity. Therefore, Cho et al
compared the results of single-session radiosurgery (17 Gy to
the 50% IDL, median) with FSRT (37.5 Gy in 15 fractions to the
85% IDL, median) in a group of 71 patients with recurrent
malignant glioma.47 Despite prognostic factors (age, perform-
ance status, tumor size) being more favorable in the SRS group,
survival was longer in the FSRT cohort (11 vs. 12 months,
respectively) and complications were lower (30% vs. 8%, respec-
tively). These results suggested that FSRT may be a more appro-
priate choice in this setting, especially for large tumors or those
in critical areas. In other reports, median survival of 7 months
was achieved in 88 patients with recurrent GBM when Taxol
(120 mg/m2) was used as a radiation sensitizer for multisession
radiosurgery (24 Gy in four sessions, mean).48,49 Patients with
tumor volume less than 30 cm3 survived significantly longer
than those with larger tumors.
Although none of these series is free from potential selection
bias, there do appear to be some objective responses to SRS in
the setting of recurrent malignant glioma. In ▶ Fig. 27.3, we
illustrate the case of a 63-year-old woman with recurrent GBM.
This tumor was treated with GKSRS using 18 Gy to the 50% IDL.
Tumor regression was achieved; she survived 23 months after
radiosurgery. Despite these observations, the literature suggests
that these treatments are ultimately palliative in nature, as local
230
failure from SRS is the norm. Currently, it remains unclear if
SRS is the best treatment for particular patient subgroups with
recurrent malignant glioma, particularly at doses that have lim-
ited toxicity. Nevertheless, SRS should be considered a reason-
able option in selected cases of focal recurrence, particularly if
other treatment options have been exhausted.
Radiosurgery for Newly Diagnosed Malignant
Glioma
In general, treatments that show some benefit at tumor recur-
rence are thought to potentially provide even greater benefit
when delivered as part of initial treatment. Because of this,
radiosurgery as a part of up-front treatment has been used at
multiple centers for some time. The publication of results from
RTOG 93–05 in 2004, the only randomized prospective trial
comparing up-front SRS followed by conventional therapy
(radiotherapy and carmustine) to conventional therapy alone
for patients with GBM, put a damper on this practice at many
institutions. RTOG 93–05 reported no advantage with radiosur-
gery boost in treating newly diagnosed GBM (< 4 cm in diame-
ter) in terms of survival (median OS of 13.6 months for patients
treated with conventional therapy vs. 13.5 months in the radio-
surgery followed by conventional therapy arm; p = 0.5711).15
However, a variety of criticisms have been leveled against the
RTOG 93–05 trial design, most typically (1) few centers have
used radiosurgery boost prior to conventional radiotherapy as
it was in 93–05,36,50,51 and (2) carmustine is no longer standard
first-line chemotherapy for GBM.9,36,51 As a result, other authors
have continued to publish on the potential utility of SRS as part
of the overall up-front treatment for high-grade gliomas.
One of the earliest reports of radiosurgery as a boost for
malignant gliomas was from the Joint Center by Loeffler et al. 52
Twenty-three GBM and 14 anaplastic astrocytoma patients
underwent radiosurgery of enhancing tissue 2 to 4 weeks after
completion of conventional radiotherapy (5940 cGy, max).
Median SRS minimum dose was 12 Gy (range 10–20 Gy) and
maximum dose was 15 Gy (range 12.5–25.0 Gy). Tumor volume
ranged from 1.2 to 72 cm3. Only 24% of patients had died at 19-
month median follow-up. This, as well as subsequent studies53,
Fig. 27.3 (a) A 63-year-old woman with recurrent
glioblastoma. The tumor was treated with Gam-
ma Knife stereotactic radiosurgery using 18 Gy to
the 50% isodose line. (b) At 9-month postster-
eotactic radiosurgery treatment, the tumor
shows regression on follow-up magnetic reso-
nance imaging.

54,55 concluded that SRS was a potentially useful adjunct in the
management of these lesions. The Joint Center for Radiation
Therapy (Boston, MA), University of Wisconsin–Madison, and
University of Florida–Gainesville, pooled their data and found
that median survival was 24 months among 115 GBM patients
treated with radiosurgery as part of initial management. 56
Additionally, Alexander et al found results similar to those pre-
viously seen with brachytherapy in terms of both benefit and
toxicity.57 Interpretation of these studies has been cautious
because they were nonrandomized, raising the possibility for
significant skewing of the results due to potential selection
bias.5,15,58,59 Several of these early studies attempted to mini-
mize the influence of selection bias on their outcomes by inter-
preting their results according to RTOG classifications of
outcome. Sarkaria et al found the median survival difficult to
assess, but the 2-year survival for GBM patients to be signifi-
cantly better than predicted,56 whereas Mehta et al showed sig-
nificant improvement over expected outcome for both median
and 2-year survival.60
Biswas et al retrospectively analyzed their experience using
SRS to treat GBM in an effort to better define what conditions
influence its efficacy.61 Their study included 33 patients treated
between 2000 and 2007, all of whom had pathological confir-
mation of GBM. Eighteen of these patients were treated with
SRS at tumor recurrence; 15 were treated up-front after com-
pletion of standard fractionated radiotherapy. The median OS
after initial diagnosis was 16.9 months and median survival
after SRS was 6.7 months. There was no statistical difference in
median OS between the groups treated with SRS at recurrence
versus those treated as part of their initial treatment paradigm.
Univariate analysis showed a difference in time to progression
for patients treated with up-front radiosurgery boost compared
with those receiving SRS at tumor recurrence (6 months vs. 3.4
months). No acute toxicity greater than grade 2 was reported.
The authors concluded that radiosurgery is well tolerated as a
part of GBM management and that further studies are needed
to more adequately define patients likely to respond to SRS.
Pouratian et al retrospectively analyzed their experience with
SRS for patients with GBM.51 Their report included 48 patients
with histologically confirmed GBM, where SRS was part of the
initial treatment paradigm (22 patients) or SRS was utilized at
tumor progression (26 patients). The patients treated at tumor
progression had longer median OS than those treated on initial
presentation, 17.4 versus 15.1 months, respectively. In their
multivariate analysis, RTOG recursive partitioning analysis
(RPA) class 3 patients fared better than other patients, as did
those patients with more extensive surgical resections and
those not dependent on steroids. Similarly, Villavicencio et al
reported their experience with SRS for treatment of GBM
patients.62 This retrospective study of 46 patients included 20
patients treated at the time of initial diagnosis and 26 treated at
tumor progression. Median OS was better for patients treated at
progression rather than as part of the initial treatment para-
digm, 21 versus 11.5 months, respectively, leading the authors
to conclude that SRS should be reserved for patients whose
tumors recur or progress after conventional therapy.
In 2012 Einstein et al reported on their phase II prospective
trial utilizing magnetic resonance spectroscopy (MRS) to define
and target high-risk tumor volumes for subsequent treatment
with SRS.63 The study included 35 patients with newly
Radiosurgery for Glial Tumors
diagnosed GBM treated between 2002 and 2007. Temozolo-
mide (TMZ) was not given to the initial 54% of patients because
the phase III trial data establishing its use had not yet been pub-
lished. The majority of patients included in the Einstein report
underwent subtotal surgical resection (27/35) and a small per-
centage (4/35) had biopsy as initial surgical management. After
a pathological diagnosis of GBM, MRS was undertaken to identi-
fy areas within the T2 MRI abnormality believed to be at high
risk for harboring residual tumor or to be at high risk for tumor
recurrence. Patients were treated with GKSRS prior to confor-
mal radiotherapy to “minimize the impact of post-radiation
changes on the MRS analysis.”63 The treatment paradigm pro-
duced a median OS of 15.8 months for the entire cohort. The
median OS stratified by RTOG RPA classification was greater
than 22 months for RPA class 3 patients (75% were still alive at
the time of their report), 18.7 months for RPA class 4, 12.5
months for RPA class 5, and 3.9 months for RPA class 6—with
statistically significant differences between the respective sur-
vival times. Comparing the groups treated with or without TMZ
showed a difference in median OS of 20.8 months (for patients
with concurrent TMZ) versus 11 months (for those not receiv-
ing TMZ). The authors reported 9 of 35 patients experiencing
grade 3 or 4 toxicity. These included one patient with post-SRS
stroke (patient on warfarin) and eight patients requiring reope-
ration (five patients with recurrent tumor and three with
symptomatic radiation necrosis). The authors concluded that
OS is improved in patients treated with MRS-targeted SRS com-
pared with historical controls.
Finally, Pannullo et al conducted a meta-analysis of current
therapeutic applications of radiosurgery in neuro-oncology. 64
As part of this meta-analysis, the authors screened studies eval-
uating the use of radiosurgery for GBM. Eleven studies were
included in their meta-analysis (which comprised about 450
total GBM patients)—nine studies were graded as providing
class III evidence and two were graded as class II evidence: one
case-control study and one prospective randomized study. Six
of the studies were case series reporting on local experience
with adjuvant or salvage SRS in the treatment of GBM. The oth-
er five studies compared SRS with a different, designated com-
parison treatment group. The ranges for median survival were
similar whether SRS was given as adjunctive initial treatment
(9.5–25 months) or as salvage therapy at progression/recur-
rence (10.2–26 months). The overall complication rate for SRS
in GBM treatment was calculated as 11.4%.
Although the impact of SRS on a typical patient with high-
grade glioma remains unknown, some patients with malignant
glioma treated with SRS do have prolonged survival. ▶ Fig. 27.4
shows the case of a 36-year-old woman with a biopsy-proven
GBM of the right temporal stem. This was treated with linear
accelerator (linac)-based SRS using 25 Gy to the 80% IDL and
59.4 Gy in 33 fractions of conventional radiotherapy. The pa-
tient remains alive today 22 years after SRS, with no evidence
of tumor recurrence or progression.
27.3 Complications
Despite the numerous series and individual anecdotal cases
presented above, it is clear that radiosurgery for gliomas may
be associated with toxicity, especially with high prescription
231
 Radiosurgery for Glial Tumors

Fig. 27.4 (a) A 36-year-old woman with biopsy-

proven glioblastoma of the right temporal stem.
The tumor was treated with linear accelerator–
based radiosurgery using 25 Gy to the 80%
isodose line immediately preceded by 59.4 Gy of
conventional radiotherapy delivered in 33 frac-
tions. (b) The patient remains alive today 22 years
post stereotactic radiosurgery treatment without
evidence of tumor recurrence or progression.

