Principles and Practice of Stereotactic Radiosurgery

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

Principles and Practice of Stereotactic Radiosurgery

EditorsLawrence S. Chin, MD William F. Regine, MDProfessor and Chairman Professor and ChairmanDepartment of Neurosurgery Department of Radiation OncologyBoston University School of Medicine University of Maryland Medical SchoolBoston, MA, USA Baltimore, MD, USA

ISBN: 978-0-387-71069-3 e-ISBN: 978-0-387-71070-9DOI: 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 connec-tion 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 identifi ed 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.

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Foreword

v

When fi rst asked to write a foreword to Principles and Practice of Stereotactic Radio-surgery, 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. Pio-neering Gamma Knife surgery during the 1970s and 1980s was often a lonely endeavor, with long fl ights 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 Stock-holm. 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 fi rst 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 refi nement 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 radia-tion therapy, or SRT.

We believed that there was a gray zone between radiosurgery and conventional radio-therapy 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 treat-ment of functional brain disorders, including epilepsy, movement disorders, obsessive-compulsive 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 stereotacti-cally 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 benefi t 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 epito-mizes the word comprehensive!

This textbook contains a wealth of information and truly encompasses the whole fi eld 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 fi eld 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

v i foreword

v i i

Preface

The 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 fi eld 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 fi eld 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. There-fore, 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 col-leagues 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 fi ve main sections, with the fi rst 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 concen-trates on the principles of radiation physics and radiobiology that explain the noninvasive, yet powerful, nature of stereotactic radiation treatments. Other topics covered include treat-ment 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 fi gure in their disciplines. We hope you fi nd 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 fi eld 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 radiosur-gery practice, and nursing issues. We also included a few topics that have controversial aspects: regulatory and reimbursement issues, medicolegal pitfalls, and radiosurgery seman-tics. In these chapters, the reader will fi nd that some author opinion is unavoidable but does not necessarily refl ect 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 fi nal form. We thank our assistants Debbie

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 radiosur-gery, Buz Hoff, Martin Weiss, Michael Apuzzo, Steven Giannotta, Howard Eisenberg, Simon Kramer, Larry Kun, and Jay Loeffl er. 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

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Contents

Foreword by Dan Leksell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiContributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

PART I The Fundamentals

1 The History of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . 3Michael Schulder and Vaibhav Patil

2 Neuroimaging in Radiosurgery Treatment Planning and Follow-up Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Clark C. Chen, Paul H. Chapman, Hanne Kooy, and Jay S. Loeffl er

3 Techniques of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . 25Chris Heller, Cheng Yu, and Michael L.J. Apuzzo

PART II Radiation Biology and Physics

4 The Physics of Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . 33Siyong Kim and Jatinder Palta

5 Radiobiological Principles Underlying Stereotactic Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51David J. Brenner

6 Experimental Radiosurgery Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Ajay Niranjan and Douglas Kondziolka

7 Treatment Planning for Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . 69David M. Shepard, Cedric Yu, Martin Murphy, Marc R. Bussière, and Frank J. Bova

8 Designing, Building and Installing a Stereotactic Radiosurgery Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Lijun Ma and Martin Murphy

PART III Stereotactic Radiosurgery Techniques

9 Gamma Knife Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Ajay Niranjan, Sait Sirin, John C. Flickinger, Ann Maitz, Douglas Kondziolka and L. Dade Lunsford

10 Linear Accelerator Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129William A. Friedman

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11 Proton Beam Radiosurgery: Physical Bases and Clinical Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Georges Noel, Markus Fitzek, Loïc Feuvret, and Jean Louis Habrand

12 Robotics and Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Cesare Giorgi and Antonio Cossu

13 CyberKnife Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171John R. Adler Jr., Alexander Muacevic, and Pantaleo Romanelli

PART IV Treatment of Disease Types

14 Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181John H. Suh, Gene H. Barnett, and William F. Regine

15 Metastatic Brain Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . 193Raymond Sawaya and David M. Wildrick

16 Brain Metastases: Whole-Brain Radiation Therapy Perspective . . . . . . 201Roy A. Patchell and William F. Regine

17 High-Grade Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207David Roberge and Luis Souhami

18 Malignant Glioma: Chemotherapy Perspective . . . . . . . . . . . . . . . . . . . . 223Roger Stupp and J. Gregory Cairncross

19 Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Carlos A. Mattozo and Antonio A.F. de Salles

20 Meningioma: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Lawrence S. Chin, Pulak Ray, and John Caridi

21 Intracranial Meningioma: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Leland Rogers, Dennis Shrieve, and Arie Perry

22 Meningioma: Systemic Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . 271Steven Grunberg

23 Acoustic Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275William M. Mendenhall, Robert J. Amdur, Robert S. Malyapa, and William A. Friedman

24 Acoustic Neuroma: Surgical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . 283Indro Chakrabarti and Steven L. Giannotta

25 Acoustic Neuromas and Other Benign Tumors: Fractionated Stereotactic Radiotherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

David W. Andrews, Greg Bednarz, Beverly Downes, and Maria Werner-Wasik

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26 Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Kintomo Takakura, Motohiro Hayashi, and Masahiro Izawa

27 Pituitary Adenomas: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . 309William T. Couldwell and Martin H. Weiss

28 Pituitary and Pituitary Region Tumors: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317Jonathan P.S. Knisely and Paul W. Sperduto

29 Pituitary and Pituitary Region Tumors: Medical Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327Mansur E. Shomali

30 Pediatric Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331Andrew Reisner, Nicholas J. Szerlip, and Lawrence S. Chin

31 Pediatric Brain Tumors: Conformal Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341Thomas E. Merchant

32 Pediatric Brain Tumors: Chemotherapy Perspective . . . . . . . . . . . . . . . . 351Amar Gajjar

33 Pineal Region Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355Gregory P. Lekovic and Andrew G. Shetter

34 Pineal Region Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . 365Alfred T. Ogden and Jeffrey N. Bruce

35 Pineal Tumors: Fractionated Radiation Therapy Perspective . . . . . . . . 371Steven E. Schild

36 Pineal Region Tumors: Chemotherapy Perspective . . . . . . . . . . . . . . . . . 377Barry Meisenberg and Lavanya Yarlagadda

