Principles and Practice of Stereotactic Radiosurgery

Principles and Practice of Stereotactic Radiosurgery Lawrence S. Chin, MD • William F. Regine, MD Editors Principles...

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Principles and Practice of Stereotactic Radiosurgery

Lawrence S. Chin, MD • William F. Regine, MD Editors

Principles and Practice of Stereotactic Radiosurgery

Editors Lawrence S. Chin, MD Professor and Chairman Department of Neurosurgery Boston University School of Medicine Boston, MA, USA

William F. Regine, MD Professor and Chairman Department of Radiation Oncology University of Maryland Medical School Baltimore, MD, USA

ISBN: 978-0-387-71069-3 e-ISBN: 978-0-387-71070-9 DOI: 10.1007/978-0-387-71070-9 Library of Congress Control Number: 2007931622 © 2008 Springer Science+Business Media, LLC. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper. 9 8 7 6 5 4 3 2 1 springer.com

Foreword hen first asked to write a foreword to Principles and Practice of Stereotactic Radiosurgery, I hesitated. There have been so many books and peer-reviewed papers written on this subject that I questioned whether another book would add much. However, after Larry and Bill shared the contents of this book with me, I had to change my mind. From my point of view, this book signals the completion of decades of hard work. Pioneering Gamma Knife surgery during the 1970s and 1980s was often a lonely endeavor, with long flights to innumerable meetings on all continents in order to speak about what we were doing in Stockholm. These talks were usually met with polite skepticism, sometimes even outright hostility, initially from neurosurgeons and later by other specialties as well. During the 1970s and 1980s, a large number of foreign colleagues came through Stockholm. The neurosurgical department at the Karolinska Hospital had a good reputation in stereotactic and functional neurosurgery, and many of the visitors later became prominent proponents of radiosurgery. In the mid-1980s, the adapted linear accelerator was pioneered by Federico Colombo in Italy and Osvaldo Betti in Argentina. Later, others joined the ranks. Nevertheless, it would take until the time of the first U.S. Gamma Knife installation in 1987 for the concept of noninvasive brain surgery to gain credibility. Slowly, the veracity of our claims from the 1970s began to take hold. By then, we already knew what the next steps would be for us; namely, the further refinement of the Gamma Knife in parallel with the incorporation of stereotactic principles, concepts of precision and accuracy, and imaging into the practice of radiotherapy in the rest of the body. In 1989, we called this stereotactic radiation therapy, or SRT. We believed that there was a gray zone between radiosurgery and conventional radiotherapy that was worthy of attention. The idea was to use increased precision as a way to allow higher doses and maybe fewer fractions in radiotherapy. This could, we thought, improve the treatment of lesions too large for radiosurgery and too small for radiotherapy. I tried to establish a collaboration with one of the major suppliers of linear accelerators in order to explore this gray zone between radiosurgery and conventional radiotherapy, but there was no interest at all at the time. With the rate of development seen over the past 10 years, one wonders what lies ahead for radiation medicine. My guess is that we will see a somewhat slower rate of development in the radiation delivery systems themselves but an increasing emphasis on the integration of radiation delivery systems with software systems such as planning, imaging, and cancer registry systems. On the clinical side, we will see the continued reemergence of radiosurgery in the treatment of functional brain disorders, including epilepsy, movement disorders, obsessivecompulsive states, and possibly severe endogenous depression. In ophthalmology, there is already exploratory work being done in, for example, glaucoma, macular degeneration, endocrine orbitopathy, and uveal melanomas. We will also see the application of stereotactically guided radiation therapy for disorders that currently are not part of standard practice. These will include the precise targeting of intra- and extraaxial spine lesions, as well as disease in the paranasal sinuses and the larynx. Radiation therapy for, for example, lung and prostate cancer will benefit from the increased precision, allowing higher doses to be delivered despite the close proximity of heart muscle and colon. This book is a very good illustration of the term helicopter perspective. It is particularly impressive in that it really approaches the whole spectrum of disease in a very thorough manner. The title of the book is actually quite humble, belying as it does the fact that all available treatment modalities are represented, compared, and put in perspective. It epitomizes the word comprehensive!

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This textbook contains a wealth of information and truly encompasses the whole field of radiosurgery, regardless of technology and regardless of which disease the reader wants to learn more about, be it in the brain, in the spine, in the eye, or elsewhere in the body. For residents and newcomers to the field and for the experienced clinician, this volume will represent an invaluable source of information as you strive to design the best therapeutic approach to your individual patients. This is a book that deserves a prominent—and easy to reach—place on our bookshelves. Dan Leksell, MD

Preface he practice of stereotactic radiosurgery has developed from an unprecedented degree of collaboration among practitioners of neurosurgery, radiation oncology, and medical physics. Because the patients and the diseases that we treat are at the intersection of surgery, radiation, and medical therapy, we felt that a full description of this field required a comprehensive and global approach to the subject. Not only would we discuss the main diseases that comprise the typical intracranial radiosurgery practice, such as brain metastases and AVMs, we would also cover the fast-growing field of extracranial radiosurgery, as well as more unusual indications such as epilepsy and psychiatric disease. We also wanted to avoid a bias toward Gamma Knife radiosurgery, which tends to dominate most publications. Therefore, we made sure that all major stereotactic radiosurgery techniques were represented. In selecting contributing authors, we felt it critical to enlist the help of our international colleagues who have been at the vanguard of expanding radiosurgery indications. After all, stereotactic radiosurgery was invented by a Swedish neurosurgeon. We organized this book into five main sections, with the first few providing important background for the rest of the book. Part One covers the history of radiosurgery, basics of neuroimaging, and a general overview of key concepts in radiosurgery. Part Two concentrates on the principles of radiation physics and radiobiology that explain the noninvasive, yet powerful, nature of stereotactic radiation treatments. Other topics covered include treatment planning and the designing of a radiosurgery unit. We think this portion of the book will be of particular interest to medical physicists, as it is intended to be a practical guide for the running and maintenance of a radiosurgery center. Part Three contains reviews of the major techniques of stereotactic radiosurgery by physicians who are considered by most to be the leading figure in their disciplines. We hope you find their insights as valuable to your practice as we did. Part Four includes eighteen chapters that describe the major disease types treated by practitioners of stereotactic radiosurgery. In each chapter, we asked the authors to provide case reports of actual patients that illustrated the approach, treatment plan, and outcome of their treatment, thus providing a blueprint to follow for those new to the specialty. One of the more unusual aspects of this book is the inclusion of “perspective” chapters that follow a main topic chapter. We felt that having minichapters written by experts in the field who might have a differing viewpoint would provide the most balanced approach to diseases that often have more than one effective treatment. The last part of this book presents topics related to patient care and the often ignored but critical socioeconomic side of stereotactic radiosurgery. The diverse subjects tackled include complication management, cost-effectiveness and quality of life, building a radiosurgery practice, and nursing issues. We also included a few topics that have controversial aspects: regulatory and reimbursement issues, medicolegal pitfalls, and radiosurgery semantics. In these chapters, the reader will find that some author opinion is unavoidable but does not necessarily reflect the views of the editors and the publisher. Our mantra for this book was to be comprehensive and balanced, but we recognize that there will always be disagreements on many of the topics discussed in this book. We hope that this book will be informative but also stimulate a healthy and constructive dialog among its readers. We must continually examine our results in this critical manner to provide the best care for our patients. This book has been the culmination of several years of planning and execution by a large number of very talented individuals. First, we are indebted to the authors of the individual chapters, who provided their time and expertise in the creation of this project. We would like to thank the editors and staff at Springer who brought dedication and excellence to this project: Beth Campbell, Paula Callaghan, Barbara Lopez-Lucio, and Brad Walsh. We thank Barbara Chernow who rounded this book into its final form. We thank our assistants Debbie

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Redmon, Yvette Green, and Michele Murphy who kept our practices humming while dealing with manuscripts, contributors, editors, and Fed-Ex. Our professional lives owe a debt to the mentors who brought us into neurosurgery, radiation oncology, and the world of radiosurgery, Buz Hoff, Martin Weiss, Michael Apuzzo, Steven Giannotta, Howard Eisenberg, Simon Kramer, Larry Kun, and Jay Loeffler. Most importantly, we thank our wives Rita and Julie, along with our children, and the rest of our family and friends for their constant love and support. Lastly, we thank our patients, colleagues, trainees, and students who provided the inspiration for this book. Lawrence S. Chin, MD William F. Regine, MD

Contents Foreword by Dan Leksell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PART I

The Fundamentals

1

The History of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . Michael Schulder and Vaibhav Patil

2

Neuroimaging in Radiosurgery Treatment Planning and Follow-up Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clark C. Chen, Paul H. Chapman, Hanne Kooy, and Jay S. Loeffler

3

Techniques of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . Chris Heller, Cheng Yu, and Michael L.J. Apuzzo

PART II

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3

9

25

Radiation Biology and Physics

4

The Physics of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . Siyong Kim and Jatinder Palta

5

Radiobiological Principles Underlying Stereotactic Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Brenner

33

51

6

Experimental Radiosurgery Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ajay Niranjan and Douglas Kondziolka

61

7

Treatment Planning for Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . David M. Shepard, Cedric Yu, Martin Murphy, Marc R. Bussière, and Frank J. Bova

69

8

Designing, Building and Installing a Stereotactic Radiosurgery Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lijun Ma and Martin Murphy

PART III

91

Stereotactic Radiosurgery Techniques

9

Gamma Knife Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ajay Niranjan, Sait Sirin, John C. Flickinger, Ann Maitz, Douglas Kondziolka and L. Dade Lunsford

107

10

Linear Accelerator Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William A. Friedman

129

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Proton Beam Radiosurgery: Physical Bases and Clinical Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Georges Noel, Markus Fitzek, Loïc Feuvret, and Jean Louis Habrand

141

12

Robotics and Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cesare Giorgi and Antonio Cossu

163

13

CyberKnife Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John R. Adler Jr., Alexander Muacevic, and Pantaleo Romanelli

171

PART IV

Treatment of Disease Types

14

Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John H. Suh, Gene H. Barnett, and William F. Regine

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15

Metastatic Brain Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . Raymond Sawaya and David M. Wildrick

193

16

Brain Metastases: Whole-Brain Radiation Therapy Perspective . . . . . . Roy A. Patchell and William F. Regine

201

17

High-Grade Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David Roberge and Luis Souhami

207

18

Malignant Glioma: Chemotherapy Perspective . . . . . . . . . . . . . . . . . . . . Roger Stupp and J. Gregory Cairncross

223

19

Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carlos A. Mattozo and Antonio A.F. de Salles

233

20

Meningioma: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lawrence S. Chin, Pulak Ray, and John Caridi

249

21

Intracranial Meningioma: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leland Rogers, Dennis Shrieve, and Arie Perry

257

22

Meningioma: Systemic Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . Steven Grunberg

271

23

Acoustic Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William M. Mendenhall, Robert J. Amdur, Robert S. Malyapa, and William A. Friedman

275

24

Acoustic Neuroma: Surgical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . Indro Chakrabarti and Steven L. Giannotta

283

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Acoustic Neuromas and Other Benign Tumors: Fractionated Stereotactic Radiotherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . David W. Andrews, Greg Bednarz, Beverly Downes, and Maria Werner-Wasik

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Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kintomo Takakura, Motohiro Hayashi, and Masahiro Izawa

299

27

Pituitary Adenomas: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . William T. Couldwell and Martin H. Weiss

309

28

Pituitary and Pituitary Region Tumors: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan P.S. Knisely and Paul W. Sperduto

317

Pituitary and Pituitary Region Tumors: Medical Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mansur E. Shomali

327

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30

Pediatric Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andrew Reisner, Nicholas J. Szerlip, and Lawrence S. Chin

31

Pediatric Brain Tumors: Conformal Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas E. Merchant

331

341

32

Pediatric Brain Tumors: Chemotherapy Perspective . . . . . . . . . . . . . . . . Amar Gajjar

351

33

Pineal Region Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gregory P. Lekovic and Andrew G. Shetter

355

34

Pineal Region Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . Alfred T. Ogden and Jeffrey N. Bruce

365

35

Pineal Tumors: Fractionated Radiation Therapy Perspective . . . . . . . . Steven E. Schild

371

36

Pineal Region Tumors: Chemotherapy Perspective . . . . . . . . . . . . . . . . . Barry Meisenberg and Lavanya Yarlagadda

377

37

Skull Base Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stefanie Milker-Zabel, Young Kwok, and Jürgen Debus

383

38

Skull Base Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . James K. Liu, Oren N. Gottfried, and William T. Couldwell

393

39

Skull Base Tumors: Fractionated Stereotactic Radiotherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . René-Olivier Mirimanoff and Alessia Pica

401

40

Head and Neck Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel T.T. Chua, Jonathan Sham, Kwan-Ngai Hung, and Lucullus Leung

411

41

Head and Neck Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . Gregory Y. Chin and Uttam K. Sinha

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Head and Neck Malignancies: Chemotherapy and Radiation Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mohan Suntharalingam, Kathleen Settle, and Kevin J. Cullen

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43

Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert L. Dodd, Iris Gibbs, John R. Adler Jr., and Steven D. Chang

431

44

Spine Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gabriel Zada and Michael Y. Wang

443

45

Spinal Metastases: Fractionated Radiation Therapy Perspective . . . . . Eric L. Chang and Almon S. Shiu

455

46

Arteriovenous Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bruce E. Pollock

459

47

Arteriovenous Malformations: Surgery Perspective . . . . . . . . . . . . . . . . Ricardo J. Komotar, Elena Vera, J. Mocco, and E. Sander Connolly Jr.

473

48

Cerebral Arteriovenous Malformations: Endovascular Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Felipe C. Albuquerque, David Fiorella, and Cameron G. McDougall

479

49

Cavernous Malformations and Other Vascular Diseases . . . . . . . . . . . . Ajay Niranjan, David Mathieu, Douglas Kondziolka, John C. Flickinger, and L. Dade Lunsford

491

50

Cerebral Cavernous Malformations: Surgical Perspective . . . . . . . . . . . Robert L. Dodd and Gary K. Steinberg

503

51

Cavernous Malformations and Other Vascular Abnormalities: Observation-Alone Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sepideh Amin-Hanjani and Frederick G. Barker II

513

52

Trigeminal Neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lawrence S. Chin, Shilpen Patel, Thomas Mattingly, and Young Kwok

519

53

Trigeminal Neuralgia: Surgical Perspective . . . . . . . . . . . . . . . . . . . . . . . . David B. Cohen, Michael Y. Oh, and Peter J. Jannetta

527

54

Trigeminal Neuralgia: Medical Management Perspective . . . . . . . . . . . Neil C. Porter

535

55

Movement Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sangjin Oh, Ajay Niranjan, and William J. Weiner

541

56

Movement Disorders: Deep-Brain Stimulation Perspective . . . . . . . . . . John Y.K. Lee, Joshua M. Rosenow, and Ali R. Rezai

549

57

Movement Disorder: Medical Perspective . . . . . . . . . . . . . . . . . . . . . . . . Sangjin Oh and William J. Weiner

559

58

Psychiatric and Pain Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jason Sheehan, Nader Pouratian, and Charles Sansur

563

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Intractable Epilepsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jean Régis, Fabrice Bartolomei, and Patrick Chauvel

573

60

Epilepsy: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Keith G. Davies and Edward Ahn

583

61

Ocular and Orbital Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gabriela Šimonová, Roman Liscˇák, and Josef Novotný Jr.

593

62

Stereotactic Body Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laura A. Dawson

611

63

Stereotactic Body Radiation Therapy: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gordon W. Wong, Rafael R. Mañon, Wolfgang Tomé, and Minesh Mehta

64

Stereotactic Body Radiation Therapy: Brachytherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Caroline L. Holloway, Desmond O’Farrell, and Phillip M. Devlin

PART V

635

643

Patient Care and Socioeconomic Issues

65

Complications and Management in Radiosurgery . . . . . . . . . . . . . . . . . . Isaac Yang, Penny K. Sneed, David A. Larson, and Michael W. McDermott

649

66

Cost-Effectiveness and Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . Minesh Mehta and May N. Tsao

663

67

Regulatory and Reimbursement Aspects of Radiosurgery . . . . . . . . . . Rebecca Emerick

673

68

Medicolegal Issues in Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . April Strang-Kutay

681

69

The Semantics of Stereotactic Radiation Therapy . . . . . . . . . . . . . . . . . . Louis Potters

687

70

Building a Radiosurgery Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N. Scott Litofsky and Andrea D’Agostino-Demers

691

71

Patient Care in Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . Terri F. Biggins

699

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

709

Contributors John R. Adler Jr., MD Professor of Neurosurgery, Stanford University Medical Center, and Attending Neurosurgeon, Stanford University Medical Center, Stanford, CA, USA Edward Ahn, MD Fellow in Neurosurgery, Department of Neurosurgery, Children’s Hospital of Boston, Boston, MA, USA Felipe C. Albuquerque, MD Assistant Director of Endovascular Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA Robert J. Amdur, MD Professor of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, USA Sepideh Amin-Hanjani, MD Assistant Professor, Neurosurgery, University of Illinois at Chicago, Chicago, IL, USA David W. Andrews, MD Professor and Vice Chairman, Chief, Division of Neuro-Oncologic Neurosurgery & Stereotactic Radiosurgery, Thomas Jefferson University, Philadelphia, PA, USA Michael L.J. Apuzzo, MD Edwin M. Todd and Trent H. Wells Professor of Neurosurgery, Radiation, Oncology, Biology and Physics, Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Frederick G. Barker II, MD Associate Professor, Department of Neurosurgery, Harvard Medical School; Associate Visiting Neurosurgeon, Brain Tumor Center, Massachusetts General Hospital, Boston, MA, USA

Gene H. Barnett, MD, FACS Professor of Surgery, Cleveland Clinic Lerner College of Medicine; Director, Brain Tumor Institute, Cleveland Clinic, Cleveland, OH, USA Fabrice Bartolomei, MD, PhD Service de Neurophysiologie Clinique, Université de la Méditerranée, Marseille, France Greg Bednarz, PhD Medical Physicist, Department of Radiation Oncology, Thomas Jefferson University, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA Terri F. Biggins, RN, BSN Patient Care Coordinator, University of Maryland, Gamma Knife Center, Baltimore, MD, USA Frank J. Bova, PhD Professor of Neurosurgery, University of Florida, Gainesville, FL, USA David J. Brenner, PhD, DSc Professor of Radiation Oncology and Public Health, Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, New York, NY, USA Jeffrey N. Bruce, MD Professor of Neurological Surgery, Department of Neurosurgery, Columbia University—College of Physicians and Surgeons, New York, NY, USA Marc R. Bussière, MSc, DABR Medical Radiation Physicist, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA J. Gregory Cairncross, MD, FRCPC Department of Clinical Neurosciences, University of Calgary, Foothills Hospital, Alberta, Canada

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John Caridi, MD Resident, Department of Neurosurgery, University of Maryland, Baltimore, MD, USA

E. Sander Connolly Jr., MD Associate Professor, Department of Neurological Surgery, Columbia University, New York, NY, USA

Indro Chakrabarti, MD, MPH Neurosurgery Chief Resident, University of Southern California, Los Angeles, CA, USA

Antonio Cossu, MTE 3DLine Medical Systems, Milano, Italy

Eric L. Chang, MD Associate Professor, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Steven D. Chang, MD Assistant Professor of Neurosurgery, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA Paul H. Chapman, MD Professor, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA Patrick Chauvel, MD Service de Neurophysiologie Clinique, Université de la Méditerranée, Marseille, France Clark C. Chen, MD, PhD Fellow, Radiosurgery, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA Gregory Y. Chin, MD Attending Physician, Department of Head and Neck Surgery, Kaiser Permanente Walnut Creek Medical Center, Walnut Creek, CA, USA Lawrence S. Chin, MD Professor and Chairman, Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA Daniel T.T. Chua, FRCR Associate Professor, Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong David B. Cohen, MD Functional Neurosurgery Fellow, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, PA, USA

William T. Couldwell, MD, PhD Professor and Joseph J. Yager Chair, Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA Kevin J. Cullen, MD Director, University of Maryland Greenebaum Cancer Center, Professor of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Andrea D’Agostino-Demers, MSN, EdD, CS, APRN, BC, NP Clinical Coordinator, Stereotactic Radiosurgery, Image-Guidance, and Functional Neurosurgery Programs, Division of Neurosurgery, UMASS Memorial Healthcare, Worcester, MA, USA Keith G. Davies, MD, FRCS Associate Professor, Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA Laura A. Dawson, MD Associate Professor, Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada Jürgen Debus, MD, PhD Department of Radiation Oncology and Radiation Therapy, University of Heidelberg, Heidelberg, Germany Antonio A.F. de Salles, MD, PhD Professor, Department of Surgery, Division of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Phillip M. Devlin, MD Assistant Professor, Department of Radiation Oncology, Harvard Medical School; and Chief, Division of Brachytherapy, Department of Radiation Oncology, Dana Farber/Brigham & Women’s Cancer Center, Boston, MA, USA

xvii

contributors

Robert L. Dodd, MD, PhD Endovascular Fellow, Department of Neurosurgery, Stanford University, Stanford, CA, USA

Cesare Giorgi, MD Neurosurgeon, Department of Computer-assisted Neuro and Radiosurgery, Ospedale S. Maria, Terni, Italy

Beverly Downes, MS Chief Medical Physicist, Stereotactic Radiosurgery Units, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA

Oren N. Gottfried, MD Resident, Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA

Rebecca Emerick, MS, MBA, CPA Executive Director, International RadioSurgery Association (IRSA), Harrisburg, PA, USA

Steven Grunberg, MD Professor of Medicine, Department of Medical Oncology, University of Vermont, Burlington, VT, USA

Loïc Feuvret Centre de protonthérapie d’Orsay-Institut Curie, Campus universitaire, Orsay, France

Jean Louis Habrand CPO-Institut Curie, Orsay, France

David Fiorella, MD, PhD Staff Neuroradiology, Department of Neuroradiology and Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH, USA Markus Fitzek, MD Radiation Oncology Center, Tufts—New England Center, Tufts University School of Medicine, Boston, MA, USA John C. Flickinger, MD Professor, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA William A. Friedman, MD Professor and Chair, Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, USA Amar Gajjar, MD Professor of Pediatrics, University of Tennessee, Director, Division of Neuro Oncology; Co-leader Neurobiology and Brain Tumor Program, Member and Co-Chair Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Motohiro Hayashi, MD, PhD Lecturer of the Department of Neurosurgery, Chief of Gamma Knife Center, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan Chris Heller, MD Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Caroline L. Holloway, MD, FRCPC Radiation Oncologist, Department of Radiation Oncology, BCCA—Centre for the Southern Interior, Kelowna, BC, Canada Kwan-Ngai Hung, FRCS Consultant Neurosurgeon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Masahiro Izawa, MD, PhD Assistant Professor, Department of Neurosurgery, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan

Steven L. Giannotta, MD Chairman, Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA

Peter J. Jannetta, MD Professor, Department of Neurosurgery, Drexel University School of Medicine; Vice-Chairman, Department of Neurosurgery, Jannetta Center for Cranial Nerve Disorders, Allegheny General Hospital, Pittsburgh, PA, USA

Iris Gibbs, MD Assistant Professor of Radiation Oncology, Stanford University, Stanford, CA, USA

Siyong Kim, PhD Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA

xviii Jonathan P.S. Knisely, MD, FRCPC Associate Professor, Department of Therapeutic Radiology, Yale University School of Medicine; and Yale Cancer Center, Yale–New Haven Hospital, New Haven, CT, USA Ricardo J. Komotar, MD Resident, Neurosurgery, Department of Neurological Surgery, Columbia University, New York, NY, USA Douglas Kondziolka, MD, FRCS, FACS Professor of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA Hanne Kooy, PhD Research Associate, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA Young Kwok, MD Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, USA David A. Larson, PhD, MD, FACR Professor of Radiation Oncology and Neurological Surgery, Director, CyberKnife Radiosurgery Program, Co-Director, Gamma Knife Radiosurgery Program, Department of Neurological Surgery and Radiation Oncology, University of California San Francisco, San Francisco, CA, USA John Y.K. Lee, MD Assistant Professor, Department of Neurosurgery, University of Pennsylvania; Medical Director, Penn Gamma Knife at Pennsylvania Hospital, University of Pennsylvania, Philadelphia, PA, USA

contributors

Roman Liscˇák, MD 3rd Faculty of Medicine, Clinical Department of Neurosurgery, Charles University; Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic N. Scott Litofsky, MD, FACS Associate Professor, Director of Neuro-Oncology, Director of Radiosurgery, Division of Neurological Surgery, University of Missouri-Columbia School of Medicine, Columbia, MO, USA James K. Liu, MD Resident, Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA Jay S. Loeffler, MD Chief Radiation Oncology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA L. Dade Lunsford, MD, FACS Professor and Chairman, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA Lijun Ma, PhD Associate Professor, Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA Ann Maitz, MSc Assistant Professor, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA Robert S. Malyapa, MD, PhD Assistant Professor, Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA

Gregory P. Lekovic, MD, PhD, JD Resident Neurological Surgery, Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ, USA

Rafael R. Mañon, MD Department of Human Oncology, University of Wisconsin Hospital, Madison, WI, USA

Lucullus Leung, PhD Physicist, Department of Clinical Oncology, Queen Mary Hospital, Pokfulam, Hong Kong

David Mathieu, MD, FRCS(C) Visiting Assistant Professor, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

xix

contributors

Thomas Mattingly, MD Resident, Department of Neurosurgery, University of Maryland, Baltimore, MD, USA Carlos A. Mattozo, MD Professor, Department of Surgery, Division of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Michael W. McDermott, MD, FRCSC Professor in Residence of Neurological Surgery, Halperin Endowed Chair, Vice Chairman, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA Cameron G. McDougall, MD Chief of Endovascular Neurosurgery, Barrow Neurological Institute— Neurosurgery, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA Minesh Mehta, MD Professor and Chairman, Department of Human Oncology, University of Wisconsin Hospital, Madison, WI, USA Barry Meisenberg, MD Professor of Medicine, Chief Division of Hematology and Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA William M. Mendenhall, MD Professor, Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, USA

Alexander Muacevic, MD CyberKnife Center Munich, Munich, Germany Martin Murphy, PhD Associate Professor, Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA Ajay Niranjan, MBBS, MS, MCh Assistant Professor of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA Georges Noel, MD Centre de lutte contre le Paul Strauss, Department of Radiotherapy, Strasbourg, France Josef Novotný Jr., MSc, PhD Assistant Professor, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA Desmond O’Farrell, CMD Senior Dosimetrist, Division of Brachytherapy, Department of Radiation Oncology, Dana Farber/Brigham & Women’s Hospital, Boston, MA, USA Alfred T. Ogden, MD Resident, Department of Neurological Surgery, Columbia University, New York, NY, USA

Thomas E. Merchant, DO, PhD Member and Chief, Division of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Michael Y. Oh, MD Assistant Professor, Department of Neurosurgery, Drexel University School of Medicine; Co-Director, Stereotactic and Functional Neurosurgery, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, PA, USA

Stefanie Milker-Zabel, MD Departments of Radiation Oncology and Radiation Therapy, Hospital of Heidelberg, Heidelberg, Germany

Sangjin Oh, MD Fellow, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

René-Olivier Mirimanoff, MD Professor, Department of Radiation Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Jatinder Palta, PhD Professor and Chief of Physics, Department of Radiation Oncology, University of Florida, Gainesville, FL, USA

J. Mocco, MD Resident, Neurosurgery, Department of Neurological Surgery, Columbia University, New York, NY, USA

Roy A. Patchell, MD Chief of Neuro-oncology, Professor of Neurology and Neurosurgery, University of Kentucky Medical Center, Lexington, KY, USA

xx

contributors

Shilpen Patel, MD Assistant Professor, Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA, USA

Ali R. Rezai, MD Director, Brain Neuromodulation Center, Jane and Lee Seidman Chair in Functional Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH, USA

Vaibhav Patil, BA Department of Neurosurgery, New Jersey Medical School, Newark, NJ, USA

David Roberge, MD Assistant Professor, Department of Oncology, Division of Radiation Oncology, McGill University, Montreal, Quebec, Canada

Arie Perry, MD Washington University, Division of Neuropathology, St. Louis, MO, USA Alessia Pica, MD Doctor, Department of Radiation Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland Bruce E. Pollock, MD Professor, Department of Neurological Surgery and Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA Neil C. Porter, MD Assistant Professor, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

Leland Rogers, MD Radiation Oncologist, GammaWest Radiation Therapy, Salt Lake City, UT, USA Pantaleo Romanelli, MD Clinical Assistant Professor, Department of Neurology, State University of New York, Stony Brook, NY, USA; Consulting Assistant Professor, Department of Neurosurgery, Stanford University, Stanford, CA, USA; Director, Functional Neurosurgery, Department of Neurosurgery, IRCCS Neuromed, Pozzilli, Italy

Nader Pouratian, MD, PhD Resident Physician, Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA

Joshua M. Rosenow, MD Assistant Professor of Neurosurgery, Director of Stereotactic and Functional Neurosurgery, Department of Neurosurgery, Feinberg School of Medicine, Northwestern University; Assistant Professor of Neurosurgery, Director of Stereotactic and Functional Neurosurgery, Northwestern Memorial Hospital, Chicago, IL, USA

Pulak Ray, MD Resident, Department of Neurosurgery, Temple University, Philadelphia, PA, USA

Charles Sansur, MD, MHSc Resident, Department of Neurosurgery, Hospital of the University of Virginia, Charlottesville, VA, USA

William F. Regine, MD Professor and Chairman, Department of Radiation Oncology, University of Maryland Medical School, Baltimore, MD, USA

Raymond Sawaya, MD Professor and Chairman, Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Jean Régis Professor, Departement de Neurochirurgie Centre Hospitalier, Er Universitaire La Timone, Marseille, France

Steven E. Schild, MD Professor, Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, USA

Andrew Reisner, MD, FACS, FAAP Neurosurgeon, Department of Pediatric Neurosurgery, Children’s Healthcare of Atlanta, Atlanta, GA, USA

Michael Schulder, MD Professor and Vice-Chairman, Department of Neurosurgery, New Jersey Medical School, Newark, NJ, USA