doses or when large lesions are treated. Potential complications 29 (13.8%).60 Additionally, the rate of reoperation in patients
from SRS for gliomas are related to two factors: the radiosurgi- treated with SRS as part of an initial treatment algorithm was
cal treatment itself and our current interpretation of the avail- reported to vary from 19 to 33%. The studies reviewed regard-
able literature as it pertains to this type of treatment for glial ing use of SRS treatment at the time of glioma progression or
lesions. Determining whether complications from treatment recurrence showed similar potential toxicities, ultimately lead-
have occurred may also be difficult. Simply distinguishing ing to the conclusion that although there may be some evidence
recurrent tumor from posttreatment radiation necrosis may for improved survival and local control with SRS as salvage glio-
require special imaging studies (such as MRS, PET, or nuclear ma treatment, this may be counter-balanced by possible
medicine spectroscopy) or even biopsy.65–70 toxicity.5
With regard to complications from the radiosurgery itself,
these are similar to the complications seen with cranial SRS for
other malignant or nonmalignant pathologies. Some of these 27.4 Summary
include the potential for tumor recurrence despite treatment,
Prior to the report of RTOG 93–05, many providers hoped this
the potential for local radionecrosis as a result of treatment,
trial would provide definitive proof either for or against the use
and the potential for radiation injury to adjacent critical neuro-
of radiosurgery as at least a component in the initial treatment
vascular structures (optic pathways, brainstem, etc.). In con-
of patients with GBM. As reviewed above, RTOG 93–05 reported
trast, some potential complications from SRS in glioma
no outcome advantage and no clear quality-of-life or cognitive
treatment are related to the quality of and our current under-
function advantage to adding radiosurgery before conventional
standing of the available salient literature (which is relatively
radiation therapy and carmustine therapy in the treatment of
limited). In regard to the depth and quality of the current litera-
GBM. However, after the 93–05 report was published a number
ture, there has been a single prospective randomized study and
of important criticisms of the study have been made.36,50,51
a small variety of other class II and III studies used to argue for
As a result, questions regarding the role for radiosurgery in
and against the use of SRS in the treatment of gliomas. This
the up-front or salvage treatment of glial tumors remain insuffi-
gives rise to the possibility that any reported positive treatment
ciently answered. Many different “camps” remain with regard
outcomes may be inappropriately overemphasized and the
to the “most acceptable” interpretation of the current literature
potential for significant treatment related toxicities may be
supporting using or withholding radiosurgery in the treatment
underappreciated.
of glial tumors. Further prospective randomized trials to answer
RTOG 93–05 reported four grade 3 late toxicities in the SRS
the remaining questions surrounding the role of SRS in the
study arm—three neurologic and one classified as “other” (all of
treatment of gliomas are not likely to be forthcoming in the
these patients received 15 Gy SRS boost)—compared with a sin-
near future. For the time being, decisions to accept or reject the
gle late grade 3 toxicity in the radiation therapy study arm. For
use of SRS treatment in these challenging cases will most fre-
the same study, the rate and type of late grade 1 and 2 toxicities
quently be made at the individual clinician level or possibly the
were similar between the SRS and radiation therapy arms.
individual institutional level based on personal experience and
Additionally in RTOG 93–05, for all patients who underwent
influenced by the imperfect literature that has been generated
salvage surgery there were more with necrosis only identified
thus far.
in the salvage pathology specimen from the SRS arm (7/28)
than from the radiation therapy arm (3/31).15
Tsao et al reported on summary data regarding complications References
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87: 449–457
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
28 Stereotactic Radiosurgery for the Management of One
to Four Brain Metastases
Sten Myrehaug, Simon S. Lo, Siavash Jabbari, Lijun Ma, Sunit Das, Aliaksandr Karotki, Eric L. Chang, and Arjun Sahgal
Key Points
● Stereotactic radiosurgery plays a dominant role in the ma-
nagement of patients with one to four brain metastases < 3
cm in size, and an alternative to surgery for tumors not re-
quiring urgent resection.
● Despite improvements in intracranial control, the addition of
whole-brain radiotherapy to stereotactic radiosurgery does
not improve overall survival and is associated with worsened
neurocognitive and quality-of-life outcomes.
● Postoperative single fraction or hypofractionated radiosur-
gery provides excellent local control while sparing radiation
exposure to the normal brain.
● Radiation technologies have evolved such that most modern
units are able to perform radiosurgery. This is increasing its
availability beyond specialized tertiary care centers; more-
over, the technology has made advances such that we can
perform frameless image-guided radiosurgery.
28.1 Introduction
An estimated 20 to 40% of cancer patients will develop brain
metastases during the course of their illness, more commonly
in patients with lung carcinoma, colorectal carcinoma, breast
carcinoma, renal cell carcinoma, or melanoma. Solitary brain
metastases are seen in 40 to 50% of presentations, with multi-
focal or leptomeningeal disease occurring in the remainder.
Brain metastases are a significant cause of morbidity and mor-
tality in cancer patients. Patients with untreated brain metastasis
have a poor prognosis, with a life expectancy of 1 to 2 months,
which can be improved slightly with the use of corticosteroid
therapy. Whole-brain radiotherapy (WBRT) has been utilized for
over 60 years, and has yielded modest gains with respect to
improvements in neurologic symptoms, intracranial disease con-
trol, and overall survival (OS). As therapeutic and technical advan-
ces in cancer treatment and medical imaging have evolved, earlier
identification of central nervous system (CNS) disease has resulted
with a greater proportion of patients presenting with a limited
number of brain metastases (i.e., one to four metastases), and the
ubiquitous use of WBRT has been questioned. This has led to the
development of more aggressive approaches to the treatment of
intracranial disease such as stereotactic radiosurgery (SRS). In the
contemporary management of patients presenting with one to
four metastases, SRS has a dominant role in treating these
patients and must be discussed with the appropriate patient.
28.2 Patient Selection
The Radiation Therapy Oncology Group (RTOG) recursive parti-
tioning analysis (RPA) has been the most commonly used prog-
nostic scale and treatment decision-making tool for patients
with brain metastases.1 This scale assesses patients based upon
performance status, age, and stability of extracranial disease,
placing patients into three RPA groups with correspondent
median survival times of 7 months, 3 to 6 months, and approx-
imately 2 months. Given the heterogeneous nature of brain
metastasis presentation and biological characteristics, the
Graded Prognostic Assessment (GPA) and diagnosis-specific
GPA (DS-GPA) scoring systems have been subsequently devel-
oped,2 incorporating more disease-specific parameters such as
the number of metastases and in some cases molecular profil-
ing. As a result, we have an improved ability to tailor individu-
alized treatment plans for patients, selecting when appropriate
focal SRS and/or surgery, and aim to maximize local control
rather than to simply temporize brain control with WBRT.
28.3 Role of Surgical Resection
In patients with solitary metastasis, good performance status,
patients and controlled extracranial disease, surgery followed by
WBRT can improve OS, local control, median time to death from
neurologic cause, and preservation of performance status as
compared with WBRT alone. Patchell et al3 established the role
of surgical resection followed by WBRT versus WBRT alone, in
the management of solitary brain metastasis, with improvement
in survival (10 vs. 4.2 months), recurrence at original site of dis-
ease (20% vs. 50%), time to recurrence, median time to death
from neurologic cause, and preservation of performance status
(8.7 vs. 1.8 months). Importantly, the role of surgical resection
for multiple brain metastases is not as defined, and the Patchell
et al study is specific to solitary metastases. Neurosurgical prin-
ciples are such that surgery is performed for patients even in
the presence of multiple metastases for large brain metastasis
(> 3 cm), those causing significant edema, and/or those causing
neurologic symptoms, as removing the tumor is the fastest way
to yield clinical improvement in a deteriorating patient.
Recommendation: Patients with solitary metastases should
have a neurosurgical consult. Any patient with a brain metasta-
sis that causes life-threatening signs or symptoms should have
a surgical consultation regardless of the number of metastases.
28.4 Postoperative Management
The routine use of WBRT was then questioned in patients with
solitary metastasis undergoing surgery, and resulted in a
randomized trial evaluating surgery alone to surgery plus
WBRT in good performance study patients with controlled
extracranial disease. Patchell et al reported that phase III study, 4
and postoperative WBRT was found to significantly reduce the
rate of local recurrence (10% vs. 46%), distant brain failures
(14% vs. 37%), and neurologic deaths (14% vs. 44%). However, OS
and duration of functional independence outcomes were simi-
lar between the two cohorts. This study ultimately concluded
that postoperative WBRT was the standard of care.
235
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
A more recent randomized trial by Kocher et al evaluated the
role of WBRT versus observation following either surgery or
SRS.5 In the surgical cohort (160 patients), postoperative WBRT
decreased intracranial disease progression at 24 months (31% vs.
54%, respectively) and the risk of neurologic death (25% vs. 43%),
while not impacting overall survival or preservation of perform-
ance status. Hence nearly a decade later, the yield of postopera-
tive WBRT was similar to the original Patchell et al trial.4
Concern has been raised over the association of WBRT with
neurotoxicity and subsequent declines in quality-of-life (QoL)
domains such as fatigue6 and cognitive impairment7 (discussed
in a later section). As a result, postoperative cavity radiation
with the use of single-fraction or hypofractionated SRS has
emerged and increasingly being practiced as a standard of care.
A review by Roberge and Souhami summarized outcomes on
492 postoperative patients treated with SRS or hypofractio-
nated SRS to the resection cavity as reported in essentially ret-
rospective and few prospective studies.8 Crude local control
(LC) was 79%, and the risk of radiation necrosis was estimated
at approximately 5%. In 2014, the Memorial Sloan Kettering
Cancer Center (New York, NY) published their phase II study9
evaluating single-fraction cavity radiosurgery (mean dose 1800
cGy), and concluded that significantly greater local control rates
could be achieved than with surgery alone. Al-Omair et al fur-
ther demonstrated that even in patients with significant prior
intracranial therapy demonstrating treatment resistance, sal-
vage postoperative hypofractionated stereotactic radiotherapy
(HSRT) can provide excellent local control with an acceptable
toxicity profile.10 Current trends in practice suggest that focal
cavity radiation will replace WBRT, with a confirmatory
randomized study underway.11
Recommendation: There is sufficient literature, albeit uncon-
trolled, and a sensible therapeutic rationale to recommend focal
radiation to the surgical cavity as an alternative option to
WBRT. However, whether single-fraction SRS or HSRT is opti-
mal remains to be determined. If available, patient enrollment
in a randomized trial comparing postoperative WBRT and SRS
is preferable.
28.5 Stereotactic Radiosurgery as
an Alternative to Surgery
There are no reported randomized trials directly comparing
surgical resection to SRS. Given the lack of randomized data, we
primarily rely on retrospective series to guide treatment deci-
sion making. Due to the nature of these studies, results and
interpretation are variable and conflicting. The study by Mua-
cevic et al attempted to randomize patients with a single
resectable brain metastasis measuring ≤ 3 cm to surgery plus
WBRT versus SRS alone.12 This study was closed early due to
poor accrual; however, based on the results of 64 patients the
authors reported similar OS (median, 9.5 vs. 10.8 months,
p = 0.8), neurologic death rates (29% vs. 11%, p = 0.3), and local
control (82% vs. 96%, p = 0.06) in the two groups. As expected,
the patients randomized to SRS alone were observed to have
more distant brain recurrences, although this difference was no
longer observed when accounting for salvage SRS. Stereotactic
radiosurgery alone was also associated with a shorter hospital-
ization, decreased corticosteroid use, decreased neurotoxicity,
236
and improved QoL scores at 6-week posttherapy. Although oth-
er retrospective series have confirmed this finding,13,14,15 a con-
trary report was published by the MD Anderson group
(Houston, TX) in 1996, who matched 13 patients treated with
SRS with 62 treated with surgical resection alone and found
that local recurrence was superior in the surgical cohort (21%
vs. 8%, respectively).16
Recommendation: Surgery should be recommended in gener-
al if tissue diagnosis is required, for solitary lesions that are sur-
gically resectable, and those metastases > 3 to 4 cm or causing
considerable edema and/or mass effect (in particular when in
the posterior fossa). Stereotactic radiosurgery is an appropriate
alternative for patients with small, multiple and/or deep
lesions, or for patients not suitable for surgical resection.
28.5.1 Stereotactic Radiosurgery with
or without Whole-Brain Radiotherapy
With the recognition that local control following conventional
WBRT alone is suboptimal,17 and treatment advances allowing
for focal radiation, the next phase of trials emerged evaluating
the role of SRS as a boost to WBRT and then as an alternative to
WBRT. The randomized trials are summarized in ▶ Table 28.1.
WBRT versus WBRT plus SRS
An early study of 27 patients with two to four brain metastases
was published in 1999 by Kondziolka et al, in which patients
were randomized to WBRT alone versus WBRT plus SRS.18 Local
failure was 100% at 1 year in patients treated with WBRT alone,
and only 8% progressed in those boosted with SRS. A statisti-
cally nonsignificant OS benefit was observed in the SRS group
(median survival (MS) 7.5 vs. 11 months). This study is contro-
versial, as the high local failure rate in the WBRT alone cohort
may reflect selection bias or lack of sufficient sample size.
The larger and more definitive study was subsequently
reported in 2004. RTOG 95–08 reported by Andrews et al 19
randomized 331 patients to WBRT with or without SRS. Stereo-
tactic radiosurgery was shown to improve local control, Karnof-
sky Performance Score (KPS) steroid dependency, and for
patients with a single brain metastasis an improvement in OS
(6.5 vs. 4.9 months for WBRT alone). In addition, a trend to sup-
port a median survival advantage for RPA class I patients (11.6
vs. 9.6 months), lung histology (5.9 vs. 3.9 months), and tumor
size > 2 cm (6.5 vs. 5.3 months) was observed in subgroup
analysis.
Tsao et al reported a meta-analysis based on these two trials
using the published outcomes20 and concluded that although
there was no difference in OS, with a hazard ratio (HR) of 1.63
(95% confidence interval [CI] 0.72–3.69, p = 0.24), LC favored
WBRT plus SRS with a HR of 2.88 (95% CI 1.63–5.08, p = 0.003).
Recommendation: If WBRT is offered to patients with one to
four brain metastases, SRS should also be considered in those
with good KPS.
SRS versus WBRT plus SRS
Three randomized studies have been reported evaluating SRS
alone to WBRT plus SRS in patients with up to three to four
metastases.5,7,21 Aoyama et al published the first study based on
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
Table 28.1 Summary of the phase III randomized controlled studies evaluating SRS and WBRT
Study Randomization % of single metastasis Primary end point
Kondziolka et al, SRS + WBRT (n = 13) 0%
199918 WBRT (n = 14)
Andrews et al, 200419 WBRT + SRS (n = 164) 56%
WBRT (n = 167) 56%
Aoyama et al, 200621 SRS (n = 67) 49%
WBRT + SRS 48%
Kocher et al, 20115 SRS (n = 100) 68%
WBRT + SRS (n = 99) 66%
Chang et al, 20097 SRS (n = 30) 60%
WBRT + SRS (n = 28) 54%
Abbreviations: SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.
132 patients randomized to SRS alone versus WBRT plus SRS 21
for patients with one to four metastases. Whole-brain radio-
therapy plus SRS was found to reduce the risk of developing
new brain metastases (63.7% vs. 41.5%, respectively) and
improve the 1-year local control rate (72.5% vs. 88.7%). How-
ever, no difference in OS (8.0 vs. 7.5 months) was identified.
Neurocognitive functioning were measured using the Mini-
Mental Status Examination (MMSE) and no significant differen-
ces were observed. However, it is well recognized that the
MMSE is suboptimal for determining neurocognitive functions
most likely to be damaged by radiation.22
To study neurocognitive changes associated with WBRT,
Chang et al reported a trial evaluating 58 patients with one to
three metastases randomized to SRS alone versus WBRT plus
SRS. The primary end point was neurocognitive changes at 4
months using the Hopkins Verbal Learning Test (HVLT), as
opposed to the MMSE.7 Worse neurocognitive function with
respect to memory at 4 months following treatment in the
WBRT plus SRS cohort was reported. This impairment in mem-
ory was observed despite better local and distant brain tumor
control in that cohort.
In 2010, Kocher et al published the results of the European
Organisation for Research and Treatment of Cancer (EORTC)
22952–26001 study, in which 359 patients with up to three
metastases were randomized following either surgical resection
or SRS to observation versus adjuvant WBRT.5 The primary end
point was time to deterioration of performance status defined
as a World Health Organization (WHO) status > 2. The addition
of WBRT, despite reducing the risk of local and distant relapse
and rate of neurologic death (28% vs. 44%), was not associated
with improvements with respect to maintaining a good per-
formance status (10.0 vs. 9.5 months, p = 0.71) or OS (median,
10.9 vs. 10.7 months, p = 0.89). A QoL analysis was also
reported, and a detriment in QoL was observed in the WBRT
arm despite gains in local control, distant brain control, and
equivalent probability of maintaining a good performance
status.23
Tsao et al performed a meta-analysis on the outcomes of local
control and distant brain control based on the published data
from these three trials.20 They concluded that the addition of
WBRT improved local control and distant brain control vs. SRS
alone. The HR for local control was 2.61 (95% CI 1.68–4.06,
p < 0.0001) and for distant brain control 2.15 (95% CI 1.55–2.99,
Local control Survival
Local control 92% 11 mo
0% 7.5 mo
Overall survival 82%
71%
Tumor recurrence 72.5% 28.4%
88.7% 38.5%
Functional independ- 69% 10.9 mo
ence 81% 10.7 mo
Neurocognition 67% 63%
100% 21%
p < 0.00001).20 Given how the EORTC reported the OS data,
meta-analyses of the Aoyama and Chang studies could only be
performed. Individually, the Aoyama et al study reported no dif-
ference in survival, whereas the Chang et al study reported a
survival advantage favoring SRS alone. A meta-analysis con-
cluded no difference in OS with a HR of 0.98 (95% CI 0.71–1.35,
p = 0.88),20 suggesting that SRS alone does not adversely impact
survival, but the larger EORTC study could not be included,
which would have increased the power of the analysis. There-
fore, as yet the potential for either treatment to influence OS is
not known.
Recommendation: If the aim is to preserve neurocognition
and QoL, then SRS alone is the preferred therapeutic option.
The drawback of SRS alone is a greater need for salvage proce-
dures, as the risk of distant brain relapse is greater, and to a
lesser extent local failure risk is also greater. If the patient is
more concerned about overall brain control and less concerned
about radiation-induced neurocognitive deficits, then WBRT
plus SRS is the preferred strategy. In either case, close imaging-
based follow-up is required to provide salvage therapy as
needed given that the risk of distant brain relapse is still on the
order of 30% despite WBRT.
28.6 Radiation Planning
28.6.1 Immobilization Systems
Traditionally, SRS has required rigid head immobilization with
an invasive head frame; this frame also afforded the reference
three-dimensional (3D) coordinate system to localize the target.
This has been the standard since the development of stereotaxis
by Leksell in the 1950s. Despite the robust immobilization and
localization capabilities of the invasive head frame, there are
significant drawbacks, including the requirement for neurosur-
gical support, making it impractical for smaller oncology cen-
ters to adopt SRS, the negative experience with head frame
placement perceived by patients, the small risk of bleeding and
infection from pin insertions for head frame placement, and the
limitation of treatment to a single fraction (SRS) in most cases.
Advances in head frame technology and the development of
on-board image guidance have allowed the development of
“frameless” SRS. The same level of precision and accuracy can
now be achieved without the use of an invasive frame. Image
237
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
guidance is a key component to accurate delivery and can
include stereoscopic X-ray or on-board computed tomography
(CT)-based systems.24 Stereoscopic X-ray systems are based on
real-time orthogonal images that are processed to yield spatial
location of the target to be tracked based on bone or a visible
fiducial.24 The process of stereoscopic X-ray image guidance is
based on the X-rays taken before treatment in reference to the
digitally reconstructed radiographs (DRRs) taken at the time of
simulation to ensure accurate patient positioning, and then sev-
eral times per minute during the beam delivery to ensure that
the position remains stable. When deviations in position are
detected, the linear accelerator (linac) position is adjusted, or
the patient position is adjusted via couch shifts, or both. The
robotic arm is the core technology fundamental to CyberKnife-
based radiation delivery.
Online CT-based image guidance has almost completely taken
the form of cone-beam CT units (CBCT).24 The key advantage is
the acquisition of high-quality 3D images such that the bony
anatomy or tumor itself can be matched to the fan-beam-based
treatment-planning CT, and directly verified at the unit console.
The disadvantage to CBCT image guidance is the time required
for image acquisition such that the treatment beam has to be
stopped, making real-time image guidance generally not possi-
ble. Multiple CBCTs during delivery are not practical due to pro-
hibitive treatment times; so robust immobilization systems
play a more important role in maintaining high precision when
relying on CBCT alone for patient or beam alignment, rather
than with stereoscopic imaging systems. This is in contrast to
alignments with stereoscopic imaging systems where rigid
immobilization may be less critical; however, they are based on
planar imaging information rather than based on the 3D imag-
ing information of CBCT.
Infrared (IR) camera guidance is gaining acceptance.25,26 This
technology relies on reflective fiducial markers, placed on the
patient’s body or immobilization device, which are tracked con-
tinuously by in-room infrared cameras during treatment. The
markers provide real-time spatial feedback of the patient’s posi-
tion, which is relayed to the beam delivery system and regis-
tered with the original stereotactic coordinates. If a deviation
beyond preset thresholds is detected, treatment delivery is
automatically halted to allow for adjustments and patient repo-
sitioning as required.26 The key issue with the use of reflective
fiducial markers is robust registration and correlation between
the shifts in the markers versus the actual target shifts inside
the patient body. Because of this, IR camera guidance is primar-
ily used for monitoring or assist in initial treatment setups
rather than being used as a primary target tracking or beam
directing tool.
28.6.2 Treatment Delivery Systems
The Gamma Knife unit is the hallmark SRS technology invented
by Lars Leksell. The current unit is a self-contained unit deliver-
ing 192 cobalt-based photon beams to an intracranial target,
with the patient immobilized using an invasive head frame.24,27
The Gamma Knife has evolved to its latest model, the Leksell
Gamma Knife Perfexion (Elekta Instruments AB, Stockholm,
Sweden). This unit allows for great versatility in treatment
planning and delivery, and this is most relevant to the treat-
ment of multiple brain metastases. Key features of the Perfexion
238
include the larger treatment volume space, making it easier to
treat tumors along the base of skull or at extreme lateral loca-
tions within the cranium, and a single tungsten collimator hel-
met now embedded into the unit and computer controlled. The
design is based on multiple rings of collimating holes drilled
directly into the one tungsten cast, creating nominal beam sizes
of 16, 8, and 4 mm in diameter at the isocenter. An eight-sliding
sector design allows each sector to slide along the outside sur-
face of the tungsten collimator and align with the different
rings of prefabricated holes to allow for 192 individual 16-, 8-,
or 4-mm-diameter focused beams. Individual sectors are
blocked, so that delivered shots can be a composite of any of the
three beam diameters or zero within any of the eight sectors.
The latest innovations include an integrated relocatable head
frame that allows for fractionated SRS and the integration of
image guidance with an on-board CBCT unit,28,29 allowing for
frameless SRS and multiple fraction treatments.
The CyberKnife (Accuray Inc., Sunnyvale, CA) is based on a
minilinac mounted onto a robotic arm that is capable of moving
the linac in all 6 degrees of freedom. Near-real-time stereo-
scopic image guidance and automated robotic beam adjustment
system allows for high-precision treatment delivery.30 Recent
advances include the introduction of the IRIS collimator system,
which is designed to improve efficiency of the treatment proc-
ess, as prior models required manual exchange the circular col-
limator if different diameter beams are required; a higher-
output linac, again with the aim to reduce treatment time; and
a new more sophisticated treatment-planning system.31
A linac-based SRS was first developed by adding a tertiary
collimator onto an existing linac head to yield small circular
beams with a minimum diameter of 0.5 to 1 cm.24 Modifications
to the treatment couch and the in-room laser system were
required to ensure submillimeter precision in delivery. The
treatment-planning strategy was based on delivering multiple
beam arcs with the focal point being the linac isocenter. As the
technology improved and SRS was increasingly being applied to
tumors, one of the first dedicated linac systems built for intra-
cranial SRS was the Novalis (Brainlab, Munich, Germany). This
unit was also one of the first to integrate a stereoscopic X-ray
system into the delivery process to ensure precision and ulti-
mately frameless SRS.
Modern linac systems are now developed with the intention
of delivering high-precision radiation. The technology has
evolved to incorporate intensity-modulated radiotherapy
(IMRT), and volume-modulated arc therapy (VMAT), which is
possible due to the development of multileaf collimators
(MLCs). Now radiosurgery can be delivered over several
minutes as opposed to hours. The precision in delivery is
ensured by image-guidance systems and robotic couch technol-
ogy. Further improvement in treatment efficiency has focused
on maximizing machine output. Flattening filter-free techni-
ques have become available that allow for higher mu/min out-
put yielding delivery of radiosurgery in a few minutes. There is
a point of caution, as the biological effects with these unprece-
dented dose rates remain unclear, with potential for increased
biological potency to affect both the tumor and the adjacent
normal tissues. As more clinical data accumulate, more knowl-
edge about the safety profile of this technology will be gained.
Although there is no doubt that add-on collimators to an
existing linac requires stringent quality assurance measures
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
to avoid catastrophic errors in delivery, intensity-modulated
radiosurgery using a MLC has its own drawbacks as well. In
particular, for lesions measuring < 1 cm, inherent uncertain-
ties in small-field dosimetry and beam-shaping concerns due
to finite leaf widths limit the use of MLC for accurate dose
delivery. Tertiary collimators are still recommended for the
treatment of small targets. Another point of caution in using
MLC-based linac SRS is in the treatment of multiple targets. It
has been shown that as the number of targets to be treated
in a single session increases, so does the integral brain dose. 32
This can become an issue in dose prescription, as in order to
maintain the same risk of radiation necrosis, using a periph-
eral isodose dose volume such as the 12-Gy volume as a sur-
rogate, one may have to reduce the dose prescribed, which
may compromise local control.33 Furthermore, the toxic effect
of this low-dose spillage to the brain doses is unknown
because the threshold dose for neurocognitive damage is not
well defined, although this may not be an issue for solitary
targets.34
28.6.3 Dose Prescription
The maximum tolerated dose of single-fraction SRS was estab-
lished according to the RTOG 90–05 dose-escalation SRS trial.
In that trial, 156 patients with recurrent tumors < 4 cm in maxi-
mal diameter were treated with size as the primary stratifica-
tion, and grade III–V neurotoxicity being the stopping end
point. This study determined that the maximum tolerable doses
for lesions < 20, 21–30, and 31–40 mm were 24, 18, and 15 Gy,
respectively.35 Further dose refinement was suggested by She-
hata et al,36 who observed that for patients with metastases <
20 mm in diameter treated with WBRT, local control improve-
ments were not seen with doses > 20 Gy, with worsening neuro-
toxicity at the expense of further dose escalation. As such,
20 Gy has been established as a standard dose for small lesions
(≤ 2 cm).
Fig. 28.1 Hypofractionated stereotactic radiotherapy (HSRT) for large intact brain metastases. A complex case with an intact large lesion that is deep
planned for HSRT with 6 Gy × 5 fractions at the maximum diameter 2.2 cm. The smaller lesion (arrow) will be treated with stereotactic radiosurgery; it
is too small (0.6 cm) for multileaf collimator-based linear accelerator HSRT.
The historic dogma of single-fraction SRS has begun to shift,
as frameless systems have allowed for HSRT, utilizing three to
five fractions to deliver ablative radiation doses. This practice
began for the treatment of large lesions (> 4 cm), lesions associ-
ated with significant mass effect or for tumors adjacent to crit-
ical organs-at-risk. The concept is that fractionation allows for
greater repair of the normal brain tissue, and hence allows for
dose escalation with a similar risk profile. Hypofractionated
stereotactic radiotherapy is increasingly being practiced with
various fractionation schemes adopted. As yet there are no
randomized trials completed to support superior efficacy and
toxicity profiles in support of HSRT as compared with single-
fraction SRS. Noteworthy series include that from Fahrig et al 37
who reported on 150 patients with 228 brain metastases
treated with three different hypofractionated radiation doses:
5 × 6 to 7 Gy, 10 × 4 Gy, and 7 × 5 Gy. For tumors > 3 cm, although
10 × 4 Gy was associated with no toxicity, improvements in res-
ponse rates were seen using the 5 × 6 to 7 Gy and 7 × 5 Gy pre-
scriptions. The suitability of this range of dose fractionation was
also described by Märtens et al,38 who found improved local
control at doses with a biological equivalent dose (BED) > 35 Gy,
and by the group at Emory39 (Atlanta, GA) who reviewed their
experience using five different fractionation schedules, and giv-
en equivalent local control, favored the high BED and single-
fraction equivalent dose (SFED) of the 6 Gy × 5 scheme. There is
one series—comparing in a retrospective fashion—single-frac-
tion SRS to 36 Gy in six fractions HSRT.40 Despite being utilized
for larger tumors or tumors in critical locations, hypofractio-
nated treatment provided equivalent progression-free survival
at 6 months and 1 year, but was associated with a favorable tox-
icity profile (5% vs. 17%, p = 0.05). Further work in a prospective
randomized fashion is required to establish the optimal dose
for HSRT, 6 Gy × 5 is the lead author’s routine practice.
▶ Fig. 28.1 illustrates a complex case where an intact large le-
sion and surgical cavity were treated at the same time focally
with 6 Gy x 5 fractions.
239
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases

Fig. 28.2 Patient treatment algorithm for patients presenting with one to four metastases. Option of therapy: *Authors’ preferred option; #Resection
of symptomatic lesion(s) followed by SRS to remaining metastases; †HSRT to large lesion and SRS to remaining metastases; +HSRT to postoperative
cavity; ^For Karnofsky Performance Score (KPS) > 70 suggest WBRT or best supportive care. SRS, stereotactic radiosurgery; HSRT, hypofractionated
radiation therapy; OBS, observation; WBRT, whole-brain radiation therapy.