37 Skull Base Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383Stefanie Milker-Zabel, Young Kwok, and Jürgen Debus

38 Skull Base Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . 393James K. Liu, Oren N. Gottfried, and William T. Couldwell

39 Skull Base Tumors: Fractionated Stereotactic Radiotherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401René-Olivier Mirimanoff and Alessia Pica

40 Head and Neck Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Daniel T.T. Chua, Jonathan Sham, Kwan-Ngai Hung, and Lucullus Leung

41 Head and Neck Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . 421Gregory Y. Chin and Uttam K. Sinha

x i i contents

42 Head and Neck Malignancies: Chemotherapy and Radiation Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425Mohan Suntharalingam, Kathleen Settle, and Kevin J. Cullen

43 Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431Robert L. Dodd, Iris Gibbs, John R. Adler Jr., and Steven D. Chang

44 Spine Tumors: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443Gabriel Zada and Michael Y. Wang

45 Spinal Metastases: Fractionated Radiation Therapy Perspective . . . . . 455Eric L. Chang and Almon S. Shiu

46 Arteriovenous Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459Bruce E. Pollock

47 Arteriovenous Malformations: Surgery Perspective . . . . . . . . . . . . . . . . 473 Ricardo J. Komotar, Elena Vera, J. Mocco, and

E. Sander Connolly Jr.

48 Cerebral Arteriovenous Malformations: Endovascular Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Felipe C. Albuquerque, David Fiorella, and Cameron G. McDougall

49 Cavernous Malformations and Other Vascular Diseases . . . . . . . . . . . . 491Ajay Niranjan, David Mathieu, Douglas Kondziolka, John C. Flickinger, and L. Dade Lunsford

50 Cerebral Cavernous Malformations: Surgical Perspective . . . . . . . . . . . 503Robert L. Dodd and Gary K. Steinberg

51 Cavernous Malformations and Other Vascular Abnormalities: Observation-Alone Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513Sepideh Amin-Hanjani and Frederick G. Barker II

52 Trigeminal Neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519Lawrence S. Chin, Shilpen Patel, Thomas Mattingly, and Young Kwok

53 Trigeminal Neuralgia: Surgical Perspective . . . . . . . . . . . . . . . . . . . . . . . . 527David B. Cohen, Michael Y. Oh, and Peter J. Jannetta

54 Trigeminal Neuralgia: Medical Management Perspective . . . . . . . . . . . 535Neil C. Porter

55 Movement Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541Sangjin Oh, Ajay Niranjan, and William J. Weiner

56 Movement Disorders: Deep-Brain Stimulation Perspective . . . . . . . . . . 549John Y.K. Lee, Joshua M. Rosenow, and Ali R. Rezai

57 Movement Disorder: Medical Perspective . . . . . . . . . . . . . . . . . . . . . . . . 559Sangjin Oh and William J. Weiner

58 Psychiatric and Pain Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563Jason Sheehan, Nader Pouratian, and Charles Sansur

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59 Intractable Epilepsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573Jean Régis, Fabrice Bartolomei, and Patrick Chauvel

60 Epilepsy: Surgery Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583Keith G. Davies and Edward Ahn

61 Ocular and Orbital Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593Gabriela Šimonová, Roman Liscák, and Josef Novotný Jr.

62 Stereotactic Body Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611Laura A. Dawson

63 Stereotactic Body Radiation Therapy: Fractionated Radiation Therapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Gordon W. Wong, Rafael R. Mañon, Wolfgang Tomé, and Minesh Mehta

64 Stereotactic Body Radiation Therapy: Brachytherapy Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643Caroline L. Holloway, Desmond O’Farrell, and Phillip M. Devlin

PART V Patient Care and Socioeconomic Issues

65 Complications and Management in Radiosurgery . . . . . . . . . . . . . . . . . . 649Isaac Yang, Penny K. Sneed, David A. Larson, and Michael W. McDermott

66 Cost-Effectiveness and Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . 663Minesh Mehta and May N. Tsao

67 Regulatory and Reimbursement Aspects of Radiosurgery . . . . . . . . . . 673Rebecca Emerick

68 Medicolegal Issues in Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . 681April Strang-Kutay

69 The Semantics of Stereotactic Radiation Therapy . . . . . . . . . . . . . . . . . . 687Louis Potters

70 Building a Radiosurgery Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691N. Scott Litofsky and Andrea D’Agostino-Demers

71 Patient Care in Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . 699Terri F. Biggins

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709

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Contributors

John R. Adler Jr., MDProfessor of Neurosurgery, Stanford

University Medical Center, and Attending Neurosurgeon, Stanford University Medical Center, Stanford, CA, USA

Edward Ahn, MDFellow in Neurosurgery, Department of

Neurosurgery, Children’s Hospital of Boston, Boston, MA, USA

Felipe C. Albuquerque, MDAssistant Director of Endovascular

Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Robert J. Amdur, MDProfessor of Radiation Oncology,

University of Florida College of Medicine, Gainesville, FL, USA

Sepideh Amin-Hanjani, MDAssistant Professor, Neurosurgery,

University of Illinois at Chicago, Chicago, IL, USA

David W. Andrews, MDProfessor and Vice Chairman, Chief,

Division of Neuro-Oncologic Neurosurgery & Stereotactic Radiosurgery, Thomas Jefferson University, Philadelphia, PA, USA

Michael L.J. Apuzzo, MDEdwin 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, MDAssociate Professor, Department of

Neurosurgery, Harvard Medical School; Associate Visiting Neurosurgeon, Brain Tumor Center, Massachusetts General Hospital, Boston, MA, USA