Louis Potters, MD, FACR South Nassau Communities Hospital, Oceanside, NY, USA

xxi

contributors

Kathleen Settle, MD Chief Resident, Department of Radiation Oncology, University of Maryland Medical Systems, Baltimore, MD, USA Jonathan Sham, MD Professor, Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Jason Sheehan, MD, PhD Assistant Professor of Neurological Surgery and Neuroscience, Department of Neurological Surgery and Neuroscience, University of Virginia, Charlottesville, VA, USA David M. Shepard, PhD Director of Medical Physics, Swedish Cancer Institute, Seattle, WA, USA Andrew G. Shetter, MD, FACS Chairman of Functional Stereotactic Neurosurgery, Division of Neurological Surgery, Director of Pain Research Laboratory, Barrow Neurological Institute, Phoenix, AZ, USA Almon S. Shiu, PhD Professor, Department of Radiation Physics, University of Texas M.D. Anderson Cancer Center; Director Stereotactic Services, Department of Radiation Physics, M.D. Anderson Cancer Center, Houston, TX, USA Mansur E. Shomali, MD, CM Clinical Assistant Professor of Medicine, University of Maryland School of Medicine, Division of Endocrinology, Union Memorial Hospital, Baltimore, MD, USA Dennis Shrieve, MD, PhD Department of Radiation Oncology, University of Utah Medical Center, Salt Lake City, UT, USA Gabriela Šimonová, MD, PhD Department of Stereotactic Radioneurosurgery, Hospital Na Homolce, Prague, Czech Republic

Uttam K. Sinha, MD Associate Professor, Chief and Program Director, Department of Otolaryngology—Head and Neck Surgery, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Sait Sirin, MD Visiting Assistant Professor, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA Penny K. Sneed, MD, FACR Professor in Residence, Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA Luis Souhami, MD Professor and Associate Director, Department of Oncology, Division of Radiation Oncology, McGill University, Montreal, Quebec, Canada Paul W. Sperduto, MD, MAPP Co-Director, Gamma Knife Center, University of Minnesota Medical Center, Minneapolis, MN, USA Gary K. Steinberg, MD, PhD Bernard and Ronni Lacroute–William Randolph Hearst Professor of Neurosurgery and the Neurosciences; Chairman, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA April Strang-Kutay, JD Attorney, Goldberg Katzman, P.C., East Petersburg, PA, USA Roger Stupp, MD Multidisciplinary Oncology Center, University of Lausanne Hospitals (CHUV), Lausanne, Switzerland John H. Suh, MD Chairman, Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA Mohan Suntharalingam, MD Professor and Vice Chairman, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA

xxii Nicholas J. Szerlip, MD Resident, Department of Neurosurgery University of Maryland School of Medicine, Baltimore, MD, USA Kintomo Takakura, MD, PhD President, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan Wolfgang Tomé, PhD Department of Human Oncology, University of Wisconsin Hospital, Madison, WI, USA May N. Tsao, MD, FRCP(C) Assistant Professor, Department of Radiation Oncology, University of Toronto, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada Elena Vera, BS Department of Neurological Surgery, Columbia University, New York, NY, USA Michael Y. Wang, MD Assistant Professor, Department of Neurological Surgery, University of Southern California, Los Angeles, CA, USA William J. Weiner, MD Professor and Chairman, Department of Neurology, University of Maryland School of Medicine; Professor and Chairman, Department of Neurology, University of Maryland Medical Center, Baltimore, MD, USA Martin H. Weiss, MD Professor of Neurological Surgery, Department of Neurological Surgery, USC; Attending Physician, Department of Neurosurgery, USC University Hospital, Los Angeles, CA, USA

contributors

Maria Werner-Wasik, MD Associate Professor, Department of Radiation Oncology, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA David M. Wildrick, PhD Surgery Publications Coordinator, Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Gordon W. Wong, MD Department of Human Oncology, University of Wisconsin Hospital, Madison, WI, USA Isaac Yang, MD Resident, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA Lavanya Yarlagadda, MD Department of Medicine, University of Maryland, Baltimore, MD, USA Cedric Yu, PhD Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA Cheng Yu, PhD Professor and Director of Radiation Oncology Physics, Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Gabriel Zada, MD Resident Physician, Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA

PA R T I

The Fundamentals

1

1

The History of Stereotactic Radiosurgery Michael Schulder and Vaibhav Patil

The Early Years The history of radiosurgery can be said to begin with the discovery of X-rays by Wilhelm Konrad Roentgen on November 26, 1895. His report, “Uber eine neue art von strahlen” (“On a new kind of ray”), appeared 6 weeks later [1]. By January 1896, X-rays were being used to treat skin cancers. The discovery of radioactivity by Becquerel in 1896, and of radium by the Curies soon after, provided another means for the use of therapeutic ionizing radiation. Neurosurgical applications were not long in following. X-rays were used to treat patients with pituitary tumors as early as 1906, and radium brachytherapy was applied to treat similar conditions at about the same time [2]. Harvey Cushing, the father of American neurosurgery, had extensive experience with both X-ray and brachytherapy treatments, although he remained skeptical of the utility of either [3]. Other neurosurgeons continued to explore the uses of ionizing radiation throughout the first half of the 20th century [4]. In 1951, Lars Leksell coined the term stereotactic radiosurgery (SRS) [5]. A ceaseless innovator, his goal was to develop a method for “the non-invasive destruction of intracranial . . . lesions that may be inaccessible or unsuitable for open surgery.” The first procedures were done using an orthovoltage X-ray tube, mounted on an early model of what is now known as the Leksell stereotactic frame, for the treatment of several patients with trigeminal neuralgia. After experimenting with particle beams and linear accelerators, Leksell and his colleagues ultimately designed the Gamma Knife (GK), containing 179 cobalt sources in a hemispheric array (Fig. 1-1). The first unit was operational in 1968. The potential of the GK to treat lesions was recognized by Leksell and colleagues early on. In the era before computed tomography (CT), these treatments were limited to patients with arteriovenous malformations (AVMs) [6] and acoustic neuromas, which could be imaged either on angiography or by polytomography, respectively [7]. At the same time, work was continuing elsewhere with focused heavy particle irradiation. Ernest Lawrence, one of the great figures of 20th century physics and a professor at the University of California Berkeley, invented the cyclotron in

1929, winning the Nobel Prize in 1939 (Fig. 1-2). In the 1950s, his brother John began a decades-long investigation of the use of heavy particles (proton beams, then helium ion beams) for the treatment of patients with pituitary and other intracranial disorders (Fig. 1-3) [8, 9]. Raymond Kjellberg, a neurosurgeon at the Harvard/Massachusetts General Hospital facility, spearheaded the use of proton beam treatments (Fig. 1-4) [10]. A large series of patients with arteriovenous malformations and pituitary tumors was amassed. Similar efforts were carried out in California with helium ions [11]. Particle beams have the advantage of depositing their energy at a distinct point known as the Bragg peak, with minimal exit dose. In practice, the beams must be carefully shaped and spread in order to treat patients with intracranial lesions. The expense of building and maintaining a cyclotron has limited the use of heavy-particle SRS to a few centers.

Acceptance The advent of CT in the mid-1970s, and magnetic resonance imaging some 10 years later, opened up the possibility of direct targeting of tumors and other “soft tissue” targets inside the skull. The 1980s saw the evolution of SRS from an esoteric technique, available at the original GK in Stockholm (and as fractionated treatments at a few heavy-particle accelerators around the world), to an emerging technology of increasing utility. As the potential horizons of SRS broadened, other investigators were able to adapt linear accelerators (“linacs”) for SRS. These devices were more available (and less expensive) than GKs or heavy-particle accelerators [12]. Working independently, in Buenos Aires, Argentina, and in Vicenza, Italy, respectively, Betti and Colombo reported the successful adaptation of linacs for SRS [13, 14]. Their systems allowed for the rotation of the linac gantry in a single plane. After several years of hacking through mounds of red tape, Lunsford and colleagues completed the installation of the first American GK at the University of Pittsburgh [15]. This group was instrumental, via an ongoing series of peer-reviewed

3

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m. schulder and v. patil

FIGURE 1-3. Particle beam accelerator, 1947. (Photo courtesy of the Lawrence Berkeley National Laboratory.)

FIGURE 1-1. Lars Leksell and his physicist colleague, Borje Larsson, preparing a patient for SRS with a particle beam accelerator in 1958. (Photo courtesy of L. Dade Lundsford, MD.)

publications, in placing the technique and clinical indications for SRS on a sound scientific basis. At about the same time, Winston and Lutz described the use of a commercially available stereotactic frame for linac radiosurgery [16]. Following in their footsteps, Loeffler and Alexander demonstrated how a linac dedicated to SRS could be a practical alternative to a GK [17]. In the late 1980s, Friedman and Bova elected not to install the second American GK unit, preferring to develop a new linac SRS system [18]. Other advantages of these linac systems, besides ubiquity and

FIGURE 1-2. Ernest Lawrence at the controls of a cyclotron. (Photo courtesy of the Lawrence Berkeley National Laboratory.)

lower cost, included the availability of collimators in a much greater variety of diameters than provided with the GK. This allowed for the use of single isocenters when treating patients whose targets were more than 18 mm in diameter, the width of the largest GK collimator. However, at around the same time, several GKs were installed in several sites around the world. As clinical experience increased, publications appeared, indications broadened, and vendors became increasingly interested, a debate emerged regarding the merits of the GK versus linac-based SRS. By now, clinical and physics studies seem to have settled the issue in that SRS can be delivered effectively

FIGURE 1-4. Raymond Kjellberg with a frame for proton beam therapy of a patient with an AVM. (Photo courtesy of Richard Wilson, Mallinckrodt Research Professor of Physics, Harvard University.)

1.

the history of stereotactic radiosurgery

5

and accurately with either method [12, 19]. Numerous reports demonstrating the efficacy of SRS with few if any short-term complications and lower costs led to the proliferation of GK and linac units around the world.

Fractionation Linac-based systems also opened up the possibility of SRS without an invasive frame. In 1992, the relocatable Gill-ThomasCosman (GTC) frame was introduced. This device relied on an attached bite block, custom molded for each patient, and was shown to have a stereotactic accuracy of just over 2 mm [20]. Although not sufficiently accurate and precise for single-session SRS, the GTC frame opened up the era of fractionated stereotactic irradiation [21, 22]. This in turn began a debate that has not been settled: what to call this new method? fractionated SRS or rather stereotactic radiation therapy (SRT)? This semantic question reflects two different underlying views of SRS. The neurosurgeon views it as a type of minimally invasive surgery, whereas the radiation oncologist sees SRS as a technique of small-volume irradiation. Advocating for “FSRS” were neurosurgeons who attached importance to the stereotactic concept, which they viewed as being “neurosurgical.” On the other hand, radiation oncologists claimed that patients were being treated with the standard fractionation schemes that practitioners knew and had been employing for decades. The GTC or similar devices were merely another means of achieving three-dimensional conformality. Confounding this controversy was the introduction of new fractionation schemes. For instance, patients with vestibular schwannomas were treated with 2500 cGy in five fractions. Other regimens have been used, including frame-based GK to treat hospitalized patients over a 5-day period [23]. Whereas SRT generally was accepted as referring to a stereotactically focused treatment using a conventional fractionation scheme, some neurosurgeons and radiation oncologists insisted that there was nothing sacrosanct about the single-fraction treatment. Who was to say that 3 or 5 doses (i.e., far fewer than usual for radiation therapy, and potentially risky to the patient if not planned and delivered with great precision) were not SRS? Different new technologies made all these options possible, but the argument was honed most precisely by the introduction of a new, robotic device. John Adler, a neurosurgeon who trained at the Brigham and Women’s Hospital in Boston, spent a fellowship year with Lars Leksell in 1985 (Adler JR, personal communication). Excited by his exposure to the GK, Adler saw the potential of SRS being extended to other areas of the body. This required a method of delivering focused radiation without a stereotactic frame. Partnering with engineers at Stanford University and with private financial backing, the CyberKnife ultimately came into being in 1994 (Fig. 1-5). The CyberKnife delivers SRS via an X-band linac with an output of 6 MV. It is nonetheless small enough to be mounted on an industrial robot, allowing for a theoretically infinite number of beams to be aimed at the target. Treatments are fashioned using an inverse planning method; to allow for practical computation times, the number of beam origins (“nodes”) and robot angles are limited. Peer-reviewed publications have

FIGURE 1-5. The first CyberKnife treatment, 1994. (Photo courtesy of John R. Adler, MD.)

demonstrated the acceptance of the CyberKnife [24–26]. These and other articles have fostered a useful debate regarding the concept of hypofractionation in SRS and indeed if such treatments are still “radiosurgical” [27, 28].

Extracranial Radiosurgery SRS was invented as a means of minimally invasive brain surgery and was expanded with the aid of digital imaging to include extracerebral, intracranial targets. Still, the concept of a highly focused, single- or several-session radiation treatment had obvious appeal for extracranial targets. The first radiosurgical moves out of the intracranial compartment were in the logical direction of the skull base and past that into the paranasal sinuses, using either GK [29, 30] or linac units [31]. Creative modifications of standard stereotactic frames were described to allow for treatment of “lower” targets [32]. The adaptation of available equipment for SRS could go only so far. Hamilton and colleagues described the first truly extracranial radiosurgical unit. This prototypical system did not rely on rigid frame fixation to the skull and was designed to provide spinal SRS [33]. The need to surgically place a clamp on a spinous process, and to treat the patient in a prone position, limited the appeal of this groundbreaking concept. With the advent of newer technologies, spinal SRS has become a reality. Reports to date have employed the CyberKnife [34] or other linac-based systems [35]. More recently still, the inevitable and logical extension of SRS to non-CNS targets has begun. Work on CyberKnife treatment of tumors of the lung [36] and prostate [37] has been published. Despite the neurosurgical origins of SRS, all advocates of this concept, in its various forms, can only welcome its spread to other specialties in which neurosurgeons will have little role to play. Table 1-1 summarizes the historical landmarks in the development of SRS.

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m. schulder and v. patil

TABLE 1-1. Historical landmarks in the development of SRS. Year

Author

Device/Event

1951

Leksell

1954

Lawrence

1962

Kjellberg

1967 1970 1980 1982 1984 1986

Leksell Steiner Fabrikant Betti/Columbo Bunge Winston/Lutz

1991 1992 1994 1997

Friedman Loeffler/Alexander Adler Krispel

Invention of SRS with rotating orthovoltage unit Heavy-particle treatment of pituitary for cancer pain Proton beam therapy of intracranial lesions Invention of GK GK SRS of AVMs Helium ion treatment of AVMs Linacs adapted for SRS Installation of commercial GK Linac SRS based on common stereotactic frame Linac system for highly conformal SRS Dedicated linac for SRS developed First CyberKnife treatment Rotating cobalt unit

Other Linac Systems and the Role of Industry The convergence of image-guidance technology and radiation delivery devices has encouraged the entry of multiple vendors into the SRS marketplace. This has reflected the undeniable logic of stereotactic localization and the resulting ability to focus radiation treatments on the smallest possible volume. Initially, in addition to the GK, there were a variety of framebased systems designed to provide single-fraction SRS. Vendors included Radionics (X-Knife), Zmed (the University of Florida system), BrainLAB, and Fischer-Leibinger. The acceptance of stereotactic fractionation by radiation oncologists, their reluctance to apply stereotactic frames, and to some extent patients’ preference for avoiding frame use have shifted the focus toward frameless systems. Long-established purveyors of linacs have begun to market stereotactic devices aimed primarily at radiation oncologists but usually with a nod toward neurosurgeons who often will prefer to treat patients with a single fraction, or at most several. Thus, Varian and Phillips (now a division of Elekta) have developed systems with integrated stereotactic localization (Trilogy and Synergy). At the same time, Radionics and BrainLAB have adapted their linac-based SRS devices for frameless use and have marketed directly to radiation oncologists. And to square the circle, American Radiosurgical, Inc., has as its sole product a modification of the GK, using a limited number of cobalt-60 sources in a rotating helmet. This industrial involvement in the advancement of SRS and related techniques results from the expense of the equipment and the need for support personnel to ensure their proper functioning. From the days of the first GK and on up to the emerging era of frameless, fractionated SRS, companies have played an invaluable role. Without them, SRS would never have come to define a new standard in patient care, as it so clearly has.

Organized Radiosurgery Neurosurgeons’ interest in SRS was slow to develop but has increased exponentially over time. In 1987, the year that the first American GK was installed at the University of Pittsburgh and early work on linac SRS had been published, there were no SRS-related presentations at the meeting of the American Association of Neurological Surgeons (AANS). By 1998, there were 31 such abstracts in addition to practical courses and seminars devoted to the topic. SRS has remained a key item of interest at the major annual meetings of the AANS and of the Congress of Neurological Surgeons. In addition, the meetings of the American and World Societies for Stereotactic and Functional Neurosurgery feature SRS as one of the main topics. The International Stereotactic Radiosurgery Society (ISRS) was founded in 1993 and held its first biannual meeting that year in Stockholm. At first, the papers presented dealt entirely with the treatment of intracranial conditions. As SRS has moved below the skull base, studies regarding patients with such conditions as tumors of the spine, lung, pancreas, and prostate have been included in the ISRS program. Thus, the expertise of clinicians in fields completely unrelated to neurosurgery is being applied to the study of SRS. Neurosurgeons comprise the single biggest specialty group in the organization, followed by radiation oncologists and medical physicists. As interest in extracranial and indeed nonneurosurgical SRS inevitably increases, the membership of ISRS no doubt will evolve to reflect this broadening of interest. The ISRS publishes a peer-reviewed collection of selected manuscripts from each meeting, entitled Radiosurgery.

Conclusion Acceptance by neurosurgeons, surgical specialists, and radiation oncologists means that as SRS evolves, it will not be a technique for “radiosurgeons” but one of the methods available to treat patients with a wide variety of disorders. At the same time, the historical role of neurosurgeons in the development of SRS, their leadership in its refinement and expansion over the last half century, their knowledge of neuroanatomy, and their understanding of central nervous system pathology and its treatment will ensure the continued active role of neurosurgeons in the ongoing growth of stereotactic radiosurgery.

References 1. Mould R. A Century of X Rays and Radioactivity in Medicine. Philadelphia: Institute of Physics Publishing, 1993. 2. Hirsch O. Uber methoden der operativen behandlung von hypophysistumoren auf endonasalem Wege. Arch Laryngol Rhinol 1910; 24. 3. Schulder M, Loeffler J, Howes A, et al. The radium bomb: Harvey Cushing and the interstitial irradiation of gliomas. J Neurosurg 1996; 84:530–532. 4. Schulder M, Rosen J. Therapeutic radiation and the neurosurgeon. Neurosurg Clin N Am 2001; 12(1):91–100, viii. 5. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 1951; 102:316–319. 6. Steiner L, Leksell L, Greitz T. Stereotaxic radiosurgery for cerebral arteriovenous malformations. Acta Chir Scand 1972; 138: 459–464.

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7. Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983; 46:797–803. 8. Kirn TF. Proton radiotherapy: some perspectives. JAMA 1988; 259:787–788. 9. Skarsgard LD. Radiobiology with heavy charged particles: a historical review. Phys Med 1998; 14(Suppl 1):1–19. 10. Kjellberg RN, Abe M. Stereotactic Bragg Peak proton beam therapy. In: Lunsford LD, ed. Modern Stereotactic Neurosurgery. Boston: Martinus Nijhoff, 1988:463–470. 11. Fabrikant J, Lyman J, Frankel K. Heavy charged particle Bragg peak radiosurgery for intracranial vascular disorders. Radiat Res Suppl 1985; 8:S244–258. 12. Podgorsak E, Pike G, Olivier A, et al. Radiosurgery with high energy photon beams: a comparison among techniques. Int J Radiat Oncol Biol Phys 1989; 16:857–865. 13. Betti O, Derechinsky V. Hyperselective encephalic irradiation with a linear accelerator. Acta Neurochir 1984; Suppl 33:385– 390. 14. Columbo F, Benedetti A, Pozza F, et al. External stereotactic irradiation by linear accelerator. Neurosurgery 1985; 16:154–160. 15. Lunsford LD, Flickinger JC, Linder G, et al. Stereotactic radiosurgery of the brain using the first United States 210 cobalt-60 source gamma knife. Neurosurgery 1989; 24:151–159. 16. Winston KR, Lutz W. Linear accelerator as a neurosurgical tool for stereotactic radiosurgery. Neurosurgery 1988; 22:454–464. 17. Loeffler J, Shrieve D, Wen P, et al. Radiosurgery for intracranial malignancies. Semin Radiat Oncol 1995; 5:225–234. 18. Friedman W, Bova F. The University of Florida radiosurgery system. Surg Neurol 1989; 32:334–342. 19. Luxton G, Petrovich Z, Joszef G, et al. Stereotactic radiosurgery: principles and comparison of treatment methods. Neurosurgery 1993; 32:241–259. 20. Gill SS, Thomas DG, Warrington AP, et al. Relocatable frame for stereotactic external beam radiotherapy. Int J Radiat Oncol Biol Phys 1991; 20:599–603. 21. Andrews DW, Silverman CL, Glass J, et al. Preservation of cranial nerve function after treatment of acoustic neurinomas with fractionated stereotactic radiotherapy. Preliminary observations in 26 patients. Stereotact Funct Neurosurg 1995; 64:165–182. 22. Combs SE, Volk S, Schulz-Ertner D, et al. Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): long-term results in 106 patients treated in a single institution. Int J Radiat Oncol Biol Phys 2005; 63:75–81.

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23. Noren G. Gamma knife radiosurgery of acoustic neurinomas. A historic perspective. Neurochirurgie 2004; 50:253–256. 24. Chang SD, Murphy M, Geis P, et al. Clinical experience with image-guided robotic radiosurgery (the CyberKnife) in the treatment of brain and spinal cord tumors. Neurol Med Chir (Tokyo) 1998; 38:780–783. 25. Ishihara H, Saito K, Nishizaki T, et al. CyberKnife radiosurgery for vestibular schwannoma. Minim Invasive Neurosurg 2004; 47: 290–293. 26. Mehta VK, Lee QT, Chang SD, et al. Image guided stereotactic radiosurgery for lesions in proximity to the anterior visual pathways: a preliminary report. Technol Cancer Res Treat 2002; 1:173– 180. 27. Adler JR Jr, Colombo F, Heilbrun MP, et al. Toward an expanded view of radiosurgery. Neurosurgery 2004; 55:1374–1376. 28. Pollock BE, Lunsford LD. A call to define stereotactic radiosurgery. Neurosurgery 2004; 55:1371–1373. 29. Firlik KS, Kondziolka D, Lunsford LD, et al. Radiosurgery for recurrent cranial base cancer arising from the head and neck. Head Neck 1996; 18:160–165; discussion 166. 30. Kondziolka D, Lunsford LD. Stereotactic radiosurgery for squamous cell carcinoma of the nasopharynx. Laryngoscope 1991; 101:519–522. 31. Kaplan ID, Adler JR, Hicks WL Jr, et al. Radiosurgery for palliation of base of skull recurrences from head and neck cancers. Cancer 1992; 70:1980–1984. 32. Samblas JM, Bustos JC, Gutierrez-Diaz JA, et al. Stereotactic radiosurgery of the foramen magnum region and upper neck lesions: technique modification. Neurol Res 1994; 16:81–82. 33. Hamilton A, Lulu B, Fosmire H, et al. Preliminary clinical experience with linear accelerator-based spinal stereotactic radiosurgery. Neurosurgery 1995; 36:311–319. 34. Gerszten PC, Welch WC. CyberKnife radiosurgery for metastatic spine tumors. Neurosurg Clin N Am 2004; 15:491–501. 35. De Salles AA, Pedroso AG, Medin P, et al. Spinal lesions treated with Novalis shaped beam intensity-modulated radiosurgery and stereotactic radiotherapy. J Neurosurg 2004; 101(Suppl 3):435–440. 36. Whyte RI, Crownover R, Murphy MJ, et al. Stereotactic radiosurgery for lung tumors: preliminary report of a phase I trial. Ann Thorac Surg 2003; 75:1097–1101. 37. King CR, Lehmann J, Adler JR, et al. CyberKnife radiotherapy for localized prostate cancer: rationale and technical feasibility. Technol Cancer Res Treat 2003; 2:25–30.

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Neuroimaging in Radiosurgery Treatment Planning and Follow-up Evaluation Clark C. Chen, Paul H. Chapman, Hanne Kooy, and Jay S. Loeffler

Introduction Radiosurgery refers to the precise delivery of a large, single dose of radiation to a focal target. The focal dose distribution allows for a positive therapeutic gain. Because of the opacity of the cranial vault, target volume definition relies entirely on the anatomic accuracy of the available imaging modalities. The need for accurate anatomic visualization is magnified by the use of higher radiation dose delivered in radiosurgery as compared with radiotherapy. To achieve maximal spatial accuracy in radiosurgical planning, an understanding of the basic principles underlying neuroimaging as well as the limitations associated with each imaging modality is mandatory. Additionally, the optimal management of patients after radiosurgery requires knowledge of the expected neuroimaging changes as they relate to clinical outcome. These issues will be reviewed in this chapter.

Imaging Modalities Since its inception with the discovery of X-rays in 1895, radiology has played a pivotal role in the diagnosis and treatment of various neurosurgical lesions. The advent of computed tomography (CT) imaging in the 1970s marked a major step forward in the application of imaging in radiotherapeutic planning by allowing improved anatomic resolution as well as calculation of electron density maps. Improved soft tissue resolution was achieved with the introduction of magnetic resonance imaging (MRI), a technique based on differential nuclear interaction rather than differential density. Advances made in computational technology in the past decade have enabled the superposition of CT and magnetic resonance (MR) images in order to maximize anatomic delineation. More recently, significant strides in functional imaging have further refined target defini-

tion in radiosurgical planning (Fig. 2-1). The following section will review the basic principles underlying the various neuroimaging modalities as well as limitations associated with each modality.

Computed Tomography Imaging Computed tomography provides cross-sectional images of the body using mathematical reconstructions based on X-ray images taken circumferentially around the subject. In practice, X-ray transmissions through the subject from a rotating emitter are detected and digitally converted into a grayscale image. Because CT images are ultimately a compilation of X-ray transmissions, the physical principles underlying the two modalities are identical; that is, structural discrimination is made based on the relative atomic composition, and therefore the electron density, of the tissue imaged. CT images, however, offer improved anatomic resolution because each image represents the synthesis of information from multiple X-ray images (Fig. 2-1a). Besides improved anatomic delineation, CT imaging aids radiosurgical planning in another way. Because the pixel intensity on a CT image reflects the electron density of the tissues imaged, the pixel intensity can be mathematically converted into electron density maps (electrons per cm3). This information can be used to define isodose lines in radiosurgical planning. Without this information, actual radiation dose delivered can deviate from the desired dose by as much as 20% as a result of tissue inhomogeneity [1]. Despite yielding improved anatomic resolution as well as electron density information, delineation of soft tissue structures by CT imaging is suboptimal, even with the aid of intravenous contrast agents. For the most part, delineation of soft tissue structures is achieved by the use of MRI, especially for targets in the cranial base.

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FIGURE 2-1. CT, MR, and MRS images from a patient with a left cerebellar tumor. (a) CT imaging without intravenous contrast shows a poorly defined left cerebellar mass with effacement of the fourth ventricle and displacement of the brain stem. (b) Intravenous contrast administration improves the anatomic resolution of the left cerebellar mass, revealing a densely enhancing mass with surrounding edema. (c) The same lesion is visualized using T1-weighted MRI. (d) MRI after gadolinium administration reveals a heterogeneously enhancing mass. The homogeneously enhancing tissue on CT is further resolved into tissues of varying intensity on MRI, demonstrating the superiority of MRI over CT in soft tissue resolution. The numbered grid corresponds with the MR spectral arrays shown in (e). The grid is placed over

normal-appearing tissue. (e) The various chemical peaks are as indicated in box 9. The thick arrow indicates the choline peak. The arrowhead represents the creatine peak. The thin arrow designates the N-acetylaspartate (NAA) peak. The MRS in box 9 is typical of normal tissue, with comparable choline and creatine peaks and a notable NAA peak. (f) The numbered MRS grid is placed over the diseased tissue. The MRS is shown in (g). (g) The various chemical peaks are labeled in box 1. The diseased tissue shows an elevated choline peak (thick arrow) relative to a diminished creatine peak (arrowhead). The NAA peak is also decreased (thin arrow) relative to normal tissue. The accumulation of lactate (double arrow) is another signature of diseased tissue.

Magnetic Resonance Imaging

source of error involves the imperfection of the input magnetic field. The input magnetic field in MRI is produced by electric currents passing through sets of mutually orthogonal coils. Ideally, the magnetic field generated should be uniform such that a linear relationship between space and resonance frequency can be established [3]. However, such uniform fields cannot be easily achieved in practice. This phenomenon is referred to as gradient field nonlinearity and tends to escalate with increasing distance from the central axis of the main magnet. For the most part, gradient field nonlinearity can be corrected computationally. Prior to correction, gradient field nonlinearity can induce spatial distortions as large as 4 mm. After computational correction, the distortion is minimized to 99%). In the early experience at the University of Pittsburgh, normal facial function was preserved in 79% of patients after 5 years and normal trigeminal nerve function was preserved in 73% [28]. These facial and trigeminal nerve preservation rates reflected the higher tumor margin dose of 18 to 20 Gy used during the CT-based planning era before 1991. In a recent study using MR-based dose planning, 13-Gy tumor margin dose was associated with no risk of new facial weakness and 3.1% risk of facial numbness (5-year actuarial rates). A margin dose of >14 Gy was associated with 2.5% risk of new facial weakness and 3.9% risk of facial numbness (5-year actuarial rates) [29]. None of the patients who had radiosurgery for intracanalicular tumor developed new facial or trigeminal neuropathy. NEUROFIBROMATOSIS TYPE 2 Patients with acoustic neuroma associated with neurofibromatosis type 2 (NF 2) represent a special challenge because of the risk of complete deafness. Unlike the solitary sporadic tumors that tend to displace the cochlear nerve, tumors associated with NF 2 tend to form nodular clusters that engulf or even infiltrate

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the cochlear nerve. Complete resection may not be always possible. Radiosurgery has been performed for patients with NF 2. Subach et al. studied 40 patients (with 45 tumors) who were treated with radiosurgery for NF 2 [35]. Serviceable hearing was preserved in 6 of 14 (43%) patients, and this rate improved to 67% after modifications made in technique in 1992. The overall tumor control rate was 98% [36]. Only one patient showed imaging-documented growth. Normal facial nerve function and trigeminal nerve function was preserved in 81% and 94% of patients, respectively. It now appears that preservation of serviceable hearing in patients with NF 2 is an attainable goal with modern radiosurgery technique.