28.7 Complications selection. There can be serious side effects with this medication,
including a greater risk of wound complications should surgery
28.7.1 Radiation Necrosis be required urgently while on the drug.44,45,46

Radiation necrosis is a serious side effect associated with intra-

cranial SRS. Symptomatic radiation necrosis rates are typically
in the order of 5%.36 However, factors such as the treatment
dose, volume, and location can modify the risk profile.41 Diag-
nosing radiation necrosis from tumor recurrence is a major
challenge given similar radiological appearances. The gold
standard is biopsy, although noninvasive modalities such as
perfusion magnetic resonance imaging (MRI), C-methionine
positron emission tomography (PET), and MR spectroscopy,
have been investigated as alternatives to tissue confirmation,
but are not sensitive or specific enough to be reliable for defini-
tive clinical diagnosis.42 Management options include observa-
tion if asymptomatic, steroids for symptomatic lesions, surgical
resection, and now bevacizumab.43 A small randomized study
showed significant improvements in patients with radiation
necrosis treated with four cycles of bevacizumab; however,
further research is required before we understand patient
28.7.2 Neurocognitive Dysfunction and
the Effect of WBRT
As mentioned previously, Chang et al reported on the pri-
mary end point of neurocognition changes at 4 months in
patients randomized to SRS alone versus WBRT plus SRS. 7
The study concluded superior outcomes for memory func-
tioning with SRS alone. Although there were several limita-
tions in this study that could have also contributed to the
poorer neurocognitive outcomes in the WBRT group, such as
greater extracranial and intracranial disease burden and
more deaths at the 4-month interval, this study was the first
to provide randomized evidence that WBRT independently
and adversely impacts neurocognition. The findings of the
trial by Chang et al were corroborated by the recent RTOG
0214 trial, which questioned the role of prophylactic cranial

240
 Stereotactic Radiosurgery for the Management of One to Four Brain Metastases
WBRT (PC-WBRT) in patients with non–small cell lung can-
cer.47 Based on HVLT assessments, PC-WBRT was shown to
adversely impact memory both at 6 months and 1 year
despite a reduction in the risk of development of brain meta-
stases in the PC-WBRT group. From the EORTC study that uti-
lized the validated EORTC Quality of Life Questionnaire C30
and the EORTC QLQ Brain Cancer Module, we learned that
quality of life (QoL) was impaired with the use of WBRT in
patients following either surgery or SRS. 23 Although many
QoL measures in patients who received WBRT normalized,
the cognitive decline domain remained clinically worse up to
1-year posttreatment.
Attempts to mitigate the deleterious effect of WBRT include
hippocampus sparing, which has been shown in some clinical
models to decrease the risk of memory loss. Early reports of the
RTOG 0933 observed a decreased rate in memory loss at 4
months compared with historical controls.48 These data show
that sparing a key center within the brain associated with mem-
ory can yield clinical improvements. Memantine was another
strategy tested to reduce the cognitive dysfunction associated
with WBRT.49 The rate of cognitive failure, defined as the
change in the Hopkins Verbal Learning Test—Revised for
Delayed Recall at 24-week posttherapy, trended toward a signif-
icant improvement with the use of memantine compared with
placebo (median decline, 0 vs. −0.9, p = 0.059), with a probabil-
ity of cognitive function failure at 24 weeks being 53.8% in the
memantine arm and 64.9% in the placebo group. These data
illustrate that although some risk to cognition can be mitigated,
the use of WBRT yields significant risk of memory dysfunction.
The best way to reduce the potential for neurocognitive side
effects is to minimize the exposure of normal brain parenchy-
ma to radiation; this was the underlying rationale for omission
of WBRT totally in the three phase III randomized trials.
28.8 Conclusion
The impact of increasingly effective systemic and targeted
therapies has made intracranial control increasingly important
for patients with metastatic disease. Stereotactic radiosurgery
has evolved as a standard of care in the up-front management
of brain metastases as compared with WBRT alone, and as com-
pared with WBRT plus SRS due to the increasing evidence of
serious toxicities with WBRT. For postoperative patients, there
is emerging data on the use of SRS, yielding promising results:
It may potentially become the preferred option for this group
of patients. Currently, the N107C trial (NCI-2011–02676,
NCT01372774), a randomized phase III trial comparing WBRT
and SRS in postoperative patients with one to four brain meta-
stases, is enrolling patients, and the results of the trial will bet-
ter define the role of SRS in this setting. Ultimately, WBRT will
be reserved for leptomeningeal disease, brain metastases aris-
ing from histologies such as small cell lung carcinoma and lym-
phoma, or miliary dissemination such that SRS is not feasible.
Our proposed patient flow algorithm is found in ▶ Fig. 28.2 for
patients with one to four metastases.
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 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases
29 Stereotactic Radiosurgery for the Management of Five
or More Brain Metastases
Christopher L. Tinkle, Steve Braunstein, Penny K. Sneed, Igor J. Barani, and David Larson
Key Points
● No prospective randomized trials have been reported to date
comparing stereotactic radiosurgery versus whole-brain ra-
diotherapy in patients with five or more brain metastases,
though at least one such trial is accruing patients.
● Numerous retrospective studies suggest that patients with a
single brain metastasis live longer than those with multiple
brain metastases, but that number of brain metastases is not
an important prognostic factor among patients with more
than one brain metastasis.
● In the well-designed, sufficiently powered, prospective Japa-
nese Leksell Gamma Knife Society 0901 trial, patients with 5
to 10 brain metastases fared no worse than those with 2 to 4
brain metastases in all end points analyzed, including overall
survival, intracranial tumor control, neurologic deterioration,
and salvage therapy.
29.1 Introduction
Optimal management of patients with intracranial metastases
remains an area of controversy and active investigation. Histor-
ically, based largely on limitations of treatment modalities at
hand, including surgical resection and early applications of ster-
eotactic radiosurgery (SRS), a patient’s total number of brain
metastases formed an important exclusion criterion for many
clinical studies. With this in mind, several phase III randomized
trials support the use of SRS for the treatment of patients with
one to four brain metastases.1–5 Studies by Kondziolka et al1
and Andrews et al2 demonstrated improved local control with
the addition of SRS to whole-brain radiotherapy (WBRT),
whereas studies by Aoyama et al,3 Chang et al,4 and Kocher et
al5 showed that withholding WBRT does not compromise over-
all survival (OS). However, each of these studies has also shown
significant improvement in both local and distant intracranial
tumor control when SRS is combined with planned WBRT.
Nevertheless, the addition of WBRT to SRS has been associated
with inferior neurocognitive outcomes in some patients.4 Ulti-
mately, results of these seminal studies have led to the general
acceptance of the use of SRS alone as a primary therapeutic op-
tion in the management of selected patients with one to four
brain metastases.
Unfortunately, whereas relatively robust class I data exist in
patients with one to four brain metastases, management deci-
sions for patients with ≥ five brain metastases have largely
relied on speculation and retrospective data, with the exception
of a recent Japanese multi-institutional prospective observatio-
nal study by Yamamoto et al.6 Still lacking are prospective
randomized controlled trials comparing SRS with WBRT for
patients with five or more metastases. Importantly, given the
comparable OS for SRS ± WBRT borne out of the trials described
above, other important end points including neurocognitive
function, health-related quality of life, functional independ-
ence, and cost-effectiveness must be considered. In an attempt
to address many of these critical questions, the North American
Gamma Knife Consortium (NAGKC) is opening the NAGKC 12–
01 study,7 a randomized controlled trial comparing SRS with
WBRT for patients with ≥ five brain metastases, with neurocog-
nitive outcomes and tumor control as primary end points. Until
such studies mature, however, physicians and patients must
rely on the limited available data. What follows is a review of
many of the published studies on SRS or WBRT for multiple
metastases, a summary of consensus statements that address
management of patients with multiple metastases, and a
description of the toxicities of SRS and WBRT.
29.2 Treatment Options
Traditional cytotoxic chemotherapy has had limited success in
treatment of brain metastases of most histologies, either in
combination with WBRT8 or alone.9 Advances in molecularly
targeted systemic therapy, including tyrosine kinase inhibitors
and immune-modulating agents, have led to recent success in
systemic monotherapy for certain histologies of brain metasta-
ses, albeit most notably in patients with smaller asymptomatic
lesions.10,11 Observation of small asymptomatic brain metasta-
ses is also an option.
Therapeutic approaches for patients with brain metastases
most commonly include surgical resection, WBRT, and/or SRS.
Surgical intervention is typically limited to single or, less com-
monly, two to three synchronous resectable brain metastases;
thus, in this chapter we focus on SRS and WBRT, including
recent strategies to lessen the risk of neurocognitive effects of
WBRT.12,13
29.2.1 Stereotactic Radiosurgery for
Five or More Brain Metastases
One of the earlier studies of SRS for multiple metastases was
reported by Serizawa et al.14 This was a single-institution retro-
spective review of patients treated with Gamma Knife stereo-
tactic radiosurgery (GKSRS) alone (62 patients) or WBRT alone
(34 patients) from 1990 to 1999 for 1 to 10 brain metastases
from non–small cell lung cancer (NSCLC). Surgical resection in
select patients preceded irradiation in both groups. Repeat SRS
to new lesions rather than WBRT was performed in the SRS
group, whereas WBRT patients received subsequent SRS. Base-
line characteristics, including number of brain metastases, did
not significantly differ. On multivariable analysis, only uncon-
trolled systemic disease, WBRT, and low Karnofsky Perform-
ance Score (KPS) were significantly associated with poor
outcome. Interestingly, mean survival time (377 vs. 199 days,
p = 0.0158), neurologic survival (p = 0.0237), and OS (p = 0.158)
favored the SRS-alone group.
243
 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases
In a subsequent study, Serizawa et al15 analyzed outcomes of
GKSRS among 2,390 patients at two institutions in Japan
treated from 1998 to 2005 with either surgery followed by SRS
or SRS alone. Prophylactic WBRT was not administered and dis-
tant intracranial disease was managed with repeat SRS if the
patient’s condition permitted. Roughly 40% of patients at each
facility had more than four brain metastases, with a mean of 6.2
and 6.5, respectively. Factors significantly associated with inferi-
or OS included active extracranial disease, male gender, and
low initial KPS score (all, p = 0.0001), whereas total number of
brain metastases (≤ 4 vs. > 4) was not significantly associated
with survival. A critical selection factor in this study was the
limitation of the total skull integral dose to 10 to 12 joules (J), a
concept put forth to integrate tumor number, tumor size, and
SRS dose to maintain an equivalent threshold dose of a single
3-Gy fraction of whole-brain irradiation. Below this threshold,
this group had not observed acute cerebral swelling.15
Nam et al16 reported a single institution’s experience with
GKSRS for 130 patients with brain metastases of various histol-
ogies treated from 2001 to 2004, including 84 patients with one
to three brain metastases and 46 with four or more. The major-
ity of these patients also received WBRT (73%). Although
median OS was significantly longer for patients with one to
three metastases compared with those with four or more (48
vs. 26 weeks, p = 0.005), the number of metastases did not sig-
nificantly predict for improved survival. Rather, recursive parti-
tioning analysis (RPA)17 class was the only variable found to be
significantly associated with survival on multivariable analysis,
leading to the authors’ recommendation that RPA, rather than
lesion number, be used to restrict the use of SRS monotherapy.
A study from the University of Pittsburgh (Pittsburgh, PA) by
Bhatnagar et al18 (▶ Table 29.1) reported outcomes for 205
patients treated from 1995 to 2005 with SRS to 4 to 18 brain
metastases of various histologies; 64% of patients had ≥ five meta-
stases. The majority of patients also received WBRT, 46% concur-
rently with SRS and 38% after progression following SRS. Median
OS for patients meeting RPA class I, II, and III criteria were 18, 9,
and 3 months, respectively, comparing favorably with historical
results with WBRT alone (7, 4, and 2 months, respectively). Multi-
variable analysis revealed total treatment volume as a significant
variable associated with improved one-year local control
(p = 0.002), whereas total treatment volume (p = 0.002), age
(p = 0.005), and RPA class (p = 0.009) were significantly associated
with improved survival. Total number of treated brain metastases
was not significantly prognostic for local control nor OS (p = 0.91
and 0.333, respectively). Thus, total treatment volume rather than
number of lesions was posited by this group as an important
selection factor for the use of SRS alone.
Park et al19 reported their institutional outcomes for 33
patients with 2 to 20 NSCLC brain metastases < 3 cm diameter
treated from 2005 to 2006 with either GKSRS (14 patients) or
WBRT (19 patients) based on physician and patient preference.
Overall survival was significantly increased for patients treated
with SRS compared with those treated with WBRT (p = 0.04),
with 1-year survival rates of 47.7% versus 10.5%, respectively.
Given the small sample size, analysis of prognostic factors was
limited to univariable analysis, which revealed control of pri-
mary tumor site (p = 0.03) and use of SRS (p = 0.04) to be signifi-
cantly associated with superior OS, whereas number of brain
metastases (< 10 vs. ≥ 10) was not (p = 0.33).
244
In an initial report by Yamamoto et al20 of 456 patients
treated from 1991 to 2004 with GKSRS for 1 to 55 brain meta-
stases (mean 6; median 2) arising from non–lung cancer pri-
mary tumors, increasing tumor number was significantly
associated with inferior OS on univariable analysis (p = 0.001).
Up-front surgical resection occurred in 23% of patients, prior
radiotherapy in 6.4%, and prior surgery and radiotherapy in
3.3%. When median OS times were compared based on number
of brain metastases, lesion number appeared to have a signifi-
cant impact on duration of survival: 1 to 4 lesions (7.4 months),
5 to 9 lesions (4.0 months), 10 to 14 lesions (7.4 months), 15 to
19 lesions (3.4 months), 20 to 29 lesions (4.9 months), and 30
or more lesions (4.6 months); p = 0.0002. However, an impor-
tant limitation to this study is the limited numbers of patients
within each group beyond five brain metastases.
An update on this study was reported by Yamamoto et al 21
with 1,676 patients with brain metastases from a variety of pri-
mary tumors treated with GKSRS from 1991 to 2006. The mean
and median lesion numbers were 7 and 3, respectively, with a
range of 1 to 85. In this analysis, patients again were grouped
by number of brain metastases, yet included comparisons of
median survival times between patients with 1 versus 2 lesions,
2 versus 3 lesions, and up to 14 versus 15 lesions. Among the
14 comparison pairs, only one versus two lesions showed a sig-
nificant median survival difference (10.2 vs. 7.2 months,
p = 0.0002), whereas the remaining pairwise comparisons did
not differ significantly. That said, there was a significant differ-
ence in median survival comparing patients with ≤ four versus ≥
five brain metastases (8.4 vs. 5.3 months, respectively,
p < 0.0001). Additionally, female patients lived longer than male
patients (9.0 vs. 5.9 months, p < 0.0001).
A more recent single-institution retrospective case-matched
study by Yamamoto et al22 (▶ Table 29.1) was undertaken to
determine the outcomes of patients with ≤ four versus ≥ five
brain metastases treated with GKSRS from 1998 to 2011. Prior
surgical resection was performed in 17% of patients, and 4.2%
had prior WBRT. With 548 patients in each group, median sur-
vival time was statistically longer in patients with ≤ four brain
metastases compared with those with ≥ five, 7.9 versus 7.0
months, respectively, p = 0.01. However, with overlapping 95%
confidence intervals of 7.0 to 8.9 months versus 6.2 to 7.8
months and a hazard ratio of 1.176, the significance is question-
able. Additionally, as noted by the authors, the difference of 27
days is likely not clinically meaningful. Furthermore, there was
no significant difference between the two groups in freedom
from neurologic death, and through the use of competing risk
analysis, there were no significant differences in local control,
use of repeat SRS, or major SRS-related complications.
Another large retrospective study was conducted by Karlsson
et al23 (▶ Table 29.1) of 1,855 patients from four institutions
treated with GKSRS from 1975 to 2007. Incomplete records lim-
ited analysis of prior treatment, but at least 13% received prior
WBRT and 22% underwent repeat SRS. Nearly half of the
patients (46%) had one brain metastasis, 22% had two, 19% had
three to four, 10% had five to eight, and 3% > eight brain meta-
stases. There was significantly longer median survival time in
patients with single versus multiple lesions, 7.5 versus 6.1
months, p < 0.0001, as well as for patients with controlled ver-
sus uncontrolled primary disease, 9.8 versus 5.2 months,
p < 0.0001, and patients < 60 versus ≥ 60 years of age, 8.3 months
 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases

Table 29.1 Selected studies of outcomes of stereotactic radiosurgery for multiple brain metastases
Study Period N Outcome(s) No. metastases Key findings
[PubMed ID]
Study type

Bhatnagar et al, 200618 1995–2005 205 OS 4–18 Median OS 8.0 months; 71% 1-year LC
[16338097] Treatment volume, age, RPA class,
Retrospective marginal dose associated with OS

Yamamoto et al, 201322 1998–2011 1,096 OS 1–4 vs. ≥ 5 Median OS 7.0 months for ≥ 5 mets vs.
[23600938] LC 7.9 months for 1–4 mets, p = 0.01
Case-matched ND No difference in LC, ND, toxicity

Karlsson et al, 200923 1975–2007 1,885 OS 1–8 + Median OS 6.1 months for ≥ 2 mets
[19199505] Age and primary tumor control asso-
Retrospective ciated with OS

Chang et al, 201024 2005–2008 323 OS 1–5 vs. 6–10 vs. 11–15 vs. > 15 Median OS 10 months for 6–10 mets
[21121789] LC No differences in OS, LC; increased
Retrospective distant progression for > 15 mets

Hunter et al, 201225 1995–2008 64 OS ≥5 Median OS 7.5 months

[22209150] KPS associated with OS
Retrospective

Raldow et al, 201226 2000–2010 103 OS 5–9 (84 patients) vs. ≥ 10 Median OS 7.6 months for 5–9 mets
[22706180] RFS (19 patients) Higher KPS associated with better OS
Retrospective

Serizawa et al, 201033 1998–2009 778 OS 1–10 (5–10 in 215 patients) Median OS 7.3 months for 5–10 mets
[20411300] NS Active systemic disease, KPS < 70, and
Retrospective NLFS male gender associated with poorer
QS OS

Yamamoto et al, 20146 2009–2012 1,194 OS 2–4 vs. 5–10 Median OS 10.8 months for 5–10 mets
[24621620] Toxicity Risk of AE 3% for 5–10 mets
Prospective trial JLGK0901 NCF Noninferior OS and toxicity for 5–10
vs. 2–4 mets; NCF analysis pending

Abbreviations: AE, adverse events; KPS, Karnofsky Performance Status; LC, local control; mets, metastases; NCF, neurocognitive function; ND, neurologic
deterioration; NLFS, new-lesion-free survival; NS, neurologic survival (survival with KPS ≥ 70); OS, overall survival; QS, qualitative survival; RFS,
recurrence-free survival; RPA, recursive partitioning analysis.