Gene H. Barnett, MD, FACSProfessor of Surgery, Cleveland Clinic

Lerner College of Medicine; Director, Brain Tumor Institute, Cleveland Clinic, Cleveland, OH, USA

Fabrice Bartolomei, MD, PhDService de Neurophysiologie Clinique, Université de la Méditerranée, Marseille, France

Greg Bednarz, PhDMedical Physicist, Department of Radiation

Oncology, Thomas Jefferson University, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA

Terri F. Biggins, RN, BSNPatient Care Coordinator, University of

Maryland, Gamma Knife Center, Baltimore, MD, USA

Frank J. Bova, PhDProfessor of Neurosurgery, University of Florida, Gainesville, FL, USA

David J. Brenner, PhD, DScProfessor 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, MDProfessor of Neurological Surgery,

Department of Neurosurgery, Columbia University—College of Physicians and Surgeons, New York, NY, USA

Marc R. Bussière, MSc, DABRMedical Radiation Physicist, Department of

Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

J. Gregory Cairncross, MD, FRCPCDepartment of Clinical Neurosciences,

University of Calgary, Foothills Hospital, Alberta, Canada

John Caridi, MDResident, Department of Neurosurgery,

University of Maryland, Baltimore, MD, USA

Indro Chakrabarti, MD, MPHNeurosurgery Chief Resident,

University of Southern California, Los Angeles, CA, USA

Eric L. Chang, MDAssociate Professor, Department of

Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Steven D. Chang, MDAssistant Professor of Neurosurgery,

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

Paul H. Chapman, MDProfessor, Department of Neurosurgery,

Massachusetts General Hospital, Boston, MA, USA

Patrick Chauvel, MDService de Neurophysiologie Clinique,

Université de la Méditerranée, Marseille, France

Clark C. Chen, MD, PhDFellow, Radiosurgery, Department of

Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

Gregory Y. Chin, MDAttending Physician, Department of Head

and Neck Surgery, Kaiser Permanente Walnut Creek Medical Center, Walnut Creek, CA, USA

Lawrence S. Chin, MDProfessor and Chairman, Department of

Neurosurgery, Boston University School of Medicine, Boston, MA, USA

Daniel T.T. Chua, FRCRAssociate Professor, Department of

Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong

David B. Cohen, MDFunctional Neurosurgery Fellow,

Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, PA, USA

E. Sander Connolly Jr., MDAssociate Professor, Department of

Neurological Surgery, Columbia University, New York, NY, USA

Antonio Cossu, MTE3DLine Medical Systems, Milano, Italy

William T. Couldwell, MD, PhDProfessor and Joseph J. Yager Chair,

Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA

Kevin J. Cullen, MDDirector, 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, FRCSAssociate Professor, Department of

Neurosurgery, Boston University School of Medicine, Boston, MA, USA

Laura A. Dawson, MDAssociate Professor, Department of

Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Jürgen Debus, MD, PhDDepartment of Radiation Oncology and

Radiation Therapy, University of Heidelberg, Heidelberg, Germany

Antonio A.F. de Salles, MD, PhDProfessor, Department of Surgery, Division

of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Phillip M. Devlin, MDAssistant 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

xv i contr ibutors

Robert L. Dodd, MD, PhDEndovascular Fellow, Department of

Neurosurgery, Stanford University, Stanford, CA, USA

Beverly Downes, MSChief Medical Physicist, Stereotactic

Radiosurgery Units, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA

Rebecca Emerick, MS, MBA, CPAExecutive Director, International

RadioSurgery Association (IRSA), Harrisburg, PA, USA

Loïc FeuvretCentre de protonthérapie d’Orsay-Institut

Curie, Campus universitaire, Orsay, France

David Fiorella, MD, PhDStaff Neuroradiology, Department of

Neuroradiology and Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH, USA

Markus Fitzek, MDRadiation Oncology Center, Tufts—New

England Center, Tufts University School of Medicine, Boston, MA, USA

John C. Flickinger, MDProfessor, Department of Neurological

Surgery, University of Pittsburgh, Pittsburgh, PA, USA

William A. Friedman, MDProfessor and Chair, Department of

Neurosurgery, University of Florida College of Medicine, Gainesville, FL, USA

Amar Gajjar, MDProfessor 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

Steven L. Giannotta, MDChairman, Department of Neurosurgery,

University of Southern California, Los Angeles, CA, USA

Iris Gibbs, MDAssistant Professor of Radiation Oncology,

Stanford University, Stanford, CA, USA

Cesare Giorgi, MDNeurosurgeon, Department of

Computer-assisted Neuro and Radiosurgery, Ospedale S. Maria, Terni, Italy

Oren N. Gottfried, MDResident, Department of Neurosurgery,

University of Utah, Salt Lake City, UT, USA

Steven Grunberg, MDProfessor of Medicine, Department of

Medical Oncology, University of Vermont, Burlington, VT, USA

Jean Louis HabrandCPO-Institut Curie, Orsay, France

Motohiro Hayashi, MD, PhDLecturer of the Department of

Neurosurgery, Chief of Gamma Knife Center, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan

Chris Heller, MDDepartment of Neurological Surgery, Keck

School of Medicine, University of Southern California, Los Angeles, CA, USA

Caroline L. Holloway, MD, FRCPCRadiation Oncologist, Department of

Radiation Oncology, BCCA—Centre for the Southern Interior, Kelowna, BC, Canada

Kwan-Ngai Hung, FRCSConsultant Neurosurgeon, Department of

Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

Masahiro Izawa, MD, PhDAssistant Professor, Department of

Neurosurgery, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan

Peter J. Jannetta, MDProfessor, 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

Siyong Kim, PhDDepartment of Radiation Oncology, Mayo

Clinic, Jacksonville, FL, USA

contr ibutors xv i i

Jonathan P.S. Knisely, MD, FRCPCAssociate 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, MDResident, Neurosurgery, Department of

