Japanese Experience With Gamma Knife Radiosurgery (Progress in Neurological Surgery Vol.22)

Japanese Experience with Gamma Knife Radiosurgery

Progress in Neurological Surgery Vol. 22

Series Editor

L. Dade Lunsford

Pittsburgh, Pa.

Japanese Experience with Gamma Knife Radiosurgery Volume Editor

Masaaki Yamamoto

Hitachi-naka

With a Foreword by

Kintomo Takakura

Tokyo

109 figures, 16 in color, and 53 tables, 2009

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Shanghai · Singapore · Tokyo · Sydney

Progress in Neurological Surgery

Masaaki Yamamoto, MD, PhD Katsuta Hospital, Mito GammaHouse Hitachi-naka, Ibaraki, Japan

Library of Congress Cataloging-in-Publication Data Japanese experience with gamma knife radiosurgery / volume editor, Masaaki Yamamoto, with a foreword by K. Takakura p. ; cm. -- (Progress in neurological surgery ; vol. 22) Includes bibliographical references and index. ISBN 978-3-8055-8604-7 (hard cover : alk. paper) 1. Radiosurgery--Japan. I. Yamamoto, Masaaki. [DNLM: 1. Radiosurgery--methods--Japan. WL 368 J35 2008 / W1 PR673 v. 22 2009] RD594.15.J36 2009 617.4’810590952--dc22 2008018520

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2009 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISSN 0079–6492 ISBN 978–3–8055–8604–7 e-ISBN 978–3–8055–8605–4

Contents

VII VIII IX XI

1 11

20

31

38 45

63

Acknowledgement Series Editor’s Note Lunsford, L.D. (Pittsburgh, Pa.) Foreword Takakura, K. (Tokyo) Preface Yamamoto, M. (Hitachi-naka) History and Present Status of Gamma Knife Radiosurgery in Japan Otto, S. (Kobe) Dose Selection for Optimal Treatment Results and Avoidance of Complications Nagano, H. (Tokyo); Nakayama, S. (Odawara); Shuto, T.; Asada, H.; Inomori, S. (Yokohama) Gamma Knife Radiosurgery for Arteriovenous Malformations: The Furukawa Experience Jokura, H.; Kawagishi, J.; Sugai, K.; Akabane, A.; Boku, N.; Takahashi, K. (Osaki) Radiosurgery for Cavernous Malformations in Basal Ganglia, Thalamus and Brainstem Kida, Y. (Komaki) Radiosurgery for Dural Arteriovenous Fistula Kida, Y. (Komaki) Gamma Knife Radiosurgery for Vestibular Schwannomas Fukuoka, S.; Takanashi, M.; Hojyo, A.; Konishi, M.; Tanaka, C.; Nakamura, H. (Sapporo) Long-Term Results of Gamma Knife Radiosurgery for 100 Consecutive Cases of Craniopharyngioma and a Treatment Strategy Kobayashi, T. (Nagoya)

V

77

96

112 122 129 142 154

170 182

191 193

VI

Long-Term Results of Stereotactic Gamma Knife Radiosurgery for Pituitary Adenomas. Specific Strategies for Different Types of Adenoma Kobayashi, T. (Nagoya) Gamma Knife Radiosurgery for Skull-Base Meningiomas Takanashi, M.; Fukuoka, S.; Hojyo, A.; Sasaki, T.; Nakagawara, J.; Nakamura, H. (Sapporo) Other Skull-Base Tumors Inoue, H.K. (Fujioka) Radiosurgery for Intracranial Gliomas Kida, Y.; Yoshimoto, M.; Hasegawa, T. (Komaki) Gamma Knife Radiosurgery for Other Primary Intra-Axial Tumors Iwai, Y.; Yamanaka, K. (Osaka) Metastatic Brain Tumors: Lung Cancer Serizawa, T. (Ichihara/Tokyo) Gamma Knife Radiosurgery for Brain Metastases of Non-Lung Cancer Origin: Focusing on Multiple Brain Lesions Yamamoto, M.; Barfod, B.E.; Urakawa, Y. (Hitachi-naka) Treatment of Functional Disorders with Gamma Knife Thalamotomy Ohye, C.; Shibazaki, T. (Takasaki) Trigeminal Neuralgia Hayashi, M. (Tokyo) Author Index Subject Index

Contents

Editor

Honorary Editor

Masaaki Yamamoto

Kintomo Takakura

Co-Editors

Seiji Fukuoka

Hiroshi K. Inoue

Hidefumi Jokura

Tatsuya Kobayashi

Acknowledgement

The editor deeply appreciates the invaluable support of four co-editors, Drs. Seiji Fukuoka, Hiroshi K. Inoue, Hidefumi Jokura and Tatsuya Kobayashi, in the preparation of this publication. The editor is also extremely grateful to Honorary Editor Kintomo Takakura for his financial support through the Japan Brain Foundation.

VII

Series Editor’s Note

Some years ago, Dr. Masaaki Yamamoto, working with many outstanding colleagues in Japan, became one of the early innovators in radiosurgery in his country. Along with Professor Takakura at the University of Tokyo, Professor Kobayashi at Nagoya, and a number of additional outstanding pioneers in radiosurgery, the field of radiosurgery was begun in Japan using the Leksell Gamma Knife in 1988 and 1989. Prior to this, many Japanese patients had been to Sweden to receive gamma knife brain surgery. The introduction of gamma knife radiosurgery in Japan required extensive efforts on the part of Professor Takakura, working with the appropriate government ministries to secure approval for installation, and many months later, reimbursement from the National Health Insurance Program. The authors of this volume have reported their experience with radiosurgery in Japan during the past 20 years. I knew that this book was in production only relatively recently, but believed that it sits well within the framework of the almost annual volumes of Progress in Neurological Surgery which are produced by Karger. As the Series Editor, I prevailed upon Dr. Yamamoto and his colleagues to place this summary of experience in Japan within the framework of the series of Progress in Neurological Surgery, volume 22. I hope that you will enjoy reading about these initial, and continuing pioneering efforts related to radiosurgery in Japan. L. Dade Lunsford, MD Pittsburgh, Pa., USA

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Foreword

In my career of five decades as a neurosurgeon, I have encountered four major events that transformed the neurosurgical field as well as the management of patients with cerebral diseases; the operating microscope followed by rapid advancement of its techniques and equipment, the advent of CT scanning and later MR imaging, stereotactic radiosurgery, and interventional neuroradiology. Progress in these four innovations continues even now, constantly changing our neurosurgical practices. Stereotactic radiosurgery is the least invasive of these advanced treatment modalities and has become our basic neurosurgical management tool in recent decades. The late Professor Lars Leksell initially used the gamma knife to treat functional disorders. However, in the four decades since, arteriovenous malformations, benign brain tumors and brain metastases have become the most common indications for gamma knife radiosurgery. Although there has been competition between conventional neurosurgery and radiosurgery, most neurosurgeons nowadays recognize these two treatment modalities as being complementary. Furthermore, it is noteworthy that the concept of gamma knife radiosurgery, described as irradiating a lesion selectively while minimizing the dose to surrounding normal tissues, is increasingly being applied to extracranial pathologies, i.e. spinal tumors and cancers of the lung, liver, pancreas, prostate, and so on. My hope is that readers will obtain accurate knowledge of gamma knife radiosurgery from this volume, utilizing it for better patient management with good quality-of-life maintenance. As the host of the 6th Congress of the International Stereotactic Radiosurgery Society (ISRS) in Kyoto in 2003, I appreciate Masaaki Yamamoto, MD, PhD and the four coeditors for publishing this volume to commemorate the ISRS Kyoto Congress. Kintomo Takakura, MD, PhD Honorary Editor Tokyo, Japan

IX

Preface

Why should a whole book be devoted to Japanese gamma knife radiosurgery experiences? First and foremost, approximately one fifth of the gamma knives in operation worldwide are in Japan, and approximately one fourth of patients undergoing gamma knife radiosurgery worldwide are treated in Japan. Second, as compared with the United States and European countries, the majority of patients are meticulously followed using high-quality neuroimaging techniques for longer periods after treatment, as Medicare costs are generally lower than in western countries. This follow-up is considered to be very important in managing a patient after radiosurgical treatment, i.e. both actual treatment results and real complication rates are thoroughly documented in Japan. Finally, most neurosurgeons as well as co-medical personnel have made dedicated and ongoing efforts to master up-to-date techniques and recent advances in managing patients by participating in meetings and training courses specially designed for gamma knife radiosurgery. In fact, as detailed in the chapter by Mr. Stephan Otto, since the Japanese Leksell Gamma Knife Society was established in the early 1990s, these meetings and/or training courses have been held annually; all participants have been able to share their clinical experiences as well as their knowledge of the basic sciences involving radiobiology and novel techniques. As a consequence of these activities, gamma knife radiosurgery in Japan is being maintained at a high level. Each contributor has more than 10 years’ experience with gamma knife radiosurgery and has been recognized internationally as a leader in his specialized field. My hope is that leaders in this field, not only in Japan but also worldwide, will gain an understanding of the full reality of gamma knife radiosurgery: good results, unfavorable results and various complications. Publication of this volume was initially planned to commemorate the 6th Congress of the International Stereotactic Radiosurgery Society held in Kyoto in 2003. Although, for a variety of reasons, it has

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taken some 5 years to get to publication, each chapter still contains new and worthwhile information. Finally, I would like to thank Bierta E. Barfod, MD and Dr. Thomas Karger and his staff who helped bring this volume to completion. Masaaki Yamamoto, MD, PhD Editor Hitachi-naka, Japan

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Preface

Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 1–10

History and Present Status of Gamma Knife Radiosurgery in Japan Stephen Otto Elekta, Kobe, Japan

Abstract The Leksell GammaKnife® has been received well by the medical community since its introduction at Tokyo University Hospital in late 1989. Knowledgeable users, working with the Elekta Company and with foreign GammaKnife users, have contributed to this success. The original indications have grown as Japanese users – again along with their foreign compatriots – found new ways to combat intracranial diseases using the Copyright © 2009 S. Karger AG, Basel GammaKnife.

The history and the present status of Leksell gamma knife radiosurgery in Japan are really about the unceasing good efforts of the pioneering doctors who brought the technology to these islands. That group, ‘the Japanese Mafia’ as Dr. Douglas Kondziolka calls them, then helped not only to spread the benefits of the technology, but also to insure that the new converts used the technology in the best clinical manner possible. Inevitably, we will have forgotten someone, and to them we apologize, but to all of them and all new users, we at Elekta express our gratitude.

The Early Years

Actually, the story started as far back as 1975 when Dr. Minoru Jimbo (Tokyo Women’s Medical University Dai-ni Hospital) first visited the Karolinska Hospital in Stockholm, Sweden, and by pure chance happened to see the Leksell gamma knife. At that time, it was the very first generation of the machine, but he was fascinated that such a device could perform neurosurgical procedures without opening the skull. It was in 1978 when he accompanied the first patient to Stockholm for treatment. He had been corresponding with Dr. Ladislau Steiner about this particular patient.

Although by that time Dr. Lars Leksell, the inventor of the gamma knife, had retired, he remained active and worked with Dr. Steiner on this first Japanese patient. By 1990, 41 Japanese patients with arteriovenous malformations (AVMs) and one with a vestibular schwannoma had been treated, 35 at the Karolinska Hospital, three at the Clinica del Sol (Buenos Aires) and the other three at the Pittsburgh University Hospital. Joining Dr. Jimbo in sending patients in those early years were Drs. Toshiyuki Shiogai and Mitsushiro Hara from Kyorin University Hospital, recently promoted to Professor Chihiro Ohye from Gunma University Hospital, Koreaki Mori of Kochi Medical University Hospital, and Junichi Nakamura from Nakamura Memorial Hospital. Particularly, one of Dr. Jimbo’s young colleagues, Dr. Masaaki Yamamoto, stayed at the Karolinska Hospital for 1 year from April, 1988, and learned the general practices of gamma knife radiosurgery. Dr. Masaaki Yamamoto is really the first Asian gamma knife radiosurgeon! Furthermore, he published the first Englishlanguage article on AVM radiosurgery from Japan in 1992; meticulous follow-up results of the aforementioned Japanese patients with AVMs have had a great impact on world pioneers in radiosurgery. All of those doctors and especially one at Tokyo University Hospital had heard about the gamma knife at international congresses and symposia which they had attended. It was Tokyo University Hospital’s Dr. Kintomo Takakura who had such a keen interest in noninvasive neurosurgical techniques that he had personally contacted Dr. Laurent Leksell, the president of Elekta AB (a Swedish company), about getting the gamma knife to Japan. For this reason, the trading house Mitsui tried to introduce the gamma knife to Japan between 1985 and 1988, but was unsuccessful. Finally, in 1987, Mr. Stig Sundberg, the president of Mansson KK (with the parent company in Sweden), met Laurent Leksell and signed an agreement with Elekta AB to represent Elekta and the gamma knife in Japan.

The Gamma Knife Model B Comes to Japan

With Tokyo University’s support, import approval for the gamma knife model B was granted on November 1, 1989. The principle investigator was Dr. Kintomo Takakura who has told me in private conversations that he had no qualms whatsoever about bringing the gamma knife to the Tokyo University Hospital. The purpose of importation was to study the effectiveness and safety of radiosurgery on brain vascular diseases and intra-cranial tumors. Now understand that it is no easy feat to haul in an 18-ton gamma knife and place it at a site, as those of you who have watched the process will know. Additionally, one needs a loading machine to load the cobalt source which itself weighs in at some 3 tons – meaning that from the rigging machines used to set the knife in place, to the

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floor where the two units will interact side-by-side for a day while loading, extreme care and planning are required. Although we have mentioned our gamma knife doctor base as including our key allies, we would be remiss to exclude other valuable support personnel. Mr. Tadayoshi Seki has been present at each and every installation. His expertise and experience have helped reduce time and expense such that new installations can be done in less than a week. Compare that with Tokyo University’s installation which took over a month! The formal installation began in March 1990. On June 19th Drs. Dan Leksell (Elekta AB), Christer Lindquist (Karolinska) and Kintomo Takakura, assisted by Tokyo University’s Dr. Shunsuke Kawamoto, began treatments, finishing on July 31st. Fourteen AVMs, five acoustic neuromas, eight meningiomas, one metastatic brain tumor, one pituitary adenoma and one pineal region tumor were totally treated during those hot and humid weeks. Dr. Takakura stated that no problems occurred during the trials. On August 17th, the application for approval containing the 30 treated patients from Tokyo University was submitted along with patient treatment results from the Karolinska (35) and Royal Hallamshire (36) facilities. In record time, the approval for marketing and sales was received on November 14, 1990 – a mere 3 months later! As Dr. Takakura told me, ‘In those days the Ministry of Education and the Ministry of Health and Welfare were quite helpful’. We might also mention that having the Tokyo University ‘seal of approval’ did not hurt the submission.

After Approval

During the clinical trials, many doctors from across Japan traveled to Tokyo University to see the gamma knife. The greatest interest came from Drs. Tatsuya Kobayashi (Komaki City Hospital), Junichi Nakamura (Nakamura Memorial), Chihiro Ohye (professor at Gunma, but sending patients to Hidaka Hospital), Hiromichi Hosoda (Chigasaki Tokushukai), Tatsuo Hirai (Fujieda Heisei), and Hidefumi Johkura and Takashi Yoshimoto (Furukawa Seiryo). There was in fact so much interest that Leksell gamma knife model Bs were installed at all those sites during 1991. The next two years saw 2 units being installed each year – Yokohama Rosai and Shin Suma Hospital in 1992 and Tokyo Women’s Medical University and Takai Hospital in 1993. 1994 and 1995 saw only 3 gamma knives installed – Osaka City General Hospital, Koyo Hospital and Wajiro Hospital. This meant a total of 14 units had been installed since the approval for importation had been issued. No Leksell gamma knives were installed in Japan in 1996.

History and Present Status of Gamma Knife Radiosurgery in Japan

3

Part of the gamma knife approval required Mansson to do postmarket surveillance for 3 years and report back results on 600 patients. In January 1992, only 10 patients were reported. Even by January of 1993, the patients reported numbered only 62. The fourth and final report was issued in May, 1995, with 614 patients from the 10 hospitals mentioned above. In May 1997, the transfer of the various import licenses and approvals to Elekta Japan was completed.

Reimbursement

In 1992, Tokyo University asked for the gamma knife to be placed in the highly advanced medical treatment category. The purpose was to obtain Japanese government reimbursement. In 1993, Nakamura Memorial Hospital also applied. By 1996, Yokohama Labor Hospital, Tokyo Women’s Medical University, and Osaka City General had joined the highly advanced medical treatment category. From the start, most hospitals had been charging patients between 1.2 and 2.3 million Japanese Yen. During the years, from the first installation until the spring of 1996, the main indications had been AVMs and various tumors. With reimbursement, however, a single category – brain metastases – grew dramatically. On average, from the start to 1996, the number of patients treated per site was around 140 per year. However, after reimbursement was announced as being in effect from April 1, 1996, at 70,000 points (or 700,000 Yen), the average number of patients jumped to 250 where it has stayed till now. Please see figure 1. Note that the lower and upper lines show the minimum and maximum number treated per year at any one institution reporting. The types of treatments are listed in figure 2. Once reimbursement was announced in 1996, 5 gamma knives were installed in 1997 and in 1998. As of this writing, 45 Leksell gamma knives have been installed in Japan (table 1). In 1998, the reimbursement rate was reduced 10% from 70,000 points (700,000 Yen) to 63,000 points (630,000 Yen). As of this writing, reimbursement remains at this level.

Hardware

The first gamma knives imported into Japan were the model Bs using the Kula treatment planning system. However, in December, 1993, a minor modification was applied for and granted to introduce the Leksell GammaPlan® treatment planning system which had been developed internally by Elekta. The major differences between these two units were ease of use and time in planning. The Kula system could not do more than 12 shots on any 1 patient.

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700

639

600 500

522

400

566

270 161 158

132 141 145

241 97

100 0

507 463

432

300 200

646 (Max)

545

260 260 268

99 100 19

24

262

107

106

27

31

252

90 74 35 38

278 (Average)

80 (Min) 41 Units

11 12 14 14 9 6 2 2 1 2 2 19 19 19 19 19 19 19 19 98 999 000 001 002 003 9 9 9 9 9 9 91 (6 2 (9 3 (11 4 (12 5 (14 6 (14 7 (19 (24 (27 (31 (35 (38 (41 s sit es ites site site site site site sites sites sites sites sites sites ) ) s) s) s) s) s) ) ) ) ) ) )

Fig. 1. Average number of patients treated in Japan.

9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0

7,681

648 AVM

662 Acoustic neuroma

857 Meningioma

459

329 Pituitary

Metastasis

Glial tumors

Fig. 2. Number of patients treated in Japan by indication.

Furthermore, it was not capable of importing images into the machine for planning. Planning required the operator to print out the dose curves and overlay them on the tumor. Planning normally took some 2–3 h per patient. All this changed with the Leksell GammaPlan. Another interesting difference from other places in the world is the import and loading of cobalt here in Japan. Hospitals may obtain cobalt only from the Japan

History and Present Status of Gamma Knife Radiosurgery in Japan

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1995 1996 1997 1998 1999 2000 2001 2002 2003

Table 1. Gamma knives installed in Japan Date of Installation

Hospital name

Present model

April, 1990 May, 1991 May, 1991 June, 1991 August, 1991 November, 1991 November, 1991 February, 1992 December, 1992 May, 1993 August, 1993 January, 1994 June, 1995 June, 1995 April, 1997 June, 1997 July, 1997 September, 1997 October, 1997 January, 1998 March, 1998 May, 1998 July, 1998 July, 1998 January, 1999 April, 1999 June, 1999 January, 2000 May, 2000 July, 2000 November, 2000 April, 2001 May, 2001 September, 2001 October, 2001 April, 2002 May, 2002 July, 2002 February, 2003 April, 2003 May, 2003 January, 2004 February, 2004 April, 2004 July, 2004

Tokyo University Hospital Komaki City Hospital Nakamura Memorial Hidaka Hospital Chigasaki Tokushukai Furukawa Seiryo Fujieda Heisei Yokohama Labor Hospital Shin Suma Tokyo Women’s Medical University Takai Hospital Osaka City General Koyo Hospital Fukuoka Wajiro Hospital NTT East Japan Hospital Fujimoto Hayasuzu Asanogawa Shiroyama Hospital North Japan Neuro Chiba Prefectural Junkanki Okamura Isshindo Mominoki Hospital Katsuta Hospital Mito GammaHouse Shin Koga Hospital Saiseikai Kumamoto Fukuoka Memorial Nagatomi Neuro Takanohashi Central Aizawa Hospital Takashima Hospital Mihara Memorial Yaen Togei Yamagata Prefectural Akita Prefectural Noken Himeji Central National Cardiovascular Okinawa Central Atsuchi Neuro Shiokawa Hospital Ehime Prefectural Central Miyazaki Hospital Rakusai Shimizu Nagoya Kyoritsu Minami Tohoku Kasai Junkanki

Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife C Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife B Leksell gamma knife C Leksell gamma knife B Leksell gamma knife C Leksell gamma knife C Leksell gamma knife C Leksell gamma knife C

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Radio-Isotope Association, a quasi-governmental agency set up to import, test, store and assist in the disposal of radioactive isotopes. Elekta Japan – and Mansson before it – has had the good luck over the years of having an excellent relationship with this fine group. They, as partners, have insured throughout the 14 years of working with radioisotopes – both during loading, as well as unloading and re-loading, procedures – that no accidents have occurred. All of us owe them our thanks for their good efforts. Finally, in 2002 and again in 2004, Elekta KK was granted marketing and sales approval for the latest in gamma knife technology – the Leksell gamma knife C with APS (automatic positioning system). This fully automatic, robotic gamma knife allows positioning to within 0.1 mm accuracy. Given its robotic functions, it allows the neurosurgeon and his/her team to increase the number of shots which allows better conformality of treatment, and being automatic actually delivers those increased shots in less time.

Education: Information Exchange

Elekta and its users have always felt that open discussion concerning their experience with the gamma knife is the most effective way of insuring conformity for increasingly better results. Several retrospective studies have shown that over time, compared to other radiosurgical and open surgical techniques, the gamma knife produces significantly lower morbidity and mortality. As Dr. Takakura noted privately, ‘Originally, there was some skepticism about the gamma knife technique here in Japan, but those doctors gradually turned around’. Much of that turn-around can be credited to the rigorous approach our users have taken to analyzing immediate and long-term results – and sharing that information with others.

Education: Users’ Meetings

There are two notables – the first is the International Leksell Gamma Knife Society Meetings, and the second is the Gamma Knife Treatment Study Group. The international meetings were held every year initially, but have since switched to a biennial format. The 6th International Meeting was held in Kyoto, Japan, in 1994. This meeting drew over 200 doctors and their families from around the world. Held at the International Exhibition Center in the mountains overlooking Kyoto, it was a perfect venue for the important topics discussed. Then Managing Director of Mansson, Stig Sundberg, has commented to me, ‘It was especially pleasing to me to have been able to have Japan as the host country, especially in such a truly Japanese city such as

History and Present Status of Gamma Knife Radiosurgery in Japan

7

Kyoto. The gamma knife had been well received in Japan because of all the hard work many early Japanese doctors had done. Their comments and suggestions not only made the meeting successful, but also insured the continued success of the gamma knife in Japan.’ Following along in its success, it was decided that more local meetings by Japanese only would be useful. By the beginning of 1995, 12 Leksell gamma knives had already been installed with two more pending. Therefore, the first Japanese Users’ Meeting was held in the spring of 1995 in Echigo-Yuzawa in Niigata. Some 25 people attended with the foreign guests being Dr. Jeremy Ganz (presently at the Gamma Knife Center, Cairo, Egypt) and Dr. Gerhardt Pendl (retired professor and chairman, Neurosurgery, Graz University). I personally had the pleasure of attending the second (and subsequent) meeting where Dr. Ladislau Steiner, now at the University of Virginia at Charlottesville, was the foreign guest speaker. At the end of the meeting, he and I had some time to ourselves on the plane and later where he kindly took the ‘new kid’ in hand to teach him some rudiments of radiosurgery. His generosity will never be forgotten. Every year since the Japanese Users’ Meeting has been held, normally with two foreign guests from either the United States or Europe attending. Additionally, in 2001, it was decided that the 2002 Japan Users’ Meeting in Sapporo would also host Asian doctors from Korea and Taiwan. At that meeting, Drs. Hung-Chi Pan (Taipei Veterans General Hospital, Taipei, Taiwan) and Dong Gyu Kim (Seoul National University Hospital, Seoul, South Korea) presented papers. The next Japanese meeting was in Sendai in January, 2005. Elekta Japan has been fortunate that almost since the start of the Users’ Meetings, a small group of our users has formed an Advisory Board to help Elekta Japan in setting up the Meetings as well as to guide users in various medical and economic matters. This insures a highly professional approach to both matters.

Education: Personnel Exchange

The users’ meetings have subsequently contributed to important constructive exchanges among the continents. This has led to collaborative papers on important topics in radiosurgery as well as student exchanges over the years. Komaki City Hospital and the University of Pittsburgh Medical Center (Drs. L. Dade Lunsford and Douglas Kondziolka) have had such exchanges for many years. Similarly, Tokyo Women’s Medical University Hospital has set up exchanges with La Timone Hospital in Marseille, France (Dr. Jean Régis) for the last 8 years. And, of course, one can not forget the University of Virginia at Charlottesville where Dr. Steiner has been working since 1990. Many Japanese doctors trained there, but Dr. Steiner has stated to me, ‘Dr. Toshifumi Kamiryo and Dr. Hiroaki

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Yamamoto contributed to the quality of both experimental animal laboratory as well as clinical work’.

Education: Clinical Start-Ups

Just as Drs. Dan Leksell and Christer Lindquist assisted in Tokyo University Hospital’s start-up, it has been a tradition that at least one established gamma knife neurosurgeon and physicist attend the first full week of clinical treatments, giving guidance as well as checking out the gamma knife’s operators on radiation safety procedures. Elekta Japan has been fortunate to have had many excellent neurosurgeons and physicists guiding a new site’s first week. Drs. Christer Lindquist, Bengt Karlsson (formerly at Karolinska), Jeremy Ganz and Bodo Lipitz (Sophiahemmet) have joined Per Nylund, Josef Novotony, Ian Peddick, Fritz Thorson, Jonas Johansson, and Per Kjall in our 40 plus starts. More recently, Japanese doctors (Drs. Seiji Fukuoka of Nakamura Memorial Hospital and Dr. Hidefumi Johkura of Furukawa Seiryo Hospital) have assumed the role of training at start-ups. This has the added advantage of insuring that native speakers are teaching in the native tongue, insuring correct and speedy information to the new users. Unfortunately, Japan is still in need of foreign physicists as medical physicists are few and far between here, but we hope that we can also change this in the near future.

Education: Key to Success

These exchanges in personnel as well as visits and lectures by visiting foreign doctors have resulted in bringing the best standard of gamma knife care to Japan and the rest of the world.

To Be Continued

Most medical articles end with a conclusion and discussion. Fortunately for us at Elekta, our doctor colleagues, and their patients, this is a story which – hopefully – does not end, but rather is just beginning. Contrary to reports that the gamma knife is ‘old technology’, reports of the gamma knife’s death (as Mark Twain might have said) are premature. With proven technology, old indications are expanded (such as the excellent work by Dr. Masaaki Yamamoto on multiple metastases), and new indications are being explored. One such – Parkinson’s disease – is being researched in a multicenter study headed by Dr. Chihiro Ohye right here in Japan.

History and Present Status of Gamma Knife Radiosurgery in Japan

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So again to all those pioneering doctors, patients, and the ones who came afterwards – such as Dr. Toshifumi Kamiryo, whose diligent work with the gamma knife was cut short by a tragic disease – we offer our thanks and best regards. Elekta looks forward to working with you in our continued fight against serious diseases.

Stephen Otto 2185 Watertown Road Long Lake, MN 55356 (USA) E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 11–19

Dose Selection for Optimal Treatment Results and Avoidance of Complications Hisato Naganoa ⭈ Satoshi Nakayamad ⭈ Takashi Shutob ⭈ Hiroyuki Asadac ⭈ Shigeo Inomorib a

Radiation Oncology Division, Tokyo-west Tokushukai Hospital, Tokyo, and bDepartment of Neurosurgery, Yokohama Rosai Hospital, and cDepartment of Neurosurgery, Yokohama Citizens Hospital, Yokohama, and dDepartment of Neurosurgery, Odawara Municipal Hospital, Odawara, Japan

Abstract What is the optimal treatment for metastatic brain tumors (MBTs)? We present our experience with gamma knife (GK) treatments for patients with five or more MBTs. Our new formula for predicting patient survival time (ST), which was derived by combining tumor control probability (TCP) calculated by Colombo’s formula and normal tissue complication probability (NTCP) estimated by Flickinger’s integrated logistic formula, was also evaluated. ST ⫽ a*[(C-NTCP)*TCP] ⫹ b; a, b, C: const. Forty-one patients (23 male, 18 female) with more than five MBTs were treated between March 1992 and February 2000. The tumors originated in the lung in 15 cases, in the breast in 8. Four patients had previously undergone whole brain irradiation (WBI). Ten patients were given concomitant WBI. Thirteen patients had additional extracranial metastatic lesions. TCP and NTCP were calculated using Excel add-in software. Cox’s proportional hazards model was used to evaluate correlations between certain variables and ST. The independent variables evaluated were patient factors (age in years and performance status), tumor factors (total volume and number of tumors in each patient), treatment factors (TCP, NTCP and marginal dose) and the values of (C-NTCP)*TCP. Total tumor number was 403 (median 7, range 5–56). The median total tumor volume was 9.8 cm3 (range 0.8–111.8 cm3). The marginal dose ranged from 8 to 22 Gy (median 16.0 Gy), TCP from 0.0% to 83% (median 15%) and NTCP from 0.0% to 31% (median 6.0%). (0.39-NTCP)*TCP ranged from 0.0 to 0.21 (median 0.055). Follow-up was 0.2 to 26.2 months, with a median of 5.4 months. Multiple-sample tests revealed no differences in STs among patients with MBTs of different origins (p ⫽ 0.50). The 50% STs of patients with MBTs originating from the breast, lung and other sites were 5.9, 7.8 and 3.5 months, respectively. Only TCP and (0.39-NTCP)*TCP were statistically significant covariates (p ⫽ 0.014, 0.001, respectively), and the latter was a more important predictor of ST than the former (␤ ⫽ ⫺2.2, ⫺14.1, respectively). The relationship between (0.39-NTCP)*TCP and ST was significant. Linear regression analysis showed this value to predict ST (p ⫽ 0.002, R2 ⫽ 0.22). The slope of the regression line for patients with MBTs originating from the breast was steeper (a ⫽ 218.2, p ⫽ 0.08, R2 ⫽ 0.41) than the slopes of regression lines for patients with tumors of other origins (lung; a ⫽ 56.8, p ⫽ 0.004, R2 ⫽ 0.49, others; a ⫽ 50.4, p ⫽ 0.03, R2 ⫽ 0.25). In treating multiple lesions, the maximum doses and dose distribution for individual lesions were often different. The formula described by Colombo is used to calculate the residual clonogenic cell number of every sub-volume of the tumor, with different doses. NTCP must also integrate every complication

probability for each sub-volume of normal brain tissue in the relatively high dose area in proximity to the tumor. Herein, we present a method for determining the irradiation dose necessary for cases with multiple Copyright © 2009 S. Karger AG, Basel brain metastases. A personal computer-aided calculation is employed.

What is the optimal treatment? How can we obtain the best possible results? We have been asking these questions since 1992 when we began performing stereotactic radiosurgery (SRS) with the gamma knife (GK). In general, neurosurgeons are primarily concerned about tumor control while radiation oncologists focus on the treatment tolerance of normal tissue. Given these different aspects of the same overall goal, we devised a new formula by combining Colombo’s tumor control probability (TCP) [1] and Flickinger’s normal tissue complication probability (NTCP) [2]. The TCP formula described by Colombo depends on the difference in radiosensitivity (represented by the variation in survival fraction at a dose of 2 Gy; SF2) of clonogens within tumors and differences among patients with the same type of tumor. We extended this formula so as to be able to evaluate multiple radiological procedures including whole brain irradiation (WBI). NTCP was estimated using Flickinger’s integrated logistic formula, based on clinical brain necrosis data. The days-per-fractions component, which was intended to compensate for overall treatment time, was omitted from our calculation (fig. 1). Starting from this radiobiological foundation, we can calculate the safety and efficacy of the treatment and concentrate our efforts on performing the procedure. The hope was that this approach would benefit our patients. Some authors believe that patients having up to four tumors with a diameter of less than 3 cm are appropriate candidates for stereotactic irradiation [3, 4]. However, in the case of GK, given its multi-portal structure, five or more tumors can be irradiated in a day within several hours so long as the tumors are not large. Patients with five or more tumors were reported to be safely and effectively treated with SRS [5–9]. We present our experience with GK treatments for patients with five or more metastatic brain tumors (MBTs) and show the usefulness of our new formula in predicting patient survival time (ST): ST ⫽ a*[(C-NTCP)*TCP] ⫹ b; a, b, C: const. Patients

Forty-one patients (23 male, 18 female) with more than five MBTs were treated between March 1992 and February 2000 in our institution. They accounted for approximately 10% of all patients with MBT(s) seen during this period. The median age was 56 years (range 26–77). WHO Performance Status (PS) was 0–2. In 15 cases, the tumors originated in the lung. The breast was the tumor origin in 8 cases. Four patients had previously undergone WBI. Ten patients were given concomitant WBI. Thirteen patients had additional extracranial metastatic lesions. Methods of Analysis

TCP and NTCP were calculated using Excel add-in software. The Poisson distribution of cases with no residual clonogenic tumor cells provides the definition of TCP, which was estimated using

12

Nagano ⭈ Nakayama ⭈ Shuto ⭈ Asada ⭈ Inomori

TCP ⫽

∫

SFi ⫽

∫

2 ind ⎧ ⎫ 1 ⎧ ⎫ ⎪ 1 ⎛ SF 2 − 0. 51 ⎞⎟ ⎪ exp⎨− ⎜ ⎬ ⋅ exp⎨− 19108 ⋅ ∑ν i ⋅ SF i ⎬d SF ⎟ ⎜ 2 0 . 15 2␲ ⋅ 0.15 i ⎭ ⎩ ⎪⎩ ⎝ ⎠ ⎪⎭ ind 2 ⎫ ⎧ ind 1 Σ n j ⋅d j ⋅(10 + d j ) 1 ⎪ 1 ⎛⎜ SF 2 − SF 2 ⎞⎟ ⎪ ind dSF ind exp⎨− ⎬ ⋅ SF 2 2⋅(10 + 2) j 2 ⎜ ⎟ 2 0 . 05 2␲ ⋅ 0.05 ⎪⎩ ⎝ ⎠ ⎪⎭

⎧⎪⎛ 2 NTCP ⫽ 1 ⫺⌸ ⎨⎜⎜ ∑ 0.526 ⋅ n j ⋅ d j i ⎪⎩⎝ j

(

)

12. 2

⎞ 72.19 ⎟⎟ ⎠

⎫⎪ + 1⎬ ⎪⎭

ind 2

−ν i 1367

Fig. 1. Colombo’s formula is extended to allow evaluation of multiple radiological procedures including whole brain irradiation (SF2; survival fraction at a dose of 2 Gy). Normal tissue complication probability is estimated using Flickinger’s integrated logistic formula. The days-per-fractions component was omitted.

Colombo’s formula [1]. This formula takes into account both tumor heterogeneity and dose distribution (dj) in each sub-volume (vi) of the tumor. Tumor heterogeneity, i.e. the difference in radiosensitivity of clonogens within the tumor, was represented by the survival fraction at a dose of 2 Gy; SF2. Colombo et al. [1] assumed the standard deviation of SF2 within a tumor of an individual patient to be 0.05 and the mean value of SF2 between patients with the same type of tumor to be 0.51 (SD ⫽ 0.15). The actual SF2 of the individual patient was not known, so the estimate was calculated assuming a normal distribution. We extended the equation to allow integration of multiple radiological treatments, including WBI [9]. NTCP was estimated using the integrated logistic formula proposed by Flickinger et al. [2]. This formula is based on clinical experience with the 50% tolerance dose for the brain 5 years after irradiation. The dose was normalized to a single fractional dose calculated from a power-law relationship over fractionation. The volume dependence was also assumed to be represented by a power-law model. The days-per-fractions component, which was intended to compensate for overall treatment time, was omitted [9] (fig. 1). ST was calculated using the Kaplan-Meier method. Multiple-sample tests were used to compare the STs of patients with MBTs of various origins (breast, lung or others). Cox’s proportional hazards model was used to evaluate correlations between some variables and ST. The independent variables evaluated were patient factors (age in years and performance status), tumor factors (total volume and number of tumors in each patient), treatment factors (TCP, NTCP and marginal dose), and the values of (C-NTCP)*TCP. Depending on the results of these analyses, linear regression analysis was applied to the above equation to determine the relation between (C-NTCP)*TCP and ST. Commercial software, Statistica (StatSoft, Inc.), was used for these calculations.

Results

Total MBT number was 403 (median 7, range 5–56), median total tumor volume 9.8 cm3 (range 0.8–111.8 cm3). The marginal dose ranged from 8 to 22 Gy (median 16.0 Gy), TCP from 0.0 to 83% (median 15%) and NTCP from 0.0 to 31% (median

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Table 1. Cox’s proportional hazard ratios of the covariates and ST: only TCP and (0.39-NTCP)*TCP were significant Minimum

Maximum

Median

Average

SD of AVG

␤

SD of ␤

p value

(0.39NTCP)*TCP

0.000

0.213

0.055

0.064

0.063

–14.1

4.4

0.001

TCP

0.000

0.831

0.146

0.225

0.239

–2.2

0.9

0.014

PS

0

2

1

1.3

0.5

0.5

0.3

0.146

Total tumor volume, cm3

0.8

16.2

20.1

0.0

0.0

0.422

56.4

11.9

0.0

0.0

0.639

Age, years

26

111.8 77

NTCP

0.000

0.312

Number of tumors

5

56

Marginal dose, Gy

8.0

22.0

9.8 56 0.060

0.078

0.071

0.6

2.9

0.833

7

9.8

8.8

0.0

0.0

0.882

16.0

15.7

3.6

0.0

0.0

0.942

6.0%). (0.39-NTCP)*TCP ranged from 0.0 to 0.21 (median 0.055) (table 1). Followup was 0.2–26.2 months, with a median of 5.4 months. As shown figure 2, multiple-sample tests revealed no differences among STs of patients with MBTs of different origins (p ⫽ 0.50). Half of all patients survived more than 5.9 months. The 50% STs of patients with MBTs originating from the breast, lung and other sites were 5.9, 7.8 and 3.5 months, respectively. As shown in table 2, the breast-origin group was younger than the lung-origin group but both had more MBTs than the other-origin group, based on the Kolmogorov-Smirnov two-sample test. Only TCP and (0.39-NTCP)*TCP were statistically significant covariates (p ⫽ 0.014, 0.001, respectively), and the latter was a more important predictor of ST than the former (␤ ⫽ ⫺2.2, ⫺14.1, respectively). Other covariates, such as patient age in years and performance status, total volume or number of tumors in each patient, NTCP and marginal dose, showed no significant correlations with ST (table 1). The relationship between (0.39-NTCP)*TCP and ST was significant. Linear regression analysis showed this value to predict ST (p ⫽ 0.002, R2 ⫽ 0.22). The slope of the regression line for patients with MBTs originating from breast cancer was steeper (a ⫽ 218.2, p ⫽ 0.08, R2 ⫽ 0.41) than those of regression lines for patients with other MBT origins (lung; a ⫽ 56.8, p ⫽ 0.004, R2 ⫽ 0.49, others; a ⫽ 50.4, p ⫽ 0.03, R2 ⫽ 0.25) (fig. 3).

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1.0

Breast Others Lung

Cumulative proportion surviving

0.8

0.6

0.4

0.2

0.0

0

6

12

18

24

30

Survival time (months) Fig. 2. Survival curve estimated by Kaplan-Meier Product-Limit method. The 50% STs of patients with MBTs originating from the breast, lung and other organs were 5.9, 7.8 and 3.5 months, respectively. Multiple-sample tests revealed no differences among these three groups (p ⫽ 0.50).

Discussion

For a solitary metastatic brain tumor of appropriate size, stereotactic irradiation (STI) has been recognized as a procedure equal or superior to surgical resection followed by WBI. STI achieved an approximately 90% local control rate and a median ST of nearly 12 months. For patients with 2–4 MBTs, combining WBI and STI or fractionated STI reportedly achieved a local control rate exceeding 80% and median survival exceeded 6 months [3, 4]. Because the GK device has multiple portals, if the lesions are spherical and do not exceed collimator size, it is relatively easy to irradiate five or more lesions within several hours. Several cases with numerous brain metastases who had good outcomes have been described and this procedure appears to be comparable to WBI in terms of survival [5–9]. Dosimetric considerations revealed that the cumulative irradiation dosage with numerous SRS targets did not exceed the threshold level for damage to the normal brain [8]. The problem we face is how to determine the maximal appropriate dose to be delivered to these lesions.

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Table 2. Patient characteristics grouped according to tumor origin: breast, lung and others Mean value

Age, years Sex (1 male/2 females) Number of tumors Total tumor volume, cm3 Marginal dose, Gy NTCP TCP (0.39-NTCP)*TCP PS Other metastasis (0 no/1 yes) Survival time, months

Kolmogorov-Smirnov two-sample test (p values)

breast

lung

others

breast to lung

lung to others

others to breast

51.6 1.0 12.6 28.2 15.6 0.087 0.115 0.035 1.6 0.5 10.0

54.0 1.5 10.6 10.6 15.8 0.080 0.310 0.093 1.1 0.2 7.2

60.5 1.6 7.9 15.6 15.7 0.072 0.205 0.052 1.2 0.3 6.4

⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10

⬍0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10

⬎0.10 ⬍0.10 ⬍0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10 ⬎0.10

In treating multiple lesions, the maximum doses and dose distribution for individual lesions were often different, despite peripheral minimal doses being equal. In these situations, radiobiological analysis focusing only on peripheral doses can result in the problem being missed. The formula developed by Colombo et al. [1] takes into account tumor heterogeneity, radiosensitivity and radiation dose distribution. The residual clonogenic cell number in every sub-volume of the tumor receiving a different dose can be calculated. NTCP is also expected to integrate all complication probabilities for each sub-volume of normal brain tissue [2], because radiation-induced damage can occur in the relatively high dose area in proximity to the tumor, but is less likely in normal brain areas far from the targets. We advocate that the irradiation dosage be determined by employing a calculation for each sub-volume of the tumor and normal tissue. The Kaplan-Meier Product-Limit method indicated median ST to be about 6 months regardless of the MBT origin (fig. 2). This value might be comparable to that achieved with WBI. Cox proportional hazards model analysis showed that TCP significantly influenced ST with a very large negative hazard ratio (␤ ⫽ ⫺2.2, p ⫽ 0.014). (0.39-NTCP)*TCP was more predictive than TCP (␤ ⫽ ⫺14.1, p ⫽ 0.001). In general, TCP and NTCP appear to increase as the radiation dose increases; however, the rising NTCP will nullify the effects of TCP on ST. As the dose increases, NTCP may approach the elevated TCP, and thereby abolish the outcome of dose escalation. This is why we use (0.39-NTCP)*TCP as a predictor of ST instead of TCP [9]. Fractionated

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Nagano ⭈ Nakayama ⭈ Shuto ⭈ Asada ⭈ Inomori

30.0

Breast y ⫽218.2x⫹2.3 R2 ⫽0.41 p ⫽0.08

Survival time (months)

25.0

20.0 Others y ⫽50.4x⫹3.7 R2 ⫽0.25 p ⫽0.03

15.0

Lung y ⫽56.8x⫹1.9 R2 ⫽0.49 p ⫽0.004

10.0

5.0

0.0 0.00

0.05

0.10 0.15 (0.39-NTCP)*TCP

0.20

0.25

Fig. 3. Linear regression analysis between (0.39-NTCP)*TCP and ST (p ⫽ 0.002, R2 ⫽ 0.22). Breast: a ⫽ 218.2, p ⫽ 0.08, R2 ⫽ 0.41. Lung: a ⫽ 56.8, p ⫽ 0.004, R2 ⫽ 0.49. Others: a ⫽ 50.4, p ⫽ 0.03, R2 ⫽ 0.25.

STI or GK boost following WBI may be a way of increasing TCP without excessive NTCP gain. In cases with numerous tumors, fractionation is impractical. Our extension of Colombo’s formula allows evaluation of how multiple radiological procedures, including WBI, will work in a variety of situations. The slope of the regression line for patients with MBTs originating from breast cancer was steeper than those of regression lines for patients with tumors of other origins (fig. 3). The reason for this difference was not clear from the analysis using the covariates shown in table 2. The powerful chemotherapy and hormonal therapy given to breast cancer patients may significantly influence ST. Nowadays, diagnosis, planning and treatment rely heavily on computers. However, decision making, the actual dose to be delivered, is based chiefly on clinical experience. Herein, we have presented an approach to determining the optimal irradiation

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0.17

0.6

0.16

0.5

0.15

0.4

0.14

0.3

0.13

NTCP TCP (0.39-NTCP)*TCP

0.2

0.12

0.1 0.0

(0.39-NTCP)*TCP

NTCP and TCP

0.7

0.11

10

12

14 16 GK marginal dose (Gy)

18

0.10

Fig. 4. Graphic representation of NTCP, TCP and (0.39-NTCP)*TCP of one patient. We irradiated seven lesions with a marginal dose of 14 Gy followed by 45 Gy/30fxs/22ds WBI.

dose in cases with multiple brain metastases. This method is based on personal computer aided calculations. Finally, we present one 73-year-old male patient who was incidentally found to have an abnormal shadow on a chest film. T1N0M1 lung adenocarcinoma was subsequently diagnosed. The brain was the only extra-pulmonary site with disease involvement, but there were seven lesions on MRI. GK was performed with a marginal dose of 14 Gy, followed by 45 Gy/30fxs/22ds WBI the next afternoon. As shown in figure 4, NTCP, TCP and (0.39-NTCP)*TCP were estimated to be 8.8, 52.7 and 0.16%, respectively. ST was predicted to be 10.9 months at the end of treatment. Two months later, costal (Rt 7th) and spinal (Th7-L2) irradiation were administered for pain relief. Four months later, he died of his primary disease. Neurological performance was well preserved until the end of this patient’s life.

Acknowledgement Dr. Yamamoto’s efforts in publishing the SRS experience in Japan are greatly appreciated. We are proud to participate in this project. Anyone wanting to try our Excel add-in program should contact Dr. H. Nagano.

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References 1

2

3

4

5

Colombo F, Francescon P, Cora S, et al: Evaluation of linear accelerator radiosurgical techniques using biophysical parameters (NTCP and TCP). Int J Radiat Oncol Biol Phys 1995;31:617–628. Flickinger JC, Lunsford LD, Wu A, et al: Treatment planning for gamma knife radiosurgery with multiple isocenters. Int J Radiat Oncol Biol Phys 1990;18: 1495–1501. Flickinger JC, Kondziolka D, Lunsford LD, et al: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28:797–802. Moriarty TM, Loeffler JS, Black PM, et al: Longterm follow-up of patients treated with stereotactic radiosurgery for single or multiple brain metastases; in Kondziolka D (ed): Radiosurgery 1996. Radiosurgery. Basel, Karger, 1996, vol 1, pp 88–91. Serizawa T, Iuchi T, Ono J, et al: Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy. J Neurosurg 2000;93(suppl 3):32–36.