versus 5.3 months, p < 0.0001. However, primary disease con-
trol appeared to be the dominant prognostic factor, as signifi-
cant differences in OS between single and multiple brain
metastases disappeared when patients with controlled or
uncontrolled primary disease were analyzed separately. Addi-
tionally, there were no significant differences in median surviv-
al between groups of patients with two versus three to four
versus five to eight versus > eight lesions, or between patients
with < four versus ≥ five lesions. The authors concluded that pa-
tient age and primary disease status should be used as limiting
parameters for treatment with SRS, rather than total number of
brain metastases.
Chang et al24 (▶ Table 29.1) evaluated 323 patients treated
from 2005 to 2008 at a single institution with SRS. Fourteen
patients with ≥ 15 brain metastases received prior WBRT.
Patients were retrospectively grouped based on number of
treated lesions: 1 to 5 (67%), 6 to 10 (18%), 11 to 15 (5%),
and > 15 (10%). Overall survival times after SRS were 10, 10,
13, and 8 months, respectively, and did not differ signifi-
cantly among groups, p = 0.554. Additionally, local tumor con-
trol also did not differ significantly among the groups of
patients, nor did radiographic changes on interval imaging.
However, median progression-free survival and time to
distant brain progression were significantly shorter for
patients with > 15 brain metastases, p = 0.03 and p = 0.014,
respectively.
Hunter et al25 (▶ Table 29.1) studied 64 patients with 5 to 10
brain metastases (median 6) treated with SRS from 1995 to
2008; 63% had received prior WBRT, 14% had concurrent WBRT,
and 23% had SRS alone. The median survival after SRS was 7.5
months overall, 6.6 months in patients with ≤ eight brain meta-
stases, and 9.9 months in those with > eight metastases (not sig-
nificant). However, higher KPS (≥ 80, p = 0.02) and prior as
opposed to concurrent radiotherapy (p = 0.03) were found to be
significantly associated with improved OS on multivariable
analysis.
A similar analysis was done by Raldow et al26 (▶ Table 29.1)
for 103 patients with ≥ five brain metastases treated from 2000
to 2010 by SRS. Eighty-two percent of patients had 5 to 9 brain
metastases, whereas 18% had 10 or more; 59% had prior treat-
ment (WBRT, 33%; SRS, 12%; or both, 15%). The median survival
times were 7.6 versus 8.3 months for patients with 5 to 9 ver-
sus ≥ 10 brain metastases, p = 0.38. Karnofsky Performance
Score was the only variable significantly associated with

245
 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases
survival time on multivariable analysis; number and total vol-
ume of brain metastases were not significant.
In an analysis of prognostic factors after salvage SRS, Cabal-
lero et al27 retrospectively reviewed 310 patients treated
with GKSRS for new, progressive, or recurrent brain metasta-
ses after WBRT. The median number of treated lesions was 4,
with a range of 1 to 35, and with more than half of patients
(53%) having 4 to 35 lesions. Median survival from SRS was
8.2 months, significantly longer in patients with a single
brain metastasis compared with those with multiple meta-
stases, 12.0 versus 7.9 months, p = 0.001. Yet, there was no
relationship between number of brain metastases and OS
among patients with multiple lesions. Favorable prognostic
factors on multivariable analysis varied by primary disease
site. The nearly 8-month median survival time led the
authors to conclude that salvage SRS is a reasonable treat-
ment option, with no evidence for a threshold related to
brain metastases number.
Several studies have restricted analysis to patients with ≥ 10
brain metastases. Suzuki et al28 reported on 24 patients without
prior WBRT with 10 to 47 lesions (mean 20) treated from 1998
to 2000 with GKSRS. With mean follow-up of only 13 weeks,
the Kaplan-Meier estimate of OS at 24 weeks was 49.3%, and
the mean KPS score improved significantly after completion of
SRS (p < 0.05). In an effort to assess cumulative whole-brain
dose in patients with a large number of brain metastases,
Yamamoto et al29 reported on 80 patients with a median of 17
lesions (range 10–43) treated with GKSRS from 1998 to 2000.
With a median tumor volume of 8.02 mL and median pre-
scribed dose of 20 Gy, the median cumulative dose to the whole
brain (excluding the tumor volume) was 4.71 Gy (range 2.16–
8.51 Gy), a dose the authors concluded was below the threshold
level of normal brain tissue necrosis.
Several groups have performed retrospective reviews to elu-
cidate potential prognostic factors of OS in patients with 10 or
more brain metastases treated with SRS. Kim et al30 reviewed
outcomes for 26 patients with 10 to 37 lesions, half of whom
had received prior WBRT, and found NSCLC histology
(p = 0.007), KPS ≥ 80 (p = 0.029), and controlled primary disease
(p = 0.02) to be associated with longer survival on univariable
analysis. In a similar analysis by Grandhi et al31 in 61 patients
with a mean of 13.2 lesions, 62% of whom had prior WBRT ±
SRS, prognostic factors on univariable analysis included < 14
brain metastases, nonmelanoma histology, controlled systemic
disease, KPS ≥ 90, and lower RPA class. Among patients with the
favorable factors, median survival was 21 months. Prior WBRT
was significantly associated with the development of new
adverse radiation effect.
In 2009, the Japanese Leksell Gamma Knife (JLGK) Society ini-
tiated a prospective multi-institutional observational cohort
study, JLGK0901, to assess whether treatment outcomes were
different in patients with 5 to 10 versus 2 to 4 brain metastases
treated with SRS, and to determine prognostic factors affecting
inferiority or noninferiority of outcomes.6 Results from this
observational study were expected to provide support for a
future randomized controlled trial testing SRS versus WBRT for
patients with 5 to 10 brain metastases. Eligibility criteria
included 1 to 10 newly diagnosed brain metastases, largest
tumor volume < 10 mL, total brain metastasis volume < 15 mL,
no cerebrospinal fluid dissemination, and KPS ≥ 70.
246
Prior to completion of the prospective trial, Serizawa per-
formed two retrospective studies incorporating the eligibility
criteria of JLGK0901. One study32 examined results of SRS as
sole treatment for 1,508 patients with 1 to 10 brain metastases
treated from 1998 to 2007 with GKSRS at two institutions in
Japan. The median survival times by number of metastases
were 11.9 months for group A (1 tumor), 8.2 months for group
B (2–4 tumors), and 7.4 months for group C (5–10 tumors).
There were significant differences in median survival for group
A versus B (p < 0.0001) and group B versus C (p = 0.0312). How-
ever, on multivariable analysis no significant difference in OS
between groups B and C was found (p = 0.103; hazard ratio
[HR] = 1.124, 95% confidence interval [CI] 0.999–1.265). The
upper limit of the 95% CI of 1.265 was within the predeter-
mined threshold of 1.3 corresponding to a noninferiority mar-
gin of 7.5% employed in the JLGK0901 study. Prognostic factors
associated with inferior outcomes included male gender
(p < 0.0001), lung primary (vs. breast, p = 0.0047), higher RPA
classification (p < 0.0001), and multiple brain metastases (group
A vs. B, p < 0.0001).
In a second study (▶ Table 29.1),33 again employing JLGK0901
eligibility criteria, 778 patients were divided into groups based
on number of brain metastases: A (1), B (2), C (3–4), D (5–6),
and group E (7–10). Mean survival times ranged from 10.7 to
7.1 months, yet were not significantly different between any
two groups. Additional outcomes of freedom from neurologic
death and survival with KPS ≥ 70 at year were also not signifi-
cantly different between any two groups; however, 1-year dis-
tant intracranial control was significantly worse for group B
versus A (p = 0.0003) and for group C versus B (p = 0.0047).
In 2014, Yamamoto et al6 (▶ Table 29.1) reported the results
pertaining to the primary end point of OS of the JLGK0901
study; assessment of secondary end points of SRS-induced
complications and neurocognitive function will continue into
2014. From 2009 to 2012, 1,194 patients were enrolled. Median
OS time after SRS was 13.9 months in the 455 patients with one
tumor, 10.8 months in the 531 patients with 2 to 4 tumors, and
10.8 months in the 208 patients with 5 to 10 tumors. Overall
survival did not significantly differ between patients with 2 to 4
vs. 5 to 10 brain metastases, with a HR of 0.97, 95% CI 0.81–
1.18, p = 0.78, and pnoninferiority < 0.0001. Incidence of neurologic
death, neurologic deterioration, local recurrence, development
of new lesions, and salvage SRS, WBRT, or surgery did not differ
significantly between the two groups of patients with multiple
tumors. Multivariable analysis showed the presence of a single
tumor, female gender, age < 65, KPS ≥ 80, stable extracranial dis-
ease, and absence of neurologic symptoms at the time of SRS to
significantly impact OS. Preliminary analysis revealed no signif-
icant difference in adverse events of any grade comparing
patients with 2 to 4 versus 5 to 10 tumors. Thus, the authors
conclude that SRS alone for the management of patients with 5
to 10 brain metastases is noninferior to SRS alone in those with
2 to 4 metastases.
29.2.2 WBRT for Five or More Brain
Metastases
Despite the fact that WBRT is generally considered the de facto
treatment of choice for patients with a more extensive intracra-
nial disease burden, there are scant data relating the number of
 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases
brain metastases to outcomes for patients with five or more
brain lesions treated with WBRT. One study that did address
this topic was reported by Nieder et al34 who analyzed 113
patients with a median of six brain metastases (range 4–50)
treated with WBRT without surgical resection or SRS. The num-
ber of brain metastases had no significant influence on OS.
Additionally, although there were too few patients who met
RPA class I criteria, there was no significant difference in OS
between RPA class II and III patients.
29.2.3 Consensus Guidelines
The majority of current consensus statements regarding ma-
nagement of brain metastases do not specifically address ma-
nagement of patients with ≥ five metastases, other than by
extrapolation from previously discussed randomized trials in
patients with one to four metastases. The European Federation
of Neurological Societies produced an evidence-based guide-
lines document in 200635 in which, without reference, the
authors claim, “In patients with more than three brain metasta-
ses WBRT with hypofractionated regimens is the treatment of
choice.” In 2009 (updated in 2011), the American College of
Radiology published appropriateness criteria using the formal
Delphi consensus process for the management of multiple brain
metastases.36 The report includes five clinical case descriptions,
but only one case representing ≥ five metastases. A theoretical
50-year-old patient with NSCLC, KPS 90, controlled primary
disease, no systemic disease, and six newly diagnosed asympto-
matic brain metastases received a score of 1 (least appropriate)
for SRS alone and a score of 8 (9 most appropriate) for WBRT
alone. Although clinical evidence was not presented, the num-
ber of lesions and lack of evidence for SRS was used to justify
these scores.
The American Association of Neurological Surgeons and Con-
gress of Neurosurgeons reviewed 11 observational studies that
support the notion that SRS alone may provide equivalent sur-
vival rates compared with WBRT in combination with SRS.37
The report, published in 2011, acknowledges the risk of poten-
tial neurocognitive deficits with the use of WBRT; however, ma-
nagement of multiple metastases is not specifically addressed.
The American Society for Radiation Oncology (ASTRO) evi-
dence-based guidelines on the role of radiation for newly diag-
nosed brain metastases were published in 2012,38 and although
not directly evaluating management of multiple metastases, the
document does state, “It is unknown if there is a cutoff for the
maximum number of targets appropriate for SRS. Total target
volume as well as number of targets may be important for
safety and efficacy.” Finally, the current National Comprehen-
sive Cancer Network (NCCN) guidelines suggest that WBRT
alone is the only appropriate therapeutic intervention for
patients with > three newly diagnosed brain metastases. 39
Although there appears to be reluctance to recommend SRS
for > three to four brain metastases in the consensus guidelines
described above, this does not appear to be the case among
practitioners of SRS.40 Physician surveys at two International
Stereotactic Radiosurgery Society meetings were conducted to
assess acceptance of treating various numbers of brain metasta-
ses. In the 2007 survey in San Francisco, the mean and median
numbers of metastases physicians would consider treating with
SRS alone were 6.7 and 5, respectively, with 55% of respondents
agreeing that treatment of ≥ five lesions was “reasonable.” In
the 2009 survey in Sendai, Japan, the mean and median number
of metastases deemed suitable for SRS alone had increased to
11 and 10, and 83% of participants felt that treating ≥ five
lesions was “reasonable.”
29.3 Complications: Toxicities and
Neurocognitive Outcomes
Limited radiation tolerance of brain tissues is well recognized,
with white matter and subcortical structures showing greatest
sensitivity in a dose-dependent fashion.41 Although the precise
mechanisms of radiation-induced brain injury remain unclear,
alterations in microvasculature and glial cell–mediated inflam-
mation are associated with late radiation toxicity.42 Moreover,
evidence suggests that radiation-sensitive, active neurogenesis
in adults is essential to hippocampal-dependent memory func-
tion.43 Recent attempts to improve functional outcomes have
included hippocampal-sparing WBRT12 and adjuvant pharma-
cological therapy, such as memantine administration,13 with
promising preliminary results.
A strong rationale for use of SRS over WBRT for brain meta-
stases is the potential sparing of neurocognitive toxicities such
as memory impairment, dementia, and loss of functional inde-
pendence. An early study on neurocognition following WBRT
estimated an 11% incidence of severe late clinical dementia,44
and a retrospective series of patients receiving WBRT for vari-
ous intracranial malignancies suggested an incidence of 32%
grade 1 to 3 toxicity at one-year post-WBRT at a median dose of
30 Gy in 10 fractions.41 A more recent meta-analysis highlights
the emergence of early neurocognitive impairment, approach-
ing 50% as early as 3 months following WBRT.45 Notably, a
challenge to accurate assessment of radiation-related neurocog-
nitive decline is the confounding effects of intracranial disease
burden and progression46 and systemic therapy. Yet, imaging
approaches reveal incidence of leukoencephalopathy ranging
between 34 and 83% at ≥ 6 months after WBRT for brain meta-
stases.47,48
The limited treatment volumes of SRS as compared with
WBRT hold the potential to reduce late neurocognitive
impairment. Early trials including SRS-only brain metastasis
treatment arms showed no overt evidence of neurologic toxic-
ity.1 Aoyama et al3 compared WBRT + SRS versus SRS alone for
one to four brain metastases and performed pre- and post-
treatment Mini-Mental Status Examination (MMSE). Neuro-
cognitive outcomes were comparable at 1 year, but there was
a trend toward improved preservation of MMSE score over
extended follow-up (22.5% vs. 42.6%, at 3 years, respectively).
The more recent randomized controlled study by Chang et al 4
comparing WBRT + SRS versus SRS alone was designed with
neurocognitive function as the primary end point, and
employed a wide battery of neurocognitive assessments. The
study was closed early due to significantly diminished neuro-
cognitive function after WBRT + SRS versus SRS alone 4-month
posttreatment (52% vs. 24% decline in immediate verbal recall,
respectively). Furthermore, newer series have also reported
significantly decreased incidence of leukoencephalopathy on
imaging after SRS alone vs. WBRT + SRS for one to two
lesions.49
247
 Stereotactic Radiosurgery for the Management of Five or More Brain Metastases
The first Radiation Therapy Oncology Group (RTOG) SRS trial,
90–05, was a dose-escalation study in recurrent brain tumors 50;
64% of patients had brain metastases, of which 22% had multi-
ple brain lesions, although only the dominant lesion received
SRS. There was no evidence of dose-limiting toxicity up to
24 Gy for lesions ≤ 20 mm, but treatment of larger lesions (21–
30 and 31–40 mm) caused unacceptable toxicity above 18 Gy
and 15 Gy, respectively, largely related to radionecrosis and
brain edema at a median of 4.5 to 5.0 months.
Of concern, SRS of multiple brain metastases can result in
larger brain volume exposed to both high dose and peripheral
dose51 with consequent increased risk of brain radiation
injury.52 Several reports of SRS for large numbers of metastases
have shown low cumulative whole-brain radiation dose. An 80-
patient series of ≥ 10 SRS-treated brain metastases showed
median cumulative whole-brain irradiation dose of 4.71 Gy
(range 2.16–8.51 Gy), with no acute or late radiation-related
toxicities reported. Moreover, a subset of these patients who
had subsequent SRS likewise did not experience any ensuing
toxicity.29
In the large series reported by Serizawa et al, 15 of 2,533
patients treated at two major Japanese centers for an average of
6.2 ± 7.6 and 6.5 ± 9.3 brain metastases, respectively, there were
no severe acute toxicities with total skull integrated dose of less
than 10 to 12 J, equivalent to approximately 3 Gy of WBRT or a
15-mL treatment volume. However, multiple studies of SRS
treatment of intracranial brain lesions, including metastases,
have shown rates of radionecrosis up to 50% depending upon
dose, volume, and tumor location.53,54 As reported by Minniti et
al,54 10-Gy volume > 12.6 mL 12-Gy volume > 10.9 mL was asso-
ciated with a risk of radionecrosis of 47%. However, only a small
fraction of patients with evidence of radionecrosis on interval
imaging were symptomatic and severe neurologic complica-
tions were rare.
There are limited data with regard to neurocognitive out-
comes following SRS treatment of patients specifically with >
four brain metastases. Recent reports comparing SRS treatment
of ≤ four versus > four lesions indicate similar limited treatment-
related toxicities. For example, the case-matched retrospective
study by Yamamoto et al22 comparing outcomes of SRS treat-
ment of patients with one to four versus ≥ five brain metastases
revealed equivalence in neurologic deterioration (13.1% vs.
9.7%) and treatment-related complications (2.7% vs. 2.0%).
The JLGK0901 prospective multi-institutional observational
study also stratified SRS outcomes by number of brain metasta-
ses.6 Overall rate of SRS-related adverse events was 9% (101/
1,194 patients). Analysis demonstrated no relationship between
the number of tumors treated and any-grade toxicity. More-
over, high-grade toxicity (grade 3–4) was present at 3% for
patients with 5 to 10 tumors, which was not significantly differ-
ent from those with one (2%) or two to four (2%) tumors. Main-
tenance of neurocognitive function at up to 36 months post-
SRS was similar among those with 1, 2 to 4, and 5 to 10 tumors
at 88 to 100%.
Finally, the recently opened North American Gamma Knife
Consortium randomized controlled trial (NAGKC 12–01),7 a
comparison of WBRT versus SRS, is specifically examining neu-
rocognitive outcomes in patients with 5 to 10 brain metastases
using a battery of neurocognitive assessment with greater
248
precision than the standard MMSE and Hopkins Verbal Learn-
ing Test.
29.4 Summary
Physicians who have traditionally favored WBRT for patients
with multiple brain metastases often argue that comprehensive
intracranial radiation is necessary to treat micrometastases,
thereby reducing the development of new intracranial metasta-
ses that could result in high rates of clinical neurologic
decline.55 Supporters of SRS alone often counterargue that the
neurocognitive effects of WBRT are very real, and that salvage
SRS, although more frequently needed in patients initially
treated with SRS alone, is safe, efficient, and effective.27 Addi-
tional arguments favoring up-front SRS, often invoked by refer-
ring physicians and patients alike, is the convenient single-day
treatment with minimal interruption in systemic therapy.
As outlined in this chapter, despite the vast heterogeneity of
the retrospective studies described, the majority of reports do
not identify the total number of brain metastases beyond a sin-
gle metastasis to be significantly associated with either local
control or OS. Rather, young age; higher KPS; controlled pri-
mary, absent, or controlled systemic disease; and smaller total
volume of brain metastases appear to be important prognostic
factors. Additionally, in the well-designed, sufficiently powered,
prospective JLGK 0901 trial, patients with 5 to 10 brain meta-
stases with total volume < 15 mL fared no worse than patients
with 2 to 4 in all end points analyzed, including OS, intracranial
tumor control, neurologic deterioration, and salvage therapy.
Thus, although we await class I evidence on survival, neurocog-
nitive function, health-related quality of life, functional inde-
pendence, and cost-effectiveness of SRS versus WBRT to help
guide treatment decision making for patients with five or more
brain metastases, it appears that, when coupled with close
active surveillance measures, SRS may be considered a viable
therapeutic option for this important and growing patient
population.56
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30 Repeat Radiosurgery for Brain Metastases
Aditya Halthore, Ami B. Raval, Michael Schulder, and Jonathan Knisely
Key Points
● Diagnosis of local progression after stereotactic radiosurgery
for brain metastases is often difficult. Specialized imaging
may help when evaluation of T1/T2 mismatch is not disposi-
tive.
● The gold standard for determining local progression remains
biopsy or resection histopathologically documenting persis-
tent/recurrent tumor.
● Repeat radiosurgery for brain metastases is a viable treat-
ment modality.
● Level I evidence evaluating repeat stereotactic radiosurgery
for brain metastases is needed.
30.1 Introduction
The management of newly diagnosed brain metastases by ster-
eotactic radiosurgery (SRS) has been shown to provide excel-
lent local control, with treated metastases showing local
control rates at 1 year approaching 90%.1,2,3 In patients who
continue to demonstrate low overall disease burden (i.e., good
performance status and few visceral metastases), maintaining
good control of brain metastases remains paramount to extend-
ing survival and preserving quality of life. Randomized control
trials comparing SRS to SRS combined with whole-brain radio-
therapy (WBRT) have shown that radiosurgery alone is not infe-
rior to combination therapy with regards to overall survival.1,2,3
As such, SRS alone has increasingly become a viable initial ma-
nagement strategy for patients with brain metastases. As radia-
tion delivery technologies and systemic therapies have
improved, patients with brain metastases are also living long
enough to experience intracranial recurrence—for example, one
retrospective review of 1,300 patients from the Cleveland Clinic
(Cleveland, OH) treated for brain metastases showed that over
2.5% of patients survived at least 5 years. 4,5 As more patients
begin to receive SRS alone for initial brain metastasis, the ques-
tion of how to manage local recurrence of metastases previ-
ously treated with radiosurgery has become increasingly
relevant.
As in the case of newly diagnosed metastases, the options for
recurrent brain metastases include but are not limited to surgi-
cal extirpation, WBRT, and repeat radiosurgery. Emerging
modalities such as magnetic resonance–guided focused laser
interstitial thermal therapy may be considered in patients
whose metastases measure less than 3 cm or show significant
failure to prior radiosurgery.6 For many patients, the risk of
morbidity from surgery outweighs its benefits, and as such, a
radiotherapeutic approach is often preferred. In patients who
have previously received SRS for metastatic intracranial disease,
repeat radiosurgery is a viable approach in the appropriate pa-
tient, although there is no level I evidence to support this claim.
In this chapter, we discuss the feasibility of repeat radiosurgery
for local metastatic recurrence in the brain, including potential
Repeat Radiosurgery for Brain Metastases
benefits and drawbacks in the context of a review of the exist-
ing literature.
30.2 Decision to Treat
The very diagnosis of progression or recurrence of brain meta-
stases previously treated with whole-brain irradiation or radio-
surgery can prove challenging. Distinguishing between
recurrence and radiation necrosis, for example, is not always
clear despite high-resolution, thin-slice structural magnetic res-
onance imaging (MRI). As such, specialized imaging such as
proton magnetic resonance spectroscopy, perfusion-weighted
MRI, and 11C-methyl-L-methionine positron emission tomogra-
phy (PET) or even a biopsy of the lesion is helpful in many cases
to confirm recurrence. More recently, literature has shown that
concordant enhancement on T1 postcontrast and T2 sequences
is more likely to represent recurrence rather than radiation
effect. Similarly, diffuse T2 signal enhancement that is discord-
ant from rim enhancement on T1 sequencing may suggest radi-
ation change, a concept known as “mismatch.”7,8,9,10,11
When considering delivery of repeat SRS for patients with
previously treated brain metastases, evaluation of prognosis is
important. Yamamoto et al (unpublished data) most recently
analyzed the recursive partitioning analysis (RPA) classification
first described by Gaspar et al (1997) along with four other
prognostic schema to identify which index provides the best
stratification of patients undergoing repeat radiosurgery for
brain metastases.12 The index with the best discrimination,
known as the “modified” RPA classification, was based on a
cohort that included 804 patients who underwent repeat SRS
(local or remote). Of these patients, 122 (15%) received repeat
SRS for local recurrence. Within the entire cohort, patients in
modified RPA classes I, II, and III had median survival times of
14.5, 7.2, and 4.5 months, respectively.10 A combination of clin-
ical judgment and stratification based on such prognostic tools
is useful in deciding who may benefit from repeat radiosurgery
and in whom such therapy may be futile.
30.3 Efficacy and Toxicity of
Repeat Radiosurgery
As with radiosurgery for the initial treatment of brain metasta-
ses, the advantages of repeat SRS are many. Repeat radiosurgery
minimizes the dose that normal brain tissue receives and pre-
serves the capability to deliver WBRT at a later date. By delaying
or avoiding WBRT altogether, the patient may be spared poten-
tially debilitating neurocognitive sequelae. This is particularly
relevant in patients who have a range of effective systemic ther-
apy options or those who have slow-growing primary histolo-
gies such as certain breast cancers, in whom life expectancy can
be measured on the order of several months to years. Further-
more, deferring WBRT in the setting of small intraparenchymal
metastases allows it to be utilized more effectively when the
number or size of metastases has progressed beyond the
251
 Repeat Radiosurgery for Brain Metastases