Neurological Surgery, Columbia University, New York, NY, USA

Douglas Kondziolka, MD, FRCS, FACSProfessor of Neurological Surgery,

University of Pittsburgh, Pittsburgh, PA, USA

Hanne Kooy, PhDResearch Associate, Department of

Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

Young Kwok, MDDepartment of Radiation Oncology,

University of Maryland Medical Center, Baltimore, MD, USA

David A. Larson, PhD, MD, FACRProfessor 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, MDAssistant Professor, Department of

Neurosurgery, University of Pennsylvania; Medical Director, Penn Gamma Knife at Pennsylvania Hospital, University of Pennsylvania, Philadelphia, PA, USA

Gregory P. Lekovic, MD, PhD, JDResident Neurological Surgery, Division of

Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ, USA

Lucullus Leung, PhDPhysicist, Department of Clinical Oncology,

Queen Mary Hospital, Pokfulam, Hong Kong

Roman Liscák, MD3rd 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, FACSAssociate 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, MDResident, Department of Neurosurgery,

University of Utah, Salt Lake City, UT, USA

Jay S. Loeffl er, MDChief Radiation Oncology, Department of

Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

L. Dade Lunsford, MD, FACSProfessor and Chairman, Department of

Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

Lijun Ma, PhDAssociate Professor, Department of

Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

Ann Maitz, MScAssistant Professor, Department of

Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

Robert S. Malyapa, MD, PhDAssistant Professor, Department of

Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA

Rafael R. Mañon, MDDepartment of Human Oncology,

University of Wisconsin Hospital, Madison, WI, USA

David Mathieu, MD, FRCS(C)Visiting Assistant Professor, Department of

Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

xv i i i contr ibutors

Thomas Mattingly, MDResident, Department of Neurosurgery,

University of Maryland, Baltimore, MD, USA

Carlos A. Mattozo, MDProfessor, Department of Surgery, Division

of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Michael W. McDermott, MD, FRCSCProfessor 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, MDChief of Endovascular Neurosurgery,

Barrow Neurological Institute—Neurosurgery, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Minesh Mehta, MDProfessor and Chairman, Department of

Human Oncology, University of Wisconsin Hospital, Madison, WI, USA

Barry Meisenberg, MDProfessor of Medicine, Chief Division of

Hematology and Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

William M. Mendenhall, MDProfessor, Department of Radiation

Oncology, University of Florida College of Medicine, Gainesville, FL, USA

Thomas E. Merchant, DO, PhDMember and Chief, Division of Radiation

Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Stefanie Milker-Zabel, MDDepartments of Radiation Oncology and

Radiation Therapy, Hospital of Heidelberg, Heidelberg, Germany

René-Olivier Mirimanoff, MDProfessor, Department of Radiation

Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

J. Mocco, MDResident, Neurosurgery, Department of

Neurological Surgery, Columbia University, New York, NY, USA

Alexander Muacevic, MDCyberKnife Center Munich, Munich,

Germany

Martin Murphy, PhDAssociate Professor, Department of

Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA

Ajay Niranjan, MBBS, MS, MChAssistant Professor of Neurological

Surgery, University of Pittsburgh, Pittsburgh, PA, USA

Georges Noel, MDCentre de lutte contre le Paul Strauss,

Department of Radiotherapy, Strasbourg, France

Josef Novotný Jr., MSc, PhDAssistant Professor, Department of

Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Desmond O’Farrell, CMDSenior Dosimetrist, Division of

Brachytherapy, Department of Radiation Oncology, Dana Farber/Brigham & Women’s Hospital, Boston, MA, USA

Alfred T. Ogden, MDResident, Department of Neurological

Surgery, Columbia University, New York, NY, USA

Michael Y. Oh, MDAssistant Professor, Department of

Neurosurgery, Drexel University School of Medicine; Co-Director, Stereotactic and Functional Neurosurgery, Department of Neurosurgery, Allegheny General Hospital, Pittsburgh, PA, USA

Sangjin Oh, MDFellow, Department of Neurology,

University of Maryland School of Medicine, Baltimore, MD, USA

Jatinder Palta, PhDProfessor and Chief of Physics, Department

of Radiation Oncology, University of Florida, Gainesville, FL, USA

Roy A. Patchell, MDChief of Neuro-oncology, Professor of

Neurology and Neurosurgery, University of Kentucky Medical Center, Lexington, KY, USA

contr ibutors x ix

Shilpen Patel, MDAssistant Professor, Department of

Radiation Oncology, University of Washington Medical Center, Seattle, WA, USA

Vaibhav Patil, BADepartment of Neurosurgery, New Jersey

Medical School, Newark, NJ, USA

Arie Perry, MDWashington University, Division of

Neuropathology, St. Louis, MO, USA

Alessia Pica, MDDoctor, Department of Radiation

Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Bruce E. Pollock, MDProfessor, Department of Neurological

Surgery and Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA

Neil C. Porter, MDAssistant Professor, Department of

Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

Louis Potters, MD, FACRSouth Nassau Communities Hospital,

Oceanside, NY, USA

Nader Pouratian, MD, PhDResident Physician, Department of

Neurological Surgery, University of Virginia, Charlottesville, VA, USA

Pulak Ray, MDResident, Department of Neurosurgery,

Temple University, Philadelphia, PA, USA

William F. Regine, MDProfessor and Chairman, Department of

Radiation Oncology, University of Maryland Medical School, Baltimore, MD, USA

Jean RégisProfessor, Departement de Neurochirurgie

Centre Hospitalier, Er Universitaire La Timone, Marseille, France

Andrew Reisner, MD, FACS, FAAPNeurosurgeon, Department of Pediatric

Neurosurgery, Children’s Healthcare of Atlanta, Atlanta, GA, USA

Ali R. Rezai, MDDirector, Brain Neuromodulation Center,

Jane and Lee Seidman Chair in Functional Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH, USA