Meningioma Radiosurgery The optimal treatment for meningioma is complete resection of tumor with its dural base; however, when meningiomas are attached to skull base cranial nerves or vascular structures, complete resection may not be possible. Multimodality management should then be considered. Recurrence rates are higher for meningiomas in critical locations where only subtotal resections are possible due to limited access and involvement of the critical structures. Radiosurgery offers an attractive option for patients with residual or recurrent meningioma as well as for patients in whom complete resection of tumor is considered attainable but only with unacceptable morbidity. Table 9-6 shows recent results of meningioma radiosurgery from various institutions [37–58]. Tumor control rates ranged from 98% (at 2 years) to 75% (at 8 years). Excellent clinical outcomes after skull base meningioma radiosurgery have been reported (Fig. 9-5). Meningiomas attached to major venous sinuses can be successfully treated by radiosurgery. Tumor regression may occur slowly over several years after radiosurgery. Radiosurgery provides long-term tumor control associated with high rate of neurologic preservation and patient satisfaction. Surgical excision is the preferred first-line approach for convexity, anterior fossa, or lateral sphenoid ridge meningiomas, which can be easily approached. For meningiomas at all other intracranial locations, radiosurgery can be offered as the first management approach unless the tumor needs debulking because of mass effect. Larger tumors involving critical locations such as optic chiasm may require combined approaches. Malignant meningiomas especially require multimodality management that includes resection, radiosurgery, and radiation therapy.

Pituitary Adenoma Radiosurgery Multimodality management is needed for patients with pituitary tumors. The primary aim of treatment for clinically nonfunctioning pituitary macroadenomas is tumor removal and preservation of visual function. Transsphenoidal surgery is the preferred approach for managing most pituitary adenomas. Radiosurgery is often indicated as an adjuvant management after partial resection or later recurrence of nonfunctioning pituitary adenomas; however, radiosurgery can be performed as the primary management of nonfunctioning adenomas in carefully selected patients such as those who have major surgical risks or for patients who decline microsurgery. Cavernous sinus invasion can occur de novo in patients with large pituitary macroadenomas but is more commonly seen as a residual tumor

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TABLE 9-6. Results of Gamma Knife radiosurgery for meningiomas. No. of patients

Author

Year

Liscak [50]

1999

53

Aichholzer [37] Roche [58] Muthukumar [52] Huffmann [43] Kim [44] Feigl [41] Kondziolka [48] Pan [55] DiBiase [39] Flickinger [42] Iwai [44]

2000 2003 1998 2005 2005 2005 1999 1998 2004 2003 2003

46 32 41 15 23 127 99 80 121 219 42

Chang [38] Nicolato [53] Eustacchio [40] Lee [49]

2003 2002 2002 2002

187 156 121 159

Kobayashi [46] Morita [51]

2001 1999

87 88

Tumor location

Cavernous sinus Skull base Petroclival Tentorial Atypical Superficial Mixed Mixed Mixed Mixed Mixed Cavernous sinus Mixed Mixed Skull base Cavernous sinus Mixed Skull base

Mean follow-up (months)

19 48 56 36 35 32 29.3 42 21 54 29 49.4 37.3 48.9 60–118 35 24.2 35

after attempted microsurgical resection. The cranial nerve complication risks and cerebrovascular risks of cavernous sinus microsurgery warrant consideration of radiosurgery. In many cases, the cavernous sinus mass can be treated while selectively sparing not only the optic apparatus but also the pituitary stalk and residual pituitary gland within the sella. Tumor growth control rates of 90% to 100% have now been confirmed by multiple centers after pituitary adenoma radiosurgery [59]. The antiproliferative effect of radiosurgery has been reported in nearly all patients who underwent Gamma Knife radiosurgery. Relatively few patients (who usually had received lower margin doses) eventually required additional treatment. For secretory adenomas, medical management is extremely useful as either first-line therapy or as an adjunct in a combined multimodality approach to overall patient management. Tumor

FIGURE 9-5. (Left) Axial contrast-enhanced T1-weighted MR image showing a skull base meningioma at the time of radiosurgery. (Right) Three-year follow-up axial contrast-enhanced T1-weighted MR image showing complete tumor disappearance.

Temporary

Persistent

100.0

3.8

0.0

15.9 13 15.3 16 16 13.8 16 12–20 14 14 11

96.0 100.0 97.5 86.6 95.6 96.4 95.0 91.0 91.7 93.2 90.5

2.0 6.2 — 6.6 43.0 2.5 14 5.0 — — 4.7

9.0 6.2 2.5 0.0 0.0 1.2 5 2.5 8.3 5.3 0.0

10.1 8.3 6.8 6.5

15.1 14.6 13 13

97.1 96.0 99.2 93.1

10.7 4.0 3.3 1.8

0.0 1.0 1.7 5.0

Diameter 25.8 10

14.5 16

93.1 95.0

10.3 2.2

3.4 12.5

Mean volume (cm )

7.8 Diameter 23.5 mm — Diameter 20 mm — 4.7 5.9 4.7 — 4.5 5 14.7

Mean margin dose (Gy)

Complications (%)

Tumor control (%)

3

12

resection is the preferred management strategy when medical management fails to normalize pituitary function. Radiosurgery is often indicated as an adjunct to control residual or recurrent secretory adenoma. The initial first stage extracavernous microsurgery is often optimal in order to reduce the subsequent tumor volume, create space between the tumor and the optic apparatus, and thus allow safe delivery of the highest dose of radiosurgery possible. The goal of radiosurgery for functional adenomas is pituitary hormone normalization. Biochemical remission for growth hormone (GH)-secreting adenomas is defined as GH level suppressed to below 1 μg/L on oral glucose tolerance test (OGTT) and normal age-related serum insulin-like growth factor-1 (IGF-1) levels. OGTT remains the gold standard for defining a cure of acromegaly. The IGF-1, however, is far more practical. Decrease of random GH to less than 2.5 μg/L is achieved more frequently than the normalization of IGF-1 but it is necessary to obtain the fulfillment of both criteria. Hormonal normalization after radiosurgery was achieved in 23% to 82% of cases in the published series [60–64]. The suppression of hormonal hyperactivity is more effective when higher doses of radiation are used. In a study at the University of Pittsburgh, 38% of recurrent tumor patients were cured (GH ≤1 μg/L), and overall, 66% had growth hormone levels ≤5 μg/L 3 to 5 years after radiosurgery [65]. The impact of radiosurgery has a latency of about 20 to 28 months [66, 67]. During this interval, hormone-suppressive medications may be beneficial. Because hormone-suppressive medication during radiosurgery may act as a radioprotective agent, this medication should be discontinued at least 6 to 8 weeks prior to the radiosurgery and may be resumed after a week. Patients with Cushing disease (adrenocorticotropic hormone [ACTH]-secreting adenomas) respond to radiosurgery, but

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more than one procedure may be needed. Often, tumor cannot be well defined during the initial imaging. In addition, there is a latency of about 14 to 18 months for maximal therapeutic response [66, 67]. In various published series, 38% to 83% hormone normalization after radiosurgery has been observed [68–71]. Most prolactinomas can be controlled successfully by dopaminergic suppressive therapy. Surgery is indicated for cases of intolerance to medical treatment, in cases where women desire to have children, or when patients are dopamine agonist resistant (5% to 10% of patients). Some patients prefer microsurgery or radiosurgery to the need for highly expensive lifelong medical treatment. In published studies of patients treated with radiosurgery, 25% to 29% showed normalization [60, 61]. The possible radioprotective effect of dopaminergic drugs should be taken into account. Because patients treated on dopamine agonist during radiosurgery had lower remission rate, it is therefore recommended that prolactinoma radiosurgery be performed during a period of drug withdrawal. New pituitary hormone deficiency has been reported in 0 to 30% of patients after radiosurgery for functional pituitary adenomas [60, 61]. The most important factor influencing hypopituitarism after radiosurgery seems to be the mean dose to the hypophysis (pituitary stalk). Vladyka et al. observed some worsening of gonadotropic, corticotropic, or thyrotropic functions 12 to 87 months after radiosurgery, usually within 4 to 5 years after radiosurgery [72]. Deterioration in pituitary functions was observed when pituitary stalk received higher doses (>15 Gy). The risk for hypopituitarism after stereotactic radiosurgery thus becomes a primary function of the anatomy of the tumor and the dose prescribed. For recurrent tumors primarily where the pituitary stalk (and even at times the residual pituitary gland) is separate from the tumor, is easily visualized, and can be excluded from higher dose, the risk of hypopituitarism is extremely small. For adenomas that cannot be visually separated from the normal gland, particularly if they extend upward to involve or compress the pituitary stalk, the risk is predominately related to the dose necessary to effectively achieve all outcome goals for the functional status of the tumor (higher for secretory than nonsecretory adenomas). Gamma Knife radiosurgery is superior to radiation therapy because there is a faster response and fewer adverse radiation effects. Response to radiosurgery is best with ACTH-producing tumors, followed by GH-producing tumors, prolactinomas having the poorest response usually because they have failed prior medical management due to their invasive nature. Hypopituitarism can be expected to occur in up to 30% within 4 to 5 years but can be avoided by minimizing radiation to pituitary stalk and hypothalamus. Somatostatin analogues and dopamine agonists may have a radioprotective effect [60, 73]. Although the radioprotective effect of these drugs was not confirmed in subsequent studies [62–64], it is advisable to stop these drugs prior to radiosurgery. Short-acting form of somatostatin analogues can be given until 2 weeks prior to GK. Long-acting somatostatin analogues should be discontinued 4 months prior to GK. Dopamine agonists should be discontinued 2 months prior to radiosurgery. After radiosurgery, once hormone levels are normal on medical therapy, somatostatin analogues should be stopped for 4 months each year to assess for biochemical cure. Similarly, dopamine agonists should be stopped for 2

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months. A panel of tests to detect hypopituitarism should be done at 6-month intervals for the first 5 years and then yearly.

Radiosurgery of Glial Tumors MALIGNANT GLIOMAS Malignant gliomas continue to represent one of the most serious challenges in neurosurgery. Radiation therapy has become the mainstay of the treatment. The observation that local control and median survival can be improved through the dose escalation is the basis for the application of radiosurgery to malignant gliomas. Radiosurgery is used for boost irradiation of patients with malignant glial tumors in addition to conventional widemargin fractionated radiotherapy. It has been used mainly for patients with tumors >3.5 cm in diameter as part of a multimodality approach to malignant gliomas. Early radiosurgery reports widely varied in the outcomes for malignant gliomas with a median survival for GBM patients ranging from 9.5 months to 26 months. These variations could result from patient selection biases and other prognostic factors [74]. We performed a retrospective study to evaluate the result of radiosurgery on 64 GBM and 43 anaplastic astrocytoma patients. The median survival for the GBM patients was 16 months after radiosurgery and 26 months after diagnosis. A 2-year survival rate was 51%. For patients with anaplastic astrocytomas, median survival after radiosurgery was 21 months and after diagnosis was 32 months. A 2-year survival rate after diagnosis was 67%. Other centers have recently reported survival rates that seem significantly improved compared with 9-month median survival and 10% 2-year actuarial rate reported for standard therapy. Nwokedi et al. compared survival between 33 patients treated with external beam radiation therapy (EBRT) alone (group 1) and 31 patients managed with EBRT plus a Gamma Knife radiosurgery (GK-SRS) boost (group 2) [75]. GK-SRS was administered to most patients within 6 weeks of the completion of EBRT. The median EBRT dose was 59.7 Gy (range, 28 to 70.2 Gy), and the median GK-SRS dose to the prescription volume was 17.1 Gy (range, 10 to 28 Gy). Both groups were comparable in age, Karnofsky performance status, extent of resection, and tumor volume. The median survival was significantly better in patients treated with EBRT plus GK-SRS (13 months in EBRT alone vs. 25 months in EBRT plus GK-SRS). Age, Karnofsky performance status, and the addition of GKSRS were all found to be significant predictors of overall survival. No acute grade 3 or grade 4 toxicity was encountered. There is a significant survival advantage using radiosurgery boost in patients with malignant glioma, especially if appropriately used with surgery and other adjuvant therapies; however, a carefully designed prospective randomized trial is needed to reliably establish survival benefit from radiosurgical boost for malignant gliomas. LOWER-GRADE GLIOMAS Low-grade gliomas have been treated with radiosurgery. Simonova et al. treated 68 patients with low-grade gliomas using Gamma Knife surgery [76]. The median patient age was 17 years and median target volume was 4200 mm3. The median marginal prescription dose was 25 Gy. Ninety-five percent of patients were treated in five daily stages. These authors reported 83% rate of partial or complete tumor regression with a median

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time to response of 18 months. In this series, the progressionfree survival was 92% at 3 years and 88% at 5 years. Moderate acute or late toxicity was noted in 5% of patients. Kida et al. treated 51 patients harboring low-grade gliomas (12 grade I astrocytomas, 39 grade II astrocytomas) using Gamma Knife [77]. The mean margin dose was 12.5 Gy for grade I and 15.7 Gy for grade II tumors. In the mean follow-up of 27.6 months, grade I astrocytomas had a response rate of 50% and a control rate of 91.7%. Grade II astrocytomas had a 46.2% response rate and an 87.2% control rate. Despite the favorable histologic characteristics and prognosis of pilocytic astrocytomas, some patients may not be cured after microsurgery because of an adverse location, recurrence, or tumor progression. Radiosurgery is an effective alternative therapeutic approach for these patients. Hadjipanayis et al. reported outcome in 38 patients harboring unresectable pilocytic astrocytomas who were treated with radiosurgery [78]. The median radiosurgical dose to the tumor margin was 15 Gy (range, 9.6 to 22.5 Gy). After radiosurgery, serial imaging demonstrated complete tumor resolution in 10 patients, reduced tumor volume in 8, stable tumor volume in 7, and delayed tumor progression in 12 patients. Three patients died of local tumor progression. Stereotactic radiosurgery is a valuable adjunctive strategy in the management of recurrent or unresectable pilocytic astrocytomas especially small-volume, sharp-bordered tumors. Radiosurgery can play an important role in the treatment of low-grade astrocytomas, and complete cure of these tumors has been achieved in at least some of the cases [78–80]. Acute complications after radiosurgery are unusual and limited to exacerbation of existing symptoms. The most frequently seen delayed complication of radiosurgical boost is tumor swelling radiation reaction in the tumor or surrounding brain swelling. Symptoms are usually controllable by steroid therapy. The reported incidence of radiation necrosis ranges from 2% to 22%. Reoperation rates ranging from 21% to 33% have been reported after radiosurgery. Neither radiation necrosis nor reoperation is associated with diminished length of survival.

Brain Metastases Radiosurgery The best initial management for brain metastases patients remains to be defined. Current options include fractionated radiation therapy alone, surgery alone, radiosurgery alone, surgery plus radiation therapy, or radiosurgery plus radiation therapy. There are several features that make brain metastases the most common indication for radiosurgery. Most brain metastases are roughly spherical and therefore can be easily targeted by radiosurgery. Brain metastases are compact targets. Although peritumoral microscopic spread is likely, conformal radiosurgery provides additional therapeutic benefit because of the fall-off zone of radiation outside the imaging-defined margin. Advances in neuroimaging have led to early diagnosis of metastases while these are still small and without significant mass effect and symptoms. Whereas single brain metastasis without mass effect is the ideal indication of radiosurgery, multiple metastases are treated when the total target volume allows for safe and effective dose delivery. Radiosurgery is not recommended for patients with large metastatic tumors causing significant mass effect. Such patients should undergo surgical excision.

FIGURE 9-6. (Left) Axial contrast-enhanced T1-weighted MR image showing left frontal brain metastases with significant surrounding edema. (Right) Six-month follow-up axial contrast-enhanced T1weighted MR image showing significant tumor shrinkage and no edema in surrounding brain parenchyma.

A large number of scientific publications define the effectiveness of radiosurgery for brain metastases (Fig. 9-6). Table 9-7 lists several large representative series of patients [81–92]. These reports include patients with various primary histologies. The local tumor control ranges from 25% to 97%, and median survival ranges from 6 to 27 months. The Gamma Knife Users Group studied the outcomes of radiosurgery in 116 patients with solitary brain metastases. Radiosurgery was part of the initial management of 71 patients, and 45 patients had recurrent tumors after prior whole-brain fractionated radiation therapy. In this study, actuarial local control rate of 67% at 2 years was reported. Shiau et al. recently reported their radiosurgery experience in 219 brain metastases in 100 patients [93]. The actuarial tumor control, defined as freedom from progression, was 82% and 77% at 6 and 12 months, respectively. These data substantially validate the clinical observation of improved local control after radiosurgery (Fig. 9-7). Although local tumor control rates have improved, mortality is usually related to the uncontrolled primary tumor or metastatic spread to other organs. In general, survival and morbidity results of radiosurgery are superior to those reported for surgical resection followed by whole-brain radiation therapy. The results show that radiosurgery is associated with high local control and low morbidity in comparison with surgical resection. When interpreting radiosurgery results, one should also take into account the facts that patients in surgical series are selected for their suitable locations and good general condition, whereas no such selection is performed for radiosurgery. On the contrary, those who are not suitable candidates for surgery either due to the eloquent brain locations or poor medical condition are included in the radiosurgery series. Rutigliano et al. performed a cost-benefit comparison of Gamma Knife radiosurgery and surgical resection for solitary brain metastases and concluded that radiosurgery had a lower uncomplicated procedure cost, a lower average complication per procedure, was more effective, and had a better incremental cost effectiveness per life-year [93].

Radiosurgery for Pineal Gland Tumors Management of pineal region tumors remains a significant challenge because of the anatomic complexity of the area and the

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TABLE 9-7. Results of Gamma Knife radiosurgery for metastatic brain tumors. Author

Year

No. of patients

Serizawa [90] Lippitz [86]

2005 2004

521 215

Nam [87] Pan [88] Gerosa [82] Gerosa [83] Petrovich [89] Sheehan [91]

2005 2005 2002 2005 2002 2002

130 191 804 504 458 273

Amendola [81]

2000

68

Hasegawa [84] Hoffman [85]

2003 2001

121 113

Simonova [92]

2000

237

Median survival (months)

9 Multiple 7.8 Single 13.7 9 14 13.5 14.5 9 7 7.8 8 12

6–12

Systemic control

Margin dose (Gy)

TPFSR 1-year

70% lung —

13% —

Median 20 Median 22

95.70% 93.9%

23% 20%

73% 74% — — 25% 78%

45% lung All lung 88% lung All NSLC 50% melanoma All NSLC

62% — 29% 31% 43% —

Mean 17.9 Mean 18 Mean 20.6 Mean 21.4 Median 18 Median 16

63.90% 91% 94% 95% 87% 86%

65% 46% 55% 60% 58%

53%

All breast

97%

15–24

0% 17%

35% lung All lung

36% 61%

Mean 18.5 Median 18

0%

43% lung

100%

84% local control 79% 81% GK alone 86% with XRT 95.3%

WBRT

Primary cancer

No No

Median 21.5

Single tumor

>50% 22% 80% 45%

100%

WBRT, whole-brain radiation therapy; TPFSR 1-year, one-year tumor progression free survival; NSLC, non–small cell lung cancer.

presence of critical brain and vascular structures. Microsurgical techniques are often successful in obtaining a tissue diagnosis; however, the likelihood of curative resection remains low. There are only few published reports on radiosurgery for pineal tumors [95, 96]. At the authors’ institution, 14 patients with parenchymal pineal tumors were treated between 1989 and 1997. Local tumor control was achieved in 13 patients while one died of tumor progressions despite chemotherapy and craniospinal irradiation prior to radiosurgery. Neuroimaging followup showed complete disappearance of tumor in 3 patients, decrease in tumor size in 7, no change in tumor size in 3, and tumor growth in 1 patient.

Radiosurgery for Skull Base Tumors Radiosurgery is a primary and adjuvant management for tumors of skull base [97–103] (Table 9-8). From September 1987 through December 2004, 238 miscellaneous skull base tumors were treated with Gamma Knife radiosurgery at the University

FIGURE 9-7. (Left) Axial contrast-enhanced T1-weighted MR image of an 80-year-old man showing a large hemangioblastoma after attempted tumor resection. Gamma Knife radiosurgery was performed using 15 Gy prescribed to the tumor margin (tumor volume, 16.6 cm3). (Right) Follow-up axial MR image shows significant regression of the tumor 4 years after Gamma Knife radiosurgery.

of Pittsburgh Medical Center. These tumors and their subsequent management are described below in more detail.

Non–Acoustic Schwannomas Thirty-five patients underwent radiosurgery for trigeminal nerve sheath tumors defined by clinical examination, high-resolution intraoperative imaging, and in selected cases prior surgery. Our results of trigeminal schwannoma have been recently published [99]. The records of 23 patients were reviewed with a median follow-up of 40 months. Twenty of 23 (91%) patients had tumor growth control, with regression noted in 15 and no further tumor growth in 5. Patients who had subsequent tumor enlargement underwent a second radiosurgical procedure. Twelve of 23 (52%) trigeminal nerve sheath tumor patients reported systemic improvement. Nine (39%) patients had no change in their symptoms. Only two patients noted new neurologic complaints such as facial weakness (one patient) and worsening of the pre-radiosurgical facial numbness (one additional patient). Of interest, trigeminal nerve sheath tumors have a much higher likelihood of developing transient but occasionally impressive short-term swelling of the tumor in the first year after radiosurgery. This is quite distinct from those patients who have undergone acoustic tumor radiosurgery. In the majority of trigeminal neuroma patients, transient swelling is followed by delayed shrinkage, often of profound degree. Therefore, it is critical that patients and referring doctors do not despair during this transient tumor enlargement phase identified by imaging and sometimes associated with temporary concomitant neurologic symptoms. Most such symptoms will resolve as the tumors regress during the next 3 to 6 months. Radiosurgery using the Gamma Knife proved to be an effective management strategy for those patients who had undergone both primary as well as adjuvant (post-microsurgery) radiosurgery [100]. Three patients underwent Gamma Knife radiosurgery for facial schwannomas, all identified at the time of prior

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TABLE 9-8. Results of Gamma Knife radiosurgery for skull base tumors. First author

Year

Diagnosis

Saringer [102] Zhang [103] Nettel [99] Pollock [101] Pan [100] Muthukumar [98] Miller [97]

2001 2002 2004 2002 2005 1998 1997

Glomus tumor Jugular foramen schwannomas Trigeminal schwannomas Non–vestibular schwannomas Trigeminal schwannomas Chordomas, chondromas Carcinomas, sarcomas

No. of patients

Mean follow-up (months)

Tumor control (%)

Complications (%)

13 27 23 23 46 15 32

60 38.7 40 43 68 40 27

100 92.5 91 96 93 73 91

0 0 8 17 8 0 3

microsurgery and associated with recurrence or subtotal prior resection. Tumors of the ninth and tenth cranial nerves pose special challenges. Twenty-six patients with jugular bulb schwannomas underwent radiosurgery between August 1987 and September 2004. Most such patients present with symptoms related to imbalance, incoordination, dysphasia, or hearing loss. A total of 12 patients had previously undergone gross total resection with tumor recurrence, and 4 patients had undergone prior partial resection. Results to date show a high likelihood of long-term tumor growth control for such tumors. In an earlier report including 17 patients, we reported a tumor control rate of 94% (8 decreased and 8 were stable in size) after jugular foramen schwannoma radiosurgery [104]. Zhang et al. reported 96% (26/27) tumor growth control with a follow-up period of 38.7 months [103]. In the series of non–vestibular schwannomas, Pollock et al. reported 96% (22/23) tumor growth control after Gamma Knife radiosurgery [101].

Craniopharyngioma Multimodality therapy is often necessary for craniopharyngioma patients because of the development of refractory cystic components of their tumors. Radiosurgery is usually part of a multimodality management when prior therapies have failed [105, 106]. Forty-three patients have undergone Gamma Knife radiosurgery as part of a primary or adjuvant management strategy for craniopharyngioma. Long-term follow-up in our patient series was available in 29 patients. The median tumor volume was 0.4 (range, 0.12 to 6.36) cm3. One to nine isocenters of different beam diameters were used. The median dose to the tumor margin was 12.5 Gy (range, 9 to 20 Gy), and the maximum dose was 25 Gy (range, 21.8 to 40 Gy). The dose to the optic apparatus was limited to less than 8 Gy. Clinical and imaging follow-up data were obtained at a median of 24 months (range, 13 to 150) from radiosurgery. Overall, 14 of 29 tumors regressed or vanished, and 10 remained stable after radiosurgery. Further tumor growth was noted in five patients, three of who underwent surgical resection and one who had repeat radiosurgery. Two additional patients needed management for cyst enlargement. One patient with prior visual defect had further vision deterioration 9 months after radiosurgery. No patient developed new-onset diabetes insipidus. We found that stereotactic radiosurgery was a reasonable option in selected patients with small recurrent or residual craniopharyngiomas. Adverse radiation risks related to adjacent cranial nerve structures or the development of new extraocular movement deficits are rare, providing that the optic nerve and

tract dose is kept lower than 8 Gy or less in a single procedure. In general, we prefer the use of multimodality management including microsurgery, radiosurgery, and intracavitary radiation rather than stereotactic or fractionated radiation therapy. The goal has been to maintain endocrinologic function whenever possible, reduce the risks of visual dysfunction, and subsequently control tumor growth. There are other reports that have similar results in the management of craniopharyngiomas using Gamma Knife [107–109].

Glomus Tumors Radiosurgery using the Gamma Knife has been performed in 16 patients in a 17-year interval. This sparse number of patients (of 7200 who had Gamma Knife radiosurgery) is accounted for by the tendency of such tumors to extend well below the skull base. When surgical resection is not feasible, we consider staged radiosurgery technologies such as linac-based radiosurgery for the extracranial component and the Gamma Knife for the intracranial portion. Some patients also have undergone elective embolization for shrinkage of their tumor or subtotal microsurgical resection. Only one patient in our series had a glomus tympanicum tumor. Gamma Knife radiosurgery appears to have a long-term, high tumor control rate of glomus tumors, paralleling the benefit provided by fractionated radiation therapy. However, the Gamma Knife provides a superior biological effective tumor dose, with better dose sparing of the adjacent brain stem and cranial nerve structures. Pollock et al. in a series including 42 patients reported 98% tumor control after glomus jugulare radiosurgery at a mean follow-up of 44 months [110]. Neurologic improvement or stability was observed in the majority of patients in published series. Centers using linac-based radiosurgery continue to support radiosurgery as an effective and safe method of treatment for glomus jugulare tumors that results in low rates of morbidity.

Hemangiomas Radiosurgery for hemangioma was performed in seven patients. Hemangiomas of neurosurgical interest are histologically benign vascular epithelial cell origin tumors that most often occur in the orbit or cavernous sinus or both. These patients tend to present with ocular symptoms or signs such as orbital pain, ophthalmoplegia, proptosis, or impaired visual acuity. They can, in fact, be diagnosed by their characteristic imaging appearance by MRI. Because they may hemorrhage dramatically at the time of attempted removal, it is prudent for

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surgeons considering biopsy or resection of such tumors to get the appropriate imaging in advance. Asymptomatic lesions do not require intervention but are often approached surgically in pursuit of a diagnosis. Symptomatic lesions require treatment. Options include en bloc resection, embolization, or radiation. Radiosurgery is a better option. In our relatively limited experience, some patients have had incomplete resection because of excessive blood loss, and one patient had undergone unsuccessful embolization. We recently reported the outcomes of four patients treated with radiosurgery with tumor doses ranging from 14 to 19 Gy at the margin [111]. All patients had symptomatic improvement, and all had shown a dramatic reduction in the overall volume of the tumor. One patient had persistent diplopia. In our early experience, stereotactic radiosurgery proved to be a very effective management strategy, which avoided potentially serious complications associated with skull base microsurgery or embolization. The other reports including 3 to 5 cases in each also achieved reduction in tumor volume after radiosurgery [112–114].

Radiosurgery appears to be a safe and effective management for small-volume tumors, but over the course of many years, especially from years 5 to 10 after initial surgery and radiosurgery, recurrence rates continue to increase [98, 118]. In such cases, repeat radiosurgery or perhaps fractionated radiation therapy and repeat radiosurgery should be considered. Most such patients require one or more microsurgical approaches for tumor cytoreduction. More recently, we have embarked on the usage of endoscopic transsphenoidal resection followed by radiosurgery. In our 1998 report, with an average of 4 years of experience, 15 patients were evaluated. In 13 cases, it was used as an adjunctive treatment and in two patients as an alternative to microsurgical resection. Eight patients had clinical improvement, three remained stable, and four died. Two of the four patients who died had tumor progression outside of the radiosurgical volumes, but two patients died of unrelated disorders. Tumor reduction was noted in 5 of 11 patients. Five patients had defined additional growth and underwent repeat resection [98].

Hemangioblastoma

Invasive Skull Base Cancers

Thirty-six patients with intracranial hemangioblastomas, usually in conjunction with the syndrome of von Hippel–Lindau disease (VHL), have been treated by radiosurgery at our center. Early experience from several centers indicated that radiosurgery could lead to tumor control or regression [115, 116] (Fig. 9-7). For the most part, we have treated tumors with documented tumor growth, which are usually solid, and almost exclusively located in the posterior fossa, cerebellum, and brain stem. Such tumors are generally treated when they have shown evidence of objective growth and neurologic symptoms develop. Prophylactic radiosurgery for hemangioblastomas in the case of VHL is not performed unless tumor growth or new symptoms are documented. Multifocality is often a characteristic of the 20% of hemangioblastomas that are associated with VHL. Radiosurgery is a potential therapeutic option for these patients where resection of multiple tumors might be precluded because of brain location. For those patients with cystic hemangioblastomas, we have less optimism related to the overall role of radiosurgery at least as a single option. Cyst-associated tumors with nonenhancing cyst cavities were controlled by including only the enhancing nodule in the target volume; however, surgical removal of a large cystic component of a tumor producing mass effect symptoms is usually appropriate followed by radiosurgery for any residual solid component. In selected cases, stereotactic aspiration of the cyst followed by subsequent radiosurgery is feasible. Repeat radiosurgery may be required over many years when other tumors show additional growth [117].

After combined otolaryngological and neurosurgical procedures, we have used adjuvant radiosurgery for invasive skull base cancers (28 patients over the past 17 years). Fourteen patients had adenocarcinomas, 13 squamous cell carcinomas, and 1 patient had a metastatic neuroendocrine tumor. In such cases, radiosurgery has been used as an adjuvant or in combination with external beam fractionated radiation therapy. Many reports have documented the role of radiosurgery as salvage procedure for malignant tumors involving the skull base [119–121].