6

7

8

9

Suzuki S, Omagari J, Nishio S, et al: Gamma knife radiosurgery for simultaneous multiple metastatic tumors. J Neurosurg 2000;93(suppl 3):30–31. Yamamoto M, Ide M, Jimbo M, et al: Gamma knife radiosurgery with numerous target points for intracranially disseminated metastases: early experience in 3 patients and experimental analysis of whole brain irradiation doses; in Kondziolka D (ed): Radiosurgery 1997. Radiosurgery. Basel, Karger, 1998, pp 94–109. Yamamoto M, Ide M, Nishio S, et al: Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment? Int J Radiat Oncol Biol Phys 2002;53:1279–1283. Nagano H, Nakayama S, Asada H, et al: Tumor Control Probability Predicts the Fate of Multiple Metastatic Brain Tumors; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 66–76.

Hisato Nagano, MD Radiation Oncology Division, Tokyo-west Tokushukai Hospital 3-1-1 Matsubara, Akishima Tokyo, 196-0003 (Japan) Tel. ⫹81 42 500 4433, Fax ⫹81 42 500 6632, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 20–30

Gamma Knife Radiosurgery for Arteriovenous Malformations: The Furukawa Experience Hidefumi Jokura ⭈ Jun Kawagishi ⭈ Kazuyuki Sugai ⭈ Atsuya Akabane ⭈ Nagatoshi Boku ⭈ Kou Takahashi Jiro Suzuki Memorial Gamma House, Furukawa Seiryou Hospital, Osaki, Japan

Abstract The Furukawa experience treating 534 patients with cerebral arteriovenous malformations using gamma knife radiosurgery (GKRS) is summarized. By repeating radiosurgery for any residual nidus after the first GKRS, the rates of cumulative complete obliteration 7 years after this initial GKRS, according to four volume categories (ⱕ1, 4ⱖ⬎1, 10ⱖ⬎4, ⬎10 cm3), were 92, 89, 68 and 43%, respectively. Bleeding after GKRS was observed in 8.1% of the patients and was more frequently seen in patients with a large nidus and history of bleeding two or more times before GKRS. Cyst formation was recognized in 4.7% of patients, two thirds of which required some form of surgical intervention. Refinement of the total GKRS Copyright © 2009 S. Karger AG, Basel system contributed to earlier and more effective nidus obliteration.

Herein, we summarize our gamma knife radiosurgery (GKRS) experience with cerebral arteriovenous malformations (AVMs) at Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital.

Materials and Methods From November 1991 through the end of 2004, we treated 534 AVM patients. Follow-up data on these patients available at the end of 2005 are included in this study. There were 320 males and 214 females. Mean age was 36.0 years and the mean Karnofsky performance status at the time of radiosurgery was 91.8. Two hundred and eighty-nine patients (54%) had a history of bleeding and 132 had suffered from symptomatic epilepsy. In 142 patients, the AVM had been found incidentally. The average nidus volume was 4.5 cm3. The most frequently used adjuvant therapy prior to GKRS was intravascular embolization and 136 patients had undergone this procedure. Eleven patients had a history of conventional fractionated radiation of 30–35 Gy, 3–10 years prior to GKRS.

a

b

Fig. 1. Dose planning in 1991 (a) and from 2000 onward (b).

Treatment System

We started treatment with the type B model of the Gamma Knife and KULA® dose-planning software in November of 1991. Conventionally subtracted serial angiography was used for target definition. Isodose curves on transparent films from the X–Y plotter were overlaid on an angiogram (fig. 1a). Three-dimensional information obtained from 0.5 Tesla magnetic resonance (MR) images was used only to check the isodose curve derived mainly from angiograms. In 1995, the Gamma Plan®, an interactive-3D planning software program, was introduced. This allowed the angiogram to be scanned into the computer together with MR images. In 1998, we upgraded to 1.5 Tesla MR imaging and this unit was directly connected to the dose-planning computer. In 2000, digital subtraction angiography with an image distortion correction system replaced conventional angiography and was connected to the dose-planning computer. These on-line connections virtually eliminated the limitation on the number of films which could be loaded onto the computer for planning. Since this upgrade, targets have been defined mainly with MR time-of-flight (TOF) source images (thickness: 1.2 mm, interval: 0.6 mm) and angiograms are used for confirmation. This change dramatically increased the number of isocenters per patient and markedly improved the conformity of dose planning (fig. 1b). In 2002, the Type C Gamma Knife, which has an automatic positioning system (APS), replaced the type B model. Treatment Policy and Parameters

Our policy is to cover the whole nidus of an AVM as the target volume. When the volume is large, we decrease the dose to the periphery rather than using volume fractionation or staged radiosurgery. If volume reduction was accomplished in the initial low-dose treatment, we re-treated the smaller residual nidus [5]. Smaller nidus volume enabled us to use a higher peripheral dose at the second GKRS. Pre-radiosurgical embolization was common until 1995, but our policy was changed due to less favorable obliteration rates and the relatively high complication risk associated with embolization itself. Prescribed peripheral doses were between 12 and 30 Gy (average 20.4 Gy). The prescribed dose was selected based primarily on the volume (fig. 2) and location of the nidus. Other factors including any history of bleeding, neurological deficits at the time of GKRS, the

GKRS for Arteriovenous Malformations

21

35

Peripheral dose (Gy)

30

25

20

15

10

5

0

10

20

30 40 Volume of nidus (cm3)

50

60

Fig. 2. Scatterogram demonstrating the relationship between nidus volume and peripheral dose.

possibility of surgical total removal and certain social factors were also taken into account. Except for a very few cases, 25 Gy was the highest peripheral dose before 2003, after which 22 Gy was the maximum. Since 2003, our policy has been not to prescribe a peripheral dose lower than 15 Gy.

Results

Follow-Up Information At least one angiographic follow-up was performed in 393 patients (73.6%). In total, there were 861 follow-up angiographic examinations. For these patients, follow-up MR images were also available. In another 94 patients, at least one follow-up MR image was available. Thus, imaging studies after GRKS were available for 487 patients (91.2%) in this series. Based on these imaging studies, complete nidus obliteration was confirmed in 289 patients. Rate of Complete Nidus Obliteration after the First GKRS Complete obliteration was confirmed in 256 patients after the first GKRS. Rates of complete obliteration after GKRS according to four volume categories (ⱕ1, 4ⱖ⬎1, 10ⱖ⬎4, ⬎10 cm3) are shown in figure 3. Smaller nidi responded better than larger

22

Jokura ⭈ Kawagishi ⭈ Sugai ⭈ Akabane ⭈ Boku ⭈ Takahashi

0 p⬍ 0.0001 0.2

Obliteration rate

⬎10 cm3 0.4 10ⱖ⬎ 4 cm3

0.6

4 ⱖ⬎ 1cm3

0.8

ⱕ1 cm3 1.0 0

2

4

6

8 Year

10

12

14

16

Fig. 3. Rates of complete obliteration after GKRS according to four volume categories (ⱕ1, 4ⱖ⬎1, 10ⱖ⬎4, ⬎10 cm3).

nidi and complete obliteration rates for the four volume categories at 5 years after GKRS were 81, 72, 52 and 25%, respectively. Rate of Complete Nidus Obliteration after Repeat GKRS In many cases, even when complete nidus obliteration was not attained with the first GKRS, marked regression of the nidus was still seen. We wait 3 years after the first GKRS. Then, if nidus regression is ongoing as compared to the prior follow-up images, we wait and repeat yearly follow-up until nidus regression has ceased. If the nidus remains unchanged, we treat the residual nidus with a second GKRS [5]. In this series, 71 patients underwent repeat GKRS. At the time of the first GKRS, the average nidus volume was 7.0 cm3 in this patient group, and was 2.7 cm3 at the time of the second GKRS. Thirty-three patients obtained complete obliteration with repeat GKRS. The complete cumulative obliteration rates for the four groups at 7 years after the first GKRS were 92, 89, 68 and 43% (fig. 4), respectively. Influence of Pre-Radiosurgical Embolization on Complete Obliteration Rates Intravascular embolization was formerly used widely in efforts to reduce AVM volume and flow. However, embolization may decrease the rate of complete obliteration by

GKRS for Arteriovenous Malformations

23

0 p ⬍0.0001

Obliteration rate

0.2

0.4

0.6 ⬎10cm3 10ⱖ⬎ 4cm3

0.8

4ⱖ⬎1cm3 ⱕ1 cm3

1.0 0

2

4

6

8 Year

10

12

14

16

Fig. 4. Rates of complete obliteration after GKRS, including repeat treatments.

making nidus definition more difficult at the time of dose planning and via recanalization of the nidus after GKRS [1, 3]. In our series, there was no difference in the rate of complete obliteration if the nidus volume at the time of GKRS was no more than 1 cm3. If the nidus was between 1 and 10 cm3 complete obliteration was less likely than without embolization, though the difference in rates was not statistically significant (fig. 5). Without prior embolization, complete obliteration rates for each of the four volume categories at 5 years after GKRS were 81, 78, 59 and 21%, respectively. Bleeding before Confirmation of Complete Obliteration The risk of bleeding between treatment and complete obliteration (latent period bleeding) is a major drawback of GKRS. In this series, 43 patients experienced latent period bleeding during the more than 40,000 person-years follow-up period. This bleeding was fatal in 5 patients while another 5 became severely disabled. Larger nidi bled significantly more often (fig. 6a) and a history of bleeding two or more times before GKRS significantly increased the risk of bleeding after GKRS (fig. 6b). If the nidus was no larger than 1 cm3 and the patient had no history of prior bleeding (n ⫽ 71), we did see not latent period bleeding. On the other hand, 8 of the 29

24

Jokura ⭈ Kawagishi ⭈ Sugai ⭈ Akabane ⭈ Boku ⭈ Takahashi

0

ⱕ1cm3

0.2

p ⫽ 0.7978

Obliteration rate

Obliteration rate

0

0.4 Embolization (⫹) Embolization (⫺)

0.6 0.8 1.0

4ⱖ⬎1cm3

0.2

p ⫽0.0961

0.4 Embolization (⫹)

0.6 0.8

Embolization (⫺)

1.0 0

2

4

6

8

10

0

1

2

3

Obliteration rate

Year 0

10 ⱖ⬎4cm3

0.2

p ⫽0.3778

4 5 Year

6

7

8

9

Embolization (⫹)

0.4 0.6

Embolization (⫺)

0.8 1.0 0

2

4

6

8

10

12

14

Year Fig. 5. Rates of complete obliteration after GKRS with and without pre-radiosurgical embolization.

Bleeding-free rate

1.0 p ⬍0.0001

0.8 0.6

ⱕ1 cm3 4 ⱖ⬎1cm3 10 ⱖ⬎4cm3 ⬎10cm3

0.4 0.2 0 0

a

p⫽ 0.0027

2

4

6

8 10 Years

12

14

No bleeding Bleeding once Bleeding twice or more

16

0 b

2

4

6

8 10 Years

12

Fig. 6. Bleeding before confirmation of complete obliteration after GKRS. a According to four volume categories (ⱕ1, 4ⱖ⬎1, 10ⱖ⬎4, ⬎10 cm3). b With and without history of bleeding prior to GKRS.

GKRS for Arteriovenous Malformations

25

14

16

Fig. 7. Delayed cyst formation after GKRS. T2-weighted MR image 57 months after GKRS for a 3-cm3 nidus in the left temporal lobe treated with 25 Gy to the periphery; a cyst was recognized adjacent to the obliterated nidus (upper left). The cyst, surrounded by a high intensity area on the T2-weighted MR image, continued to grow until 68 months after GKRS (upper middle). The cyst stopped growing and the high intensity area had disappeared 91 months after GKRS (upper right). T2-weighted MR image at the time of GKRS for a left medial temporal 7 cm3 nidus treated with 20 Gy to the periphery (lower left). Twelve months later, a cyst surrounded by a high intensity area on the T2-weighted MR image was recognized (lower middle). The cyst and the high-intensity area regressed spontaneously 23 months after GKRS (lower right).

patients in whom the nidus was larger than 10 cm3 and who had a history of bleeding, experienced bleeding again. The rate of bleeding at 10 years after GKRS in these patients was thus high, 32%. Delayed Cyst Formation after GKRS Some types of cyst formation after GKRS have been reported [2, 4, 6, 7, 9, 10]. During follow-up, we recognized two types of delayed cyst formation. One was the simple type (fig. 7). These cysts did not show wall enhancement, there was no fluid-fluid level of the contents and signal intensity was close to that of cerebrospinal fluid. In some cases, we recognized a small cavity due to prior bleeding, ischemia or embolization at the time of GKRS and the cyst had formed via expansion of this cavity adjacent to the

26

Jokura ⭈ Kawagishi ⭈ Sugai ⭈ Akabane ⭈ Boku ⭈ Takahashi

Fig. 8. Delayed cyst mimicking cavernoma after GKRS. A case with a 6.3 cm3 thalamic AVM was treated with 20 Gy to the nidus periphery. T2-weighted MR image (upper left) and gadoliniumenhanced T1-weighted image (upper right) 54 months after GKRS. A case with a 1.0 cm3 cerebellar AVM was treated with 25 Gy to the nidus periphery. T2-weighted MR image (lower left) and gadolinium-enhanced T1-weighted image (lower right) 132 months after GKRS.

nidus. These cysts expanded as long as they were surrounded by a T2 high-intensity area (T2HIA) but many stopped growing or shrunk spontaneously when the T2HIA disappeared. We saw this type of cyst in 17 patients (3.2%). The time until cyst recognition was 12–139 months, 60 months on average. Nidus size and persistent T2HIA after GKRS were significantly associated with cyst formation. In 7 patients, the cyst became symptomatic and in four implantation of Ommaya’s reservoir and aspiration of the contents was necessary. In two others, surgical opening of the cyst wall together with removal of the obliterated nidus was carried out. In all cases, symptoms improved after surgical intervention. The other type of cyst was more aggressive in nature (fig. 8). These cysts were multilobular, with wall enhancement and some showed fluid-fluid

GKRS for Arteriovenous Malformations

27

15.7

Number of isocenters

14 12

18 mm 14 mm 8 mm 4 mm

16 14

10 8

3.5 3.0

6 4

1.3

Size of collimator

16

1.0

0

12 10 6.0

8 6 4

2.0

2

2 a

11.4

⫺1 ml 1–4 ml 4–10 ml ⬎10 ml

b

0

⫺1ml

1–4ml 4–10ml ⬎10ml

Fig. 9. Average isocenter numbers per treatment before (a) and after (b) introduction of TOF MR images for dose planning.

levels within the cavity. They were surrounded by a T2HIA and in some there was a low intensity rim on T2-weighted images indicating hemosiderin deposition. We saw this type of cyst in eight cases (1.5%). The time until cyst recognition was 40–147 months, 88 months on average. Two of these patients had a history of prior conventional radiation and two others had undergone repeat GKRS. All were symptomatic and in five the lesions were surgically removed. In all cases, the T2HIA in the surrounding brain disappeared rapidly and the symptoms improved. Surgical specimens showed degenerated nidus, hematomas at various stages, numerous neovascularizations, coagulation necrosis, gliosis of the adjacent brain and on occasion structures pathologically indistinguishable from cavernous angioma [8, 11]. In addition to these cyst formations, we saw transient neurological deficits in 2 cases and minor permanent neurological deficits in two others, due to radiation-induced edema and/or necrosis. Impact of Dose-Planning Refinement on the Results of GKRS for AVMs There have been innovations in the GKRS dose-planning technology for AVMs. The introduction of the Gamma Plan® and routine use of TOF source images have had the greatest impact among these innovations, which have dramatically increased the number of isocenters (fig. 9) and greatly improved dose-planning. Rates of complete obliteration have improved significantly since the introduction of TOF images, as compared to the pre-TOF era (fig. 10). It was anticipated that earlier complete obliteration would reduce the number of patients experiencing latent period bleeding. In fact, latent period bleeding diminished after TOF introduction in all nidus volume categories except more than 10 cm3, but the differences do not reach statistical significance.

28

Jokura ⭈ Kawagishi ⭈ Sugai ⭈ Akabane ⭈ Boku ⭈ Takahashi

0

ⱕ1 cm3

0.2

Obliteration rate

Obliteration rate

0

0.4 p ⫽0.0027

0.6

Before TOF

0.8 After TOF

1.0 0

2

4

4ⱖ⬎1cm3

0.2 0.4 p⫽ 0.0022

0.6

Before TOF

0.8

After TOF

1.0

6

8

10

Year

0

1

2

3

4 5 Year

6

7

Obliteration rate

0 10ⱖ⬎4cm3

0.2 0.4

Before TOF

0.6

p ⫽0.0279

0.8

After TOF

1.0 0

2

4

6

8

10

12

14

Year Fig. 10. Rates of complete obliteration after GKRS before and after introduction of TOF MR images for dose planning.

Conclusions

In our series, confirmed rates of complete obliteration 5 years after the first GKRS in four volume categories (ⱕ1, 4ⱖ⬎1, 10ⱖ⬎4, ⬎10 cm3) were 81, 72, 52 and 25%, respectively. When a residual nidus after the first GKRS was retreated with GKRS a second time, rates of complete obliteration at 7 years after the first GKRS were 92, 89, 68 and 43%, respectively. Pre-radiosurgical embolization decreased the rate of complete obliteration for nidi between 1 and 10 cm3 but the difference did not reach statistical significance. Nidus size and a history of more than two bleeding episodes prior to GKRS were significantly associated with a higher rate of latent period bleeding. Delayed cyst formation was observed in 25 cases (4.6%). In these 25 patients, 13 cysts became symptomatic and surgical intervention was performed in 11 cases. In all cases, symptoms improved after surgery. No radiation-induced tumors have been observed, to date, and there have been no treatment related deaths. GKRS for small AVMs (⬍4 cm3) has been shown to be very effective and safe and, when the nidus is

GKRS for Arteriovenous Malformations

29

8

9

very small (ⱕ1 cm3) and there is no history of prior bleeding, GKRS is a reasonable treatment option even if the nidus is located in a surgically accessible area. On the contrary, when nidus volume exceeded 4 cm3, the rate of complete obliteration was less than 70% and the risks of latent period bleeding and cyst formation increased. Thus, in this volume range, the risks of surgical removal versus GKRS should be carefully considered. For a nidus larger than 10 cm3 single GKRS results have been far from satisfactory, but repeat GKRS for the residual nidus is one approach to dealing with such a large volume. Fractionating the volume delivered to a nidus is another option for treating a large nidus, but more results obtained with this treatment policy are needed before any conclusions can be drawn [12].

References 1

2

3

4

5

Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 2007;60: 443–451. Flickinger JC, Kondziolka D, Lunsford LD, Pollock BE, Yamamoto M, Gorman DA, Schomberg PJ, Sneed P, Larson D, Smith V, McDermott MW, Miyawaki L, Chilton J, Morantz RA, Young B, Jokura H, Liscak R: A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys 1999;44:67–74. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD: An analysis of the dose-response for arteriovenous malformation radiosurgery and other factors affecting obliteration. Radiother Oncol 2002;63:347–354. Izawa M, Chernov M, Hayashi M, Nakaya K, Kamikawa S, Kato K, Higa T, Ujiie H, Kasuya H, Kawamata T, Okada Y, Kubo O, Iseki H, Hori T, Takakura K: Management and prognosis of cysts developed on long-term follow-up after Gamma Knife radiosurgery for intracranial arteriovenous malformations. Surg Neurol 2007;68:400–406. Karlsson B, Jokura H, Yamamoto M, Söderman M, Lax I: Is repeated radiosurgery an alternative to staged radiosurgery for very large brain arteriovenous malformations? J Neurosurg 2007;107:740–744.

6 Kihlström L, Guo WY, Karlsson B, Lindquist C, Lindqvist M: Magnetic resonance imaging of obliterated arteriovenous malformations up to 23 years after radiosurgery. J Neurosurg 1997;86:589–593. 7 Kurita H, Sasaki T, Kawamoto S, Taniguchi M, Kitanaka C, Nakaguchi H, Kirino T: Chronic encapsulated expanding hematoma in association with gamma knife stereotactic radiosurgery for a cerebral arteriovenous malformation: case report. J Neurosurg 1996;84:874–878. 8 Olivero WC, Deshmukh P, Gujrati M: Radiationinduced cavernous angioma mimicking metastatic disease. Br J Neurosurg 2000;14:575–578. 9 Pan HC, Sheehan J, Stroila M, Steiner M, Steiner L: Late cyst formation following gamma knife surgery of arteriovenous malformations. J Neurosurg 2005; 102(suppl):124–127. 10 Pollock BE, Gorman DA, Coffey RJ: Patient outcomes after arteriovenous malformation radiosurgical management: results based on a 5- to 14-year follow-up study. Neurosurgery 2003;52:1291–1296. 11 Pozzati E, Giangaspero F, Marliani F, Acciarri N: Occult cerebrovascular malformations after irradiation. Neurosurgery 1996;39:677–682. 12 Sirin S, Kondziolka D, Niranjan A, Flickinger JC, Maitz AH, Lunsford LD: Prospective staged volume radiosurgery for large arteriovenous malformations: indications and outcomes in otherwise untreatable patients. Neurosurgery 2006;58:17–27.

Hidefumi Jokura, MD Jiro Suzuki Memorial Gamma House, Furukawa Seiryou Hospital 3–1–3–5, Furukawa Minami-Machi Osaki City, Miyagi 989-6511 (Japan) Tel. ⫹81 229 22 9911, Fax ⫹81 229 22 9922, E-Mail [email protected]

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Jokura ⭈ Kawagishi ⭈ Sugai ⭈ Akabane ⭈ Boku ⭈ Takahashi

Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 31–37

Radiosurgery for Cavernous Malformations in Basal Ganglia, Thalamus and Brainstem Yoshihisa Kida Department of Neurosurgery, Komaki City Hospital, Komaki, Japan

Abstract Long-term results of radiosurgery for cavernous malformations in basal ganglia and the brainstem are presented. Eighty-four cases, 50 males and 34 females, ranging in age from 10 to 68 years (mean: 38.2 years) are described. The lesions were located in the brainstem (63), thalamus (14) or basal ganglia (7). The mean lesion size was 14.3 mm. Mean maximum and marginal treatment doses were 23.3 and 13.4 Gy, respectively. Brainstem lesions were significantly smaller than the lesions in basal ganglia and the thalamus. During a mean follow-up of 55 months, nearly half of the lesions showed some shrinkage, while in the other half there were no obvious changes. Only 4 of the 84 (4.8%) showed progression. Rebleeding occurred in 14 cases (16.7%),16 times in total. Among these, 12 hemorrhages occurred during the first 24 months after radiosurgery, and the incidence decreased markedly thereafter. Bleeding rates during the first and second years were 9.5 and 4.7%/year/case, respectively. However, the rate significantly decreased thereafter. As for complications, perifocal edema was seen in 18% of basal gangliathalamus and in 3.2% of brainstem lesion cases. In conclusion, radiosurgery for cavernous malformations of the basal ganglia-thalamus and brainstem is warranted because a decreased bleeding rate and lower Copyright © 2009 S. Karger AG, Basel morbidity can be expected.

Although the majority of cavernous malformations in the central nervous system are clinically silent, some become symptomatic with hemorrhage, convulsive seizure and mass effects [1–5]. Once hemorrhage or epilepsy occurs, frequent episodes may occur and convulsive seizures are often intractable [1, 6]. In general, supratentorial lesions are surgically resectable, but lesions in the brainstem and basal ganglia apparently are not. This study focused on radiosurgery for symptomatic lesions in such eloquent areas. Long-term follow-up, lesion control, hemorrhage rate after treatment, and functional results are presented.

Table 1. Characteristics of cavernous malformation cases Location

Number of cases

Sex

Age years

Thalamus Basal ganglia Midbrain Pons Medulla

14 7 18 42 3

M (9), F (5) M (2), F (5) M (9), F (9) M (29), F (13) M (1), F (2)

40.4 32.0 39.2 38.0 30.3

Total and mean

84

M (50), F (34)

38.2

Table 2. Radiosurgical dose and lesion size Location

Lesion size mm

Maximum dose Gy

Marginal dose Gy

Thalamus (n ⫽ 14) Basal ganglia (n ⫽ 7) Midbrain (n ⫽ 18) Pons (n ⫽ 42) Medulla (n ⫽ 3)

16.5 16.9 11.3 14.8 8.3

28.6 26.5 19.9 22.7 20.0

15.2 15.6 12.2 12.9 12.9

Total and mean

14.3

23.3

13.4

Materials and Methods Current indications for radiosurgery are symptomatic lesions in and around the basal ganglia, the thalamus and the brainstem, less than 30 mm in mean diameter and not associated with a progressive deterioration of neurological signs. There were 84 cases, 50 males and 34 females, ages ranging from 10 to 68 years (mean 38.2 years). The lesions were located in the brainstem (63), thalamus (14) and basal ganglia (7). The characteristics of the cases are shown in table 1. Almost all presented with hemorrhage, once in 38, twice in 26 and more than 3 times in 15. The others presented with either convulsive seizures (2) or neurological deficits without overt hemorrhage (3). After radiosurgery, follow-up studies were performed every three months during the first year and every 6 months thereafter. Mean lesion size was compared with that at radiosurgery and described as CR (complete remission), PR (partial remission), MR (minor response), NC (no change) or PG (progression).

Results

Treatment Dose Lesion size and radiosurgical dose are shown in table 2. Mean lesion size was 14.3 mm. Mean maximum and marginal treatment doses were 23.3 and 13.4 Gy, respectively. Brainstem lesions were significantly smaller than lesions in the basal

32

Kida

Table 3. Responses of cavernous malformations on MRI Location

PR

MR

NC

PG

Total

Basal ganglia and thalamus, n

6

5

10

1

22

Brainstem, n

20

11

28

3

62

Total, n (%)

26 (31)

16 (19)

38 (45)

4 (5)

84

Half showed apparent shrinkage. PR ⫽ Partial remission; MR ⫽ minor response; NC ⫽ no change; PG ⫽ progression.

ganglia and thalamus. Conversely, the maximum and marginal doses for brainstem lesions were significantly lower than those for basal ganglia and the thalamus. In general, brainstem lesions were treated with a marginal dose of ⬍13 Gy. Response on MRI During a mean follow-up of 55 months, nearly half of the lesions showed some shrinkage. There were no obvious changes in the rest. Only 4 of the 84 (4.8%) showed lesion progression. Basal ganglia-thalamus and brainstem responses are shown separately in table 3. Rebleeding, Perifocal Edema and New Lesions Rebleeding occurred in 14 cases (16.7%) and 16 times in total, representing a 4.2%/year/case rebleeding rate. There were 12 hemorrhages in the first 24 months after radiosurgery, but the incidence decreased markedly thereafter. The bleeding rates during the first and second years were 9.5 and 4.7%/year/case, respectively. The rate was lower 3–5 years after treatment and only 2 hemorrhages occurred after 5 years. Hemorrhage-free survival in this series is shown in figure 1. There was no major difference in hemorrhage-free survival between basal ganglia-thalamus and brainstem lesions. Concerning hemorrhagic episodes prior to radiosurgery, the hemorrhage rate was highest for those who had already suffered 2 hemorrhages. Multiple hemorrhages, more than 3 times, dramatically decreased after radiosurgery. In fact, hemorrhage-free survival following 3 or more episodes was better than that of cases with 1 and 2 hemorrhages (fig. 2). A typical case with 5 hemorrhagic episodes is shown in figure 3. As for complications, perifocal edema was seen in 18% of basal ganglia-thalamus and in 3.2% of brainstem lesion cases. De novo cavernous malformation lesions were identified in 2 cases and new cyst formation in one. Five patients died, 2 of cavernous malformation progression, 2 of unrelated causes and one for an unknown reason (table 4).

Radiosurgery of Cavernous Malformation

33

Hemorrhage-free survival

1.0 0.8 0.6 0.4 0.2 0 0

20

40

60 80 Months

100

120

140

Fig. 1. Hemorrhage-free survival after radiosurgery. 䊉 ⫽ Basal ganglia; 䊊 ⫽ brainstem.

1.0

Percentage

0.8 0.6 0.4 0.2 0 0

20

40

60 80 Months

100

120

140

Fig. 2. Hemorrhage-free survival in relation to the number of hemorrhagic episodes before radiosurgery (Kaplan-Meier method). ⵧ ⫽ One and two hemorrhages; 䊊 ⫽ 3 or more hemorrhages.

34

Kida

Fig. 3. Cavernous malformation in left brainstem and cerebellum: patient presented with frequent hemorrhages (5 in 1 year), and was treated with gamma knife radiosurgery using 13 Gy at the margin. The lesion shows moderate shrinkage 90 months later. There were no further episodes of bleeding and no neurological deterioration.

Table 4. Complications and rebleeding after radiosurgery Location

Rebleeding

Perifocal edema

New lesion or cyst

Death

Basal ganglia and thalamus (n ⫽ 22)

2 (9.1)

4 (18.2)

1 (4.5)

1 (4.5)

Brainstem (n ⫽ 62)

12 (19.4)

2 (3.2)

2 (3.2)

4 (6.4)

Total (n ⫽ 84)

14 (16.7)

6 (7.1)

3 (3.6)

5 (6.0)

Rebleeding was more frequent in cases with brainstem lesions. Conversely, the incidence of perifocal edema was higher in cases with basal ganglia and thalamus lesions. Percentages are shown in parentheses.

Discussion

Cavernous malformations are generally silent for long periods and are often found incidentally. However, it is well known that these lesions can cause hemorrhage and have a fulminant course with repetitive hemorrhage [7]. Thus, treating silent lesions is generally not warranted, and it is important to carefully evaluate the real hemorrhage risk after a single hemorrhage in terms of the natural history of symptomatic lesions. Kondziolka et al. [8] estimated the hemorrhage rate after a single hemorrhage to be about 4.5%/year/case. Similarly, Kupersmith et al. [9] demonstrated the natural history of brainstem cavernous malformation, in which the bleeding and rebleeding rates were estimated to be 2.5 and 5.1%, respectively. These rebleeding rates contrast with the 21% rate reported by Fritschi et al. [10], and the 30% rate reported by Porter et al. [11]. These symptomatic lesions are apparently indications for treatment. Supratentorial and cerebellar lesions are surgically accessible and can be resected

Radiosurgery of Cavernous Malformation

35

without serious morbidities [12–14], but lesions in the basal ganglia and brainstem are difficult to totally eliminate. Only exophytic lesions in the brainstem have been considered an appropriate indication for surgical intervention. Although some investigators have reported good postoperative results for brainstem lesions, these results are associated with an apparent selection bias and more importantly depend on the surgeon’s skill [15–17]. Radiosurgery for cavernous malformation has been carried out since similar vascular anomalies like AVM showed excellent results [18–21]. However, radiosurgery for cavernous malformations has always been controversial, because it is difficult to confirm postradiosurgical effects on cavernous malformation and hemorrhagic episodes, and because relatively frequent complications have been reported with this treatment. Both rebleeding and perifocal edema after radiosurgery can be hazardous for the patient. Kondziolka et al. [21] reported that the hemorrhage rate after radiosurgery was markedly decreased when compared with the natural history after the first hemorrhage. Other investigators have obtained similar results, but no definite conclusion has been drawn. Our intention is not to totally eradicate cavernous malformation with radiosurgery, but to transform active lesions into silent ones. If no further bleeding occurs, there would presumably be no further neurological deterioration. In our experience, relatively frequent episodes of bleeding from cavernous malformations occurred in the first 2 years after radiosurgery. However, the bleeding rate decreased markedly thereafter and there is no bleeding after 7 years. In accordance with this decreased bleeding rate, MRI findings subsequently changed. In fact, half of the lesions demonstrated some shrinkage, and only 5% showed progression on MRI. This is in sharp contrast to the natural history reported by Kupersmith et al. [9], in which only 18% shrank and the majority of lesions were unchanged (66.7%) or enlarged (15%).

Conclusion

Long-term results of radiosurgery for 84 cases with cavernous malformations in the basal ganglia (7), thalamus (14) and brainstem (63) are presented. The mean lesion size was 14.3 mm. Mean maximum and marginal treatment doses were 23.3 and 13.4 Gy, respectively. During a mean follow-up of 55 months, nearly half of the lesions showed some shrinkage, while in the other half there were no obvious changes. Rebleeding occurred in 14 cases (16.7%), 16 times in total, representing a 4.2%/year/case rebleeding rate. Among these, 12 hemorrhages occurred during the first 24 months after radiosurgery, and the incidence decreased markedly thereafter. Bleeding rates during the first and second years were 9.5 and 4.7%/year/case, respectively. However, the rate significantly decreased thereafter. In conclusion, radiosurgery for cavernous malformations of the basal ganglia-thalamus and brainstem is warranted because a decreased bleeding rate and lower morbidity can be expected.

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Kida

References 1 Awad IA, Robinson JR: Cavernous malformations and epilepsy; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, American Association of Neurological Surgeons, 1991, pp 49–63. 2 Lobato RD, Perez C, Rivas JJ, Cordobes F: Clinical, radiological, and pathological spectrum of angiographically occult intracranial vascular malformations: analysis of 21 cases and review of the literature. J Neurosurg 1988;68:518–531. 3 Curling OD, Kelly DL, Elster AD, et al: An analysis of the natural history of cavernous angioma. J Neurosurg 1991;75:702–708. 4 Robinson JR, Awad IA, Little JR: Natural history of the cavernous angioma. J Neurosurg 1991;75:709–714. 5 Zabramski JM, Wascher TM, Spetzler RF, et al: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 1994; 80:422–432. 6 Duffau H, Capelle L, Sichez JP, Faillot T, Bitar A, Arthuis F, Van Effenterre R, Fohanno D: Early radiologically proven rebleeding from intracranial cavernous angiomas: report of 6 cases and review of the literature. Acta Neurochir (Wien) 1997;139:914–922. 7 Maraire JN, Awad IA: Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591–605. 8 Kondziolka D, Lunsford LD, Kestle JRW: The natural history of cerebral cavernous malformations. J Neurosurg 1995;83:820–824. 9 Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, Jafar J, Mandel G, De Lara F: Natural history of brainstem cavernous malformations. Neurosurgery 2001;48:47–54. 10 Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM: Cavernous malformations of the brainstem: a review of 139 cases. Acta Neurochir (Wien) 1994;130: 35–46. 11 Porter PJ, Willinsky RA, Harper W, Wallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 1997;87:190–197.

12 Casazza M, Broggi G, Franzini A, Avanzini G, Spreafico R, Brocchi M, Valentini MC: Supratentorial cavernous angiomas and epileptic seizure: preoperative course and postoperative outcome. Neurosurgery 1996;39;26–34. 13 Cohen DS, Zubay GP, Goodman RR: Seizure outcome after lesionectomy for cavernous malformations. J Neurosurg 1995;83:237–242. 14 Amin-Hanjani S, Ogilvy CS, Ojemann RG, Crowell RM: Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 1998;42:1220–1228. 15 Cantore G, Missori P, Santoro A: Cavernous angiomas of the brainstem: intra-axial anatomical pitfalls and surgical strategies. Surg Neurol 1999;52:84–94. 16 Porter RW, Detwiler PW, Spetzler RF, Lawton MT, Baskin JJ, Derksen PT, Zabranski JM: Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 1999;90:50–58. 17 Wang CW, Liu AL, Zhang J, Sun B, Zhao Y: Surgical management of brainstem cavernous malformations: report of 137 cases. Surg Neurol 2003;59:444–454. 18 Amin-Hanjani S, Ogilvy CS, Candia GJ, Lyons S, Chapman PH: Stereotactic radiosurgery for cavernous malformations: Kjellberg’s experience with proton beam therapy in 98 cases at the Harvard cyclotron. Neurosurgery 1998;42:1229–1238. 19 Chang SD, Levy RP, Adler JR, Martin DP, Krakovitz PR, Steinberg GK: Stereotactic radiosurgery of angiographically occult vascular malformations: 14year experience. Neurosurgery 1998;43:213–221. 20 Kondziolka D, Lunsford LD, Coffey RJ, Bissonette DJ, Flickinger JC: Stereotactic radiosurgery of angiographically occult vascular malformations: Indications and preliminary experience. Neurosurgery 1990;27: 892–900. 21 Kondziolka D, Lunsford D, Flickinger JC, Kestle JRW: Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995;83:825–831.

Yoshihisa Kida, MD Department of Neurosurgery, Komaki City Hospital 1-20, Jhobusi Komaki, Aichi 485–8520 (Japan) Tel. ⫹81 568 76 4131, Fax ⫹81 568 76 4145, E-Mail [email protected]

Radiosurgery of Cavernous Malformation

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 38–44

Radiosurgery for Dural Arteriovenous Fistula Yoshihisa Kida Department of Neurosurgery, Komaki City Hospital, Komaki, Japan

Abstract The early results of radiosurgery for dural arteriovenous fistula (DAVF) are reported. Thirteen cases of DAVF, 9 males and 4 females, ranging in age from 39 to 74 years (mean 54.3), are presented. None underwent surgical resection, but 7 of the 13 did receive embolization. DAVF locations were the cavernous sinus (4), transverse-sigmoid (2), tentorium (4), and the anterior skull base, cranio-cervical junction, and superior sagittal sinus in 1 case each. The DAVF lesions were 14.9 mm in mean diameter and were treated with a mean marginal dose of 18.9 Gy (range 15–24 Gy). Follow-up studies (mean, 24 months) showed excellent neurological recovery as well as disappearance or shrinkage of the DAVF nidus. In conclusion, DAVF showed Copyright © 2009 S. Karger AG, Basel a remarkable response similar to that for AVM radiosurgery.

Dural arteriovenous malformation (DAVF) is a well-recognized disease entity [1–3]. DAVFs are found in and around venous sinuses such as the cavernous, transverse, sigmoid and sagittal sinuses, or the anterior skull base and craniocervical junction. DAVF treatment is either for surgical resection or an endovascular technique with intraarterial or intravenous embolization. However, results are not always satisfactory, because of incomplete resection or partial embolization. Recently, a radiosurgical technique for DAVF has had the promise of being a possible treatment modality because precise localization and persistent post-treatment occlusion of DAVF are obtained. We started treating DAVFs several years ago, and now have sufficient follow-up. The long-term effects of radiosurgery and the role of radiosurgery in DAVF are discussed.

Cases and Methods Current radiosurgery indications for DAV are a well-defined small nidus and that emergent treatment is not required. The present 13 cases, 9 males and 4 females, ranged in age from 39 to 68 with a mean of 54.3 years. The locations of DAVF were the cavernous sinus in 4 cases, transverse-sigmoid sinus in 2 cases, tentorium in 4 cases, and the anterior skull base, superior sagittal sinus and craniocervical junction in 1 case each. None had undergone surgical resection, but 7 of the 13 (54%) cases

Table 1. Characteristics of DAVF cases Case

Site

Initial sign

Symptoms

Prior therapy

1) 65 F

CCF

headache

impaired VA Ophthalmoparesis

embolization

2) 45 M

transversesigmoid

impaired VA

epilepsy hemianopsia

none

3) 49 M

CCJ

vertigo

exophthalmus

embolization ⫻ 2

4) 58 F

CCF

exophthalmus

exophthalmus

embolization ⫻ 2

5) 60 F

CCF

diplopia

chemosis

embolization

6) 46 M

tentorial

headache nausea

VIth N palsy Vth N palsy

embolization

7) 74 F

transversesigmoid

SAH

none

none

8) 59 M

frontal base

convulsion

none

embolization ⫻ 2

9) 56 M

tentorial

headache

none

none

10) 43 M

temporal

epilepsy

none

embolization ⫻ 2

11) 45 M

tentorial

dysesthesia LOC

dysesthesia (right face)

none

12) 68 M

CCF

diplopia

IIIrd N palsy

none

13) 39 M

superior sagittal

headache epilepsy

dysphasia hemiparesis

none

CCF ⫽ Carotid-cavernous fistula; CCJ ⫽ craniocervical junction; SAH ⫽ subarachnoid bleeding; VA ⫽ visual acuity; LOC ⫽ loss of consciousness.

had previously been treated by an endovascular technique (table 1). Following cerebral angiography and enhanced MRI, dose planning for DAVF was done with Gamma-plan software (Elekta AB). Careful nidus evaluations were required for conformal dose planning, after which radiosurgery with the gamma knife was performed. Subsequently, follow-up studies were conducted every 3 months during the first year and every 6 months thereafter until complete DAVF obliteration was confirmed. The lesions were evaluated as showing CR (complete remission), PR (partial remission), MR (minor response), NC (no change) or PG (progression) in comparison with findings at radiosurgery.

Results

Location, lesion size, maximum dose and marginal dose are presented in table 2. Although the majority of DAVF nidi were well visualized, an obscure or indefinite

Radiosurgery of DAVF

39

Table 2. Lesion size, flow rate, and radiosurgical doses for DAVFs Case

Site

Nidus size

Flow

Maximum dose Gy

Marginal dose Gy

1) 65 F 2) 45 M 3) 49 M 4) 58 F 5) 60 F 6) 46 M 7) 74 F 8) 59 M 9) 56 M 10) 43 M 11) 45 M 12) 68 M 13) 39 M

CCF transverse-sigmoid CCJ CCF CCF tentorium transverse-sigmoid frontal base tentorium temporal tentorium CCF superior sagittal

22.5 mm 22.3 9.0 11.5 10.7 20.2 9.4 16.7 15.0 8.7 19.7 13.1 14.4

high high low low low medium high medium high low medium medium slow

30 40 24 24 32 29 34 40 36 30 30 34 40

15 20 18 15.6 16 16 22.1 24 18 21 22.5 17 20

Table 3. Neuroradiological and neurological outcomes Case

Site

Follow-up months

Response

Neurological symptoms

1) 65 F 2) 45 M 3) 49 M 4) 58 F 5) 60 F 6) 46 M 7) 74 F 8) 59 M 9) 56 M 10) 43 M 11) 45 M 12) 68 M 13) 39 M

CCF transverse-sigmoid CCJ CCF CCF tentorium transverse-sigmoid frontal base tentorium temporal tentorium ccf superior sagittal

46 72 36 12 9 36 18 16 18 9 6 17 12

NC PR CR CR CR PR NC PR PR NC PR CR CR

no change improved improved improved improved improved improved improved improved no change no change improved improved

CR ⫽ Complete remission; PR ⫽ partial remission; MR ⫽ minor response; NC ⫽ no change.

nidus was seen in a few cases. Since the lesions were not particularly large (8.7–22.5 mm: mean 14.9 mm) and sufficiently far from eloquent brain structures, most were treated with high marginal doses of more than 18 Gy (mean: 18.9 Gy). None were treated with a marginal dose below 15 Gy, and 6 lesions were treated

40

Kida

Marginal dose (Gy)

25 24 23 22 21 20 19 18 17 16 15 14

CR MR NC PR

8

10

12

14

16 18 Size (mm)

20

22

24

Fig. 1. Scattergram of relationships among lesion size, marginal dose and response. No obvious relationships exist.

with marginal doses exceeding 20 Gy. DAVF flow rates are evaluated as high, medium and low using angiography. A high flow rate was apparent in the early phase in 4 cases, a medium flow rate in 4, and a low flow rate was seen in the late arterial phase in 5. During the mean follow-up of 24 months, the majority of cases demonstrated an early neurological response, including amelioration of headache, improved ocular movement, and reduced ocular pain and exophthalmus. New bleeding was seen in 1 case after treatment. Follow-up angiographic and MRI studies showed CR in 5, PR in 5, MR in 0 and NC in 3. None of the lesions showed progression. During the follow-up of 23.6 months, the response rate was 76.9% (10/13), including 5 with complete obliterations (38.5%). According to location, 3 of 4 CCFs were completely obliterated at a mean follow-up of 12.6 months after the radiosurgery. Neurological improvement was evident in 10, and there was no change in 3 (table 3). As to flow rates of the DAVF at radiosurgery, 4/5 (80%) had a low flow rate, 1/4 (25%) medium and none a high flow rate. The absence of a high flow rate indicates that these lesions showed earlier obliteration. Thus, the lower the flow rate, the more quickly complete obliteration is achieved. Scatteragrams for lesion volume and marginal dose indicated that these two factors did not correlate with DAVF obliteration (fig. 1). There have been no serious complications to date, but intracerebral bleeding was seen after treatment in 1 case. In another case, a second radiosurgery was required because of incomplete obliteration 3 years after the first treatment.

Radiosurgery of DAVF

41

a

b Fig. 2. Dural AVF in the parietal lobe treated with a marginal dose of 20 Gy (a) showing complete obliteration 12 months post-treatment (b).

Illustrative Cases

Case 1 A 39-year-old man presented with intracranial hemorrhage, associated with speech disturbance and right hand weakness. Angiography disclosed a DAVF fed by the middle meningeal artery and draining into the sagittal sinus, with an apparent low flow rate. Radiosurgery for this DAVF, 14.4 mm in mean diameter, was performed with a 20-Gy marginal dose. The DAVF showed shrinkage at 6 months and complete occlusion at 12 months. There have been no complications during follow-up (fig. 2). Case 2 A 68-year-old man, presenting with diplopia and ptosis, had a DAVF in the right cavernous sinus. He underwent gamma knife treatment with a 17-Gy marginal dose. Complete CCF obliteration was confirmed 17 months later, along with improvement of third cranial nerve palsy and chemosis (fig. 3).

Discussion

With recent advances in detection and imaging techniques, it is not difficult to identify a DAVF in the central nervous system. These lesions apparently involve the venous sinuses, and can cause bleeding from leptomeningeal reflux and may even induce chronic intracranial hypertension [1–4]. Lesions presenting with acute and progressive neurological signs such as intracranial bleeding or progressive exophthalmos, usually require emergency surgery or embolization. However, such fulminant cases are rare, and most have subclinical or chronic symptoms, including persistent headache, tinnitus and bruits. Surgical resection is often difficult because of location

42

Kida

a

b Fig. 3. Dural AVF in the cavernous sinus, treated with a 17-Gy marginal dose (a) showing complete obliteration 17 months post-treatment (b).

and the risk of serious neurological deficits. Endovascular embolization via the arterial or venous route has been applied in many DAVF cases. However, it can be difficult to completely obliterate the lesion and only partial obliteration is achieved in some cases. In other cases, neither the venous nor the arterial approach is feasible. With sufficient experience in treating cerebral AVM, radiosurgery appears to be a promising treatment method because it can induce slow but consistent obliteration of abnormal vessels without causing recanalization. There have been only a few reports of radiosurgery for DAVF [5–9]. Excellent CCF obliteration was reported by Guo et al. [7], in agreement with our results. In fact, 3 of 4 CCFs in our series were obliterated early in follow-up associated with early improvement of neurological deficits. One failure was apparently due to incomplete coverage of the DAVF nidus. The most important issue in radiosurgery for DAVF is localizing the nidus. This is especially true for CCF because many feeding and draining vessels exist in and around the cavernous sinus, often bilaterally. A relatively wide area is treated in CCF cases in our institute. Recently, treatments combining endovascular and radiosurgical techniques have been reported by several investigators [6, 9]. The two treatment modalities are apparently complimentary since early neurological improvement, with an endovascular technique, and consistent obliteration with radiosurgery can be expected. With such a combination, it is necessary to decide which procedure should be done first. Some authors have insisted that embolization should be done first because the resulting smaller volume can more easily be treated radiosurgically. In contrast, others have advocated that radiosurgery be done first since embolization often obscures the nidus margin of DAVF.