David Roberge, MDAssistant Professor, Department of

Oncology, Division of Radiation Oncology, McGill University, Montreal, Quebec, Canada

Leland Rogers, MDRadiation Oncologist, GammaWest

Radiation Therapy, Salt Lake City, UT, USA

Pantaleo Romanelli, MDClinical 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

Joshua M. Rosenow, MDAssistant 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

Charles Sansur, MD, MHScResident, Department of Neurosurgery,

Hospital of the University of Virginia, Charlottesville, VA, USA

Raymond Sawaya, MDProfessor and Chairman, Department of

Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Steven E. Schild, MDProfessor, Department of Radiation

Oncology, Mayo Clinic, Scottsdale, AZ, USA

Michael Schulder, MDProfessor and Vice-Chairman, Department

of Neurosurgery, New Jersey Medical School, Newark, NJ, USA

xx contr ibutors

Kathleen Settle, MDChief Resident, Department of Radiation

Oncology, University of Maryland Medical Systems, Baltimore, MD, USA

Jonathan Sham, MDProfessor, Department of Clinical

Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong

Jason Sheehan, MD, PhDAssistant Professor of Neurological Surgery

and Neuroscience, Department of Neurological Surgery and Neuroscience, University of Virginia, Charlottesville, VA, USA

David M. Shepard, PhDDirector of Medical Physics, Swedish

Cancer Institute, Seattle, WA, USA

Andrew G. Shetter, MD, FACSChairman of Functional Stereotactic

Neurosurgery, Division of Neurological Surgery, Director of Pain Research Laboratory, Barrow Neurological Institute, Phoenix, AZ, USA

Almon S. Shiu, PhDProfessor, 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, CMClinical Assistant Professor of Medicine,

University of Maryland School of Medicine, Division of Endocrinology, Union Memorial Hospital, Baltimore, MD, USA

Dennis Shrieve, MD, PhDDepartment of Radiation Oncology,

University of Utah Medical Center, Salt Lake City, UT, USA

Gabriela Šimonová, MD, PhDDepartment of Stereotactic

Radioneurosurgery, Hospital Na Homolce, Prague, Czech Republic

Uttam K. Sinha, MDAssociate 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, MDVisiting Assistant Professor, Department of

Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

Penny K. Sneed, MD, FACRProfessor in Residence, Department of

Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

Luis Souhami, MDProfessor and Associate Director,

Department of Oncology, Division of Radiation Oncology, McGill University, Montreal, Quebec, Canada

Paul W. Sperduto, MD, MAPPCo-Director, Gamma Knife Center,

University of Minnesota Medical Center, Minneapolis, MN, USA

Gary K. Steinberg, MD, PhDBernard 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, JDAttorney, Goldberg Katzman, P.C., East

Petersburg, PA, USA

Roger Stupp, MDMultidisciplinary Oncology Center,

University of Lausanne Hospitals (CHUV), Lausanne, Switzerland

John H. Suh, MDChairman, Department of Radiation

Oncology, Cleveland Clinic, Cleveland, OH, USA

Mohan Suntharalingam, MDProfessor and Vice Chairman, Department

of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA

contr ibutors xx i

Nicholas J. Szerlip, MDResident, Department of Neurosurgery

University of Maryland School of Medicine, Baltimore, MD, USA

Kintomo Takakura, MD, PhDPresident, Tokyo Women’s Medical

University, Shinjuku, Tokyo, Japan

Wolfgang Tomé, PhDDepartment 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, BSDepartment of Neurological Surgery,

Columbia University, New York, NY, USA

Michael Y. Wang, MDAssistant Professor, Department of

Neurological Surgery, University of Southern California, Los Angeles, CA, USA

William J. Weiner, MDProfessor 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, MDProfessor of Neurological Surgery,

Department of Neurological Surgery, USC; Attending Physician, Department of Neurosurgery, USC University Hospital, Los Angeles, CA, USA

Maria Werner-Wasik, MDAssociate Professor, Department of

Radiation Oncology, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA

David M. Wildrick, PhDSurgery Publications Coordinator,

Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Gordon W. Wong, MDDepartment of Human Oncology,

University of Wisconsin Hospital, Madison, WI, USA

Isaac Yang, MDResident, Department of Neurological

Surgery, University of California San Francisco, San Francisco, CA, USA

Lavanya Yarlagadda, MDDepartment of Medicine, University of

Maryland, Baltimore, MD, USA

Cedric Yu, PhDDepartment of Radiation Oncology,

University of Maryland School of Medicine, Baltimore, MD, USA

Cheng Yu, PhDProfessor and Director of Radiation

Oncology Physics, Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Gabriel Zada, MDResident Physician, Department of

Neurosurgery, University of Southern California, Los Angeles, CA, USA

xx i i contr ibutors

1

PART I

The Fundamentals

3

The History of Stereotactic Radiosurgery

Michael Schulder and Vaibhav Patil

1

The Early Years

The history of radiosurgery can be said to begin with the dis-covery 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 discov-ery of radioactivity by Becquerel in 1896, and of radium by the Curies soon after, provided another means for the use of ther-apeutic ionizing radiation. Neurosurgical applications were not long in following. X-rays were used to treat patients with pitu-itary 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 treat-ments, although he remained skeptical of the utility of either [3]. Other neurosurgeons continued to explore the uses of ion-izing radiation throughout the fi rst half of the 20th century [4].

In 1951, Lars Leksell coined the term stereotactic radiosur-gery (SRS) [5]. A ceaseless innovator, his goal was to develop a method for “the non-invasive destruction of intracranial . . . le-sions that may be inaccessible or unsuitable for open surgery.” The fi rst 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 ulti-mately designed the Gamma Knife (GK), containing 179 cobalt sources in a hemispheric array (Fig. 1-1). The fi rst 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 fi gures 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, spear-headed 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 investi-gators 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 indepen-dently, in Buenos Aires, Argentina, and in Vicenza, Italy, respectively, Betti and Colombo reported the successful adap-tation 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 fi rst American GK at the University of Pittsburgh [15]. This group was instrumental, via an ongoing series of peer-reviewed

4 m . schulder and v . pat il

publications, in placing the technique and clinical indications for SRS on a sound scientifi c 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, Loeffl er 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

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 inter-ested, 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 1-1. 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.)