Chordoma and Chondrosarcoma During our 17-year experience, 26 patients with chordoma and 17 patients with chondrosarcomas have undergone management with radiosurgery. We continue to regard these tumors as difficult tumors to manage. Almost invariably, they require multimodality management over the course of many years. These invasive tumors provide a management challenge because of their critical location and their tendency to aggressively recur locally despite multimodality treatment. Radiosurgery has been used both as a primary and adjuvant management strategy.

Radiosurgery for Functional Brain Disorders Trigeminal Neuralgia Radiosurgery Our current experience included 513 patients, managed since 1992. There were 305 (60%) women and 208 men. The mean age was 68 years (range, 16 to 92 years), and the mean duration of symptoms was 8 years. Our last detailed review studied 220 consecutive radiosurgery procedures for typical trigeminal neuralgia, all performed between 1992 and 1998 [122]. All 220 patients had trigeminal neuralgia that was idiopathic, longstanding, and refractory to medication therapy. Most of the patients had a long history of medical treatment with the median symptom duration of 96 months (range, 3 to 564 months). Pain was predominately distributed in the V2 and V3 distributions of the trigeminal nerve (29.5%), followed by V2 alone (22.3%) and V3 alone (13.2%). Prior surgery was performed in 135 (61.4%) patients, including microvascular decompression, glycerol rhizotomy, radiofrequency rhizotomy, balloon microcompression, peripheral neurectomy, or ethanol injections. Thus, the majority of patients represented both medical and surgical failures. In the remaining 85 (38.6%) patients, radiosurgery was the first surgical procedure performed. The median central dose at trigeminal nerve was 80 Gy (Fig. 9-8). The pain relief after radiosurgery was graded into four categories: excellent, good, fair, and poor. Complete pain relief without the use of any

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FIGURE 9-8. (Left) Axial contrast-enhanced T1-weighted MR image showing trigeminal neuralgia radiosurgery dose plan. (Right) Axial contrast-enhanced T1-weighted MR image of the same patient 6 months later shows contrast enhancement at the site of radiosurgery.

medication was defined as an excellent outcome. We recommended all patients with complete pain relief to taper off their medications, and some patients were in the process of tapering at the time of evaluation (or refused to taper off because of the fear of a recurrence). Those patients with complete pain relief but who were still using some medication were considered as good outcomes. Patients with partial pain relief (more than 50% pain relief) were considered to have a fair outcome [11]. No pain relief or less than 50% pain relief were considered as poor. Placement within a category was decided by the patient rather than by the physician. Criteria for improvement included a reduction in both the frequency and severity of pain attacks. Of the 220 patients, 47 (25.1%) required further additional surgical procedures because of poor pain control. These patients were considered as treatment failures (poor outcome), and the results after the additional procedure were excluded from this analysis. Most of the patients responded to radiosurgery within 6 months of the procedure (median, 2 months). The first evaluation was performed for all patients within 6 months after radiosurgery. At the initial follow-up assessment, excellent results were obtained in 105 (47.7%) patients, and excellent plus good results were found in 139 (63.2%) patients. More than 50% pain relief (excellent, good, or fair) was noted in 181 (82.3%) patients. At the last follow-up evaluation, 88 (40%) patients had excellent outcomes, 121 (55.9%) patients had excellent plus good outcomes, and 152 (69.1%) patients were fair or better. Thirty (13.6%) patients had recurrence of pain after the initial achievement of pain relief (25 patients after complete relief, 5 patients after more than 50% relief) between 2 and 58 months after radiosurgery. Recurrences occurred at a mean of 15.4 months from irradiation. The median time to achieving more than 50% pain relief (excellent, good, or fair) was 2 months (2.0 ± 0.05), and median time to achieving complete pain relief (good or excellent) was also 2 months (2.0 ± 5.1). At 6 months after treatment, 81.4 ± 2.6% patients had achieved more than 50% pain relief, and by 12 months, 85.6 ± 2.47% (actuarial statistics). Complete pain relief (good or excellent) was achieved in 64.9 ± 3.2% of the patients at 6 months, 70.3 ± 3.16% by 1 year, and in 75.4 ± 3.49% of patients by 33 months.

Prior authors, including our group, noted a latency interval to pain relief of approximately 1 to 2 months; however, approximately 15% of patients had no improvement in their pain even after 12 months. The duration of pain relief after initial response in all patients was also analyzed. Patients who never responded to radiosurgery were recorded as having a relief duration of zero months. More than 50% pain relief (excellent, good, or fair) was achieved and maintained in 76% of patients at 1 year, 71% of patients at 2 years, 67% of patients at 3 years, 65% of patients at 3.5 years, and 56% of patients at 5 years. Complete pain relief (excellent or good) was achieved and maintained in 63.6 ± 3.3% of patients at 1 year, 59.2 ± 3.5% of patients at 2 years, and 56.6 ± 3.8% of patients at 3 years. A history of no prior surgery was the only factor significantly associated (p = 0.01) with achieving and maintaining complete pain relief. No patient sustained an early complication after any radiosurgery procedure. Seventeen patients (7.7%) developed increased facial paresthesia and/or facial numbness that lasted more than 6 months. Others have noted a dry eye, without significant facial numbness. The median time to developing paresthesia was 8 months (range, 1 to 19 months). After 19 months, no patient developed any new sensory symptoms. No patient developed a mastication deficit after radiosurgery or noted problems in facial motor function. One patient (0.4%) developed deafferentation pain after radiosurgery. The low incidence of complications is the greatest advantage of stereotactic radiosurgery compared with all other surgical options. In this study, less than 10% of patients developed increased facial paresthesia and/or facial sensory loss. The majority of our patients described their numbness or paresthesia as minor and not bothersome. Radiosurgery can be repeated if pain returns after initial relief. We advocate repeat radiosurgery only if complete pain relief had been achieved with subsequent recurrence [123]. We advocate a maximum dose of 50 to 60 Gy at a second procedure, and usually target a volume anterior to the prior target. Doing so has led to a pain response similar to that after primary radiosurgery in properly selected patients.

Movement Disorder Radiosurgery There is a small subset of movement disorder patients who have conditions that may make them unacceptable candidates for invasive stereotactic neurosurgical intervention. Such conditions are chronic use of anticoagulants and severe cardiac or respiratory disease. In addition, very elderly and noncompliant patients are usually considered poor surgical candidates. Finally, some patients voluntarily choose a less-invasive alternative to open stereotactic technique. Stereotactic radiosurgery is an option for this subset of patients with movement disorders. Gamma Knife is the preferred radiosurgical tool for treatment of movement disorders.

Radiosurgical Targets for Functional Disorders VIM nucleus of the thalamus is targeted for tremor patients. In our series, we determined the VIM coordinates based on the position of the nucleus relative to the AC-PC line and the anatomic information gathered from very-high-resolution MRI.

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Current planning software incorporates computerized atlases, which can be registered with the images and can be projected on MR images. The x, y, and z coordinates can be determined for the target using either SurgiPlan (Elekta Corp, Georgia), GammaPlan (Elekta Corp) or Multiview (Elekta Corp). Duma et al. reported results of radiosurgical pallidotomy for Parkinson disease. The target localization of globus pallidus interna (GPi) was determined by coordinates based on anatomic information gathered from very-high-resolution MRI and subjective surgeon correlation with the Schaltenbrand atlas. The 50% isodose line of a single or double isocenter 4-mm collimator plan was placed at the center of GPi. Keep et al. performed radiosurgical subthalamotomy using a primary target of 13 mm lateral to, 2 mm posterior to the midpoint of, and 5 mm inferior to the AC-PC line. This was optimized using atlas reference and experience. We are hesitant to perform radiosurgical pallidotomy because of the nearby optic tract. Friehs et al. reported targeting the center of the heads of the caudate nuclei bilaterally to treat the bradykinesia and rigidity of parkinsonism, and Pan et al. targeted the anterior portion of the VL nucleus for dystonia.

Gamma Knife Thalamotomy We have previously reported our experience with the treatment of essential tremor (ET) and Parkinson disease (PD) tremor using Gamma Knife radiosurgery. Niranjan et al. evaluated 11 patients managed with Gamma Knife thalamotomy for essential and multiple sclerosis (MS)–related tremor [124]. All patients noted improvement in action tremor. Six of eight ET patients had complete tremor arrest, and the violent action tremor in all three patients with MS was improved. One patient developed transient arm weakness. Duma et al. treated 42 patients with tremor from PD or ET with VIM thalamotomy using Gamma Knife. Median time of onset of improvement was 2 months (range, 1 week to 8 months) [125]. No change in tremor occurred in four Gamma Knife thalamotomies (8.6%), “mild” improvement was seen in 4 (8.6%), “good” improvement was seen in 13 (28%), and “excellent” improvement in 13 (28%). In 12 thalamotomies (26%), the tremor was eliminated completely. The high-dose (160 Gy mean maximum dose) thalamotomy lesion was more effective at reducing tremor than the low dose (120 Gy mean maximum dose). One patient, after bilateral treatment, suffered a mild acute dysarthria 1 week after GK thalamotomy. Ohye et al. reported 36 Gamma Knife thalamotomies in 31 patients. Maximum dose was 150 Gy in the first 6 cases, which was subsequently reduced to 130 Gy [126, 127]. In two patients undergoing repeat procedures, the dose was decreased to 120 Gy. In all cases except one, a single 4-mm isocenter was used. In their 15 cases with more than 2 years follow-up, a clinically good result was seen in 87%, with no noticeable side effects. In a more recent report, these authors have compared the results of 51 patients who had thalamotomy after reloading of Gamma Knife with that of previous patients. The authors confirmed two different patterns of post-radiosurgical lesions on follow-up imaging. One was a round punchedout lesion with enhancing borders with good symmetry, 7 to 8 mm in diameter to the enhancing edges. The second type of lesion seen extended to surrounding areas including the capsule with “rail-like” high signal along the border of the thalamus and

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GP. Young et al. in a large series of patients reviewed their use of GK thalamotomy for the treatment of tremor [128]. Their series included 102 patients with parkinsonian tremor, 52 patients with essential tremor, and 4 patients with tremor of other etiology. The single 4-mm collimator was used with doses varying from 110 to 160 Gy. At a median follow-up of 52.5 months (range, 11 to 93 months), 76% were tremor free, and 12% were “nearly free of tremor.” Thus, there was failure in 12%. In 52 patients with disabling ET, median follow-up was 26 months. At 1 year, 92% were completely or nearly tremor free; after 4 years of follow-up this percentage decreased to 88%. One patient experienced a transient complication of contralateral balance disturbance; one patient had mild contralateral paresthesia in the face and upper extremity without detectable sensory deficit and no impairment of function. A third patient had a mild weakness and dysphasia. All complications were believed to be due to lesions that became larger than expected. The overall complication rate was 1.3%.

Gamma Knife Pallidotomy Duma et al. performed Gamma Knife pallidotomy on 18 patients with medically recalcitrant and disabling symptoms of PD. Fifteen patients were treated using a single 4-mm collimator with a median central dose of 160 Gy (range, 90 to 165 Gy) [125]. Three patients were treated using a combination of two 4-mm shots with a dose of 160 Gy. Only 6 patients (33%) showed improvement in rigidity and dyskinesia. Three patients (17%) were unchanged, and nine patients (50%) worsened. Of the six patients with improvement, two exhibited visual field deficits. Overall, four (22%) patients had a visual field deficit, three patients had speech and/or swallowing difficulties, three had worsening of their gait, and one patient had numbness in the contralateral hemibody. Nine patients (50%) had one or more complications related to treatment. Okun et al. reported similar complications of GK pallidotomy in a report describing eight patients seen in an 8-month period referred for complications of GK radiosurgery [129]. Complications included hemiplegia, homonymous field cut, weakness, dysarthria, hypophonia, aphasia, hemihypesthesia, and pseudobulbar laughter. Friedman et al. had similar experience [130]. They described their results in four patients using Gamma Knife pallidotomy in advanced disease. No patient improved in a significant manner within the follow-up interval of 18 months. One patient experienced an improvement in his dyskinesia, but also became transiently psychotic and demented. The other three patients suffered no adverse effects.

Other Functional Targets Friehs et al. reported the efficacy of GKRS caudatotomy for the treatment of the bradykinesia and rigidity of parkinsonism [131]. One month after treatment, 6 of 10 patients showed clear benefit from bilateral 4-mm head of caudate lesions without any treatment-related complications. Keep et al. reported radiosurgical subthalamotomy using the GK in a single case report [132]. The 73-year-old patient received 120 Gy central dose using the 4-mm collimator helmet. At 2 weeks, she was able to reduce her Sinemet dose. At 5 weeks, she had no tremor, rigidity, or dyskinesia and walked easily with improved balance while using only a one-point cane for support. At 3

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months, she had partial return of increased motor tone and cogwheel rigidity. At 1 year, after medication adjustments, she was able to move with ease and had no tremor. Imaging at 42 months showed a well-demarcated signal focus corresponding with the subthalamic nucleus. Pan et al. reported two patients who underwent radiosurgery for torsion spasm to evaluate the efficacy of Gamma Knife radiosurgery as an alternative treatment. The target was located at the anterior portion of the ventrolateral nucleus. The maximum doses were 150 Gy and 145 Gy, respectively. Double isocenters with a 4-mm collimator were used. Follow-up lasted for 18 months and 8 months, respectively. Both patients had excellent clinical improvement 2 to 3 months after Gamma Knife radiosurgery, respectively. The authors concluded that Gamma Knife radiosurgery might be a safe and efficient treatment for torsion spasm. Gamma Knife radiosurgical thalamotomy is a safe and effective alternative to invasive radiofrequency or DBS. This is not the case with radiosurgical pallidotomy. The paucity of radiosurgical pallidotomy reports in the literature reflects a lack of enthusiasm in the procedure. Subtle differences in lesion targeting have the potential to affect outcome. Without physiologic feedback, differentiation of internal and external globus pallidus is impossible during gamma pallidotomy. The lack of clinical improvement may therefore have been attributable to inaccurate physiologic lesioning within the GP without physiologic monitoring. The high complication rate of 50% in pallidotomy series is likely due to the variability and unpredictability of the lesion size when the globus pallidus serves as the target. This unpredictability and variability is not seen in the VIM thalamotomy series. It seems that there is a differential sensitivity to radiation between these two locations. Historically, the pallidum has exhibited a “supersensitivity” to hypoxia, and this may be the reason for higher complication rate. The pallidum is known to contain high levels of iron, which typically rises with age. It has been hypothesized that the presence of iron within this structure may catalyze free-radical reactions causing toxicity to the aging brain.

Conclusion In the past 15 years, we have witnessed dramatic improvements in the stereotactic radiosurgery technologies. Gamma Knife radiosurgery now offers better image-handling features including image fusion; faster, more compact platforms that make the calculations almost real-time; automated patient positioning reducing the potential for human error; and the inverse treatment planning. In the future, more accurate imaging techniques and improved software to handle those images as well as advanced inverse planning software will provide better treatment resulting in better patient outcomes.

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Linear Accelerator Radiosurgery William A. Friedman

Introduction Stereotactic radiosurgery (SRS) is a minimally invasive treatment modality that delivers a large, single dose of radiation to a specific intracranial target while sparing surrounding 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. Because destructive doses are used, however, any normal structure included in the target volume is subject to damage. The basis for SRS was conceived more than 40 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 non–target tissues along the path of any given beam. His team’s implementation of this concept culminated in the development of the Gamma Knife. The modern Gamma Knife employs 201 fixed cobalt radiation sources in a fixed hemispherical array, such that all 201 photon beams are focused on a single point. The patient is stereotactically positioned in the Gamma Knife so that the intracranial target coincides with the isocenter of radiation. Using variable collimation, beam blocking, and multiple isocenters, the radiation target volume is shaped to conform to the intracranial target. An alternate radiosurgical solution using a linear accelerator (linac) was first described in 1984 by Betti et al. [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 oncologists, radiation physicists, and computer programmers began development of the University of Florida linac-based radiosurgery system [8]. This system has been used to treat more than 2000 patients at the University of Florida since May 1988 and is in use at multiple sites worldwide. Many other commercial versions of radiosurgical systems are currently available, includ-

ing the BrainLAB system, the Radionics (X-knife) system, the Accuray (CyberKnife) system, and others. Most linac radiosurgical systems rely on the same basic paradigm: A collimated X-ray beam is focused on a stereotactically identified intracranial target. The gantry of the linac rotates around the patient, producing an arc of radiation focused on the target (Figs. 10-1 and 10-2). The patient couch is then rotated in the horizontal plane and another arc performed. In this manner, multiple non-coplanar arcs of radiation intersect at the target volume and produce a high target dose, with minimal radiation to surrounding brain. This dose concentration method is exactly analogous to the multiple intersecting beams of cobalt radiation in the Gamma Knife. The target dose distribution can be tailored by varying collimator sizes, eliminating undesirable arcs, manipulating arc angles, using multiple isocenters, and differentially weighting the isocenters [9]. In our center, multiple isocenters are used to achieve highly conformal dose distributions, exactly analogous to the Gamma Knife technique (Fig. 10-3). Some linear accelerator systems use an alternative approach that relies upon a computer-driven multileaf collimator to generate nonspherical beam shapes that are conformal to the beam’s-eye view of the tumor. The multileaf collimator can be adjusted statically or dynamically as the linear accelerator 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. Achievable dose distributions are similar for linac-based and Gamma Knife systems. With both systems, it is possible to achieve dose distributions that conform closely to the shape of the intracranial target, thus sparing the maximum amount of normal brain. Recent advances in stereotactic imaging and computer technology for dose planning, as well as refinements in radiation delivery systems, have led to improved efficacy, fewer complications, and a remarkable amount of interest in the various applications of SRS. Perhaps of equal importance is the fact that increasing amounts of scientific evidence have persuaded the majority of the international neurosurgical community that radiosurgery is a viable treatment option for selected patients suffering from a variety of challenging neurosurgical disorders. This chapter will present a brief description of linac radiosurgical technique, followed by a review of the more common applications of stereotactic radiosurgery in the treatment of

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FIGURE 10-1. Linear accelerators are the preferred device, worldwide, for conventional radiotherapy. They accelerate electrons to near light speed, then collide them with a heavy metal (like tungsten) in the head of the machine. The collision mainly produces heat, but a small percentage of the energy is converted into highly energetic photons. These photons, because they are electronically produced, are called Xrays. The X-radiation is collimated and focused on the target.

FIGURE 10-3. This choroidal fissure AVM required four 1-cm isocenters to produce a conformal plan. The inner line (70% isodose) is the prescription dose line. The outer line (35% isodose) is half of the prescription dose.

FIGURE 10-2. This diagram shows an add-on device, designed to improve the accuracy of the linear accelerator, in place. The linac arcs around the patient, with its beam always focused on the stereotactically

positioned target. The patient is then moved to a new horizontal (table) position and another arc performed. The result is multiple, noncoplanar arcs of radiation, all converging on the target point.

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intracranial disease (benign tumors, malignant tumors, and arteriovenous malformations).

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with these difficult tumors continue to be less than optimal [10–12]. A significant amount of experience has been accumulated using SRS in the treatment of schwannomas and meningiomas. We will focus on each of these tumor types in turn.

Linac Radiosurgery Technique Although the details of radiosurgical treatment techniques differ somewhat from system to system, the basic paradigm is quite similar everywhere. Following is a detailed description of a typical 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 physical, 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 a.m. 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 outpatient 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 treatmentplanning computer. The CT images are quickly processed so that each pixel has an anteroposterior, lateral, and vertical stereotactic coordinate, all related to the head ring previously applied to the patient’s head. Using image fusion software, the nonstereotactic MRI is fused, pixel for pixel, with the stereotactic CT. The “pre-plan” performed the day before is, likewise, fused to the stereotactic CT. Final dosimetry then begins and continues until the neurosurgeon, radiation oncologist, and radiation physicist are satisfied that an optimal dose plan has been developed. A variety 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 (see Fig. 10-3) while delivering a minimal dose of radiation to all surrounding neural structures. A detailed discussion of dosimetric options is available in Chapter 7. When dose planning is complete, the radiosurgical device is attached to the linac. The patient then is attached to the device and treated. The head ring is removed and, after a short observation period, the patient is discharged. The radiosurgical device is disconnected from the linac, which is then ready for conventional usage. Close clinical and radiologic follow-up is arranged at appropriate intervals depending on the pathology treated and the condition of the patient.

Radiosurgery for Benign Tumors SRS has proved useful for the treatment of a variety of benign intracranial neoplasms. These tumors commonly arise from the skull base, where their dramatic impact on quality of life belies their benign histology and small size. Despite progressive improvement in microsurgical techniques, outcomes for patients

Vestibular Schwannomas Among benign intracranial tumors, vestibular schwannoma (acoustic neuroma) has to date been the most frequent target for stereotactic radiosurgery. This common tumor (representing approximately 10% of all primary brain tumors) is a benign proliferation of Schwann cells arising from the myelin sheath of the vestibular branches of the eighth cranial nerve. These tumors are slightly more common in women, present at an average age of 50 years, and occur bilaterally in patients with neurofibromatosis type 2. Leksell first used stereotactic radiosurgery to treat a vestibular schwannoma in 1969 [13]. SRS is a logical alternative treatment modality for this tumor for several reasons. A vestibular schwannoma is typically well demarcated from surrounding tissues on neuroimaging studies. The sharp borders of this noninvasive tumor make it a convenient match for the characteristically steep dose gradient produced at the boundary of a radiosurgical target. This allows the radiosurgeon to minimize radiation of normal tissue. Excellent spatial resolution on gadolinium-enhanced MRI facilitates radiosurgical dose planning. These tumors typically occur in an older population that may be less fit for microsurgical resection under general anesthesia. Finally, the location of these tumors at the skull base in close proximity to multiple critical neurologic structures (i.e., cranial nerves, brain stem) leads to appreciable surgical morbidity and rare mortality even in expert hands. This makes the concept of an effective, less invasive, less morbid alternative treatment that can be performed in a single day under local anesthesia quite attractive. Whether or not radiosurgery fits this description has been extensively debated. Certainly, the role of radiosurgery is limited by its inability to expeditiously relieve mass effect in patients for whom this is necessary. The radiobiology of SRS also requires lower, potentially less effective doses for higher target volumes in order to avoid complications. This limits the use of SRS to the treatment of smaller tumors. Despite these limitations, there is a growing body of literature that substantiates the claim that radiosurgery is a safe and effective alternative therapy for acoustic schwannomas. The published experience using linac-based radiosurgery for the treatment of vestibular schwannomas is relatively limited compared with the Gamma Knife literature. Foote et al. [14] performed an analysis of risk factors associated with radiosurgery for vestibular schwannoma at University of Florida (UF). The aim of this study was to identify factors associated with delayed cranial neuropathy after radiosurgery for vestibular schwannoma (VS) and to determine how such factors may be manipulated to minimize the incidence of radiosurgical complications while maintaining high rates of tumor control. From July 1988 to June 1998, 149 cases of VS were treated using linear accelerator radiosurgery at the University of Florida. In each of these cases, the patient’s tumor and brain stem were contoured in 1-mm slices on the original radiosurgical targeting images. Resulting tumor and brain-stem volumes were coupled

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with the original radiosurgery plans to generate dose-volume histograms. Various tumor dimensions were also measured to estimate the length of cranial nerve that would be irradiated. Patient follow-up data, including evidence of cranial neuropathy and radiographic tumor control, were obtained from a prospectively maintained, computerized database. The authors performed statistical analyses to compare the incidence of posttreatment cranial neuropathies or tumor growth between patient strata defined by risk factors of interest. One hundred thirty-nine of the 149 patients were included in the analysis of complications. The median duration of clinical follow-up for this group was 36 months (range, 18 to 94 months). The tumor control analysis included 133 patients. The median duration of radiology follow-up in this group was 34 months (range, 6 to 94 months). The overall 2-year actuarial incidences of facial and trigeminal neuropathies were 11.8% and 9.5%, respectively. In 41 patients treated before 1994, the incidences of facial and trigeminal neuropathies were both 29%, but in the 108 patients treated since January 1994, these rates declined to 5% and 2%, respectively. An evaluation of multiple risk factor models showed that maximum radiation dose to the brain stem, treatment era (pre-1994 compared with 1994 or later), and prior surgical resection were all simultaneously informative predictors of cranial neuropathy risk. The radiation dose prescribed to the tumor margin could be substituted for the maximum dose to the brain stem with a small loss in predictive strength. The overall radiologic tumor control rate was 93% (59% tumors regressed, 34% remained stable, and 7.5% enlarged), and the 5-year actuarial tumor control rate was 87% (95% confidence interval [CI], 76% to 98%). Based on this study, the authors currently recommend a peripheral dose of 12.5 Gy for almost all acoustics as that dose most likely to yield long-term tumor control without causing cranial neuropathy. Spiegelmann et al. [15, 16] have reported their experience. They reviewed the methods and results of linac radiosurgery in 44 patients with acoustic neuromas who were treated between 1993 and 1997. CT scanning was selected as the stereotactic imaging modality for target definition. A single, conformally shaped isocenter was used in the treatment of 40 patients; two or three isocenters were used in four patients who harbored very irregular tumors. The radiation dose directed to the tumor border was the only parameter that changed during the study period: In the first 24 patients who were treated the dose was 15 to 20 Gy, whereas in the last 20 patients the dose was reduced to 11 to 14 Gy. After a mean follow-up period of 32 months (range, 12 to 60 months), 98% of the tumors were controlled. The actuarial hearing preservation rate was 71%. New transient facial neuropathy developed in 24% of the patients and persisted to a mild degree in 8%. Radiation dose correlated significantly with the incidence of cranial neuropathy, particularly in large tumors (≥4 cm3). Several reports on smaller series of patients treated with linac-based radiosurgery for vestibular schwannomas have been published in recent years. Martens et al. reported on 14 patients with at least 1 year of follow-up after radiosurgery on the linac unit in the University Hospital in Ghent, Belgium [17]. A mean marginal dose of 19.4 Gy (range, 16 to 20 Gy) was delivered to the 70% isodose line with a single isocenter. Mean follow-up duration was 19 months (range, 12 to 24 months). During this relatively short follow-up interval, 100% radiographic tumor

control has been achieved (29% regressed, 71% stable, zero enlarged). Rates of delayed facial and trigeminal neuropathy were 21% and 14%, respectively, and two of three facial nerve deficits resolved. Preoperative hearing was preserved 50% of the time. Valentino and Raimondi reported on 23 patients treated with linac radiosurgery in Rome, Italy [18]. Five of these had neurofibromatosis and seven (30%) had undergone previous surgery. Total radiation dose to the tumor margin ranged from 12 to 45 Gy (median, 30 Gy) and was delivered in one to five sessions. One or two isocenters were used, and mean duration of follow-up was 40 months (range, 24 to 46 months). Results using this less conventional method of multisession radiosurgery were comparable with other radiosurgical techniques. Tumor control was achieved in 96% of patients (38% regressed, 58% stable, 4% enlarged), facial and trigeminal neuropathies each occurred at a rate of 4%, and “hearing was preserved at almost the same level as that prior to radiosurgery in all patients.” The use of linac radiosurgery for acoustics is briefly discussed in reports by Delaney [19] and Barcia [20]. In addition, fractionated stereotactic radiation therapy (SRT) has been used as an alternative management for vestibular schwannomas [1, 5]. This method is proposed as a way of exploiting the precision of stereotactic radiation delivery to minimize dose to normal brain while employing lower fractionated doses in an effort to minimize complications. Thus far, most radiosurgeons feel that optimal results can be achieved with highly conformal singlefraction radiosurgery while sparing the patient the inconvenience of a prolonged treatment course. As of April 2005, the University of Florida experience with vestibular schwannomas comprised 386 patients. The indications for radiosurgery were age >60 (180 cases), failed surgery (81), preference (118), medical infirmity (6). The median treatment volume was 2 cm3. With a median follow-up of 32 months for the entire group, 108 tumors are unchanged, 154 are smaller (Figs. 10-4 and 10-5), and 11 (4%) tumors are larger. Only four

FIGURE 10-4. Pretreatment MRI scan shows left-sided vestibular schwannoma.

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FIGURE 10-5. Four years after treatment, the MRI scan shows the schwannoma of Fig. 10-4 to be much smaller.

(1%) patients have required surgery because of tumor growth after radiosurgery.

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 curative. 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 [21, 22]. 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 radiation therapy and radiosurgery, either as a primary or adjuvant approach. Simpson, in a classic paper, described the relationship between completeness of surgical resection and tumor recurrence [23]. A grade I resection, which is complete tumor removal 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 resection is complete tumor removal without dural resection or coagulation. Grade IV resection is subtotal, and grade V resection is simple decompression. Recurrence rates in the grades IV and V groups basically reflect the natural history of the tumor, with high rates of recurrence over time. Unfortunately, some common meningioma locations, such as the cavernous 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 locations and in the elderly. Pollock and colleagues recently analyzed 198 patients with meningiomas less than 35 mm in diameter treated with either

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surgical resection or Gamma Knife radiosurgery [24]. 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 grades 2, 3, and 4 resections. Complications were lower in the radiosurgery group. Multiple linear accelerator radiosurgical series have been published [25–28]. Hakim and colleagues described the largest such series, and the only one to report actuarial statistics [29]. One hundred twenty-seven patients with 155 meningiomas were treated. Actuarial tumor control for patients with benign tumors was 89.3% at 5 years. Six (4.7%) patients had permanent radiation-induced complications. The University of Florida report on linear accelerator radiosurgery treatment of meningiomas is the largest yet published [30]. 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 (Figs. 10-6 and 10-7). 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 control and treatment morbidity rates compare well with all other published series. We found that reliance on imaging characteristics rather than surgical pathology did not yield a high incidence of missed diagnoses. During the time interval of this study, only two patients were treated as presumed meningiomas and later found to have other diagnoses. One had a dural-based metastasis that was surgically excised when it enlarged. The other had a heman-

FIGURE 10-6. MRI scan shows right cavernous sinus meningioma. The patient presented with a sixth nerve paresis.

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FIGURE 10-7. Three years later, the meningioma of Fig. 10-6 is barely visible. The sixth nerve paresis is completely resolved. We believe that radiosurgery is the treatment of choice for many cavernous sinus meningiomas.

giopericytoma of the lateral cavernous sinus that was surgically excised when it enlarged.

Radiosurgery for Malignant Tumors Malignant tumors are radiobiologically more amenable to fractionated radiotherapy than benign lesions. Malignancies tend to infiltrate surrounding brain, resulting in poorly definable tumor margins. A priori, these two traits of cerebral malignancies would seem to make radiosurgery an unattractive treatment option. Nevertheless, SRS has proved to be a useful weapon in the armamentarium against malignant brain tumors. The most common applications of SRS to malignant tumors are the treatment of cerebral metastases and the delivery of an adjuvant focal radiation “boost” to malignant gliomas.