Conclusion

Radiosurgery for dural arterovenous fistulas produced excellent results. In fact, 5 of 13 were completely obliterated and another 5 demonstrated marked shrinkage of the

Radiosurgery of DAVF

43

lesions as well as neurological improvement. No adverse effects were seen in the mean follow-up of 24 months. Therefore, radiosurgery is a very promising treatment method for DAVF.

References 1

2

3

4

5

Borden JA, Wu JK, Shcart WA: A proposed classification for spinal and cranial dural arteriovenous fistulous malformations and implications for treatment. J Neurosurg 1995;82:166–179. Cognard C, Gobin YP, Pierot L: Cerebral dural arterio-venous fistulas: clinical and angiographic correlation with revised classification of venous drainage. Radiology 1995;194:671–680. Davies MA, TerBrugge K, Willinsky R, et al: The validity of classification for the clinical presentations of intracranial dural arteriovenous fistulas. J Neurosurg 1996;85:830–837. Brown RD Jr, Wiebers DO, Nichols DA: Intracranial dural arteriovenous fistulae: angiographic predictors of intracranial hemorrhage and clinical outcome in nonsurgical patients. J Neurosurg 1994;81:531–538. Chandler HC Jr, Friedman WA: Successful radiosurgical treatment of a dural arteriovenous malformation: case report. Neurosurgery 1993;33:139–142.

6

7

8

9

Friedman WA, Bova FJ, Mendenhall WM: Linear accelerator radiosurgery for arteriovenous malformations: the relationship of size to outcome. J Neurosurg 1995;82:180–189. Guo WY, Pan DHC, Wu HM: Radiosurgery as a treatment alternative for dural arteriovenous fistulas of the cavernous sinus. AJNR 1998;19:1081–1087. Pan DHC, Chung WY, Guo WY, Wu HM, Liu KD, Shiau CY, Wang LW: Stereotactic radiosurgery for the treatment of dural arteriovenous fistulas involving the transverse-sigmoid sinus. J Neurosurg 2002; 96:823–829. Pollock BE, Nichols DA, Garrity JA, Gorman DA, Stafford SL: Stereotactic radiosurgery and particular embolization for cavernous sinus dural arteriovenous fistulae. Neurosurgery 1999;45:459–467.

Yoshihisa Kida, MD Department of Neurosurgery, Komaki City Hospital 1-20, Jhobusi Komaki, Aichi 485–8520 (Japan) Tel. ⫹81 568 76 4131, Fax ⫹81 568 76 4145, E-Mail [email protected]

44

Kida

Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 45–62

Gamma Knife Radiosurgery for Vestibular Schwannomas Seiji Fukuokaa ⭈ Masami Takanashia ⭈ Atsufumi Hojyoa ⭈ Masanori Konishib ⭈ Chiharu Tanakac ⭈ Hirohiko Nakamuraa Departments of aNeurosurgery, bOtolaryngology, and cNeurology, Nakamura Memorial Hospital, Sapporo, Japan

Abstract The purpose of this study was to analyze tumor control and possible complications of gamma knife radiosurgery (GKRS) in patients with vestibular schwannomas using low marginal doses and conformal multiple shots to fit irregular tumor shapes. The authors evaluated 152 patients with more than 5 years of follow-up. Marginal doses were 9–15 Gy (median 12 Gy), with corresponding treatment volumes ranging from 0.1 to 18.7 cm3 (median 2.0 cm3). The number of isocenters varied from 2 to 24 shots (median 9 shots). The actuarial tumor control rates were 94% at 5 years and 92.4% at 8 years. Larger tumors (p ⬍ 0.0001) and those in younger patients (p ⫽ 0.018) tended to recur significantly more often. Useful hearing, facial and trigeminal functions were preserved at 71, 100 and 97.4%, respectively. Seventeen percent of all patients developed transient dizziness, with dizziness persisting in 2% of the total. Fifty-six other patients not included in the long-term evaluation consecutively underwent caloric testing and static stabilometry as well as neurological exanimations to evaluate vestibular function in detail, both before and after GKRS. The results revealed 90% of the patients to have already developed vestibular dysfunction prior to the treatment despite reported symptoms of dizziness. GKRS did not significantly affect vestibular function. Hydrocephalus was recognized in 5.3% of all patients, and tended to occur in cases with larger tumors (p ⫽ 0.0024). GKRS provides a safe and effective therapy for small to medium-sized tumors. However, indications for larger tumors must be carefully considered, as they are more difficult to Copyright © 2009 S. Karger AG, Basel control and liable to produce ataxia due to transient expansion.

Gamma knife radiosurgery is generally recognized as a safe and effective treatment modality [1–3, 6, 10, 14]. Recent concerns have focused on the marginal dose, and conformity, in treating vestibular schwannomas with the gamma knife to improve control rates and optimize functional outcome. While it is theoretically reasonable that a higher marginal dose is likely to control a tumor better than a lower marginal dose, the dosage has typically been reduced to protect facial nerve function and/or hearing [1, 10]. Facial nerve function is not compromised with a marginal dose of 13–14 Gy or less [1, 10, 14] just as hearing can be largely preserved below this dosage

Table 1. Summary of characteristics of 152 patients with vestibular schwannomas

Values Gender Male Female

61 91

Age, years Range Mean (median)

22–83 54 (54)

Previous surgery No Yes

107 45

Tumor size, cm3 Range Mean (median)

0.1–18.6 2.8 (2.0)

Maximum dose, Gy Range Mean (median)

17.1–30.0 25.5 (24)

Marginal dose, Gy Range Mean (median)

9–15 12.8 (12.0)

Number of isocenters Range Mean (median)

2–18 9.1 (9)

[1, 12, 14]. Clearly, it is very important to ascertain the minimal marginal dose to achieve a satisfactory control rate. Meanwhile, conformity is also a key element, because the ability to render conformal multiple shots to fit the irregular shape of vestibular schwannomas is essential to both protecting cranial nerves from excessive radiation, as well as to covering the entire tumor as precisely as possible. Since May 1991 [2, 3], we have consistently applied the low dose, conformal multiple isocenter strategy in such cases. Our results, in terms of control rate and functional outcome, are reported herein.

Clinical Materials and Methods From May 1991 to May 2003, 383 consecutive patients harboring unilateral vestibular schwannomas were treated by gamma knife at Nakamura Memorial Hospital in Sapporo, Japan. To evaluate both the long-term control rate and functional outcome, 157 patients who were treated between May 1991 and May 1998 were followed-up. The follow-up period was at least 5 years. Five cases were lost to followup during this period, leaving 152. The patients’ characteristics are presented in table 1. Sixty-one patients were men and 91 were women, ranging in age from 22 to 83, with a mean age of 54.

46

Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

Fig. 1. Classification of hearing acuity in 152 patients prior to GKRS according to Gardner-Robertson scale.

Fig. 2. Classification of facial nerve function in 152 patients prior to GKRS according to House-Brackmann scale.

I : 34 cases II : 25 III : 46 IV : 5 V : 42

I : 135 cases II : 4 III : 7 IV : 3 V :3 VI : 0

Hearing acuity was assessed using the Gardner-Robertson classification, and facial nerve function was evaluated with the House-Brackmann grading system. Figures 1 and 2 show pretreatment hearing and facial nerve function, respectively. Fifty-nine patients (39%) had useful or serviceable hearing (Gardner-Robertson classifications I and II) and 135 (89%) demonstrated normal facial nerve function (House-Brackmann grade I) before GKRS.

GKRS for Vestibular Schwannomas

47

a

b

c

d

Fig. 3. Enhanced MRI images before and after GKRS in a 50-year-old man with right vestibular schwannoma. a Before GKRS, b 1 year after, c 3 years after, d 11 years after GKRS. After early shrinkage, there was no marked change in the tumor.

Gamma Knife Procedure

After fixing the Leksell frame, to enable dose planning, patients underwent thin-slice enhanced MRI and CT imaging. Tumor volumes ranged from 0.1 to 18.7 cm3, with a median volume of 2.0 cm3. Tumor margins were irradiated with 9–15 Gy, the median dose being 12.0 Gy. Multiple isocenters were used to match the marginal isodose line to the irregular shapes of the tumors, with a median of 9 shots. The number of isocenters was 8.8 ⫾ 2.4 using KULA (65 patients), and 9.2 ⫾ 3.3 with the GammaPlan (87 patients). There was no difference in terms of isocenters using these two softwares (p ⫽ 0.366). Follow-Up

An increase or decrease in tumor size was defined as a quantifiable change of 1 mm or more in diameter. Cranial nerve function was evaluated according to the Gardner-Robertson classification and House-Brackmann grading system. The actuarial tumor control rate and hearing preservation rate were calculated employing the Kaplan-Meier product-limit method. The stepwise multivariate Cox proportional hazards model or linear regression was used to analyze what factors could affect these rates. We assessed the following factors: age, gender, history of previous surgery, tumor size, maximum dose, marginal dose, number of isocenters, and dose planning using KULA or GammaPlan software.

Results

Tumor Control After treatment, some tumors showed early shrinkage (fig. 3). While 53% of tumors initially showed expansion at some stage during the 3- to 24-month postoperative period (fig. 4), these tumors eventually decreased in size from their maximum peaks at 3–47 months after the initial increase. Tumor control was defined as no additional treatment being required after gamma knife radiosurgery (GKRS). The actuarial tumor control rates were 94% at 5 years and 92.4% at 8 years (fig. 5). As to delayed control failure, one case underwent surgical

48

Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

a

c

b

d

e

Fig. 4. Enhanced MRI showing transient tumor expansion in a 49-year-old woman. a Before GKRS, b 6 months after GKRS, c 1 year after, d 3 years after, e 6 years after. The patient suffered from mild facial numbness before GKRS, and developed moderate numbness 6–12 months after the treatment. Currently, 6 years post-treatment, slight facial numbness persists.

%

100

Fig. 5. Graph showing actuarial tumor control rate in 152 patients after GKRS. Control rates are 94% at 5 years and 92.4% at 8 years.

50

0

0

1

2

3

4

5 6 Years

7

8

9

10

extirpation 8 years after GKRS due to a chronic intratumoral hemorrhage (fig. 6). The intraoperatively obtained specimens showed the MIB-1 index to be 2–3% before GKRS and 0% at 8 years after the treatment (fig. 7). Chronic hemorrhage is apparently a rare cause of re-expansion. Multivariate analysis showed age (p ⫽ 0.018) and tumor volume (p ⬍ 0.0001) to correlate significantly with control failure. Tumors in younger patients (mean 42, range 24–55) tended to recur more frequently than those in older patients (mean 54, range 22–83). Patients were arbitrarily divided into 2 groups according to tumor volume. One consisted of tumor volumes less than 8 cm3, or approximately 2.5 cm in mean diameter (143 patients), and the other consisted of tumor volumes greater than 8 cm3 (9 patients). The actuarial control rates were 94.2 and 62.5% at 5 years, respectively (p ⬍ 0.0001, log-rank test, fig. 8). The mean tumor volume in successfully controlled cases was 2.5 cm3, while that in the uncontrolled group was 7.4 cm3. All tumors were completely controlled when the volume was 2 cm3 or less.

GKRS for Vestibular Schwannomas

49

Fig. 6. Axial enhanced MRI images (a, b, c, d1, e1, f1) documenting serial changes in right vestibular schwannoma. a Before surgical extirpation, b before GKRS, c expansion at 3 years after GKRS, d1 some shrinkage at 6 years after GKRS, d2 non-enhanced T1WI shows no hemorrhage, e1 reexpansion at 7 years after GKRS, e2 HIA on non-enhanced T1WI implies bleeding, f1 further expansion at 8 years after GKRS, f2 HIA (bleeding) increased on T2WI.

a

b

c

d1

e1

f1

d2

e2

f2

Pathological Findings One female patient developed ataxia due to tumor expansion 6 months after GKRS, necessitating partial removal of the tumor 18 months after GKRS due to persistent symptoms. She had already undergone 3 previous surgeries. It should be noted that the tumor showed slight shrinkage from its maximum size. The tumor, 18.7 cm3 in volume, had been irradiated with a marginal dose of 9 Gy. A pathological specimen from the tumor showed thickening or obliteration of tumor vessels and apoptosis (fig. 9). These findings were thought to be attributable to gamma knife irradiation, and to have contributed to the gradual decrease in tumor size. SPECT Findings Fifteen selected patients underwent thallium chloride SPECT imaging prior to, 1 year after, and 2 years after GKRS. The brain perfusion imaging agent 99mTc-HAS-D was also used as a tracer, allowing in vivo measurement of tumor vascularity in early images or permeability in delayed images [8]. The index of early uptake of 99mTcHSA-D, which significantly reflects tumor vascularity, decreased from 1.7 ⫾ 0.3

50

Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

a

b Fig. 7. Specimens showing MIB-1 index of 2–3% before GKRS (a) and 0% at 8 years after GKRS (b). HE. ⫻200.

100 96%

%

Fig. 8. Graph comparing actuarial control rates after GKRS for vestibular schwannomas in patients with tumor volumes of 8 cm3 or less (solid line) compared to those with tumor volumes greater than 8 cm3 (broken line). There was a statistically significant difference between the control rates of these two groups (p ⬍ 0.0001).

62.5%

50

0

0

20

40

60 80 Months

100

120

140

pretreatment to 1.5 ⫾ 0.2 at 1 year after GKRS (p ⫽ 0.02, Wilcoxon signed – rank test). This was similarly followed by a decrease in the tumor volume from 3.9 ⫾ 2.4 to 2.4 ⫾ 2.1 over 2 years (p ⫽ 0.01, Wilcoxon signed-rank test) (fig. 10). This implies that the obliteration of tumor vessels was one of the causes of tumor shrinkage after GKRS. This finding is consistent with the pathological findings presented in figure 9.

GKRS for Vestibular Schwannomas

51

a

b Fig. 9. Photograph of vestibular schwannoma specimen. a Some tumor cells with irregularly shaped nuclei and intimal thickening or obliteration of the tumor vessels can be seen. HE. ⫻200. Reprinted with permission from Fukuoka S: Jpn J Neurosurg 1997;6:90–96. b Presence of positively stained cells representing DNA fragmentation, indicative of apoptosis. Tunnel method. ⫻200.

4

Fig. 10. Graph showing changes in tumor volume and the index values obtained from thallium chloride SPECT with 99mTc-HAS-D, before, 1 year after and 2 years after GKRS. The index of the 99mTcHAS-D early image showed significant reduction (*p ⫽ 0.02) 1 year after GKRS followed by a reduction in tumor volume (**p ⫽ 0.01) 2 years after GKRS.

3 ** 2 * 1

0

Tumor volume HAS-D delayed TI HAS-D early Before

1 year

2 years

Hearing Preservation The actuarial preservation rate of useful hearing in 59 patients was 81% at 3 years, 74% at 5 years, and 71% thereafter (fig. 11). In cases in which hearing was maintained at the same class over the first 3 years after GKRS, there was no subsequent deterioration. However, some patients experienced early deterioration of hearing from class I to II within 1 year. In such cases, hearing tended to worsen from class 2 to 3 more

52

Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

%

100

Fig. 11. Graph showing actuarial useful hearing preservation rate after GKRS in 59 patients with useful hearing (Gardner-Robertson class I–II).

50

0

3 years : 81% 5 years : 74% 6 years : 71%

0

1

2

3

4

5 6 Years

7

8

9

10

60 Class III

50

dB

40 Fig. 12. Graph demonstrating posttreatment hearing changes in a patient with class I hearing prior to GKRS. Hearing deteriorated to class II within 1 year and had stabilized at that level by 5 years, then further deteriorated from class II to class III at 6 years.

Class II

30 20

Class I

10 0 Pre-GKRS 10

20

30

40 50 Months

60

70

than 3 years after GKRS (fig. 12). These gradual deteriorations impacted delayed worsening of the actuarial hearing preservation rate in this series. Actuarial preservation rates for discernible hearing function (Gardner-Robertson classifications I–IV) were 97% at 5 years and 92% at 10 years (fig. 13). No factors correlated significantly with the hearing preservation rate. Facial Nerve Function Transient facial weakness was found in 2 (1.3%) patients (deteriorating from HouseBrackmann grade I to II). One patient developed facial paresis 4 months after GKRS, but she had fully recovered 3 years after treatment. The marginal dose had been 15 Gy. After this experience, we decided to reduce the maximum marginal dose to 14 Gy. Another case developed facial weakness 3 months after GKRS, but showed

GKRS for Vestibular Schwannomas

53

100

%

5 years : 97% 10 years : 92%

Fig. 13. Graph showing actuarial hearing preservation rate after GKRS in 110 patients who initially demonstrated any discernible hearing function (Gardner-Robertson class I–IV).

a

b

50

0

0

1

c

2

3

4

5 6 Years

7

8

9

10

d

Fig. 14. Axial enhanced MRI demonstrating transient expansion of vestibular schwannoma in a patient temporarily suffering from trigeminal neuralgia. a Before GKRS, b 4 months after GKRS, the patient developed trigeminal neuralgia due to the tumor compressing the trigeminal nerve, c 8 months after GKRS, the patient was pain free due to tumor shrinkage, d 3 years after GKRS, marked shrinkage is apparent.

complete recovery 4 months post-treatment. In this case, the marginal dose was 12 Gy. No patients developed persistent facial palsy. Trigeminal Nerve Function Seven patients (4.6%) developed facial numbness or pain (fig. 14) 1 to 25 months after GKRS. The pain was transient, but the numbness persisted in 4 patients (2.6%). Hydrocephalus Eight patients (5.3%) developed hydrocephalus 6–15 months (mean 11 months) after GKRS. Two patients already had ventricular enlargement prior to GKRS. All 8

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Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

patients exhibited headaches or gait disturbance, and each successfully underwent a ventriculo-peritoneal shunt placement. The protein content of cerebrospinal fluid obtained from the lumbar subarachnoid space ranged from 78 to 862 mg/dl (median 145 mg/dl) – extremely high values. Multivariate analysis showed tumor volume to be the only factor (p ⫽ 0.0024, linear regression method) correlated with this disease. More attention must be paid to ventricular size, and symptoms such as headache or gait disturbance, especially during the critical period shortly after the treatment. Vestibular Function Twenty-six patients (17%) experienced worsening dizziness, or developed dizziness, 3–42 months after GKRS. Of these 26 patients, 20 (76%) experienced dizziness within 8 months of having undergone GKRS. In most cases, this condition gradually disappeared after a period of 1–48 months (median 6) from the onset due to vestibular compensation. Three patients (2%) suffered persistent mild dizziness. Further Detailed Evaluation of Vestibular Nerve Function In order to assess vestibular nerve function in more detail, 56 consecutive patients not included in this follow-up series underwent a battery of neurological and neurootological examinations, both before and after GKRS. All were treated between May 2000 and March 2002. The analysis included neurological examinations such as ocular movement, standing on one leg and arm deviation tests, as well as otological tests evaluating caloric stimulation and stabilometry. Clinical symptoms of dizziness were also monitored. The clinical results of this additional study are summarized in table 2. Thirty-nine patients (70%) had histories of dizziness. Of these, 22 (56%) still suffered from dizziness immediately prior to GKRS, 12 (55%) of whom recovered after gamma knife treatment. After GKRS, 8 cases (14% of the total 56) showed a transient worsening of dizziness but recovered postoperatively, 4–24 months later. Two patients (3.6%) suffered from mild persistent dizziness after GKRS. The neurological examinations showed that, of the 56 patients, 89% exhibited saccadic eye movement, 89% were unstable on one foot, and 91% had a positive result for the arm deviation test. These findings clearly demonstrate that approximately 90% of patients with vestibular schwannomas have vestibular dysfunction, prior to GKRS, clinically or subclinically. This is true even of patients with no history of dizziness. Neuro-otologically, caloric stimulation demonstrated that the ratio of normal to abnormal results did not change to a statistical degree 1, 6 or 12 months after treatment as compared with the value prior to GKRS (table 3). Computerized static stabilometry was also carried out (fig. 15). This is a reliable and non-invasive technique for evaluating the equilibrium function which measures a patient’s standing center of pressure (COP). The values obtained (total length and marginal area) are thought to indicate the degree of stability or vestibulospinal function. Statistical analysis showed no significant changes in the ratio between these two at 1, 6 and 12 months later (fig. 16a–c).

GKRS for Vestibular Schwannomas

55

Table 2. Clinical course of dizziness before and after GKRS in 56 successive patients (parallel study) Dizziness history

Total

(⫹) 39

(–) 17

56

Dizziness on GKRS

Recovery Unchanged Transient deterioration Persistent deterioration

(⫹) 22 12 6 3

(–) 17 15 1

13 4

8 (14%)

1

1

0

2 (3.6%)

Table 3. Change in caloric stimulation results prior to and 1, 6 and 12 months after GKRS

Abnormal Normal

Before GKRS

1 month after

6 months after

12 months after

75% (42/56) 25% (14/56)

65% (15/23) 13% (3/23)

72% (23/32) 6% (2/32)

38% (6/16) 6% (1/16)

Before GKRS, 42 patients (75%) showed abnormal and 14 (25%) showed normal findings in caloric testing. Post-treatment, 15, 23 and 6 patients showed similar abnormal findings at 1, 6 and 12 months, respectively. Meanwhile, of the 14 patients yielding normal pretreatment results, normal values were maintained at 1, 6 and 12 months for 3, 2 and 1 patient, respectively. ␹2 test showed no significant difference in any period.

These findings strongly suggest that GKRS does not affect vestibular function in such tumor patients. The changes in total length and marginal area may reflect the transient worsening of dizziness in each patient (fig. 17).

Discussion

Tumor Control Transient expansion appears to be relatively common. This phenomenon should not be misdiagnosed as control failure. However, one patient had to undergo surgical removal

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Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

Fig. 15. Stabilometry. Patients are required to stand on a pressure sensitive stabilometric platform with both eyes open and then closed, for 1 min each. A computer analyzes the patient’s standing center of pressure (COP) movement.

18 months after GKRS due to tumor compression to the brain stem caused by transient expansion. Larger tumors tend to cause compression-related symptoms due to their expansion, and become less controllable. Small to medium-sized tumors (mean diameter less than 2.5 cm) without perifocal edema appear to be good indications. GKRS is thought to gradually impact vestibular schwannomas in two ways; by necrosis [9] and hyalinization of tumor vessels [2, 7]. We demonstrated significantly decreased early uptake of 99mTc-HAS-D followed by a reduction in tumor size (fig. 8). Additionally, Linsky et al. [9] reported an experimental study in which mural hyalinization was found in transplanted tumor tissue after gamma knife irradiation. Moreover, we previously reported apoptosis to occur after GKRS [4]. These mechanisms likely contribute to the observed gradual decrease in size. Hearing Preservation There are two aspects to preservation of hearing; namely useful hearing and any discernible hearing. The preservation of useful hearing is critical to maintaining a good quality of life, especially in cases where the patient has only one functioning ear (fig. 18). Recently reported preservation rates are 70–80% [1, 3, 14]. Flickinger et al. [1] reported that useful hearing was preserved in 73.5% of cases with better conformal

GKRS for Vestibular Schwannomas

57

Fig. 16. a The measurement and correlation of stabilometric marginal area and total length before and 1 month after GKRS. b The measurement and correlation of stabilometric marginal area and total length before and 6 months after GKRS. c The measurement and correlation of stabilometric marginal area and total length before and 12 months after GKRS.

Marginal area (open eyes) 35 p⫽0.4982 30 25 20 15 10 5 0 Before 1 month after

Total length (open eyes) 400 350 p⫽0.1752 300 250 200 150 100 50 0 Before 1 month after

Marginal area (closed eyes) Total length (closed eyes) 1,000 120 p⫽0.8353 p⫽0.1079 100 800 80 600 60 400 40 200 20 0 0 Before 1 month Before 1 month after after a

dose planning and more isocenters, as well as a reduced marginal dose of 13 Gy as the median value. It was also noted that hearing preservation had stabilized 3 years after GKRS. In this study, useful hearing preservation rates were 81 and 71% at 3 and 6 years, respectively. The further decline in the useful hearing preservation rate 3 years after GKRS is explained in figure 11. A longer follow-up in cases with early hearing deterioration is necessary. The optimal dose for preserving useful hearing while simultaneously ensuring a reasonable control rate has yet to be determined. As in the case shown in figure 18, a marginal dose of 9 Gy would be appropriate to preserve hearing in a patient with contralateral deafness. However, as there are no definitive data concerning the long-term control of such tumors with a lower dose of 9 Gy, a marginal dose of 12–13 Gy with multiple conformal shots seems to be the best current strategy for obtaining a relatively high preservation rate of useful hearing as well as a reasonable control rate. Facial and Vestibular Nerve Functions Recent studies have found no facial palsy with a marginal dose below 13–14 Gy [1, 14]. Utilizing a median dose of 12 Gy, range 9–15 Gy, the incidence of permanent

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Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

45 40 35 30 25 20 15 10 5 0

Marginal area (open eyes)

350 y⫽0.315⫹ 0.926x; R⫽0.836

200 150 100 0

2

4

6

8

10 12 14 16

Marginal area (closed eyes)

60

y ⫽0.838⫹0.95x; R ⫽0.854

50

50

300

20

200

10

100 0

80

120

160

200

Total length (closed eyes) y ⫽40.593⫹0.76x; R⫽0.77

500 400

5 10 15 20 25 30 35 40 45

40

600

30

0

0

700

40

b

y ⫽ 13.863⫹0.882x; R⫽ 0.724

300 250

70

0

Total length (open eyes)

400

50

150

250

350

450

550

facial weakness developing after GKRS in our series was zero. The median number of isocenters was 9, significantly more than in previous studies, which typically used from 4 to 6 [1, 12, 13]. This strategy of using multiple, conformal shots to fit the irregular shape of the tumor might have contributed to the absence of permanent facial palsy in our series, with marginal dosages ranging from 9 to 15 Gy. Additionally, the recently developed automatic positioning system (APS) available with the C model gamma knife allows the application of more shots (fig. 19), much more easily and quickly than before. It is not unreasonable to anticipate better results, in terms of functional outcome as well as tumor control, in coming years with this new system. As noted, the majority of patients in a parallel study had already demonstrated the presence of some vestibular dysfunction before GKRS, and neither caloric stimulation nor stabilometry showed any significant change after treatment. These findings demonstrate that GKRS does not significantly alter vestibular function in patients with such tumors. However, 23–26% [3, 11, 14] of patients developed or experienced increased dizziness after GKRS, which has the potential to lower quality of life in elderly patients. More research is necessary in this area to address this issue.

GKRS for Vestibular Schwannomas

59

Marginal area (open eyes)

60

300

50

y ⫽⫺1.237⫹1.075x; R ⫽0.874

40

y ⫽⫺12.397⫹1.119x; R⫽0.699

250 200

30

150

20

100

10 0

Total length (open eyes)

350

50 0

2

4

6

8

0

10 12 14 16

Marginal area (closed eyes)

100 90 80 70 60 50 40 30 20 10 0 c 0

40

80

200

160

Total length (closed eyes)

600 500

y ⫽ ⫺2.072⫹1.265x; R⫽0.93

120

y ⫽1.347⫹1.029x; R⫽0.832

400 300 200 100

5 10 15 20 25 30 35 40 45

0

50

150

250

350

450

550

Fig. 16. (continued)

10

cm

5 0 ⫺5 ⫺10 ⫺10 ⫺5

a

0 cm

Marginal area (cm2) Total length (cm)

5

10 ⫺10 ⫺5 4.25

0 cm

5

10 ⫺10 ⫺5

48.54

144.99

5

10

5.90

493.36 b

0 cm

118.29 c

Fig. 17. Stabilometric change in a 62-year-old woman who developed transient dizziness after GKRS. a Stabilometry demonstrated a slightly higher than average value for total length prior to GKRS. b The values of total length and marginal area increased markedly, as the patient developed dizziness, 25 days after GKRS. c 18 months after GKRS, the patient no longer suffered from dizziness and stabilometry had essentially normalized.

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Fukuoka ⭈ Takanashi ⭈ Hojyo ⭈ Konishi ⭈ Tanaka ⭈ Nakamura

a

b

c

d

Fig. 18. Serial changes in tumor size after GKRS in a 49-year-old woman with left vestibular schwannoma. a Before GKRS, b 10 months after GKRS, c 4 years after, d10 years after. This patient had left hearing only due to acute otitis media in the right ear that had damaged right hearing function in early childhood. The pre-GKRS level of hearing was 40 dB. The patient underwent GKRS with a marginal dose of 9 Gy, and maintains 41.3 dB of left hearing at 10 years.

a

b Fig. 19. Recent dose planning for vestibular schwannoma. a The figure shows dose planning with 2 shots from an 8-mm collimator and 19 shots from a 4-mm collimator. Red circles represent the 50% isodose line of each shot. The yellow line, which traces the tumor margin, is the sum of each isodose line calculated by computer using the GammaPlan. b Various isodose lines of 70, 50, and 30% show sharp dose fall-offs.

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61

Conclusion

Gamma knife radiosurgery, when using low doses and conformal multiple shots, achieves a high rate of hearing preservation without permanent facial palsy, as well as providing better than average control. However, careful long-term follow-up is necessary to further understand the causes of, and means of avoiding, specific phenomena such as transient expansion, hydrocephalus, malignant transformation [5, 15], and delayed chronic hemorrhages when employing this treatment for vestibular schwannomas.

References 1

2

3

4

5

6

7

Flickinger JC, Kondziolka D, Niranjan A, Lunsford LD: Results of acoustic neuroma radiosurgery: an analysis of 5 years’ experience using current methods. J Neurosurg 2001;94:1–6. Fukuoka S, Seo Y, Nakagawara J, et al: Gamma knife radiosurgery for acoustic neurinomas. 1. The analysis of tumor control (in Japanese with English abstract). Jpn J Neurosurg 1997;6:90–96. Fukuoka S, Takanashi M, Seo Y, et al: Gamma knife radiosurgery for acoustic neurinomas-part 2:Functional outcome. Jpn J Neurosurg 1997;6:180–185. (In Japanese with English abstract). Fukuoka S, Oka K, Seo Y, Takanashi M, Sumi Y, Nakamura H, Nakamura J, Ikawa F: Apoptosis following gamma knife radiosurgery in a case of acoustic schwannoma. Stereotact Funct Neurosurg 1998;70: 88–94. Hanabusa K, Morikawa A, Murata T, Taki W: Acoustic neuroma with malignant transformation: case report. J Neurosurg 2001;95:518–521. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC: Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med. 1998;339: 1426–1433. Linskey ME, Martinez AJ, Kondziolka D, Flickinger JC, Maitz AH, Whiteside T, Lunsford LD: The radiobiology of human acoustic schwannoma xenografts after stereotactic radiosurgery evaluated in the subrenal capsule of athymic mice. J Neurosurg 1993;78:645–653.

8 Nakagawara J, Fukuoka S, Takahashi S, Takanashi M, Satoh K, Suematsu K, et al: Assessment of vascularity and permeability in brain tumor using SPECT and 99mTc- DTPA-human serum albumin in relation to 201Tl SPECT (in Japanese with English abstract). Kaku Igaku 1994;31:117–124. 9 Noren G, Arndt J, Hindmarsh T: Stereotactic radiosurgery in cases of acoustic neurinoma: further experiences. Neurosurgery 1983;13:12–22. 10 Noren G, Karlbom A, Brantberg K, Lax I, Mosskin M: Gamma knife radiosurgery for acoustic neurinomas. Neurosurgeons 1995;14:159–163. 11 Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Kelsey SF, Jannetta PJ: Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery 1995;36:215–229. 12 Pollock BE, Lunsford LD, Flickinger JC, Clyde BL, Kondziolka D: Vestibular schwannoma management. I. Failed microsurgery and the role of delayed stereotactic radiosurgery. J Neurosurg 1998;89:944–948. 13 Prasad D, Steiner M, Steiner L: Gamma surgery for vestibular schwannoma. J Neurosurg 2000;92: 745–759. 14 Regis J, Pellet W, Delsanti C, Dufour H, Roche PH, Thomassin JM, Zanaret M, Peragut JC: Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 2002;97: 1091–1100. 15 Shin M, Ueki K, Kurita H, Kirino T: Malignant transformation of a vestibular schwannoma after gamma knife radiosurgery. Lancet 2002;360:309–310.

Seiji Fukuoka, MD Department of Neurosurgery, Nakamura Memorial Hospital South-1, West-14, Chuo-ku Sapporo, Hokkaido 060-8570 (Japan) Tel. ⫹81 11 231 8555, Fax ⫹81 11 231 8387, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 63–76

Long-Term Results of Gamma Knife Radiosurgery for 100 Consecutive Cases of Craniopharyngioma and a Treatment Strategy Tatsuya Kobayashi Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital, Nagoya, Japan

Abstract A new treatment strategy using the gamma knife is proposed, based on evaluation of long-term results of gamma knife radiosurgery for residual or recurrent craniopharyngioma after microsurgery. A total of 98 of 107 patients were followed up for a mean of 65.5 months after radiosurgery. The mean volume of tumor was 3.5 ml. Tumors were treated with a marginal dose of 11.5 Gy using a mean of 4.5 isocenters. Final overall results: complete response 19.4%, partial response 67.4%, tumor control rate 79.6% and progression rate 20.4%. Age (for adults) and nature of tumor (cystic or mixed) were statistically significantly favorable and unfavorable prognostic factors, respectively. Patient outcome was excellent in 45 cases, good in 23, fair in 4 and poor in 3. Sixteen patients died and deterioration of visual and endocrinological functions were found as side effects in 6 patients (6.1%). The strategy is for a small tumor between the retrochiasm and anterior stalk to be treated by gamma knife radiotherapy with 10–12 Gy, allowing cure Copyright © 2009 S. Karger AG, Basel without neuroendocrine deficits.

Craniopharyngioma is a benign tumor thought to be derived from a residual cell nest of stomodeum. However, treatment has been controversial. Total removal by microsurgery is ideal but complete removal without deterioration of neurological functions has been difficult because of the proximity of tumors to the hypothalamus, pituitary gland and optic pathway. It has also been reported that the recurrence rate is not low even after ‘total’ removal [7, 19]. Another strategy is combined treatment with partial removal of the tumor and fractionated focal irradiation. Cure or complete control of the tumor has also been difficult and late radiation injury to surrounding organs can produce major side effects [3, 5, 17]. Recently, stereotactic radiosurgery has been found to be effective and safe for the treatment of craniopharyngioma [2, 9, 10, 18]. This report is a retrospective analysis evaluating the long-term results of 100 patients treated by gamma knife radiosurgery performed

Table 1. Characteristics of 100 cases and tumor responses to GK radiosurgery

Age, mean Child Adult

37.4 4 15

33.4 16 31

33.2 6 8

27 12 8

33.6 38 62

Nature of tumor Solid Cystic Mixed Prior therapy #

12 6 1 23

22 7 18 66

3 6 5 26

3 5 12 57

40 24 36 172

Surgery Subtotal removal Partial removal Biopsy Ommaya Shunt Chemotherapy Radiotherapy

7 13 2 0 1 0 0

5 45 5 10 1 3 6

4 15 1 6 0 0 2

8 34 2 10 3 0 5

24 107 10 26 5 3 13

Size of tumor I: ⬍1 cm II: 1–2 cm III: 2–3 cm IV: ⬎3 cm

4 12 2 1

7 23 14 3

2 7 3 2

0 8 7 5

13 50 26 11

Final responses Number (n ⫽ 98) %

CR 19 19.4

PR 47 48

NC 12 12.2

PG 20 20.4

Total 98 100

over a 12-year period from 1991 to 2003. A strategy for treating craniopharyngiomas using the gamma knife is also presented.

Material and Methods One hundred and seven craniopharyngioma cases were treated with the gamma knife at Komaki City Hospital during the period from 1991 to 2003. One hundred were followed up for more than 6 months after treatment. Characteristics of the cases are listed in table 1. There were 38 children (age at diagnosis less than 15) and 62 adults. The male to female ratio was 55:45. Forty tumors were classified as solid, 24 as cystic and 36 as mixed. Mean tumor diameter was less than 20 mm in 63 cases and more than 20 mm in 37. Treatments administered prior to gamma knife radiosurgery were operations which included subtotal removal in 24, partial removal in 107, biopsy in 10, placement of an Ommaya reservoir in 26 and of a V-P shunt in 5. Fractionated focal irradiation, 13 cases, and chemotherapy using bleomycin, in 3 cases, were combined with surgical treatments (table 1). The dose planning for gamma knife radiosurgery was based on T1-weighted enhanced 3D MR images obtained with the GammaPlan. Accurate and safe dose planning was attempted using small multiple isocenters as well as a lower marginal dose in case the tumor was located close to the optic pathways. The mean tumor diameter was18.8 mm, mean volume 5.8 ml. The tumors were treated

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Table 2. Annual changes in dose planning for GK treatment (123 lesions/107 cases) Lesion # 1991.8–1995.5 1995.7–1997.2 1997.3–1999.2 1999.2–2002.12 Mean

Mean diameter mm

Mean volume ml

Isocenters

Maximum dose

Marginal dose

30 31 31 31

19.1 21.4 18.6 16.3

5.1 10.1 5.0 3.1

4.5 5.6 4.2 3.8

24.7 22.8 20.6 19.2

12.7 11.4 11.1 10.7

123

18.8

5.8

4.54

21.8

11.5

Table 3. Overall GK radiosurgery results (n ⫽ 98): mean follow-up: 65.5 months

CR ⫽ 19 PR ⫽ 47 NC ⫽ 12 PG ⫽ 20

CR rate response rate control rate progression rate

⫽ 19.4% ⫽ 67.3% ⫽ 79.5% ⫽ 20.4%

with a mean maximum dose of 21.8 Gy and a marginal dose of 11.5 Gy using an average of 4.5 isocenters. The mean dose to the optic nerve was below 10.7 Gy in the most recent 31 cases but 12.7 Gy in the 30 earliest cases. The treated tumor volume was smaller in the most recent cases and larger in the earliest cases (table 2). After treatment, patients were followed up every 3–6 months with repeated MRIs and by assessing changes in neuro-endocrinological state and side effects. The MRI findings were classified into four groups: complete response (CR ⫽ disappeared), partial response (PR ⫽ more than 25% decrease in tumor size), no change (NC ⫽ no change or less than 25% decrease) and progression (PG ⫽ increase in tumor size). Changes in neurological and endocrine symptoms were assessed using clinical records or questionnaire responses. The final outcome was asked of patients. Univariate statistical analysis (␹2 test) was conducted on the factors related to the effects of gamma knife radiosurgery.

Results

The mean follow-up period of 100 cases was 65.5 (6–148) months, median 63 months. Final overall responses were assessable in 98 cases: CR in 19 (19.4%), PR in 47 (48%), NC in 12 (12.2%) and PG in 20 (20.4%). Therefore, CR, response, tumor control and progression rates of 19.4, 67.4, 79.6 and 20.4%, respectively, were obtained (table 3). The 20 cases who showed PG had a mean age of 27.0 and the child to adult ratio was 12:8. The nature of the tumor was solid in 3 and cyst-mixed in 17. As to previous treatments, there were 2.47 surgeries per person and 5 patients underwent radiation therapy. The tumor was more than 2 cm in diameter in 12 cases. The

Long-Term Results of GKRS for Craniopharyngioma

65

Table 4. Changes in neurological and endocrinological symptoms after GK radiosurgery (n ⫽ 91) Improved (%) CR PR NC PG Total

Unchanged (%)

Deteriorated

Total

7 (36.8) 7 (19.4) 2 (15.3) 1 ( 4.3)

12 (63.2) 24 (66.6) 10 (76.9) 13 (56.5)

– 5 (13.9) 1 ( 7.7) 9 (39.1)

19 36 13 23

17 (18.7)

59 (64.8)

15 (16.5)

91

cause of tumor progression was cyst enlargement in 9 (45%), regrowth of the tumor in 8 (40%) and new lesions in 3 cases (15%). These tumors were treated by reoperation in 14 and a second gamma knife radiosurgery in one case. There were no further treatments in the other 5 cases. The outcome was excellent in 1, good in 4, fair in 3, poor in 2 and death in 8 cases. There were 16 deaths in this series. Seven (10.6%) of these patients had responded well (CR or PR) to treatment and 9 (28.1%) had not (NC or PG). The mean time until death was 44.8 months after gamma knife radiosurgery. The cause of death was progression of the tumor in 6 (37.5%), other in 9 (56.3%) and unknown in 1 (6.2%) case. The other causes included hypothalamichypopituitarism in 4, stroke in 2, and infection, heart attack and head injury in one each. Changes in neurological and endocrinological symptoms were examined in 91 cases. Overall, there was improvement in 17 (18.7%), no change in 59 (64.8%) and deterioration in 15 (16.5%). Symptoms frequently improved in the CR group (36.8%) while deterioration was common in the PG group (39.1%) (table 4). Among the improved cases, 10 had visual and 7 hypothalamic-pituitary function improvements. Among the 15 cases showing deterioration, 2 had visual and 2 had endocrine disturbances. New neurological symptoms developed in two cases, i.e. loss of consciousness and hemiparesis in one each. Another 9 cases deteriorated due to cyst enlargement. In the final assessment, 2 cases with visual (2.2%) and 2 with endocrine (2.2%) disturbances were thought to have serious side effects of gamma knife radiosurgery. The outcomes of 91 patients were assessed by inquiring directly or by questionnaire. The patients were classified into four groups: (1) excellent: doing their jobs well or attending school independently without severe neurological deficits, (2) good: unable to work at a job but working at home independently with minor neurological or endocrinological deficits, (3) fair: staying home and fully dependent on care givers, (4) poor: bedridden or requiring medicare. Death was due to tumor progression or other causes. Overall, outcomes were excellent in 45, good in 23, fair in 4, poor in 3 and death in 16 cases. Excellent results were frequently obtained in CR cases (89.5%) and in only 5.5% of PG cases. Death was most common in PG cases (44.4%) (table 5).

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Table 5. Outcomes of craniopharyngioma patients after GK radiosurgery (n ⫽ 91) Group

Excellent

Good

Fair

Poor

Dead

Total

CR PR NC PG

17 (89.5) 23 (53.5) 4 (36.4) 1 (5.5)

1 (5.3) 14 (32.6) 4 (36.4) 4 (22.2)

– – 1 (9.1) 3 (16.7)

– – 1 (9.1) 2 (11.1)

1 (5.3) 6 (13.9) 1 (9.1) 8 (44.4)

19 43 11 18

Total

45 (49.5)

23 (25.3)

4 (4.3)

3 (3.3)

16 (17.6)

91

Case Presentations Case 1. A 9-year-old boy with short stature developed visual acuity deterioration in his left eye (1.0, 0.2) and bitemporal hemianopsia in October, 1991. A suprasellar tumor was subtotally removed by the right frontotemporal approach. His visual symptoms normalized but a small residual tumor was identified in the retrochiasmal area in contact with the pituitary stalk 3 months after surgery. Mean tumor diameter was 13.6 mm. This residual tumor was treated with gamma knife radiosurgery using a marginal dose of 15 Gy and 5 isocenters. The tumor was decreased in size at 12 months and diminished (CR) at 15 months after this treatment, and has been stable for 116 months to date (fig. 1a). The patient’s mental and physical development normalized and he graduated from university without deficits 11 years after treatment (fig. 1b). Case 2. A 52-year-old male had been diagnosed as having a suprasellar solid tumor and hydrocephalus by MRI in January, 1999. The patient had memory loss and loss of visual acuity (0.2, 0.2) on admission. The solid tumor was biopsied through a lamina terminalis approach. A small residual tumor in the third ventricle was treated with gamma knife radiosurgery on January 28th. The mean tumor diameter was 15.9 mm. The tumor was treated with a maximum dose of 15 Gy and a marginal dose of 9.85 Gy. The patient’s memory loss improved and his visual acuity normalized. The tumor showed a marked response, i.e. CR, at 6 months after treatment and has been stable for 30 months to date. The patient is enjoying life with no neurological deficits (fig. 2). Case 3. A 40-year-old male was diagnosed with, and treated for, craniopharyngioma at the age of 18. Three partial removals were followed by radiotherapy over a 20-year period. The patient had severe visual loss (0, 0.01) with diabetes insipidus and hypopituitarism. MRI showed a large recurrent mixed suprasellar tumor involving the third ventricle. A fourth surgery was refused. The tumor diameter was 28.7 mm with a volume of 12.4 ml. Gamma knife radiosurgery with a maximum dose of 25 Gy, marginal dose of 11.25 Gy, and 8 isocenters was performed in March of 1995. The tumor responded very well and his symptoms have been stable for 7 years (fig. 3).

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67

a

Preoperatively

GK

12 months

116 months

Fig. 1. a MRIs of craniopharyngioma during and after GK radiosurgery. A suprasellar solid mass compressing the optic nerve (left) was subtotally removed and a small residual tumor (13.6 mm) in the retrochiasmal region was treated by gamma knife radiosurgery using a marginal dose of 15 Gy and 5 isocenters (RS). The tumor was decreased in size at 12 months [12], CR was obtained at 15 months, and the tumor has been stable for more than 116 months to date (116). b Photographs obtained at and 11 years after GK radiosurgery. Mental and physical development normalized after treatment and the patient graduated from university. He had neither neurological nor endocrinological deficits.

Case 4. A 17-year-old boy presented with initial symptoms of headache, nausea and vomiting in March of 1988. CT revealed a suprasellar tumor and hydrocephalus. Subtotal removal of the tumor was performed with V-P shunt placement. Tumor recurrence was identified and an Ommaya reservoir system was placed in the cystic portion in August of 1992. A recurrent tumor was again totally removed in March, 1993. Thereafter, the patient had permanent diabetes insipidus. The tumor regrowth was mixed type, had a mean diameter of 26.2 mm and was treated by gamma knife radiosurgery with a maximum dose of 24 Gy and a marginal dose of 12 Gy. Although the solid part of the tumor markedly decreased in size, the two cysts enlarged producing signs of increased intracranial pressure at 6 months after treatment (fig. 4). Case 5. An 18-year-old female presented with severe headache, nausea and vomiting on July 30, 1999. MRI revealed a huge cyst in the right frontal lobe and continuous suprasellar solid mass. Diagnostic biopsy and cyst drainage through an Ommaya

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20 years 162 cm 63 kg

9 years 122.3 cm 23.6 kg b

11 years later

at GK Patient

Father

Father

Patient

system were achieved by craniotomy on August 7. The collapsed cyst wall and solid tumor were treated with gamma knife radiosurgery using a maximum dose of 16 Gy, a marginal dose of 10.4 Gy and 6 isocenters in September of 1999. The tumor showed a good response (PR) at 30 months after treatment and the patient had neither neurological nor endocrinological deficits (fig. 5). She recently married and is currently 4 months pregnant. Case 6. A 26-year-old female had begun to gain weight and had visual disturbances. Tumors had been surgically removed twice and 60 Gy focal radiotherapy had been administered during the previous 5 years. The small recurrent suprasellar tumor was treated with gamma knife radiosurgery using a marginal dose of 18 Gy (fig. 6a). The tumor decreased in size with central necrosis at 9 months, but right lower quadrantic hemianopsia developed at 11 months after treatment (fig. 6b).