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

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

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 h i story of stereotact ic rad iosurgery 5

and accurately with either method [12, 19]. Numerous reports demonstrating the effi cacy 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-Thomas-Cosman (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 suffi ciently accurate and precise for single-session SRS, the GTC frame opened up the era of fractionated stereo-tactic 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 refl ects 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 tech-nique 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 prac-titioners 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 fi ve 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 neu-rosurgeons 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 radia-tion 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 argu-ment 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 fi nancial 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 infi nite number of beams to be aimed at the target. Treatments are fashioned using an inverse planning method; to allow for practi-cal computation times, the number of beam origins (“nodes”) and robot angles are limited. Peer-reviewed publications have

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 treat-ments 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 treat-ment had obvious appeal for extracranial targets. The fi rst 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 modifi cations 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 fi rst truly extracranial radiosurgical unit. This prototypical system did not rely on rigid frame fi xation 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 posi-tion, 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 treat-ment of tumors of the lung [36] and prostate [37] has been published. Despite the neurosurgical origins of SRS, all advo-cates 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 devel-opment of SRS.

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

6 m . schulder and v . pat il

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 refl ected 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 frame-based 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 reluc-tance 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 neurosur-geons who often will prefer to treat patients with a single frac-tion, 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 modifi cation 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 equip-ment and the need for support personnel to ensure their proper functioning. From the days of the fi rst 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 defi ne 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 fi rst 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 semi-nars 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 Func-tional Neurosurgery feature SRS as one of the main topics.

The International Stereotactic Radiosurgery Society (ISRS) was founded in 1993 and held its fi rst biannual meeting that year in Stockholm. At fi rst, the papers presented dealt entirely with the treatment of intracranial conditions. As SRS has moved below the skull base, studies regarding patients with such condi-tions as tumors of the spine, lung, pancreas, and prostate have been included in the ISRS program. Thus, the expertise of clini-cians in fi elds completely unrelated to neurosurgery is being applied to the study of SRS. Neurosurgeons comprise the single biggest specialty group in the organization, followed by radia-tion oncologists and medical physicists. As interest in extracra-nial and indeed nonneurosurgical SRS inevitably increases, the membership of ISRS no doubt will evolve to refl ect this broad-ening of interest. The ISRS publishes a peer-reviewed collec-tion of selected manuscripts from each meeting, entitled Radiosurgery.

Conclusion

Acceptance by neurosurgeons, surgical specialists, and radia-tion 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 refi nement 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 neurosur-geons 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 hypo-physistumoren auf endonasalem Wege. Arch Laryngol Rhinol 1910; 24.

3. Schulder M, Loeffl er 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 neurosur-geon. 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 cere-bral arteriovenous malformations. Acta Chir Scand 1972; 138:459–464.

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

Year Author Device/Event

1951 Leksell Invention of SRS with rotating orthovoltage unit

1954 Lawrence Heavy-particle treatment of pituitary for cancer pain

1962 Kjellberg Proton beam therapy of intracranial lesions

1967 Leksell Invention of GK

1970 Steiner GK SRS of AVMs

1980 Fabrikant Helium ion treatment of AVMs

1982 Betti/Columbo Linacs adapted for SRS

1984 Bunge Installation of commercial GK

1986 Winston/Lutz Linac SRS based on common stereotactic frame

1991 Friedman Linac system for highly conformal SRS

1992 Loeffl er/Alexander Dedicated linac for SRS developed

1994 Adler First CyberKnife treatment

1997 Krispel Rotating cobalt unit

1 . the h i story of stereotact ic rad iosurgery 7

7. Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychia-try 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 his-torical 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 radio-surgery of the brain using the fi rst 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. Loeffl er 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 acous-tic 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.

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 treat-ment 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 path-ways: 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 defi ne stereotactic radiosur-gery. 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 squa-mous cell carcinoma of the nasopharynx. Laryngoscope 1991; 101:519–522.

31. Kaplan ID, Adler JR, Hicks WL Jr, et al. Radiosurgery for pallia-tion 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 modifi cation. Neurol Res 1994; 16:81–82.

33. Hamilton A, Lulu B, Fosmire H, et al. Preliminary clinical experi-ence with linear accelerator-based spinal stereotactic radiosur-gery. 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 radiosur-gery 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.

9

Neuroimaging in Radiosurgery Treatment

Planning and Follow-up Evaluation

Clark C. Chen, Paul H. Chapman, Hanne Kooy, and Jay S. Loeffl er

2

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 defi nition relies entirely on the ana-tomic accuracy of the available imaging modalities. The need for accurate anatomic visualization is magnifi ed by the use of higher radiation dose delivered in radiosurgery as compared with radiotherapy. To achieve maximal spatial accuracy in radiosur-gical planning, an understanding of the basic principles underly-ing neuroimaging as well as the limitations associated with each imaging modality is mandatory. Additionally, the optimal man-agement 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, radiol-ogy has played a pivotal role in the diagnosis and treatment of various neurosurgical lesions. The advent of computed tomo-graphy (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 computa-tional technology in the past decade have enabled the superpo-sition of CT and magnetic resonance (MR) images in order to maximize anatomic deline ation. More recently, signifi cant strides in functional imaging have further refi ned target defi ni-

tion in radiosurgical planning (Fig. 2-1). The following section will review the basic principles underlying the various neuroim-aging 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 identi-cal; that is, structural discrimination is made based on the rela-tive atomic composition, and therefore the electron density, of the tissue imaged. CT images, however, offer improved ana-tomic 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 inten-sity on a CT image refl ects 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 defi ne 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 struc-tures by CT imaging is suboptimal, even with the aid of intra-venous 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.