Cerebral Metastases Metastatic brain tumors are up to 10 times more common than primary brain tumors with an annual incidence of between 80,000 and 150,000 new cases each year [31]. Fifteen percent to 40% of cancer patients will be diagnosed with a brain metastasis during the course of their illness. Once a brain metastasis has been diagnosed, the median life expectancy is less than 1 year; however, in many patients, aggressive treatment of metastatic disease has been shown to restore neurologic function and prevent further neurologic manifestations. Debate exists concerning the optimum treatment for metastatic brain disease. In autopsy series, brain metastases occur in up to 50% of cancer patients [32]. Approximately 30% to 40% present with a solitary metastasis. Brain metastases frequently cause debilitating symptoms that can seriously impact the patient’s quality

of life. With no treatment or steroid therapy alone, survival is limited (1 to 2 months). Whole-brain radiotherapy (WBRT) extends median survival, but the duration of survival is typically low (3 to 4 months). Several randomized trials have suggested that, when possible, surgery followed by WBRT is superior to WBRT alone. Patchell et al. reported a randomized clinical trial involving 46 patients with a single metastasis and well-controlled systemic disease [33]. They found a significant improvement in survival (40 weeks vs. 15 weeks) and local recurrences in the CNS (20% vs. 52%) for patients in the surgery plus WBRT arm of the study. Likewise, Noordijk et al. randomized 66 patients and found a significant survival advantage (10 vs. 6 months) for the combination therapy arm [34]. In contrast, Mintz et al. studied a group of 84 patients and did not show an advantage of surgery plus radiotherapy over radiotherapy alone [35]. It has been suggested that the inclusion of a higher percentage of patients with active systemic disease and lower performance scores did not allow the benefit of improved local control to affect survival in this series. Haines points out that survival and quality of life are the most important outcomes measures in evaluating a clinical treatment for cancer [36]. Surrogate end points, like local control, are inherently unreliable, especially when the definition of local control is changed. This applies to a comparison of radiosurgery with surgery for brain metastasis. In surgical series, local control means no visible tumor on follow-up scans. In radiosurgical series, local control means no growth (or sometime minimal growth) on follow-up scans. These end points are unlikely to be equivalent. In addition, comparison of current results to historical controls is fraught with hazard to selection bias. This issue led to erroneous conclusions about the efficacy of brachytherapy for malignant gliomas and to overly optimistic reports regarding the efficacy of intraarterial chemotherapy. Of equal import is the difficulty and variability of reporting standards for local control. Few series provide actuarial local control. They simply provide a “raw” number at an arbitrary point in time. Less commonly appreciated is the difficulty in documenting local control. Many of these patients die away from the medical center where radiosurgery was performed. It is frequently impossible to determine from family or local physician telephone interview whether the proximate cause of death was loss of local control, new intracranial disease (loss of regional control), or systemic disease. Most radiosurgical series have assumed that, unless an MRI was performed documenting local loss of local control prior to death, local control was maintained. This assumption may lead to a systematic overestimation of local control rates. Sturm [37–39], Black [40, 41], and Adler [42–44] published early reports on linear accelerator radiosurgery for brain metastases. Alexander [41] reported on 248 patients. Median tumor volume was 3 cm3 and median tumor dose was 15 Gy. Median survival was 9.4 months. Actuarial local control was 85% at 1 year and 65% at 2 years. Auchter et al. reported a multi-institutional study of 122 patients [45]. Actuarial 1- and 2-year survivals were 53% and 30%, respectively. Local control was 86%. Many other linac series have been reported [39, 46–53]. As radiosurgery has emerged as a treatment option, clinicians have attempted to define prognostic factors, which may help to define patient populations most likely to benefit from

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radiosurgical treatment [54–56]. Multiple factors have been discerned from retrospective analysis and include Karnofsky performance scale score, status of systemic disease, histology, number of metastases, volume of metastases, time interval between the diagnosis of the primary lesion and the metastatic lesion, pattern of enhancement [57, 58], the Radiation Therapy Oncology Group (RTOG) recursive partitioning categories [59], and radiation dose. Recently, the University of Florida published their experience with radiosurgery for brain metastases [60]. Three hundred eighty-three patients were treated. Median survival was 9 months. Melanoma histology and increasing number of metastases predicted poorer survival. Increasing age, somewhat surprisingly, slightly improved survival, possibly because younger patients tended to have more radioresistant histologies. Actuarial local control was 75% (Figs. 10-8 and 10-9). Increasing dose provided better control, and eloquent location was also associated with better control (possibly because eloquent tumors tended to be discovered at a smaller size). Regional control was poorer in melanoma or breast patients and in those with synchronous presentation of brain metastasis and primary tumor. In this retrospective analysis, whole-brain radiotherapy did not improve regional control.

Malignant Gliomas Current conventional treatment for malignant gliomas involves a combination of surgery, radiation, and, often, chemotherapy. The prognosis in these patients remains poor [61]. The majority of recurrences occur within 2 cm of the enhancing lesion as seen on initial imaging. Gross total excision may be associated with prolonged median survival in patients with malignant gliomas. Some studies have shown that other aggressive local therapies, such as interstitial brachytherapy, may favorably impact survival [62–64]. Radiosurgery is another attempt at forestalling local recurrence by aggressive local therapy.

FIGURE 10-8. The patient with known breast carcinoma presented with symptomatic pontine lesions. She was treated with radiosurgery (15 Gy to the 80% isodose line).

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FIGURE 10-9. Three years later, the site of the lesion of Fig. 10-8 was barely visible.

Malignant gliomas account for approximately 40% of the 17,000 primary brain tumors diagnosed annually in the United States. The prognosis for long-term survival remains poor. More than 80% of recurrences are found within 2 cm of the original tumor site. Many attempts have been made to improve long-term survival by improving local control [65, 66]. Such therapies include aggressive surgical removal, brachytherapy, chemotherapy wafers, and radiosurgery. In this retrospective study, we have attempted to ascertain whether the use of radiosurgical boost, whether given as part of initial tumor therapy or at the time of recurrence, increases survival compared to historical controls. A number of linear accelerator radiosurgery series have been published. Shrieve and colleagues reported on 32 patients receiving interstitial brachytherapy and 86 patients receiving radiosurgical boost [67]. They found similar survival rates between the two groups and recommended radiosurgery because of its outpatient, noninvasive nature. Hall and colleagues reported 35 patients and believed that radiosurgery did confer a survival advantage, with fewer complications than brachytherapy [68]. Buatti et al., at the University of Florida, reported on 11 patients treated with radiosurgical boost [65]. No significant survival advantage was found. Likewise, Masciopinto and colleagues [69] reported on 31 patients so treated and found that the “curative value of radiosurgery is significantly limited by peripheral recurrence.” Other studies include those of Regine [70], Prisco [71], and Gannett [72]. A recurring theme in all retrospective studies of brain tumor therapies is the question of selection bias influencing the results of therapy more than the therapy itself. In an attempt to control for selection bias in retrospective treatment trials for malignant gliomas [73], Curran [74] developed the recursive partitioning analysis categories, and Sarkaria and colleagues used this methodology to analyze 115 patients from three institutions treated with linear accelerator radiosurgery [75]. They found that patients treated with radiosurgery had a significantly improved 2-year and median survival compared with RTOG

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historical controls. The improvement was seen predominately in the worst prognostic classes (3 to 6 classes). Kondziolka performed a similar analysis on 65 patients who underwent upfront radiosurgery [76]. He also found that patients in RTOG classes 3 to 5 appeared to benefit. At the University of Florida, we have retrospectively reviewed 100 patients with WHO grade III and IV malignant gliomas who received SRS boost therapy for residual or recurrent enhancing disease [77]. The patients in our study were divided into recursive partitioning analysis (RPA) classifications for comparison with historical controls. Class III and IV patients had median survival times very similar to the historical controls. Class V patients demonstrated an increase in median survival (15.6 vs. 8.9 months) and 2-year survival rate (12.5% vs. 6%) compared with historical controls. Eloquent location correlated with poorer survival. This may be due to the selection of less aggressive therapies for this group of patients. Recurrence at time of radiosurgery was associated with longer survival. Very probably, this reflects the fact that patients judged “eligible” for radiosurgery at time of recurrence are already selected for longer survival than the average patient treated up front. However, it remains possible that radiosurgery at time of recurrence is truly more effective than upfront radiosurgery. What about drawbacks of the recursive partitioning technique? The RTOG classes used are broad and do not include all known prognostic variables, most notably tumor size. In addition, important linear variables like age, mental status, and KPS are converted into binary ones. This approach, therefore, is flawed, as are all attempts at retrospective analysis. Irish and colleagues, in an analysis of 101 consecutive malignant glioma patients, have shown that those “eligible” for radiosurgery have a median survival of 23.4 months, compared with 8.6 months for “ineligible” patients [78]. Likewise, Curran found a marked survival advantage in radiosurgery “eligible” versus “ineligible” patients [79]. The only complete solution to the issue of selection bias affecting outcome is a prospective randomized study. Such a study has been performed and the results recently published. RTOG Study 93-05 randomized patients with glioblastoma into two treatment arms [80]. One received postoperative radiosurgery, followed by conventional radiotherapy and BCNU chemotherapy. The other arm received radiotherapy and chemotherapy without radiosurgery. At a median follow-up time of 61 months, the median survival in the radiosurgery group was 13.5 months compared with 13.6 months in the standard treatment arm. There were no significant differences in 2or 3-year survival, patterns of failure, or quality of life between the two groups. Notably, RTOG 93-05 did not address the use of radiosurgery for recurrent malignant gliomas.

Arteriovenous Malformations Patient Selection Open surgery is generally favored if an arteriovenous malformation (AVM) is amenable to low-risk resection (e.g., low Spetzler-Martin grade, young healthy patient) or is believed to be at high risk for hemorrhage during the latency period

between radiosurgical treatment and AVM obliteration (e.g., associated aneurysm, prior hemorrhage, large AVM with diffuse morphology, venous outflow obstruction). Radiosurgery is favored when the AVM nidus is small (5 mm thickness). Few indications remain for radioactive plaques (mainly small anterior tumors) and enucleation (massive ocular involvement) [62].

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CNS Malignancies Base of the Skull and Upper Cervical Spine Chordomas and Chondrosarcomas Chordomas and low-grade chondrosarcomas of the skull base and upper cervical spine (see Table 11-3) [63–70] represent a paradigm for three-dimensional conformal proton therapy for many reasons: (1) both are radioresistant, that is, poorly controlled with the conventional doses administered in the literature. Surgery plus conventional radiotherapy (i.e., with doses below 60 Gy) yield a 5-year local control rate of 17% to 33% [71–73] and an overall survival rate of 33% to 90% [63, 74–77]. (2) Both are rarely totally resectable, because they are located in sites of difficult surgical access: sphenoid body, petrous bone, clivus, spinal canal. This makes in turn escalated doses suitable. (3) Both lie along and even abut sensitive anatomic structures whose injury could be lethal or highly damaging such as optic nerves, chiasm, brain stem, and spinal cord. (4) Both are located in bony areas that are clearly visible on imaging (especially CT scan) and so easily delineated on three-dimensional simulation and accurately positioned for treatment using bony landmarks. The limited number of new cases per year was also compatible with the time-consuming process that was made necessary for patient setup. The Bragg peak with its sharp lateral and distal dose fall-off proves theoretically of major interest in such challenging situations, and this led to early clinical experiments in Boston in the late 1970s. The impact of dose escalation was clearly suggested through nonrandomized studies that ranged between 55.8 CGE and 83 CGE [23, 63–65, 78–82] delivered with protons (alone or in combination with photons). Local control was switched to 59% to 100%, according to various prognosticators: the strongest one was the pathologic type with chondrosarcomas faring better than chordomas: 59% to 78% for chordomas versus 78% to 100% for chondrosarcomas [23, 64, 65, 78, 80, 83]. Also of prognostic value (but less convincingly) were evidenced: tumor volume, local extension, and finally gender in chordomas alone (females having a less favorable outcome) [84]. However, this last prognostic factor remains unclear [85]. Interestingly, in the Boston historical series of 141 patients, on 26 local relapses (18%), only 6 of 26 were found after doses ≥70 CGE and 15 of 26 after doses below that level. The main reason for underdosage was the compliance with a dose-constraint due to the proximity of an organ at risk [83]. These findings led the Proton Radiation Oncology Group (PROG) to explore in a randomized fashion two dose-levels (PROG 25– 86): (1) 66.6 versus 72 CGE in the low-risk group (i.e., all chondrosarcomas and male chordomas), and (2) 72 versus 79 CGE in the high-risk group (i.e., all cervical sites and female chordomas). Results are still pending. In a similar population, Noel et al. showed the importance of quality of radiation, in terms of dose-uniformity within the GTV, a finding also related to underdosed areas [23]. Two other findings from our experience should also be mentioned: the delay between treatment and failure that rarely exceeds 3 years. The possibility in few cases is of regional failures that can take the form of tumor seeding within nodal drainage, and/or surgical route, which is highly typical of chordomas.

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TABLE 11-3. Chordoma (CH) and chondrosarcoma (CS) of the base of the skull and upper cervical spine. Type of study

Dose/fractionation/aim

Results

68

P

69 CGE, 1.8 CGE, 80% protons

CH CS

58

P

71 CGE (65–79)

Munzenrider and Liebsch [65]

CH CS

621

P

67 CGE (66–83)

Noel et al. [22, 23, 66]

CH CS

67

P

67 CGE (60–70), 1/3 protons

Igaki et al. [67]

CH

13

P

72 CGE (63–95)

Weber et al. [68]

CH CS

29

P

68–74 CGE

Baumert et al. [69]

Brain

7

TP

Lomax et al. [70]

Miscellaneous

9

TP

Large range of total dose but same dose for photon and proton dosimetry. Study of the distribution of dose of three types of irradiation Ph, IMRT, Pr

Median follow-up 34 months 5-year LC: 82% 10-year LC: 58% Median follow-up 33 months CH 5-year LC: 59% CH5-year OS: 79% CS 5-year LC: 75% CS 5-year OS: 100% Median follow-up 41 months CH 5-, 10-year LC: 73%, 54% CH 5-, 10-year OS: 80%, 54% CS 5-, 10-year LC: 98%, 94% CS 5-, 10-year LC: 91%, 88% Median follow-up 29–31 months CH 4-year LC: 53.8% CH 5-year OS: 80.5% CS 3-year LC: 85% CS 4-year OS: 75% Median follow-up 69.3 months CH 5-year LC: 46% CH 5-year OS: 66;7% Median follow-up 29 months CH 3-year LC: 87.5% CH 3-year OS: 90% CS 3-year LC: 100% CS 3-year OS: 93.8% Mean CI Photons Protons 1.5 (1.15–2.03) 1.2 (1.05–1.38)

Authors

Tumors

Austin-Seymour et al. [78]

CH CS

Hug et al. [104]

No. of cases

healthy tissues irradiated with Pr vs. Ph/ IMRT. Tumor coverage with Pr vs. Ph and equal to IMRT.

CI, conformity index; IMRT, intensity-modulated radiotherapy (using photons); LC, local control rate; OS, overall survival rate; P, prospective-retrospective series; Ph, photons; Pr, protons; TP, theoretical publication.

Lower spinal/paraspinal conditions proved extraordinarily difficult to manage using the fixed beamlines only available at that time and are generally excluded from these studies [86]. Nonetheless, Hug et al. reported on a limited series of 20 patients an outcome close to the rest of the population: 56% and 100% 5-year local control in chordomas and chondrosarcomas, respectively. Total dose ranged from 55 to 82 CGE. Five of 16 chordomas and 0 of 4 chondrosarcomas failed. There was a tendency for improved local control as far as patients treated upfront with radiation rather than at the time of relapse, patients who underwent total/subtotal removal, and those who received a dose above 77 CGE [87]. Salvage therapy after proton therapy has been considered as purely symptomatic in the absence of demonstrated chemosensitivity and of possibility of reirradiation within 5 years. The introduction of recent biological agents (Glivec) could pave new avenues in these situations as well as less advanced presentations [88].

Meningiomas The indication for proton therapy is definitely more controversial in this tumor type. The main reason is that no clear-cut

dose-response relationship has been evidenced so far (Table 11-4) [89–94]. The initial study by Austin-Seymour et al. in 13 patients was a mixture of benign, malignant, and atypical variants. Median dose was 59.4 CGE (range, 54 to 71.6) and followup 26 months. Local control was 100% [90]. Gudjonsson et al. described results of a hypofractionated regime in 19 patients, delivering 26 CGE in 6 fractions. With a median follow-up of 36 months, local control was again 100% [89]. Miralbell et al. reported on 11 patients treated with photons and protons after incomplete surgery. With a median follow-up of 53 months, no relapse was observed against 6 of 25 patients with comparable tumors irradiated with photons alone [91]. Later on, the HCL published the results of 46 patients with benign meningiomas. Median dose delivered in tumor volume was 59 CGE. Median follow-up was 53 months. Five- and 10-year local control rates were 100% and 88%, respectively, and overall survival rates were 93% and 77%, respectively [24]. The same group published the results in 31 malignant or atypical meningiomas irradiated either conventionally with photons alone or with an escalated dose by a combination of photons and protons. Fiveyear local control rates were 17% and 80%, respectively [93]. Seventeen patients treated at the CPO with a combination of photons and protons to a slightly escalated dose were recently

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TABLE 11-4. Meningiomas. Authors

Tumors

Gudjonsson et al. [89]

Benign, atypical, malignant meningiomas Benign, atypical, malignant meningiomas Benign, atypical, malignant meningiomas Benign, atypical, malignant meningiomas Benign meningiomas

Austin-Seymour et al. [90] Miralbell et al. [91]

Noel et al. [92]

Wenkel et al. [24]

Hug et al. [93]

Noel et al. [94]

No. of cases

Benign, atypical, malignant meningiomas Benign meningiomas

Type of study


Results

19

P

36 CGE in 4 Fr

Median follow-up 36 months No tumoral progression

13

P

59.4 CGE, 1.8 CGE/Fr

Follow-up ≥26 months No tumoral progression

11

P

Combination of photon-protons 54–69 CGE 1.8 CGE/Fr

Median follow-up 53 months No tumoral progression

17

P

Combination of photon-protons 61 CGE 1.8 CGE/Fr

46

P

59 CGE (53–74)

31

P

50–72 CGE

51

P

60.6 CGE Clinical improvement

Median follow-up 37 months 4-year LC: 82.4% 5-year OS: 88.9% Median follow-up 53 months 5- and 10-year LC: 100% and 88% 5- and 10-year OS: 93% and 77% 5-year LC: Photons: 17% Protons: 80% ocular symptoms: 68.8% other symptoms: 67%

Fr, fraction(s); LC, local control rate; OS, overall survival rate; P, prospective/retrospective.

analyzed. Patients were irradiated after surgery or at the time of relapse after surgery. Median follow-up was 37 months. Four-year local control and 5-year overall survival were 87.5% and 88.9%, respectively. The median disease-free interval was increased by 24 months for the patients treated after relapse, a figure similar to the disease-free interval between surgery and relapse [92, 95]. Our group also brought out the outcome of 51 patients with purely benign meningiomas. The main finding was the improvement in functional outcome (67% cases) and especially ocular preservation (68.8%) [94].

Gliomas The survival of patients diagnosed with a glioblastoma multiform is dismal (Table 11-5). It has been demonstrated that the majority of patients will fail locally (i.e., within 2 cm around the macroscopic tumor extension). The positive impact of dose-

escalation has been shown using brachytherapy or radiosurgical boosts with photons. Blomquist and Carlsson suggested a proton-based strategy in grades III to IV gliomas: (1) surgical removal of the bulky tumor, (2) high-precision, high-dose proton beam fractionated irradiation in a limited volume encompassing the area at risk plus minimal margin around [96]. The 90-Gy dose level has been investigated through multiple studies: Tatsuzaki et al. conducted dosimetric investigations showing that at this level using protons, none of the brain stem received 60 Gy/CGE compared with 5 cm3 with photons, and that the volume of “nontarget” brain receiving >70 CGE was almost doubled by photons (175 cm3 and 94 cm3, respectively). The reverse side of the coin was a superior dose to the skin delivered with protons alone (63 vs. 45 CGE) [25]. Baumert et al. compared the dose-distribution between modulated-intensity protons and photons using multileaf collimator in seven cases of brain tumors. The conformity index (CI) was better

TABLE 11-5. Brain gliomas. Authors

Tumors

Tatsuzaki et al. [25]

Glioblastoma

No. of cases

1

Type of study


Results

TP

60 Gy/CGE + 30 Gy/CGE (boost) Comparison of normal irradiated volume

20

Phase II

68,2 CGE, 1.8/Fr, grade II 79.7 CGE, 1.8/Fr, grade III Dose escalation

23

Phase II

90 CGE, 1.8/Fr, 2 Fr/day, at least 33% of the total dose with Pr Dose escalation

Photons Protons Normal brain 175 cm3 94 cm3 Brain stem 5 cm3 0 cm3 Max. dose chiasm 60 Gy 60 CGE Max. dose skin 45 Gy 63 CGE Grade III: median survival 29 Grade II not reached 5-year OS grade II: 71% 5-year OS grade III: 23% No increase in LC rate or time of relapse Median survival: 20 months 1-, 2-, 3-year OS: 78%, 34%, 18% Survival: 5–11 months compared with photons

Fitzek et al. [17]

Grade II–III gliomas

Fitzek et al. [16]

Glioblastoma

LC, local control rate; Fr, fraction(s); Pr, protons; OS, overall survival rate; TP, theoretical publication.

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for protons than for photons for complex or concave lesions, or when the target volume was close to critical structures. In other cases, the CI was comparable for both modalities. The number of beams was lower with protons than with photons, which suggests a decrease in the integral dose to the brain [69]. Fitzek et al. reported clinical outcome of a phase II trial that enrolled 23 patients irradiated for a glioblastoma. This institutional study explored a dose of 90 CGE delivered predominately with protons and accelerated fractionation. The median survival time was 20 months, with 4 patients being alive 22 to 60 months after diagnosis. Analysis according to the RTOG prognostic criteria or MRC indices showed a 5- to 11-month increase in median survival time compared with patients treated conventionally in the literature. Radiation necrosis was evidenced in 7 of 29 patients, and survival was significantly shortened in patients treated at the time of failure (p = 0.01). Tumor relapse occurred most commonly in areas that received doses >70 CGE; conversely, only one case failed in the 90-CGE volume. The authors concluded that future investigations should aim to cover more widely areas at risk to 90 CGE, although in practice this is rarely achievable due to the risk of radiation necrosis [16]. Another phase II trial was reported by the same group in 20 patients with less aggressive gliomas (grades II to III of the Daumas-Duport classification). Prescribed dose were 68.2 CGE in grade II and 79.7 CGE in grade III. Five-year overall survival (OS) rates were 71% and 23%, respectively. The authors concluded that tumor recurrence was neither prevented nor noticeably delayed in these patients compared with the published series on photons [17].

Arteriovenous Malformations Single-dose proton therapy at MGH in the early 1960s gave the impetus to radiosurgical programs worldwide (Table 11-6). A single dose of 10 to 50 CGE was delivered according to the tumor size and radiobiological data sets as mentioned above. Obliteration rate was 20% and complication rate 3% [5]. In an updated series of 95 patients, Amin-Hanjani et al. reported a 17% (before irradiation) to 9% (after irradiation) reduction of the annual hemorrhage rate, but the complication rate was substantial: 26.5%, including 16.3% permanent neurologic deficits and 3% death [27]. Seifert et al. reported a 16% obliteration rate for German patients treated with protons in the United States. They observed clinical improvement in 44%, stability in 27%, and worsening in 29% cases. An unexpected finding was that therapy was less effective (and so not recommended) for

lesions >3 cm [97], which contradicts dosimetric considerations that plead for the superiority of protons in lesions >4 cm [98]. Recently, Vernimmen et al. reported the experience of a South Africa proton center regarding 64 patients treated for predominately large intracranial AVMs. Irradiation was delivered according to a hypofractionated schedule and dose ranged between 18.4 and 22 single-fraction equivalent CGE. Obliterations were observed in 67% of the lesions with a volume inferior to 14 cm3 and 43% in those with volume superior to 14 cm3. Grade IV complications were reported in 3% of the patients [30].

Vestibular Schwannoma This is another typical case for monofractionated radiosurgery. Weber et al. reported the results of 88 patients with vestibular schwannomas that were treated at HCL with proton beam stereotactic radiosurgery. Two to four convergent fixed beams of 160-MeV protons were applied. The median cross section and target volume were 16 mm and 1.4 cm3, respectively. Previous surgical resection had been made possible in 15 (17%) patients. Facial and trigeminal nerves functions were normal in 79 (89.8%) patients. Eight (9%) patients had good or excellent hearing, and 13 (15%) patients a useful hearing. A median dose of 12 CGE was prescribed to the 70% to 108% isodose lines. Median follow-up was 38.7 months. The actuarial 2- and 5-year tumor control rates were 95.3% and 93.6%, respectively. The actuarial 5-year cumulative radiologic reduction rate was 94.7%. Of the 21 patients (24%) with functional hearing, 7 retained “serviceable” hearing ability. Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% and 89.4%, respectively. Univariate analysis revealed that prescribed dose (p = 0.005), maximum dose (p = 0.006), and the inhomogeneity index (p = 0.03) were associated with a significant risk of long-term facial neuropathy [99, 100]. These results compare favorably with other published radiosurgical series. In summary, current knowledge on proton therapy in skull base and probably spinal canal low-grade sarcomas make proton therapy highly suitable in a majority of patients both in terms of oncologic outcome and quality of life. The place of surgical resection remains crucial because it can greatly improve ballistics to critical structures, and possibly by reducing tumor burden. Randomized studies (and possibly meta-analyses) might confirm these findings as the number of patients submitted to this approach is expanding. The introduction of modern technologies especially isocentric gantries should make possible

TABLE 11-6. Arteriovenous malformations. Authors

Tumors

No. of cases

Type of study


Results

Kjellberg et al. [5]

AVM

75

P

10.5–50 CGE, 1 Fr

Amin-Hanjani et al. [27] Vernimmen et al. [30]

AVM

95

P

AVM

64

P

Median max. dose: 18.3 CGE (8–36.7), 1 Fr 18.38–22.05 SFEGyE

Complete occlusion rate: 20% Partial occlusion rate: 56% Death: 2 cases Reduction hemorrhage risk: 17% to 9% Complication: 26.6% Median follow-up: 62 months Obliteration rate for lesion >14 cm3: 67% Obliteration rate for lesion >14 cm3: 43% Complication: 3%

Fr, fraction(s); P, prospective; SFEGyE, single-fraction equivalent Gy equivalent.

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proton beam radiosurgery

the management of a variety of spinal/paraspinal malignancies in the future. PT remains controversial in meningiomas although it represents an elegant option for sparing normal tissues. In high-grade gliomas, PT has been disappointing despite substantial tumor dose increase. Future directions should explore combined chemoradiation and light ions.

Pediatric Tumors Despite the prominent role held by chemotherapy in this age group, radiotherapy still plays a crucial role in most solid tumors especially those located in the brain (approximately 20% of cases). There is a considerable amount of data indicating that radiotherapy even at low dose can induce severe sideeffects especially in young children (Table 11-7) [101–106]. For example in the CNS, it can affect cognitive function and pituitary-driven growth at >20 Gy in whole brain, sellar area, auditory function at >30 Gy in cochlea, and so forth. Another major concern comes from irradiation of bones in the prepubertal age, with impairment of growth plates at >15 Gy. Carcinogenicity has also represented a serious threat, especially in the usual combined chemo-radiation approaches. A salient feature of proton dose-distribution that can be of considerable interest in this age group is the absolute reduction of the integral dose (mainly due to the lack of “exit” beam) that minimizes areas receiving low and moderate doses around the target. On the other hand, there are practical serious limitations that have made this approach still almost confidential in this indication, to mention a few: (1) The rarity of pediatric oncology centers (correlated with the rarity of the disease itself) that are restricted to a few places not necessarily close to a particle center. This comes along with the unique expertise required from radiation oncologists, physicists, and technologists involved. (2) The difficulty for performing extensive and uncomfortable daily setups without the help of deep sedation and even general anesthesia in the youngest patients. There is obviously a need for careful patient selection through preliminary dosimetric investigations in order for example to define the merits of different technological approaches like conformal photons or IMRT. In a comparative study between protons and conformal photons, in optical pathway gliomas, Fuss et al. showed that the CI (ratio of GTV to non-GTV encompassed in the 95% isodose) was better with protons than with photons. They also showed that doses delivered with protons in normal optic nerve, chiasm, pituitary gland, and temporal lobes were respectively reduced by 47%, 11%, 13%, and 39% compared with those delivered with photons [101]. For tumors located in the posterior fossa, Lin et al. showed that cochlea received 25% of the proton dose versus 75% of photons. Furthermore, 40% of temporal lobes were fully spared from protons, whereas 90% were exposed to photons to a minimum 30% of the total dose [31]. Based on theoretical models, Miralbell et al. reported a potential 10% drop in the predictable risk of IQ decline in medulloblastoma treated with CNS irradiation by the age of 4 years, using protons compared with photons. NTCP (normal tissue complication probabilities) values were also lowered by protons but to a modest extent when compared with highly conformal photons [107]. The same authors compared both techniques in cervical irradiation to 27 Gy at the age of 2 to 3

153

years. As far as cervical spine, the volume receiving ≥50% dose was fivefold using photons versus of protons (i.e., 100% vs. 20%). As far as heart, the difference was even more striking (≥45% dose, photons; 100%, protons; 0% volume). Low doses to thyroid, liver, and gonads were similarly reduced. The authors’ estimates of “height sparing effect” by protons was of the order 10 cm [32]. It is interesting to mention that most authors acknowledge that the benefit of protons increases with tumor size, a datum of special interest in brain malignancies [26, 70, 98]. Similarly, reduction of the carcinogenic risks is of primary concern in this age group and can be expected from protons (see above) [102]. The Swiss group developed mathematical algorithms based on radioprotection estimates to quantify these risks [108]. Carcinogenic risk between “rival” techniques (i.e., conformal photons/protons, and photons/ protons IMRT) were appraised: in parameningeal rhabdomyosarcomas, the “protective” effect of protons was ≥2-fold, and in medulloblastoma, 8- to 15-fold [109]. Elegant beam arrangements are made possible with protons as mentioned previously. Sophisticated patch techniques make sparing of abutting critical organs feasible. Impressive sparing of highly sensitive structures such as growing plates has been brought out in retinoblastomas by Krengli [102], orbital rhabdomyosarcomas, and lumbar neuroblastomas by Hug [104]. Recent theoretical study including cases of retinoblastoma, medulloblastoma, and pelvic sarcoma cases concluded that protons delivered superior target dose coverage and sparing of normal structure. In pelvic sarcoma studied in this series, none of the ovaries received dose superior to 2 Gy; furthermore, as expected, proton lowdose volume is greatly inferior to that obtained with IMRT. These volumes receiving low dose of irradiation have been suspected to be the site of radiation-induced secondary cancer [103]. Clinical series on the use of protons in children are still scarce. The Boston group reported on 18 children aged 4 to 18 years with a skull base chordoma/chondrosarcoma. With a median 72 months follow-up, 5-year OS and RFS were 68% and 63%, respectively. The complication rate was limited to one temporal lobe necrosis [64]. The preliminary Orsay experience was reported by Noel et al. on 17 children (median age, 12 years), with skull base sarcomas as the main indication, who received combined photon-proton irradiation (approximately 50%–50% of the dose). With a median 27 months follow-up (range, 3 to 81), 3-year local control was 91.7% and 1-, 2-, and 3-year OS 93.3%, 83%, and 83%, respectively. One child failed in-field and one at the margin. No late side-effect was reported although follow-up is definitely short [18, 106]. McAllister et al. at Loma Linda University Medical Center (LLUMC) reported on 28 children treated for grades 2 to 4 glioma. At the time of analysis, three were dead from disease, one was alive with tumor progression, and the others were with NED. Complication rate was low [105]. Hug et al. reported on 27 children treated by protons for low-grade malignancies. Six relapsed, four died, and the others were with NED and complicationfree. A subgroup of six children with optic glioma had visual preservation or improvement [21]. Giant cell tumors seen in the pediatric age are regarded as benign conditions, although they can behave aggressively. In this situation, high-dose proton therapy is warranted (just as in the adult sarcomas) and can induce prolonged remissions [110].