Discussion

The long-term results of combined surgery and fractionated radiotherapy were reported by Fischer et al. [4] and Hetelekidis et al. [6]. They found that the 10-year

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GK 15/9.8 Gy

30 months

Fig. 2. Follow-up MRIs and photographs after GK radiosurgery. MRI revealed a suprasellar, solid mass and hydrocephalus in this patient with memory loss and visual acuity disturbance. After biopsy via the lamina terminalis approach, a small tumor in the third ventricle (15.9 mm) was treated by GK radiosurgery with a marginal dose of 9.85 Gy. The tumor showed CR at 6 months and has been stable for more than 3 years, to date, with improvement of symptoms.

At GK

60 months

Fig. 3. Follow-up MRIs of recurrent craniopharyngioma treated by GK. A large recurrent, mixed suprasellar tumor (28.7 mm) involving the third ventricle was found after multiple partial removals and radiotherapy over a 20-year period (left). The tumor was treated with a marginal dose of 11.25 Gy (RS) and showed a marked response (PR). Tumor size has been stable for more than 7 years, to date, without changes in symptoms.

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GK

6 months

Fig. 4. Follow-up MRIs of recurrent craniopharyngioma treated by GK. A mixed tumor (26.2 mm) recurring after surgical removal was treated with a marginal dose of 12 Gy. Although the solid portion of the tumor decreased markedly in size, two cysts enlarged to produce intracranial hypertension at 6 months after treatment.

Preoperatively

Ommaya RS

30 months

Fig. 5. Follow-up MRIs of large cystic craniopharyngioma treated by GK. A huge cyst in the right frontal lobe and a suprasellar solid tumor are shown (left). Craniotomy allowed diagnostic biopsy and cyst drainage through Ommaya reservoir system. The collapsed cyst wall and residual solid tumor were treated with gamma knife radiosurgery using a marginal dose of 10.4 Gy with 6 isocenters (RS). The tumor showed a good response (PR) at 30 months (30).

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26 F; 18.9 mm, 30/18 Gy

a

At GK

At GK

9 months after

11 months after

b

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Table 6. Effects of GK radiosurgery and related factors

CR ⫹ PR (66) NC (12) PG (20)

Age (child/adult)

Nature solid/C⫹M

Tumor size I ⫹ II/III ⫹ IV

Previous surgeries (mean times)

20:46 4:8 8:12

34:32 3:9 3:17

46:20 9:3 8:12

89 (1.41) 26 (1.86) 57 (2.48)

survival rate was excellent in child-type craniopharyngiomas but neuro-endocrinological deficits were serious side effects. Intracavitary irradiation using radioisotopes [1, 8], and more recently stereotactic radiosurgery [1, 9], have been used to achieve interstitial irradiation as a new modality of radiation therapy. The gamma knife delivers high-dose irradiation and can be targeted even to a relatively small intracranial volume in a single session without significant irradiation of the surrounding brain [13]. Gamma knife radiosurgery for craniopharyngioma was initially reported by Leksell et al. [13] and Backlund et al. [1], who obtained good results in some cases. However, numerous studies have been conducted [2, 9, 10, 18] since MRI became available for dose planning and follow-up study. Kobayashi et al. [9] reported that a higher response rate, including disappearance of the tumor (CR), was obtained for solid tumors with gamma knife treatment using relatively low marginal doses. Our previous report presented the results of 33 cases with a mean follow-up of 42.1 months. The response rate of 81.8% was high, the control rate was 84.8% and there were several CR cases (30%). However, the PG was also as high as 15.1%, due to enlargement of the cysts after the treatment [10]. Chung et al. [2] reported similar results from their experience with 31 patients followed-up for 36 months. However, the current results indicate that lower response and higher progression rates with radiosurgery are probably due to longer follow-up time and lower marginal doses. The factors related to better responses (CR and PR) to radiosurgery were adult, solid tumor, fewer previous treatments, and smaller tumors. Among these factors, only being an adult was significantly favorable (p ⫽ 0.046). Factors predicting tumor progression after radiosurgery were child, cystic or mixed tumor, several previous treatments, and larger tumors. Among these factors, the nature of the tumor (cyst) was the only significant predictor of tumor progression (p ⫽ 0.035) (table 6).

Fig. 6. a MRI findings of suprasellar, recurrent tumor at GK and 9 months after treatment. Tumor decreased in size with central necrosis. b Visual field change at GK and 11 months after treatment. Radiosurgery: lower quadratic homonymous hemianopsia was demonstrated.

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Transcallosal

‘R’ site Residual Recurrence

Transventricle

Trans lamina terminal

‘R’ site

OPN Ant.

T

Hypothalamus Stalk MB

Post.

Pons

Fig. 7. Schematic drawing of small residual tumor at the ‘R site’ after removal and surgical view of residual tumor involving optic nerve and pituitary stalk. From Kanno T (ed): Brain Tumor Surgery. Tokyo, Neuron Pub. Co., 2002, fig. 11, p. 47.

Because 45% of cystic tumors showed progression due to cyst enlargement, strategies other than radiosurgery are necessary to control cysts. Backlund et al. [1] described a strategy for treating the solid portion radiosurgically and the cystic portion with internal irradiation in 1972, and this approach was confirmed to be very useful by us in 1981 [8]. Another option is placement of an Ommaya reservoir system in the cystic portion [15]. Radiosurgery can be safely performed after collapse of the cyst, as shown by case 4. It is also important to understand that the site of origin of craniopharyngiomas is basically the anterior portion of the pituitary stalk from the floor of the third ventricle to the pituitary gland. Small residual or recurrent tumors can persist or arise, even after extensive removal, at this location (so called ‘R-site’), as in our cases 1 and 2. At this site, tumor tissue always adheres tightly to the optic nerve and pituitary stalk, making it difficult to remove without seriously damaging visual functions or causing diabetes insipidus (fig. 7). A strategy is necessary to treat such small remaining tumors with gamma knife radiosurgery instead of total removal, allowing permanent cure without neuro-endocrinological deficits to be achieved in patients such as our cases 1 and 2. As to the radiosensitivity of a tumor, craniopharyngiomas may be more sensitive to radiation not only in fractionated therapy [4, 6] but also in radiosurgery [1, 2, 9, 10].

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It has also been emphasized that craniopharyngioma is effectively treated with a low marginal dose of around 10 Gy, a dose thought to be tolerable for the optic nerve [12]. The marginal dose was 12.8 Gy in our previous study [10] but was decreased to 11.5 Gy in this series. The present results thus suggest that the optimal dose for this tumor may be 10–12 Gy. From the viewpoint of radiation biology, Larson et al. [11] reported that the tolerance of the surrounding normal brain is higher when multiple small isocenters are used than with a single large isocenter. Marks et al. [14] also stated that a tolerable dose to normal brain is related to the volume of an adjacent tumor. The excellent results obtained in our case 1, in whom a small cystic tumor (1.3 ml) adhering to the optic nerve was treated with a marginal dose of 15 Gy using 5 isocenters, illustrates how well the optic nerve tolerates the high-dose radiation. However, caution must be exercised in using a higher dose, even for small tumors, in cases undergoing re-irradiation such as our case 6. Another possible approach to saving optic function is stereotactic radiotherapy for craniopharyngioma, which might reduce side effects involving the surrounding brain and enhance effects on the tumor [16]. However, long-term results for a significant number of cases are necessary to evaluate these effects.

Conclusions

One hundred and seven craniopharyngioma cases were treated by gamma knife between 1991 and 2003. One hundred were followed-up for 6–148 (mean of 65.5) months. Mean tumor diameter and volume were 18.8 mm and 5.8 ml. The tumors were treated with a maximum dose of 21.8 Gy, a marginal dose of 11.5 Gy, and a mean of 4.5 isocenters. Overall, CR was obtained in 19 cases, PR in 47, NC in 12 and PG in 20. The CR rate was thus 19.4%, response rate 67.4%, control rate 79.6% and progression rate 20.4%. Seventeen of 20 cases with PG had cystic-mixed tumors and the cause of PG was cyst enlargement in 9 cases, tumor regrowth in 8 and a new lesion in 3. Among significant prognostic factors, being an adult was good while cystic and mixed tumors were bad. Changes in neurological and pituitary-hypothalamic symptoms after gamma knife radiosurgery were evaluated in 91 patients. Overall, improvement was seen in 17 (18.7%), no change in 59 (64.8%) and deterioration in 15 (16.5%). Two had visual and two others endocrine disturbances, thought to be side effects of gamma knife radiosurgery. Outcomes were reported for 91 patients: excellent in 45, good in 23, fair in 4, poor in 3 and death in 16. In conclusion, stereotactic gamma knife radiosurgery is safe and effective as adjuvant or boost therapy for residual and/or recurrent craniopharyngiomas after surgical removal, and has acceptable side effects. As a treatment strategy, small residual or recurrent tumors at the so-called ‘R site’ are indications for gamma knife radiosurgery

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instead of total removal, as permanent cure with no neuroendocrinological deficits can be expected in such patients.

References 1 Backlund EO, Johanson L, Sarby B: Study on craniopharyngiomas. II. Treatment by stereotaxis and radiosurgery. Acta Chir Scand 1972;138:749–759. 2 Chung WY, Pan DHC, Shiau CY, et al: Gamma knife radfiosurgery for craniopharyngiomas. J Neurosurg 2000;93(suppl 3):47–56. 3 Ellenberg L, McComb JG, Siegel SE: Factors affecting intellectual outcome in pediatric brain tumor patients. Neurosurgery 1987;21:638–644. 4 Fischer EG, Welch K, Shillito J, et al: Craniopharyngiomas in children: long-term effects of conservative surgical procedures combined with radiation therapy. J Neurosurg 1990;73:534–540. 5 Glauser TT, Packer RJ: Cognitive deficits in longterm survivors of childhood brain tumors. Childs Nerv Syst 1991;7:12. 6 Hetelekidis S, Barnes PD, Tao M, et al: Twenty-year experience in childhood craniopharyngioma. Int J Radiat Oncol Biol Phys 1993;27:189–195. 7 Hoffman HJ, DeSilva M, Humphreys RP, et al: Aggressive surgical management of craniopharyngioma in children. J Neurosurg 1992;76:47–52. 8 Kobayashi T, Kageyama N, Ohara K: Internal irradiation for cystic craniopharyngioma. J Neurosurg 1981;55:896–903. 9 Kobayashi T, Tanaka T, Kida Y: Stereotactic gamma knife radiosurgery for craniopharyngiomas. Pediatr Neurosurg 1994;21(suppl 1):69–74. 10 Kobayashi T, Kida Y, Mori Y: Effects and prognostic factors in the treatment of craniopharyngioma by gamma knife; in Kondziolka D (ed): Radiosurgery 1999. Radiosurgery. Basel, Karger, 2000, vol 3, pp 192–204.

11 Larson DA, Flickinger JC, Loeffler JS: The radiobiology of radiosurgery. Int J Radiat Oncol Biol Phys 1993;25:557–561. 12 Leber KA, Bergloeff J, Pendle G: Dose response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998;88:43–50. 13 Leksell L, Backlund EO, Johanson L: Treatment of craniopharyngioma. Acta Chir Scand 1967;133: 345–350. 14 Marks LB, Spencer DP: The influence of volume on the tolerance of the brain to radiosurgery. J Neurosurg 1991;75:177–180. 15 Takizawa T, Hirai T, Fujii M, et al: Gamma knife treatment of craniopharyngioma. Stereotact Radiother (Jpn) 1997;1:55–61. 16 Tarbell NJ, Scott M, Gouminerva LC, et al: Craniopharyngioma: preliminary results of stereotactic radiation therapy; in Kondziolka D (ed): Radiosurgery 1995. Radiosurgery. Basel, Karger, 1996, vol 1, pp 75–82. 17 Thomsett HJ, Conte FA, Kaplan SC, et al: Endocrine and neurologic outcome in childhood craniopharyngioma: review of effect of treatment in 42 patients. J Pediatr 1980;97:728–735. 18 Ulfarsson E, Lindquist C, Roberts M, et al: Gamma knife radiosurgery for craniopharyngiomas: longterm results in the first Swedish patients. J Neurosurg 2002;97(suppl 5):613–622. 19 Yasagil MG, Curic M, Kis M, et al: The total removal of craniopharyngiomas: approaches and long-term results in 144 patients. J Neurosurg 1992;73:3–11.

Tatsuya Kobayashi, MD, PhD Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital 1–172 Hokke, Nakagawa ku Nagoya, Aichi 454-0933 (Japan) Tel. ⫹81 52 362 5151, Fax ⫹81 52 362 5151, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 77–95

Long-Term Results of Stereotactic Gamma Knife Radiosurgery for Pituitary Adenomas Specific Strategies for Different Types of Adenoma

Tatsuya Kobayashi Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital, Nagoya, Japan

Abstract Long-term results of gamma knife radiosurgery for pituitary adenomas are presented and treatment strategies for different adenoma types are discussed. Two hundred and sixty-seven patients with pituitary adenoma have been treated by gamma knife radiosurgery during the past 12 years. There were 131 cases of nonfunctioning and 136 cases of functioning adenomas, in which 71 GH-producing, 33 PRL-producing and 32 ACTH-producing adenomas were included. Retreatment with the gamma knife was done in 8 cases because of large tumors or uncontrolled hormones. Micro- and small adenomas could be cured by gamma knife radiosurgery alone. Surgical or chemical debulking was necessary before radiosurgery for a large tumor with extrasellar extension. Retreatment was effective and safe in some cases. Nonfunctioning adenomas showed higher control rates than functioning adenomas even with lower dose treatment. Cushing disease showed the best response because of the smallest tumor size with the highest dose treatment. Acromegaly and prolactinoma were difficult to control because of larger tumors with lower dose treatment. The rate of hormone normalization was also high in Cushing disease but lower in prolactinoma and lowest in acromegaly. High-dose treatment was necessary for functioning adenomas to control tumor growth and oversecretion of hormones. In conclusion, gamma knife radiosurgery was effective and safe for the treatment of pituitary adenomas. However, the treatment strategies should be specific to each adenoma type according to the radiosensitivity, chemosensitivity and Copyright © 2009 S. Karger AG, Basel biological nature of the tumor.

The history of radiation therapy for pituitary adenomas is quite long and focal fractionated irradiation has been the standard for more than half a century. This procedure has been performed not only for residual or recurrent tumor after surgical removal but also for initial treatment. Stereotactic radiosurgery for pituitary adenomas also has a long history, which includes proton beam irradiation to the pituitary gland by Lawrence [17] in the 1950s, and the same therapy for pituitary adenomas by Kjellberg [11] in the 1960s. At almost the same time, gamma knife radiosurgery for

Table 1. Changes in clinical signs of nonfunctioning adenoma after GK radiosurgery (n ⫽ 53)

Visual disturbance (n ⫽ 47) Endocrinopathy (n ⫽ 49) Other signs (n ⫽ 45): headache, neuralgia

Improved or unchanged

Deteriorated

No signs

15 (31.9%) 7 (14.3) 6 (13.3)

2 (4.3%) 4 (8.2) 2 (4.5)

19 (40.4%) 24 (49.0) 34 (75.6)

11 (23.4%) 14 (28.5) 3 (6.6)

New symptoms: 2 (3.8%) (n ⫽ 53). Memory disturbance, incontinence (demented), hemiparesis (subdural hematoma).

pituitary tumors was developed by Leksell [18], followed by Rähn [27] using this innovation for Cushing disease in the 1980s. Since high-resolution MRI was introduced into dose planning in the 1990s, small- or micro-adenomas can now be diagnosed precisely and selective irradiation of the tumor has become possible [6, 19, 30]. Pituitary adenomas are divided into nonfunctioning adenomas (NFA) and functioning adenomas (FA). The latter are subclassified into GHproducing adenomas (GHA), prolactin-producing adenomas (PRLA), ACTH-producing adenomas (ACTHA) and other adenomas. The total number of cases undergoing gamma knife treatment over the past 12 years at Komaki City Hospital is 4,521, of which 1,594 cases (36.3%) had benign brain tumors. Pituitary adenomas accounted for 267 cases (5.9%). There were 131 NFA and 136 FA cases, of which 71 had GHA, 33 PRLA and 32 ACTHA. Retrospective analysis of long-term outcomes of gamma knife radiosurgery for these adenomas are presented. Changes in tumors were evaluated by MRI using the five-grade system proposed by the Brain Tumor Registry of Japan: CR (tumor disappearance), PR (volume decrease ⬎50%), MR (25–50% decrease in volume), NC (no change or decrease ⬍25%) and PG (enlarged). Control of hormone secretion was assessed in FA cases. Mean follow-up of all cases was 50.2 months.

Nonfunctioning Pituitary Adenomas As to the characteristics and dose planning for the 71 NFA cases, previous treatments were surgical removal in 65 (91.5%) and focal fractionated irradiation in 12 (16.9%). The mean age was 50.4 years and the male to female ratio was 31:40. The mean tumor diameter was 29.2 mm, and the tumor was treated with a mean maximum dose of 28.2 Gy and a marginal dose of 14.1 Gy. Results

Tumor changes were followed up with MRI in 60 cases for more than 3 years. The tumor disappeared (CR) in 5, decreased in size (PR ⫹ MR) in 38, was unchanged (NC) in 15 and enlarged (PG) in 2 cases. The CR, response, control and progression rates were thus 8.3, 71.7, 96.7 and 3.3%, respectively.

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Table 2. Patient satisfaction with GK radiosurgery for nonfunctioning adenoma (n ⫽ 49)1

Satisfied

44 (89.8%)

Dissatisfied (1) Required medication for hypopituitarism (2) Anxiety about recurrence (3) Headache (4) Visual disturbance (5) No improvement of symptoms

5 (10.2%)

1

Clinical records and questionnaire.

Changes in clinical signs and symptoms after treatment were assessed based on clinical records and/or questionnaires in 53 cases. Improved or unchanged visual functions were documented in 26 of 47 cases (55.3%) and deterioration in 2 (4.3%), while 19 (40.4%) cases had never had visual disturbances. Endocrinopathy improved or was unchanged in 21 of 49 cases (42.8%) and worsened in 4 (8.2%). Twenty-four cases (49%) had never experienced endocrinopathy. New symptoms, dementia and chronic subdural hematoma, developed in 2 cases (table 1). Outcomes were excellent (return to work) in 32 cases (64%), good (work at home) in 14 (28%), fair (bed ridden) in 2 (4.0%), poor (disabled) in 1 (2%) and death in 1 (2%). We inquired about patient satisfaction with gamma knife treatment. Forty-four of 49 cases (89.8%) were satisfied and 5 (10.2%) were dissatisfied. The reasons for dissatisfaction were: (1) no improvement of symptoms, (2) anxiety about recurrence, (3) continuation of medication, (4) visual difficulties and so on (table 2). Case Presentation

Case 1. A 69-year-old female had an enormous adenoma with massive suprasellar extension, which was initially debulked during transsphenoidal surgery, followed by decompression and detachment from the optic nerves. The residual adenoma (26.4 mm) was treated with the gamma knife using a marginal dose of 15 Gy. The tumor was smaller (PR) at 12 months (fig. 1).

GH-Producing Adenoma (Acromegaly) Seventy-one patients with acromegaly were treated by gamma knife radiosurgery. Sixty-seven were followed up for more than 1 year after treatment. Mean age was 47 (19–83) years and the male to female ratio was 23:44. Treatments prior to gamma knife radiosurgery were surgical removal (49 cases), medications (42) and radiation therapy (2). Gamma knife radiosurgery was the initial treatment in 9 cases. The mean tumor diameter was 19.2 (7.3–32.9) mm, mean volume 5.4 ml. Residual or recurrent tumors were treated with a mean maximum dose of 35.3 Gy and a marginal dose of 18.9 Gy. Results

Mean follow-up time was 63.3 (13–142) months and tumor changes were evaluated by MRI in 49 cases. The tumor disappeared (CR) in one, was decreased in size (PR) in 31, and unchanged (NC) in 17 cases. None of the tumors enlarged (PG). Serum GH levels were measured pre- and posttreatment in 42 cases. Postoperatively, the GH level was below 1 ng/ml (normal) in 2 (4.8%), below 2 ng/ml in 5 (11.9%), below 5 ng/ml in 10 (23.8%), decreased by more than 50% in 9 (21.4%),

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Nonfunctioning adenoma

Fig. 1. Huge nonfunctioning adenoma with suprasellar extension and 3D strategy. Tumor was initially debulked surgically, followed by decompression of and detachment from the optic nerves. The residual tumor was treated with gamma knife radiosurgery using a marginal dose of 13 Gy. PR was demonstrated at 12 months.

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Table 3. GH changes after GK radiosurgery: n ⫽ 42, follow-up (FU) ⫽ 36.0 (3–102) months

Table 4. IGF-1 changes after GK radiosurgery: n ⫽ 27, FU ⫽ 32.5 (6–85) months

Normalized (GH ⬍1.0 ng/ml) Nearly normal (GH ⬍2.0 ng/ml) Significant decrease (GH ⬍5.0 ng/ml) Decreased (⬎50%) No change (ⱕ50% decrease or unchanged) Increased

⫽ 2 (4.8%) ⫽ 5 (11.9%) ⫽ 10 (23.8%) ⫽ 9 (21.4%) ⫽ 9 (21.4%) ⫽ 7 (16.7%) 42 (100%)

Significantly decreased (IGF-1 ⬍400 ng/ml) Decreased (IGF-1 ⱖ400 ng/ml; decrease ⬎50%) No change Increased

⫽ 11 (40.7%) ⫽ 8 (29.6%) ⫽ 5 (18.5%) ⫽ 3 (11.1%) 27 (100%)

Table 5. Changes in visual and endocrine disturbances of acromegaly after GK radiosurgery: 47/67 (70.1%)1

Visual (Va, VF) (n ⫽ 45) Endocrine (n ⫽ 41) Nausea, headache (n ⫽ 41)

Deteriorated

Improved

No change

No deficits

5 (11.1%) 6 (14.6) 2 (4.9)

2 (4.4%) 4 (9.7) 1 (2.4)

10 (22.2%) 12 (29.3) 7 (17.1)

28 (62.3%) 19 (46.3) 31 (75.6)

1

Inquiries to patients and doctors.

unchanged in 9 (21.4%) and increased in 7 (16.7%) cases (table 3). Serum IGF-1 was measured in 27 cases. Posttreatment, the IGF-1 level was below 400 ng/ml in 11 cases (40.7%) and changes essentially paralleled those of GH levels (table 4). Outcomes were excellent in 25 (55.6%), good in 15 (33.3%) and fair in 2 (4.4%) cases. Three patients (6.7%) died, 1 each of colon cancer, traumatic subarachnoid hemorrhage (SAH) and hypopituitarism. These deaths were not tumor related. Clinical results and side effects were evaluated by interview or questionnaire. Visual functions were subjectively improved or unchanged in 26.6%, had deteriorated in 11.1% and 62.3% had never had any visual deficits. Endocrinopathy was improved or unchanged in 39%, worse in 14.5% and 46.3% had never experienced endocrinopathy (table 5). Twenty-four patients (66.7%) were satisfied with gamma knife radiosurgery, 10 (27.8%) were dissatisfied and 2 (5.5%) did not respond. The main cause of dissatisfaction was that GH had not decreased, such that there were no changes in symptoms or MRI findings (table 6). Case Presentations

Case 2. A 46-year-old female had an intrasellar macroadenoma, with a mean diameter of 23.1 mm, which was treated with a marginal dose of 16 Gy because medical treatment had failed. The tumor

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Table 6. Patient satisfaction with GK radiosurgery for acromegaly: 39/67 (58.2%)1

Satisfied Dissatisfied No decrease of GH No change of symptoms No change of MRI findings Others: tinnitus, double vision, adrenal insufficiency, thyroid dysfunction Semi-satisfied

24 (66.7%) 10 (27.8%) 11 2 2

2 (5.5%)

1

Inquiries to patients.

46 F; 23.1 mm, 32/16 Gy 23.1

32–16

GH 53 ng/ml IGF-1 760

97 M

GH 7.76 ng/ml IGF-1 290

Fig. 2. Tumor and GH changes in intrasellar macroadenoma with acromegaly after GK radiosurgery. An intrasellar macroadenoma was treated with a marginal dose of 16 Gy because medical treatment had failed. The tumor slowly decreased in size and showed CR at 97 months with significantly decreased GH and IGF-1.

gradually decreased in size and showed CR at 97 months with significantly decreased GH and IGF1 levels (7.76 and 290 ng/ml) (fig. 2). Case 3. A 57-year-old female had an enormous adenoma with suprasellar extension. The tumor was initially debulked by intracranial surgery, with optic nerve decompression. The residual tumor (32.9 mm and 18.7 ml) was then treated with a marginal dose of 12 Gy. The tumor showed PR at 36 months after treatment. A second gamma knife treatment, with a marginal dose of 14 Gy, was performed to further reduce the tumor (27.0 mm and 10.3 ml) and thereby control GH secretion. The tumor showed further size reduction and the GH level was decreased 8 years after the initial treatment (fig. 3).

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57 F

GH 310 ng/ml IGF-1 920

GH 38.5 ng/ml IGF-1 1,100

Fig. 3. Tumor and GH changes of huge adenoma with suprasellar extension in acromegaly after GK radiosurgery. Tumor was initially treated by surgical debulking, with decompression of and detachment from the optic nerves. Residual tumor was treated with a marginal dose of 12 Gy and the tumor showed PR at 36 months. A second GK radiosurgery was performed with 14 Gy because GH secretion was not controlled. The tumor showed a further size reduction and hormone levels were significantly decreased at 8 years.

PRL-Producing Adenoma Thirty cases with PRL-producing pituitary adenomas were treated. Twenty-seven were followedup for more than a year and a half (mean follow-up of 37.4 (18–70) months). Mean age was 34 (16–61) years and the male to female ratio was 7:20. Previous treatments included bromocriptine (BC) in 10, surgery alone in 2, a combination of BC and surgery in 12, and gamma knife radiosurgery as the initial therapy in 3 cases. Mean adenoma diameter was 17.7 (8.4–34.6) mm, mean volume 4.6 (0.3–21.8) ml. Five patients had microadenomas less than 10 mm in diameter, 12 had small adenomas (10–20 mm) and 10 had macroadenomas (⬎20 mm). The tumor location was cavernous sinus in 17 cases and intrasellar in 10. These tumors were treated with a mean maximum dose of 33.8 (20–50) Gy and a marginal dose of 18.4 (12–30) Gy using a mean of 3.6 isocenters. Results

Tumor size changes were examined in 24 cases by MRI after gamma knife radiosurgery. The tumor showed CR in 1, PR in 13, MR in 6 and NC in 4 cases. None showed PG. Thus CR, response and control rates were 4.2, 58.3 and 100%, respectively. Hormonal changes were followed-up in 23

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Table 7. Prolactin (PRL) changes after GK radiosurgery for prolactinoma (n ⫽ 23)

Good control (⬍10 ng/ml)1 Significant decrease (⬍100 ng/ml) No change Poor control (⬎100 ng/ml)

10 8 3 2

Six with BC ⫹ 4 without BC (normalization ⫽ 17.4%). Hormonal decrease rate ⫽ 78.3%. 1 Normal hormonal control 10/23 ⫽ 43.5%.

28 F, 8.4mm, 50/30 Gy Gamma knife

39 M

Changes of PRL Ch(1) 67 ng/ml

GK 19

*Without BC (3 months) 9.8

(15 months) 6.1*

Fig. 4. Tumor and PRL changes of micro-prolactinoma after GK radiosurgery. An intrasellar microadenoma was initially treated by GK radiosurgery with a marginal dose of 30 Gy because of drug intolerance. The tumor showed PR at 39 months but PRL had normalized at 15 months after treatment.

cases. Good control of the serum PRL level (⬍10 ng/ml) was obtained in 10 cases (43.5%), 4 (17.4%) of whom achieved normalization without BC administration. Significant decreases (⬍100 ng/ml) were obtained in 8 cases (34.8%), no change in 3 (13.0%) and poor control (⬎100 ng/ml) in 2 (8.7%). Serum PRL was thus significantly decreased in 18 cases (78.3%) (table 7). There were no side effects related to gamma knife radiosurgery. The three microadenomas treated only with radiosurgery showed lower responses, in terms of tumor reduction and hormone control, than the combined treatment groups. As to tumor size, larger adenomas showed better responses in terms of decreased size but PRL levels dropped more quickly in smaller adenomas.

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48 M; 34.6 mm, 24/12 Gy

Diagnosis (92.4.9) Chemotherapy BC (5–37.5 mg) Gamma knife 96.3.22

FU (49 months)

00.4.14

Fig. 5. MRI changes of huge prolactinoma after medication and GK radiosurgery. A huge adenoma with suprasellar extension was initially treated with BC for 4 years, which resulted in a marked reduction of tumor size and significantly decreased PRL. A residual tumor was treated by GK radiosurgery with a marginal dose of 12 Gy and showed further size reduction with normalized PRL, while the patient was on drug therapy, at 49 months.

Case Presentations

Case 4. A 28-year-old female had an intrasellar microadenoma (8.4 mm in diameter), which was initially treated by gamma knife radiosurgery with a marginal dose of 30 Gy because of drug intoxication. The adenoma showed PR and the serum PRL level had normalized at 39 months (fig. 4). Case 5. A 52-year-old male had an enormous adenoma with suprasellar extension (⬎32 ml). The patient showed visual disturbances with elevation of serum PRL (4,200 ng/ml). Treatment with BC for 4 years resulted in a marked reduction in tumor size and significantly decreased PRL. The residual tumor (34.6 mm) was treated by gamma knife radiosurgery with a marginal dose of 12 Gy. The tumor showed a further decrease in size and the PRL level had normalized with BC administration at 67 months after gamma knife radiosurgery (fig. 5).

ACTH-Producing Adenoma (Cushing Disease) Thirty patients with ACTH-producing adenomas have been treated, to date. Twenty-five were followed for more than two and half years (mean, 64.1 months). Characteristics of the cases include a mean age of 34.8 (10–56) years, male to female ratio of 8:17 and a mean disease duration before gamma knife surgery of 9.7 (1–25) years. Characteristic signs and symptoms were found in most of the cases (table 8). Prior treatments included surgical removal via the transsphenoidal approach, 24 times in 18 patients, and via the intracranial approach in 3. Conventional radiotherapy had been

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Table 8. Changes in characteristic signs and symptoms of Cushing disease after GK radiosurgery

Before GK

After GK

Obesity Hypertension Moon face Nelson syndrome Hypertrichosis Acne vulgaris Hypopituitarism Buffalo hump Stria cutis Dysmenorrhea Facial flushing Visual disturbances Dwarfism Diabetes mellitus Pigmentation of skin Thirst Osteoporosis

18 10 10 7 6 5 5 5 4 3 2 2 2 2 2 1 1

14 8 7 3 4 3 0 4 3 0 1 0 1 2 1 0 0

Total

85

51 (60%)

performed in six cases. Gamma knife radiosurgery was the initial therapy in 4 patients. Bilateral adrenalectomy had been performed in 7 patients. Twenty-one patients had been given medical treatment. Tumor Characteristics and Dose Planning

Mean tumor diameter was 16.1 mm, mean volume 3.24 ml. The tumors were classified into three groups: microadenoma (⬍10 mm in diameter) (5 cases), small adenoma (10–20 mm) (13) and macroadenoma (⬎20 mm) (7). Twelve of the adenomas were located in the cavernous sinus, 11 in the sella and one was diffuse. One tumor was located ectopically at the clivus. As to dose planning, the mean maximum dose was 49.4 Gy and the marginal dose 28.7 Gy, using a mean of 3.8 isocenters. Results

Tumor changes were evaluated by MRI in 20 patients: CR in 6, PR in 11, MR in 2 and NC in one case. There were no PG cases. The CR, response and tumor control rates were 30, 85 and 100%, respectively. The dose-volume relationship correlated well with tumor effects. Small and microadenomas showed a significantly higher CR rate (83.2%) than larger tumors (p ⫽ 0.01). An 83.2% CR rate was achieved using a maximum dose of at least 55 Gy and/or a marginal dose of 40 Gy. Serial changes in serum ACTH and cortisol levels were evaluated in 20 cases. Normal ACTH and cortisol levels are defined as less than 50 pg/ml and 10 ␮g/dl, respectively. Both levels were normal in 7, significantly decreased in 5 and decreased in 5 cases (table 9). In other words, suppression of hormone secretion was successful in 85% of cases. Hormone levels were unchanged in 3 cases but none showed increases. Four response groups were thus distinguishable: normalized (7), significantly decreased (5), decreased (5), and unchanged (3) (fig. 6). The changes in characteristic signs and symptoms before and after gamma knife surgery are shown in table 8. The most common symptoms were obesity, hypertension and moon face: 25 (76.3%) of 38 cases showed improvement

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Cushing disease pg/ml ␮g/dl 800

80

700

70

600

60

500

50

400

40

300

30

200

20

100 ACTH

10 F

#21

ACTH Cortisol

#11 #20 #23 #22

#7 #16 #24

#15 #17 #19

GK

6

12

18 Months

24

#3 #4 #5 #1 #2 #18 #12 #6 #10 30

36

Fig. 6. Serial ACTH and cortisol changes in Cushing disease after GK radiosurgery. Serial serum ACTH and cortisol changes were evaluated in 20 cases. Four distinct response groups were identified: normalized (7), significantly decreased (5), decreased (5) and unchanged (3). No patient had increased hormone levels.

Table 9. ACTH and cortisol changes in Cushing disease after GK radiosurgery (n ⫽ 20)

Decreased to normal level Significantly decreased Decreased No change Increased

7 normalized ⫽ 35%1 5 significantly decreased ⫽ 60% 5 decreased ⫽ 85% 3 0

Normal: ACTH ⬍50 pg/ml, cortisol ⬍10 ␮g/dl.

1

of these symptoms. Nelson syndrome, hypopituitarism, dysmenorrhoea and visual disturbances improved in only three (17.6%) of 17 affected patients. The overall clinical improvement rate was 60%. Clinical outcomes were excellent in 8, good in 5, fair in 4 and poor in 4 cases. One patient died of a stroke and renal failure. A favorable outcome was obtained in 17 of 22 (77.3%) cases. Illustrative Cases

Case 6. A 10-year-old girl presented with obesity and dwarfism in 1993. Her serum ACTH and cortisol levels were 170 ng/ml and 22 ␮g/dl, respectively. An intrasellar microadenoma, 5 mm in diameter, was detected by high-resolution MRI. Because of her concha type sella, the tumor was initially treated with gamma knife radiosurgery in April, 1996, with a marginal dose of 50 Gy. The tumor disappeared (CR) in 8 months, and moon face and obesity gradually improved over the following 5 months. Her hormone levels had normalized 12 months after treatment (fig. 7).

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11 F, 5 ⫻ 5 ⫻ 5mm 84/50Gy

78 M

Gamma knife

2003.3

Fig. 7. Tumor and symptom changes in Cushing disease with microadenoma after GK radiosurgery. An intrasellar microadenoma was initially treated by GK radiosurgery with a marginal dose of 50 Gy because the patient had concha-type sellae. CR was confirmed at 8 months. The patient’s moon face and obesity had improved at 5 months and hormone levels were normal at 12 months after treatment.

Case 7. A 29-year-old woman with Cushing disease underwent transsphenoidal surgery in 1985, intracranial surgery in 1992 and 50 Gy of fractionated radiotherapy in 1993. A small adenoma (14.3 mm in diameter) recurred at the left cavernous sinus and hormone levels became uncontrollable (ACTH 580 ng/ml, cortisol 36 ␮g/dl). The tumor was treated with a marginal dose of 48 Gy. Normalization of hormone levels and CR of the tumor were both confirmed 14 months after gamma knife radiosurgery (fig. 8).

Discussion

Standardized treatment of pituitary adenomas has been a combination of surgical removal, medical management and radiation therapy. Fractionated radiation therapy [3, 20, 28] has been used to control tumor growth and hormone secretion, for primary as well as residual or recurrent tumors after initial treatments. Significant effects have been obtained but may take a long time to appear [28] and the side effects of radiation therapy are potentially significant. Hypothalamic-pituitary hypofunction [3, 28] is most frequent, followed by deterioration of visual functions and mental or memory disturbances [20]. The recently advanced stereotactic radiosurgery has been applied to the

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Cushing disease:

Fig. 8. Changes in recurrent, small adenoma of Cushing disease after GK radiosurgery. After two surgical removals and radiation therapy (50 Gy), a small tumor recurred in the left cavernous sinus and hormone levels were uncontrollable. The tumor was treated with a marginal dose of 48 Gy and showed CR with normalization of hormone levels at 14 months after treatment.

treatment of pituitary tumors [4, 6, 27, 30, 32]. Gamma knife radiosurgery based on high resolution MRI has made selective irradiation of pituitary adenomas possible without significant side effects [5, 10, 23–25, 29, 33, 34]. This modality has also been shown to produce different effects in different tumor types [3, 30]. (1) NFAs are the most common pituitary adenomas and are pathologically described as chromophobic adenomas. The initial treatment is tumor removal via transsphenoidal or intracranial surgery, depending on the adenoma site. Recurrent or residual tumors have been treated by fractionated radiotherapy [3, 20, 28]. However, radiotherapy is now being replaced by stereotactic radiosurgery, with or without adjunct radiotherapy, and better results have been obtained. There have been only a few reports on GK treatment specific to NFA, while there are numerous publications on multi-tumor types. Wowra et al. [33] reported long-term changes in tumors with a

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significant volume reduction from 1.7 (pre-GK) to 0.6 ml, at a mean follow-up of 55 months, in 45 NFA treated with a marginal dose of 16 Gy and the actuarial recurrencefree survival rate was 93%. There were no neurological deficits but partial pituitary insufficiency was demonstrated in 10%. Sheehan et al. [29] stated that the tumor control rate was 100% for microadenomas and 97% for macroadenomas in 42 NFA treated with a marginal dose of 16 Gy. There was no worsening of endocrinopathy but visual functions deteriorated in 2 cases (4.7%). These results correlated well with our present tumor control rate of 96.7%, visual function deterioration rate of 4.3% and endocrinopathy rate of 8.2%, despite the tumor size and marginal dose being different. Also, the NFA in our series were too large (13.1 ml) for high doses (14.1 Gy). In the dose planning for such large tumors with suprasellar extension, optic nerve decompression, detachment of tumor tissue from the optic nerve and debulking of the tumor (3D strategy [13]) are important and must be achieved before gamma knife radiosurgery, as illustrated by our case 1. (2) GH-producing adenomas have been considered not only the most difficult tumors to control but also the most difficult in which to achieve hormone level normalization [2, 23, 30]. This is attributable to the tumor already being too large for highdose therapy, medications to reduce GH levels making the tumor resistant to radiation therapy [15, 16], complications such as visceromegaly, hypertension and diabetes mellitus often reducing quality of life [3] and also being potentially life threatening [1], and to the radiosensitivity of the GH adenoma itself possibly being lower than that of other pituitary adenomas [28, 30]. There are several reports on GH-producing adenomas treated by GK radiosurgery [10, 14, 15, 23, 34]. However, the results are difficult to compare with each other because of the variety of treatment conditions, different criteria for hormone level normalization, biases and so on. However, in our present series, the rate of GH secretion control was low due probably to the tumors being larger and the marginal dose lower than in previous reports. When tumor size is limited to no more than 20 mm in diameter in this series, the mean marginal dose becomes 20.2 Gy and the rate of GH control is increased. Therefore, it is important to carefully establish indications regarding the size and dose to obtain better results, and a tumor diameter less than 15 mm [23] and a marginal dose exceeding 25 Gy [14] have been proposed. Although no correlation between tumor reduction and normalization of hormone levels [14] was found, the goals of treatment have been to normalize hormone production and reduce rates of mortality or morbidity associated with uncontrolled hormone secretion [1]. To normalize hormone secretion, retreatment with gamma knife radiosurgery using a low dose for a large tumor may be indicated, as demonstrated in our case 3. However, the definition of normal hormone levels for acromegaly has been evolving year by year [7, 8]. The criteria that have been proposed include less than 1 ng/ml of GH [23], a normal IGF-1 value for patient age and gender [2, 10, 26], or both [7] although parallel responses can not always be expected [2, 26]. (3) PRL-producing adenomas are characteristically more common in relatively young females and produce symptoms of galactorrhea and amenorrhea. The initial

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treatment of prolactinoma is dopamine agonist administration [22], which has achieved normalization of PRL levels and tumor reduction. However, cure has not been achieved with medication alone and it is often difficult to continue due to side effects. According to Molitch [22], the PRL level normalized in 71.2% of microadenoma and 31.8% of macroadenoma patients after surgical removal. Normalization of PRL was as high as 70–80%, with restoration of menstruation in 80–90% and tumor reduction in 40%, with BC. Salinger et al. [28] stated that the total disease-free survivals at 5 and 10 years were 91 and 89%, respectively, with radiotherapy. There are a small number of reports on gamma knife treatment of prolactinoma. Lim et al. [19] treated 19 patients with a marginal dose of 30–35 Gy and followed them up for a mean period of 25.5 months. The tumor decreased in 92% and was unchanged in 8%. PRL normalized in 55.5%, decreased in 33.3% and was unchanged in 11.2%. Landolt et al. [16] reported the results of 20 patients treated with a marginal dose of 25 Gy. PRL normalized in 5 patients (25%) without medication, a dopamine agonist, which was stopped after GK treatment. Eleven patients (55%) had normal PRL levels with medication and 4 cases (20%) were unresponsive to treatment. The author emphasized the importance of the radioprotective effect of dopamine agonists. Pan et al. [25] reported a large series of 164 cases initially treated by gamma knife radiosurgery with a marginal dose of 31.2 Gy, in which the mean tumor size was 13.4 mm and mean follow-up was 33.2 months. The tumor decreased in 74 (57.8%), was unchanged in 52 (40.6%) and enlarged in 2 (1.6%) cases. PRL normalized without medications in 16 (20.8%), decreased in 28 (36.4%), was unchanged in 27 (35.0%) and relapsed in 6 (7.8%). Unchanged, high PRL levels responded well to dopamine agonists after gamma knife radiosurgery. Our present results were almost identical, in terms of both tumor response and PRL control, to those of Pan et al. [25], despite the differences in tumor size and the marginal dose. It also must be emphasized that tumor reduction by BC (chemodebulking) is effective and less invasive than surgical removal prior to radiosurgery, as demonstrated in our case 5. (4) Initial treatment of Cushing disease has long been surgical removal by the Hardy method [31] with or without medical therapy [21]. Residual or recurrent adenomas have been treated with focal fractionated radiotherapy [9]. With 40–50 Gy fractionated radiotherapy and medication after surgical removal, the rate of cortisol normalization was 24% and that of tumor remission was 40% [21]. The recently developed transsphenoidal surgery for selective removal of small and microadenomas producing Cushing disease achieved excellent remission rates of 86–92% within a short period of time, although the relapse rate was 2–23.8% [31]. The first report of gamma knife radiosurgery for Cushing disease was by Rähn et al. [27] in 1980. At that time, before the advent of CT and MRI, dose planning aimed at irradiating all intrasellar tissue in 18 patients. Long-term results were reported by Degerblad et al. [4] that the remission rate was 48% but hypopituitarism developed in 54.5% of cases. However, selective adenomectomy by gamma knife radiosurgery actually became possible in the 1990s when MRI was introduced into dose planning.

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Table 10. Comparative results of GK radiosurgery for different pituitary adenoma types Tumor type n, mean FU

Size, diameter (vol)

Dose max. marg.

Tumor CR %

RR %

Control Hormone % normalized %

Significantly decreased %

Decreased %

Nonfunctioning adenoma, 60, ⬎36 months

29.2 (13.1)

28.2 14.1

8.3

71.3

96.7

–

–

–

Cushing disease, 30, 64.1 months

16.1 (3.2)

49.4 28.7

30.0

85.0

100

35.0

60.0

85.0

PRL-producing adenoma, 27, 37.4 months

17.7 (4.6)

33.8 18.4

4.2

58.3

100

17.4

43.5

78.5

Acromegaly, 67, 63.3 M

19.2 (5.4)

35.3 18.9

2.0

65.3

100

4.8

40.5

61.9

Ganz et al. [6], in 1993, used a marginal dose of 25 Gy in 4 Cushing disease and 3 Nelson syndrome cases. The tumor was reduced in size in 57% (4/7) and hormonal remission was obtained in 2, improvement in 4 and there was no change in 1 case. In 1996, Witt et al. [32] treated 16 cases with a follow-up of 20 months. The response rate was 30% (5/15) but the control rate was 88% (15/17). Hormone normalization was obtained in 8 (50%), improvement in 2 (12.5%) and no change in 4 (25%). There were no large series of patients with long-term follow-up prior to our report [12] in 2002. For 25 cases treated with a marginal dose of 28.7 Gy and with a mean follow-up of 5.3 years, the tumor diminished in 30%, the response rate was 85% and the control rate was 100%. Both hormone levels normalized in 35%, decreased significantly in 60% and decreased in 85%. These results were apparently superior to those of previous reports, allowing us to conclude that gamma knife radiosurgery is safe and effective for the treatment of Cushing disease as an adjuvant or initial therapy, as shown in our case 6, when selective and accurate dose planning is performed. (5) Regarding the difference in responses among adenomas to gamma knife radiosurgery, control of tumor growth and hormone secretion in our study were compared with those of previous reports [12, 13] (table 10). It is difficult, however, to compare ACTH-producing adenomas and other tumors because a Cushing adenoma can be as small as 16.1 mm in diameter while the marginal dose used was the largest at 28.7 Gy. However, it is possible to compare prolactinomas and GH-producing adenomas. The rate of PRL normalization was higher than that for GH, despite the marginal dose for the former being lower. Although nonfunctioning adenomas were the largest tumors

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and the marginal dose used was the lowest among adenomas, the tumor response rate was between that of Cushing disease and prolactinoma. This raises the possibility that the radiosensitivity of nonfunctioning adenomas might be higher than that of prolactinomas and GH-producing adenomas. We can tentatively conclude that the tumor control effect of gamma knife radiosurgery is highest in Cushing disease, followed by nonfunctioning adenoma, and then prolactinoma and GH-producing adenoma. However, hormone control effects are better in Cushing disease followed by prolactinoma, and then GH-producing adenoma.

Summary and Conclusions

Long-term effects of gamma knife radiosurgery on nonfunctioning, GH-producing, PRL-producing and ACTH-producing pituitary adenomas are presented. Different effects were specific to each clinicopathological type, although the response to gamma knife radiosurgery is common to pituitary adenomas and is quicker and safer than the response to conventional radiotherapy. The treatment strategy, therefore, should be specific to each tumor type. Nonfunctioning adenomas, which were the largest tumors but were treated with the lowest dose, should initially be surgically removed and any residual or recurrent tumors are a good indication for gamma knife radiosurgery. A 3D strategy is indicated for larger tumors compressing the optic nerves before gamma knife radiosurgery. The goals of treatment in functioning adenomas are to normalize hormone oversecretion and to control tumor growth. GH-producing adenomas are thought to be the most difficult to cure because these tumors are very large and receive the smallest doses among functioning pituitary adenomas (FPAs). The initial treatment is thus to debulk the tumor surgically or with medications, allowing high-dose curative treatment by gamma knife radiosurgery. The initial treatment for prolactinoma is dopamine agonists which normalize PRL and significantly reduce the tumor volume. However, surgical removal or gamma knife radiosurgery is indicated for cases with incurable tumors, those who are unresponsive or who cannot tolerate the drugs. ACTH-producing adenoma is the best indication for gamma knife radiosurgery, because these tumors are the smallest FPAs and the highest doses can be administered safely and successfully. In conclusion, gamma knife radiosurgery was effective and safe not only for adjuvant but also for initial treatment of all pituitary adenomas, when tumors were small and relatively high doses were used. The complete response rate was low but a high control rate was obtained in all tumors. Responses to treatments were specific to each type of adenoma. Therefore, treatment strategies should be specific to different adenoma types. The goals of treatment are to normalize hormone over-secretion and to control tumor growth. Small or microfunctioning adenomas can be cured with gamma knife radiosurgery alone. A 3D strategy is applicable to larger tumors compressing the optic nerves.