10 c .c . chen et al .

Magnetic Resonance Imaging

The human body consists primarily of fat and water, both having a high content of hydrogen atoms. MRI exploits the nuclear spin property of these hydrogen atoms as a means to attain soft tissue resolution. In MRI, a radiofrequency pulse is applied to the imaged subject. As a result, the nuclear spin states of these atoms shift from that of equilibrium to that of excitation. To return to their equilibrium state, the law of energy conservation dictates that an energy equal to that absorbed must be emitted. The energy release between nuclear spin state transitions can be measured and analyzed. Because the process of energy absorption and emission is affected by the local chemical environment, hydrogen atoms in soft tissues of varying chemical composition will absorb and emit differential energy. Mathematical transformation of this information yields fi ne-resolution maps of soft tissue structures (Fig. 2-1c, d). Because tumor and normal tissues often differ in chemical com-position [2], the same principle allows delineation of these tissue types.

Because of the complexity of the nuclear interactions involved in MRI, the modality is subject to many sources of error, resulting in distortion of the image obtained. One such

source of error involves the imperfection of the input magnetic fi eld. The input magnetic fi eld in MRI is produced by electric currents passing through sets of mutually orthogonal coils. Ideally, the magnetic fi eld generated should be uniform such that a linear relationship between space and resonance fre-quency can be established [3]. However, such uniform fi elds cannot be easily achieved in practice. This phenomenon is referred to as gradient fi eld nonlinearity and tends to escalate with increasing distance from the central axis of the main magnet. For the most part, gradient fi eld nonlinearity can be corrected computationally. Prior to correction, gradient fi eld nonlinearity can induce spatial distortions as large as 4 mm. After computational correction, the distortion is minimized to <1 mm [4].

A more complex MR distortion that is more diffi cult to correct computationally involves electromagnetic interactions between the imaged tissue and the input magnetic fi eld. This distortion is often referred to as resonance offset. Resonance offset occurs because hydrogen atoms carry with them an inher-ent magnetic fi eld. Thus, placement of hydrogen-bearing tissues in a magnetic fi eld necessarily induces a perturbation in the input magnetic fi eld. This perturbation disrupts the linear rela-tionship between space and resonance frequency as to produce

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 defi ned left cerebellar mass with effacement of the fourth ven-tricle 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 indi-cated in box 9. The thick arrow indicates the choline peak. The arrow-head 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 accu-mulation of lactate (double arrow) is another signature of diseased tissue.

2 . neuro imag ing in rad iosurgery planning and evaluat ion 11

geometric distortions. The physics of this perturbation is complex because it depends on the inherent magnetic proper-ties as well as the volume and shape of the imaged object. Reso-nance offset distortions tend to be largest at the interface of materials that differ in magnetic properties, such as at the air-water interface. In anatomic imaging, this translates into large distortions at the air-bone or air-tissue interfaces. Studies reveal that distortions at these interfaces can be as large as 2 mm [3, 5, 6].

Although the development of higher-strength magnets has allowed for improved resolution of soft tissue structures as well as minimization of geometric distortions related to gradient fi eld nonlinearity, higher-strength magnets do not address the issue of resonance offset. Because resonance offset is a product of the input magnetic fi eld and the local fi eld imposed by the imaged tissue, increasing the strength of the input magnetic fi eld will magnify the effects of resonance offset [7].

The accuracy of MR as a stand-alone imaging modality has been determined by a number of investigators [8–12]. Most investigators report a localization uncertainty of 2 to 3 mm [8–11], but maximal absolute errors of 7 to 8 mm have also been reported [12]. These studies reveal that error in fi ducial localiza-tion is amplifi ed by subsequent mathematical transformation. Though the degree of localization uncertainty varies between studies, the reported uncertainty consistently remains greater than 1 mm, failing to achieve the current radiosurgical standard set forth by the American Society of Therapeutic Radiology and Oncology (ASTRO) [13–15].

Another downside of MRI as it pertains to radiosurgical planning is the absence of electron density information (see earlier “Computed Tomography Imaging” section). Contrary to CT imaging where the image is derived based on differential electron density, pixel intensities in MR images bear no correla-tion with electron density. For radiosurgical planning using MR as the only imaging modality, image processing and assignment of hypothetical electron density values are required. Such strat-egies have led to suboptimal radiosurgical plans [16].

Motion artifact is another consideration affecting spatial accuracy in MRI. The prolonged duration required for image acquisition increases the potential for patient movement. Even with a cooperative patient, motion artifact occurs with breath-ing and internal physiologic motions. The resultant motion compromises the accuracy of spatial resolution.

Though MRI is inadequate as a stand-alone modality in radiosurgical planning, combining MR and CT images has led to radiosurgical plans that are superior to plans derived from each modality alone [17–20]. For example, Shuman et al. reported that the incorporation of MR information into CT-based radiotherapy plans resulted in better defi nition of tumor volume in 53% of the cases [18]. These observations have led to the development of algorithms for superimposing MR and CT images.

CT-MR Image Integration

The differences between CT and MRI illustrate the conceptual distinction between geometric and diagnostic accuracy. Although CT imaging is geometrically accurate due to absence of spatial distortion effects, disease tissues are often missed by this modality. As such, CT imaging is diagnostically inaccurate.

On the other hand, due to enhanced soft tissue resolution, MRI affords enhanced diagnostic accuracy; however, the spatial accuracy is limited due to MR distortion effects.

Algorithms have been developed to maximally utilize the different types of information afforded by CT and MRI (Fig. 2-2). Simple approaches to image integration involve manual superposition of equivalent views of MR and CT images, using bony landmarks as correlation points. Such approaches, however, are labor intensive and error-prone with uncertainties of up to 8 mm [21].