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TABLE 11-7. Pediatric cancers. No. of cases

Type of study

Authors

Tumors


Results

Lin et al. [31]

Posterior fossa

9

TP

54 Gy/CGE Comparison 3D Ph and Pr

Fuss et al. [101]

Optic glioma

7

TP

50.4–50 Gy/CGE Dose distribution comparison for Pr, 3D conformal Ph, standard pH (std)

Krengli et al. [102]

Retinoblastoma

1

TP

Lee et al. [103]

Retinoblastoma

3

TP

46 CGE in GTV, 40 CGE in CTV Proton beam arrangements for various intraocular tumor locations Comparison of different technique of Ph including IMRT and proton

% prescribed Pr PH dose in cochlea 25% 75% Pr: 40% temporal lobes excluded irradiated volume PH: 90% temporal lobes received ≥31% of prescribed dose CI 3D Ph Std Ph Pr 2.9 7.3 2.3 Reduction of dose/Pr 3D Ph Std Ph Contralateral optic 47% 77% nerve 11% 16% Chiasm 13% 16% Pituitary 39% 54% Temporal lobes PT risks K2 + cosmetic / functional sequelae

Mean % volume/ technique 5 Gy orbit 20 Gy optic nerve 25 Gy cochlea 10 Gy pituitary 10 Gy thyroid 10 Gy lung 10 Gy kidney 15 Gy heart 5 Gy ovary 20 Gy vertebra 30 Gy bowel

3D RT 25 53 64 91 24 15 18 2 100 20 11

IMRT 69 55 33 81 100 14 15 59 29 29 12

Medulloblastoma

3

Pelvic sarcoma

3

Hug et al. [104]

Neuroblastoma

1

P

34.2 CGE Dose distribution

50% ipsilateral kidney 95%) and was nearly universally safe; one patient with a history of conventional radiation therapy and three courses of perioptic radiosurgery suffered a radiationinduced optic nerve injury. This experience is remarkable for the high incidence of visual function preservation and tumor control in what was otherwise a particularly challenging group of patients; nearly all had a history of either surgical resection (sometimes multiple) and/or conventional radiotherapy.

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Spinal Indications In the first reported use of image-guided robotics to perform spinal radiosurgery, Ryu and co-workers demonstrated the safety and short-term efficacy for a variety of neoplastic and vascular lesions [21]. Surgical implantation of fiducials into adjacent vertebral segments was necessary for tracking the ablated spinal lesion. There were no adverse events related to the implantation of fiducials. Given the appreciable uncertainty about the spinal cord’s tolerance to radiosurgery, hypofractionation, using two to five fractions, was utilized in nearly all cases. Subsequent to the above investigation, Gerstzen and coworkers found in their clinical series of 125 patients that singlefraction spinal radiosurgery was safe and effective under most circumstances [22]. A mean tumor dose of 14 Gy as prescribed to the 80% isodose was used (Fig. 13-6). Most patients’ lesions

Vestibular Schwannomas Small- to moderate-sized vestibular schwannomas can be treated with single or fractionated radiosurgical regimes. Since 1999, the CyberKnife at Stanford University has been used to treat more than 350 patients with vestibular schwannoma, delivering 18 to 21 Gy in three sessions separated by 24 hours. To date, only three patients within this cohort has shown evidence of tumor progression, and in no case was treatment-related trigeminal or facial nerve dysfunction observed. Among those patients with Gardner-Robertson grade I or II hearing preoperatively, 74% retained these hearing levels after an average 4 years of follow-up. Furthermore, there were no cases of total hearing loss [18].

Trigeminal Neuralgia Radiosurgical rhizotomy, most commonly performed with the Gamma Knife, is well-established in the management of trigeminal neuralgia. However, after more than a decade of experience, treatment latencies and the overall response rate continue to be less than ideal. With the goal of overcoming these limitations, the standard Gamma Knife trigeminal rhizotomy has been modified by using the capacity of the CyberKnife to deliver non-isocentric plans. Rapid onset of pain relief after CyberKnife treatment was first reported in a small series of patients by Romanelli and co-workers [19]. A more recent and larger multi-institutional study confirmed these results [20]. In this later study, a prescribed dose of 60 to 70 Gy was delivered to a 6- to 8-mm length of the retrogasserian region of the trigeminal nerve. The median latency to pain relief was only 7 days. Initial pain control was ranked as excellent in 88% of patients, whereas three patients reported no pain relief and two experienced only a moderate reduction of pain. Although pain relief appeared durable in 78% of this cohort, half of the patients in this series eventually developed facial numbness. Because a clear relationship was observed between the length of the trigeminal nerve treated and the onset of numbness, a gradual dose and volume de-escalation was subsequently conducted. The current parameters used for trigeminal rhizotomy at Stanford include a 6-mm length of nerve and dose prescriptions of 60 Gy marginal and 75 Gy Dmax.

FIGURE 13-6. Examples of CyberKnife treatment planning for a T12 spinal metastasis from a renal cell carcinoma. Isodose distribution is overlaid on both axial (a) and coronal (b) MRI scans. In this case, the selected treatment dose was 18 Gy prescribed to the 70% isodose. Note the steep dose gradient adjacent to the spinal cord.

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were metastatic (108 cases), and 59% of them had been treated previously with conventional irradiation. The authors reported an improvement in pain scores in 74 of 79 patients with axial and radicular pain prior to radiosurgery. No acute radiation toxicity or new neurologic deficits occurred during the median 18-month follow-up. Meanwhile, Degen et al. [23] treated 51 patients with 72 spinal tumors (58 metastatic and 14 primary) with multiple-session CyberKnife radiosurgery. After a mean follow-up of 1 year, there were significant and durable reductions in pain scores as well as a maintenance of physical and mental quality of life measures. Side effects were mild and selflimiting. Because by nature the spinal cord is fragile, poorly vascularized, and highly sensitive to radiation damage, the findings of both of the above studies are remarkable. The benefits are even more impressive when one considers that a significant percentage of patients in these series had undergone previous conventional irradiation. Furthermore, the relative safety of this procedure at these institutions reinforces claims about the overall system accuracy of robotic radiosurgery. In management of brain tumors, radiosurgery is often used as one component of a multimodality approach. The same philosophy can also be applied to spinal lesions. As an example, CyberKnife radiosurgery has been combined with kyphoplasty to address pathologic compression fractures [24]. This is a new treatment paradigm for metastatic spinal tumors. By coupling two minimally invasive procedures, the risk of major surgical complications is lessened, treatment costs are lowered, and quality of life is improved. Even more integrated radiosurgical approaches are likely to emerge in the future that will further change the classic surgical management of many spinal lesions. One of the more important nonneoplastic applications of CyberKnife spinal radiosurgery is the treatment of intramedullary spinal cord arteriovenous malformations (SCAVMs). Alternative therapies for this specific group of AVMs, which include embolization and surgery, have only a limited role and are almost never curative. Because there are so few viable treatment options for most cases of SCAVM, spinal radiosurgery could prove a welcome new therapeutic tool. With this in mind, 21 patients with intramedullary spinal cord AVMs (11 cervical, 7 thoracic, 3 lumbar) were treated with the CyberKnife between 1997 and 2006 as part of a gradual dose escalation study at Stanford University. Preliminary findings from this experience have been reported [25]. However, for the entire series of patients, radiosurgery was delivered in one to five sessions to an average AVM volume of 1.8 cm3 using an average marginal dose of 19.5 Gy. Patients were followed with annual MRI and angiography every 3 years. Average follow-up now exceeds 2.5 years. Among the six patients studied with posttreatment angiography, AVM obliteration was partial in four and complete in two. Significant AVM obliteration has been observed on MRI in nearly every case that was more than 1 year from radiosurgery; AVM involution appears complete in three cases and confirmatory angiography is pending. Not surprisingly, the radiologic outcome to date suggests that more aggressive radiosurgical regimens (generally using fewer fractions) correlate with a higher rate of AVM obliteration. No patients suffered post-SRS hemorrhage or any significant neurologic deterioration attributable to SRS. Despite the still-evolving radiosurgical experience with SCAVM, it seems safe to say that the CyberKnife now offers an important new treatment option for these challenging lesions.

Intrathoracic and Intraabdominal Lesions The past half decade has witnessed an explosion of interest in using ever more precise irradiation to treat lesions of the chest and abdomen. All these procedures combine noninvasive external immobilization and targeting with conventional medical linacs [26–31]. Meanwhile, a review of the preliminary stereotactic radiotherapy experience treating liver malignancies has been recently provided by Fuss and Thomas [32]. Image-guided robotic radiosurgery adds a powerful and versatile tool to this field. In fact, because of Synchrony’s unique capabilities for tracking and correcting for respiratory motion, the CyberKnife may eventually have its biggest clinical impact in treating lesions of the chest, abdomen, and pelvis. Consistent with this idea, multiple clinical trials are now under way worldwide to assess the utility of CyberKnife ablation of lung tumors. It is important to reiterate that tumor targeting and tracking with Synchrony requires the implantation of radiopaque fiducials near the lesion [33, 34]. Gold seeds are preferred because they are inert, readily inserted, and easy to image with the CyberKnife’s imaging module. The feasibility of CyberKnife radiosurgical ablation for pulmonary lesions was first investigated in 23 patients with biopsyproven lung tumors (15 primary and 8 metastatic lesions) by Whyte and co-workers [35] in a pilot study. After CT-guided percutaneous fiducial placement, each patient was treated with 15 Gy in a single fraction. Although radiosurgery itself was well tolerated, several patients experienced complications as a result of the implantation of fiducials. After limited postsurgical follow-up, radiographic progression was found only in two patients; the follow-up period ranged from 1 to 26 months (mean, 7 months). Because several local failures were subsequently observed, the radiosurgical dose for lung cancer has been gradually escalated. Le et al. [36] conducted a phase I dose-escalation study to assess the effects of single-fraction CyberKnife radiosurgery in patients with inoperable T1–2N0 non–small cell lung cancers (NSCLCs) or solitary lung metastases. Doses ranging from 15 to 30 Gy were tested in 32 patients. At 1 year, doses greater than 20 Gy prevented local progression of NSCLC in 91% of patients, whereas doses less than or equal to 20 Gy resulted in only a 54% freedom from local progression. However, higher doses (25 to 30 Gy) were also associated with serious complications in patients with prior radiotherapy and larger midline tumors. NSCLCs responded better than metastatic tumors. The authors concluded that single-fraction CyberKnife was feasible and effective, but in selected cases, single fractions of 25 Gy or more may be unacceptably toxic. These results are consistent with those emerging during the past decade showing that high-dose stereotactic radiotherapy can be effective for NSCLC, but they also suggest that a hypofractionated approach may be required to minimize complications. The treatment of pancreatic adenocarcinomas with CyberKnife radiosurgery was first reported by Romanelli et al. [19]. Twelve patients were treated with 15, 20, or 25 Gy delivered as a single fraction. The treatment was well tolerated, values of the pancreatic cancer marker CA 19–9 were decreased in most patients, and all patients with pain prior to treatment experienced improvement within days. These preliminary results were expanded upon by Koong and associates [37], who observed local control of tumor growth with a single dose of

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25 Gy, without serious gastrointestinal toxicity. In a later paper [38], CyberKnife radiosurgery was delivered as a boost after conventional intensity-modulated radiotherapy (IMRT; 45 Gy delivered in 1.8-Gy fractions) and concurrent chemotherapy (5-fluorouracil or capecitabine). Although high rates of tumor control were achieved (15 of 16 patients were free from local progression until death), the incidence of complications increased significantly above that observed with radiosurgery alone. In addition, there was no improvement in survival. This finding encouraged the authors to subsequently forego IMRT in such patients in favor of radiosurgery alone, with or without adjuvant chemotherapy. Although CyberKnife radiosurgery has proved highly effective in achieving local control and palliating symptoms, survival continues to be largely dictated by the frequent occurrence of regional metastases. Nevertheless, control of pancreatic tumors itself is an impressive accomplishment; if such an effect could be combined with more effective systemic therapies, noninvasive radiosurgical ablation holds out the promise of prolonging survival. Although preliminary, the above results with abdominal and thoracic tumors have been encouraging. Nevertheless, much more evidence is needed to establish a definite role for robotic radiosurgery in managing nonneurologic disorders. In this regard, multiple clinical trials are under way worldwide that seek to discover if CyberKnife radiosurgery can substantially impact the overall clinical outcome for a broad range of extracranial indications.

Future Directions Stated simply, the CyberKnife was developed to enable the safe, accurate, and effective application of radiosurgery throughout the body. Future enhancements in the CyberKnife will be largely dictated by the experiences of ongoing clinical studies as well as the creativity of medical professionals in radiosurgery. Nevertheless, certain improvements seem likely. For example, the radiation output of the CyberKnife linac is likely to increase. In addition to shortening the length of treatment, this development should enable progressively smaller collimators to create ever more conformal treatment volumes. Given the relative youth of the CyberKnife concept, one can readily envision how a number of similar subsystems will be optimized with time. Fiducial targeting of lesions within the major body cavities is both robust and extremely accurate. However, the implantation process can be technically demanding, adds to the complexity of the overall radiosurgical procedure, and is modestly invasive. In the case of lung treatment, pneumothorax is not uncommon. Although the challenges are considerable, a technology for targeting intraabdominal and thoracic lesions without fiducials will be a clear improvement in robotic radiosurgery. Recent research suggests that motion compensation without implanted gold markers may be clinically practical [39]. Such technology would considerably simplify treatment protocols and enhance patient comfort and safety. The proposed method for fiducial-less targeting extends the current CyberKnife X-ray image correlation targeting system by also incorporating breathing motion into the pretreatment DRR library. Using four-dimensional imaging and image registration, several pretreatment CT scans are acquired at different stages of the respiratory cycle. A large array of DRRs are

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then computed from each CT volume. In effect, each of these synthetic images incorporates both patient and respiratory movement. Similar to the current process, throughout radiosurgery live X-ray images are compared with the precalculated DRRs. However, the new comparison group would include synthetic X-rays that also reflect a range of respiratory states. In performing two-dimensional–two-dimensional (2D-2D) registrations, the best matching DRR is identified, thereby enabling the current phase of the breathing cycle and the location of the tumor to be determined. With dynamic motion compensation (i.e., Synchrony), the treatment beams move synchronously with the target, and the beam strikes the target region approximately as planned. However, some tumors deform or rotate with respiration, and tissue surrounding the tumor may exhibit a different motion pattern than the tumor itself. Information on the relative motion of organs with respect to treatment beams (during the actual radiosurgery) can be incorporated into the planning process, thus further improving the overall precision and safety of the treatment. This could be of particular benefit when treating lesions close to the spinal cord where the precise dose tolerance can be critical. Current robotic systems use only cylindrical collimators. However, multileaf collimators in combination with robotic systems could potentially further reduce treatment time and improve treatment conformality. Given the flexibility with which the CyberKnife can configure treatment beams, a relatively simple multileaf collimator might be utilized instead of the more standard microleafed device used in conventional radiation therapy. On the other hand, the same improvement in time efficiency might also be achieved by further increasing linac output, which unlike multileaf collimation would not sacrifice beam penumbra. Whether taken alone or in aggregate, these technical improvements may in turn usher in new clinical radiosurgical applications that have yet to be envisioned. Although future technological developments have the potential to improve the process and clinical outcome of robotic radiosurgery, we are equally excited by the prospects for improving our basic radiobiological understanding of large-fraction irradiation. A number of important questions remain unanswered. The biggest of these continues to be what are the optimal doses and fractionation schemes for specific tumor entities, particularly within the thoracic and abdominal cavities. Furthermore, the combination of radiosurgery with new systemic immunotherapies and chemotherapies, which attack microscopic malignancies, and may in fact be radiation sensitizers, are likely to play a vital role for improving future clinical outcomes.

Conclusion Radiosurgery is in the midst of a technological revolution. The recent introduction of image guidance and robotic delivery has dramatically expanded the scope of this field. As inevitable improvements in neuroimaging and computer technology emerge over the coming years, they will serve as an impetus for further improvements in robotic radiosurgical technology. This perspective stems in large part from the inherent, and somewhat unique, flexibility of the CyberKnife’s basic design. As the full extent of this vision is realized, the concept of radiosurgical ablation will continue to expand into new anatomic

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regions and disorders. This evolution will also require that surgeons of nearly all stripes and radiation oncologists reexamine some of the basic tenets encompassed within their respective disciplines.

References 1. Chang SD, Main W, Martin DP, et al. An analysis of the accuracy of the CyberKnife: a robotic frameless stereotactic radiosurgical system. Neurosurgery 2003; 52:140–146; discussion 146–147. 2. Yu C, Main W, Taylor D, et al. An anthropomorphic phantom study of the accuracy of CyberKnife spinal radiosurgery. Neurosurgery 2004; 55:1138–1149. 3. Ho AK, Fu D, Cotrutz C, et al. A study of the accuracy of CyberKnife spinal radiosurgery using skeletal structure tracking. Neurosurgery 2007; 60(2 Suppl 1):ONS147–156. 4. Gierga DP, Chen GT, Kung JH, et al. Quantification of respiration-induced abdominal tumor motion and its impact on IMRT dose distributions. Int J Radiat Oncol Biol Phys 2004; 58: 1584–1595. 5. Kaus MR, Netsch T, Kabus S, et al. Estimation of organ motion from 4D CT for 4D radiation therapy planning of lung cancer. Presented at Medical Image Computing and Computer-Assisted Intervention—MICCAI 2004, 7th International Conference, Saint-Malo, France, September 26–29, 2004. 6. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001; 50:265–278. 7. Mageras GS, Pevsner A, Yorke ED, et al. Measurement of lung tumor motion using respiration-correlated CT. Int J Radiat Oncol Biol Phys 2004; 60:933–941. 8. Plathow C, Ley S, Fink C, et al. Analysis of intrathoracic tumor mobility during whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol Phys 2004; 59:952–959. 9. Shirato H, Seppenwoolde Y, Kitamura K, et al. Intrafractional tumor motion: lung and liver. Semin Radiat Oncol 2004; 14:10–18. 10. Webb S. Conformal intensity-modulated radiotherapy (IMRT) delivered by robotic linac—testing IMRT to the limit? Phys Med Biol 1999; 44:1639–1654. 11. Webb S. Conformal intensity-modulated radiotherapy (IMRT) delivered by robotic linac—conformality versus efficiency of dose delivery. Phys Med Biol 2000; 45:1715–1730. 12. Li JG, Xing L. Inverse planning incorporating organ motion. Med Phys 2000; 27:1573–1578. 13. Unkelbach J, Oelfke U. Incorporating organ movements in inverse planning: assessing dose uncertainties by Bayesian inference. Phys Med Biol 2005; 50:121–139. 14. Schlaefer A, Fisseler J, Dieterich S, et al. Feasibility of fourdimensional conformal planning for robotic radiosurgery. Med Phys 2005; 32:3786–3792. 15. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD. Visual field preservation after multisession CyberKnife radiosurgery for perioptic lesions. Neurosurgery 2006; 59(2):244–254. 16. Mehta VK, Lee QT, Chang SD, et al. Image guided stereotactic radiosurgery for lesions in proximity to the anterior visual pathways: a preliminary report. Technol Cancer Res Treat 2002; 1:173–180. 17. Pham CJ, Chang SD, Gibbs IC, et al. Preliminary visual field preservation after staged CyberKnife radiosurgery for perioptic lesions. Neurosurgery 2004; 54:799–810; discussion 810–812. 18. Chang SD, Gibbs IC, Sakamoto GT, et al. Staged stereotactic irradiation for acoustic neuroma. Neurosurgery 2005; 56:1254– 1261; discussion 1261–1253. 19. Romanelli P, Heit G, Chang SD, et al. CyberKnife radiosurgery for trigeminal neuralgia. Stereotact Funct Neurosurg 2003; 81: 105–109.

20. Lim M, Villavicencio AT, Burneikiene S, et al. CyberKnife radiosurgery for idiopathic trigeminal neuralgia. Neurosurg Focus 2005; 18:E9. 21. Ryu S, Fang Yin F, Rock J, et al. Image-guided and intensitymodulated radiosurgery for patients with spinal metastasis. Cancer 2003; 97:2013–2018. 22. Gerszten PC, Ozhasoglu C, Burton SA, et al. CyberKnife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery 2004; 55:89–98; discussion 98–99. 23. Degen JW, Gagnon GJ, Voyadzis JM, et al. CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine 2005; 2:540–549. 24. Gerszten PC, Germanwala A, Burton SA, et al. Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures. J Neurosurg Spine 2005; 3:296–301. 25. Sinclair J, Chang SD, Gibbs IC, Adler JR Jr. Multisession CyberKnife radiosurgery for intramedullary spinal cord arteriovenous malformations. Neurosurgery 2006; 58:1081–1089; discussion 1081–1089. 26. Bilsky MH, Yamada Y, Yenice KM, et al. Intensity-modulated stereotactic radiotherapy of paraspinal tumors: a preliminary report. Neurosurgery 2004; 54:823–830; discussion 830–821. 27. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001; 19:164–170. 28. Shiu AS, Chang EL, Ye JS, et al. Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 2003; 57:605–613. 29. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003; 124: 1946–1955. 30. Uematsu M, Shioda A, Suda A, et al. Computed tomographyguided frameless stereotactic radiotherapy for stage I non-small cell lung cancer: a 5-year experience. Int J Radiat Oncol Biol Phys 2001; 51:666–670. 31. Yenice KM, Lovelock DM, Hunt MA, et al. CT image-guided intensity-modulated therapy for paraspinal tumors using stereotactic immobilization. Int J Radiat Oncol Biol Phys 2003; 55: 583–593. 32. Fuss M, Thomas CR Jr. Stereotactic body radiation therapy: an ablative treatment option for primary and secondary liver tumors. Ann Surg Oncol 2004; 11:130–138. 33. Schweikard A, Glosser G, Bodduluri M, et al. Robotic motion compensation for respiratory movement during radiosurgery. Comput Aided Surg 2000; 5:263–277. 34. Schweikard A, Shiomi H, Adler J. Respiration tracking in radiosurgery. Med Phys 2004; 31:2738–2741. 35. Whyte RI, Crownover R, Murphy MJ, et al. Stereotactic radiosurgery for lung tumors: preliminary report of a phase I trial. Ann Thorac Surg 2003; 75:1097–1101. 36. Le QT, Loo BW, Ho A, et al. Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol. 2006 Oct; 1(8):802–809. 37. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004; 58:1017–1021. 38. Koong AC, Christofferson E, Le QT, et al. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2005; 63:320–323. 39. Schweikard A, Shiomi H, Adler JR. Respiration tracking in radiosurgery without fiducials. Int J Med Robotics Comput Assist Surg 2005; 1:19–27.

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Treatment of Disease Types

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1 4

Brain Metastases John H. Suh, Gene H. Barnett, and William F. Regine

Introduction Brain metastases are a significant cause of morbidity and mortality that affects an estimated 20% to 30% of cancer patients [1]. The annual incidence in the United States has been estimated to be as high as 170,000 cases [2]. Brain metastases most commonly originate from tumors of the lung, breast, renal cells, and colon and from melanoma. In some cases, the primary is unknown. Multiple lesions are seen more frequently with melanoma and lung cancer, whereas single lesions are more common with breast, colon, and renal cell cancer. An estimated 30% to 40% of patients with a brain metastasis present with a single lesion [3]. Despite improvements in imaging, surgical technique, and radiation delivery, the prognosis for these patients remains dismal. Patients who receive no treatment have a median survival of only 1 month. Those who are treated with steroids survive a median of 1 to 2 months, and those who undergo whole-brain radiation therapy survive for a median of 4 to 7 months after therapy [4–7]. As a result, the development of brain metastasis is one of the most feared complications of cancer patients, and it represents a therapeutic challenge to neurosurgeons, radiation oncologists, medical oncologists, and neuro-oncologists. Historically, the treatment of brain metastasis has included whole-brain radiation therapy (WBRT), which was first reported in the 1950s and early 1960s [8, 9]. Response to WBRT is best among patients with small cell lung cancer, lymphoma, and germ cell tumors. The Radiation Therapy Oncology Group (RTOG) conducted numerous trials from 1971 through 1993 to investigate various fractionation schemes and doses of WBRT, which are listed in Table 14-1 [10–18]. In addition, the RTOG has investigated the use of hyperfractionation and radiation sensitizers such as bromodeoxyuridine and found no improvement in overall survival. Based on these studies, the use of 3000 cGy in 10 fractions became a popular fractionation scheme to consider for patients with brain metastases. Although neurologic symptoms improved in the majority of patients, local control was low resulting in neurologic death in 25% to 54% of patients [10]. Given the poor prognosis for patients with brain metastases, alternative strategies to improve outcomes have been explored. Stereotactic radiosurgery (SRS) is a technique that

delivers a single, high dose of ionizing radiation using stereotactically directed narrow beams to small intracranial targets while sparing the surrounding brain tissue [19]. Since Sturm’s initial report of 12 lesions treated on a modified linear accelerator, a number of papers have corroborated the benefit of SRS in newly diagnosed and recurrent brain metastases [20]. Currently, brain metastases represent the most common indication for SRS. Although SRS has become an important treatment option, its use has also sparked controversy about the appropriate treatment for patients with brain metastases. This chapter will review the prognostic factors, surgical results, rationale for SRS, results of surgery compared with SRS, the institutional results of SRS with WBRT and SRS alone, the results of completed phase II/III clinical trials, complications of SRS, and future direction of SRS for brain metastases.

Prognostic Factors The most commonly used prognostic scale for patients with brain metastasis is the RTOG recursive partitioning analysis (RPA) [21]. This scale divides patients into three classes based on 1200 consecutive patients enrolled in three RTOG trials from 1979 to 1993. The vast majority of these patients had unresectable and/or multiple metastases but received standard doses of WBRT. Table 14-2 lists the various classes and their components. The most important factors include extracranial metastases, patient age, Karnofsky performance status, and control of primary tumor. A study from Lagerwaald and colleagues reviewed 1292 patients with brain metastases [22]. In this Dutch study, lung cancer was the most common primary disease (56%). Median survival was 3.4 months, and the 1-year and 2-year survivals were 12% and 4%, respectively. The most important factors were treatment modality, performance status, extracranial disease burden, and response to steroid treatment.

Surgery Given the low local control rates associated with WBRT alone, surgical removal of tumors—particularly single or symptomatic lesions—was explored in hopes of improving local control and

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TABLE 14-1. Prospective Radiation Therapy Oncology Group (RTOG) brain metastases studies (1971–1993). Protocol

Year

No. patients

Total dose/no. fractions

Median survival

RTOG 6901 [10]

1971–1973

RTOG 7361 [11]

1973–1976

RTOG 6901 [12] RTOG 7361 [12] Ultrarapid RTOG 7606 [13] Favorable patients RTOG 8528 [14]

1971–1973 1973–1976

233 217 233 227 447 228 227 26 33

30 Gy/10 Fx/2 weeks 30 Gy/15 Fx/3 weeks 40 Gy/15 Fx/3 weeks 40 Gy/20 Fx/4 weeks 20 Gy/5 Fx/1 week 30 Gy/10 Fx/2 weeks 40 Gy/15 Fx/3 weeks 10 Gy/1 Fx/1 day 12 Gy/2 Fx/2 days

21 weeks 18 weeks 18 weeks 16 weeks 15 weeks 15 weeks 18 weeks 15 weeks 13 weeks

RTOG 9104 [15]

1991–1995

RTOG 7916 [16] Misonidazole

1979–1983

130 125 30 53 44 36 213 216 193 200 196 190

18 weeks 17 weeks 4.8 months 5.4 months 7.2 months 8.2 months 4.5 months 4.5 months 4.5 months 4.1 months 3.1 months 3.9 months

RTOG 8905 [17] BrdU

1989–1993

30 Gy/10 Fx/2 weeks 50 Gy/20 Fx/4 weeks 48 Gy/1.6 Gy bid 54.5 Gy/1.6 Gy bid 64 Gy/1.6 Gy bid 70.4 Gy/1.6 Gy bid 30 Gy/10 Fx 54.4 Gy/1.6 Gy bid 30 Gy/10 Fx/2 weeks 5 Gy/6 Fx/3 weeks 30 Gy/10 Fx + Miso 5 Gy/6 Fx + Miso 37.5 Gy/15 Fx/3 weeks 37.5 Gy/15 + BrdU

1976–1979 1986–1989

36 34

6.1 months 4.3 months

Fx, fraction; bid, twice daily; Miso, misonidazole; BrdU, bromodeoxyuridine. Source: Adapted from Sneed PK, Larson DA, Wara WM. Neurosurg Clin N Am 1996; 7:505–515.