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References 1 Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS: Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-1 concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab 2004;89: 1613–1617. 2 Barken AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, Sandler HM: Pituitary irradiation is ineffective in normalizing plasma insulinlike growth factor 1 in patients with acromegaly. J Clin Endocrinol Metab 1997;82:3187–3191. 3 Brada M, Rajan B, Traish D, Ashley S, Holmes-Sellors PJ, Uttley D: The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol 1993;38:571–578. 4 Degerblad M, Rahn T, Bergstrand G, Thoren M: Long-term results of stereotactic radiosurgery to the pituitary gland in Cushing disease. Acta Endocrinol 1986;112:310–314. 5 Feigl GC, Bonelli CM, Berghold A, Mokry M: Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 2002;97(suppl 5): 415–421. 6 Ganz JC, Backlund EO, Thorsen FA: The effects of gamma knife surgery of pituitary adenomas on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 1993;61(suppl 1):30–37. 7 Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Was J, Von Werder K, Melmed S: Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000;85: 526–529. 8 Gutt B, Hatzack C, Morrison K, Pollinger B, Schopohl J: Conventional pituitary irradiation is effective in normalising plasma IGF-1 in patients with acromegaly. Eur J Endocrinol 2001;144:109–116. 9 Howlett TA, Plowman PN, Wass JAH, Rees LH, Jones AE, Besser GM: Megavoltage pituitary irradiation of Cushing disease and Nelson’s syndrome: long-term follow-up. Clin Endocrinol 1989;31:309–323. 10 Ikeda H, Jokura H, Yoshimoto T: Transsphenoidal surgery and adjuvant gamma knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg 2001;95:285–291. 11 Kjellberg RH: Stereotactic Bragg Peak Proton Radiosurgery Method. Amsterdam, Elsevier, 1979. 12 Kobayashi T, Kida Y, Mori Y: Gamma knife radiosurgery in the treatment of Cushing disease: longterm results. J Neurosurg 2002;97(suppl 5):422–432. 13 Kobayashi T: A strategy for treating sellar-parasellar tumors based on long-term results of microsurgery and gamma knife radiosurgery; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 1–12.

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14 Landolt AM, Haller D, Lomax N, Scheib S, Schubinger O, Siegfried J, Wellis G: Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 1998;88:1002–1008. 15 Landolt AM, Haller D, Lomax N, Scheib SG, Schubinger O, Siegfried J, Wellis G: Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab 2000;85:1287–1289. 16 Landolt AM, Lomax N: Gamma knife radiosurgery for prolactinomas. J Neurosurg 2000;93(suppl 3): 14–18. 17 Lawrence JH: Proton irradiation of the pituitary. Cancer; 1957;10:795–798. 18 Leksell L: The stereotactic method and radiosurgery of the brain. Acta Chir Scand 1951;102:316–319. 19 Lim YJ, Leem W, Kim TS, Rhee BA, Kim GK: Four years’ experience in the treatment of pituitary adenomas with gamma knife radiosurgery. Stereotact Funct Neurosurg 1996;70(suppl 1):95–109. 20 McCollough WM, Marcus RB, Rhoton AL Jr, Ballinger WE, Million RR: Long-term follow-up of radiotherapy for pituitary adenoma: the absence of late recurrence after ⬎4500 cGy. Int J Radiat Oncol Biol Phys 1991;21:607–614. 21 Miller JW, Crapo L: The medical treatment of Cushing’s syndrome. Endocr Rev 1993;14:443–458. 22 Molitch ME: Medical treatment of prolactinomas. Endocrinol Metab Clin North Am 1999;28:143–169. 23 Niranjan A, Szeifert GT, Kondziolka D, Flickinger JC, Maitz AH, Lunsford LD: Gamma knife radiosurgery for growth hormone-secreting pituitary adenomas; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 93–101. 24 Pollock BE, Nippoldt TB, Stafford SL, Foote RL, Abboud CF: Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas; factors associated with endocrine normalization. J Neurosurg 2002;97:525–530. 25 Pan L, Zhang N, Wang EM, Wang BJ, Dai JZ, Cai PW: Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg 2000;93(suppl 3):10–13. 26 Powell JS, Wardlaw SL, Post KD, Freda PU: Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 2000;85:2068–2071. 27 Rahn T, Thoren M, Hall K, Backlund EO: Stereotactic radiosurgery in Cushing’s syndrome: acute radiation effects. Surg Neurol 1980;14:85–92. 28 Salinger DJ, Brady LW, Miyamoto CT: Radiation therapy in the treatment of pituitary adenomas. Am J Clin Oncol 1992;15:467–473.

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29 Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD: Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma. J Neurosurg 2002;97 (suppl 5):408–414. 30 Thoren M, Rähn T, Guo W, Werner S: Stereotactic radiosurgery with the cobalt-60 gamma unit in the treatment of growth hormone-producing pituitary tumors. Neurosurgery 1991;29:663–668. 31 Tindall GT, Herring CJ, Clark RV: Cushing’s disease: results of transsphenoidal microsurgery with emphasis on surgical failures. J Neurosurg 1990;72:363–369.

32 Witt TC, Kondziolka D, Flickinger JC, Lunsford LD: Gamma knife radiosurgery for pituitary tumors; in Lunsford LD, Kondziolka D, Flickinger JC (eds): Gamma Knife Brain Surgery. Prog Neurol Surg. Basel, Karger, 1998, vol 14, pp 114–127. 33 Wowra B, Stummer W: Efficacy of gamma knife radiosurgery for nonfunctioning pituitary adenomas: a quantitative follow-up with magnetic resonance imaging-based volumetric analysis. J Neurosurg 2002;97(suppl 5):429–432. 34 Zhang N, Pan L, Wang EM, Dai JZ, Wang BJ, Cai PW: Radiosurgery for growth hormone-producing pituitary adenomas. J Neurosurg 2000;93(suppl 3):6–9.

Tatsuya Kobayashi, MD, PhD Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital 1–172 Hokke, Nakagawa ku Nagoya, Aichi 454-0933 (Japan) Tel. ⫹81 52 362 5151, Fax ⫹81 52 362 5151, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 96–111

Gamma Knife Radiosurgery for Skull-Base Meningiomas Masami Takanashi ⭈ Seiji Fukuoka ⭈ Atsufumi Hojyo ⭈ Takehiko Sasaki ⭈ Jyoji Nakagawara ⭈ Hirohiko Nakamura Department of Neurosurgery, Nakamura Memorial Hospital, Sapporo, Japan

Abstract Objective: The primary purpose of this study was to evaluate the efficacy of gamma knife radiosurgery (GKRS) when used as a treatment modality for cavernous sinus or posterior fossa skull-base meningiomas (SBMs), with particular attention given to whether or not intentional partial resection followed by GKRS constitutes an appropriate combination treatment method for larger SBMs. Patients and Methods: Of the 101 SBM patients in this series, 38 were classified as having cavernous sinus meningiomas (CSMs), and 63 presented with posterior fossa meningiomas (PFMs). The patients with no history of prior surgery (19 CSMs, 57 PFMs) were treated according to a set protocol. Small to medium-sized SBMs were treated by GKRS only. To minimize the risk of functional deficits, larger tumors were treated with the combination of intentional partial resection followed by GKRS. Residual or recurrent tumors in patients who had undergone extirpations prior to GKRS (19 CSMs, 6 PFMs) are not eligible for this treatment method (due to the surgeries not being performed as part of a combination strategy designed to preserve neurological function as the first priority). Results: The mean follow-up period was 51.9 months (range, 6–144 months). The overall tumor control rates were 95.5% in CSMs and 98.4% in PFMs. Nearly all tumors treated with GKRS alone were well controlled and the patients had no deficits. Furthermore, none of the patients who had undergone prior surgeries experienced new neurological deficits after GKRS. While new neurological deficits appeared far less often in those receiving the combination of partial resection with subsequent GKRS, extirpations tended to be associated with not only a higher incidence of new deficits but also a significant increase in the worsening of already-existing deficits. Conclusion: Our results indicate that GKRS is a safe and effective primary treatment for SBMs with small to moderate tumor volumes. We also found that larger SBMs compressing the optic pathway or brain stem can be effectively treated, minimizing any possible functional damage, by Copyright © 2009 S. Karger AG, Basel a combination of partial resection with subsequent GKRS.

Over the last decade, operative results for skull-base meningiomas (SBMs) have improved due to advances in microsurgical techniques, neuromonitoring and postoperative intensive care [3, 5, 20]. However, radical surgical extirpation of the tumor does not generally lead to functional improvement and is associated with a high risk of postoperative morbidity [5, 21, 24]. Furthermore, tumor recurrence and progression necessitating additional adjuvant treatment are quite common [2, 4, 5, 15].

Table 1. Clinical data of 101 patients with SBMs

Number of tumors Male/female Mean age, years (range) Mean tumor volume, cm3 (range) Mean marginal dose, Gy (range) Number of isocenters (shot) (range)

Overall

Cavernous sinus meningiomas

Posterior fossa meningiomas

101 32/69 56.7 (18–90) 5.3 (0.22–23.2) 14.4 (9–25) 12.1 (2–25)

38 18/20 56 (25–80) 8.6 (2.2–23.2) 14.8 (9–25) 13.9 (7–24)

63 14/49 57.1 (18–90) 3.1 (0.22–11.1) 13.6 (9–25) 11.1 (2–25)

To address these concerns, in the early 1990s, radiosurgery was first used to treat selected SBM patients, with the primary aim of controlling tumor growth while preserving neurological status and minimizing side effects. Recently, the effectiveness of gamma knife radiosurgery (GKRS) as primary or adjuvant treatment of such SBMs has been evaluated and reported [1, 6, 8, 16]. While the best treatment for large SBMs remains a controversial issue, recent reports have recommended GKRS as an appropriate and effective primary treatment modality for small to medium-sized SBMs [6, 11, 12, 17, 19, 22, 23]. We report our experience in treating SBMs, in addition to discussing and evaluating the appropriateness of GKRS as a primary therapy for small to medium-sized tumors, and combination therapy proceeded by partial resection for larger tumors.

Patients and Methods From 1991 through 2003, 110 patients with SBMs located in the cavernous sinus or posterior fossa were treated by GKRS at Nakamura Memorial Hospital. Patients with multiple meningiomas or malignant meningioma were excluded from this study, leaving 101 patients in this series. Of these, 38 presented with CSMs and 63 had PFMs (table 1). Thirty-two patients were male and 69 were female, with a mean age of 55.6 years (range 20–80 years). The mean follow-up period was 51.9 months (range 6–144 months). Tumor locations are listed in table 2: 38 cavernous sinus, 19 petrous apex, 38 petrous (cerebello-pontine angle), 5 petroclivus, and 1 foramen magnum. Neurological deficits at the time of GKRS treatment are listed in table 3. Among those with CSMs, deficits related to visual pathways and extraocular cranial nerves were characteristically numerous, while deficits related to facial and cochlear nerve components were extremely common in the PFM patients. Thirty of the 38 CSM patients (79%) and 14 of the 63 PFM patients (22%) had undergone surgery prior to GKRS. The most appropriate therapeutic approach was based on evaluation of clinical signs and symptoms, as well as tumor volume, location and risks to adjacent cranial nerves and brain structures, especially the visual pathway and brainstem. A SBM patient, with no prior surgical history, requesting GKRS is typically treated according to a set protocol. The strategy for CSMs is as follows (fig. 1). Tumors less than 5 cm3 in volume rarely compress optic pathways or the brainstem, and thus are generally treated by GKRS as the primary procedure.

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Table 2. Tumor locations of 101 SBMs

Cavernous sinus Posterior fossa Petrous apex Petrous (CP angle) Petroclivus Foramen magnum

38 19 38 5 1

Total

Table 3. Classification of 101 neurological deficits found at time of GKRS for SBMs

Neurological deficits

Visual field defect Reduced visual acuity Oculomotor nerve palsy Trochlear nerve palsy Trigeminal nerve palsy Abducens nerve palsy Facial nerve palsy Hearing dysfunction Hemiparesis Dizziness Numbness of upper limbs

101

Number of patients CSM

PFM

all

10 12 19 5 18 9 1 2 1 – –

– – – – 18 3 6 24 2 9 1

10 12 19 5 36 12 7 26 3 9 1

The treatment strategy for tumors with volumes between 5 and 10 cm3 depends on the degree of compression affecting the optic apparatus or brainstem structures, in addition to the presence and degree of clinical signs. Tumors with volumes greater than 10 cm3 typically require intentional partial resection (IPR) prior to GKRS to optimize the radiosurgical treatment. Reducing the tumor volume with IPR decompresses critical structures, such as the visual pathway and brainstem, thereby minimizing the risks associated with the subsequent GKRS. However, in our present series, there were two exceptions to this rule. Both patients had CSMs larger than 10 cm3 and were treated with GKRS alone. One patient was unable to undergo surgery due to a debilitating medical condition (severe renal failure), while the other demonstrated only mild tumor compression of the visual pathway and brainstem, thereby making treatment by GKRS alone a viable option. Patients with residual or recurrent CSMs after preceding surgeries (13 and 6 cases, respectively) were generally treated with GKRS alone. There was also one exception, a patient who had already undergone two surgeries but required an additional partial resection due to the tumor volume being deemed too large for GKRS. Similarly, patients with residual or recurrent PFMs (4 and 2 cases, respectively) underwent GKRS. The first priority of these resections, performed as a combination therapy with GKRS, was not preservation of neurological function. The procedures are thus defined as extirpation (EXT), which is quite different, both procedurally and in terms of the goal of surgery, from IPR.

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CSM 10 cm3⬍

5–10 cm3

⬍5cm3

Compression of optic nerve or brain stem Severe IPR

Minimal or mild GKRS

Fig. 1. Treatment strategy for CSMs.

PFM 8 cm3⬍

4–8 cm3

⬍4cm3

Brain stem compression

Severe IPR Fig. 2. Treatment strategy for PFMs.

Minimal or mild GKRS

The strategy for PFMss is as follows (fig. 2). Tumors less than 4 cm3 in volume tend not to compress brainstem structures, making GKRS an appropriate primary treatment. The strategy for tumors ranging from 4 to 8 cm3 in volume depends on the degree of brainstem compression. Tumors with volumes larger than 8 cm3 require IPR, prior to GKRS, to optimize the radiosurgical treatment. Reducing the tumor volume (with minimal neurological deficits) decompresses the brainstem. In this series, 1 patient with a PFM (CP angle) greater than 8 cm3 was unable to undergo surgery due to a debilitating medical condition (severe pulmonary emphysema and asthma) and was treated by GKRS alone. Three different treatment protocols, GKRS, IPR-GKRS and EXT-GKRS, were evaluated and compared in terms of functional preservation and control rate. The numbers of patients receiving

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99

Table 4. Classification of 101 patients with SBMs according to operative procedure and type of meningioma

Location

Number of patients total

GK

EXT-GKRS

IPR-GKRS

CSM PFM

38 63

8 49

19 6

11 8

Total

101

57

25

19

EXT ⫽ Extirpation; IPR ⫽ intentional partial resection.

a

b Fig. 3. Dose planning. a, b The arrow indicates the area near the optic nerve which was irradiated with a ⬍15 Gy marginal dose (yellow line). The optic nerve is located outside of the green 9-Gy isodose line. However, as can be seen, the majority of the tumor was covered by the 15-Gy dose.

each type of treatment are listed in table 4. Of the 101 patients in this study, 8 with CSMs and 49 with PFMs were treated with GKRS, 11 with CSMs and 8 with PFMs by IPR-GKRS, and 19 with CSMs and 6 with PFMs by EXT-GKRS. The doses delivered to the tumors were determined according to their volumes and radiobiological risks to adjacent cranial nerves. To protect radiation-sensitive critical structures, the irradiation dose to the visual pathway was limited to 9 Gy or less, and that to the brainstem varied from 9 Gy to a maximum of 15 Gy [9, 16]. This strategy necessitates part of the area near the visual pathway or brainstem being irradiated with a reduced dose, while the attachment or base of the tumor is fully covered with conformal marginal isodose lines (fig. 3). The mean tumor volume at the time of GKRS was 5.3 cm3 (range 0.22–23.2 cm3). Conformal multiple shots were used in all patients, with the mean number of isocenters being 12.1 (range 2–25). The mean dose delivered to the tumor was 14.4 (range 9–25 Gy), and the mean follow-up period was 51.9 months (range 6–144 months). Follow-up MRI was done at 6-month intervals for the first 5 years, and at 1-year intervals thereafter, allowing effective and accurate evaluation of tumor control and changes in neurological status.

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a

b

c

d Fig. 4. Coronal T1-weighted enhanced MR images illustrating a CSM in a 72-year-old man with left oculomotor and abducens nerve palsies. a Dose planning: The majority of the tumor (indicated by the blue line) was covered by the 15-Gy isodose (yellow) boundary, whereas the optic chiasm was irradiated with ⬍9 Gy. The arrow shows the lower dose area (between the blue line and the yellow marginal isodose line). b Prior to GKRS. c 12 months after GKRS, the tumor showed a significant volume reduction with resolution of oculomotor and abducens nerve palsies. d 24 months after GKRS.

Results

Cavernous Sinus Meningiomas Thirty-eight CSM cases were analyzed and evaluated. The mean patient age was 56 years (range 25–80 years), and the mean tumor volume was 8.6 cm3 (range 2.2–23.2 cm3). The tumors were treated with a mean dose of 15.6 Gy (range 9–25 Gy) at the margin. The mean follow-up period was 60 months (range 6–144 months). In accordance with our therapeutic approach, the 38 CSM patients were divided into three groups based on treatment modality; 8 patients (21%) received GKRS only (fig. 4), 11 (29%) IPR-GKRS (fig. 5), and 19 (50%) EXT-GKR (fig. 6). In the GKRS,

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a

c

e

b

d

f

Fig. 5. a, b Axial and coronal T1-weighted enhanced MR images illustrating a CSM in a 66-year-old man with visual field loss and left oculomotor nerve palsy. c, d IPR and GKRS were performed. The tumor margin was covered with a 20-Gy isodose, whereas the visual pathway was irradiated with less than 9 Gy. e, f Follow-up MR images obtained 61 months after GKRS showed significant volume reductions with improvement of visual field loss and oculomotor nerve palsy.

IPR-GKRS and EXT-GKRS groups, the respective mean tumor volumes were 7.8 cm3 (range 4–14.8 cm3), 9.0 cm3 (range 2.2–17.3 cm3) and 8.7 cm3 (range 2.6–23.2 cm3). Similarly, the respective mean doses to the tumor margin were 14.5 Gy (range 9–17.5 Gy), 15.2 Gy (range 12–20 Gy) and 14.7 Gy (range 10–25 Gy) (table 5). Tumor Control In 1 patient, tumor recurrence was seen 35 months after GKRS. The overall actuarial tumor control rate was 95.5% (fig. 7). Clinical Evaluation Prior to GKRS, 77 neurological deficits were identified in 36 of the 38 patients (95%). After GKRS, the actuarial functional improvement rate per patient was 50.8% over 26 months.

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a

c

e

b

d

f

Fig. 6. a, b Axial and coronal T1-weighted enhanced MR images illustrating a CSM in a 46-year-old woman with right visual acuity deterioration. The patient underwent surgical resection, and developed right visual disturbance, in addition to oculomotor, trochlear and abducens nerve palsies, postoperatively. c, d GKRS was performed for the residual tumor with a marginal dose of 18 Gy. e, f Follow-up MR images obtained 111 months after radiosurgery showed a significant volume reduction, but there was no improvement in neurological deficits.

Table 5. Characteristics of 38 CSM patients according to treatment modality Treatment

Number of patients

Tumor volume, cm3

Dose delivered, Gy

GKRS alone IPR-GKRS EXT-GKRS

7 11 20

7.8 (4–14.8) 9.0 (2.2–17.3) 8.7 (2.6–23.2)

14.5 (9–17.5) 15.2 (12–20) 14.7 (10–25)

Total

38

8.6

14.8

EXT ⫽ Extirpation; IPR ⫽ intentional partial resection.

As shown in table 6, the GKRS group (8 cases) initially presented with 2 oculomotor, 3 trigeminal and 1 abducens nerve palsy. Both the oculomotor and 1 of the 3 trigeminal nerve palsies improved after GKRS treatment.

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100 80 60 %

50.8%

40 20 0 Fig. 7. The actuarial rate of functional improvement for all patients with CSMs after GKRS.

0

20

40

60

80 100 120 140 160 Months

Table 6. Improvement of neurological deficits in 38 CSM patients treated by GKRS alone

Number of deficits total

showing improvement

Oculomotor nerve palsy Trigeminal nerve palsy Abducens nerve palsy

2 3 1

2 1 0

Total

6

3

Table 7 summarizes the neurological deficit improvements after GKRS in CSM patients who had undergone surgeries prior to GKRS. The IPR-GKRS group (11 cases) initially had 3 instances each of visual field defect and reduced visual acuity, in addition to 2 oculomotor, 1 trochlear, 4 trigeminal and 2 abducens nerve palsies. No previously existing deficit deteriorated as a result of IPR, although 4 new deficits, all mild in nature, appeared after the resections. In this group, 4 of the 11 initially existing deficits (36%) and 2 of the 4 (50%) new deficits improved after GKRS. The EXT-GKRS group (19 cases) included several combinations of deficits, including 7 cases with visual field defects, 9 with reduced visual acuity, 1 with hemiparesis and 2 with hearing dysfunction, as well as 15 oculomotor, 4 trochlear, 11 trigeminal, 1 facial and 6 abducens nerve palsies. In this group, 11 of the 32 (34%)

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Table 7. Improvement of neurological deficits after GKRS in CSM patients who had undergone surgeries prior to GKRS Neurological deficits

Number of deficits showing improvement preoperative deficits

postoperative deficits

IPR-GKRS EXT-GKRS

IPR-GKRS

EXT-GKRS

worsened

new

worsened

new

Visual field loss Visual disturbance Oculomotor nerve palsy Trochlear nerve palsy Trigeminal nerve palsy Abducens nerve palsy Facial nerve palsy Hearing dysfunction Hemiparesis

1 (3) 2 (3) 1 (2) 0 (1) 0 (2) – – – –

2 (6) 4 (8) 3 (9) 0 (1) 1 (5) 1 (2) – 0 (1) –

– – – – – – – – –

– – – – 1 (2) 1 (2) – – –

0 (1) 2 (4) 1 (2) – 0 (2) – – – –

1 (1) 0 (1) 1 (6) 0 (3) 1 (6) 0 (4) 0 (1) 0 (1) 0 (1)

Total

4 (11)

11 (32)

–

2 (4)

3 (9)

3 (24)

EXT ⫽ Extirpation; IPR ⫽ intentional partial resection. Number of neurological deficits at time of GKRS is shown in parentheses.

initially existing deficits improved after GKRS. In 14 of the 19 patients (74%), 24 new deficits appeared after EXT and 9 preexisting neurological deficits became worse. Of these preexisting deficits (9/32 ⫽ 28%), 3 (33%) improved after GKRS. The 24 new deficits were one visual field defect, one reduced visual acuity, one hearing dysfunction and 1 hemiparesis, in addition to 6 oculomotor, 3 trochlear, 6 trigeminal, 1 facial and 4 abducens nerve palsies. All the new deficits tended to be moderate to severe, and only 3 of 24 (12.5%) improved after GKRS in these 14 patients. In contrast, 2 of the 4 new deficits in the 11 IPR-GKRS patients improved after radiosurgery. Deficits associated with EXT were far less likely to improve after GKRS than those associated with IPR. Posterior Fossa Meningiomas Sixty-three PFMs were analyzed and evaluated. Of the total, 19 were petrous apex, 38 petrous (CP angle), 5 petroclivus and 1 foramen magnum. The mean patient age was 56.9 years (range 18–90), and the mean tumor volume was 3.2 cm3 (range 0.22–20 cm3). The tumors were irradiated with a mean dose of 13.6 Gy (range 9–25 Gy) at the margin. When the tumor was in proximity to the brainstem, the irradiation dose to

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a

c

b

Fig. 8. Axial T1-weighted enhanced MR images illustrating a right cerebello-pontine angle meningioma in a 64-year-old man with left hemiparesis. a MR images reveal a large recurrent tumor 9 years postoperatively. b IPR and then GKRS were performed. The tumor margin compressing the brainstem was covered by an 11-Gy isodose line (yellow). The tumor was largely covered by a 14-Gy isodose (margin indicated by inner green line). c Follow-up MR images obtained 37 months after GKRS show volume reduction, with a clinical improvement in left hemiparesis.

Table 8. Treatment parameters of 63 patients with PFMs Treatment

Number of patients

Tumor volume, cm3

Dose delivered, Gy

GK IPR-GKRS EXT-GKRS Total

49 8 6 63

3.3 (0.7–11.1) 3.4 (0.1–7.8) 1.5 (0.2–2.3) 3.1

13.1 (9–18) 13.5 (11–15) 16.2 (13–25) 13.6

EXT ⫽ Extirpation; IPR ⫽ intentional partial resection. % range showing improvement in neurological deficits is shown in parentheses.

brainstem structures was restricted to less than 15 Gy. The mean follow-up period was 46.8 months (range 6–133 months). In accordance with our therapeutic approach, the 63 PFMs were divided into 3 groups, based on the treatment modality; 49 patients (78%) received GKRS only, 8 (13%) combined IPR-GKRS (fig. 8), and 6 (9%) EXT-GKRS (table 8). The mean tumor volume was smaller in the PFM (3.1 cm3) than in the CSM (8.4 cm3) groups, allowing GKRS to be used as the primary treatment modality for a larger number of PFM patients. The respective mean tumor volumes in the GKRS, IPR-GKRS and EXT-GKRS groups were 3.4 cm3 (range 0.7–12.9 cm3), 3.4 cm3 (range 0.1–7.8 cm3) and 1.5 cm3 (range 0.2–2.3 cm3). Similarly, the mean doses delivered to the tumor margin were 13.1 Gy

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Table 9. Improvement of neurological deficits in PFM patients treated by GKRS only

Number of deficits total

showing improvement

Trigeminal nerve palsy Facial nerve palsy Hearing dysfunction Dizziness

12 1 12 8

7 1 5 4

Total

33

17

(range 9–18 Gy), 13.5 Gy (range 11–15 Gy) and 16.2 Gy (range 13–25 Gy), respectively (table 8). Tumor Control In 1 patient, tumor recurrence was seen 31 months after GKRS. The overall tumor control rate was 98.4%. Clinical Evaluation Improvements in preexisting neurological deficits after GKRS, in 49 patients, are presented in table 9. Four of 8 (50%) with dizziness, 5 of 12 (42%) with hearing dysfunction, 7 of 12 (58%) with trigeminal nerve palsy, and 1 patient with facial nerve palsy showed improvement. Table 10 classifies the deficits experienced by patients in the IPR-GKRS and EXTGKRS groups before and after operative treatment. In the 8 IPR-GKRS group patients, prior to any surgery, 13 deficits were noted; 3 trigeminal nerve palsies, 1 facial palsy, 6 hearing dysfunctions, 1 hemiparesis, 1 dizziness and 1 numbness of the upper limbs. Two of these initially existing deficits (2/13 ⫽ 15%) worsened postoperatively. Conversely, 3 of the initially existing deficits (3/13 ⫽ 23%) and the only deficit appearing after surgery improved after GKRS. Also, in comparison to IPRs, exacerbation or new neurological deficits often followed EXT. As shown in table 10, 11 of 12 (92%) new deficits appeared after completion of EXT. These include 1 abducens palsy, 4 facial nerve palsies, 5 hearing dysfunctions and 1 hemiparesis. Furthermore, 2 of 5 (40%) initially existing deficits worsened after EXT. In the EXT-GKRS group, only 1 of the 11 (9%) deficits that appeared after surgical procedures showed any improvement after GKRS. Similarly, just 1 of the 5 (20%) initially existing deficits showed positive change following GKRS. In addition, as demonstrated in table 10, 2 of the 5 (40%) initially existing deficits further deteriorated after EXT and none improved after GKRS.

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Table 10. Improvement of neurological deficits after GKRS in PFM patients who had undergone prior surgeries Neurological deficits

Number of deficits showing improvement preoperative deficits

postoperative deficits

IPR-GKRS

IPR-GKRS

EXT-GKRS

EXT-GKRS

worsened

new

worsened

new

Trigeminal nerve palsy Abducens nerve palsy Facial nerve palsy Hearing dysfunction Hemiparesis Dizziness Numbness

1 (3) – 0 (1) 0 (6) 1 (1) 0 (1) 1 (1)

0 (3) 0 (1) – 1 (1) – – –

– – – 0 (1) – 0 (1) –

– 1 (1) – – – – –

– 0 (1) – 1 (1) – – –

– 0 (1) 1 (4) 0 (5) 0 (1) – –

Total

3 (13)

1 (5)

0 (2)

1 (1)

1 (2)

1 (11)

EXT ⫽ Extirpation; IPR ⫽ intentional partial resection. Number of neurological deficits at time of GKRS is shown in parentheses.

Discussion

Cavernous Sinus Meningiomas Despite the development of innovative microsurgical techniques, gross total excision is performed in less than 76% of the reported cases [4, 5, 14]. Furthermore, tumor recurrence rates range from 6 to 25%, and recent studies still report postoperative mortality rates of 2–7%, with permanent morbidity rates ranging from 10 to 59% [2, 4, 5, 14, 20]. The expediency of GKRS for CSMs has been described by a number of practitioners [6, 11, 12, 18, 22]. In their reports, tumor control rates range from 86.4 to 100%, the rate of clinical improvement from 20 to 57% [6, 11, 12, 18, 22]. In our series of 38 CSMs, the actuarial tumor control and clinical improvement rates were 95.5 and 50.8%, respectively. In addition, none of our patients experienced any new neurological deficits after GKRS. As part of our strategy for conducting effective dose planning, the periphery of the tumor near the optic apparatus or brain stem is irradiated with a dosage lower than the marginal dose. Despite this practice, almost all tumors are well controlled. While the good outcomes are most likely due to the obliteration of tumor vessels or hyalinization [10] at the base or attachment, which is fully irradiated, we also speculate that a marginal dose of 9 Gy might be effective in controlling the tumor.

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Several studies also found GKRS to be effective as a primary treatment for smallto-moderate-sized SBMs (including CSMs), and have emphasized both the low morbidity rate and good control features of GKRS [1, 8]. In our series, 8 CSMs treated with GKRS alone were safely and effectively controlled without recurrence. No clinical deterioration was observed, and 3 of the 6 preexisting neurological deficits improved after GKRS. In particular, all oculomotor nerve palsies showed improvement. GKRS thus appears to offer an effective, primary treatment alternative for selected small-to-moderate-sized CSMs. Recently, to preserve cranial nerve function, partial resections of large tumors have come to be recommended as an adjunct, which optimizes GKRS [14, 17]. GKRS is reportedly an effective treatment modality in combination with such partial resections [6, 7, 14, 17]. In our strategy, large tumors are treated by IPR to preserve neurological function prior to GKRS. In the IPR-GKRS group, tumors were all controlled and their neurological functions were well preserved. Deficits accompanying IPR were all mild. In comparison, however, new appearance or worsening of preexisting neurological deficits often followed EXT. A significantly greater number of deficits associated with EXT were moderate to severe. Moreover, deficits resulting from EXT demonstrated minimal improvement after subsequent GKRS. This was especially apparent with oculomotor nerve palsies, with only 1 of 6 (17%) deficits, which developed after EXT, improving. In contrast, 6 of 13 (46%) initially existing deficits improved. From these findings, oculomotor nerve palsies may improve after GKRS, while palsies resulting from surgical injuries tend to have a poor prognosis. Combining IPR with subsequent GKRS is recommended for preserving cranial nerve function and optimizing the radiosurgical approach. Posterior Fossa Meningiomas Recently published microsurgical studies report gross total resection in less than 89% of operative cases, leaving the very real risk of residual tumor regrowth and a need for additional treatment [3, 13]. In such cases, combined treatment protocols consist of microsurgery with adjuvant GKRS [3, 13, 23]. However, in various centers and institutes, GKRS is performed not only as an ancillary therapy but also as a primary treatment, particularly in the management of selected small-to-medium-sized tumors, to achieve functional preservation and tumor control [12, 13, 19, 23]. In our series, 49 of 63 patients with PFMs (78%) received GKRS alone. The mean tumor volume of this group was relatively small (mean 3.3 cm3, range 0.7–11.1 cm3), such that the tumors could be treated by GKRS with an optimal marginal dose as the primary treatment process, with little risk of neurological deterioration. The 49 tumors given GKRS only were all well controlled except in one recurrent case, in whom tumor growth was detected 31 months after radiosurgery. However, this patient did not experience neurological deterioration. Seventeen of 33 preexisting neurological deficits (52%) showed clinical improvement after GKRS.

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a

b Fig. 9. a Axial T1-weighted MR images illustrating a right petrous meningioma in a 60-year-old woman. b GKRS was performed. The dose delivered to the tumor margin was 13 Gy. The attachment, or base of the tumor, was covered with a marginal dose exceeding 13 Gy (yellow line). The irradiation dose to the facial and cochlear nerves was under 11 Gy (green line).

However, despite the efficacy of GKRS, surgical removal should be considered for the treatment of larger tumors compressing brainstem structures. Recent reports recommend combining IPR with subsequent GKRS for larger SBMs [3, 19]. In our series, 11 new deficits appeared in 6 patients after EXT, while only 1 was seen in 8 patients who had undergone IPR. Furthermore, very few of the new deficits associated with EXT improved after GKRS (only 1 of 11). IPRs are recommended for minimizing neurological deterioration when surgical resections are performed to optimize the subsequent GKRS. New deficits appearing after EXT included several facial and cochlear nerve palsies (4 and 5, respectively), with only 1 of the facial nerve palsies improving. In GKRS treatment for PFMs, the irradiation dose to the area near the facial and cochlear nerves was kept below 12 Gy to protect these radiation-sensitive areas (fig. 9). Large tumors, which compress these nerves and/or the brainstem, should be treated by IPR followed by GKRS to preserve neurological function.

Conclusion

In this study, 101 SBM (38 CSM and 68 PFM) cases were analyzed and evaluated. GKRS is recommended as a safe and effective primary treatment for SBMs with small-to-moderate tumor volumes. Larger SBMs, which compress the optic pathway or brainstem, should be treated by a combination of IPR followed by GKRS, to minimize functional damage. Due to the often slow and unpredictable growth of tumors, a valid analysis and evaluation of treatment strategies for SBMs necessarily involves long-term follow-up.

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References 1 Aichholzer M, Bertalanffy A, Dietrich W, Roessler K, Pfisterer W, Ungersboeck K, Heimberger K, Kitz K: Gamma knife radiosurgery of skull base meningiomas. Acta Neurochir (Wien) 2000;142:647–653. 2 Chan RC, Thompson GB: Morbidity, mortality, and quality of life following surgery for intracranial meningiomas: a retrospective study in 257 cases. J Neurosurg 1984;60:52–60. 3 Couldwell WT, Fukushima T, Giannotta SL, Weiss MH: Petroclival meningiomas: surgical experience in 109 cases. J Neurosurg 1996;84:20–28. 4 DeJesus O, Sekhar LN, Parikh HK, Wright DC, Wagner DP: Long-term follow-up of patients with meningiomas involving the cavernous sinus: recurrence, progression, and quality of life. Neurosurgery 1996;39:915–920. 5 DeMonte F, Smith HK, al-Mefty O: Outcome of aggressive removal of cavernous sinus meningiomas. J Neurosurg 1994;81:245–251. 6 Duma CM, Lunsford LD, Kondziolka D, Harsh GR 4th, Flickinger JC: Stereotactic radiosurgery of cavernous sinus meningiomas as an addition or alternative to microsurgery. Neurosurgery 1993;32:699–705. 7 Ganz JC, Backlund EO, Thorsen FA: The results of gamma knife surgery of meningiomas, related to size of tumor and dose. Stereotact Funct Neurosurg 1993;61:23–29. 8 Kondziolka D, Lunsford LD, Coffey RJ, Flickinger JC: Stereotactic radiosurgery of meningiomas. J Neurosurg 1991;74:552–559. 9 Leber KA, Bergloff J, Pendl G: Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998;88:43–50. 10 Linskey ME, Martinez AJ, Kondziolka D, Flickinger JC, Maitz AH, Whiteside T, Lunsford LD: The radiobiology of human acoustic schwannoma xenografts after stereotactic radiosurgery evaluated in the subrenal capsule of athymic mice. J Neurosurg 1993;78: 645–653. 11 Liscak R, Simonova G, Vymazal J, Janouskova L, Vladyka V: Gamma knife radiosurgery of meningiomas in the cavernous sinus region. Acta Neurochir (Wien) 1999;141:473–480. 12 Morita A, Coffey RJ, Foote RL, Schiff D, Gorman D: Risk of injury to cranial nerves after gamma knife radiosurgery for skull base meningiomas: experience in 88 patients. J Neurosurg 1999;90:42–49.

13 Nicolato A, Foroni R, Pellegrino M, Ferraresi P, Alessandrini F, Gerosa M, Bricolo A: Gamma knife radiosurgery in meningiomas of the posterior fossa. Experience with 62 treated lesions. Minim Invasive Neurosurg 2001;44:211–217. 14 Nicolato A, Foroni R, Alessandrini F, Bricolo A, Gerosa M: Radiosurgical treatment of cavernous sinus meningiomas: experience with 122 treated patients. Neurosurgery 2002;51:1153–1161. 15 Ojemann RG: Skull-base surgery: a perspective. J Neurosurg 1992;76:569–570. 16 Pendl G, Schrottner O, Eustacchio S, Feichtinger K, Ganz J: Stereotactic radiosurgery of skull base meningiomas. Minim Invasive Neurosurg 1997;40:87–90. 17 Pendl G, Eustacchio S, Unger F: Radiosurgery as alternative treatment for skull base meningiomas. J Clin Neurosci 2001;8:12–14. 18 Roche PH, Regis J, Dugour H, Fournier HD, Delsanti C, Pallet W, Grisoli F, Peragut JC: Gamma knife radiosurgery in the management of cavernous sinus meningiomas. J Neurosurg 2000;93:68–73. 19 Roche PH, Pellet W, Fuentes S, Thomassin JM, Regis J: Gamma knife radiosurgical management of petroclival meningiomas: results and indications. Acta Neurochir (Wien) 2003;45:883–888. 20 Samii M, Carvalho GA, Tatagiba M, Mathies C: Surgical management of meningiomas originating in Meckel’s cave. Neurosurgery 1997;41:767–775. 21 Sekhar LN, Wright DC, Richardson R, Monacci W: Petroclival and foramen magnum meningiomas: surgical approaches and pitfalls. J Neurooncol 1996; 29:249–259. 22 Shin M, Kurita H, Sasaki T, Kawamoto S, Tago M, Kawahara N, Morita A, Ueki K, Kirino T: Analysis of treatment outcome after stereotactic radiosurgery for cavernous sinus meningiomas. J Neurosug 2001;95: 435–439. 23 Subach BR, Lunsford LD, Kondziolka D, Maitz AH, Flickinger JC: Management of petroclival meningiomas by stereotactic radiosurgery. Neurosurgery 1998;42:437–445. 24 Suzuki M, Mizoi K, Yoshimoto T: Should meningiomas involving the cavernous sinus be totally resected? Surg Neurol 1995;44:3–13.

Masami Takanashi, MD Department of Neurosurgery, Nakamura Memorial Hospital South-1, West-14, Chuo-ku Sapporo, Hokkaido 060-8570 (Japan) Tel. ⫹81 11 231 8555, Fax ⫹81 11 231 8387

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Other Skull-Base Tumors Hiroshi K. Inoue Restorative Neurosurgery, Institute of Neural Organization, Fujioka, Japan

Abstract Therapeutic policy and radiosurgical results for nonvestibular schwannomas and chordomas are reported. Fourteen patients with nonvestibular schwannomas treated with marginal doses of 12–15 Gy were followed for 5–13 years. All patients except one were stable and did not require additional treatments. Seven patients with chordomas were treated with marginal doses of 14–20 Gy. Five of them showed unchanged or decreased size of tumors during the follow-up of 4.5–7 years. Two patients required a second treatment and 1 died due to tumor progression outside of the treatment volume. No adverse effects were experienced in any of these patients. Gamma knife radiosurgery is an effective treatment for nonvestibular schwannomas and chordomas. However, multisession radiosurgery may be Copyright © 2009 S. Karger AG, Basel required for aggressive chordomas.

Gamma knife radiosurgery is a relatively noninvasive treatment modality for neurosurgical patients. However, therapeutic strategies for radiosurgery differ depending on operators as well as concomitant microsurgery, even within the same institute. The author’s radiosurgery policy emphasizes achieving an ultimate goal of no treatment-related morbidity. When we started performing radiosurgery in 1991, the author decided to use lower doses than reported previously, with the intention of also employing microsurgery when radiosurgery failed to control lesions. Long-term follow-up of patients receiving low-dose treatment (up to 12 Gy) for vestibular schwannomas revealed better results in terms of functional preservation than those previously reported [1]. Results of medium-dose treatment (up to 20 Gy) for arteriovenous malformations also showed fewer complications than described previously [2]. In this chapter, our therapeutic policy and the results of treating other skull-base tumors, nonvestibular schwannomas and chordomas are described.

Nonvestibular Schwannomas

Surgical morbidity for trigeminal, jugular foramen region, and hypoglossal schwannomas is not negligible and postoperative deficits such as diplopia, dysphagia, and dysarthria can be burdensome for patients for the remainder of their lives. Other surgical complications such as facial numbness, dry eye, vertigo, cerebrospinal fluid retention, nuchal pain, and prolonged hospitalization have higher incidences than with routine craniotomy in patients undergoing surgery via a subtemporal or posterior fossa approach. Patients with radiosurgical indications for our therapeutic policy include those with minor symptoms or tumors recurring after removal. Radiosurgical treatment strategies for nonvestibular schwannomas were the same as for vestibular schwannomas, the exception being jugular foramen and hypoglossal tumors situated mainly in the foramen and extracranial space but not the posterior fossa.

Patients Between May 1991 and December 1998, 14 patients with nonvestibular schwannomas were treated with gamma knife radiosurgery and followed for 5–13 years after treatment. There were 9 males and 5 females, 31–74 years old. Affected cranial nerves included the trigeminal (n ⫽ 3), facial (n ⫽ 1), jugular foramen region (n ⫽ 6), and hypoglossal (n ⫽ 4). Symptoms included facial pain, hypoesthesia, dizziness, dysphagia, auditory disturbance, shoulder pain, and tongue atrophy. Three tumors were found incidentally. Three patients had recurrent tumors 7 months to 6 years after surgical removal. Eight tumors including all three trigeminal tumors were treated with a marginal dose of 12 Gy to achieve functional preservation. Six tumors, situated mainly within and/or outside of the skull, were treated with marginal doses of 13 to 15 Gy. The median isodose volume prescribed was 5.5 ml (range 0.5–19.2 ml).

Results During follow-up, 1 patient died of heart failure. Eleven of 13 tumors were stable or decreased in size. One of the three trigeminal schwannoma patients experienced improvement in facial sensation after treatment. None of our patients experienced adverse effects. One patient with a hypoglossal schwannoma underwent tumor removal surgery because of tumor enlargement 10 months after treatment. In another patient, tumor growth was observed 3 years after treatment but there were no neurological changes. No further growth was recognized up to 5 years after treatment (case 3).

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a

b

c Fig. 1. a MR images from a patient without lower cranial nerve symptoms show a jugular foramen tumor. b The tumor situated in the foramen and extracranial space was treated with a marginal dose of 12 Gy at a 50% isodose volume (yellow line). c The central portion of the tumor was hypointense 2 years after radiosurgery but, overall, the tumor had decreased in size 5 years after treatment. No cranial nerve side effects developed.

Case Presentations Case 1. A 43-year-old man presented with headache and hypertension. Magnetic resonance (MR) imaging revealed a tumor in the jugular foramen region (fig. 1a). No lower cranial nerve symptoms were evident. The clinical diagnosis of schwannoma was based on other imaging studies, i.e. computerized tomography (CT) and angiography. The patient wanted treatment but preferred radiosurgery over operative excision. The tumor was treated with a marginal dose of 12 Gy at a 50% isodose volume (fig. 1b). Gd-enhanced MR imaging showed central hypointensity 2 years after treatment and then a decrease in tumor size 5 years after treatment (fig. 1c). No neurological changes have been seen to date. Case 2. A 31-year-old man had a recurrent tumor of the hypoglossal nerve 4 years after surgical excision (fig. 2a). His symptoms included dysphagia, dysarthria, auditory disturbance, and right-sided facial weakness. The tumor was treated with a marginal

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Inoue

a

b Fig. 2. a MR images obtained 4 years after removal of a right hypoglossal schwannoma show a recurrent tumor in the enlarged hypoglossal canal. The tumor was treated with a marginal dose of 14 Gy. b The tumor was decreased in size 12 years after radiosurgery.

dose of 14 Gy. The tumor decreased in size thereafter (fig. 2b) and no neurological changes have been observed in the 12 years to date since radiosurgery. Case 3. A 67-year-old man presented with tongue atrophy and headache. A tumor at the right jugular foramen revealed by imaging studies was diagnosed as a schwannoma (fig. 3a). The tumor was treated with a marginal dose of 14 Gy. An increase in size was evident 3 years after radiosurgery (fig. 3b). There were no neurological changes, however, and further imaging studies showed no change in size 5 years after treatment (fig. 3c).

Discussion This study showed long-term follow-up results of low-dose radisosurgery for nonvestibular schwannomas. Low-dose radiosurgery for vestibular and nonvestibular schwannomas had no adverse effects on cranial nerves [1]. In trigeminal schwannomas, higher dose treatment was associated with some morbidity, particularly trigeminal nerve dysfunction, after radiosurgery [3]. No adverse effects on lower cranial nerves have occurred with treatment of jugular and hypoglossal schwannomas, even at higher doses [3]. The radiosensitivity of the lower cranial nerves seems to be lower than that of the trigeminal and facial nerves. Improvement of clinical symptoms has been reported after treatment of trigeminal schwannomas [4, 5], as confirmed in this study. Decompression of the trigeminal nerve due to shrinkage of the tumor mass may lead to functional recovery after radiosurgery as well as recovery of hearing in patients with vestibular schwannomas [6, 7]. Five of our 6 patients with jugular foramen schwannomas were initially treated radiosurgically. No clinical deterioration, such as the swallowing difficulty often encountered after operative

Other Skull-Base Tumors

115

a

b

c Fig. 3. a MR images from a patient with right-sided tongue atrophy show a jugular foramen tumor. The tumor was treated with a marginal dose of 14 Gy. b MR images obtained 3 years after radiosurgery show enlargement of the tumor, although there was no change in clinical status. c No further growth was found 5 years after treatment.

excision, occurred in any radiosurgery patient. This was true despite the relatively high dose used as compared to vestibular schwannomas. Radiosurgical treatment of jugular foramen schwannomas appears to be far superior to that for vestibular schwannomas. One of our 4 patients with hypoglossal schwannomas underwent operative excision due to tumor enlargement 10 months after radiosurgery. Postradiosurgical steroid administration might also be effective in reducing swelling, as is the case with vestibular tumors. Recurrent and residual hypoglossal schwannomas were effectively controlled without adverse effects by radiosurgery. It is concluded that gamma knife radiosurgery is effective, with very low treatment-related morbidity, for nonvestibular schwannomas, especially trigeminal and jugular foramen schwannomas. However, large or cystic tumors compressing the brain stem should be treated microsurgically to preserve cranial nerve functions, as reported for large vestibular schwannomas [1].