capability of SRS or when the location of new metastases war- The evidence base for salvage radiosurgery following initial
rants a fractionated partial or whole-brain approach (e.g., for whole-brain therapy is somewhat larger and may shed light on
disease involving the leptomeninges or optic apparatus). Repeat the ability of repeat irradiation to provide effective local control
stereotactic radiosurgery, due to its inherently high dose per while avoiding normal tissue toxicity.17,18,19,20 In RTOG 9005,
fraction, may also afford better local control in radioresistant Shaw and colleagues demonstrated low rates of necrosis and
histologies such as melanoma, renal cell carcinoma, and sarco- local progression in the context of dose escalation SRS after
mas.13 Finally, patients who have a good performance status whole-brain irradiation for primary brain tumors and metasta-
may be candidates for further systemic therapy, which can be ses.18 In this study, the incidence of radionecrosis was 11% at 24
initiated more quickly with a single-fraction approach to brain months and local tumor progression occurred in 48% of all
metastasis treatment than with protracted fractionation. patients. In a retrospective series of 111 patients by Chao et al,
The potential downside of repeat radiosurgery pertains to treatment with salvage radiosurgery following initial WBRT
the composite dose delivered over multiple sessions, which if yielded a median survival of 10.4 months for patients with
high enough, can lead to symptomatic edema and radiation local-only recurrence, and two patients developed pathologi-
necrosis.14,15 Increased volume of metastasis treated as well as cally confirmed radiation necrosis within 1.5 years after SRS. 17
decreased interval between first and second treatments both
contribute to the risk of brain toxicity. Location may also play a
role in the clinical evaluation for possible repeat SRS—repeated 30.4 Clinical Vignette
doses delivered to a metastasis near the optic chiasm, for exam-
A 49-year-old woman with a history of triple-negative invasive
ple, may cause permanent visual impairment, whereas the
ductal carcinoma of the left breast was treated with mastec-
same total dose delivered to a peripheral lesion in noneloquent
tomy, systemic chemotherapy, and adjuvant radiotherapy. Four-
cortex may tend to be more innocuous.
teen months after definitive management, she developed gait
With regard to the outcome and toxicity profiles of repeat
instability and dizziness, for which diagnostic workup demon-
radiosurgery for local recurrence of brain metastases, there is
strated two large brain metastases. She underwent resection of
no level I evidence. However, two case series have retrospec-
a left frontal metastasis and subsequently received 24 Gy in
tively examined the outcome of patients with recurrent brain
three fractions to the resection bed. A smaller left parietal le-
metastases who received repeat local SRS.14,16 In a retrospective
sion was also treated in a single fraction of 20 Gy (▶ Fig. 30.1).
analysis by Kwon et al, 43 patients underwent repeat SRS, of
Surveillance imaging 5 months thereafter demonstrated stable
whom 30 were treated with repeat local SRS (16 patients had
disease within the original resection bed and left parietal meta-
local retreatment only and 14 had both repeat local and new
stasis; however, a new left frontal dural-based lesion inferior to
remote treatments).16 Median survival among the 43 re-treated
the resection bed was noted and treated with 20 Gy in one
patients was 68 weeks after the first SRS procedure and 32
weeks after the second procedure. Of the 30 patients who died
of known causes, 16 died of systemic progression of disease
whereas 14 died of neurologic compromise. The actuarial sur-
vival rate after second SRS was 58% and 28% at 6 months and 1
year, respectively. The intracranial progression-free rate was 91
and 86% at 6 months and 1 year, respectively. Nineteen percent
of the 43 patients developed symptomatic radiation necrosis.
Multivariate analysis of prognostic factors identified only RPA
class (I and II vs. III) as statistically significant, with median sur-
vival difference of 42 and 36 versus 12 weeks, respectively.
Number of lesions, tumor volume, and time interval between
treatments did not statistically impact survival. Aside from the
typical drawbacks of a retrospective study with limited cohort
size, conclusions from this study are confounded by the fact
that patients receiving remote SRS treatment were included in
the cohort—these patients may have presumably had better
survival and lower radiation necrosis rates than patients receiv-
ing local-only treatment.
Yamanaka et al published the results of a series of 41 patients
who received repeat Gamma Knife radiosurgery for brain meta-
stases.14 Only four patients (with eight targets) included in the
study received repeat SRS after local tumor recurrence. Local
control rate was on average 7.5 months after the first treatment
and 4.7 months after the second stereotactic procedure. Three
of these patients developed local recurrence and one developed Fig. 30.1 T1-weighted magnetic resonance imaging of brain with
histologically proven radiation necrosis in the unreported fol- gadolinium and superimposed dosimetry demonstrating left frontal
low-up period, a fact that the authors speculated was due to a resection cavity treated with 24 Gy in three fractions (target volume
theoretical resistance to high dose-per-fraction radiation and 30.7 cc) and left parietal metastasis treated with 20 Gy in one fraction
(target volume 10.4 cc). Isodose lines for 12, 20, and 24 Gy are shown.
large volume targets at the time of second SRS.

252

Fig. 30.2 T1-weighted magnetic resonance imaging with gadolinium performed 3 months after initial stereotactic radiosurgery (SRS) treatment.
Superimposed SRS dosimetry for new left frontal dural-based lesion treated with 20 Gy in one fraction is shown (target volume 6.5 cc). Planning was
constrained due to proximity to previous SRS treatment. Isodose lines for 12, 19, and 20 Gy are shown.
fraction (▶ Fig. 30.2). Follow-up imaging of the patient per-
formed 6 months after her initial SRS demonstrated enlarge-
ment and increased enhancement of the left parietal lesion;
however, MR perfusion and single-photon emission computed
tomography (SPECT) imaging demonstrated the lesions to be
consistent with radiation necrosis. The patient was then fol-
lowed with short-interval surveillance imaging, which showed
stable disease until 10 months after her original SRS, when she
developed worsening neurologic symptoms, including head-
ache and dizziness. Both the left frontal and left parietal lesions
demonstrated significant enlargement with increased edema,
contrast enhancement, and mass effect. She underwent gross
total resection of the left frontal lesion and subtotal resection of
the left parietal lesion, with pathological findings consistent
with tumor recurrence at both sites. Both the left frontal lesion
and left parietal resection beds were subsequently treated with
Gamma Knife radiosurgery (▶ Fig. 30.3a,b). Magnetic resonance
imaging performed approximately 1 month after her Gamma
Knife radiosurgery demonstrated all three resection beds—left
superior frontal, left inferior frontal, and left parietal—to have
decreased size, stable-to-decreased contrast enhancement, and
decreased mass effect (▶ Fig. 30.4).
30.5 National Consensus
Guidelines
The American Society for Therapeutic Radiology and Oncology
(ASTRO) published a set of guidelines in 2005 that reviews the
role of radiosurgery in the management of brain metastases. 21
In particular, the review primarily cites level II-2 and II-3 evi-
dence that shows improved local response and 1-year survival
for SRS salvage after whole-brain irradiation. The authors of
Repeat Radiosurgery for Brain Metastases
this guideline acknowledge a potential selection bias in the
existing literature, as it is not clear whether favorable patient
prognostic characteristics or radiosurgery is responsible for the
apparent improvement in outcomes. In 2012, guidelines for
appropriate care published by an expert panel of the American
College of Radiology (ACR) recommended considering SRS as a
viable option for salvage therapy after recurrent remote or local
metastases following initial whole-brain irradiation, surgery, or
even radiosurgery.22 They wrote that if recurrence can be
detected prior to development of neurologic symptoms, SRS
may be the most effective option for management. Importantly,
however, neither the ACR nor ASTRO guidelines described
above distinguish between local and remote intracranial
recurrence.
30.6 Summary
When considering repeat SRS for locally recurrent brain meta-
stases, a diagnosis of recurrence must first be confirmed, as
radiation-induced changes may be present following initial
radiotherapy and can mimic tumor on postcontrast MRI. Once a
diagnosis has been established, the existing literature provides
level II and III evidence that may support the use of SRS for sal-
vage, particularly in patients with good performance status and
prognosis in whom systemic options may still remain. Repeat
radiosurgery at typical doses has a reasonable chance of local
control, and the majority of patients do not appear to develop
radionecrosis. We propose a framework here that outlines
potential clinical pathways for patients with local recurrence
previously treated with radiosurgery (▶ Fig. 30.5). At this time,
the precise role of radiosurgery in the management of recurrent
brain metastases treated previously by radiosurgery or radio-
therapy is not known. As the number of patients treated with
253
 Repeat Radiosurgery for Brain Metastases

Fig. 30.3 T1-weighted magnetic resonance

imaging with gadolinium demonstrating recur-
rence of left frontal and left parietal lesions 10
months after initial treatment and superimposed
Gamma Knife dosimetry. (a) The left frontal
lesion recurred after initial resection and adjuvant
stereotactic radiosurgery (SRS); it was resected
and treated with a single fraction of 16 Gy to a
target volume of 3.4 cc. (b) The left parietal
lesion recurred after initial SRS alone; it was
resected and treated with a single fraction of
16 Gy to a target volume of 20.1 cc. Isodose lines
for 12, 16, and 30 Gy are shown.

Fig. 30.4 T1-weighted magnetic resonance imaging with gadolinium demonstrating three sites of previous stereotactic radiosurgery (SRS). Both left
frontal lesion (asterisk) and left parietal lesion (red arrow) were treated with repeat SRS. Left dural-based metastasis is also shown (white arrow). All
three lesions demonstrate decreased size, stable-to-decreased contrast enhancement, and decreased mass effect compared with prior imaging.

254

Fig. 30.5 Proposed algorithm for patients with local recurrence of brain metastases previously treated by stereotactic radiosurgery. MR, magnetic
resonance; PET, positron emission tomography; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.
SRS alone for an initial presentation of brain metastases
increases, the need for further studies that provide level I evi-
dence will be critical to evaluate the potential use of repeat
radiosurgery in recurrent brain metastases.
References
[1] 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
[2] Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain
metastases treated with radiosurgery or radiosurgery plus whole-brain irra-
diation: a randomised controlled trial. Lancet Oncol 2009; 10: 1037–1044
[3] 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
[4] Chao ST, Barnett GH, Liu SW, et al. Five-year survivors of brain metastases: a
single-institution report of 32 patients. Int J Radiat Oncol Biol Phys 2006; 66:
801–809
[5] Varlotto JM, Flickinger JC, Niranjan A, Bhatnagar AK, Kondziolka D, Lunsford
LD. Analysis of tumor control and toxicity in patients who have survived at
Repeat Radiosurgery for Brain Metastases
least one year after radiosurgery for brain metastases. Int J Radiat Oncol Biol
Phys 2003; 57: 452–464
[6] Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic
resonance imaging-guided focused laser interstitial thermal therapy for in-
tracranial lesions: single-institution series. Neurosurgery 2013; 73: 1007–
1017
[7] Plowman PN. Stereotactic radiosurgery. VIII. The classification of postradia-
[8]
tion reactions. Br J Neurosurg 1999; 13: 256–264
Chernov M, Hayashi M, Izawa M, et al. Differentiation of the radiation-in-
duced necrosis and tumor recurrence after gamma knife radiosurgery for
brain metastases: importance of multi-voxel proton MRS. Minim Invasive
Neurosurg 2005; 48: 228–234
[9] Kickingereder P, Dorn F, Blau T, et al. Differentiation of local tumor recurrence
from radiation-induced changes after stereotactic radiosurgery for treatment
of brain metastasis: case report and review of the literature. Radiat Oncol
2013; 8: 52
[10] Yamamoto M, Sato Y, Serizawa T, et al. Subclassification of recursive parti-
tioning analysis Class II patients with brain metastases treated radiosurgi-
cally. Int J Radiat Oncol Biol Phys 2012; 83: 1399–1405
[11] Kano H, Kondziolka D, Lobato-Polo J, Zorro O, Flickinger JC, Lunsford LD. T1/
T2 matching to differentiate tumor growth from radiation effects after ster-
eotactic radiosurgery. Neurosurgery 2010; 66: 486–491, discussion 491–492
[12] Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of
prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain
metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–751
255
 Repeat Radiosurgery for Brain Metastases
[13] Manon R, O’Neill A, Knisely J, et al. Eastern Cooperative Oncology Group.
Phase II trial of radiosurgery for one to three newly diagnosed brain metasta-
ses from renal cell carcinoma, melanoma, and sarcoma: an Eastern Coopera-
tive Oncology Group study (E 6397). J Clin Oncol 2005; 23: 8870–8876
[14] Yamanaka K, Iwai Y, Yasui T, et al. Gamma Knife radiosurgery for metastatic
brain tumor: the usefulness of repeated Gamma Knife radiosurgery for recur-
rent cases. Stereotact Funct Neurosurg 1999; 72 (Suppl 1): 73–80
[15] Johnson M, Baschnagel AM, Chen PY, et al. Analysis of risk factors for develop-
ment of radiation necrosis following gamma knife radiosurgery for brain
metastases. Intl J Rad Oncol 2013; 87: 279–280
[16] Kwon KY, Kong DS, Lee JI, Nam DH, Park K, Kim JH. Outcome of repeated ra-
diosurgery for recurrent metastatic brain tumors. Clin Neurol Neurosurg
2007; 109: 132–137
[17] Chao ST, Barnett GH, Vogelbaum MA, et al. Salvage stereotactic radiosurgery
effectively treats recurrences from whole-brain radiation therapy. Cancer
2008; 113: 2198–2204
256
[18] Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recur-
rent previously irradiated primary brain tumors and brain metastases: final
report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 2000; 47: 291–
298
[19] Loeffler JS, Kooy HM, Wen PY, et al. The treatment of recurrent brain metasta-
ses with stereotactic radiosurgery. J Clin Oncol 1990; 8: 576–582
[20] Davey P, O’Brien PF, Schwartz ML, Cooper PW. A phase I/II study of salvage
radiosurgery in the treatment of recurrent brain metastases. Br J Neurosurg
1994; 8: 717–723
[21] Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic
Radiology and Oncology (ASTRO) evidence-based review of the role of radio-
surgery for brain metastases. Int J Radiat Oncol Biol Phys 2005; 63: 37–46
[22] Patel SH, Robbins JR, Gore EM, et al. Expert Panel on Radiation Oncology–
Brain Metastases. ACR Appropriateness Criteria® follow-up and retreatment
of brain metastases. Am J Clin Oncol 2012; 35: 302–306
 31 Promising Advances in Radiosurgery:
Part VIII Where Are the Frontiers? 258