TABLE 14-2. RTOG RPA classes for brain metastases. Factors


Class I

Age 20 Gy resulted in higher-grade 3 and 4 neurotoxicity (5.9% vs. 1.9% for those receiving 3 Gy per fraction [59]. In addition, some believe that patients can be effectively managed by repeat SRS rather than WBRT. Several trials of prophylactic irradiation (PCI) have demonstrated a decrease in the development of brain metastases but no survival advantage [61–63]. A recent study from Brigham

TABLE 14-5. Neurocognitive testing used for phase III brain metastases trial. Test

Neurocognitive domain

Hopkins Verbal Learning Test (recall) Hopkins Verbal Learning Test (recognition) Hopkins Verbal Learning Test (delay) Trailmaking A Trailmaking B Controlled oral word association Grooved pegboard dominant hand Grooved pegboard nondominant hand

Memory Memory Memory Executive Executive Executive Fine motor Fine motor

Source: Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol 1984; 2:253–259.

14.

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this study, and others of similar design, current and future developing brain tumor/metastases studies have and will more routinely incorporate baseline and follow-up neuropsychometric testing as an inherent part of study design and patient outcome evaluation. This is particularly important as it is becoming increasingly evident that neurologic/neurocognitive decline seen in cancer patients is multifactorial and not due to the effects of radiation therapy alone. This has been demonstrated in recent publications implicating the potential significant impact of other treatment modalities such as chemotherapy and/or surgery on neurologic/neurocognitive function [69–73]. In addition to the potential toxicity concerns of WBRT, a randomized trial from Patchell that showed no survival benefit to WBRT is often quoted as a reason why WBRT should not be given. This phase III randomized trial of 95 patients compared surgery alone with surgery followed by WBRT for patients with a single brain metastasis [74]. The addition of WBRT to surgery decreased the chance for neurologic death (14% vs. 44%, p = 0.003), decreased local recurrence (10% vs. 46%, p < 0.01), and decreased tumor recurrence anywhere in the brain (XX% vs. 70%, p < 0.001). The majority of patients (61%) received WBRT at time of recurrence resulting in a large crossover of the observation arm to WBRT. Survival was not different, although the study’s end point was local control and thus it was not powered to demonstrate a survival advantage [75]. It is also important to note that patients who undergo SRS alone may be at higher risk for morbidity associated with brain tumor recurrence. A retrospective study from the University of Kentucky reviewed 36 patients with newly diagnosed brain metastases—22 had a single lesion [76]. These patients were treated with SRS alone. Seventeen of the 36 (44%) patients developed recurrent brain metastases. Of the 17 patients, 12 (71%) were symptomatic and 10 (59%) had neurologic deficits.

Large Institutional/Multi-Institutional Results of SRS Alone Sneed reported on a UCSF retrospective study of outcomes of patients with one to four metastases treated by SRS alone compared with WBRT plus SRS [54]. Physician preference and referral patterns influenced the use of upfront WBRT. The patients had similar median survivals (11.1 months for SRS alone vs. 11.3 months for WBRT plus SRS) and local tumor control rates (71% vs. 79%). The incidence of distant brain metastasis was, however, significantly higher in the SRS-only group versus WBRT and SRS (72% vs. 31%). Despite the higher rate of distant brain metastases, these metastases were controlled with salvage therapies including WBRT, partial brain radiotherapy, SRS, and surgery. The authors concluded that survival was not compromised by the omission of WBRT. Another retrospective paper from Hasegawa reviewed 172 patients with brain metastases (3.5 cm or less in diameter) managed by SRS alone [77]. One hundred twenty-one patients had follow-up imaging with 80% of patients having solitary lesions. The median survival was 8 months, and the local tumor control rate was 87%. At 2 years, the local control rate, distant brain control, and total intracranial control rates were 75%, 41%, and 27%, respectively. Tumor volume significantly

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predicted for local control (p = 0.02) with tumor volumes of at least 4 cm3 having local control rate of 49% at 1 and 2 years. Based on these results, the authors advocated avoiding WBRT for selected patients with one or two tumors with good control of their primary cancer, better KPS (90 or higher), and younger age (1). The goal was to accrue 480 patients. The study is temporarily suspended secondary to poor accrual.

Complications Associated with SRS Acute Complications Acute complications during the first week after SRS are uncommon. Some of the complications include headache after frame removal, infection of the pin sites, nausea and vomiting, seizures, transient worsening of preexisting neurologic conditions, and fatigue. The incidence of severe headaches after frame removal is low [51]. Nausea/vomiting can be minimized if the dose to the area postrema is kept below 375 cGy [39]. The risk for seizures has been reported to range from 2% to 6% [41, 42, 51]. The risk for seizures is higher for patients with cortical lesions and for those with history of seizures. For these patients, anticonvulsants should be therapeutic or considered, and the steroid dose should be increased.

Subacute Complications These complications occur within the first 6 months after SRS. Alopecia has been reported in 5.6% of patients [41]. These patients had superficial tumors that resulted in a dose of 4.4 Gy to the scalp. Neurologic deterioration can occur in some patients, which is usually treated with steroids.

Chronic Complications Radiation necrosis represents the most serious chronic complication. In general, the risk of radiation necrosis increases with higher doses, prior radiation therapy, and larger tumor volumes. This entity can be difficult to distinguish from tumor recurrence on MRI and may require the use of surgery, positron emission tomography (PET), and/or magnetic resonance spectroscopy (MRS). RTOG 9005 was a phase I/II trial to determine the maximum tolerated radiosurgery dose for patients with recurrent primary brain tumors or brain metastases treated previously with

TABLE 14-6. RTOG CNS toxicity criteria used for RTOG 9005. Grade 1 Grade 2 Grade 3 Grade 4

Grade 5

Mild neurologic symptoms; No medication required Moderate neurologic symptoms; Outpatient medication required (e.g., steroids) Severe neurologic symptoms; Outpatient or inpatient medication required Life-threatening neurologic symptoms (e.g., uncontrolled seizure, paralysis, coma); includes clinically and radiographically suspected radiation necrosis and histologically proven radiation necrosis at time of operation Death

Source: Hasegawa T, Kondziolka D, Flickinger JC, et al. Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery 2003; 52:1318–1326.

fractionated radiation therapy [82]. In this trial, the maximum tolerated doses were inversely correlated with the maximum tumor diameter. The doses were 24 Gy for a tumor ≤20 mm in diameter, 18 Gy for a tumor 21 to 30 mm in diameter, and 15 Gy for a tumor 31 to 40 mm in diameter. Of note, investigators were reluctant to escalate the dose for tumors ≤20 mm in diameter even though the maximum tolerated dose was not reached. The rate of radiation necrosis was 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months after SRS, respectively. Other factors that predicted for grades 3 to 5 neurotoxicity were tumor dose and KPS. Table 14-6 lists the RTOG CNS toxicity criteria used for RTOG 9005. The incidence of complications was also associated with tumor dose and KPS. The study also reported on physics and quality control assessments (MD/PD ratio, a measure of dose homogeneity, and PIV/TV ratio, a measure of conformity of the treated volume relative to target volume) that are useful for all tumors treated by SRS [83]. Valery reported on 377 patients with 760 lesions treated with linear accelerator–based SRS. Seven patients had severe complications including nine patients who developed radiation necrosis. The median tumor volume was 4.9 cm3. The median prescribed tumor dose was 15.6 Gy. The only factor that influenced the risk for radiation necrosis was the conformality index [84]. The general management strategy for radiation necrosis is to decrease the edema and necrosis. Usually, high doses of steroids are used to minimize neurologic deterioration. If the patient becomes symptomatic despite steroids, surgical resection can be considered. In some cases, hyperbaric oxygen has been used for patients who are poor surgical candidates, have multiple areas of radiation necrosis, or have a surgically inaccessible lesion. In a retrospective review of 40 patients, 90% reported subjective improvement and 80% had objective neurologic improvement [85]. Steroids were discontinued or decreased in two thirds of patients. A randomized trial is under way at the University of Cincinnati comparing surgery with hyperbaric oxygen.

Future Directions Based on the results of RTOG 9508, a randomized trial, RTOG 0525, is ongoing for NSCLC patients with one to three brain metastases. The primary end point of the study is survival.

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Another phase II study (PCYC-0224) is evaluating the use of motexafin gadolinium, a radiation sensitizer, with WBRT (37.5 Gy in 15 fractions) with SRS for patients with one to four metastases. Others are incorporating newer imaging modalities such as MRS and PET to aid in planning or to deliver higher doses to certain regions of the target [86–87].

Conclusion Stereotactic radiosurgery has an important role in the management of brain metastases. Retrospective studies have shown the benefits of SRS as sole treatment, as an adjunct to WBRT, and as salvage treatment after WBRT in some patients. Retrospective studies suggest that patients who undergo SRS or surgery have comparable outcomes. The results of RTOG 9508 provide level 1 evidence of a survival benefit of SRS and WBRT compared with WBRT alone for patients with a single lesion. For patients with two to three lesions, the use of SRS and WBRT can be considered based on performance status, extent and activity of extracranial disease, and steroid use. The omission of WBRT has been driven by the concerns of the potential risks of WBRT and apparent lack of survival benefit of WBRT rather than evidence from prospective clinical studies. The potential side effects of WBRT need to be balanced with the risk for neurologic and neurocognitive decline of uncontrolled brain metastases and the additional cost of more frequent scans. Recent phase III trials have shown that many patients with brain metastases have neurocognitive deficits prior to WBRT. As the prognosis improves for cancer patients, the challenge of improving survival while limiting acute and long-term side effects will continue to make the management of brain metastases controversial. We encourage the participation of patients with brain metastases in clinical trials to improve outcomes and to help answer many important questions about management of this very common disease.

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1 5

Metastatic Brain Tumors: Surgery Perspective Raymond Sawaya and David M. Wildrick

Introduction Metastatic brain tumors occur more frequently than other intracranial neoplasms and are a serious complication of systemic cancer [1]. Their annual incidence exceeds 100,000 [2, 3] and is on the rise as patients live longer from improved treatments for extracranial cancer [4, 5]. Thus, patients with brain metastases constitute a significant fraction of the case load in the neurosurgery services at many oncologic care centers. Early in the 1900s, the results of surgical treatment of single brain metastases were disappointing [6], with patients seldom showing a median survival time of longer than 6 months [7]. Although this was longer than the 4- to 6-week survival time typical of patients with untreated brain metastases, the surgical morbidity was high (15% to 50%) [8], and whole-brain radiation therapy (WBRT) alone was frequently favored for management of patients with brain metastases. Since then, the Radiation Therapy Oncology Group (RTOG) has demonstrated that treatment of brain metastasis patients with WBRT alone can extend their median survival time to 16 weeks [9–11]. In addition, two independent, prospective randomized studies showed that surgery plus WBRT offered a survival advantage superior to WBRT alone in such patients [12, 13]. Since Leksell demonstrated the utility of focused beams of high-energy X-rays in the ablation of intracranial tumors [14, 15], the technique of stereotactic radiosurgery (SRS) has continued to evolve. During the 1990s, SRS was increasingly used in the management of brain metastases, with some investigators recently claiming that SRS alone produces results similar to those obtained by combining SRS and WBRT, or potentially even equivalent to the outcome with surgical resection [16–20]. With this in mind and because of the ease of use of SRS and the perception that it costs less than conventional surgery, some have even suggested that most metastatic brain tumors should be managed exclusively with SRS. This controversial notion has already led to treatment of some series of brain metastasis patients with SRS alone followed by observation [18, 19]. At The University of Texas M. D. Anderson Cancer Center (“M. D. Anderson”), SRS is regarded as a specialized tool to be used judiciously, as a given patient’s situation dictates, rather than as a generalized treatment modality for brain metastases. We continue to see surgical resection as playing the central role in the management of patients with a limited number of brain

metastases [4, 21–24]. In this chapter, we present our view of the relative roles of surgery and SRS in terms of issues concerning patient selection, treatment outcome, cost-effectiveness of the treatment, and the patients’ quality of life. These differences are summarized in Table 15-1 [25–27].

Patient Selection When a patient presents with a brain metastasis and symptoms of mass effect, there is seldom a dispute that the lesion should be removed surgically. Similarly, when a patient with a brain metastasis presents in too poor a medical condition to be a surgical candidate (or declines surgery), SRS represents a logical treatment modality. Other patients with single brain metastases can be sorted into three groups. The first group has relatively large lesions (exceeding 3 cm in maximum diameter) that can only be effectively removed by surgical resection. Treatment of these tumors with SRS is not effective because the radiation dose must be reduced as the tumor size increases to prevent damage to surrounding brain tissue. This relationship was clearly demonstrated by Mehta et al. [25], who showed that with SRS, the rate of complete response (CR; total disappearance of the magnetic resonance [MR] image of the lesion after SRS) falls off dramatically with tumor volume such that if a tumor 2 cm3 in volume has a 50% CR rate, an 8- to 9-cm3 lesion shows about a 20% CR rate (Fig. 15-1). Patients in the second group have very small lesions (less than 10 mm in maximum diameter) that are not surgically accessible and are located deep within the brain. In this situation, SRS provides an effective alternative to resection, superior to WBRT, which was the only treatment previously available. The third group of patients are those who have metastases that are less than 3 cm in maximum diameter and are surgically accessible. Whether surgery or SRS is the best treatment for these lesions is the subject of much current debate. The 3-cm upper size limit referred to above is probably too high for adequate SRS treatment. At M. D. Anderson, a recent study of 153 brain metastases from melanoma treated with SRS [28] showed that the 1-year local control rate of smaller tumors with a maximum diameter of no more than 1.5 cm (volume = 2 cm3) was superior to that of larger lesions (75.2% and 42.3%, respectively; p < 0.05). Moreover, another

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TABLE 15-1. Differences between surgery and stereotactic radiosurgery in the treatment of brain metastasis.

Patient selection Tissue diagnosis Lesion size Surgical candidate Treatment outcome Tumor status Local control Local recurrence rate Median survival time Complications Presentation Major neurological Mortality (30-day)†

Surgical resection

Stereotactic radiosurgery

Confirms the lesion is a tumor Large, ≥1.5 cm*; especially if there is mass effect Yes

Cannot confirm the lesion is a tumor Small, ≤2.0 cm*; significant mass effect absent No (or patient declines surgery)

Removed (≥94% on average) [4] 85% for >40 months (up to 5 years) [23] 8% [23] to 12% [4] 10 [13] to 16.4 [23] months

Not removed 85% at 12 months; 65% at 24 months [25] 30% [26] to 47% [27] 7.5 [23] to 14 [16] months

Usually immediate

Frequently delayed; necrosis may necessitate surgical resection 25% in eloquent brain (RTOG grade 3) [24] 1.8%

Cost-effectiveness

7% in eloquent brain; 6% overall [4] 70), and a non– radiosensitive tumor. They then compared the outcome of these 122 patients with that of the patients in the prospective randomized surgical series of Patchell et al. [13] and Noordijk et al. [12]. The actuarial median survival time after treatment with SRS plus WBRT was 56 weeks compared with 40 weeks [13] and 43 weeks [12], respectively, after surgery plus WBRT. The median duration of functional independence was 44 weeks after SRS and WBRT [16] compared with 38 weeks [13] and 33 weeks [12], respectively, after surgery and WBRT. These results indicated to Auchter et al. [16] that SRS plus WBRT produced outcomes for patients with single brain metastases that were comparable with, if not better than, surgery plus WBRT. Cho and coworkers [31] retrospectively reviewed a series of 225 single brain metastases in patients treated with either WBRT alone, SRS plus WBRT, or surgery and WBRT. There was a similar distribution of prognostic factors such as age, sex, KPS score, and metastasis location in these three groups except for extracranial cancer, which was 14% higher in the group treated with SRS and WBRT. The actuarial median survival times for patients treated with SRS and WBRT (9.8 months) and surgery plus WBRT (10.5 months) were nearly identical, but both were significantly better than for those treated with WBRT alone (3.8 months). Other more recent retrospective studies have also labeled resection and SRS as equally effective in the treatment of small to moderately sized brain metastases [32]. At M. D. Anderson, Bindal and coworkers [23] also retrospectively compared surgical resection and SRS treatment of brain metastases. Thirty-one patients treated with SRS were followed prospectively, and 62 patients treated with conventional surgery were retrospectively matched to those in the SRS group. Patients were matched according to primary tumor histology, extent of systemic disease, preoperative KPS score, time to brain metastasis, number of brain metastases, and patient age and sex. WBRT treatment was similar in both groups, and patient eligibility criteria for SRS were the same as for surgery. Lesions treated by SRS were limited to those 12 months) of brain metastases treated with WBRT develop dementia. However, virtually all of the patients in that sample who developed dementia had been treated with atypically large radiation fractionation schedules. The patients treated with fraction sizes less than 3.0 Gy per day did not develop clinically apparent dementia. Thus, the actual frequency of radiationrelated dementia when using convention fractionation schedules is not known but is certainly less than 11%. In any event, the frequency of long-term neuropsychological side effects of WBRT in adult brain metastases patients appears to have been overestimated and seems to be within the acceptable range when modern fractionation schemes are employed.

WBRT in the Treatment of Multiple Brain Metastases Because the majority of patients have multiple metastases, the efficacy data for WBRT comes in a large part from treatment of patients with multiple brain metastases. There is little doubt that WBRT is effective for multiple metastases, and it is used routinely. The main controversy regarding the treatment of multiple metastases involves the use of radiosurgery (either with or without WBRT). To date, there have been three randomized trials [20–22] assessing the efficacy of radiosurgery in the treatment of multiple metastases. The first randomized trial was reported by Kondziolka et al. [20]. In that study, 27 patients with multiple brain metastases were randomized to treatment with WBRTalone or WBRT plus a radiosurgery boost. The study was stopped early because the authors claimed to have found a large difference in the recurrence rates in favor of radiosurgery. Unfortunately, the study used nonstandard end points to measure recurrence. The investigators used any change in measurement of the lesion rather than the more usual 25% increase in diameter. No attempt was made to control for steroid use, radiation changes, or other factors that might produce small fluctuations in lesion size on magnetic resonance imaging

(MRI). Also, a study with only 27 patients in it lacked the statistical power to support any meaningful conclusion, regardless of p values. As a result, this study was uninterpretable. A second study reported in abstract form by Chougule et al. [21] randomized patients with one to three brain metastases to treatment with radiosurgery-alone, radiosurgery plus WBRT, or WBRT-alone. The study had 109 patients. There was no statistically significant difference in survival among the three treatment arms. Median survival times for the radiosurgery, radiosurgery plus WBRT, and the WBRT-alone treated groups were 7, 5, and 9 months, respectively. Local control rates in the brain were also not significantly different. This trial suffered from several methodological problems. The most serious error was that 51 of the patients had had surgery for at least one symptomatic brain metastasis prior to entry into the study. No attempt was made to stratify for previous surgery or to otherwise ensure that surgical patients were equally distributed among the treatment groups. The inclusion of the surgical patients effectively made this a six-arm trial (the original three subdivided again into surgically treated patients and nonsurgically treated patients), and therefore, the size of this trial was not large enough to support a meaningful analysis. Also, because surgery is in all probability an effective therapy for brain metastases, the nonrandom distribution of surgically treated patients among the treatment arms substantially weakened the trial. Therefore, this study, although ostensibly negative, is really uninterpretable. A third study was reported by Andrews et al. [22] This study (RTOG 9508) contained 333 evaluable patients with one to three brain metastases who were randomized to treatment with either WBRT (37.5 Gy) plus radiosurgery or WBRT (37.5 Gy) alone. The primary end point was survival. Overall, there was no significant difference in survival between the two treatment groups (median, 6.5 months for radiosurgery plus WBRT and 5.7 months for WBRT-alone, p = 0.1356). There was no survival benefit from radiosurgery in patients with multiple metastases (median, 5.8 months for radiosurgery plus WBRT and 6.7 months for WBRT-alone, p = 0.9776). (However, for patients with single metastases, there was a significant survival advantage favoring radiosurgery, median 6.5 months vs. 4.9 months, p = 0.0393). Lower posttreatment Karnofsky scores and steroid dependence were more common in the WBRT-alone group. Multiple subgroup analyses were made and a benefit for radiosurgery plus WBRT was found in several subgroups that included patients with single and multiple metastases. These subgroups were RPA class 1 patients, patients with metastases size equal to or larger than 2 cm, and lung cancer patients with squamous cell histology. However, these subset analyses were not prespecified, and the p values needed for significance should have been adjusted for inflation of type I error. When this was done, none of these subgroup analyses showed a positive benefit for radiosurgery [23]. So, for multiple brain metastases, this was a completely negative trial with regard to the major end points prevention of death due to neurologic causes and overall survival. Radiosurgery has been put to the test in the treatment of multiple metastases and has not been established as effective. Therefore, based on the best available evidence, WBRT-alone is the treatment of choice for most patients with multiple brain metastases (and the word “multiple” in this context means more than one).

16.

brain metastases: whole-brain radiation therapy perspective

WBRT in the Treatment of Single Brain Metastases For the treatment of single brain metastases, randomized trials have established the superiority of focal treatment (either conventional surgery or radiosurgery) plus WBRT over treatment with WBRT-alone. Therefore, good-prognosis patients with single brain metastases should be treated with upfront surgery or radiosurgery. However, with the establishment of the efficacy of focal treatments for single brain metastases, a new controversy has arisen as to whether adjuvant WBRT is really necessary after a “complete resection” or “successful” treatment with radiosurgery. Adjuvant WBRT is thought to be of benefit because there may be residual disease in the tumor bed or at distant microscopic sites in the brain. However, brain metastases tend to be discrete masses that are theoretically capable of being removed totally or destroyed, and so WBRT may not be necessary after “successful” focal therapy. There are several reasons for eliminating WBRT. First, WBRT has adverse, long-term neuropsychological side effects. Second, there are also the costs and time commitment of the patient that must be considered. And finally, there is the possibility that WBRT may simply not be needed at all. It is theoretically possible to remove single brain metastases by surgery totally or to control them with radiosurgery. Furthermore, neuroimaging has improved, and it may now be possible to detect reliably additional metastases that may be present and treat these with additional focal therapy. If these last two statements are true, then there would be little justification for adjuvant WBRT. On the other hand, compelling reasons exist for giving adjuvant WBRT. As a practical matter, it is probably impossible to remove completely all metastases with conventional surgery, and radiosurgery does not completely control the tumors. In addition, neuroimaging may not have reached the point yet where we can be absolutely certain that all metastases are being detected, and therefore some type of additional treatment may be needed. Also, although WBRT does have side effects, these side effects may not be as severe or as common as was previously thought. Furthermore, most patients with brain metastases have relatively limited overall survival times, and so the really serious long-term side effects are usually not an issue in their care. Two randomized trials [24, 25] have addressed the question of adjuvant WBRT in conjunction with focal treatment. A study published in 1999 by Patchell et al. [24] examined the effect of WBRT in conjunction with conventional surgery. In that study, 95 patients who had single brain metastases that were completely surgically resected were randomized to treatment with postoperative WBRT (50.4 Gy) or to observation with no further treatment of the brain metastasis (until recurrence). Recurrence of tumor anywhere in the brain was less frequent in the radiotherapy group than in the observation group (18% vs. 70%, p < 0.001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (10% vs. 46%, p < 0.001) and at other sites in the brain (14% vs. 37%, p < 0.01). As a result, patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 of 43 who died [14%] vs. 17 of 39 [44%]; p = 0.003). There was no significant difference between the two

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groups in overall length of survival or the length of time that patients remained functionally independent. The effect of WBRT in association with radiosurgery was examined in a randomized trial conducted by the Japanese Radiation Oncology Study Group and reported in abstract form by Aoyama et al. [25] In that study, 132 patients with one to four brain metastases were randomized to treatment WBRT plus radiosurgery or with radiosurgery-alone. The WBRT total dose was 30 Gy. The radiosurgery dose was 18 to 25 Gy at the periphery of the lesion in the radiosurgery-alone group and was reduced by 30% in the WBRT plus radiosurgery group. The median survival time was 7.5 months in the WBRT plus radiosurgery group and 8.0 months in the radiosurgery-alone group, p = 0.42. The 12-month brain metastases recurrence rates were significantly (p < 0.001) different (47% in the WBRT plus radiosurgery group and 76% in the radiosurgery-alone group). Death due to neurologic causes and neurologic functioning were not significantly different between the two groups. Despite the fact that both of the randomized trials [24, 25] showed clearly that WBRT prevented recurrences, these studies have actually provoked controversy rather than settling the issue. Results of these trials have been used as reasons both to give and not to give adjuvant WBRT. The justification for not giving WBRT holds that because no survival difference was found in either of the trials, WBRT really adds nothing to the treatment. This argument fails on several counts. The Patchell study [24] used tumor recurrence as the primary end point and was not designed either to show a difference in survival or to rule one out. There was actually an increase of 11% in survival time in the WBRT group when compared with the observation group. The relative risk of improved survival with WBRT was 1.1. However, this was not a statistically significant difference. Because there was a statistically significant reduction in death due to neurologic causes, ultimately adjuvant WBRT might have had some positive impact on overall survival time. The estimated sample size required to detect a significant difference of 11% in overall survival with adequate power would have been 1005 patients per group or 2010 patients total. For practical reasons, the study could not be designed to have this large of a sample size and, therefore, was not designed to detect moderate differences in survival, even one as large as 11%. There is an even stronger reason for discounting the apparent lack of efficacy of postoperative WBRT with regard to length of survival in the Patchell trial [24]. Recurrence of tumor in the brain was the primary end point of that randomized trial, and this end point was the only truly direct measure of the effects of adjuvant WBRT. Up until recurrence of tumor, the two treatment groups were distinct, and the patients in each had received the treatment assigned by randomization. However, at recurrence, no specific treatment was mandated by the study design, and as a result, patients received a variety of additional treatments. There was an extremely large crossover of the observation group to WBRT. Of the 32 patients in observation group who developed recurrent brain metastases, 28 patients got WBRT. Overall, that means that 61% (28 patients of 46 total) in the “no WBRT” observation arm were, in fact, treated ultimately with WBRT. For the purposes of length of survival and functional independence, the study was virtually a comparison of surgery plus immediate WBRT versus surgery plus delayed

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WBRT. This substantially diluted the effect of WBRT given immediately postoperatively because WBRT probably improved the length of survival and functional independence in the observation group. Therefore, for all the reasons given above, the Patchell study did not “prove” that WBRT had no positive effect on survival. The Aoyama trial [25] also failed to find any difference in survival with the addition of WBRT. This study differed in design from the Patchell study and was devised with survival as the primary end point; it was originally powered to be able to detect a 30% or greater difference with 89 patients per treatment arm. (Given that the Patchell study [24] and numerous retrospective studies had failed to find a difference in survival even close to 30%, the Aoyama study [25] should have been powered as an equivalence trial [if survival was going to be used as the primary end point].) The study was stopped after an interim analysis at 132 patients indicated that the study was not going to show a statistically significant difference in survival, even if all of the 178 patients originally projected to be in the trial had been randomized. Therefore, any negative conclusion based on the original power calculation, that is, that there was no more than a 30% difference in survival (or any other reasonable difference), cannot be supported. This study also had an 11% crossover that further eroded the strength of any conclusions about survival. In addition, about half of the patients in both treatment arms had multiple brain metastases. The study by Andrews et al. [22] failed to establish the efficacy of radiosurgery in the treatment of multiple metastases, and so the inclusion of these patients is problematic and further reduces the number of valid patients on which to base a conclusion about survival benefit. Thus, like the Patchell trial [24] before it, this Aoyama study [25] was unable to show that there was no difference in survival. Therefore, arguments based on the supposed lack of efficacy of (immediate) postoperative WBRT on survival are based on a misunderstanding of the design and limits of the randomized trials. In addition, the Aoyama study demonstrated that omitting WBRT does not produce any difference in either gross neurologic or neurocognitive functioning. From this information, Aoyama et al. [25] and the Journal of the American Medical Association (JAMA) editorial writer [26] concluded that the addition of WBRT is not necessary and can be safely omitted in the treatment of most patients with brain metastases. However, even if one takes the data presented in the paper at face value, it is possible to draw exactly the opposite conclusion. As stated by the authors and the editorial writer, the main reason for not giving WBRT is to avoid the long-term neurotoxic effects of WBRT. Yet, this study found no difference in neurologic functioning, neurocognitive functioning, gross radiation-induced side effects, or survival times between the two groups. In fact, deterioration in neurologic function attributable to progression of brain metastases was observed in 59% of patients in the WBRT group and 86% in the SRS-alone group (p = 0.05) indicating a significantly higher rate of neurologic deterioration as a consequence of tumor progression in patients when WBRT is withheld. Thus, at very least, WBRT appears to significantly reduce the recurrence of brain metastases without demonstrable neurotoxicity. Therefore, the trial by Aoyama et al. [25] seems to support strongly the use of WBRT

as upfront treatment in the management of most patients with brain metastases. The most forceful argument in favor of adjuvant WBRT involves an examination of the effects of not giving WBRT. Patients who do not receive adjuvant WBRT suffer substantially more recurrent brain metastases than patients who are treated with WBRT. As previously noted, the harmful side effects of WBRT appear to have been overestimated in the past and are probably in the acceptable range. Unfortunately, the same cannot be said of the side effects of recurrence of brain metastases. Several studies [27, 28] have demonstrated that the recurrence of brain metastases has a negative effect on the neurocognitive functioning of patients. A study by Regine et al. [27] found that in 36 patients with brain metastases treated with SRS alone, 47% had recurrence of brain metastases and 71% of the recurrences were symptomatic. Significantly, 59% of the patients with recurrent tumors had associated neurologic deficits and 17% were unable to undergo salvage brain therapy because of their overall poor general status associated with brain tumor recurrence. These findings are now substantiated by the level 1 evidence provided by the Aoyama phase III trial where deterioration in neurologic function attributable to progression of brain metastases was observed in 59% of patients in the WBRT group versus 86% in the SRS-alone group (p = 0.05); indicating a significantly higher rate of neurologic deterioration as a consequence of tumor progression in patients when WBRT is withheld [25]. Another study by Regine et al. [28] showed that, at 3 months after treatment, patients treated for brain metastases with WBRT had greater negative changes in their mini-mental status examinations with uncontrolled brain tumors than they did with controlled brain tumors (−6.3 points versus −0.5 points, p = 0.02). Also relevant (but perhaps somewhat farther afield) was a study by Taylor et al. [29] showing that, in patients with primary brain tumors at 12 months after treatment, changes in mini-mental status examinations were worse in patients with uncontrolled tumors (−2.42 points) than in patients with controlled tumors (+0.076 points) (p = 0.0046). All of the patients in this study had received large total doses of conventional radiation therapy. These studies all strongly suggest that uncontrolled brain tumors result in a substantial decrease in mental performance and that this reduction far outweighs any decrement seen with cranial radiation therapy. Therefore, the side effects of recurrent tumors are worse than the side effects of preventive treatment. This is an extremely strong argument for the use of adjuvant WBRT in association with focal therapy.