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Inoue

Chordomas

Surgical morbidity for chordomas is not low, especially when gross total removal is intended using aggressive skull base surgery. Cerebrospinal fluid leaks, cranial nerve palsies, and pharyngeal wound complications can be difficult to manage and are often encountered in recurrent tumors. Our therapeutic policy for chordomas is minimally invasive excision (from biopsy to subtotal removal for functional preservation) followed by radiosurgery with the goal of avoiding treatment-related morbidity. A marginal dose of 14 Gy or more is used to treat chordomas because of the higher recurrence rate as compared with schwannomas.

Patients Between October 1996 and October 1999, 7 patients with chordomas were treated with gamma knife radiosurgery and followed for 4.5–7 years after treatment. There were 3 males and 5 females 31–73 years of age. The tumor sites were the clivus (n ⫽ 3), parasellar region (n ⫽ 2), and nasopharynx (n ⫽ 2). All 7 patients underwent surgery including tumor biopsy. Tumors in the nasopharynx were treated with a marginal dose of 18–20 Gy. Other tumors were treated with a marginal dose of 14 Gy or more depending on the surrounding brain stem or cranial nerve structures, except in one patient with a tumor close to the optic pathway. The median isodose volume prescribed was 13.6 ml (range 5.3–42.3 ml).

Results Five of seven tumors were stable or decreased in size. One patient underwent tumor excision 5 years after radiosurgery and then a second radiosurgical procedure for residual tumor in the clivus (case 2). One patient had large tumors extending into the nasopharynx necessitating staged treatments. The second radiosurgery was performed 4 months after the initial treatment (case 3). The tumors decreased in size but the patient subsequently died due to tumor progression outside of the treatment volume. No adverse effects have been recognized to date in any of our patients.

Case Presentations Case 1. A 31-year-old man presented with diplopia and a visual field defect of the left eye. MR imaging showed a tumor in the clivus extending into the suprasellar region (fig. 4a). The tumor was partially removed and residual tumor tissue was irradiated

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117

a

b

c Fig. 4. a MR images from a patient with residual chordoma. b The tumor was treated with a marginal dose of 14 Gy. c The tumor had decreased in size 7 years after radiosurgery.

with a marginal dose of 14 Gy at a 35% isodose volume (fig. 4b). The tumor had decreased in size on images obtained 7 years after radiosurgery and there were no neurological deficits after treatment (fig. 4c). Case 2. A 48-year-old female presented with diplopia. A tumor was found in the clivus on MR imaging and diagnosed as a chordoma from tumor biopsy. The tumor was treated with a marginal dose of 15 Gy (fig. 5a). Diplopia disappeared 18 months after radiosurgery, but tumor regrowth was seen on MR images obtained 5 years after radiosurgery at the time of diplopia recurrence (fig. 5b). The tumor was partially resected and residual tumor tissue was re-irradiated with a marginal dose of 15 Gy. The tumor had decreased in size 12 months after radiosurgery (fig. 5c) and diplopia again disappeared. Case 3. A 65-year-old female had large recurrent tumors. She had undergone surgical excision 6 times during the 6-year period before radiosurgery. She was referred for gamma knife radiosurgery of large recurrent tumors at the skull base extending to the nasopharynx (fig. 6a). The right-sided tumor was treated with a marginal dose of 20 Gy. This tumor had decreased in size 4 months after the first radiosurgery (fig. 6b) but a large tumor at the clivus had extended into the pharynx (fig. 6c). The latter was treated with a marginal dose of 18 Gy (fig. 6d). Although radiosurgery was temporarily effective, tumor regrowth was eventually detected outside the treatment volume and she died 3 and a half years after radiosurgery.

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a

b

c Fig. 5. a MR images from a patient with diplopia. A tumor in the upper part of the clivus was treated with a marginal dose of 15 Gy. b Tumor regrowth extending to the lower part of the clivus was found 5 years after the first treatment (left). The recurrent tumor was partially resected and again treated radiosurgically (right). c The tumor had decreased in size and the diplopia was gone 12 months after the second radiosurgery.

Discussion Histologically, chordomas are not malignant and some tumors grow very slowly for long periods, possibly exceeding 10 years. However, this tumor has no capsule and tumor cells extend into bone tissue, especially into the bone marrow, although metastases to other organs are very rare as compared with malignant tumors. Recurrence after gross total removal does occasionally occur and new lesions outside of the original region may appear, especially in females [8], as described herein. Treatment results of conventional radiotherapy for chordomas are not satisfactory [9]. There may be roles for radiosurgery, as well as proton radiation therapy [8], in the treatment of chordomas. Recent reports have shown improved local tumor control and survival rates of 5–10 years [10, 11]. However, recurrence outside of the treatment volume is still a major problem. Detection of the tumor margin and identifying any marginal tumor cells will be essential in future imaging examinations. Larger treatment volumes

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119

a

b

c

d Fig. 6. a MR images of recurrent chordomas after six surgical excisions. One tumor (arrows) was treated with a marginal dose of 20 Gy. b This tumor had decreased in size 4 months after radiosurgery (arrows). c There was another recurrent tumor (arrows) in the clivus. d The tumor grew rapidly during the 4 months after the initial radiosurgery (arrows). This tumor was treated with a marginal dose of 18 Gy.

extending to the delineated tumor margin are a possible treatment option based on the long-term results of radiosurgery. Fractionated radiosurgery may also effectively increase the treatment volume and decrease adverse effects on surrounding structures [12]. It is concluded that gamma knife radiosurgery is an effective and minimally invasive treatment for chordomas, especially recurrent skull base tumors. However, aggressive tumors, seen mainly in females, may require other treatment approaches for tumor cells invading surrounding structures.

References 1

120

Inoue HK: Low-dose radiosurgery for large vestibular schwannomas: long-term results of functional preservation. J Neurosurg 2005;102(suppl):111–113.

2

Inoue HK: Long-term results of gamma knife surgery for arteriovenous malformations: 10- to 15-year follow-up in patients treated with lower doses. J Neurosurg 2006;105(suppl):64–68.

Inoue

3

4

5

6

7

Pollock BE, Foote RL, Stafford SL: Stereotactic radiosurgery: the preferred management for patients with nonvestibular schwannomas? Int J Radiat Oncol Biol Phys 2002;52:1002–1007. Huang CF, Kondziolka D, Flickinger JC, et al: Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery 1999;45:11–16. Zabel A, Debus J, Thilmann C, et al: Management of benign cranial nonacoustic schwannomas by fractionated stereotactic radiotherapy. Int J Cancer 2001; 96:356–362. Iwai Y, Yamanaka K, Shiotani M, et al: Radiosurgery for acoustic neuromas: results of low-dose treatment. Neurosurgery 2003;53:282–287. Flickinger JC, Kondziolka D, Niranjan A, et al: Results of acoustic neuroma radiosurgery: an analysis of 5 years’ experience using current methods. J Neurosurg 2001;94:1–6.

8 Hug EB, Slater JD: Proton radiation therapy for chordomas and chondrosarcomas of the skull base. Neurosurg Clin N Am 2000;11:627–638. 9 Zorlu F, Gurkaynak M, Yildiz F, et al: Conventional external radiotherapy in the management of clivus chordomas with overt residual disease. Neurol Sci 2000;21:203–207. 10 Muthukumar N, Kondziolka D, Lunsford LD, et al: Stereotactic radiosurgery for chordoma and chondrosarcoma: further experiences. Int J Radiat Oncol Biol Phys 1998;41:387–392. 11 Crockard HA, Steel T, Plowman N, et al: A multidisciplinary team approach to skull base chordomas. J Neurosurg 2001;95:175–183. 12 Inoue HK, Hayashi S, Ishihara J, et al: Fractionated gamma knife radiosurgery for malignant gliomas: neurobiological effects and FDG-PET studies. Stereotact Funct Neurosurg 1995;64(suppl):249–257.

Hiroshi K. Inoue, MD Institute of Neural Organization 407–12 Kobayashi Fujioka, Gunma 375-0021 (Japan) Fax ⫹81 274 23 3006, E-Mail [email protected]

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Radiosurgery for Intracranial Gliomas Yoshihisa Kida ⭈ Masayuki Yoshimoto ⭈ Toshinori Hasegawa Department of Neurosurgery, Komaki City Hospital, Komaki, Japan

Abstract Long-term results of radiosurgery for GI to GIV astrocytomas are described. We have treated 172 astrocytoma cases in total, including 25 GI cases, 52 GII cases, 41 GIII cases and 54 GIV astrocytoma cases. There were 81 males and 91 females, with a mean age of 14.8 for GI, 33 for GII, 45.8 for GIII and 52.4 years for GIV. The maximum and marginal doses for GI astrocytomas were significantly lower than those for the other three grades due to their proximity to the optic nerves. GII to GIV tumors were treated with an approximately 30 Gy mean maximum dose and a 15-Gy mean marginal dose. The response rate of GI tumors exceeded 35%, while that of GII was 50%. However, the response rates of GIII and GIV astrocytomas were very low. Likewise, the tumor control rates were very high for GI and GII tumors, and were very low for GIII and GIV tumors. These results suggest differences in tumor infiltration and malignant activity at the periphery, and indicate the high effiCopyright © 2009 S. Karger AG, Basel cacy of radiosurgery as well as its limitations.

Despite recent advances in the treatment of brain tumors, intracranial gliomas are not well controlled with current treatment modalities such as operative resection, radiotherapy and chemotherapy. Radiosurgery is among the promising new treatment modalities and several reports on radiosurgery results have been published. High-grade gliomas generally show infiltrating growth, while many low-grade gliomas are well localized. In radiosurgery, a clear tumor margin is required for delivery of a sufficiently high irradiation dose to the restricted volume. Since the installation of our gamma knife in 1991, we have radiosurgically treated several cases with low-grade or high-grade gliomas. Herein, the results of long-term follow-up of various gliomas are reported and the role of radiosurgery is discussed in relation to astrocytoma tumor grade.

Materials and Methods The current indications for radiosurgery are as follows: (1) histologically confirmed tumor, (2) after the standard therapy such as operative resection or radiotherapy, (3) all tumors are surgically

Table 1. Characteristics of glioma cases

Gliomas

Number of cases

Gender

Age (mean) years

1) GI

25

male (10) female (15)

2–47 (14.8)

2) GII

52

male (27) female (25)

4–77 (33.0)

3) GIII

41

male (22) female (19)

3–77 (45.8)

4) GIV

54

male (22) female (32)

11–80 (52.4)

inaccessible, (4) tumor sizes are acceptable for radiosurgery (less than 30 mm in mean diameter), and (5) not associated with diffuse cerebrospinal fluid dissemination. Treatment results for GI-IV astrocytomas are presented. There were 172 astocytoma cases in total, including 25 GI, 52 GII, 41 GIII and 54 GIV astrocytoma cases. There were 81 males and 91 females, with a mean age of 14.8 for GI, 33 for GII, 45.8 for GIII and 52.4 years for GIV (table 1). The majority of GI astrocytomas were located in and around the optic nerve and optic chiasm. Radiosurgery was performed under local anesthesia during a 3-day admission. After treatment, all patients had follow-up studies including neurological and MRI examinations every 3 months during the first year and every 6 months thereafter. The mean tumor size at final follow-up was compared with that at radiosurgery, and responses were evaluated as CR (complete remission), PR (partial remission), MR (minor response), NC (no change) and PG (progression). The response rate, defined as CR⫹PR/total, and the tumor control rate, defined as CR⫹PR⫹MR⫹NC/total, were calculated and compared.

Results

Radiosurgery Tumor size, maximum and marginal doses are presented in table 2. The mean tumor size clearly increases with rising tumor grade. The maximum and marginal doses of GI astrocytomas are lower than the other three grades because of their proximity to the optic nerves. GII to GIV tumors were treated with an approximately 30 Gy mean maximum dose and a 15-Gy mean marginal dose. Summary of Responses Response and control rates are illustrated in figure 1. The response rate for GI tumors exceeded 35%, while that for GII was 50%. However, the response rates for GIII and GIV astrocytomas were very low. Similarly, tumor control rates were extremely high for GI and GII tumors, and very low for GIII and GIV. In fact, many low-grade

Astrocytomas

123

%

90 80 70 60

Table 2. Radiosurgery for gliomas

50 40 30 20 10 0

Fig. 1. Response and tumor control rates of various astrocytomas after radiosurgery.

Response Control

GI

GII

GIII

Glio

Astrocytoma stage

Tumor size, mm (mean)

Maximum dose, Gy

Morginal dose, Gy

1) GI 2) GII 3) GIII 4) GIV

10.8–41.2 (23.7) 8.1–59.6 (25.7) 12.5–54.5 (28.9) 7–48.3 (29.0)

10–36 (24) 22–40 (29.7) 16–20 (29.6) 16–50 (29.5)

6.5–18 (12.3) 9–20.4 (15.0) 8–20 (14.7) 8–25 (14.7)

gliomas showed excellent tumor control in association with tumor shrinkage or disappearance during follow-up (fig. 2). Tumors did recur at the periphery on rare occasions, but were controlled with a second radiosurgery. On the contrary, the response and tumor control rates for glioblastomas were 10 and 30%, respectively, and with a few exceptions such as tumor deposits, many glioblastomas showed early progression even after radiosurgery (fig. 3). Progression-Free and Survival Curves With the mean follow-up of 26 months, only 3 of 25 GI astrocytomas showed progression. Progression-free survival was extremely high at 5 years and even longer after radiosurgery. With the same mean follow-up period, 10 of 52 GII astrocytomas demonstrated early progression before 2 years, while others showed good tumor control, indicating an almost 80% progression-free survival rate at 5 years (fig. 4a). However, the situation is entirely different for high grade gliomas. Survival durations

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a

b Fig. 2. Remarkable responses of low-grade astrocytomas to radiosurgery. a Optic glioma treated with 12 Gy at the margin (left) shows marked shrinkage 41 months after treatment (right). b GII astrocytoma treated with 15 Gy at the margin (left) has disappeared 28 months after treatment (center). No tumor recurrence was found 9 years later (right).

Preoperatively

GK (24/12 Gy)

3 months

Fig. 3. Responses of glioblastomas to radiosurgery. The tumor in the right insula was first treated surgically (left). The residual tumor was treated with radiosurgery, 12 Gy at the margins (center), and showed a marked shrinkage at 3 months. The tumor recurred soon after, however.

Astrocytomas

125

1

Percentage

0.8 0.6 0.4

GI astrocytoma GI GII astrocytoma GII

0.2 0 0

20

40

60 80 Months

a 1

Table 3. Survival after radiosurgery for malignant glioma

Percentage

120

140

GIII astrocytoma GIII Glioblastoma Glioblastoma

0.8 Fig. 4. Survival curves for astrocytoma patients following radiosurgery. a Progressionfree survival of GI and GII astrocytoma patients. b Survival curves of GIII and GIV astrocytoma patients. Median survival of GIII and GIV astrocytoma patients after radiosurgery: 34 and14 months, respectively.

100

0.6 0.4 0.2 0 0

b

10

20

30

40 50 Months

60

70

80

Timing from

Histology

Median survival, months

Diagnosis Radiosurgery Diagnosis Radiosurgery

glioblastoma glioblastoma GIII astrocytoma GIII astrocytoma

27 14 68 35

of patients with GIII and GIV astrocytomas are very short even after radiosurgery (fig. 4b). The estimated survival durations after diagnosis and radiosurgery for GIII were 35 and 68 months, respectively. The survival durations of glioblastoma patients after radiosurgery and diagnosis were 14 and 27 months, respectively (table 3).

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Discussion

Gliomas tend to grow in an infiltrating fashion, and this is clearly the case for highgrade gliomas. However, low-grade gliomas are often well circumscribed, showing very localized enhancement on MRI. These are not truly infiltrative tumors, for which radiosurgery is indicated. On the contrary, malignant gliomas demonstrate highly infiltrative growth and tumor margins are often invisible with various neuroimaging techniques, making radiosurgery difficult. Recently, MRI spectroscopy or positron emission tomography studies with fluorodeoxyglucose or methionine have been carried in order to delineate the tumor margin more clearly. In our series, it is apparent that low-grade gliomas respond well to treatment. showing remarkable tumor shrinkage or disappearance. In fact, many pilocytic astrocytomas involving the optic pathway demonstrate early positive responses as well as preservation of visual function. In cases with recurrence after radiosurgery, it was quite possible to repeat the treatment and achieve excellent tumor control. These results are in agreement with those in the literature [1, 2], and are much better than nonradiosurgical treatment outcomes [3–6]. As for radiosurgery for GII astrocytomas, good responses similar to those for GI tumors have been reported. Again, the responses are better than with standard treatment [7–9]. However, the situation is entirely different for high-grade gliomas. Radiosurgery after the standard treatment generally confers minimally additive benefits [10–12]. The stratified protocol studies for glioblastoma and anaplastic astrocytoma reportedly demonstrate a longer survival with radiosurgery than the standard treatment. However, the survival benefits obtained are apparently small. Apparent glioblastoma shrinkage was only seen in small and disseminated solitary tumors. Although central low-signal intensity is commonly observed within a few months, subsequently infiltrating tumor always occurs. Survival durations are well known to be extremely different, depending on glioma grade. According to the Japanese Brain Tumor Registry [13], the median survival of low-grade glioma patients is reportedly 50 months, but is much shorter for those with anaplastic gliomas and glioblastomas. In our series, the median survival of low-grade glioma patients was excellent, but that of high-grade glioma cases was not. These results apparently reflect the efficacy and the limitations of radiosurgical treatment for gliomas. In other words, very good results are obtained for well-circumscribed tumors, but only limited effects for high-grade gliomas, possibly because of the infiltrative growth or invasiveness into the surrounding brain of the latter. These results suggest that tumor responses vary greatly depending on astrocytoma grade. Malignant transformation and progression to a higher tumor grade have been reported after repeat operative procedures, and after radiochemotherapy. We have experienced only a few cases of grade progression during follow-up after radiosurgery, and these patients had GII and GIII astrocytomas. Whether or not radiosurgery promotes worsening of histopathological grade remains an unsolved issue.

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Complications like perifocal edema with neurological deterioration may not be particularly infrequent, for any tumor grade, in which the tumor and surrounding brain show simultaneous swelling. There seems to be no major difference in morbidity between lowgrade and high-grade gliomas after radiosurgery. However, even early morbidities may be concealed with the relatively early deterioration in some high grade gliomas cases.

Conclusion

There is a broad range of major disparities in tumor responses to radiosurgery for various intracranial gliomas, possibly due to the activity of the brain tumor itself as well as to the variable invasiveness into the surrounding brain. Low-grade gliomas demonstrated an excellent response, with a long progression-free survival. In contrast, the high-grade gliomas showed only a limited responsiveness and survival was short. In performing radiosurgery for high-grade gliomas, special techniques are needed to clearly delineate the tumor margin.

References 1

2

3

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Somaza SC, Kondziolka D, Lunsford LD, Flickinger JC, Bissonette DJ, Albright AL: Early outcome after radiosurgery for growing pilocytic astrocytomas in children. Pediatr Neurosurg 1996;25:109–115. Grabb PA, Lunsford LD, Albright AL, Kondziolka D, Flickinger JC: Stereotactic radiosurgery for glial neoplasms of childhood. Neurosurgery 1996;38:696–702. Alvord EC, Lofton S: Gliomas of the optic nerve or chiasm: outcome by patient age, tumor site, and treatment. J Neurosurg 1988;68:85–98. Rodriguez LA, Edwards MSB, Levin VA: Management of hypothalamic gliomas in children: an analysis of 33 cases. Neurosurgery 1990;26:242–247. Sutton LN, Molloy PT, Sernyak H, Goldwein J, Phillips PL, Rorke LB, Moshang T, Lange B, Packer RJ: Long-term outcome of hypothalamic/chiasmatic astrocytomas in children treated with conservative surgery. J Neurosurg 1995;83:583–589. Flickinger JC, Torres C, Deutsch M: Management of low-grade gliomas of the optic nerve and chiasm. Cancer 1988;61:635–642.

7 Piepmeier J, Christopher S, Spencer D: Variation in the natural history and survival of patients with supratentorial low-grade astrocytomas. Neurosurgery 1996;38:872–879. 8 Pollack IF, Classen D, Al-Shboul Q: Low-grade gliomas of the cerebral hemisphere in children: an analysis of 71 cases. J Neurosurg 1995;82:536–547. 9 Soffietti R, Chio A, Giordana MT: Prognostic factors in well-differentiated cerebral astrocytomas in adult. Neurosurgery 1989;24:686–692. 10 Chamberlain MC, Barba D, Kormanik P, Shea WMC: Stereotactic radiosurgery for recurrent gliomas. Cancer 1994;74:1342–1347. 11 Kondziolka D, Flickinger JC, Bissonette DJ, Bozik M, Lunsford LD: Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 1997;41:776–785. 12 Masciopinto JE, Levin AB, Mehta MP, Rhode BS: Stereotactic radiosurgery for glioblastoma: a final report of 31 patients. J Neurosurg 1995;82:530–535. 13 The Brain Tumor Registry Committee of Japan; The Japanese Pathological Society: General Rules for Clinical and Pathological Studies on Brain Tumors, ed 2. Tokyo, Kanehara, 2002, pp 1–55.

Yoshihisa Kida, MD Department of Neurosurgery, Komaki City Hospital 1–20, Jhobusi Komaki, Aichi 485-8520 (Japan) Tel. ⫹81 568 76 4131, Fax ⫹81 568 76 4145, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 129–141

Gamma Knife Radiosurgery for Other Primary Intra-Axial Tumors Yoshiyasu Iwai ⭈ Kazuhiro Yamanaka Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan

Abstract We report the usefulness of gamma knife radiosurgery for hemangioblastomas, hemangiopericytomas, germ cell tumors and pineal parenchymal tumors, and primary central nervous system lymphoma (PCNSL). In hemangioblastomas, small solid tumors can be treated very effectively. Hemangiopericytomas are still difficult to control due to their aggressiveness and metastasis to other organs. However, radiosurgery is a useful alternative to repeat craniotomy for recurrence. Radiosurgery is a reasonable option to control residual and recurrent germ cell tumors and pineoblastomas. Although the prognosis is poor for PCNSL patients, gamma knife radiosurgery, even with a relatively low tumor margin dose, is an effective treatCopyright © 2009 S. Karger AG, Basel ment for controlling PCNSL.

Radiosurgery has been shown to be effective for arteriovenous malformations, acoustic neuromas, meningiomas and metastases. In this chapter, we will discuss radiosurgery for hemangioblastoma, hemangiopericytoma, germ cell tumors and pineal parenchymal tumors, as well as primary central nervous system lymphoma (PCNSL).

Hemangioblastomas

Hemangioblastoma is a benign tumor originating mainly in the posterior fossa. It is a highly vascular benign neoplasm. The reported incidence is 1.7% of all primary intracranial neoplasms [21]. Hemangioblastoma is an indication for radiosurgery, because this tumor is usually small, rounded and well delineated, and von Hippel-Lindau patients often have multiple lesions [14]. To achieve better results with microsurgery, radiosurgery for hemangioblastoma should: (1) be safe, i.e. minimal radiation injury of eloquent areas; (2) shrink the tumor or at least stop its growth long-term, and (3) prevent expansion or formation of cysts [14].

We treated 8 hemangioblastoma patients between January 1994 and December 2003. These patients account for only 0.4% of the 1,836 patients with intracranial tumors treated during this period. There were 7 females and 1 male. Mean age was 49 years (range 29–71 years), and the total number of lesions was 13. Four patients had multiple lesions, 12 tumors were located in the cerebellum and 1 in the falx. Twelve lesions were solid and 1 was cystic. None of these patients received embolization or radiation therapy. Before radiosurgery, 6 patients underwent 1–5 surgical resections (average 2.3). In 2 patients, radiosurgery was performed for recurrence at a previous operative site. In 4 patients, radiosurgery was performed for new lesions developing after surgery. Two other patients underwent radiosurgery as primary treatment for tumors detected on magnetic resonance (MR) images. The tumor volumes ranged from 0.1 to 6.2 ml (mean 1.9 ml). The tumor margin dose was 14 to 20 Gy (mean 15.1 Gy) and the tumor was covered with a 50–80% isodose (mean 55.4% isodose). All patients were followed up for 12–84 months (mean 61 months). Eleven tumors decreased in size (85%) and 2 (15%) were unchanged at final follow-up. We achieved 100% tumor growth control. In 2 patients (15%), there was deterioration in neurological status as compared to the pre-radiosurgical level because of radiation injury or associated hydrocephalus. One patient suffered transient expansion of the tumor 6–30 months after radiosurgery (fig. 1). The other patient required a ventricle-peritoneal shunt 2 months after radiosurgery for management of brain edema, a consequence of radiation injury. In 1 patient, a transient asymptomatic cyst formed 24 months after radiosurgery but had disappeared at 48 months (fig. 2). In 2 patients, the new lesions were treated operatively after radiosurgery. All patients were stable at final follow-up. Previously reported mean marginal doses ranged from 10 to 25 Gy for hemangioblastoma radiosurgery [1, 8, 14, 16]. Niemelä et al. [14] reported a recommended dose of 10 to 15 Gy. Pan et al. [16] reported 15–20 Gy to be adequate to achieve tumor growth control. Jawahar et al. [8], however, reported smaller tumor volumes and higher radiosurgical doses (⬎18 Gy) to significantly improve outcomes. We used a mean of 15.1 Gy for the tumor margin and achieved a high rate of tumor growth control. Chang et al. [1] reported a 23% incidence of radiation necrosis with a mean marginal dose of 23.3 Gy. Pan et al. [16] reported an 8% incidence of transient radiation injury. Niemelä et al. [14] reported 1 patient with 2 lesions treated with 25 Gy at the tumor margin. Their patient developed radiation edema and required shunt placement and prolonged corticosteroid treatment. Two (25%) of our patients had radiation injuries. The tumor volumes in these patients were 4.1 and 6.2 ml and the respective tumor margin doses were 16 and 14 Gy. Pan et al. [16] noted lesion enlargement in 2 of their 3 cystic hemangioblastoma patients (67%). Niemelä et al. [14] reported that 3 of their 5 patients (60%) showed cyst enlargement after radiosurgery. Jawahar et al. [8], however, achieved cystic

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Fig. 1. T1-weighted axial MR images in a 56-year-old female with multiple hemangioblastomas but no neurological deficits. The patient underwent surgery five times for hemangioblastoma at the posterior fossa and spinal cord. Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 16 Gy (a). T1-weighted axial MR images obtained 6 months after gamma knife radiosurgery revealed enlargement of the tumor with radiation injury (b). MR imaging 3 years after radiosurgery revealed the tumor to be decreased in size (c).

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Fig. 2. T1-weighted axial MR images in a 51-year-old female with multiple hemangioblastomas but no neurological deficits. The patient underwent surgery twice for hemangioblastoma. Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 20 Gy (a). T1-weighted axial MR images obtained two years after gamma knife radiosurgery revealed cyst formation (b). MR imaging 6 years after radiosurgery revealed the tumor to be decreased in size (c).

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tumor control in 7 of 10 patients (70%). In our series, only 1 patient developed a cystic hemangioblastoma and this patient was treated radiosurgically since the lesion was located at the medulla. Only the solid portion of the cyst was irradiated. In this patient, the cyst had decreased in size 12 months after radiosurgery, but longer followup is required. Based on previous reports and our experience, small solid hemangioblastomas can be treated very effectively using 14–16 Gy as the tumor margin dose. Indications for radiosurgical treatment of cystic tumors must be considered carefully, particularly the tumor location. Deep-seated tumors can be surgically resected, but with high morbidity. If the cystic tumor is small, however, irradiating the solid portion of the tumor may be effective. We recommend that patients with hemangioblastomas be followed carefully and that small new lesions be treated radiosurgically.

Hemangiopericytoma

Hemangiopericytoma is a rare highly vascular neoplasm thought to be derived from pericytes, cells found anywhere that capillaries occur throughout the body [15]. These tumors account for 0.2% of primary intracranial tumors in Japan [21]. Hemangiopericytomas have a predilection for both local and distant central nervous system recurrences and exhibit a marked tendency to metastasize, as compared with malignant meningeal tumors, and intracranial lesions often recur and may then metastasize to other organs especially the lung [5]. Recently, radiosurgery has been used to treat residual and recurrent hemangiopericytomas. We treated 5 patients, 3 males and 2 females, with hemangiopericytomas radiosurgically. Mean age was 48 years (35–60 years). Four patients had one lesion and one had two. Two tumors were located in the cavernous sinus, one in the posterior fossa, one in the petrous bone, and one in the middle fossa. Before radiosurgery, operations and local radiation therapy were performed in 3 patients and an operation only in 1. In 1 patient, the initially diagnosed cavernous hemangioma at the middle fossa was treated radiosurgically. Four years after radiosurgery, the tumor showed regrowth, necessitating surgical resection. Histologically, the lesion was a hemangiopericytoma. One patient already had lung and bone metastases. The tumor volumes of the 5 patients ranged from 4.5 to 18.8 ml (mean 11.0 ml), the tumor margin dose from 12 to 16 Gy (mean 13.7 Gy). The five patients were followed for 10–48 months (mean 34 months) after radiosurgery. One tumor had decreased in size (16.7%), three were unchanged (50%), and two lesions had increased (33.3%) in size at final follow-up (fig. 3). The other patient with tumor growth underwent partial removal of the tumor mass and local radiation. The tumor had stabilized 3 years after external beam radiation. Two of our 5 patients died, one due to lung metastasis 10 months after radiosurgery and the other to

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Fig. 3. T1-weighted axial MR images from a 56-year-old male with hemangiopericytoma. The patient received seven surgeries and local radiation therapy for posterior fossa tumors. Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 12 Gy for the cavernous sinus tumor (a). T1-weighted axial MR images obtained 6 months after gamma knife radiosurgery revealed a marked reduction in tumor size (b). MR imaging 36 months after radiosurgery revealed the tumor to be increased in size with a new lesion at the cerebellum (c).

intracranial tumor regrowth 42 months after radiosurgery. Of the three surviving patients, one underwent surgery three times for new intracranial lesions and one was operated on due to tumor regrowth. Coffey et al. [2] first reported 5 patients undergoing radiosurgery for hemangiopericytomas, all of which showed dramatic tumor shrinkage 6–10 months after radiosurgery. Payne et al. [18] reported follow-up results a mean of 2.5 years after radiosurgery; 87% of tumors were controlled. Sheehan et al. [20] treated 14 patients with a mean radiation dose 15 Gy, achieving 79% tumor growth control with only 29% of their patients developing remote metastasis. Ecker et al. [4] reported a 5-year survival rate of 93%, and emphasized that radiosurgery is highly effective for treating recurrence. They used a mean radiation dose of 16 Gy and the mean follow-up was 3.5 years. The tumors disappeared in 5 (11%) and decreased in 10 (22%) of 45 cases. Forty-two (93%) of 45 tumors were controlled. We used relatively low doses (mean 13.6 Gy) as compared to previous reports (15–16 Gy for the tumor margin), but for better long-term tumor growth control, approximately 16 Gy would be the optimal dose for tumor margins. Hemangiopericytomas are still difficult to control tumors due to their aggressiveness and metastasis to other organs. However, radiosurgery is a useful alternative to repeat craniotomy for recurrence.

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Germ Cell Tumor

Germ cell tumors account for 2.4% of primary brain tumors and pineal parenchymal tumors for 0.3%. Among pineal tumors, 71% are germ cell tumors, 8.9% pineal parenchymal tumors and others, such as gliomas, epidermoid tumors and meningiomas [21]. Germ cell tumors are treated with surgery, radiation and chemotherapy [11]. The role of radiosurgery in germ cell and pineal parenchymal tumor treatment is considered to be limited to residual tumors and recurrence after other treatments. We describe our gamma knife radiosurgery results for germ cell and pineal parenchymal tumors. We treated 25 patients with germ cell and pineal parenchymal tumors from January 1994 to December 2003, using gamma knife radiosurgery. These patients account for 1.4% of the 1,836 patients with intracranial tumors treated during this period. The patient age range was 1.8–33 years (mean 17.4 years). Twenty patients were male and 5 female. The histology was germinoma in 16, malignant germ cell tumor in 7 and pineoblastoma in 2 patients. For germinomas, the mean patient age was 16.8 years (8–33 years). There were 12 males and 2 females. Before radiosurgery, chemotherapy using cisplatin or carboplatin and etoposide was administered to 13 patients while 2 received both chemotherapy and radiation therapy. Radiosurgery was performed for residual tumors after chemotherapy in 13 patients and recurrence after chemotherapy and radiation in 2. The tumor location was pineal in 9, suprasellar in 6, basal ganglia in 2, medulla in 1, corpus callosum in 1, and internal auditory canal in 1. For malignant germ cell tumors, the mean patient age was 20.3 years (11–33 years). There were 6 males and 2 females. The treatments before radiosurgery were chemotherapy in 3 patients, surgery and chemotherapy in 1, surgery, chemotherapy and radiation in 1 and only chemotherapy in 1. Radiosurgery was performed for residual tumors in 5 patients and recurrence in 3. The tumor location was suprasellar in 3 patients, lateral ventricle in 3, pineal in 2, basal ganglia in 2 and frontal lobe in 1. We also experienced 2 patients with pineoblastomas. Their ages were 1.8 and 17 years, 1 was male and the other female. In both patients, the tumor was disseminated. One patient underwent radiosurgery for a residual tumor after surgery and chemotherapy. For the other patient, radiosurgery was performed to eliminate residual tumor tissue after biopsy, chemotherapy and whole brain and whole spinal radiation therapy. General anesthesia was administered in children younger than 10 years of age. The germinoma tumor volume was 1.7–2.9 ml (mean 1.0 ml) and the tumor margin dose was relatively low at 8–16 Gy (mean 12.3 Gy). The malignant germ cell tumor volume was 2.3 ml (0.6–8.1 ml), the tumor margin dose 10–23 Gy (mean 17.6 Gy). The

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Fig. 4. T1-weighted axial MR images in a 24-year-old male with a germinoma causing diplopia. Images obtained at diagnosis revealed two tumors to be situated near the pineal gland and frontally (a, b). The patient received three courses of chemotherapy using carboplatin and etoposide. Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 10 Gy for the pineal lesion and 12 Gy for that in the left frontal lobe (c, d). T1weighted axial MR images obtained 22 months after gamma knife radiosurgery revealed disappearance of the tumor (e, f).

pineoblastoma tumor volume was 0.01–14.5 ml (mean 3.4 ml), and the tumor margin dose 10–20 Gy (mean 15.6 Gy). Suprasellar tumors were also treated with relatively low doses as compared with other lesions because the optic apparatus should not be irradiated with more than 10 Gy. The germinoma patients were followed for 3–84 months (mean 38.5 months) after radiosurgery. Eleven tumors (52%) disappeared, 8 decreased in size (38%) and 2 increased in size (10%) (fig. 4). Control of tumor growth was seen in 90% of patients during follow-up. In 2 patients with tumor regrowth, radiosurgery was performed for residual tumors after chemotherapy and the doses were 10 and 12 Gy at the tumor margin. Regrowth was detected 36 and 48 months after radiosurgery, necessitating

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whole brain and spinal cord radiation therapy. Clinical status was unchanged in 11 patients and deteriorated in 4. Of the 4 patients with clinical deterioration, 2 had tumor growth and 2 radiation injury. Of the latter 2, 1 experienced hearing loss due to radiation of the internal auditory canal and 1 with basal ganglia irradiation had a visual field defect 3 months after radiosurgery due to radiation injury of the optic tract. In 8 patients (62%), dissemination occurred despite control of local tumor growth. The administration of whole brain and spinal cord radiation therapy was curative. None of these patients experienced recurrence in the 6 months to 7 years (mean 4.7 years) of follow-up after radiation therapy and all have survived without impairment. Patients with malignant germ cell tumors were followed for 6 months to 10 years (mean 31.5 months). Tumors decreased in size in 5 (46%), disappeared in 3 (27%), were unchanged in 2 (18%) and increased in size in 1 (9%). Three patients died due to disease progression. One patient developed diplopia, due to radiation injury to the area surrounding a pineal lesion, 6–24 months after radiosurgery. This patient received radiation therapy after radiosurgery. The 2 patients with pineoblastomas were followed 6 and 7 months. All five lesions decreased in size. In 1 patient (1.8 years old), dissemination occurred after radiosurgery, necessitating chemotherapy and whole brain radiation therapy. This patient ultimately died due to dissemination. In the other patient, tumor growth was controlled 6 months after radiosurgery (fig. 5). Whole brain plus whole spinal cord radiation therapy has been the standard treatment for germinoma [17]. In Japan, recently, chemotherapy and local radiation therapy for germinomas have achieved high disease remission rates [11]. The goal is to reduce the radiation dose delivered to the nervous system by combining radiation with chemotherapy. Regine et al. [19] reported using only radiosurgery on a germinoma in 1 patient. Kobayashi et al. [9] reported the possibility of initially treating pineal tumors radiosurgically based on good responses in their 3 patients without a histological diagnosis. We used radiosurgery instead of local radiation therapy in order to decrease radiation effects on the central nervous system. We achieved a 46% disease-free survival rate with this treatment, but tumor control failed in 54% of our patients. These results show radiosurgery to be effective while reducing the risk of radiation side effects in approximately half of patients. However, boost radiosurgery delivered to a narrow field is not adequate to achieve tumor control. For malignant germ cell tumors, radiosurgery is useful for residual and recurrent tumors after chemotherapy and radiation therapy [6]. However, there is a tendency for dissemination to the neural axis and disease control is still difficult to achieve. Kochi et al. [10] achieved relatively good outcomes by combining chemotherapy, radiation therapy and surgery for malignant germ cell tumors. Radiosurgery is a potential adjuvant therapy for such malignant tumors. Radiosurgery appeared to be a reasonable option for delivering boost irradiation to control residual and recurrent germ cell tumors and pineoblastomas, but these

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Fig. 5. T1-weighted axial MR images from a 17-year-old female with pineoblastoma with hydrocephalus. Images obtained at diagnosis revealed pineal and infundibular tumors (a). The patient received chemotherapy and whole brain plus whole spinal cord radiation therapy. Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 14 Gy for the pineal lesion and 10 Gy for the infundibular lesion (b). T1-weighted axial MR images obtained 6 months after gamma knife radiosurgery revealed the tumors to be unchanged in size (c).

tumors still have a strong tendency to disseminate and survival is limited. We also anticipate a role for radiosurgery in the initial treatment of germinomas.

Primary Central Nervous System Lymphoma

PCNSL is a relatively uncommon malignant tumor accounting for 2.9% of all intracranial primary tumors [21]. Chemotherapy and radiation, after histological diagnosis, have become the standard treatment. With this initial treatment, responses are relatively poor. Mean survival is only 39.3 months even in the best report [7]. We treated and were able to follow 15 PCNSL patients from January 1994 to December 2003. The age range was 39–77 years (mean 63.3 years). There were 7 males and 8 females. Treatments before radiosurgery were operation, chemotherapy and radiation in 7 patients, operation and radiation in 1, only chemotherapy in 1, only operation in 1 because of age (77 years old), only steroid administration in 1, and only radiation in 1. Radiosurgery was used for the residual tumor after previous treatment in 9 patients (60%) and recurrence and regrowth in 6 (40%) (fig. 6). The interval between the initial diagnosis and radiosurgery was 1–84 months (mean 26 months). Eight patients (53%) had multiple lesions and 7 (47%) had single lesions. The total number of lesions was 48. Twenty-six tumors (54%) were lobar, 14 (29%)

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Fig. 6. T1-weighted axial MR images in a 66-year-old female with malignant lymphoma causing disorientation. The patient received three courses of chemotherapy (carboplatin and etoposide) before radiosurgery. Images obtained at diagnosis (a). Images were obtained at the time of gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 14 Gy in five lesions (b). T1weighted axial MR images obtained 20 months after gamma knife radiosurgery revealed disappearance of the tumor (c).

cerebellar, 7 (15%) basal ganglia and paraventricle and one (2%) brain stem. The radiation dose was selected based on the radiosensitivity of the malignant lymphoma and was reduced if there had been previous radiation therapy. Tumor volumes ranged from 0.13 to 42.3 ml (mean 4.3 ml). The tumor margin dose was 8–15 Gy (mean 13.9 Gy). These patients were followed for 1–96 months (mean 17.5 months) after radiosurgery. Follow-up radiological images were obtained for 40 lesions. Twenty-five tumors (63%) disappeared, 13 (32%) decreased in size and 2 (5%) increased in size. Control of tumor growth was achieved in 95%. One of the patients with tumor enlargement showed regrowth 96 months after radiosurgery and radiation necrosis was diagnosed by methionine-positron emission tomography examination [22]. In the other patient with lesion regrowth, chemotherapy using methotrexate was administered but there was no decrease in size and radiosurgery was performed again. Seven patients died during follow-up and the cause of death was intracranial recurrence in 3 (44%) (fig. 7), deterioration of general condition in 2 (28%), and deterioration of brain function in 2 (28%). The median survival time after radiosurgery was 36 months and the median survival time after diagnosis was 93 months (fig. 8). Recently, the combination of chemotherapy and radiation therapy has produced a mean survival of 39.3 months using high-dose methotrexate chemotherapy [7]. Reports of radiosurgery for PCNSL are rare [3, 12, 13]. Dong et al. [3] reported

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a Fig. 7. T1-weighted axial MR images in a 64-year-old female with malignant lymphoma causing disorientation and hemiparesis. The patient underwent surgery, radiation therapy and high-dose chemotherapy for recurrence. However, the tumor recurred. Images were obtained at the time of the first gamma knife treatment. Radiosurgery was performed with a tumor margin dose of 16 Gy (a). T1weighted axial MR image obtained at the second gamma knife radiosurgery revealed tumor recurrence extending from the right midbrain to the thalamus (b).

Diagnosis till death Radiosurgery till death

Survival (%)

100 80 60 40 20 0 Fig. 8. Survival of patients with PCNSL after diagnosis and radiosurgery.

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excellent PCNSL results for radiosurgery. They used radiosurgery as the initial treatment for 44 patients. The mean dose at the tumor margin was 17.97 Gy. Thirty-eight patients (86.4%) experienced complete remission, the other 6 (13.4%) a partial response. Furthermore, control of tumor growth was achieved in 100%. However, 28

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patients (63.6%) experienced intracranial recurrence and median survival was 26.5 months. We used radiosurgery for recurrence, after chemotherapy and radiation therapy in most patients. The rate of tumor growth control was high even with relatively lowdose treatment (mean tumor margin dose of 13.9 Gy). In our patients, median survival after radiosurgery was 36 months and median survival after diagnosis was 93 months. This represents very long-term survival as compared to other reports [7], suggesting that our radiosurgically treated patients with PCNSL may be able to expect long-term survival. Among patients with a poor prognosis, recurrence may be diffuse intracranially such that radiosurgery is not indicated. Radiosurgery is an effective tool for the control of PCNSL, even with relatively low tumor margin doses. The prognosis is poor, however, if multiple new lesions and CSF dissemination develop after radiosurgery. Radiosurgery is a potentially useful salvage treatment for PCNSL patients.

Conclusion

Radiosurgery is useful for primary intracranial tumors such as hemangioblastomas and as adjuvant therapy for residual and recurrent tumors especially those associated with germ cell tumors and PCNSL.

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Chang SD, Meisel JA, Hancock SL, et al: Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery. Neurosurgery 1998;43:28–34. Coffey RJ, Cascino TL, Shaw EG: Radiosurgical treatment of recurrent hemangiopericytomas of the meninges: preliminary results. J Neurosurg 1993;78: 903–908. Dong Y, Pan L, Wang B, et al: Stereotactic radiosurgery in the treatment of primary central nervous system lymphoma. Chin Med J (Eng) 2003;116: 1166–1170. Ecker RD, Marsh WR, Pollock BE, et al: Hemangiopericytoma in the central nervous system: treatment, pathological features, and long-term follow up in 38 patients. J Neurosurg 2003;98:1182–1187. Galanis E, Buckner JC, Scheithauer BW, et al: Management of recurrent meningeal hemangiopericytomas. Cancer 1998;82:1915–1920. Hasegawa T, Kondziolka D, Hadjipanayis CG, et al: The role of radiosurgery for the treatment of pineal parenchymal tumors. Neurosurgery 2002;51:880–889.

7 Hiraga S, Arita N, Ohnishi T, et al: Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg 1999;91:221–230. 8 Jawahar A, Kondziolka D, Garces YI, et al: Stereotactic radiosurgery for hemangioblastomas of the brain. Acta Neurochir 2000;142:641–644. 9 Kobayashi T, Kida Y, Mori Y: Stereotactic gamma knife radiosurgery for pineal and related tumors. J Neurooncol 2001;54:301–309. 10 Kochi M, Itoyama Y, Shiraishi S, et al: Successful treatment of intracranial nongerminomatous malignant germ cell tumors by administering neoadjuvant chemotherapy and radiation therapy before excision of residual tumors. J Neurosurg 2003;99: 106–114. 11 Matsutani M, Sano K, Takakura K, et al: Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Child’s Nerv Syst 1998;14:59–62.

Iwai ⭈ Yamanaka

12 Nakatomi H, Sasaki T, Kawamoto S, et al: Primary cavernous sinus malignant lymphoma treated by gamma knife radiosurgery: case report and review of the literature. Surg Neurol 1996;46:272–278. 13 Nicolato A, Gerosa MA, Foroni R, et al: Gamma knife radiosurgery in AIDS-related primary central nervous system lymphoma. Stereotact Func Neurosurg 1995;64(suppl 1):42–45. 14 Niemelä M, Lim YJ, Söderman M, et al: Gamma knife radiosurgery in 11 hemangioblastomas. J Neurosurg 1996;85:591–596. 15 Nunnery EW, Kahn LB, Reddick RL, et al: Hemangiopericytoma: a light microscopic and ultrastructural study. Cancer 1981;47:906–914. 16 Pan L, Wang EM, Wang BJ, et al: Gamma knife radiosurgery for hemangioblastomas. Stereotact Funct Neurosurg 1998;70(suppl 1):179–186. 17 Paulino AC, Wen BC, Mohideen MN: Controversies in the management of intracranial germinomas. Oncology 1999;13:513–521.

18 Payne BR, Prasad D, Steiner M, et al: Gamma surgery for hemangiopericytomas. Acta Neurochir 2000; 142:527–536. 19 Regine WF, Hodes JE, Patchel RA: Intracranial germinoma: treatment with radiosurgery alone: case report. J Neurooncol 1998;37:75–77. 20 Sheehan J, Kondziolka D, Flickinger J, et al: Radiosurgery for treatment of recurrent intracranial hemangiopericytoma. Neurosurgery 2002;51:905–910. 21 The Brain Tumor Registration Committee of Japan: Report of brain tumor registry of Japan (1969–1996). Neurol Med Chir 2003;43:5. 22 Tsuyuguchi N, Sunada I, Iwai Y, et al: Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible? J Neurosurg 2003;98:1056–1064.