Radiosurgical Horizon

VIII
 Promising Advances in Radiosurgery: Where Are the Frontiers?
31 Promising Advances in Radiosurgery: Where Are the
Frontiers?
Brian D. Kavanagh
Key Points
● Big data may help to refine the quality and outcomes associ-
ated with radiosurgery.
● Charged particles may play an expanded role in stereotactic
radiosurgery and stereotactic body radiotherapy.
● Molecularly targeted agents may augment the efficacy and
safety of stereotactic radiosurgery.
31.1 Introduction
The notable successes achieved in the past half century in the
clinical implementation of stereotactic radiosurgery (SRS) are
well chronicled throughout the preceding chapters of this text.
A high level of understanding has been achieved in the area of
technical refinements, from image guidance to beam optimiza-
tion and modulation to safety and quality measures. There are
also abundant published data concerning the use of SRS in a
wide range of clinical indications, from the treatment of func-
tional neurologic disorders to the ablation of primary and
metastatic tumor deposits. It is, therefore, tempting to conclude
that there might be few if any remaining unrecognized frontiers
for investigation. Have all problems been solved, all questions
answered? Where might we or should we go from here? Will
SRS look or feel any different 50 years from now?
One or another variation of the expression, “It is tough to
make predictions, especially about the future” has been attrib-
uted to pundits as far away from each other in the intellectual
spectrum of human thinking as the Nobel Prize–winning physi-
cist, Niels Bohr, and the legendary baseball icon, Yogi Berra, 1
and numerous others in between. This timeless caveat is often
invoked prior to speculation about what lies ahead and here
would serve similarly to acknowledge the uncertainty associ-
ated with trying to foresee upcoming trends. Nevertheless, it
can be useful to consider the emerging opportunities for devel-
oping SRS that are suggested by current investigational efforts.
In this piece, a handful of predictions is offered in the spirit of
knowing that they might all be incorrect and yet hoping that at
least by mentioning them, dialogue leading to better ideas is
stimulated.
31.2 Prediction 1: The Particle
Strikes Back
The first modality used for SRS in the 1950s was a proton
beam,2 although limitations in the capacity for image guidance
and other technical challenges dampened enthusiasm for this
modality in all but a few centers as cobalt-60 and linear acceler-
ator–based devices gained traction. In recent years, however,
the proliferation of clinical proton and carbon therapy facilities
258
has prompted renewed interest in proton SRS. Recent reports
document the safety and efficacy of proton SRS in a variety of
clinical settings traditionally approached with photon-based
SRS,3,4,5,6 and further investigations are ongoing to explore oth-
er applications for proton SRS that might combine properties of
charged particles that are not currently exploited to their fullest
potential. For example, as discussed by Bert and Durante in an
overview of workshop on particle radiosurgery held in Austria
in 2013, there are opportunities to perform proton imaging and
even “proton microscopy” to reveal tumor and normal tissue
properties not presently captured by X-ray imaging, and their
incorporation into so-called theranostic strategies for a variety
of conditions is an intriguing possibility.7 Much work remains
to improve our understanding of all particle interactions with
human tissues, but likely there will be forthcoming insights that
yield progress for a variety of benign and malignant disease.
31.3 Prediction 2: Big Data Will
Teach Us about Radiosurgery
The advent of the electronic medical record has ushered in a
new era in medicine where enormous amounts of data are
potentially retrievable. With proper attention to methodologi-
cal detail, large-scale observational studies are fertile ground
for harvesting new insights about how we can improve the
quality of medical care rendered to the population. One bias to
overcome, ironically, was pointed out in 2010 in an editorial in
the Journal of the American Medical Association, namely, that “a
generation of clinicians has been taught that randomized con-
trolled trials (RCTs) can find truth, whereas observational stud-
ies are inherently flawed.”8 The reality is that although the RCT
will remain an important tool for testing medical hypotheses,
the traditional methods of advancing medical knowledge via
classic prospective clinical trials have become expensive and at
times unwieldy, limiting their feasibility to address all ques-
tions of clinical importance, especially when the issue is a mat-
ter of trying to identify small differences in outcomes between
established treatments. For proper statistical power in a RCT to
detect the superiority of a novel approach that might be a few
percent better than the accepted gold standard, thousands of
patients would have to be enrolled.
In 2014, the American Association of Neurological Surgeons
(AANS) and the American Society for Radiation Oncology
(ASTRO) entered into a partnership to launch a prospective SRS
registry. The AANS had already managed a very large and very
successful spine surgery registry that has yielded a number of
published papers offering insights into matters of quality assur-
ance, patient selection, cost-effectiveness, and patient-reported
outcomes.9,10,11 There is good reason to expect that the AANS
and ASTRO SRS Registry will provide equally valuable knowl-
edge of the type that can only be gleaned from the study of
large numbers of patients (thousands and thousands) and that
is unobtainable from other sources.
 Promising Advances in Radiosurgery: Where Are the Frontiers?
31.4 Prediction 3: SRS Will Be
Combined with Novel Molecular
Agents and Nanoparticles for the
Purpose of Reducing Side Effects
and Enhancing Therapeutic
Efficacy
Stereotactic radiosurgery is understood to achieve beneficial
effects through a variety of mechanisms that include impair-
ment of the reproductive machinery of neoplastic cells and
apoptotic cell death in endothelial cells, among other effects.
But we are only beginning to accumulate enough layers of
understanding of the complex cellular signaling events that are
triggered by SRS to allow us to exploit new molecular agents
that selectively modulate pathways leading to normal brain
injury or tumor response. Likely in the coming decades, we will
begin to incorporate agents that might, for example, inhibit gly-
cogen synthase kinase (GSK)-3β or block Kv1.3 channels, there-
by affording normal tissue protection that could allow for dose
escalation.12,13 Likewise, the burgeoning field of nanomedicine
will almost certainly find its way into an interface with SRS,
either in the context of the use of gold nanoparticles as radio-
sensitizers14,15 or perhaps in the setting of designing targeted
nanoparticles that are specifically drawn to irradiated tissue to
facilitate drug delivery to tumors or regions of functional disor-
der in the brain.16
31.5 Prediction 4: SRS as Applied
for Human Patients Will Be
Refined by Lessons Learned from
Man’s Best Friend
Techniques in cancer management for the veterinary popula-
tion have become very sophisticated in recent years, paralleling
progress made in the human population. For veterinary radia-
tion oncology specifically, there is a dissemination of high tech-
nology that might be surprising to those unfamiliar with the
field, and thousands of domestic animals are treated with ther-
apeutic irradiation annually.17 There is frequently an opportu-
nity for mutually beneficial learning from the act of comparing
and contrasting how treatments are administered and tolerated
in conditions of sometimes widely different anatomical config-
urations. In the area of SRS, technology of a quality and com-
plexity identical to that used in human patients is commonly
implemented.18,19 One of the interesting features about canine
oncology in particular is that given the shorter life span of dogs,
often events happen in a more compressed time frame, with
differing tissue growth kinetics, providing an opportunity to
observe radiation effects and learn lessons quickly. It would be
wise for neurosurgeons and radiation oncologists to follow
developments in the field of veterinary SRS in the coming years
because likely there will be insights gained that have transla-
tional value to the human patient population.
References
[1] Cf. multiple discussions, e.g., http://en.wikiquote.org/wiki/Niels_Bohr#Dis-
puted and http://quoteinvestigator.com/2013/10/20/no-predict/, both ac-
cessed August 25, 2014, and Hill B, Proceedings of the Meeting, J R Stat Soc
Ser A Gen 1956; 119: 147
[2] Larsson B, Leksell L, Rexed B, Sourander P, Mair W, Andersson B. The high-en-
ergy proton beam as a neurosurgical tool. Nature 1958; 182: 1222–1223
[3] Walcott BP, Hattangadi-Gluth JA, Stapleton CJ, Ogilvy CS, Chapman PH,
Loeffler JS. Proton beam stereotactic radiosurgery for pediatric cerebral
arteriovenous malformations. Neurosurgery 2014; 74: 367–373, discus-
sion 374
[4] Halasz LM, Bussière MR, Dennis ER, et al. Proton stereotactic radiosurgery for
the treatment of benign meningiomas. Int J Radiat Oncol Biol Phys 2011; 81:
1428–1435
[5] Petit JH, Biller BM, Yock TI, et al. Proton stereotactic radiotherapy for persis-
tent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab
2008; 93: 393–399
[6] Lettmaier S. Radiosurgery in trigeminal neuralgia. Phys Med 2014; 30:
592–595
[7] Bert C, Durante M. Particle radiosurgery: a new frontier of physics in medi-
cine. Phys Med 2014; 30: 535–538
[8] Concato J. Is it time for medicine-based evidence? JAMA 2012; 307: 1641–
1643
[9] Godil SS, Parker SL, Zuckerman SL, et al. Determining the quality and effec-
tiveness of surgical spine care: patient satisfaction is not a valid proxy. Spine J
2013; 13: 1006–1012
[10] Ghogawala Z, Shaffrey CI, Asher AL, et al. The efficacy of lumbar discectomy
and single-level fusion for spondylolisthesis: results from the NeuroPoint-SD
registry: clinical article. J Neurosurg Spine 2013; 19: 555–563
[11] Mummaneni PV, Whitmore RG, Curran JN, et al. Cost-effectiveness of lumbar
discectomy and single-level fusion for spondylolisthesis: experience with the
NeuroPoint-SD registry. Neurosurg Focus 2014; 36: E3
[12] Jiang X, Perez-Torres CJ, Thotala D, et al. A GSK-3β inhibitor protects
against radiation necrosis in mouse brain. Int J Radiat Oncol Biol Phys
2014; 89: 714–721
[13] Peng Y, Lu K, Li Z, et al. Blockade of Kv1.3 channels ameliorates radiation-in-
duced brain injury. Neuro-oncol 2014; 16: 528–539
[14] Hainfeld JF, Smilowitz HM, O’Connor MJ, Dilmanian FA, Slatkin DN. Gold
nanoparticle imaging and radiotherapy of brain tumors in mice. Nanomedi-
cine (Lond) 2013; 8: 1601–1609
[15] Joh DY, Sun L, Stangl M, et al. Selective targeting of brain tumors with gold
nanoparticle-induced radiosensitization. PLoS ONE 2013; 8: e62425
[16] Passarella RJ, Spratt DE, van der Ende AE, et al. Targeted nanoparticles that
deliver a sustained, specific release of Paclitaxel to irradiated tumors. Cancer
Res 2010; 70: 4550–4559
[17] Farrelly J, McEntee MC. A survey of veterinary radiation facilities in 2010. Vet
Radiol Ultrasound 2014
[18] Mariani CL, Schubert TA, House RA, et al. Frameless stereotactic radiosurgery
for the treatment of primary intracranial tumours in dogs. Vet Comp Oncol
2013
[19] Glasser SA, Charney S, Dervisis NG, et al. Use of an image-guided robotic ra-
diosurgery system for the treatment of canine nonlymphomatous nasal tu-
mors. J Am Anim Hosp Assoc 2014; 50: 96–104
259
 Index
1 Agent combinations 259 Brain metastases, see Cancer and cancer –– angiographically occult vascular
American Association of Physicists in classifications malformations (AOVMs) 81, 83
1 to 4 metastases 235 Medicine (AAPM) protocols 32 – five or more 243 –– arteriovenous malformations
– See also Metastases American Society for Therapeutic Radi- – one to four 235 (AVMs) 81
ology and Oncology (ASTRO) 247, – repeat radiosurgery for 251 –– classification 82
253 Brain Tumor Cooperative Group –– de novo formations 82
5 Angioarchitecture 91 (BTCG) 226 – overviews of 81, 89
5 or more metastases 243 Angiographically occult vascular mal- Brain Tumor Study Group (BTSG) 226 – references for 89
– See also Metastases formations (AOVMs) 81, 83 Brainstem, dose tolerance of 53 – stereotactic radiosurgery (SRS)
Angiomas, cavernous 81 Brown-Séquard syndrome 54 for 83
– See also Cerebral cavernomas (CCMs) BRW frames 31 –– critical considerations for 85, 86
A Antisecreting medications 116 BTCG, see Brain Tumor Cooperative –– epilepsy effects of 84
AOVMs, see Angiographically occult Group (BTCG) ––– See also Epilepsy
AAPM protocols, see American Associa-
vascular malformations (AOVMs) BTSG, see Brain Tumor Study Group –– hemorrage risks 88
tion of Physicists in Medicine
ARMD, see Age-related macular degen- (BTSG) –– hemorrhage rate effects of 84
(AAPM) protocols
eration (ARMD) Bunge, Hernan 8 –– morbidity after 88
Ablation, see Radiofrequency (RF) abla-
Arteriovenous fistulas, see Dural arte- Burchiel classification 160, 160 –– rationales for 84
tion
riovenous fistulas (DAVFs) –– reviews of 85, 87
Acromegaly 111, 113–114
Arteriovenous malformations – treatment options for 83, 84
Activities of Daily Living (ADLs) 169
(AVMs) 68 C Chadwick, James 11
Acute radiation injuries 112
– decision-tree algorithm for 68, 69 Callosotomy, corpus 197 Charged particle equilibrium (CPE) 32
– See also Radiation injuries
– dural arteriovenous fistulas Cancers and cancer classifications, see Charged particle therapy 121
Adenomas, pituitary 107
(DAVFs) 78, 79 Metastases Chescotta, Roberto 8
– overviews of 107, 117
– future directions for 78–79 – adenomas, pituitary 107 Chondrosarcomas 128
– prognoses for 115
– historical perspectives of 68 – cerebral cavernomas (CCMs) 81 – classification of 128
– references for 117
– large 76, 77–78 – chondrosarcomas 128 – definition of 128
– special considerations for 115
– lesional epilepsy and 194 – chordomas 120 – North American Gamma Knife Con-
– sterotactic radiosurgery (SRS)
–– See also Lesional epilepsy – epileptogenic tumors 194 sortium (NAGKC) reports on 129,
for 108
– overviews of 68 – glial tumors 226 129, 130
–– clinical outcomes, acromegaly 111,
– references for 79 – glomus tumors 226 – overviews of 128–129
113–114
– stereotactic radiosurgery (SRS) – hamartomas, hypothalamic – references for 130
–– clinical outcomes, Cushing dis-
for 68 (HHs) 182 – sterotactic radiosurgery (SRS)
ease 111, 111–112
–– adverse effects of 75 – hemangioblastomas 146 for 128
–– clinical outcomes, nonfunctioning
–– bleeding risks of 74, 74 – meningiomas 102 – treatment options for 128
pituitary adenomas 110
–– outcomes for 73, 74 – pediatric brain tumors 210 –– radiotherapy (RT) 128
–– complications of 112
–– post-surgical obliteration 75 – schwannomas, see Schwannomas –– surgical resections 128
–– cranial neuropathy and 114
–– preradiosurgical embolization 77 –– nonvestibular cranial nerve Chordomas 120
–– critical structures, dose limitations
–– procedures for 72, 73 (NVCNS) 137 – complications of 125, 126
to 109
–– repeat 76 –– vestibular (VSs) 150 – definition of 120
–– dose selection criteria 108
––– See also Repeat radiosurgery Cavernomas 81 – epidemiology of 120
–– efficacy of 116
– University of Pittsburgh experien- – See also Cerebral cavernomas (CCMs) – histopathology of 120
–– frame placement 108
ces 69, 70 Cavernous angiomas 81 – overviews of 120, 126
–– histological entities and 116
ASTRO, see American Society for Thera- – See also Cerebral cavernomas (CCMs) – pathogenesis of 120
–– historical perspectives of 107
peutic Radiology and Oncology (AS- Cavernous hemangiomas 81 – radiographic features of 120
–– hypopituitarism and 114
TRO) – See also Cerebral cavernomas (CCMs) – references for 126
–– hypothalamic dysfunction and 114
Astrocytomas, pilocytic (PAs) 226 Cavernous malformations (CMs) 81, – stereotactic radiosurgery (SRS)
–– optic neuritis and 114
Auditory apparatus, dose tolerance 194 for 121, 123
–– patient selection criteria 107
of 54 – See also Cerebral cavernomas (CCMs) – treatment options for 121
–– pre-surgical evaluations 107
AVMs, see Arteriovenous malforma- CBCT, see Cone-beam computed to- –– charged particle therapy 121
–– principles of 108
tions (AVMs) mography (CBCT) –– conventional radiation therapy 121
–– radiation injuries, acute 112
CCMs, see Cerebral cavernomas (CCMs) –– surgical management 121
–– radiation injuries, early de-
Central nervous system (CNS) toler- Choroidal neovascular membranes
layed 114 B ance 52 (CNVMs) 207
–– radiation injuries, late delayed 115
Backlund, Erik-Olaf 5–6, 7–8 – critical structures 52 Choroidal neovascularization
–– radiation necrosis and 115
Bainbridge, Kenneth 12 –– auditory apparatus 54 (CNV) 207
–– radiographic images 108
Barrow Neurologic Institute (BNI) Pain –– brain 52 Circular collimators/cones 49, 49, 50
–– techniques 108
Intensty Scale 160, 160 –– brainstem 53 – See also Collimators
–– treatment planning 108, 109
Barrow’s classification 91 –– optic pathway 54 Clarke, Robert H. 3, 12
–– whole-sellar 116
Beam shaping and delivery 33 –– spinal cord 54 Clinical hemorrhage, see Hemorrhage,
– treatment options for 115
Betti, Osvaldo 8 – overviews of 52, 55 clinical
–– antisecreting medications, radiore-
Bilateral pallidotomy 172 – radiation necrosis treatments 55 Clinical target volumes (CTVs) 35
sistant effects of 116
– See also Pallidotomy – references for 56 CMs, see Cavernous malformations
–– external beam radiation therapy
Bilateral trigeminal neuralgia 164 Cerebral cavernomas (CCMs) 81 (CMs)
(EBRT) 115
– See also Trigeminal neuralgia – clinical hemorrhage and 81 CNS tolerance, see Central nervous sys-
–– up-front radiosurgery 116
Bite plates 47, 48–49 –– definition of 82 tem (CNS) tolerance
Adjustable Nomogrip TALON devi-
BNT Pain Intensity Scale, see Barrow –– morbidity of 82 CNV, see Choroidal neovascularization
ces 31
Neurologic Institute (BNI) Pain In- –– risk of 82 (CNV)
ADLs, see Activities of Daily Living
tensty Scale – hemispheric/superficial 81 CNVMs, see Choroidal neovascular
(ADLs)
Boost therapy 211 – natural history of 81, 83 membranes (CNVMs)
Age-related macular degeneration
Borden-Shuicart system 91 Cognard system 91
(ARMD) 207

260
 Index

Collimators 49 DAVFs, see Dural arteriovenous fistulas – machine-specific reference (msr) 32