Advances in computational technology have allowed for the development of automated algorithms for superposition of CT and MR images in three-dimensional space. One way of integrating CT and MR images requires that the patient be placed in an immobilization device, such as the stereotactic frame. The immobilization device minimizes motion artifacts and ensures that the images are acquired in a predetermined manner. Fiduciary markers are used to establish the spatial relationship between the target and the head frame. Addition-ally, they serve as coregistration points between the MR and CT images. Because image acquisition and correlative points are fi xed in space in a predetermined way, this mode of image fusion is sometimes referred to as prospective image coregistra-tion [14].

Alternatively, image coregistration can be done with images that are not acquired in a predetermined manner. This mode of image fusion is also known as retrospective coregistration. Ret-rospective image coregistration relies on matching correspond-ing anatomic landmarks instead of fi duciary markers. The CT and MR images are integrated on the basis of aligning these anatomic landmarks [22]. Various computational techniques, including point matching [23], line matching, and iterative matching [24], have been developed for retrospective image superposition. Whether one method is superior to another remains an area of research. In general, with proper training and quality control, most current algorithms will coregister MR and CT images to an uncertainty of 1 to 2 mm using prospective registration and of 2 to 3 mm using retrospective registration [14].

Contrast Administration

Contrast administration takes advantage of the observation that disease processes, such as tumor growth, often result in vascular encroachment or faulty angiogenesis [2]. These pro-cesses allow contrast material to escape the vasculature and preferentially accumulate in the diseased tissue. The accumula-tion of contrast material can be easily visualized on CT or MRI (Fig. 2-1b, d). In malignant gliomas for instance, contrast enhancement correlates with diseased tissue. Kelly et al. evalu-ated 195 brain tumor biopsies acquired from various locations relative to the contrast-enhancing regions of CT or MRI scans and showed that the regions of contrast enhancement best cor-related with regions of tumor burden [25].

Because contrast-enhancing volumes are used for radio-surgery target defi nition, diseased tissues without contrast enhancement often escape therapy. Investigators have used various functional imaging modalities to address this issue. Although these modalities hold tremendous promise, they are limited by poor anatomic resolution. As such, functional imaging

12 c .c . chen et al .

is most useful in conjunction with traditional anatomic imaging modalities. In many instances, the clinical applications of func-tional imaging remain investigational.

Positron Emission Tomography and Single-Photon-Emission Computed Tomography

One type of functional imaging relies on visualizing tracer mol-ecules that preferentially accumulate in diseased tissues. This type of imaging includes positron emission tomography (PET) and single-photon-emission computed tomography (SPECT). PET is designed to detect the preferential accumulation of posi-tron-emitting radioactive tracer compounds in the diseased tissue. The emitted positron collides with an electron to yield opposing gamma rays. These emissions are detected by a gamma-ray camera, thereby generating images of regional radioactivity (Fig. 2-3). Similarly, SPECT is designed to detect the preferential accumulation of tracer compounds bearing photon-emitting isotopes. Photon emission is detected by a rotating gamma camera detection system and reconstructed into three-dimensional tomographic images.

In tumor neuroimaging, the enhanced metabolic state of the tumor cells is often exploited to achieve preferential tracer accumulation in these tissues. For instance, 18-fl uorodeoxyglu-cose (18F-FDG), a commonly used PET tracer, is preferentially transported into tumor cells relative to normal cells due to an

intense upregulation of glucose metabolism in tumor cells. Once inside the cell, 18F-FDG undergoes phosphorylation to yield an intermediate that cannot undergo further metabolic processing or cellular export. The phosphorylated intermediate is, therefore, preferentially transported into tumor cells and trapped there [26].

Studies investigating the use of 18F-FDG in guiding radio-surgery for treatment of gliomas yielded mixed results. Tralins et al. reported a series of 27 patients who underwent conven-tional MR or CT scanning as well as 18F-FDG PET. In this study, a multivariate analysis revealed 18F-FDG PET fi ndings as the only variable that retained statistical signifi cance in pre-dicting time to tumor progression and overall survival. More-over, the 18F-FDG PET defi ned target volumes differing from those defi ned by MR or CT imaging by at least 25% in all patients [27]. Gross et al., on the other hand, reported that regions of 18F-FDG abnormal uptake closely correlated with regions of contrast enhancement in their 18 patients. In a minor-ity of patients, 18F-FDG PET did affect target volume defi ni-tion. These changes, however, were not associated with improved survival when compared with historical controls [28]. Likewise, Prado et al. reported that the inclusion of PET scan data minimally altered radiation planning in most patients [29].

These confl icting data can, in part, be attributed to the vari-ability and subjectivity involved in PET image interpretation.

FIGURE 2-2. Fusion of MR and CT images in radiosurgical planning. (a) CT image of a patient with left frontal metastatic lesion. The image is selected to illustrate the continuity of the ventricular contour and the cranial vault as landmarks to gauge the spatial discrepancy when com-paring MR and CT images. The lesion is not shown in (a). (b) Equiva-lent T1-weighted MR image of the CT image shown in (a). Again, note the continuity of the ventricular contour and the cranial vault. (c) Superposition of (a) and (b) without correction of MR distortion shows spatial discrepancy as evidenced by the discontinuity of ventricular contour and the cranial vault at the transition point. The CT-derived image is shown on the top-half panel. The MR image is shown on the

bottom-half panel. (d) After computational correction of MR distor-tion, continuity of the transition point is restored and various anatomic landmarks are coregistered. (e) Three-dimensional view of the meta-static lesion in relation to the stereotactic frame and a surface rendering of the patients head. The lines interconnecting the small red, green, and yellow spheres indicate the planes through which radiation is delivered. (f) Axial, (g) sagittal, and (h) coronal views of the lesion on MRI after correcting for MR distortion effects. The colored lines represent the various isodose contours. The magnitude of the radiation delivered is shown in the right lower corner of each panel.