Yoshiyasu Iwai, MD Department of Neurosurgery, Osaka City General Hospital 2–13–22, Miyakojima-hondohri, Miyakojima-ku Osaka, 534-0021 (Japan) Tel. ⫹81 6 6929 1221, Fax ⫹81 6 6929 1091, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 142–153

Metastatic Brain Tumors: Lung Cancer Toru Serizawa Gamma Knife House, Chiba Cardiovascular Center, Ichihara, and Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan

Abstract Objective: To present the results of gamma knife surgery (GKS) for brain metastases from lung cancer, without whole-brain radiation therapy (WBRT), at Chiba Cardiovascular Center. Methods: Four hundred and forty-three consecutive patients satisfying the following 5 criteria were analyzed: (1) no prior WBRT; (2) ⱕ25 lesions; (3) ⱕ4 tumors with a diameter of 20 mm or more; (4) no surgically inaccessible large (ⱖ35 mm) tumors, and (5) life expectancy exceeding 3 months. Large tumors were totally removed and all smaller lesions were treated with GKS. New lesions detected with follow-up magnetic resonance imaging were appropriately re-treated with GKS. Overall survival (OS), neurological survival (NS), qualitative survival (QS) and new lesion-free survival (NLFS) curves were calculated and the prognostic values of covariates were obtained. Results: In total, 805 separate sessions were required to treat 4,626 lesions. The lung cancer histologies were adenocarcinoma in 294 patients, squamous cell in 52, small cell in 56, large cell in 9, and others/undetermined in 32. The median OS period was 8.9 months. On multivariate analysis, significant prognostic factors for OS were extracranial disease (risk factor: active), KPS score (⬍70) and gender (male). NS and QS at 1 year were 86.9 and 80.1%, respectively. The only significant poor prognostic factor for NS was carcinomatous meningitis. A low Karnofsky performance status (KPS) score, numerous (⬎10) brain lesions and carcinomatous meningitis were significant factors influencing QS. NLFS at 6 months was 70.0%. Conclusion: In terms of NS and QS, GKS alone for metastatic brain tumors from lung cancer provides Copyright © 2009 S. Karger AG, Basel excellent palliation for selected patients without carcinomatous meningitis.

The efficacy of radiosurgery for cases with a few small metastatic brain tumors is now well established, but the necessity of upfront whole-brain radiation therapy (WBRT) with radiosurgery, and limitations of the indications for gamma knife surgery (GKS) remain controversial [2–3, 5–7]. This is a retrospective review of GKS, without upfront WBRT, for brain metastases from lung cancer. All patients were treated with the same protocol, by the author, at one institution.

Patients and Methods Among 487 cases with brain metastases from lung cancer treated with GKS at Chiba Cardiovascular Center from January 1998 through December 2003, 443 consecutive patients who satisfied the

80 70

Fig. 1. Lesion number and size limits for GKS. The limits of brain lesion number and size for GKS, in a single session at Chiba Cardiovascular Center are demonstrated. The curve indicates a total skull internal dose of 10,000 mJ calculated using the GammaPlan, with 20 Gy (50%) peripheral doses.

Number

60 50 40 30 20 10 0

0

5

10

15 20 25 Tumor size (mm)

30

35

following 5 criteria were analyzed: (1) no prior WBRT; (2) ⱕ25 lesions; (3) ⱕ4 tumors with a diameter of 20 mm or more; (4) no surgically inaccessible large (ⱖ35 mm) tumors, and (5) life expectancy exceeding 3 months. All metastatic lesions were diagnosed on gadolinium-enhanced magnetic resonance imaging (MRI) (1.5 Tesla, Magnetom Vision, Siemens) with a 5-mm slice thickness and no gaps. At diagnosis of brain metastases, the primary physician evaluated systemic disease status using X-ray films, computerized tomographic (CT) scanning and radionuclide scanning. The protocol was the same for large tumors (ⱖ35 mm), all of which were surgically removed, while smaller lesions (⬍35 mm) were treated with GKS. Additional GKS to the tumor bed was performed with 18–20 Gy when the neurosurgeon considered the lesion to have been incompletely resected. New distant lesions detected by gadolinium-enhanced MRI were appropriately re-treated with GKS, if the patient’s condition allowed. The total skull internal dose (TSID) calculated with the Leksell GammaPlanTM (Elekta Instruments, Atlanta, Ga., USA) for each radiosurgical procedure was less than 10,000 mJ, thus preventing acute brain swelling, as previously reported [3, 5]. This 10,000-mJ TSID is equivalent to 3 Gy of whole brain irradiation. According to this TSID criterion, if the lesions were scattered and similar in size, the upper numerical limit was approximately 25 for tiny (8 mm), 10 for small (14 mm) and 4 for medium-sized lesions (25 mm), with 20 Gy at the periphery (fig. 1). If the calculated TSID was over 10,000 mJ, the radiosurgical procedure was divided into two sessions with an interval of at least 1 day. Chemotherapy protocols were determined by primary physicians. Neurological and neuroradiological evaluations were performed every 1–3 months after initial GKS. Control of the GKS-treated lesion was defined as the absence of any significant increase in tumor diameter (⬍10%), as confirmed by axial or coronal MRI. Thallium-201 chloride (Tl) SPECT, as previously reported [4], was employed to differentiate tumor recurrence from radiation injury. With these measurement methods, a high (⬎5.0) Tl index indicates tumor recurrence, a low (⬍3.0) index radiation injury. In lesions with an intermediate (ⱖ3.0, ⱕ5.0) index, Tl SPECT studies were repeated until the index exceeded 5.0 or was less than 3.0. Neurological death was defined as death due to all forms of intracranial disease, including tumor recurrence, carcinomatous meningitis, cerebral dissemination, and other unrelated intracranial diseases. Impaired activity of daily life (ADL) was defined as an impaired neurological status as reflected by a Karnofsky performance status (KPS) score ⬍70 (functionally dependent). A distant new lesion was defined as the appearance of a new brain metastasis at a site different from the original one.

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The intervals from the date of initial referral to our center until the date of death (overall survival, OS), neurological death (neurological survival, NS), impaired ADL (qualitative survival, QS), and the appearance of new distant lesions (new lesion-free survival, NLFS) were calculated by the Kaplan-Meier method. Tumor progression-free survival for all lesions treated with GKS during the observation period was also analyzed. Prognostic values of the individual covariates for OS, NS, QS and NLFS were obtained with the Cox proportional hazards model. The following 13 dichotomized covariates were entered: age (ⱖ65 vs. ⬍65 years); gender (male vs. female); pretreatment KPS score (ⱖ70 vs. ⬍70); extracranial lesion status (controlled vs. active); simultaneous (synchronous) versus later (metachronous) detection of metastasis, lung cancer histology (non-small cell vs. small cell cancer); number of brain lesions (⬎10 vs. ⱕ10); maximum lesion diameter (ⱖ25 vs. ⬍25 mm); initial tumor volume (⬎10 vs. ⱕ10 cm3); presence of carcinomatous meningitis at initial enhanced MRI (yes vs. no); presence of posterior fossa lesion (yes vs. no); chemotherapy (yes vs. no) and craniotomy (yes vs. no). Covariates that emerged as significant on univariate analyses were included in the multivariate model, verified by stepwise methods in the final model. All computations were performed using StatView 5.0 (SAS Institute Inc., Cary, N.C., USA). p ⬍ 0.05 was considered statistically significant.

Results

The distributions of patient and treatment factors are summarized in table 1. In total, 805 separate GKS procedures were required to treat 4,626 lesions. The median number of lesions treated with the initial GKS was 4, range 1–25. During follow-up, the number of GKS procedures averaged 1.9 ⫾ 1.5, varying between 1 and 13 (fig. 2), and the mean number of lesions treated with GKS per patient was 10.4 ⫾ 14.0, range 1–69. The mean calculated tumor volume was 0.72 ⫾ 2.10 cm3. The minimum dose applied to the tumor margin was 15–33.3 Gy (mean ⫾ SD: 20.8 ⫾ 2.1 Gy, median: 20 Gy) with a 74.3% isodose contour (range 23–99%). In 13 cases (2.9%), GKS was intentionally fractionated into two sessions with a 1-day to 3-week interval, because the calculated TSID exceeded 10,000 mJ at one session. In 30 of 66 (45.5%) large resected tumors, the tumor bed was additionally irradiated with 18–20 Gy using GKS. The lung cancer histologies were adenocarcinoma in 294 (66.4%), squamous cell carcinoma in 52 (11.7%), small cell carcinoma in 56 (12.6%), large cell carcinoma in 9 (2.0%), and others/undetermined in 32 patients (7.2%). The tumor progression-free survival rates were 97.2% at 1 year and 94.8% at 2 years. Figure 3 shows cumulative tumor progression-free survival curves according to tumor volume. Differences were statistically significant (p ⬍ 0.0001). Among 74 tumors recurring after GKS, re-GKS was performed for 45 and surgery for 8. The median OS period was 8.9 months (fig. 4). In multivariate analysis, significant prognostic factors for OS were active extracranial disease (p ⬍ 0.0001), low pretreatment KPS score (p ⬍ 0.0001) and male gender (p ⬍ 0.0001), as shown in table 2. NS and QS at 1 year were 86.9% and 80.1%, respectively (fig. 5, 6). Of the 306 mortalities, 56 (12.6%) were attributed to neurological death. Causes of neurological death were carcinomatous meningitis in 25, cerebral dissemination in 15, recurrence of the treated lesion in 8, progression of an untreated

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Table 1. Distribution of patient characteristics Characteristics

Metastatic Lung Cancer

Age ⬍65 years ⱖ65 years

208 235

Sex Male Female

331 112

Extracranial disease Controlled Active

56 387

Pretreatment KPS score ⬍70 ⱖ70

62 381

Histology Non-SCLC SCLC

387 56

Number of brain lesions ⱕ10 ⬎10

365 (single 94) 78

Maximum lesion size ⬍25 mm ⱖ25 mm

109 334

Total tumor volume ⱕ10 cm3 ⬎10 cm3

365 78

Carcinomatous meningitis Yes No

40 403

Posterior fossa lesion Yes No

194 249

Chemotherapy Yes No

156 287

Craniotomy Yes No

66 377

Metastasis Synchronous Metachronous

268 175

145

2 (44 cases, 9.9%)

Fig. 2. Number of salvage treatments. The number of salvage treatments with GKS was zero in 267 cases (60.3%), one in 89 (20.0%), two in 44 (9.9%), three in 17 (3.8%), four in 13 (2.9%), ⱖ5 in 13 (2.9%).

4

1 (89 cases, 20.0%)

Tumor progression-free rate

Fig. 3. Tumor progression-free survival. Cumulative tumor progression-free survival curves, according to tumor volume, are shown. The definitions of tiny, small, medium and large lesions are ⱕ1.0 cm3, ⬎1.0 but ⱕ4.0 cm3, ⬎4.0 but ⱕ10.0 cm3, and ⬎10.0 cm3, respectively. The mean prescribed doses were 21.0 Gy in 3,942 tiny, 20.4 Gy in 454 small, 19.3 Gy in 176 medium-sized, and 17.6 Gy in 52 large lesions. There were statistically significant differences among survival curves (p ⬍ 0.0001).

3

ⱖ5

No salvage treatment (267 cases, 60.3%)

Tiny (ⱕ1 cm3)

1.0

Small (1⬍, ⱕ4 cm3)

0.8

Medium (4⬍, ⱕ10 cm3)

0.6 0.4

Large (⬎10 cm3)

0.2 0 0

1

2

3 Years

4

5

6

0

1

2

3 Years

4

5

6

Overall survival rate

1.0 0.8 0.6 0.4 0.2 0 Fig. 4. The overall survival curve is presented. The median overall survival was 8.9 months.

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Neurological survival rate

Fig. 5. The neurological survival curve is shown. The neurological death-free rate following GKS was 86.9% at one year.

1.0 0.8 0.6 0.4 0.2 0 0

1

2

3 Years

4

5

6

Table 2. Prognostic variables for overall survival Variables

High-risk group

p value*

HR*

Age Sex Systemic disease Initial KPS score Histology Number of lesions Maximum lesion size Total tumor volume Presence of CM Posterior fossa lesion Chemotherapy Microsurgery Metastasis

⬍65 male active ⬍70 non-SCLC ⬎10 ⱖ25 mm ⬎10 cm3 yes yes no no metachronous

0.9183 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.7402 0.0953 0.4299 0.0601 0.0365 0.0365 0.1734 0.5402 0.8913

1.012 1.890 3.268 2.278 1.061 1.277 1.107 1.292 1.347 1.272 1.181 1.098 1.016

p value**

HR**

⬍0.0001 ⬍0.0001 ⬍0.0001

1.812 3.333 2.734

*Univariate analysis; **multivariate analysis (Cox’s proportional hazards model). HR ⫽ Hazard ratio; CM ⫽ carcinomatous meningitis.

lesion in 6 and other in 2. Among 84 cases with functional dependence due to brain lesions, the causes were carcinomatous meningitis in 25, radiation injury in 20, cerebral dissemination in 15, recurrence of the treated lesion in 8, progression of an untreated lesion in 6, and other in 2. The only significant poor prognostic factor for NS was carcinomatous meningitis (p ⬍ 0.0001), as shown in table 3. Figure 7 compares the NS curves of cases with and without carcinomatous meningitis.

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Qualitative survival rate

1.0 0.8 0.6 0.4 0.2 0

Fig. 6. The qualitative survival curve is presented. The functional dependent-free rate was 80.1% at 1 year.

0

1

2

3

4

5

Years

Table 3. Prognostic variables for neurological survival Variable

High-risk group

p value*

HR*

Age Sex Systemic disease Initial KPS score Histology Number of lesions Maximum lesion size Total tumor volume Presence of CM Posterior fossa lesion Chemotherapy Microsurgery Metastasis

⬍65 male active ⬍70 SCLC ⬎10 ⱖ25 mm ⬎10 cm3 yes yes no yes metachronous

0.8727 0.0693 0.0125 0.0932 0.4572 0.0198 0.3693 0.0548 ⬍0.0001 0.0024 0.5089 0.2398 0.9182

1.044 1.726 2.786 1.910 1.297 2.079 1.300 1.770 5.484 2.311 1.170 1.446 1.030

p value**

HR**

⬍0.0001

5.484

*Univariate analysis; **multivariate analysis (Cox’s proportional hazards model). HR ⫽ Hazard ratio; CM ⫽ carcinomatous meningitis.

Neurological survival in patients without carcinomatous meningitis at initial MRI was 90.5% at 1 year. Poor pretreatment KPS (p ⫽ 0.0005), numerous (⬎10) brain lesions (p ⫽ 0.0207) and carcinomatous meningitis (p ⬍ 0.0001) were confirmed to be significant factors influencing QS in multivariate analysis (table 4). NLFS at 6 months was 70.0% (fig. 8). According to multivariate analysis, new lesions were more frequent in patients who were less than 65 years old (p ⫽ 0.0165) and had active extracranial disease (p ⫽ 0.0017), as shown in table 5.

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Neurological survival rate

Fig. 7. The neurological survival curves of cases with and without carcinomatous meningitis are presented for comparison. Neurological survival in patients without carcinomatous meningitis at initial MRI was 90.5% at 1 year.

1.0 0.8 Carcinomatous meningitis⫺

0.6 0.4

Carcinomatous meningitis⫹

0.2 0 0

1

2

3 Years

4

5

6

Table 4. Prognostic variables for qualitative survival Variable

High-risk group

p value*

HR*

Age Sex Systemic disease Initial KPS score Histology Number of lesions Maximum lesion size Total tumor volume Presence of CM Posterior fossa lesion Chemotherapy Microsurgery Metastasis

ⱖ65 male active ⬍70 SCLC ⬎10 ⱖ25 mm ⬎10 cm3 yes yes yes yes metachronous

0.5399 0.0272 0.0002 0.0024 0.3384 0.0013 0.1887 0.0224 ⬍0.0001 0.0092 0.8141 0.7446 0.9538

1.145 1.701 2.639 2.420 1.294 2.299 1.366 1.745 4.449 1.779 1.055 1.092 1.014

p value**

HR**

0.0005

2.786

0.0207

1.862

⬍0.0001

4.267

*Univariate analysis; **multivariate analysis (Cox’s proportional hazards model). HR ⫽ Hazard ratio; CM ⫽ carcinomatous meningitis.

Discussion

In Japan, lung cancer has long been the most common primary site of metastatic brain tumors and in the author’s center 69.3% of metastatic disease is of lung cancer origin. Excellent results have been reported using radiosurgery for a few small metastatic brain tumors arising from various systemic cancers [2, 6, 7]. However,

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149

1.0

NLFS rate

0.8 0.6 0.4 0.2 0 0

Fig. 8. The NLFS curve is shown. The NLFS rate was 70.0% at 6 months.

1

2

3 Years

4

5

6

Table 5. Prognostic variables for NLFS Variable

High-risk group

p value*

HR*

p value**

HR**

Age Sex Systemic disease Initial KPS score Histology Number of lesions Maximum lesion size Total tumor volume Presence of CM Posterior fossa lesion Chemotherapy Microsurgery Metastasis

⬍65 male active ⱖ70 SCLC ⬎10 ⬍25 mm ⬎10 cm3 no yes yes no synchronous

0.0116 0.0594 0.0013 0.5086 0.0529 0.0824 0.7688 0.2961 0.2559 0.0408 0.3575 0.1071 0.3132

1.449 1.347 1.976 1.185 1.473 1.397 1.050 1.203 1.447 1.352 1.148 1.399 1.163

0.0165

1.423

0.0017

1.946

*Univariate analysis; **multivariate analysis (Cox’s proportional hazards model). HR ⫽ Hazard ratio; CM ⫽ carcinomatous meningitis.

most reports evaluated only OS, which depends mainly on extracranial disease status and pretreatment KPS score [2, 6, 7]. NS and QS should be considered in discussing the results of treating brain metastases. In this retrospective study, a very large series of results for GKS without upfront WBRT for brain metastases from lung cancer was carefully reviewed. The same treatment protocol at a single institute, with special attention to NS and QS, was used for all patients.

150

Serizawa

Indications for GKS Alone for Metastatic Brain Tumors Factors limiting GKS in a single session include not only the number, but also the size of lesions. However, most earlier reviews focused solely on number. Both the number and the size of lesions affect the TSID, which provides information on the limitations of GKS in a single session [3, 5]. A TSID of 10,000 mJ is equivalent to 3 Gy of whole brain irradiation. This is the WBRT one-fraction dose used for metastatic brain tumors (30 Gy/10 fractions). With this energy limit, 25 tiny (8 mm), 10 small (14 mm) or 4 medium-sized (25 mm) lesions would be the numerical limits of a single GKS session, if the peripheral dose is 20 Gy, with the GammaPlan. Adverse early radiation effects such as acute brain swelling were not observed in the present series with TSID below 10,000 mJ. Yang et al. [8] and Yamamoto et al. [9], using higher radiation doses than allowed by the criteria employed herein, reported the safety of GKS for numerous brain metastases. In our protocol, however, the radiosurgical procedure was divided into two sessions with an interval of no less than 1 day, if TSID exceeded 10,000 mJ. Furthermore, the present study found patients with carcinomatous meningitis to have significantly poorer NS and QS results. The present criteria indicating GKS alone to be suitable for treating metastatic brain tumors from lung cancer are: (1) no surgically inaccessible large (⬎35 mm) tumors, (2) no findings of carcinomatous meningitis on initial MRI, (3) limited number of tumors and TSID irradiation dose within 10,000 mJ, and (4) life expectancy exceeding 3 months. Small Cell Lung Cancer WBRT has long been the gold standard for metastatic brain tumors from small cell lung cancer (SCLC) because the characteristically rapid spread results in numerous microscopic brain metastases [1]. Few reports to date have focused on radiosurgery for metastatic brain tumors from SCLC [5]. In this study, the only significant poor prognostic factor for SCLC versus non-SCLC was NLFS. More careful follow-up MRI and intensive salvage GKS for new lesions may be more crucial for SCLC patients than is currently appreciated. However, GKS appears to be as effective for metastatic brain tumors from SCLC as it is for those from non-SCLC, as already reported [5]. New Distant Lesions and Salvage Treatment Since the advent of CT scanning, it has come to be widely believed that even patients with only a single metastatic lesion have microscopic metastases [1, 2]. Modern highresolution MRI can detect tumors only a few millimeters in diameter. The survival period may be too short for invisible metastases or true new lesions to be identified on follow-up MRI or to cause neurological symptoms. Chemotherapy may, of course, play an additional role in controlling microscopic lesions, especially in SCLC. The author’s experience suggests that local control is the most important clinical goal for patients with brain metastases and that it is not necessary to treat invisible metastases. Indeed, over 60% of patients in this series did not require salvage treatment. If new lesions are detected, appropriate salvage treatment, taking patient condition into

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consideration, may be warranted. WBRT should be used only with great caution because of its invasive nature. The current study demonstrates that a local GKS treatment protocol without upfront WBRT can provide highly satisfactory results in selected patients with close observation and appropriate salvage treatment. Differentiating Tumor Recurrence from Radiation Injury We routinely use Tl SPECT to differentiate tumor recurrence from radiation injury [4]. When the Tl index was ⬎5 the lesion was diagnosed as tumor recurrence, ⬍3 as radiation injury. In cases with a Tl index between 3 and 5, Tl SPECT studies were repeated monthly until the Tl index was ⬎5 or ⬍3. If the Tl SPECT suggested tumor recurrence, the options were surgery, re-GKS and observation, according to the size and location of the recurrent lesion and patient condition. Hypofractionated (usually 3 sessions) stereotactic radiotherapy with GKS, at an interval of 2–3 weeks, has been introduced in the author’s institution for large (⬎10 cm3) recurrent tumors.

Conclusions

In terms of NS and QS, GKS without upfront WBRT for brain metastases from lung cancer provides excellent palliation considering the patients’ short life expectancies. GKS alone is an alternative to WBRT for patients meeting the following four criteria: (1) no surgically inaccessible large (⬎35 mm) tumors, (2) no findings of carcinomatous meningitis on initial MRI, (3) limited number of tumors and TSID within 10,000 mJ, and (4) life expectancy exceeding 3 months. However, careful follow-up MRI and appropriate salvage treatment are essential to preventing neurological death and maintaining favorable ADL.

References 1

2

3

152

Arriagada R, Le Chevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Nat Cancer Inst 1995;87:183–190. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45:427–737. Serizawa T, Iuchi T, Ono J, et al: Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy. J Neurosurg 2000;93(suppl 3):32–36.

4

5

6

Serizawa T, Ono J, Odaki M, et al: Differentiation between tumor recurrence and radiation injury after gamma knife radiosurgery for metastatic brain tumors: value of serial thallium-201 chloride SPECT (Japanese with English abstract). Jpn J Neurosurg (Tokyo) 2001;10:726–732. Serizawa T, Ono J, Iuchi T, et al: Gamma knife radiosurgery for metastatic brain tumors from lung cancer: comparison between small cell cancer and non-small cell cancer. J Neurosurg 2002;97(suppl 5): 484–488. Sneed PK, Lamborn KR, Forstner JM, et al: Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 1999; 43:549–558.

Serizawa

7

8

Sneed PK, Suh JH, Goetsch SJ, et al: A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 2002;53:519–526. Yang CC, Ting J, Wu X, et al: Dose volume histogram analysis of the gamma knife radiosurgery treating twenty-five metastatic intracranial tumors. Stereotact Funct Neurosurg 1998;70:41–49.

9

Yamamoto M, Ide M, Nishio S, et al: Gamma knife radiosurgery for numerous brain metastases: is this a safe treatment? Int J Radiat Oncol Biol Phys 2002;53:1279–1283.

Toru Serizawa, MD, PhD Tokyo Gamma Unit Center, Tsukiji Neurological Clinic 1-9-9 Tsukiji, Chuoku Tokyo, 104-0045 (Japan) Tel. ⫹81 3 6226 3546, Fax ⫹81 3 6226 3637, E-Mail [email protected]

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Yamamoto M (ed): Japanese Experience with Gamma Knife Radiosurgery. Prog Neurol Surg. Basel, Karger, 2009, vol 22, pp 154–169

Gamma Knife Radiosurgery for Brain Metastases of Non-Lung Cancer Origin: Focusing on Multiple Brain Lesions Masaaki Yamamoto ⭈ Bierta E. Barfod ⭈ Yoichi Urakawa Katsuta Hospital Mito GammaHouse, Hitachi-naka, Japan

Abstract We describe postradiosurgical treatment outcomes of our consecutive series of 456 patients (220 females, 236 males, mean age; 60.5 years, range 19–86 years) who underwent gamma knife (GK) treatment for brain metastases originating from non-lung cancers, focusing particularly on GK treatment for multiple lesions. The most common primary cancers were breast (122; 26.8%), followed by lower alimentary tract (105; 23.0%), uro-genital (100; 21.9%), upper alimentary tract (56; 12.3%), others (41; 9.0%) and unknown (32; 7.0%). Mean and median tumor numbers were 6 and 2, respectively, range 1–55. The mean and median survival times were 12.7 and 7.0 months after GK radiosurgery. Postradiosurgical survival rates were 52.7% at 6, 29.0% at 12, 19.1% at 18, 13.5% at 24, 6.5% at 36 and 5.0% at 60 months. Number of lesions, maximum and cumulative tumor volumes, non-symptomatic, well-controlled primary tumors, no non-brain metastatic lesions, Karnofsky performance status better than 80%, having prior surgery and having at least two procedures were significant predictive factors for survival. Although tumor number was demonstrated to have a significant impact on the duration of survival, approximately 85% of patients with brain metastases died of Copyright © 2009 S. Karger AG, Basel causes other than brain disease progression, regardless of tumor number.

Stereotactic radiosurgery is being used as primary management or booster treatment with whole brain radiation therapy (WBRT) in an increasing number of patients with metastatic cancers, be they radiosensitive or radioresistant, single or multiple [1–22]. Recent studies have shown that stereotactic radiosurgery, whether combined with WBRT or not, is an effective management strategy for single cerebral metastases (METs), comparable to combination treatment involving surgery and WBRT [4, 11, 20, 23–25]. Furthermore, Moriarty et al. [16] and Young et al. [22] reported that, based on their treatment results for 353 (643 lesions) and 109 (288) patients, respectively, radiosurgical treatment of multiple brain METs produced rates of tumor control, as well as survival rates, similar to those obtained with this treatment for single METs. Nevertheless, in their reports as well as several recently described series of brain

Table 1. Patient characteristics Gender, female/male

236/220 patients

Mean age, years

60.4 (range 19.0–86.0) Minimum

Lesions Number/patient Minimum volume (cm3)/patient Mean volume (cm3)/patient Maximum volume (cm3)/patient Cumulative volume (cm3)/patient

1 0.002 0.021 0.023 0.041

Average/median

Maximum

6/2 3.6/0.23 5.2/2.3 8.7/5.7 12.1/7.3

55 55.6 61.0 89.3 122.0

Number of patients Primary tumors Breast Lower alimentary tract Urogenital Upper alimentary tract Others Unknown

122 (26.8%) 105 (23.0%) 100 (21.9%) 56 (12.3%) 41 (9.0%) 32 (7.0%)

METs treated radiosurgically, multiple lesions have numbered two to four in most cases [1, 2, 4, 5, 12, 13, 15, 16, 18, 19, 21, 22, 26]. Recently, Suzuki et al. [27] reported their preliminary GK radiosurgery experience for numerous brain METs. However, their cohort was too small to allow any conclusions to be drawn. Therefore, very little information is available on stereotactic radiosurgery for patients with multiple metastatic lesions. In this chapter, we describe postradiosurgical treatment outcomes of our consecutive series of 456 patients who underwent GK treatment for brain METs originating from non-lung cancers, focusing particularly on GK treatment for multiple lesions.

Patients and Methods Patient Population

Among our consecutive series of 1,209 patients who underwent GK radiosurgery for brain METs during the 13-year period from December of 1991 to December of 2004, 456 with tumors of nonlung origin were selected for this study. Table 1 summarizes the clinical characteristics. There were 220 females and 236 males. The mean age at the time of radiosurgery was 60.4 years, range 19.0–86.0. Mean and median lesion numbers were 6 and 2, respectively, range 1–55. Cumulative tumor volumes ranged from 0.041 to 122.0 cm3, the median being 7.3 cm3, and mean tumor volumes from 0.021 to 61.0 cm3, median 2.3 cm3. The most common primary cancers were breast

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Table 2. Patient characteristics, continued Patients, n (%) Primary tumor status Well controlled Not controlled

204 (44.7) 252 (55.3)

Non-brain METs Active Inactive

308 (67.5) 148 (32.5)

Karnofsky performance status 80% or better 70% or worse

321 (70.4) 135 (29.6)

Symptomatic Yes No

335 (74.5) 121 (26.5)

Previous treatment Surgery Surgery and radiotherapy Radiotherapy Radiosurgery

105 (23.0) 15 (3.3) 29 (6.4) 8 (1.8)

(122; 26.8%, including 3 male patients), followed by lower alimentary tract (105; 23.0%), urogenital (100; 21.9%), upper alimentary tract (56; 12.3%), others (41; 9.0%) and unknown (32; 7.0%). As shown in table 2, the condition of the primary cancer was reported by the primary corresponding physician to be well controlled in 204 patients (44.7%) and not well controlled (including ‘unknown’) in the other 252 (55.3%). At the time of radiosurgery, 308 patients (67.5%) had nonbrain METs. Karnofsky performance status (KPS) at the time of treatment was 80% or better in 321 patients (70.4%) and 70% or worse in the remaining 135 (29.6%). In 321 patients (74.5%), a neuroimaging examination was performed after lesions manifested with various symptoms, while brain METs were demonstrated by routine magnetic resonance (MR) imaging before the patient became symptomatic in the other 121 (26.5%). As to prior treatment, surgical removal was performed in 105 patients (23.0%), fractionated radiotherapy in 29 (6.4%), a combination of the two modalities in 15 (3.3%), and 8 had received radiosurgery at other facilities. At the end of March, 2007, the follow-up records of all 456 patients were analyzed. If the followup records were insufficient or the patient was alive at the time of the most recent follow-up, one of the authors (M.Y.) called the patient or his/her relatives to confirm the patient’s condition. If the patient had died, the date and cause of death, post-treatment condition, brain status before death, and so on, were documented. Postradiosurgically, steroids were administered for 5 days to most patients. Considerable numbers of patients received further steroid therapy, osmotherapy, and chemotherapy, as well as anticonvulsant treatment. These treatments were selected and administered by the referring physician. Radiosurgical Techniques

A stereotactic coordinate frame (Leksell Model G stereotactic coordinate frame manufactured by Elekta Instruments AB, Stockholm, Sweden) was applied under local anesthesia, supplemented with

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mild sedation in some cases. Before this procedure, corticosteroid therapy was initiated in all patients. When we started this type of treatment, only short Z-slides were available. Therefore, it was not possible to treat all brain lesions located in the posterior fossa and the high vertex in one frame position. Because of the X-coordinate limitation (50.0–150.0 mm), it was also not possible to cover multiple lesions located in both temporal lobes. Under these conditions, frame replacement was required in 19 patients. The two procedures were performed in 1 day in 7 patients, and in 2 days in 12, continuously in 9 and with a 2- to 4-week interval in 3. In recent years, however, most patients could be treated in one frame position because of three technical advances. First, long Z-slides became available, which allowed us to treat all lesions, even if some were located in the posterior fossa and others in the high vertex, regardless of distances between lesions. Second, we started treating patients in the lateral position when some lesions were present outside the range of the X-coordinate between 50.0 and 150.0 mm. Finally, a specially designed Y-Z slide, which expands the X-coordinate up to a range of 37.5–162.5 mm, was very recently introduced. This innovation has remarkably reduced treatment in the lateral position. A preradiosurgical MR examination was performed 1 day before treatment in most cases, 2 days before in a few. This study included T1- and T2-weighted axial images and T1-weighed axial and coronal images, with gadolinium (Gd) enhancement, the slice thickness of which was 5 mm. For target coordinate determination and dose-planning, stereotactic Gd-enhanced T1-weighted axial MR images with a slice thickness of 2 mm, multiple slices of which covered the entire brain, were obtained. Coronal MR images were used in a limited number of patients whose lesions were located in the very high vertex. According to previously published reports, an irradiation dose of 15–20 Gy at the tumor periphery with stereotactic radiosurgery achieved approximately 80% tumor control in cases with solitary or multiple metastatic tumors. Because of the limited life expectancies of these patients, a prompt effect was needed. Therefore, we selected an irradiation dose of 20 Gy or more (maximum 25 Gy) for all tumor margins in 70% of patients. However, as the brain had already been irradiated or the cumulative tumor volume was relatively large, the dose was reduced in the other 30%. As a result, the median dose at the tumor periphery was 20.0 Gy, range 10.0–27.0 Gy, and the median dose at the tumor center (maximum dose) was 36.00 Gy, range 20.0–50.0 Gy. As described in detail elsewhere [28], we fixed the frame with the patient in the supine position using a specially designed adapter firmly fixed to the operating table. This procedure takes 15 min and an additional 30 min are required for stereotactic MR imaging examination. The time for lesion detection and dose-planning varied, depending on lesion number, and ranged from 5 to 150 min. Statistical A nalysis

One of the outcome parameters measured was overall survival. Median survival times were computed using the Kaplan-Meier method [29]. Two or more curves were compared using the log-rank test. Univariate analysis was used for continuous variables such as age, number of lesions, mean, maximum and cumulative volumes and radiosurgical doses. The usual threshold for significance (p ⬍ 0.05) was chosen for all analyses.

Results

Outcomes At the end of March, 2007, 28 of the 456 patients were still alive. The mean and the median survival periods were 51.6 and 50.0 months, respectively, range 16.7–96.9 months, in this select group of patients. Excluding 1 patient lost to follow-up, the remaining 427 were confirmed to have died, with mean and median post-GK periods of 8.8 and 6.0

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Fig. 1. Overall survival. 1.0 Months after GK 6 12 18 24 36 48 60

Fraction survival

0.8 0.6 0.4 0.2

Survival rates 52.7% 29.0% 19.1% 13.5% 6.5% 5.0% 5.0%

0 0

12 24 36 Months after GK radiosurgery

48

months, respectively, range 2 days to 46.9 months. Causes of death could not be determined in 60 patients, but were confirmed in the remaining 396; non-brain diseases in 349 (88.1%), progression of brain METs in 37 (9.3%) and both in 10 (2.5%). In the 349 patients who died due to the primary cancer or its non-brain METs, good brain condition was maintained until one to several days before death. Postradiosurgically, 2 patients, in whom more than 40 targets had been irradiated, complained of considerable pain over the entire scalp for 2–4 weeks and mild, diffuse hair loss. However, there have been no major complications thus far. Additional courses of GK radiosurgery for de novo METs were required in 134 patients (29.4%); twice in 95 (20.8%), three times in 28 (6.1%), four in 7 (1.5%), five in 3 (0.7%) and seven in 1 (0.2%). Follow-up MR images were recommended at 1-month intervals for 3 months after treatment and every 2–3 months thereafter in all patients. However, follow-up MR images of adequate quality were obtained more than 3 months after radiosurgery in only 40% of patients, mainly due to multiple examinations required to check for other organ involvement and/or worsening general condition. An analysis of postradiosurgical MR images cannot be considered to reflect the cohort; rather, there may be a large bias in a group consisting only of patients in good condition. Thus, neither tumor control rates nor recurrence rates are described in this article. Factors Predicting Survival The mean and median survival times of the patients in this study population, using the Kaplan-Meier method, were 12.7 and 7.0 months after GK radiosurgery. Postradiosurgical survival rates were 52.7% at 6, 29.0% at 12, 19.1% at 18, 13.5% at 24, 6.5% at 36 and 5.0% at 60 months (fig. 1). As shown in table 3, among eight factors (age, number of lesions,

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Table 3. Predictive factors for survival period: univariate analysis Age Number of lesions Minimum volume Mean volume of all lesions Maximum volume Cumulative volume of all lesions Doses at lesion periphery Maximum doses

p value

95% CI

0.1333 0.0013 0.2303 0.0559 0.0003 ⬍0.0001 0.0658 0.8766

0.998/1.013 1.007/1.030 0.995/1.021 1.000/1.023 1.007/1.023 1.007/1.018 0.646/1.002 0.983/1.015

Table 4. Predictive factors for survival period: Kaplan-Meier method

Gender, female/male Symptomatic, yes/no Primary tumor status, good/poor Non-brain METs, yes/no KPS: 80% or better/70% or worse Radiotherapy, yes/no Surgery, yes/no Procedures: 1/2 or more

Median survival, months

p values (log-rank)

7.3/6.0 6.0/8.8 10.8/4.4 5.2/8.9 8.4/2.7 8.4/6.5 8.0/6.0 4.4/12.2

0.1123 0.0007 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.5475 0.0438 ⬍0.0001

minimum, mean, maximum and cumulative volumes, and maximum and minimum doses), univariate analysis showed number of lesions (p ⫽ 0.0013) and maximum (p ⫽ 0.0003) and cumulative tumor volumes (p ⬍ 0.0001) to be significant predictive factors for survival. Using the Kaplan-Meier method (table 4), six clinical variables were found to significantly influence survival duration: (1) being nonsymptomatic (8.8 vs. 6.0 months, p ⫽ 0.0007), (2) well-controlled primary tumors (10.8 vs. 4.4, p ⬍ 0.0001), (3) no nonbrain metastatic lesions (8.9 vs. 5.2, p ⬍ 0.0001), (4) KPS better than 80% (8.4 vs. 2.7, p ⬍ 0.0001), (5) having prior surgery (8.0 vs. 6.0, p ⫽ 0.0438), and (6) having two or more procedures (12.2 vs. 4.4, p ⬍ 0.0001). As shown in table 5, there were no significant differences in survival periods between the two genders, according to the primary tumor site. Female patients with primary tumors involving the breast, urogenital organs, and other organs survived significantly longer than those with either upper or

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1.0 No. of Median survival tumors period (months) 7.4 1–4 5–9 4.0 10–14 7.4 15–19 3.4 20–29 4.9 30 or more 4.6

Fraction survival

0.8

0.6

0.4

p⫽ 0.0002

0.2

0 0

12

24 36 Months after GK radiosurgery

48

Fig. 2. Survival: tumor numbers.

Table 5. Predictive factors for survival period: Kaplan-Meier Method, continued Primary tumor

Number of patients (male/female)

Median survival, months (male/female)

p values (log-rank)

Breast Lower alimentary tract Urogenital Upper alimentary tract Others Unknown

3/119 63/41 64/36 45/11 25/16 19/13

6.0/8.4 4.2/4.3 7.6/9.9 4.9/5.1 6.0/9.2 7.7/6.5 0.1014/0.0015*

0.3535 0.6129 0.5048 0.5865 0.2125 0.7891

*p values (log-rank).

lower alimentary tract malignancies (8.4, 9.9 and 9.2 months vs. 4.3 and 5.1, respectively, p ⫽ 0.0015), though this was not the case in male patients (p ⫽ 0.1014). As described above, the univariate analysis showed an increased tumor number treated with GK radiosurgery to be among the apparently unfavorable factors determining survival periods. Also, as shown in figure 2, the Kaplan-Meier analysis

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No. of tumors (no. of patients) 0%

20%

40%

60%

80%

100%

1–4 (267) 5–9 (61) 10–14 (25) 15–19 (14) 20–29 (20) 30– (9) Brain

Both

Non-brain

Fig. 3. Causes of death: tumor numbers.

demonstrated tumor number to have a significant impact on the duration of survival (p ⫽ 0.0002). However, approximately 85% of patients with brain METs died of causes other than brain disease progression, regardless of tumor number (fig. 3).

Illustrative Cases

Patient 1 A 63-year-old female patient was admitted to our facility on October 18, 2000, for treatment of multiple brain tumors which manifested with frequent nausea and left oculomotor nerve palsy at the beginning of September. This patient had undergone surgical treatment for a left breast cancer on March 22, 1993. Preradiosurgical MR images demonstrated 48 tumors, the volumes of which ranged from 0.022 to 4.1 cm3, the cumulative and mean volumes being 31.463 and 0.655 cm3, respectively (fig. 4a). Although two dose planning protocols were required to completely cover the lesions, 45 target points were selected; 36 targets using a 14-mm and the remaining 9 using an 8-mm collimator. The selected dose at each tumor margin was 15 Gy or more and the maximum dose was 30 Gy. Entire lesions could be irradiated with one frame position. However, because the total irradiation time exceeded 7 h, 35 shots were administered on the first day and the remaining 10 on the following day; the patient went to bed with the frame on her head. The mean dose to the WB was determined to be 11 Gy or slightly more. The patient noted symptom amelioration as early as a few days after irradiation and 2 weeks later her symptoms had nearly disappeared. Serial MR imaging studies

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a

b Fig. 4. Magnetic resonance images from patient 1, obtained on October 17, 2000 (a, before radiosurgery), and on April 20, 2001 (b, 6 months after radiosurgery).

demonstrated disappearance or remarkable shrinkage of all treated tumors (fig. 4b). Although this patient experienced periodic hypopotassemia, her brain condition remained excellent for 7 postradiosurgical months without WBRT. However, she died due to acute pulmonary failure caused by lung METs on May 31, 2001. Patient 2 A 54-year-old male patient was admitted to our facility on January 17, 2004, for treatment of multiple brain tumors which manifested with headache at the beginning of January. This patient had undergone radiotherapy and chemotherapy for an esophageal cancer in July–November, 2002. Preradiosurgical MR images demonstrated four tumors, the volumes of which ranged from 0.016 to 3.2 cm3, the cumulative and mean volumes being 4.647 and 1.162 cm3, respectively (fig. 5a). At the time of GK radiosurgery, 10 target points were selected; eight targets using a 14-mm and the remaining two using an 8-mm collimator. The selected dose at each tumor margin was 24 Gy or more and the maximum dose was 40 Gy. Thereafter, six

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a

b Fig. 5. Magnetic resonance images from patient 2, obtained on January 17, 2004 (a, before radiosurgery), and on June 6, 2007 (b, 41 months after the first radiosurgery) and positron emission tomography using 14C-labelled methionine performed on March 6, 2007 (c).

additional GK procedures were required for de novo metastatic lesions, as described below: Second GK on June 5, 2004 (three lesions) Third GK on October 23, 2004 (two lesions) Fourth GK on May 6, 2005 (four lesions) Fifth GK on February 11, 2006 (seven lesions) Sixth GK on September 19, 2006 (one lesion) Seventh GK on March 9, 2007 (three lesions). The most recent follow-up MR images obtained on June 6, 2007 demonstrated the total of 24 irradiated tumors to be well controlled although several of these lesions were still visible as enhanced areas and delayed cyst formation was recognized (fig. 5b). In addition, positron emission tomography using 11C-labelled methionine showed the entire brain to be free of tumor activity (fig. 5c). Although tube feeding through an artificial percutaneous gastric fistula has been required, this patient has survived in good condition thus far.

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c Fig. 5. (continued)

Patient 3 A 39-year-old female patient was admitted to our facility on April 30, 2002, for treatment of multiple brain tumors which manifested with headache at the beginning of April. This patient had undergone surgery for a left breast cancer on August 2, 1996 and radiotherapy for local recurrence in February–March, 2000. Preradiosurgical MR images demonstrated 19 tumors, the volumes of which ranged from 0.009 to 6.2 cm3, the cumulative and mean volumes being 24.213 and 1.275 cm3, respectively (fig. 6a). At the time of GK radiosurgery, 47 target points were selected; one target using an 18mm, 36 using a 14-mm and the remaining eight using an 8-mm collimator. The selected dose at each tumor margin was 18 Gy or more and the maximum dose was 30 Gy. MR images obtained on May 7, 2003 showed all irradiated tumors to be well controlled (fig. 6b). Thereafter, four additional GK procedures were required for de novo metastatic lesions as described below: Second GK on April 1, 2004 (five lesions) Third GK on December 30, 2004 (two lesions) Fourth GK on April 10, 2005 (five lesions) Fifth GK on October 28, 2005 (five lesions). During the above-mentioned period, this patient underwent placement of an Ommaya reservoir for a right temporal cyst on September 9, 2004. Thereafter, occasional aspirations

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a

b Fig. 6. Magnetic resonance images from patient 3, obtained on April 30, 2002 (a, before radiosurgery), April 7, 2003 (b, 12 months after the first radiosurgery) and on December 26, 2005 (c, 43 months after the first radiosurgery) and positron emission tomography using 14C-labelled methionine performed on December 22, 2005 (d).

every few months were required. The most recent follow-up MR images obtained on December 26, 2005, demonstrated the total of 36 irradiated tumors to be well controlled although several of these lesions were still visible as enhanced areas (fig. 6c). Furthermore, positron emission tomography using 11C-labelled methionine showed no tumor activities anywhere in the brain (fig. 6d). Although this patient had mild memory disturbances, her KPS was maintained at the 70–80% level until March 29, 2006, when she was found dead in her bathroom.

Discussion

The development of multiple brain METs portends a poor prognosis [23, 30, 31]. Without treatment, remarkable clinical deterioration occurs within a few weeks after diagnosis and the median survival time is 1–3 months [32]. Such patients have been treated with WBRT, chemotherapy, corticosteroids, or combinations of these modalities

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c

d Fig. 6. (continued)

[31]. In particular, WBRT, alone or combined with chemotherapy, can clearly prolong survival, in patients in whom the lesions are radiosensitive. In some patients, however, WBRT is contraindicated because of prior brain radiation, or is unlikely to be effective because of the radioresistant nature of the tumor. In yet other patients, the availability of an alternative treatment for brain METs allows WBRT to be reserved for subsequent treatment attempts, or to be postponed relative to the course of another management strategy, such as very extensive chemotherapy and/or radiation therapy for spinal lesions or other organ involvement, which are also urgent. Radiation therapy for the entire neuroaxis or simultaneous irradiation of the whole brain and another part of the body may produce severe bone marrow depression, preventing the use of chemotherapeutic agents against the systemic tumor and perhaps even preventing a full course of radiation therapy. Therefore, we consider patients with numerous METs to be potential candidates for stereotactic radiosurgery, instead of WBRT, if all imaged lesions can be irradiated. Most fortunately, we already live in a new era when a metastatic brain tumor with a volume of 0.005 cm3 or even slightly smaller can be detected with thin slice, post-enhanced MR images. Such tiny tumors are only rarely identified on routine

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macroscopic observation at autopsy. Also, a single metastatic lesion can now be irradiated with a sharply focused irradiation technique. We no longer need to indiscriminately irradiate the innocent normal brain as was formerly done with WBRT, possibly leaving the patient at risk for future dementia. In fact, diffuse white matter changes (DWMC) on T2-weighted MR images, considered to represent a possible risk for future dementia, are often seen after WBRT. In our recent analyses of 45 patients who had undergone WBRT for brain METs, MR images obtained 6–42 (mean; 16) months after WBRT demonstrated DWMC in 21 (47%). DWMC occurred in 8, 50, 63 and 84% of the patients, respectively, 6, 12, 18 and 24 months after WBRT. In contrast, MR images obtained 7–56 (mean; 14) months after treatment demonstrated no DWMC in any of the 60 patients who underwent GK radiosurgery for five or more (mean and maximum tumor numbers; 13 and 48, respectively) brain METs. Furthermore, as we reported previously [33–35], the integral dose to the normal brain, and critical structures such as the brain stem and the optic apparatus, does not exceed the threshold level for radiation necrosis even if 10 or more METs are treated using the GK. As is well known, stereotactic radiosurgery is an attractive therapeutic option because it is minimally invasive (it can be performed even in patients with disseminated organ involvement whose general condition is poor) and necessitates only a brief hospital stay. This allows the patient to maximize any remaining time with his/her family. If each lesion is sufficiently small (less than 3.0 cm in maximum diameter), a relatively high control rate (80–90% or more) can be expected and relatively early symptom palliation can be attained, even if the lesion is radioresistant. Furthermore, stereotactic radiosurgery prevents neither radiation therapy for other parts of the body nor chemotherapy. Even major surgery for another lesion can be carried out the day after radiosurgical treatment. Also, in contrast to WBRT, stereotactic radiosurgery can be repeated, at a considerable interval, and patients never lose all of their hair; there will be a small area of transient hair loss if a treated lesion is located superficially. Before GK radiosurgery use became widespread, if 20–30, or even more, brain METs originating from a radioresistant tumor were demonstrated on neuroimaging, or if multiple brain METs originating from a radiosensitive tumor appeared after WBRT, the cause of death was usually brain tumor progression. Therefore, most physicians felt somewhat helpless when faced with a patient who had numerous brain METs, and would discontinue more aggressive treatment for the original tumors or non-brain METs. However, our experience suggests a promising role for stereotactic radiosurgery in treating brain dissemination. Nowadays, as described herein, more than 80% of such patients do not die due to brain tumor progression. This means that physicians can reasonably reconsider more aggressive treatment for the original tumors or non-brain METs. Thus, such a patient can expect to survive significantly longer and in better condition. Finally, we should always keep in mind the words of Lindquist and Steiner [36], ‘Although effective, it must be realized that radiosurgery at best only kills intracranial

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tumor cells. Suffering should not be prolonged by treatment of terminal patients. Which tumors should be treated? How many tumors can and should be treated?’ A gradual decrease in consciousness level due to intracranial dissemination, which occurs sooner or later, might be Nature’s way of relieving the suffering of terminal patients. Recent advances in multidisciplinary management strategies have, however, allowed physicians to relieve much of the suffering of end-stage patients. Furthermore, we believe that as physicians we should not shrink from the challenge of treating a patient with very difficult to manage disorders, provided that the patient wants to continue treatment. Therefore, we advocate that all detectable tumors, if sufficiently small, be treated, even though the treatment procedure reported herein is time-consuming and somewhat laborious. A considerable effort on the part of all members of the radiosurgical treatment team is required.