– See also Devices
– circular/cones 49, 49, 50
– multileaf (MLCs) 49, 49
Colombo, Federico 8, 13
Complications, see Radiation injuries
– chordomas 125, 126
– dural arteriovenous fistulas
(DAVFs) 96, 98
– glial tumors 231
– metastases, five or more 247
– metastases, one to four 240
– nonvestibular cranial nerve schwan-
nomas (NVCNS) 143
– pediatric brain tumors 221
– pituitary adenomas 112
– radiation necrosis 55, 115
– trigeminal neuralgia 163
– vestibular schwannomas (VSs) 154
Cone-beam computed tomography
(CBCT) 37
Cones, see Circular collimators/cones
Conformity vs. inhomogeneity 35
Conventional radiation therapy 121
Cooper, Irving 3
Corpus callosotomy 197
Couch-mounted positioning sys-
tems 45
– See also Positioning systems
CPE, see Charged particle equilibrium
(CPE)
Cranial nerve (CN) schwanommas, see
Nonvestibular cranial nerve schwan-
nomas (NVCNS)
Cranial neuropathy 114
Craniopharyngiomas 217
Creutz, Edward 11
Critical structures 52
– Central nervous system (CNS) toler-
ance, dose limitations 52, 55, 109
– dose tolerance 52, 55, 109
–– auditory apparatus 54
–– brain 52, 52
–– brainstem 53
–– dose-volume histogram (DVH) anal-
yses 52
–– limitation overviews 109
–– optic pathway 54
–– organs-at-risk (OARs) data 55, 56
–– Quantitative Analysis of Normal Tis-
sue Effects in the CLinic (QUANTEC)
report 52
–– spinal cord 54
– overivews of 52, 55
– radiation necrosis treatments 55
– references for 56
CTVs, see Clinical target volumes (CTVs)
Cushing disease 111, 111–112
CyberKnife 16
– current configuations of 17
– extracranial radiosurgery applica-
tions of 17
– frame vs. frameless techniques 17
– historical perspectives of 16
– image guidance and 16
– linear accelerator (linac) technology
and 16, 17
– overviews of 16
– references for 18
D – See also Movement disorders
Davenport, Lee 12
(DAVFs)
DBS, see Deep brain stimulatin (DBS)
De novo formations 82
– See also Cerebral cavernomas (CCMs)
Deep brain stimulation (DBS) 168–169,
172, 174, 174
Delayed radiation injuries, see Radia-
tion injuries
Derechinsky, Victor 13
Detectors 32
Devices 39
– collimators 49
–– circular/cones 49, 49, 50
–– multileaf (MLCs) 49, 49
– CyberKnife 16
– Gamma Knife 2
– overviews of 42, 42, 43, 50
– positioning systems, comparisons
of 43
– positioning systems, minimally-inva-
sive 43
–– comparisons of 43
–– couch-mounted 45
–– floor-mounted 44, 45
–– floor-stand 44, 45
–– Gamma Knife 44
–– imaging-dependent 46
–– linear accelerator (linac) frame sys-
tems 44
– positioning systems, noninvasive 46
–– comparisons of 46
–– immobilization 47
––– See also Immobilization
–– localization 48
––– See also Localization
– references for 50
Diagnostic-specific Graded Prognostic
Assessment (DS-GPA) 235
Digital reconstructed radiographs
(RDDs) 37
Dosimetry 203
DS-GPA, see Diagnostic-specific Graded
Prognostic Assessment (DS-GPA)
Dural arteriovenous fistulas
(DAVFs) 78, 79, 91
– angioarchitecture of 91
– classification of 91
–– Barrow’s 91
–– Borden-Shuicart system 91
–– Cognard system 91
– clinical manifestations of 92, 92
– natural history of 96
– overviews of 91, 98
– references for 98
– special considerations for 96
– steroeotactic radiosurgery (SRS)
for 93
–– clinical outcomes 94, 94, 95
–– complications of 95, 96
–– dose prescriptions 94
–– follow-up programs 94
–– frame placements 93
–– principles 93
–– radiographic images 93
–– treatment planning 94
– treatment options for 93
–– management strategies 97, 98
–– selection criteria 97
–– sinus recanalization roles 97
Dystonia 168
E – nonstandard 31
Ear canal immobilization 47
– See also Immobilization
Early delayed/subacute radiation inju-
ries 52, 114
– See also Radiation injuries
EBRT, see External beam radiation ther-
apy (EBRT)
Eclipse plans 36, 36, 43
Edlefsen, Niels 11
Electronic data and medical re-
cords 258
Embolization, preradiosurgical 77
End-to-end tests 38
Ependymomas 211, 212–213
Epilepsy 193
– lesional 194
–– arteriovenous malformations
(AVMs) 194
––– See also Arteriovenous malforma-
tions (AVMS)
–– cavernous malformations
(CMs) 194
–– cerebral cavernomas (CCMs)
and 84
––– See also Cerebral cavernomas
(CCMs)
–– epileptogenic tumors 194
–– hypothalamic hamartomas (HHs)
and 194
––– See also Hypothalamic hamarto-
mas (HHs)
– other nonlesional 197
–– corpus callosotomy 197
–– neocortical foci 197
– overviews of 193, 198
– physiological 195
–– clinical outcomes for 195
–– medial temporal lobe epilepsy
(MTLE) 195
–– morbidities of 196
–– neurocognition and 197
–– secondary outcomes of 197
–– seizure remission for 195, 195, 196
–– treatment protocols for 196
– references for 198
– stereotactic radiosurgery (SRS)
for 193
–– experimental models of 193
–– radiation mechanisms of 193
Epileptogenic tumors 194
Essential tremor (ET) 174
– See also See Movement disorders
ET, see Essential tremor (ET)
Exophthalmos refratory to connserva-
tive treatments 207
Experimental models 193
External beam radiation therapy
(EBRT) 115
Extracranial radiosurgery applica-
tions 17
Eye fixation 202
Eye-related disorders, see Ocular disor-
ders
F 228
Factor-VIII immune reactions 64
Fields 30
– charged particle equilibrium
(CPE) 32
– effects of 32
– plan-class-specific reference
(pcsr) 32
– problems of 31
– small 30–32
Fistulas, see Dural arteriovenous fistu-
las (DAVFs)
Five or more metastases 243
– See also Metastases
Fixation, eye 202
Floor-mounted/floor-stand positioning
systems 44, 45
– See also Positioning systems
Forster, David 7
Forward vs. inverse techniques 33
Fractionation 20
– effects estimate calculations 22, 22
– high-dose single fractions 20
– limitations of 23
– multiple small-dose fractions 20
Future directions 226
– electronic data and medical re-
cords 258
– human-veterinary radiation oncol-
ogy parallels 259
– nanoparticles 259
– novel molecular agent combina-
tions 259
– of linear accelerator (linac) radiosur-
gery 14
– overviews 255, 258
– proton-based techniques 258
– references 259
– side effect reductions 259
– therapeutic efficacy enhance-
ments 259
G
G-Frames, Leskell 31
Gamma Knife 2
– clinical experiences with 3–4, 4, 5–7
– clinical outcomes with 3, 3
– current configurations of 7
– first designs of 5
– future directions for 8
– historical perpsectives of 2
– overviews of 2, 2, 8, 44
– prototypes of 7
– references for 9
– term derivation of 5
GBMs, see Glioblastomas (GBMs)
Gill-Thomas-Cosman (GTC) frames 31
Glaucoma 206, 206
Glial tumors 226
– glioblastomas (GBMs) 226, 229, 230,
232
– gliomas 226
–– high-grade 228, 229
–– low-grade 228
–– malignant, newly-diagnosed 230,
232
–– malignant, recurrent 229, 229, 230
– optic nerve tumors 226
– overviews of 226, 232
– pilocytic astrocytomas (PAs) 226,
– references for 232
– stereotactic radiosurgery (SRS)
for 226
–– Brain Tumor Cooperative Group
(BTCG) studies 226

261
 Index
–– Brain Tumor Study Group (BTSG)
studies 226
–– complications of 231
–– Radiation Therapy Oncology Group
(RTOG) studies 229
– treatment options for 226
Glioblastomas (GBMs) 226, 229, 230,
232
Gliomas 226
– See also Glial tumors
– high-grade 228, 229
– low-grade 228
– malignant 229
–– newly-diagnosed 230, 232
–– recurrent 229, 229, 230
– pediatric 215
Glomus tumors 226
– glomus jugular tumors 134
– overviews of 132, 136
– references for 136
– stereotactic radiosurgery (SRS)
for 132
–– clinical outcomes of 134, 135
–– dose planning 132
–– dose prescription 133
–– evaluations 134
–– meta-analyses of 134
–– patient selection criteria for 135
–– postoperative care 134
–– stereotactic imaging 132, 133
– University of Pittsburgh experience
with 132
GPA, see Graded Prognostic Assessment
(GPA)
Graded Prognostic Assessment
(GPA) 235
Granit, Ragnar 2
Grantry-mounted vs. room-mounted
systems 37
Greuter, Matthias 7, 7
Gross tumor volumes (GTVs) 35
GTC frames, see Gill-Thomas-Cosman
(GTC) frames
GTVs, see Gross tumor volumes (GTVs)
H – lesional epilepsy and 194
Hamartomas, hypothalamic (HHs) 182
– classification of 182
– definition of 182
– histology of 182, 183
– imaging findings for 182
– lesional epilepsy and 194
–– See also Epilepsy
– natural history of 183, 184–185
– overviews of 182, 190
– physiology of 182
– references for 191
– stereotactic radiosurgery (SRS)
for 184
–– action mechanisms of 189
–– Gamma Knife techniques 189, 189,
190
–– reviews of 187, 188
–– technique comparisons 186
–– vs. open surgical procedures 186
Harvard Cyclotron Laboratory 12, 12
Hearing toxicity 54
Hemangioblastomas 146
– overviews of 146, 148
– references for 149
– stereotactic radiosurgery (SRS)
for 146, 147–148
262
–– multicenter retrospective trials 148
–– techniques 146
– treatment options for 146
–– fractionated radio therapy (RT) 146
–– surgical resections 146
– von Hippel-Lindau (VHL) disease
and 146
Hemangioblastomas, ocular 207
Hemangiomas, cavernous 81
– See also Cerebral cavernomas (CCMs)
Hemispheric/superficial cerebral caver-
nomas (CCMs) 81
– See also Cerebral cavernomas (CCMs)
Hemorrhage, clinical 81
– rate effects of 84
– risks 88
HHs, see Hypothalamic hamartomas
(HHs)
Hickman, Roger W. 12
Hidden target tests 38
High-grade gliomas 228, 229
– See also Gliomas
Historical perspectives 16
– Gamma Knife 2
– of linear accelerator (linac) radiosur-
gery 11
– of proton beam radiosurgery 11
Hopkins Verbal Learning Test
(HVLT) 236, 240
Horsley, Victor A. H. 3, 12
Hot spots 35
HRST, see Hypofractionated stereotactic
radiosurgery (HRST)
Human-veterinary radiation oncology
parallels 259
HVLT, see Hopkins Verbal Learning Test
(HVLT)
Hypofractionated stereotactic radiosur-
gery (HRST) 239
Hypopituitarism 114
Hypothalamic dysfunction 114
Hypothalamic hamartomas (HHs) 182
– classification of 182
– definition of 182
– histology of 182, 183
– imaging findings for 182
–– See also Epilepsy
– natural history of 183, 184–185
– overviews of 182, 190
– physiology of 182
– references for 191
– stereotactic radiosurgery (SRS)
for 184
–– action mechanisms of 189
–– complications of 188
–– Gamma Knife techniques 189, 189,
190
–– reviews of 187, 188
–– technique comparisons 186
–– vs. open surgical procedures 186
I (HHs)
IAEA protocols, see International
Atomic Energy Agency (IAEA) proto-
cols
Image guidance techniques 36
– comparisons of 36
– cone-beam computed tomography
(CBCT) 37
– digital reconstructed radiographs
(RDDs) and 37
Imaging-dependent positioning sys-
tems 46
– See also Positioning systems
Immobilization 47
– See also Noninvasive positioning sys-
tems
– bite plates 47, 48–49
– ear canal 47
– eye fixation 202
– thermoplastic masks 47, 47
Infrared guidance 37
Inhomogeneity vs. conformity 35
International Atomic Energy Agency
(IAEA) protocols 32
Inverse vs. forward techniques 33
Ionization 193
– definition of 193
– overviews of 193, 198
– references for 198
Isocentric vs. nonisocentric techni-
ques 34
J – See also Gliomas
Jernberg, Bengt 6
K Lutz, Wendell 13
Karnosky Performace Score (KPS) 240
Kilovoltage-megavoltage (kV-MV) im-
age pairings 37
Kjellberg, Raymond 8, 12
KPS, see Karnosky Performace Score
(KPS)
L ity 35
Large arteriovenous malformations
(AVMs) 76, 77–78
– See also Arteriovenous malforma-
tions
Late delayed radiation injuries 115
– See also Radiation injuries
Late Effects Normal Tissues, subjective,
objective, management, and analytic
(LENT SOMA) scoring system 204
Late stage 58
Lawrence, Ernest Orlando 11
Lawrence, John H. 8, 11
LENT SOMA scoring system, see Late Ef-
fects Normal Tissues, subjective, ob-
jective, management, and analytic
(LENT SOMA) scoring system
Lesional epilepsy 194
– See also Epilepsy
– arteriovenous malformations
(AVMs) 194
– cavernous malformations (CMs) 194
– epileptogenic tumors 194
– hypothalamic hamartomas (HHs)
and 194
–– See also Hypothalamic hamartomas
Leskell frames 3–4, 31
Leskell Gamma Knife 2
– See also Gamma Knife
Leskell, Lars 6
– Gamma Knife and 2
– linear acceleration radiotherapy
and 11
– proton beam radiosurgery and 11
– Stereotaxic Method and Radiosur-
gery of the Brain 11
Linac radiosurgery, see Linear accelera-
tor (linac) radiosurgery
Lindquist, Christer 7
Linear accelerator (linac) radiosur-
gery 11
– frame systems 44
–– See also Minimally-invasive posi-
tioning systems
– future directions for 13, 14
– historical perspectives of 11
– overviews of 11
– physics of 30
– references for 14
– stereotactic principles of 12
Linear-quadratic (LQ) models 22
Localization 48
– manual target 6, 6
– multiplanar X-ray imaging 48
– optical tracking 48
– surface monitoring 48
Low-grade gliomas 228
LQ models, see Linear-quadratic (LQ)
models
Lunsford, L. Dade 5, 8
M
Machine-specific reference (msr) 32
Manhattan Project 12
Manual target localization 6, 6
Margins 35
– dose conformity vs. inhomogene-
– eclipse plans 35, 36, 36
– hot spots 35
– margin assumption 35
– multimodality imaging registra-
tion 36
– planning target volumes (PTVs) 35
– prescription isodose spillover 35
Masks, thermoplastic 47, 47
Medial temporal lobe epilepsy
(MTLE) 195
– See also Physiological epilepsy
Medical records, electronic 258
Meningiomas 102
– classification of 103
–– location-specific series 103, 104–
105
–– major series 103
– overviews of 102, 105
– pediatric 216, 216
– references for 105
– stereotactic radiogurgery (SRS)
for 102
–– historical perspectives of 102
–– techniques 102
– sterotactic radiosurgery (SRS)
for 105
Metastases, see Cancers and cancer
classifications
– carcinomas, orbital/uveal 207
– five or more 243
–– American Society for Therapeutic
Radiology and Oncology (ASTRO)
National Concensus Guidelines
for 247
–– clinical outcomes 245
–– complications 247