WBRT for Recurrent Brain Metastases Brain metastases often recur, and CNS progression may be accompanied by systemic tumor progression and a decline in functional status. In general, the same types of treatment used for newly diagnosed brain metastases are also available for recurrent tumors. However, the type of previous therapy may limit the therapeutic options available at recurrence, and the development of radioresistance is not uncommon.

16.

brain metastases: whole-brain radiation therapy perspective

If patients have not already had WBRT, they should be treated with it on recurrence. However, often patients with recurrences have already been treated with WBRT, and this limits the amount of subsequent radiation that can be given safely. The amount of additional radiation that can be offered is usually in the range of 1500 to 2500 cGy, a total dose usually inadequate to control tumor growth. Several retrospective studies [30–34] have attempted to asses the efficacy of salvage WBRT. It is difficult to assess efficacy from these reports. Rates of improvement ranged from 27% to 70%; however, the range of duration of response was fairly uniform and was 2.5 to 3 months. The median survival ranged from 1.8 to 4.0 months. Relatively few long-term complications were reported; however, because the median survival is quite short, most patients did not live long enough to develop the long-term complications of radiation. The problem with the interpretation of these studies is that they often used different end-point measurements for improvement and had heterogeneous patient populations. Some included patients with poor performance status and extensive disease and others selected out favorable subgroups for radiation. One recommendation based on a retrospective study [30] is to restrict reirradiation to patients who showed an initial favorable response to radiotherapy, had a longer disease-free interval, and who remain in good general condition when the cerebral recurrence develops. However, even in this favorable subgroup, only 42% of patients showed symptomatic improvement, and the median survival after reirradiation was 5 months. Despite such relatively poor results, additional radiotherapy is frequently one of the few treatment options for patients with recurrent disease.

References 1. Berk L. An overview of radiotherapy trials for the treatment of brain metastases. Oncology 1995; 9:1205–1219. 2. Posner JB. Management of brain metastases. Rev Neurol 1992; 148:477–487. 3. Cairncross JG, Posner JB. The management of brain metastases. In: Walker MD, ed. Oncology of the Nervous System. Boston: Martinus Nijhoff, 1983:341–377. 4. Horton J, Baxter DH, Olson KB. The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol Radium Ther Nucl Med 1971; 111:334–335. 5. Markesbery WR, Brooks WH, Gupta GD, et al. Treatment for patients with cerebral metastases. Arch Neurol 1978; 35:754–756. 6. Ruderman NB, Hall TC. Use of glucocorticoids in the palliative treatment of metastatic brain tumors. Cancer 1965; 18:298–306. 7. Chang DB, Yang PC, Luh KT, et al. Late survival of non-small cell lung cancer patients with brain metastases. Chest 1992; 101: 1293–1297. 8. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980; 6: 1–9. 9. Gelber RD, Larson M, Borgelt BB, et al. Equivalence of radiation schedules for the palliative treatment of brain metastases in patients with favorable prognosis. Cancer 1981; 48:1749–1753. 10. Kurtz JM, Gelber RD, Brady LW, et al. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981; 7:891–895.

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11. Deiner-West M, Dobbins TW, Phillips TL, et al. Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys 1989; 16:669–673. 12. Epstein BE, Scott CB, Sause WT, et al. Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of the Radiation Therapy Oncology Group 85–28. Cancer 1993; 7:1362–1367. 13. Murray KJ, Scott C, Greenberg H, et al. A randomized phase III study of accelerated hyperfractionated versus standard radiation in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997; 39:571–574. 14. Hoskins PJ, Crow J, Ford HT. The influence of extent and local management on the outcome of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 1990; 19:111–115. 15. Eyre HJ, Ohlsen JD, Frank J, et al. Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to the brain. J Neuro-Oncology 1984; 2:325–330. 16. Komarnicky LT, Phillips TL, Martz K, et al. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 1991; 20:53–58. 17. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003; 21:2529–2536. 18. Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral as an adjunct to whole brain radiation therapy for brain metastases. J Clin Oncol 2006; 24:106–114. 19. DeAngelis LM, Mandell LR, Thaler HT, et al. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 1989; 24:798–805. 20. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45:427–434. 21. Chougule PB, Burton-Williams M, Saris S, et al. Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 2000; 48:114. 22. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial. Lancet 2004; 363:1665– 1672. 23. Elveen T, Andrews DW. Summary of RTOG 95-01 phase III randomized trial of whole brain radiation with and without stereotactic radiosurgery boost, including presentation of a clinical case study. Am J Oncol Rev 2004; 3:592–600. 24. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280:1485–1489. 25. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs Stereotactic radiosurgery alone for the treatment of brain metastases. JAMA 2006; 295: 2483–2491. 26. Raizer J. Radiosurgery and whole-brain radiation therapy for brain metastases. JAMA 2006; 295:2535–2536. 27. Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with acceleratedfraction vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys 2001; 51:711–717.

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28. Regine WF, Huhn JL, Patchell RA, et al. Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery al in patients with newly diagnosed brain metastases: results and implications. Int J Radiat Oncol Biol Phys 2002; 52:333–338. 29. Taylor BV, Buckner JC, Cascino TL, et al. Effects of radiation and chemotherapy on cognitive function in patients with highgrade gliomas. J Clin Oncol 1998; 16:2195–2201. 30. Hocht S, Wiegel T, Hinkelbein W. Reirradiation for recurrent brain metastases. Controversies in Neuro-Oncology. Front Radiat Oncol Basal 1999; 33:327–331.

31. Hazuka MB, Kinzie JJ. Brain metastases: results and effects of reirradiation. Int J Radiat Oncol Biol Phys 1988; 15:433–437. 32. Kurup P, Reddy S, Hendrickson FR. Results of re-irradiation for cerebral metastases. Cancer 1980; 46:2587–2589. 33. Wong WW, Schild SE, Sawyer TE, et al. Analysis of outcome in patients reirradiated for brain metastases. Int J Rad Oncol Biol Phys 1996; 34:585–590. 34. Cooper JS, Steinfeld AD, Lerch IA. Cerebral metastases: value of reirradiation in selected patients. Radiology 1990; 174:883– 885.

1 7

High-Grade Gliomas David Roberge and Luis Souhami

Introduction Primary brain tumors are classified according to their predominant cell type. Glial neoplasms are the most common primary intracranial malignancies and are classified as astrocytic tumors, oligodendroglial tumors, and ependymal tumors. Astrocytomas are the most common variant of glioma, and most adult astrocytomas are of high grade. Of these, glioblastoma multiforme (GBM), or astrocytoma grade IV, represents the most common subtype [1], making this the most common malignant tumor in adults. Despite the best contemporary use of surgery, radiation, and chemotherapy, long-term survival of patients with GBM has been distinctly uncommon. In unselected series, the 5-year survival has been as low as 2% [2, 3]. Anaplastic astrocytoma (AA), or astrocytoma grade III, represents less than 20% of malignant gliomas and is associated with a more favorable outcome [1, 4]. For the scope of this chapter, only high-grade astrocytic tumors will be discussed. High-grade astrocytic tumors are infiltrating tumors that can rapidly enlarge, resulting in various signs and symptoms, such as focal or generalized seizures, headache, visual disturbances, speech disturbances, changes in mental status, and motor or sensory deficits. Malignant glial tumors are thought to evolve from an accumulation of multiple genetic aberrations in normal precursor cells. In a stepwise fashion, this accumulation of deleterious genetic alterations may lead to transformation to a low-grade glioma and to the subsequent aggressive phenotype associated with high-grade tumors. Several molecular studies have generated multiple markers linked with malignant gliomas, including chromosomal deletion, addition, mutation, and gene amplification, which may have important clinical implications [5]. Both GBM and AA can be of two types based on their clinical presentation. Primary high-grade astrocytomas occur de novo and are associated with short duration of symptoms and worse prognosis, and secondary high-grade gliomas often occur in patients with a previous low-grade astrocytoma, suggesting a different pathogenesis [6]. High-grade glioma (HGG) is a local disease. Distant spread is a rare event, and 90% of recurrences are located within 2 cm of the original enhancing lesion [7–10]. Overall, the prognosis of HGG is related to tumor grade, performance status, age, and treatment. Five other prognostic factors were

incorporated in a 1993 prognostic scheme based on recursive partitioning analysis (RPA) of the individual patient data from three Radiation Therapy Oncology Group (RTOG) trials [4]. Using several prognostic variables (Table 17-1), patients were divided into six classes with median survivals ranging from 4.7 to 58.6 months. The RPA classification is now frequently used in the comparison of treatment results from different series. Despite intermittent waves of enthusiasm regarding various treatment modalities, the survival of patients with HGG has not increased substantially from 1950 to 2000. In this chapter, we describe and contextualize the use of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (F-SRT) in the management of primary and recurrent malignant gliomas.

Historical Perspective The poor prognosis of HGG is known for many years. In 1926, Bailey and Cushing, in reference to what they at the time called “spongioblastoma multiforme,” made the following observation: “Operative procedures, howsoever radical [block extirpations repeated on signs of recurrence; saturation with X-rays or radium emanations after wide decompression with or without surgical interference with the tumor], have apparently done little more than to prolong life, save vision, and alleviate headache for an average of a few months. . . . Whether deep Roentgenization ever does more than hold the growth temporarily in check is problematical” [11]. By the time Elvidge, Penfield, and Cone published their “McGill series” in 1937, the name “glioblastoma multiforme” had become widely accepted, and neurosurgery was still faced with the same “difficult human problem” posed by these patients [12]. Thirteen years after the publication of Elvidge and colleagues [12], a case history was published as part of a paper reviewing 70 glioblastoma multiforme patients treated at the Montefiore Hospital [13] (Case Study 17-1). The described case represented the longest surviving patient in the literature of the day [13]. Prognostic factors for

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TABLE 17-1. RTOG recursive partitioning analysis classes. Class

Definition


Two-year survival (%)

I

Age 70

Median 90 (50–100)

61% >70

Median tumorvolume (cm3)

20 (8–46)

16 (2–60)

24 (2–115)

14 (6–23)

6.5 (1–31)†

50

EBRT

45–60 Gy in 14/18 patients

0–66

Median 59.4 (44–62)

Median 60 (54–60)

GBM all, mean 60 Gy

60 Gy accelerated

73/78

All 24/31 >59 Gy

Median followup (months)

10 (3–22)

30 (living)

6 (minimum)

—

25 (minimum)

—

Number of reoperation

0/2

—

0/10

0/4

3/22†

1/14

20/39

—

Prognostic factors on multivariate analysis

—

Age, KPS, extent of surgery*

KPS*

Reoperation*

Age, KPS†

None significant

Age

Age, SRS

9.5

8.8

*Univariate analysis. †

For entire group, including recurrent tumors.

Questions may arise about the timing of the radiosurgery boost in the RTOG trial. Although both pre- and post-EBRT boosts have been used, a look at Table 17-4 will reveal that post-EBRT boosts are more common in reported phase II data. At the time of the study design in 1993, the choice of an upfront boost for the RTOG 93-05 trial was motivated primarily by three factors: (1) to benefit from controlling potential accelera-

TABLE 17-5. Comparison of survival results between radiosurgery and RTOG treated patients based on recursive partitioning analysis. Radiosurgery RPA

3 4 5

RTOG


Two-year OS


Two-year OS

38.1 19.6 13.1

75% 34% 21%

17.9 11.1 8.9

35% 15% 6%

ted tumor repopulation, (2) to avoid exclusion of any patient entering the radiosurgical arm because of tumor progression during the EBRT, and (3) to avoid the bias inherent in selecting patients after fractionated radiotherapy. Two reports on the use of a focal boost post-EBRT published at that time [59, 65] showed that a large proportion of patients (10% to 47%) developed tumor progression while undergoing the EBRT. Even with the strategy of an upfront SRS boost, 7% of the patients in the SRS arm had to be excluded because of tumor progression. Biologically early intensification of the radiation seems favorable, and there is no convincing evidence that a postEBRT SRS boost is radiobiologically advantageous over a preEBRT SRS boost. Case series of post-EBRT boosts cannot report patient outcomes on an intent to treat basis and have included patients receiving radiosurgery up to a mean of 6.2 months after their diagnosis [49]. The additional bias introduced by including patients who still have small nonprogressing tumors and a good

214


FIGURE 17-3. Patient H.L., a 73-year-old gentleman treated for glioblastoma multiforme on the radiosurgery arm of RTOG 93-05. Prior to 60 Gy of EBRT, the residual tumor in the left temporal lobe was boosted using a three-isocenter plan using the McGill dynamic stereo-

tactic technique. (a) Fifteen grays was delivered to the 50% isodose surface, as per protocol guidelines. (b) The tumor failed locally 13 months later.

performance status several months after their initial diagnosis is obvious. Of interest, despite using a different temporal sequence of their boost implants, in the two randomized trials of stereotactic brachytherapy boost [35, 66], both had similar results, failing to demonstrate a survival benefit for this technique when given either before or after the EBRT. A summary of the relative merits of pre- and post-EBRT SRS is presented in Table 17-6. Although the phase III data do not unequivocally disprove any benefit to post-EBRT radiosurgical boosts, there is no reason to believe that this approach is superior. Thus, the best evidence currently available does not support an improvement in median survival after the addition a SRS to

a standard treatment regimen for GBM. There is also no evidence of an improvement in quality of life or a change in pattern of failure. There is, however, an increase in both acute and late radiation-related toxicity. These results are not surprising in a disease where surgical excision of the radiosurgery target is not curative.

100

Single Fraction Stereotactic Radiosurgery for Recurrent HGGs Treatment of recurrent HGG is essentially palliative; cases of patients surviving more than 5 years are anecdotal. Strategies available [67] include reoperation, chemotherapy, EBRT reirradiation, SRS, F-SRT, interstitial brachytherapy, supportive care, and so forth. Each of these modalities has its own toxicities and indications. Currently published phase III studies support

RT Survival Rate

80

SRS+RT TABLE 17-6. Timing of SRS in the primary management of HGG.

60

Pros

40

20

SRS before EBRT

SRS after EBRT

Increases number of eligible patients All patients will receive protocol program Decreases selection bias

Better definition of tumor margins Target may be smaller

0 0

6

12

18 24 30 36 Months FIGURE 17-4. Overall survival by treatment arm on RTOG 9305. (Reprinted from Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004; 60:853–860. With permission from Elsevier.)

Cons

Patients not fully recovered from surgery Radiosurgery potentially delivered to a larger target Because of postoperative changes, imaging less satisfactory

SRS may be planned far ahead Patients fully recovered from surgery Target may enlarge Tumor may grow beyond 4 cm Performance status may deteriorate Selection bias

17.

high-grade gliomas

215

FIGURE 17-5. Patient C.B., a 55-year-old, was treated for a left frontal GBM on the radiotherapy-only arm of the EORTC/NCIC protocol. His disease progressed soon after the end of radiotherapy, and he was given temozolomide. The tumor progressed after the second cycle of temozolomide. The patient was switched to BCNU chemotherapy, and his disease remained stable. Ten months after EBRT, there was evidence of further disease progression and he was treated with SRS. (a) Two

isocenters were treated using the McGill dynamic stereotactic technique. A dose of 15 Gy was prescribed to the 50% isodose surface. (b) He subsequently developed what was believed to be an area of asymptomatic radionecrosis, managed conservatively. (c) He was well until the tumor progressed a second time, 3 years after SRS. This second failure was at an edge of the tumor bed outside the radiosurgery target volume (arrow), and repeat SRS was recently performed.

an improvement in median survival from the use of BCNU polymers [68] and an improvement in softer measures of outcome from the use of oral temozolomide [67, 69, 70]. There are no phase III trials of radiosurgery for recurrent tumors. Only very selected cases are candidates for SRS at recurrence. Figure 17-5 illustrates the case of a patient treated at our institution with apparent clinical benefit. A 1994 series from the University of California San Diego included 15 patients with recurrent HGG [71]. Doses prescribed ranged from 12 to 15 Gy based on the target volume. Of the total group of 20 patients, 7 have suffered intracranial pressure–related acute toxicity (fatal in 1 patient), and 1 has suffered from a late somnolence syndrome. Outcome was not reported by tumor type. In 1995, the experience of the University of Minnesota was published [72]. A total of 35 recurrent tumors (26 GBM, 9 AA) had been treated with single doses of radiation (7.5 to 40 Gy). The median survival for all patients from the time of SRS was 8 months. The actuarial rate of necrosis requiring surgery was 14% (the overall reoperation rate was 31%). Despite SRS, 85% of recurrences were local or marginal. In 1999, this experience was updated to include a total of 46 patients and then had a median survival of 11 months [73]. Kondziolka et al. reported on the University of Pittsburgh experience treating 42 patients with recurrent HGG [49]. Median survival from radiosurgery was favorable, 30 months for GBM, 31 for AA. There were no cases of acute toxicity, and three patients experiences late radiosurgery-related morbidity. Overall 22 of 107 (21%) of patients in this series required craniotomy after SRS. Additional institutional series can be found in Table 17-7 [74]. Common themes from these series are as follows:

Fractionated Stereotactic Radiotherapy

• Despite median survivals of 7.5 to 30 months [49, 71], only 1 patient is reported as surviving 5 years after radiosurgery (0.5%) [49]. • Toxicity is incompletely reported with up to 46% of patients experiencing treatment complications [71]. • Reported prognostic factors include histology, age, KPS, and tumor volume [49, 73, 74].

When introduced by Leksell more than 50 years ago [75], stereotactic radiosurgery was intended as a means of creating a “radiation injury.” The intent at that time was to destroy brain tissue, not selectively inactivate tumor cells intertwined with normal brain tissue. In an attempt to decrease complications through normal tissue repair and to potentially increase efficacy by allowing reoxygenation and cell-cycle reassortment, several centers have treated small series of patients with F-SRT. Often, these series are of patients with recurrent, previously irradiated lesions where there was a concern for toxicity. Beginning in 1987, patients were treated at our institution with a regimen of 42 Gy given in fractions of 7 Gy on alternating days over 2 weeks [76]. For these treatments, rigid immobilization was performed with a halo-type frame [77]. Since this early experience, the general trend for F-SRT has been toward smaller fractions using noninvasive immobilization. Authors from the Royal Marsden Hospital have reported a series of 33 patients treated with F-SRT for recurrent primary brain tumors [41]. This was a dose-escalation study conducted from January 1989 to July 1994. All of these patients had been previously irradiated. Doses ranged from 4 to 10 daily fractions of 5 Gy. The median survival of the 21 patients with recurrent HGG (11 AA, 10 GBM) was 9.6 months. A matched-pair analysis was performed using patients treated for their recurrence with nitrosourea-based chemotherapy. There was a small, statistically significant difference in median survival favoring the RT cohort. Late toxicity (not graded) was seen in 36% of the patients. At Thomas Jefferson University, from November 1994 to September 1996, 20 patients with recurrent (or persistent) HGG after external beam radiation were treated with F-SRT [42]. Three different regimens were used: 24 Gy in daily fractions of 3 Gy, 30 Gy in daily fractions of 3 Gy, and 35 Gy in daily fractions of 3.5 Gy. Median survival from the completion of F-SRT was 10.5 months. There were no grade 3 to 4 acute or late toxicities. Between April 1991 and January 1998, 71 patients with recurrent tumors (13% anaplastic oligodendrogliomas, 87%

216


TABLE 17-7. Results of SRS for recurrent HGGs. Author

Selch [82]

Chamberlain [59]

Shrieve [62]

Kondziolka [41]

Cho [86]

Larson [40]

Larson [40]

Institution

UCLA

UCSD

Harvard

University of Pittsburgh

University of Minnesota

UCSF

UCSF

Date of publication

1993

1994

1995

1997

1999

2002

2002

Number of patients

17

13

86

42

46

26*

54

Histology

12 GBM 5 AA

5 GBM 8 AA

86 GBM (14 transformed from LGG)

19 GBM 23 AA

27 GBM 15 AA 4 AO

GBM 14, GRIII 12

GBM 39, GRIII 15

Time from diagnosis (months)

Median 8

Median 15 (4–96)

Median 10.3 (2.3–115)

GBM mean 18.9, AA mean 19.8

Median 10 (1–166)

GBM median 12 (3–50), GRIII median 43 (7–175)

GBM median 7 (2–70), GRIII median 35 (2–145)

KPS

100% > 70

Median 70 (50–100)

90 (70–100)

Mean KPS 90 (50–100)†

Median 70 (40–90)

90 (70–100)

Median 70 (40–90)

Median tumor volume, cm3 (range)

28.6 (6–121)

36 (3–50.6)

10.1 (2.2–83)

6.5 (0.9–31)†

30 (3–125)

GBM 8 (1.6–29.7), GRIII 2.7 (0.4–13.4)

GBM 9.1 (0.3–29.1), GRIII 6 (0.3–20.3)

Median peripheral dose Gy (range)

24.4 (mean)

12.5 (12–15.7)

13 (6–20)

15.5 (12–25)†

17 (9–40)

GBM 15 (12–17.5), GRIII 16.5 (15–18)

GBM 16 (10–20), GRIII 17 (15–18.5)


10

GBM 15 AA 7.5

10.2

GBM 30 AA 31

11 (1–36)

GBM 38 weeks, GRIII 68 weeks

GBM 44 weeks, GRIII 59 weeks

1-year survival (%)

—

GBM 40 AA 12.5

—

45

42

—

42

2-year survival (%)

—

—

19

—

—

—

—

Median prescription isodose (range)

64

80

80 (50–100)

50 (40–90)†

50 (40–90)

25–30

50 (45–55)

Median age (range)

49 (27–79)

36 (17–62)

46 (9–77)

GBM 51 (3–72), AA 45 (3–73)†

48 (16–75)

GBM 53 (22–74), GRIII 44 (24–62)

GBM 50 (21–77), GRIII 35 (24–58)

Prior Chemo

—

100%

33%

—

57%

—

—

Prior EBRT

—

100%

100%

—

100% (median 60 Gy)

100%

100%

Median follow-up (months)

7 (3–14)

17.5 (6.8–45.1)

—

—

—

—

Reoperations

5/17

(46% complication rate)

19/86

3/22†

22%

—

—

Prognostic factors on multivariate analysis

—

—

Age, tumor volume‡

Age, KPS†

KPS, tumor grade

—

—

Survivors >5 years

None

None

None

1 (74 months)

None

None

None

8

GRIII, grade III glial tumors. *Patients treated on a protocol with Marimastat. †Including patients treated for a primary glioma. ‡Univariate analysis.

high-grade astrocytomas, 15% of these were dedifferentiated low-grade tumors) were treated at the University of Minnesota Hospital. A total of 46 of the patients in this retrospective review were treated with SRS and 25 with F-SRT [73]. For the SRS cases, the median minimum peripheral dose was 17 Gy. F-SRT was delivered to a median of 37.5 Gy in 15 fractions. The median survival from stereotactic irradiation was 11 months for SRS and 12 for F-SRT (p = 0.3). Acute complications were seen in 40% of both groups. Late complications (clinical/pathologic necrosis or cranial nerve palsy) were seen more commonly in the SRS group, 30% versus 8% (p < 0.05). The authors concluded that as the F-SRT group had worse prognostic factors, a similar median survival, and less late toxicity, it might represent a better treatment option for recurrent HGGs.

Table 17-3 summarizes some of the larger published singleinstitution series of F-SRT for HGG. Fraction sizes range from 2.5 Gy to 7 Gy for what are mostly recurrent tumors. Median survival for variable patient populations ranges from 7 to 20 months. Complication rates are incompletely reported and range from none to 27% grade IV [41, 42]. The same issues of bias that plagued the experience with single-fraction SRS apply to the younger experience utilizing F-SRT. Treatment options for recurrent lesions are numerous. If stereotactic radiation is used, the choice of fractionation may represent a compromise between convenience and risk of radionecrosis. A more definitive answer may not soon come for F-SRT. The EORTC and the Medical Research Council (MRC) had

17.

high-grade gliomas

217

FIGURE 17-6. Patient T.V., a 71-year-old, was treated on RTOG BR0023. As per protocol, five weekly fractions of 5 Gy were delivered concurrently with 50 Gy of EBRT. (a) The F-SRT was prescribed to the

80% isodose and delivered using five static, non-coplanar micro-multileaf beams. (b) The patient declined adjuvant chemotherapy and recurred locally within weeks of radiotherapy.

jointly initiated a randomized trial of F-SRT in the primary management of HGGs [78]. The patients eligible for this study were those with ≤4 cm WHO grade III to IV gliomas, age 40 mm, 7 Gy for smaller targets) of F-SRT that were delivered using 3D conformal radiotherapy (3DCRT) (GK and cone-based SRS systems were not permitted). EBRT (50 Gy) was followed by 6 cycles of BCNU (80 mg/m2 for 3 days every 8 weeks) chemotherapy. A total of 76 patients were analyzed. Treatments were well tolerated with only one acute grade 4 (lethargy) and one late grade 3 (necrosis) toxicity observed. The median survival was 12.5 months, and no survival difference was seen when results were compared with the RTOG historical database. Thus, although feasible and well tolerated, this dose-intense, accelerated regimen does not appear to improve survival. This larger RTOG trial represents more definitive evidence that a hypofractionated boost strategy may be of limited value. The case of a patient treated on this trial is presented in Figure 17-6.

Treatment Toxicities Significant acute complications (i.e., those occurring within days to weeks of treatment) are unusual and generally self-limited. Occasionally, an exacerbation of existing symptoms may occur, particularly in patients with moderate brain edema and with larger lesions (3 to 4 cm). Most patients will respond to increasing doses of corticosteroids. Late complications attributable to SRS are usually defined as necrosis within the treatment volume. In patients with GBM, distinguishing radiation-induced necrosis from tumor recurrence is not infrequently a very difficult problem and may lead to an overestimation of the rate of treatment-induced complications. The rate of reoperation for ranges from 0 [55] to 54% [50]. However, viable cells are identified in the majority of such reoperation specimens. Pure necrosis without residual tumor cells is a rare event.

218


In the review involving three institutions and 115 patients [60], late complications occurred in 16% of the patients. Radiation necrosis was diagnosed in the majority of the patients (17/19) either by reoperation or by imaging evaluation. Prolonged corticosteroid therapy was required in 47% of the patients. In the recent RTOG randomized trial (RTOG 93-05), there were four cases (5%) of grade III radiation toxicity in the SRS arm and no cases in the standard arm. Of the 28 patients in the SRS arm undergoing subsequent salvage surgery, 7 (25%) had only necrosis in the resection specimen compared with 3 of 31 patients (9.6%) in the standard arm. Clark et al. [82], from McGill University, have described a single number parameter for use during F-SRT that may be used to represent effective dosage to intracranial structures that are irradiated with inhomogeneous dose distribution having steep dose gradients. Evaluating biologically effective dosevolume histograms, the authors obtained an integral biologically effective dose (IBED) for each case and demonstrated a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiation therapy. Using α/β ratio of 2.5 as representative of the dose-response of brain-stem tissue, they were able to establish a threshold value in the region of 60 Gy2.5. The determination of the IBED can be a valuable parameter to be used as a guide to determine the appropriate treatment volume and fractionation regimen that will minimize toxicity to surrounding vital structures in patients undergoing F-SRT.

Future Directions in Stereotactic Radiation for Glial Neoplasms New strategies in the application of stereotactic radiation for malignant gliomas include changes in planning and fractionation; concurrent use of chemotherapy; and use of radiation modifiers and biological agents. Results of Temple University and of Staten Island looking at chemotherapy (cis-platinum and Taxol [Taxol; BristolMeyers–Squibb, Princeton, NJ]) and F-SRS for recurrent glioma have been reported [40, 83]. Retrospectively, these results are similar to patients treated without chemotherapy, and further use of these agents with SRS is unlikely. Other treatment strategies that were brewing in the laboratories of the University of Pennsylvania include radioprotection of normal tissue [84, 85] or tumor sensitization through gene transfer [86]. In view of the recent data regarding temozolomide, new trials in the treatment of HGG will have to incorporate this agent. Because the European intergroup randomized trial was closed prematurely and therefore will be unable to demonstrate a level 1 benefit to F-SRT, the approach will likely fade in favor of integrating new agents with conventional EBRT. At McGill University, we are currently treating selected patients with a hypofractionated regimen of 60 Gy in 20 fractions. The first 20 patients treated using this dose scheme without chemotherapy had a median survival of 8.1 months [87]. With a median followup of 7 months, no late toxicity was observed. With the addition of concurrent temozolomide for the latest 35 patients, the median survival is now 14.4 months. A phase I trial (NCI-T99-0041) investigating the sensitization of SRS with gadolinium texaphyrin was recently closed. In

this trial, GBM patients with a KPS >60 and a tumor 52 Gy. For skull base benign meningiomas, a 5- and 10-year PFS rate of 92% and 83%, respectively, has been reported after XRT [35]. Atypical and malignant meningiomas differ from their benign counterparts in that they frequently recur after complete excision and are more often fatal. Milosevic et al. [36] studied the role of XRT for those lesions and found that young

FIGURE 19-1. (A) MRI scan from case 1 showing recurrence of an atypical meningioma in left tentorium 45 months after initial resection. (B) Treatment plan with shaped beans, 14 Gy, 90% isodose line, volume

Case Study 19-1 A 47-year-old woman had a left frontotemporal atypical meningioma that was resected on January 1998. On October 2001, she presented with headaches, and the MRI scan revealed a small recurrence (Fig. 19-1A). She was treated by SRS, 14 Gy delivered to 90% isodose line, volume of 1.07 cm3 (Fig. 19-1B). The follow-up scan 33 months after treatment showed a stable tentorial lesion (not shown) but a new lesion (arrow) in the floor of the left medial cranial fossa (Fig. 19-2A). The patient was retreated with 18 Gy delivered to 90% isodose line, volume of 0.65 cm3 (Fig. 19-2B). The last follow-up MRI scan in January 2005 showed both lesions decreasing in size (Fig. 19-3).

age (

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