–– Mini-Mental Status Examination
(MMSE) 247
–– National Comprehensive Cancer
Network (NCCN) concensus guide-
lines 247
–– neurocognitive outcomes 247
–– overviews of 243, 248
–– references for 248
–– stereotactic radiosurgery (SRS)
for 243
–– toxicities 247
–– treatment options for 243
–– whole-brain radiotherapy (WBRT)
for 246
– one to four 235
–– complications of 240
–– diagnostic-specific Graded Prognos-
tic Assessment (DS-GPA) and 235
–– dose prescriptions 239
–– Graded Prognostic Assessment
(GPA) and 235
–– Hopkins Verbal Learning Test
(HVLT) 236, 240
–– hypofractionated stereotactic radio-
surgery (HRST) 235, 239
–– immobilization systems 237
–– Karnosky Performace Score (KPS)
and 240, 241
–– Mini-Mental Status Examination
(MMSE) and 236
–– neurocognitive dysfunction
and 240
–– overviews of 235, 241
–– postoperative management 235
–– prophylactic cranial whole-brain ra-
diotherapy (PC-WBRT) and 240
–– Quality of Life Questionnaire
(QLQ) 240
–– radiation necrosis and 240
–– Radiation Therapy Oncology Group
(RTOG) recursive partitioning anal-
yses (RPA) and 235
–– references for 241
–– reviews of 237
–– stereotactic radiosurgery (SRS)
for 236
–– surgical resections 235
–– treatment delivery systems 238
–– treatment planning 237
–– whole-brain radiotherapy (WBRT)
for 236
– pediatric 211
– repeat radiosurgery for 251
–– American Society for Therapeutic
Radiology and Oncology (ASTRO)
National Concensus Guidelines
for 253
–– clinical experiences 252, 252, 253
–– decision-making criteria for 251,
255
–– efficacy of 251
–– overviews of 251, 253
–– references for 255
–– toxicity of 251
Micro-multileaf collimators (MLCs) 30,
49
– See also Collimators
Mini-Mental Status Examination
(MMSE) 236, 247
Minimally-invasive positioning sys-
tems 43
– See also Positioning systems
– comparisons of 43
– couch-mounted 45
– floor-mounted 44, 45
– floor-stand 44, 45
– Gamma Knife 44
– imaging-dependent 46
– linear accelerator (linac) frame sys-
tems 44
MLCs, see Multileaf collimators (MLCs)
MMSE, see Mini-Mental Status Exami-
nation (MMSE)
Models 27
– experimental 193
– linear-quadratic (LQ) 22
– neuropathy 24
Modulation, dose 164
Molecular agent combinations 259
Morphological appearance 61, 61
Movement disorders 168
– definition of 168
– future directions of 174
– overviews of 168, 174
– references for 175
– stereotactic radiosurgery (SRS)
for 168
–– indications for 168
–– indirect targeting 169
–– patient selection criteria 168
–– radiosurgical pallidotomy 172, 173
––– See also Pallidotomy
–– radiosurgical subthalamotomy 174
–– radiosurgical thalamotomy 169,
170–172
––– See also Thalamotomy
– treatment options for 168
–– deep brain stimulation (DBS) 169,
172, 174, 174
–– radiofrequency (RF) ablation 168–
169
– Tremor Rating Scale and 169
– Unified Parkinson’s Disease Rating
Scale (UPDRS) and 168, 171, 174
MS-related tirgeminal neuralgia, see
Multiple sclerosis (MS)-related trige-
minal neuralgia
msr, see Machine-specific reference
(msr)
MTLE, see Medial temporal lobe epi-
lepsy (MTLE)
Multileaf collimators (MLCs) 49, 49
– See also Collimators
Multiplanar X-ray imaging 48
Multiple sclerosis (MS)-related trigemi-
nal neuralgia 164
– See also Trigeminal neuralgia
Myelopathy, radiation 54
Myokemia 54
N – See also Pituitary adenomas
NAGKC reports, see North American
Gamma Knife Consortium (NAGKC)
reports
Nanoparticles 259
National Comprehensive Cancer Net-
work (NCCN) 247
NCCN, see National Comprehensive
Cancer Network (NCCN)
Necrosis, radiation 55, 115
– See also Radiation injuries
Necrotic stage 58
Neocortical foci 197
Neuralgia, trigeminal 160
– as suicide disease 160
– classification of 160, 160
–– Barrow Neurologic Institute (BNI)
Pain Intensty Scale 160, 160
–– Burchiel 160, 160
– clinical scenarios for 165
–– computed tomography (CT)-based
treatment planning 165
–– linear accelerator (linac)-based ap-
proaches 165
–– repeat surgeries 165, 165
– overviews of 160, 165
– pathophysiology of 160
– population-specific considerations
for 164
–– bilateral trigeminal neuralgia 164
–– multiple sclerosis (MS)-related tri-
geminal neuralgia 164
–– type II trigeminal neuralgia 164
– references for 166
– stereotactic radiosurgery (SRS)
for 162
–– clinical outcomes for 162
–– complications of 163
–– dose modulation 164
–– dose rate effects 164
–– isocenter location 163
–– pain outcomes 162
–– quality-of-life (QOL) and 162
–– response factors 162
–– targeting 163
–– treatment planning 163
– treatment options for 161
–– medical management 161, 161
–– percutaneous rhizotomy 162
Neuritis, optic 114
Neuroanatomy 177
Neurocognition 58, 197
Neurocognitive dysfunction 240
Neuropathology fundamentals 58
– analyses 62
– effectiveness 62
– historical perspectives of 58, 59
– materials 59, 60
– overviews of 58, 65
– references for 66
– results 60, 61
–– acute-type reactions 60–61, 62
–– chronic-type/end-stage reac-
tions 61, 63
–– enhanced apoptotic activities 62,
64
–– Factor-VIII immune reactions 64
–– morphological appearance 11, 61
–– subacute-type reactions 61, 63
Neuropathy 24, 114
Nomogrip TALON devices 31
Nonfunctioning pituitary adeno-
mas 110
Noninvasive positioning systems 46
– See also Positioning systems
– comparisons of 46
– immobilization 205
–– bite plates 47, 48–49
–– ear canal 47
–– thermoplastic masks 47, 47
– localization 48
–– multiplanar X-ray imaging 48
–– optical tracking 48
–– surface monitoring 48
Nonisocentric vs. isocentric techni-
ques 34
Nonlesional epilepsy 197
Index
– See also Physiological epilepsy
– corpus callosotomy 197
– neocortical foci 197
Nonstandard fields 31
– See also Fields
Nonvestibular cranial nerve schwanno-
mas (NVCNS) 137
– overviews of 137, 143
– references for 144
– stereotactic radiosurgery (SRS)
for 138
–– complications of 143
–– techniques 138, 140–142
– treatment options for 138
–– complications of 142
–– fractionated radiotherapy 141
–– microsurgery 137, 138, 139
Noren, George 7
North American Gamma Knife Consor-
tium (NAGKC) reports 129, 129, 130
Novel molecular agent combina-
tions 259
NVCNS, see Nonvestibular cranial nerve
schwannomas (NVCNS)
O
OARs data, see Organs-at-risk (OARs)
data
Obsessive-compulsive disorder
(OCD) 177
– comorbidities of 177
– definition of 177
– neuroanatomy of 177
– overviews of 177, 179
– pathophysiology of 177
– references for 180
– stereotactic radiosurgery (SRS) for
–– clinical outcomes 178
–– deep brain stimulatin (DBS)
and 179
–– patient selection criteria 178
–– reviews of 180
–– target selection criteria 105, 177
–– techniques 178
– treatment options for 177
–– neurosurgery 177
–– pharmacotherapy 177
OCD, see Obsessive-compulsive disor-
der (OCD)
Ocular disorders 202
– age-related macular degeneration
(ARMD) 207
–– choroidal neovascular membranes
(CNVMs) and 207
–– choroidal neovascularization (CNV)
and 207
– exophthalmos refratory to connser-
vative treatments 207
– glaucoma 206, 206
– hemangioblastomas, ocular 207
– overviews of 202, 208
– rare 207
–– carcinomas, orbital/uveal metasta-
ses 207
–– rentinoblastomas 207
– references for 208
– stereotactic radiosurgery (SRS)
for 202
–– dosimetry 203
–– eye fixation 202
–– technical issues 202
–– treatment planning 203
263
 Index
– uveal melanomas 203
–– clinical manifestations of 203, 205
–– complications of 204
–– Late Effects Normal Tissues, subjec-
tive, objective, management, and
analytic (LENT SOMA) scoring sys-
tem 204, 204
–– natural history of 203
–– prognoses for 205
–– reviews of 204, 204
–– treatment decision criteria 205
– von Hippel-Lindau disease 207
Olivecrona, Herbet 2, 2, 3
One to four metastases 235
– See also Metastases
Open surgical procedures 186
Opthalmic-related disorders, see Ocular
disorders
Optic nerve tumors 226
Optic neuritis 114
Optic pathway, dose tolerance of 54
Optical guidance 37
Optical tracking 48
Orbital carcinomas 207
Organs-at-risk (OARs) data 55, 55
– See also Critical structures
P mounted systems 37
Pain scales 160, 160
Pallidotomy 172
– complications of 173
– for movement disorders 172
–– See also Movement disorders
– outcomes of 173
– overviews of 174
– reviews of 173
– unilateral vs. bilateral 172
– vs. radiofrequency (RF) pallidoto-
my 173
Parkinson disease (PD) 168
– See also Movement disorders
PAs, see See Pilocytic astrocytomas
(PAs)
PC-WBRT, see Prophylactic cranial
whole-brain radiotherapy (PC-
WBRT)
pcsr, see Plan-class-specifc reference
(pcsr)
PD, see Parkinson disease (PD)
Pediatric brain tumors 210
– overviews of 210, 221
– references for 222
– technical issues 210, 210
– treatment options 211
–– boost therapy 211
–– complications of 221
–– for astrocytomas, low-grade 213,
214–215
–– for craniopharyngiomas 217, 219
–– for ependymomas 211, 212–213
–– for gliomas, high-grade 215
–– for medulloblastomas 215
–– for meningiomas 216, 216
–– for pineal tumors 220
–– for pituitary adenomas 219
–– for recurrent disease, salvage ther-
apy 211
–– for schwannomas, vestibular 216,
217
–– stereotactic radiosurgery (SRS) as
sole postoperative treatment 213
Percutaneous rhizotomy 162
264
Pharmacotherapy 177
Physics fundamentals 30
– beam shaping and delivery 33
– clinical implementations and 39
– detectors 32
–– American Association of Physicists
in Medicine (AAPM) protocols 32
–– International Atomic Energy Agency
(IAEA) protocols 32
– fields 30
–– charged particle equilibrium
(CPE) 32
–– effects of 32
–– machine-specific reference
(msr) 32
–– nonstandard 31–32
–– plan-class-specific reference
(pcsr) 32
–– problems of 31
–– small 30–32
– high-dose gradients 30
– image guidance techniques 36
–– comparisons of 36
–– cone-beam computed tomography
(CBCT) 37
–– digital reconstructed radiographs
(RDDs) and 37
–– grantry-mounted vs. room-
–– infrared 37
–– kilovoltage (kV) S-ray tubes 37
–– magnetic-resonance (MR)-based 37
–– optical 37
–– stereoscopic 2d X-ray imaging 37
–– volumetric 3D X-ray imaging 37
– immobilization techniques 31
–– frameless 31
–– frames 31
–– frames, relocatable 31
–– masks 31
– localization, precision/accuracy
of 30
– margins 35
–– dose conformity vs. inhomogene-
ity 35, 35, 36
–– eclipse plans 35, 36, 36
–– hot spots 35
–– margin assumption 35
–– multimodality imaging registra-
tion 36
–– planning target volumes (PTVs) 35
–– prescription isodose spillover 35
– overviews of 30
– physical principles 30
– quality assurance (QA) and safety 38
–– end-to-end tests 38
–– hidden target tests 38
–– importance of 38
–– Winston-Lutz tests 38
– references for 39
– small fields 30
– stereotactic radiosurgery/stereotac-
tic radiotherapy (SRS/SRT) pro-
grams 32, 39
––
–– clinial implementation of 39
–– comparisons of 30
–– proton 32
–– training for 39
– technical challenges 31
– treatment planning 33
–– challenges of 33
–– clinical target volumes (CTVs) 35
–– features of 33
–– forward vs. inverse techniques 33
–– gross tumor volumes (GTVs) 35
–– isocentric vs. nonisocentric techni-
ques 33, 34
–– planning target volumes (PTVs) 33,
35
–– steep dose falloffs 33
Physiological epilepsy 195
– See also Epilepsy
– clinical outcomes for 195
– medial temporal lobe epilepsy
(MTLE) 195
– morbidities of 196
– neurocognition and 197
– other nonlesional 197
–– corpus callosotomy 197
–– neocortical foci 197
– secondary outcomes of 197
– seizure remission for 195, 195, 196
– treatment protocols for 196
Pilocytic astrocytomas (PAs) 226, 228
Pineal tumors 220
Pituitary adenomas 107
– overviews of 107, 117
– pediatric 219
– prognoses for 115
– references for 117
– special considerations for 115
– sterotactic radiosurgery (SRS)
for 108
–– clinical outcomes, acromegaly 111,
113–114
–– clinical outcomes, Cushing dis-
ease 111, 111–112
–– clinical outcomes, functioning pitui-
tary adenomas 110, 111–114
–– clinical outcomes, nonfunctioning
pituitary adenomas 110
–– complications of 112
–– cranial neuropathy and 114
–– critical structures, dose limitations
to 109
–– dose selection criteria 108
–– efficacy of 116
–– frame placement 108
–– histological entities and 116
–– historical perspectives of 107
–– hypopituitarism and 114
–– hypothalamic dysfunction and 114
–– optic neuritis and 114
–– patient selection criteria 107
–– pre-surgical evaluations 107
–– principles of 108
–– radiation injuries, acute 112
–– radiation injuries, early de-
layed 114
–– radiation injuries, late delayed 115
–– radiation necrosis and 115
–– radiographic images 108
–– techniques 108
–– treatment planning 108, 109
–– whole-sellar 116
– treatment options for 115
–– antisecreting medications, radiore-
sistant effects of 116
–– external beam radiation therapy
(EBRT) 115
–– up-front radiosurgery 116
Plan-class-specific reference (pcsr) 32
Planning target volumes (PTVs) 35
Positioning systems 43
– See also Devices
– minimally-invasive 43
–– comparisons of 43
–– couch-mounted 45
–– floor-mounted 44, 45
–– floor-stand 44, 45
–– Gamma Knife 44
–– imaging-dependent 46
–– linac frame systems 44
– noninvasive 46
–– comparisons of 46
–– immobilization 47
––– See also Immobilization
Pre-surgical evaluations 107
Preradiosurgical embolization 77
Prophylactic cranial whole-brain radio-
therapy (PC-WBRT) 240
PTVs, see Planning target volumes
(PTVs)
Q
QA, see Quality assurance (QA) and
safety
QLQ, see Quality of Life Questionnaire
(QLQ)
QOL considerations, see Quality-of-life
(QOL) consideratons
Quality assurance (QA) and safety 38
– end-to-end tests 38
– hidden target tests 38
– importance of 38
– Winston-Lutz tests 38
Quality of Life Questionnaire
(QLQ) 240
Quality-of-life (QOL) consideratons 162
QUANTEC report, see Quantitative
Analysis of Normal Tissue Effects in
the Clinic (QUANTEC) report
Quantitative Analysis of Normal Tissue
Effects in the Clinic (QUANTEC) re-
port 52
R
Radiation injuries, see Complications
– acute 112
– early delayed/subacute 52, 114
– late delayed 115
– myelopathy 54
– necrosis 115
Radiation mechanisms 193
Radiation Therapy Oncology Group
(RTOG) 229, 235
Radiobiology 20
– fractionation 20
–– effects estimate calculations 22, 22
–– high-dose single fractions 20
–– limitations of 23
–– multiple small-dose fractions 20
– future directions of 27
– models 27
–– linear-quadratic (LQ) 22
–– neuropathy 24
– optic nerve tolerance doses 23
– overviews of 20
– parameter assessments 24, 24
– radiation injury reactions 26, 26
– Radiation Therapy Oncology Group
(RTOG) Dose-Escalation Study 27, 27
– references for 28
– tissue radiation mechanisms 21, 21

–– dose-response curves 21, 21
–– therapeutic ratio 21
–– therapeutic window 21
– tumor hypoxia 27, 28
Radiofrequency (RF) ablation 168–169
Radiofrequency (RF) pallidotomy 173
Radioresistant vs. radiosensitive
cells 193
Radiosurgery, see Stereotactic radiosur-
gery (SRS)
– radiosurgical pallidotomy 172
–– complications of 173
–– for movement disorders 172
––– See also Movement disorders
–– outcomes of 173
–– overviews of 174
–– reviews of 173
–– techniques 172
–– unilateral vs. bilateral 172
–– vs. radiofrequency (RF) 173
– radiosurgical subthalamotomy 174
–– complications of 174
–– for movement disorders 174
––– See also Movement disorders
–– overviews of 174
–– subthalamic nucleus (STN) tar-
gets 174
– radiosurgical thalamotomy 169
–– complications of 171
–– efficacy of 171
–– for movement disorders 169
––– See also Movement disorders
–– outcomes of 170
–– overviews of 169, 172
–– reviews of 171
–– targeting 169
––– See also indirect, ventralis inter-
medius (VIM) targets
–– techniques 169
–– timing of 171
– repeat 251
–– American Society for Therapeutic
Radiology and Oncology (ASTRO)
National Concensus Guidelines
for 253
–– decision-making criteria for 251
–– efficacy of 251
–– overviews of 251, 253
–– references for 255
–– toxicity of 251
– repeat radiosurgery
–– clinical experiences 252, 252, 253
–– decision-making criteria for 255
– up-front 116
Radiotherapy (RT) 128
Rähn, Tiit 7
Rand, Robert 7
RDDs, see Digital reconstructed radio-
graphs (RDDs)
Recanalization, sinus 97
Recursive partitioning analyses
(RPA) 235
Reichert, Traugott 3
Relocatable frames 31
Rentinoblastomas 207
Repeat radiosurgery 251
– See also See also Metastases
– American Society for Therapeutic Ra-
diology and Oncology (ASTRO) Na-
tional Concensus Guidelines for 253
– clinical experiences 252, 252, 253
– decision-making criteria for 251,
255
– efficacy of 251
– for arteriovenous malformations
(AVMs) 76
–– See also Arteriovenous malforma-
tion (AVMs)
– overviews of 251, 253
– references for 255
– toxicity of 251
Resections, surgical 128, 146, 235
Resorption stage 58
RF ablation, see Radiofrequency (RF)
ablation
Rhizotomy, percutaneous 162
RPA, see Recursive partitioning analyses
(RPA)
RT, see Radiotherapy (RT)
RTOG, see Radiation Therapy Oncology
Group (RTOG)
Rutherford, Ernest 11
S – for pediatric brain tumors 210
Salorio, Juan Barcia 8
Salvage therapy 211
Schwannomas 137, 150
– nonvestibular cranial nerve
(NVCNS) 137
–– complications of 142–143
–– fractionated radiotherapy 141
–– microsurgery 137, 138, 139
–– overviews of 137, 143
–– references for 144
–– stereotactic radiosurgery (SRS)
for 138
–– treatment options for 138
– vestibular (VSs) 150
–– historical perspectives of 150
–– overviews of 150, 155
–– references for 156
–– stereotactic radiosurgery (SRS)
for 151
–– treatment options for 150
Seizure remission 195, 195, 196
Sensorineural hearing loss (SNHL) 54
Shrinking field methods 229
SIADH, see Syndrome of inappropriate
antidiuretic secretion (SIADH)
Sinus recanalization 97
Small fields 30
SNHL, see Sensorineural hearing loss
(SNHL)
Spinal cord, dose tolerance of 54
SRS, see Stereotactic radiosurgery (SRS)
SRS/SRT programs, see Stereotactic ra-
diosurgery/stereotactic radiotherapy
(SRS/SRT) programs
STAR system, see Stereotactic Align-
ment for Radiosurgery (STAR) sys-
tem
Steep dose falloffs 33
Steiner, Ladislau 7
Stereotactic Alignment for Radiosur-
gery (STAR) system 12, 13
Stereotactic radiosurgery (SRS) 20, 30,
42, 58, 58
– critical structures and 52
– definition of 42, 58
– devices for 42
–– CyberKnife 16
–– GammaKnife 2
– for arteriovenous malformations
(AVMs) 68
– for brain metastases, see Brain meta-
stases
–– five or more metastases 243
–– one to four metastases 235
–– repeat radiosurgery 251
– for cerebral cavernomas (CCMs) 81
– for chondrosarcomas 128
– for chordomas 120
– for dural arteriovenous fistulas
(DAVFs) 91
– for epilepsy 193
– for glial tumors 226
– for glomus tumors 132
– for hemangioblastomas 146
– for hypolthalamic hamartomas
(HHs) 182
– for meningiomas 102
– for movement disorders 168
– for obsessive-compulsive disorder
(OCD) 177
– for ocular disorders 202
– for pituitary adenomas 107
– for schwannomas 137, 150
–– nonvestibular cranial nerve
(NVCNs) 137
–– vestibular (VSs) 150
– for trigeminal neuralgia 160
– future directions of 258
– historical perspectives of 58
–– See also Historical perspectives
–– CyberKnife 16
–– Gamma Knife 2
–– linear accelerator (linac) radiosur-
gery 11
–– proton beam radiosurgery 11
– neuropathology of 58
– physics of 20, 30
– radiobiology of 20
– schwannomas 137
– tolerance, central nervous system
(CNS) 52
Stereotactic radiosurgery/stereotactic
radiotherapy (SRS/SRT) pro-
grams 32, 39
Stereotactic, definition of 43
STN targets, see Subthalamic nucleus
(STN) targets
Stone, Robert 11
Street Jabez C. 12
Structures, critical 52
– See also Critical structures
Sturm, Volker 8
Subacute radiation injuries, see Early
delayed/subacute radiation injuries
Subthalamic nucleus (STN) targets 174
Subthalamotomy, radiosurgical 174
– complications of 171, 174
– efficacy of 171
– for movement disorders 169, 174
–– See also Movement disorders
– outcomes of 170
– overviews of 169, 172, 174
– reviews of 171
– subthalamic nucleus (STN) tar-
gets 174
– targeting 169
–– indirect 169
–– ventralis intermedius (VIM) tar-
gets 169–170, 170, 172
– techniques 169
– timing of 171
Suicide diseases 160
Index
Superficial/hemispheric cerebral caver-
nomas (CCMs) 81
– See also Cerebral cavernomas (CCMs)
Surface monitoring 48
Surgical resections 128, 146, 235
Sweet, William 12
Syndrome of inappropriate antidiuretic
secretion (SIADH) 186
T
Tallairach, Jean 3
TALON frames 31
Thalamotomy, radiosurgical 169
Therapeutic ratio 21
Therapeutic window 21
Thermoplastic masks 47, 47
Tic douloureux 160
– See also Trigeminal neuralgia
Tissue radiation mechanisms 21, 21
Tobias, Cornelius A. 11
Tremor Rating Scale 169
Tremor-dominant Parkinson disease
(PD) 169
– See also Movement disorders
Trigeminal neuralgia 160
– as suicide disease 160
– classification of 160, 160
–– Barrow Neurologic Institute (BNI)
Pain Intensty Scale 160, 160
–– Burchiel 160, 160
– clinical scenarios for 165
–– computed tomography (CT)-based
treatment planning 165
–– linear accelerator (linac)-based ap-
proaches 165
–– repeat surgeries 165, 165
– overviews of 160, 165
– pathophysiology of 160
– population-specific considerations
for 164
–– bilateral trigeminal neuralgia 164
–– multiple sclerosis (MS)-related tri-
geminal neuralgia 164
–– type II trigeminal neuralgia 164
– references for 166
– stereotactic radiosurgery (SRS)
for 162
–– clinical outcomes for 162
–– complications of 163
–– dose modulation 164
–– dose rate effects 164
–– isocenter location 163
–– pain outcomes 162
–– quality-of-life (QOL) and 162
–– response factors 162
–– targeting 163
–– treatment planning 163
– treatment options for 161
–– medical management 161, 161
–– percutaneous rhizotomy 162
U
Unified Parkinson’s Disease Rating
Scale (UPDRS) 168, 169, 174
Unilateral vs. bilateral pallidotomy 172
Up-front radiosurgery 116
UPDRS, see Unified Parkinson's Disease
Rating Scale (UPDRS)
Uveal carcinomas 207
265
 Index

–– efficacy of 154 Veterinary-human radiation oncology

V –– large Koos stage IV manage-
Ventralis intermedius (VIM) tar-
gets 169–170, 170, 172
Vestibular schwannomas (VSs) 150
– See also Schwannomas
– historical perspectives of 150
– overviews of 150, 155
– references for 156
– stereotactic radiosurgery (SRS)
for 151
–– complications of 154
ment 154, 156
–– reviews of 152
–– Timone Hospital prospective co-
hort 143, 153
– treatment options for 150
–– clinical interviews 150
–– follow-ups 150
–– wait-and-see strategies 150
parallels 259
VIM targets, see Ventralis intermedius
(VIM) targets
VMAT, see Volume-modulated arc ther-
apy (VMAT)
Volume-modulated arc therapy
(VMAT) 30
Volumetric 3D X-ray imaging 37
von Hippel-Lindau disease 207
W
Wait-and-see strategies 150
WBRT, see Whole-brain radiotherapy
(WBRT)
Whole-brain radiotherapy
(WBRT) 236, 246, 251
Whole-sellar sterotactic radiosurgery
(SRS) 116
Wilson, Robert A. 11, 12
Winston-Lutz tests 38
Wycis, Henry 3

266