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17 Muacevic A, Kreth FW, Horstmann GA, SchmidElsaesser R, Wowra B, Steiger HJ, Reulen HJ: Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 1999;91: 35–43. 18 Serizawa T, Iuchi T, Ono J, Saeki N, Osato K, Odaira M, Ushikubo O, Hirai S, Sato M, Matsuda S: Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy. J Neurosurg 2000;93(suppl 3):32–36. 19 Somaza S, Kondziolka D, Lunsford LD, Kirkwood JM, Flickinger JC: Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 1993;79:661–666. 20 Sturm V, Kober B, Höver KH, Schlegel W, Boesecke R, Pastyr O, Hartmann GH, Schabbert S, Winkel K, Kunze S, Lorenz WJ: Stereotactic percutaneous single dose irradiation of brain metastases with a linear accelerator. Int J Radiat Oncol Biol Phys 1987;13: 279–282. 21 Voges J, Treuer H, Erdmann J, Schlegel W, Pastyr O, Müller RP, Sturm V: Linac radiosurgery in brain metastases. Acta Neurochir 1994;62(suppl):72–76. 22 Young RF, Jacques DB, Duma C, Rand RW, Henderson J, Vermeulen SS, Grimm P, Blasko JC, Posewitz A, Copcutt B, Bolles GE, Breeze RE, Pribil SG, Winston K, Johnson SD: Gamma knife radiosurgery for treatment of multiple brain metastases; in Kondziolka D (ed): Radiosurgery 1995. Basel, Karger, 1996, pp 92–101. 23 Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ: Multiple brain metastases are associated with poor survival in patients with surgery and radiotherapy. J Clin Oncol 1993; 11:369–373. 24 Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, MacDonald JS, Young B: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500. 25 Valentino V: The results of radiosurgical management of 139 single cerebral metastases. Acta Neurochir 1995;62(suppl):95–100.

26 Davey P, O’Brien PF, Schwartz ML, Cooper PW: A phase I/II study of salvage radiosurgery in the treatment of recurrent brain metastases. Br J Neurosurg 1994;8:717–723. 27 Suzuki S, Omagari J, Nishio S, Nishiye E, Fukui M: Gamma knife radiosurgery for simultaneous multiple metastatic tumors. J Neurosurg 2000;3(suppl 3): 30–31. 28 Yamamoto M: Gamma knife radiosurgery: Technology, applications, and future directions. Neurosurg Clin N Am 1999;10:181–202. 29 Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457–481. 30 Davey P, O’Brien P: Disposition of cerebral metastases from malignant melanoma: implications for radiosurgery. Neurosurgery 1991;28:8–15. 31 Little JR, Frankel A: Meningeal carcinomatosis; in Wilkins RH, Rengachary SS (eds): Neurosurgery, ed 2. New York, McGraw-Hill, 1996, pp 829–832. 32 Wasserstrom WR, Glass JP, Posner JB: Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–772. 33 Kamiryo T, Yamamoto M, Barfod BE, Urakawa T: Dose absorbed by normal brain stem and optic apparatus in gamma knife surgery for ten or more metastases; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 77–81. 34 Yamamoto M, Ide M, Jimbo M, Aiba M, Ito M, Hirai H, Usukura M: Gamma knife radiosurgery with numerous target points for intracranially disseminated metastases: early experience in three patients and experimental analysis of whole brain irradiation doses; in Kondziolka D (ed): Radiosurgery 1997. Basel, Karger, 1998, vol 2, pp 94–109. 35 Yamamoto M, Ide M, Nishio S, Urakawa Y: Gamma knife radiosurgery for numerous brain metastases: is this a safe treatment? Int J Radiat Oncol Biol Phys 2002;53:1279–1283. 36 Lindquist C, Steiner L: Radiosurgery for tumors; in Wilkins RH, Rengachary SS (eds): Neurosurgery, ed 2. New York, McGraw-Hill, 1996, pp 1887–1907.

Masaaki Yamamoto, MD, PhD Katsuta Hospital Mito GammaHouse 5125–2 Nakane Hitachi-naka, Ibaraki 312-0011 (Japan) Tel. ⫹81 29 271 0011, Fax ⫹81 29 274 1475, E-Mail [email protected]

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Treatment of Functional Disorders with Gamma Knife Thalamotomy Chihiro Ohye ⭈ Tohru Shibazaki Hidaka Hospital, Functional and Gamma Knife Surgery Center, Takasaki, Japan

Abstract Gamma knife (GK) thalamotomy for functional disorders, primarily Parkinson disease and central pain, are described herein. The goal was to extend our present indications for selective thalamotomy. Our target for tremor surgery is about 45% of the thalamic length. Thus, this principle was applied to deciding the GK thalamotomy target. In most of our cases, the protocol was 130 Gy, delivered in one shot with a 4-mm collimator. The time courses of thalamic lesion changes and clinical improvement after irradiation were assessed. Thus, despite thalamic reaction changes being variable, we achieved a clinical success rate of Copyright © 2009 S. Karger AG, Basel approximately 80% with negligible complications.

Treatment of functional disorders with the gamma knife (GK) lags behind that in other fields, such as brain tumors, mainly because the target of functional disorders is not visualized. Global statistics (2006) demonstrate GK to be used for only 7.6% of functional disorder treatments, with the proportion in Japan (2002) being even lower, only about 4%. Since the GK was installed at our facility, we have become increasingly interested in treating patients with a variety of movement disorders and central pain using the GK, as pioneered by Leksell in 1968. This represents an extension of selective thalamotomy facilitated by microrecording [15], and the optimal target thereby defined can be transferred from that of selective thalamotomy [17–19, 21]. Thus, we began by attempting mainly cases with tremor type Parkinson disease (PD). Herein, we describe the principal technique used in this specialized field, focusing particularly on clinical results related to the thalamic lesion produced by GK irradiation.

Involuntary Movement

Indications The following criteria were used for selecting patients: (1) Tremor and/or rigid-type PD not responsive to drug therapy. (2) Elderly or otherwise at-risk patient. (3) No psychiatric problems. (4) No other severe complications such as hypertension, diabetes mellitus or cerebral infarction. (5) Refusal of open surgery. (6) Acceptance of delayed effect (approximately 6 months). Having now accumulated nearly a decade of experience, we have become convinced of the safety and reliability of GK thalamotomy, as described in the following section. We carefully explain to each patient and his or her family the advantages and disadvantages of different operations, and the final decision is often made by the patient him/herself. Full consensus regarding the treatment is obtained in every case. Hospitalization In our facility, as a rule, patients are hospitalized for 3 days. On day 1, general physical and laboratory examinations (blood analysis, urinalysis), X-rays of the chest and cranium, electrocardiography, electroencephalography, electromyography and computerized tomography (CT) are performed. These data reveal whether any cortical atrophy or deformity of the thalamus exists, and allow us to measure the distances necessary for the operation by simulating the operative trajectory (distance from cortical surface to intended target, width of the thalamus, etc.). All examination data obtained are shown to the patients and the details of the operative procedures are explained. On the second day, GK thalamotomy is performed under local anesthesia. Details of the operative procedures will be described in the next section, followed by target planning and dosimetry. Next, the patient is escorted to the GK room and the irradiation treatment begins. It usually takes about 1 h to complete the treatment, and the entire procedure is finished at approximately 13:00 h. The patient is requested to remain calm, avoiding strenuous activity, for the remainder of the day. A mild headache may develop just after release of the stereotactic frame. Pain may also persist at the site of pin screw placement for some time. On the third day, the patient is allowed to go home and there are generally no problems with discharge.

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Operation On the second day, we start with fixation of the stereotactic frame (Leksell G-frame) on the patient’s skull. The patient maintains a seated posture during frame fixation. Care is taken regarding the angle of the frame relative to head position, avoiding respiratory compromise when the head is fixed to the headrest during magnetic resonance imaging (MRI) examination and GK irradiation. Next, we obtain MR and CT images. For MRI, 2-mm slices of T2-weighted (FASE) images are used to obtain axial images from the level of the lateral ventricle to the cerebral aqueduct, and 2-mm slices for proton density weighted axial and coronal images at the level of the thalamus. All images including CT are then transferred to the Leksell Surgiplan and Gammaplan [25]. The Surgiplan is employed for target planning. Generally, with plotting of the ventricular system on FASE images, superimposing these images on the CT images allows us to examine whether significant displacement or dislocation exists on MRI. In most cases, a difference within 1 mm is acceptable in target planning, though such differences, if any, should be kept in mind. Target planning is among the most important processes in GK thalamotomy. As described previously [14, 15], the optimal treatment target for tremors is the lateral part of the thalamic ventralis intermedius nucleus (Vim). However, a computerized imaging system can not clearly define the subnucleus. Therefore, as with routine stereotactic thalamotomy, we initially depend on the posterior commissure (PC), precisely defined by FASE imaging. This point is then modified according to the most appropriate coordinates derived from our personal experience with microrecording-guided stereotactic thalamotomy: 7 mm anterior to the PC, 4 mm above the level of the intercommissural (IC) line, and 2 mm medial to the thalamocapsular border (about 16 mm from the midline). These parameters are shown in figure 1. For a patient who has already undergone unilateral surgery, target planning is more easily performed on the contralateral side because we can see the thalamic lesion on MRI. Another useful and important clue to accurately identifying the Vim nucleus on MRI comes from an anatomical study on the human thalamus [2], i.e. each thalamic nucleus is represented more constantly by the percentage of thalamic length, than by the distance from the PC. We applied this concept and the Vim nucleus was found to be at a length of 45% from the anterior tip of the thalamus in the horizontal plane [20, 22, 24] (fig. 2). In fact, this is quite a reliable criterion for the Vim zone on MRI. Therefore, as a practical first step, the tentative target is determined with reference to the PC and then corrected according to the percentage of thalamic length. For dose planning, the target coordinate values are transferred to the GK. Examining the dose distribution curve projected on axial and coronal planes, we verify the safety of planning for our standard maximum dose of 130 Gy (fig. 3). We must be careful not to excessively invade (10–15% isodose curve) the internal capsule and the main sensory nucleus of the ventralis caudalis (VC) located posteriorly. A plug-

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Fig. 1. Schematic illustration of GK thalamotomy target planning: lateral view of the posterior portion of the human thalamus. The horizontal line at the base is the posterior part of the IC line referring to the PC. The circle with the star in the center denotes the recommended zone for GK thalamotomy treatment of tremor. This zone is derived from the distribution of kinesthetic and tremor related Vim neurons shown in the upper right inset, with the effective area of coagulation being demarcated by the dashed lines between B and A, and between A and C. Lines A, B and C (interval 3-mm each) are three parallel tracks of the coagulation needle or recording electrode through the thalamic ventral oral (VO) or ventral intermedius (Vim, area with oblique zigzag lines) nucleus. The standard angle between the IC line and needle insertion is about 45 degrees, the central needle (A) being oriented to 5 mm anterior to the PC.

ging pattern is applied mainly to avoid the internal capsule and ocular lens. In general, about 30–50 plugs are used. It is noteworthy that in our initial series, the target center was intentionally displaced at least 2 mm more medially and anteriorly from the actual target to avoid possible damage to the internal capsule and sensory nucleus. However, after extensive experience, especially with the irregular high signal zone surrounding the focus, we found normal neuronal activity to be preserved [18]. Therefore, such displacement is rarely carried out at present. Another important change in our strategy is that the cobalt source was reloaded in July, 2001, and this renewal influenced the time courses of clinical changes and thalamic reaction, as described below.

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Vim: 45% Fig. 2. Semi-schematic illustration of the relative position of the Vim nucleus (45% in relation to the entire thalamic length) on the axial plane of the MRI (left, a circle with a 50% isodose center) in a case with PD and on the standard atlas of the human thalamus (right, enclosed area [24]). Approximately 4 mm above the IC line corresponds to our center of irradiation.

Results

Since 1992, we have operated on 85 patients with involuntary movement disorders (mainly tremor type PD, essential tremor, etc.) and 15 with central pain. Our first conclusion is that GK thalamotomy for tremor of whatever cause is 80% successful. However, for central pain cases, the success rate is about 60%. The details of clinical changes are discussed separately below. Clinical Course after Irradiation After GK irradiation, the clinical course of tremor reduction is characterized by slow changes taking several months, in general, contrasting with the immediate effect of radiofrequency coagulation. The first case in our series (150 Gy was used on our earliest 6 cases), an elderly lady with Parkinsonian tremor, had a slow recovery course. Her tremor began to diminish around 1 year after treatment and had largely and rapidly subsided within 1 month thereafter [17]. In fact, clinical improvement can be greatly accelerated, as shown below. Thalamic Reaction MRI follow-up revealed variable thalamic reactions among cases. Thalamic lesions became visible only after 3 months. In general, two reaction types were seen thereafter. One was a round, restricted low signal zone surrounded by a ring-like high signal area

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56 M, PD (rigid type)

Fig. 3. The dose planning for GK thalamotomy on MRIs (proton-density images) using Surgiplan. The 50% and 15% isodose circles are drawn. In the upper part, axial (left), coronal (right, upper) and sagittal (right, lower) images, and in the lower part, serial axial images are shown.

(fig. 4). This was usually a round high signal zone with an ambiguous border. These lesions mostly remained unchanged over the next 3 months, but some increased in volume up to several hundred mm3. The other type was an irregularly shaped high signal area extending on occasion to the internal capsule or medial thalamic area. Often, it was accompanied by a high signal streak along the thalmocapsular border or rail-like appearance along the thalamocapsular and pallidocapsular borders [19, 21]. In our early series, these two reaction types were seen in almost equal numbers but, after reloading, the restricted type became predominant. However, we could not predict which type of reaction would occur before or even at the time of irradiation. We still do not know the subsequent pathological sequence explaining these changes, except that the central low signal zone may correspond to the actual necrotic area. In any case, no remarkable complications were experienced. Sequential, systematic examinations of the thalamic lesion revealed relatively complicated features [19]. However, at present, we cannot predict such thalamic reactions. There is a tendency for younger patients and smaller lesions to have better outcomes (including rapid wound healing), but this is not always the case. Therefore, regular follow up is essential.

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75 F, PD (6 m after left GK thalamotomy)

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Fig. 4. Two types of thalamic reaction after GK thalamotomy for PD. Left: A small round high signal lesion after 6 m. Right hand tremor showed improvement. Right: A small low signal surrounded by a round high signal zone with short streaks along the thalamocapsular border. Good clinical improvement was obtained by UPDRS.

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We noticed that, after reloading, thalamic reactions tended to be restricted rather than enlarged. Furthermore, the clinical improvement occurred more rapidly, as mentioned above, mostly within about 6 months instead of 1 year as in earlier series. The time course of clinical improvement parallels that of Unified Parkinson Disease Rating Scale (UPDRS), as presented in figure 5. Intrigued by

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this observation, we are now investigating the relationship between ‘dose rates’ and more rapid clinical improvement as well as the smaller, more restricted lesion [19]. Re-Operation with Microrecording We had four cases requiring re-operation in our early series, in which the clinical effect was insufficient even after more than 1 year of observation. In such cases, routine stereotactic thalamotomy with microrecording has been performed [18]. In these patients with insufficient results, the irradiated area was often too medial or anterior, such that the true point crucial for tremor arrest had escaped direct irradiation. Thus, a new target was set at a point 1–2 mm more posterior-lateral, within the area of the previous irradiation center, usually within the surrounding high signal zone. Introducing a microrecording electrode at this point of presumed damage to the Vim nucleus, quite surprisingly, showed nearly normal activity, including kinesthetic responses, and rhythmic grouped discharges time-locked to the corresponding peripheral tremor. After coagulation of this point, the tremor stopped immediately with no apparent complications. We speculated that the high signal area surrounding the irradiation center had escaped damage by the GK beam and that it contained surviving neurons with essentially normal functions. GK Thalamotomy after Stereotactic Thalamotomy A strategy with a reverse order is also possible, i.e. using GK thalamotomy for early tremor recurrence after thalamotomy aided by microrecording. In our recent series, there were 11 such cases. In these cases, we endeavored to extend the previous lesion in a more suitable direction covering more of the Vim nucleus with the GK, considering the peripheral topography of this nucleus and the location of residual tremor, in the given case. This approach ultimately produced complete arrest of the tremor within 1 year. Sequential thalamic lesion changes in a case with essential tremor are shown in figure 6.

GK Thalamotomy for Central Pain

Intractable pain can develop after thalamic damage (hemorrhage or infarction), and similar continuous pain may also result from putaminal vascular damage [10, 13, 16]. Both symptom complexes are referred to as central pain. Central pain has long been recognized to be associated with severe physical and mental conditions which are difficult to treat. As our experience with stereotactic thalamotomy using microrecording in cases with central pain revealed abnormal neuronal activities, such as irregular burst discharges

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20 F, essential tremor (Left GK thalamotomy, 14 months after thalamotomy)

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Fig. 6. a MR images illustrating target planning for re-operation (left GK thalamotomy) 14 months after left stereotactic thalamotomy in a case with an essential tremor. On the left is a coagulative lesion in the left thalamus at the time of GK thalamotomy. The reversed FASE image on the right shows additional target planning for GK thalamotomy. The anterolateral part of the previous lesion is targeted in this case. b Sequential changes in the thalamic lesion after the GK irradiation shown in a. MR images were obtained at 3 months, 6 months, 1 year and 1.5 years. Clinical improvement became apparent at approximately 6m after irradiation and nearly complete resolution was seen at 1.5 years. Note that the lesion initially enlarged but then shrank.

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Fig. 7. Dose planning using the Kula system in our first GK thalamotomy case with central pain. The residual lesion of the initial thalamic hemorrhage was enlarged, also covering the anterior part of the Vim area.

suggesting disorganization in and around the thalamic main sensory nucleus of the VC [10], we used the GK for such central pain cases. The basic concept is to diminish abnormal neuronal activity in the area surrounding the originally damaged thalamic VC nucleus, thereby destroying the abnormal hyperactive Vim zone. Technically, we use the technique described above for movement disorders. Visualization of the initial thalamic damage facilitates targeting. Irradiation covers the area partly overlapping the original thalamic damage, the usual 130 Gy being delivered in one shot (except in two early cases) using the 4-mm collimator. An example of our dose planning for thalamic pain is presented in figure 7. This was our first GK thalamotomy performed in 1992, in a patient who had suffered a left thalamic hemorrhage. He had severe intractable pain, in the right half of his body, which was unresponsive to medications. His left thalamus was irradiated with 150 Gy overlapping the hemorrhagic lesion. Pain was only mildly reduced by this treatment. Surprisingly, he was admitted in 2002, 10 years later, for re-bleeding, again in the same left thalamus. Although he was extremely exhausted, his pain had not been as severely debilitating. During the 19 years, to date, since we started GK thalamotomy, 15 cases in total have been treated, for a success rate of nearly 60%. We have the impression that among central pain cases, the most effective outcomes are achieved for patients complaining of deep pain or muscle pain originating from somewhere deep in the extremities. This type of deep pain was often expressed as severe muscle compression, or as pain exaggerated by compression of the affected part or by active and passive movements of the painful area. After a 6- to 12-month delay, the intractable pain became milder and more tolerable, thereby reducing the psychological impact. However, it should be kept in mind that paresthesia, which often coexists to some extent with deep pain, showed no amelioration.

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Conclusions

We have outlined our experience with GK thalamotomy for PD and central pain. The basic concept was derived from our experience performing selective thalamotomy with microrecording. Proposed 3D coordinates of the tentative target point are: 2 mm from the thalamocapsular border and 4 mm above the level of the IC line. These values are routinely further adjusted by taking anatomical features into account [2]. Employing this method, we obtained satisfactory results overall, with an approximately 80% success rate for the tremor and rigidity of PD and related disorders. The value of this approach for akinesia and pure gait disturbances, such as freezing, remains an open question. Thalamic neuronal reactions to high-dose GK irradiation delivered in a single fraction, as in our facility [1, 5–9, 11], are quite different from routine radiotherapy. Therefore, we should follow patients long-term to assess ongoing clinical changes and thalamic reactions [3, 4]. The maximum dose used is thus one of the essential factors in avoiding severe complications [23]. The standard 130-Gy dose in our series appears to be safe and effective, and is not particularly associated with complications. Standardized target planning is another essential factor. As described herein, as well as in previous reports, the configuration of the thalamus, (its length, relative position of the PC and so on) is highly variable among individuals [19]. In the setting of GK thalamotomy without a direct visible target on computerized images and no method to compensate for these individual variations, extensive experience with routine stereotactic thalamic surgery is highly recommended. We are now conducting a multicenter trial to address this subject, with the ultimate goal of achieving safe and reliable GK treatment for PD. We have performed only a limited number of GK treatments for patients suffering from central pain. In these cases as well, we rely on physiological findings obtained during the prior microrecording thalamotomy. Neuronal activity adjacent to the damaged thalamic VC nucleus was revealed to be abnormal, showing many irregular burst discharges and distorted peripheral projection topography [10, 13]. Thus, we sought to coagulate the adjacent area, for example in the Vim nucleus, just anterior to the Vc nucleus. As the Vim probably receives information from muscle spindles, this would be a reasonable approach to reducing deep pain. We are also attempting to treat cases with central pain based on this theory.

References 1 Berry RJ, Hall EJ, Forster DW, et al: Survival of mammalian cells exposed to X-rays at ultra-high dose rate. Br J Radiol 1969;42:102–107. 2 Brierley JB, Beck E: The significance in human stereotactic brain surgery of individual variations in the diencephalons and globus pallidus. J Neurol Neurosurg Psychiatry 1959;22:287–298.

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3 Flickinger JC, Lunsford LD, Wu A, et al: Predicted dose- volume isoeffect curves for stereotactic radiosurgery with the 60Co gamma unit. Acta Oncol 1991;30:363–367. 4 Flickinger JC, Kondziolka D, Lunsford LD: Radiobiological analysis of tissue responses following radiosurgery. Technol Cancer Res Treat 2003;2:87–92.

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5 Friedman DP, Goldman W, Flanders AE, et al: Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation- preliminary experience. Radiology 1999;212:143–150. 6 Friehs GM, Noren G, Ohye C, et al: Lesion size following gamma knife treatment for functional disorders. Stereotact Funct Neurosurg 1996;66(suppl 1): 320–328. 7 Friehs GM, Ojakangas CL, Pachatz P, et al: Thalamotomy and caudatotomy with the gamma knife as a treatment for parkinsonism with a comment on lesion sizes. Stereotact Funct Neurosurg 1995;64 (suppl 1):209–221. 8 Friehs GM, Ojakangas CL, Pachatz P, et al: Lesion size following gamma knife treatment for functional disorders. Stereotact Funct Neurosurg 1996;66(suppl 1): 320–328. 9 Hall EJ: Radiobiology for the Radiologist, ed 4. Tokyo, Shinohara, 1995. 10 Hirato M: Pathophysiology of central pain. 2. Electrophysiological characteristics in patients with thalamic pain and its pathophysiology (in Japanese). Kitakanto Igaku 1990;40:541–566. 11 Kondziolka D, Lunsford LD, Flickinger JC: The radiobiology of radiosurgery. Neurosurg Clin N Am 1999;10:157–166. 12 Leksell L: Gamma thalamotomy in two cases of intractable pain. Acta Chir Scand 1968;134:585–595. 13 Lenz FA, Gracely RH, Baker FH, et al: Reorganization of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due to nervous system injury. J Com Neurol 1998;399:125–138. 14 Ohye C: Functional organization of the human thalamus; in Steriade M, Jones EG, McCormick DA (eds): Thalamus. Amsterdam, Elsevier, 1997, pp 517–542.

15 Ohye C: Thalamotomy for Parkinson’s disease and other types of tremor. 1. Historical background and technique; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw Hill, 1998, pp 1167–1178. 16 Ohye C: Stereotactic treatment of central pain. Stereotact Funct Neurosurg 1998;70:71–76. 17 Ohye C, Shibazaki T, Hirato H, et al: Gamma thalamotomy for parkinsonian and other kinds of tremor. Stereotact Funct Neurosurg 1995;66(suppl 1):333–342. 18 Ohye C, Shibazaki T, Ishihara J, et al: Evaluation of gamma thalamotomy for parkinsonian and other tremors: survival of neurons adjacent to the thalamic lesion after gamma thalamotomy. J Neurosurg 2000;93(suppl 3):120–127. 19 Ohye C, Shibazaki T, Sato S: Gamma knife thalamotomy for movement disorders: evaluation of the thalamic lesion and clinical results. J Neurosurg 2005;102(suppl):234–240. 20 Ohye C, Shibazaki T, Sato S: Location of the thalamic Vim nucleus: its relation to the whole thalamic length (in Japanese). Funct Neurosurg 2002;41:52–53. 21 Ohye C, Shibazaki T, Zhang J, et al: Thalamic lesions produced by gamma thalamotomy for movement disorders. J Neurosurg 2002;97(suppl 5):600–666. 22 Ohye C, Shibazaki T, Sato S, et al: Distribution of thalamic ventralis intermedius neurons and its relation to gamma thalamotomy (in Japanese). Funct Neurosurg 2003;42:108–109. 23 Okun MS, Stover NP, Subramanian T, et al: Complications of gamma knife surgery for Parkinson disease. Arch Neurol 2000;58:1995–2002. 24 Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme, 1977. 25 Shibazaki T, Ohye C: Leksell Gamma Plan (in Japanese). Front Neurosurg, No 2, New Technology Toward the 21st Century, 2000, pp 369–374.

Chihiro Ohye, MD Hidaka Hospital, Functional Gamma Knife Surgery Center 886 Nakao-machi Takasaki, Gunma 370–0001 (Japan) Tel. ⫹81 27 362 6201, Fax ⫹81 27 362 8901, E-Mail [email protected]

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Trigeminal Neuralgia Motohiro Hayashi Department of Neurosurgery, Neurological Institute, Tokyo Women’s Medical University, Tokyo, Japan

Abstract We completed a retrospective study of 270 patients with essential trigeminal neuralgia treated by gamma knife surgery. The target was localized on the retro-Gasserian portion of the nerve with 90 Gy at maximum. Among them, 150 patients were followed up more than 2 years. They were divided into 2 groups: pre-APS (41 patients) and post-APS (109 patients) treated by model C-APS since 2003. In the post-APS group, initial electric discharge was observed in 98.2% and at the last follow-up of at least 2 years in 79.8%. Complete recurrence was observed in 4.7% and postoperative complications were observed in 29.4%. These results were much better than those of the pre-APS group. There is no doubt that precise dose planning, C-APS treatment, so-called ‘robotized micro radiosurgery’, is important for Copyright © 2009 S. Karger AG, Basel improved treatment results.

Gamma knife surgery (GKS) has become one of the most advanced neurosurgical treatments available. It is well known to be a minimally invasive surgical procedure that can control tumor growth, and moreover is efficacious and safe for control of functional disorders without craniotomy. Recently, we have focused on the management of intractable pain, particularly trigeminal neuralgia (TGN) that has become a functional disease commonly treated by GKS worldwide. Many clinical reports have demonstrated that GKS can provide satisfactory results for patients without significant complications. In this chapter, we will present our institution’s experience with GKS in the treatment of TGN.

Treatment Options for TGN in General

In treating patients with TGN, we would normally administer carbamazepine. When the effect is insufficient, we must consider surgical procedures such as glycerol rhizotomy, thermocoagulation, micro-balloon compression, and microvascular decompression. The initial pain-free rate is reportedly 74–94%, and the recurrence rate 16–45% [1–3].

Recently, GKS has been regarded as an alternative treatment for TGN. For the elderly patients in whom surgery has failed and who suffer from significant risks associated with general anesthesia, the least invasive treatment, GKS, is particularly recommended.

Treatment Concept for TGN in GKS

In GKS for TGN, we normally use only 1 isocenter with a 4-mm collimator, and place it at the trigeminal nerve on the affected side. There are two different means of nerve target positioning. One target is exclusively the root entry zone (REZ), which is 2–4 mm from the brain stem and the neuroanatomical border between oligodendrocytes and Schwann cells. This strategy is favored by the Pittsburgh group. Another target is the retro-gasserian region (RGR), which is located at the trigeminal incisula. This is the approach of the Marseille group. In our institute, the RGR method is employed for two main reasons. (1) Efficacy and Safety: The RGR target is adequately far from the brain stem for an optimal dose (90 Gy at maximum) to the nerve. To date, we have achieved greater effectiveness while avoiding damage to the brain stem that could occur with high dose irradiation. (2) Efficacy and Accuracy: It is possible to precisely correct the magnetic resonance imaging (MRI) distortion by using computerized tomographic (CT)/MRI fusion images, because RGR targeting requires a bone landmark; the trigeminal incisula at the top of the petrous bone. On the contrary, it is impossible to directly correct MRI distortion with REZ targeting.

Patient Eligibility

In the field of functional radiosurgery, appropriate patient selection is critical. TGN should be regarded as apparent TGN, to be confirmed clinically. Table 1 presents the features of six subjects with a tentative diagnosis of TGN. Before concluding that GKS can be done, all subjects must be fully informed. Our treatment aim is to prevent or reduce ‘electric discharge’.

GKS Procedure for TGN

With frame fixation of the head, the frame must be placed parallel to the trigeminal nerve (fig. 1). Anatomical information regarding the nerve should also be confirmed. Next, we consider MRI sequence selection. Our aim is good visualization of the nerve in the cerebellopontine cistern. Therefore, we normally use ultra-thin slice (0.5 mm) 3D heavily T2-weighted and thin slice (1.0 mm) axial CT bone images. Before dose

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Table 1. Treatment indications and diagnostic criteria for essential TGN

(1) Electric discharge (2) Unique topography (not bilateral) (3) No neurological deficit (no sensory abnormality of face, no corneal hyporeflex) (4) No other type of pain (no atypical pain) (5) Trigger (touch and face washing/tooth brushing/mastication/speech/etc., swallowing) (6) Initial effect of carbamazepine

Fig. 1. Frame application. The frame should be parallel to the trigeminal nerve to demonstrate it in ‘one axial image’ for as long as possible.

planning, we obtain MRI/CT fusion images. We use RGR targeting, and an irradiation dose of 90 Gy, at maximum, taking into account the cerebellopontine cistern space. If the cistern is narrow, however, we use a beam plugging technique to modify the 20% isodose line (18 Gy area), making it parallel to the surface of the brain stem, thus avoiding excessive radiation of the brain stem (fig. 2). We assess the existence of MRI distortion using the MRI/CT fusion images and if any is detected, the amount of distortion is calculated precisely. After confirming the degree of distortion between CT and MRI images, we can correctly adjust using an APS (automatic positioning system) of the 0.1-mm level (fig. 3). The most important aspect of TGN is radiosurgery that delivers sufficient energy to the nerve with the smallest possible collimator. This means that the isocenter should fall precisely on the center of the true

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Fig. 2. Dose planning on 2D images. The target should be on the trigeminal nerve at the RGR with a 4 mm diameter for each isocenter. If the cerebellopontine cistern is too narrow, it will be necessary to avoid excessive irradiation to the brain stem using a beam-plugging technique.

trigeminal nerve. This precision is achieved using 3D images (fig. 4) in the final stage of dose planning.

Efficacy and Clinical Outcome

Two hundred and seventy patients (including 2 undergoing a second GKS) with TGN have been treated by GKS in our institution with RGR targeting. Among them, 150 followed up for more than 2 years were clinically evaluated. Initial pain reduction was observed in 97.3% (146/150), pain relief was complete in 77.3% (116/150). Significant effects were delayed for 1–90 (mean 28.4) days. True recurrence was observed in 10.2% (15/146). Delayed recurrence was detected at 6–9 (mean 7.7) months. Postoperative complications (hypoesthesia and dysesthesia) developed in 28% (42/150), but there were no mortalities. In those who received GKS only once, this rate was 4% (6/150). We also investigated clinical outcome according to the following treatment factors: (1) First-generation group (1998–2001): treatment using model B without complete fusion images: 29 cases (27 cases with follow-up). (2) Second-generation group (2002): treatment using model B with complete fusion images: 14 cases (all with follow-up).

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Fig. 3. Dose planning on workspace. This MRI was distorted by 0.8 mm in the Z axis. The target position (coordinate) was adjusted with CT scan bone images.

(3) Third-generation group (2003–2006): treatment using model C-APS with complete fusion images: 227 cases (109 cases with follow-up). Initial significant pain reduction was observed in 92.6% (25/27) of the first group, 100% of the second (14/14) and 98.2% of the third (107/109). The respective pain free rates were 63% (17/27), 85.7% (12/14), and 79.8% (87/109). Those for true recurrence were 24% (6/25), 28.6% (4/14), and 4.7% (5/107). Postoperative complication rates were 22.2% (6/27), 28.6% (4/14), and 29.4% (32/109). At our institution, no significant predictive parameters have been identified from our clinical results. The parameters examined include age, gender, affected side, topology, carbamazepine dose, delay of onset, previous intervention, cistern space, nerve atrophy, etc.

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Fig. 4. Dose planning on 3D images. It is necessary to confirm ‘dose planning’ on 3D images as a final check. This figure demonstrates the anatomical relationship and dose planning information. The nerve was irradiated at the RGR to maintain a distance to the vessel crossing the nerve.

Discussion

Optimal Targeting TGN is the most common functional disease that can be controlled well by GKS. This has already been established by single isocenter irradiation with a 4-mm collimator. However, clinical outcomes differ markedly among institutions. Regis et al. [3] (Marseille group) reported the clinical outcomes of 110 patients with RGR targeting in their prospective study. The initial pain-free rate was 97.2%

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(104/107), and the delay in effects was seen at 26.2 days on average (1 day to 6 months). True recurrence was observed in 14.4% (15/104) and postoperative complications in 4.5% (5/107). On the other hand, Kondziolka et al. [4, 5] (Pittsburgh group) reported their clinical experience with 220 patients in whom the initial painfree rate was 70.3%, that of true recurrence 13.6%, and postoperative complications were seen in 10.2%. Fukuoka [6] evaluated treatment data (1,145 cases) and clinical outcomes from multiple Japanese facilities and found that targeting position varies among institutions. REZ targeting was more widely used in Japan (69.4%) than RGR targeting (20.4%). MRI/CT fusion images were not used in all institutions. Significant pain reduction was observed in 85% (973/1,145) of cases, approximately 70% (800/1,145) of whom had initial pain relief, and the delay in effects was 30 days on average (1–120 days). True recurrence was observed in 9.5% (109/1,145), and delayed recurrence at 6.4 months on average (0–48 months). Postoperative complications developed in 12.3% (141/1,145), including 1.4% (16/1,145) with severe complaints. Clinical outcomes at our institution, particularly for the third group (model C-APS with MRI/CT fusion images), were close to those of the Marseille group. So far, we have regarded RGR targeting as being more advantageous than REZ targeting in terms of both efficacy and safety. The reasons are: (1) it is possible to irradiate with an optimal dose (90 Gy) taking care to protect the brain stem, and (2) more accurate treatment with availability of MRI/CT fusion images. Indications for Elderly Patients with Intractable TGN In order to confirm GKS indications for elderly patients (more than 65 years old) suffering from intractable TGN, Hayashi et al. [7] investigated 69 elderly subjects from the Marseille prospective study of 110 patients. Three issues were considered: (1) Comparison of clinical outcomes between elderly and younger groups: Initial pain relief was observed in 95.7% of the elderly group (vs. 100% of the younger group), true recurrence in 16.7% (vs. 10.5% of the younger group), and postoperative complications in 2.9% (vs. 5.4% of the younger group). As to the response of TGN to GKS, the younger group had slightly more favorable results than the elderly group. However, results were apparently acceptable for elderly patients. (2) Comparison of clinical outcome between previous surgical intervention (PSI) and no previous surgical intervention (NPSI) groups: Initial pain relief was observed in 92.6% (PSI) and 97.6% (NPSI), true recurrence in 20% (PSI) and 24.4% (NPSI), and postoperative complications in 12% (PSI) and 9.8% (NPSI). The NPSI group had better results than the PSI group, indicating that elderly patients with TGN should undergo GKS as the critical procedure before surgical intervention. (3) Comparison of clinical outcomes between the 90-Gy and lower dose groups: Initial pain relief was observed in 96.8% of the 90-Gy group (vs. 94.7% in the lower dose group), true recurrence in 12.9% (vs. 27.8% in the lower dose group), and postoperative complications in 3.2% (vs. 2.6% in the lower dose group). Notably, the

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TGN

Young

Elderly, MS, etc. MVD

Patient selection

Percutaneous treatment

V2, 3

RF

V1

Balloon

Ineffective

Gamma knife

Fig. 5. Flow chart of the treatment indications for trigeminal neuralgia. MS ⫽ Multiple sclerosis; RF ⫽ radiofrequency; balloon ⫽ micro-balloon compression; MVD ⫽ microvascular decompression.

rate of true recurrence was significantly higher in the lower dose group (p ⬍ 0.05). On the other hand, the rates of postoperative complications did not differ significantly. Thus, 90 Gy appears to be an optimal dose for elderly patients. In treating elderly patients with TGN, we recommend using the optimal radiosurgical dose (90 Gy at maximum) before any surgical intervention. Overall Management and Treatment Indications for TGN If the patient is relatively young, we recommend surgical intervention first, because the long-term effects of TGN radiosurgery are not yet known. Surgical procedures should be selected according to localization of pain, severity of vessel involvement, and patient choice (fig. 5). If surgical procedures fail or the effect is inadequate, we recommend GKS. If the patient is older, we recommend GKS as the first treatment for TGN prior to a surgical procedure (fig. 5). Likewise, in young patients, if surgery fails or the effect is inadequate, we recommend a second GKS or other surgical procedures as necessitated by the patient’s condition.

Conclusions

Over 20,000 cases in total suffering from TGN have been treated by GKS worldwide. Moreover, many published reports on clinical results and strategies have emphasized that GKS provides satisfactory results to most patients with few severe complications.

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To date, TGN has been widely accepted as an indication for GKS in the functional disease field. However, its mechanism of action has not yet been elucidated. If GKS produces destructive change in the nerve itself, patients will have sensory loss affecting half of the face. A 90-Gy dose appears to be sufficient to produce a functional effect, termed the ‘biological differential effect’, on the normal nerve/CNS without tissue ablation. This concept is anticipated to play an important role in the treatment of other functional diseases. Epilepsy and cancer pain have been managed with pituitary radiosurgery. Therefore, both basic and clinical studies are needed to confirm the efficacy and safety of GK radiosurgery for functional diseases. Of course, clinically, we need a much longer follow-up after treatment to evaluate whether GKS is an appropriate treatment for patients suffering from TGN.

References 1

2

3

4

Mullan S, Lichtor T: Percutaneous microcompression of the trigeminal ganglion for trigeminal neuralgia. J Neurosurg 1983;59:1007–1012. Barker FG, Janetta PG, Bissonette DJ, et al: The longterm outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med 1996;334: 1077–1083. Régis J, Bartolomei F, Metellus P, et al: Radiosurgery for trigeminal neuralgia and epilepsy: application of radiosurgery. Neurosurg Clin N Am 1999;10:359–377. Kondziolka D, Lunsford D, Flickinger JC, et al: Stereotactic radiosurgery for trigeminal neuralgia: a multi-institutional study using the gamma unit. J Neurosurg 1996;84:940–945.

5

6

7

Maesawa S, Salame C, Flickinger JC, et al: Clinical outcomes after stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2001;94: 14–18. Fukuoka S: Gamma knife radiosurgery for trigeminal neuralgia: multi-institute study of 1145 cases in Japan. 12th Leksell Int Conf Gamma Knife Society, Vienna, 2004. Hayashi M, Ochiai T, Murata N, et al: Gamma knife surgery for essential trigeminal neuralgia: advantages in new treatment strategy with robotized microradiosurgery; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2006, vol 6, pp 260–267.

Motohiro Hayashi, MD, DMSc Department of Neurosurgery, Neurological Institute, Tokyo Women’s Medical University 8–1, Kawada-cho, Shinjuku-ku Tokyo, 162-8666 (Japan) Tel. ⫹81 3 3341 6878, Fax ⫹81 3 3341 6878, E-Mail [email protected]

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Author Index

Akabane, A. 20 Asada, H. 11 Barfod, B.E. 154 Boku, N. 20 Fukuoka, S. 45, 96 Hasegawa, T. 122 Hayashi, M. 182 Hojyo, A. 45, 96 Inomori, S. 11 Inoue, H.K. 112 Iwai, Y. 129 Jokura, H. 20 Kawagishi, J. 20 Kida, Y. 31, 38, 122 Kobayashi, T. 63, 77 Konishi, M. 45 Lunsford, L.D. VIII

Nagano, H. 11 Nakagawara, J. 96 Nakamura, H. 45, 96 Nakayama, S. 11 Ohye, C. 170 Otto, S. 1 Sasaki, T. 96 Serizawa, T. 142 Shibazaki, T. 170 Sugai, K. 20 Shuto, T. 11 Takakura, K. IX Takahashi, K. 20 Takanashi, M. 45, 96 Tanaka, C. 45 Urakawa, Y. 154 Yamamoto, M. XI, 154 Yamanaka, K. 129 Yoshimoto, M. 122

191

Subject Index

Adrenocorticotropic hormone-producing pituitary adenoma, Gamma knife radiosurgery 85–88, 91, 93 Arteriovenous malformation (AVM) dural arteriovenous fistula Gamma knife radiosurgery case studies 42 complications 41 endovascular technique combination 43 indications 38, 39 outcomes 41, 43 overview 38 patient characteristics 39, 40 Furukawa Seiryo Hospital Gamma knife radiosurgery bleeding risks 24–26 complete obliteration rates 22 delayed cyst formation after surgery 26–28 dose-planning refinement effects on outcomes 28, 29 embolization effects 23–25 first surgery 22, 23 follow-up 22 repeat surgery 23 treatment policy and parameters 21, 22 treatment system 21 Astrocytoma, see Glioma Basal ganglia cavernous malformation, see Cavernous malformation Brain metastasis lung cancer Gamma knife radiosurgery

indications 151 pathology 144 patient characteristics 142, 143 prognostic factors 144, 147–150 radiation injury differentiation from tumor recurrence 152 salvage treatment 146, 151, 152 small cell lung cancer 151 survival curves 144, 146–149 treatment planning 143–145 multiple lesion Gamma knife radiosurgery case presentations 161–165 outcomes 157, 158 patient characteristics 155, 156 prognostic factors 158–161 prospects 167, 168 treatment planning and administration 156, 157 survival time prediction 12–18 whole brain radiation therapy 142, 154, 166, 167 Brainstem cavernous malformation, see Cavernous malformation Cavernous malformation, central nervous system Gamma knife radiosurgery goals 36 indications 32 perifocal edema 33, 35 rebleeding rates 33–35 response 33

193

Cavernous malformation, central nervous system Gamma knife radiosurgery (cont.) treatment dose 32, 33 symptomatic lesions 31 Cavernous sinus meningioma, see Skull-base meningioma Central pain, Gamma knife thalamotomy 177, 179, 180 Chordoma, Gamma knife radiosurgery case presentations 117, 118 outcomes 117, 119, 120 patient characteristics 117 Cobalt, import and loading 5, 7 Craniopharyngioma, Gamma knife radiosurgery case presentations 67–72 follow-up 65 origins of tumors 63, 74 outcomes classification 66, 67 long-term 69, 73 neurological and endocrinological outcomes 66 response rates 73 overview 63, 64 patient characteristics 64–66 prognostic factors 75 radiosensitivity 74, 75 treatment planning 64, 65, 75 Dural arteriovenous fistula, see Arteriovenous malformation Education clinical start-ups 9 information exchange 7 personnel exchange 8, 9 user meetings 7, 8 Facial nerve function, vestibular schwannoma Gamma knife radiosurgery 45, 53, 54, 58, 59 Gamma knife thalamotomy central pain 177, 179, 180 frequency of use 170 involuntary movement hospitalization 171 indications 171 outcomes 173–177, 180

194

re-operation 177, 178 technique 171–173 Germ cell tumor epidemiology 134 Gamma knife radiosurgery 134–137 Glioma, Gamma knife radiosurgery patient characteristics 121, 122 response rates by grade 123–125, 127 survival curves 124, 126, 127 treatment planning 123 Growth hormone-producing pituitary adenoma, Gamma knife radiosurgery 79, 81–83, 90 Hearing preservation, vestibular schwannoma Gamma knife radiosurgery 45, 52, 53, 57, 58 Hemangioblastoma epidemiology 129 Gamma knife radiosurgery 130–132 Hemangiopericytoma epidemiology 132 Gamma knife radiosurgery 132, 133 Historical perspective, Gamma knife radiosurgery in Japan approval for marketing and sales 3 cobalt import and loading 5, 7 early years 1, 2 education clinical start-ups 9 information exchange 7 personnel exchange 8, 9 user meetings 7, 8 growth in early 1990s 3, 4 indications over time 5 installation dates, locations, and models 6 Model B at Tokyo University hospital 2, 3 number of patients treated 5 reimbursement 4 treatment planning systems 4, 5, 7 Hydrocephalus, vestibular schwannoma Gamma knife radiosurgery 54, 55 Lung cancer, Gamma knife radiosurgery of brain metastasis indications 151 pathology 144 patient characteristics 142, 143 prognostic factors 144, 147–150 radiation injury differentiation from tumor recurrence 152 salvage treatment 146, 151, 152

Subject Index

small cell lung cancer 151 survival curves 144, 146–149 treatment planning 143–145 Lymphoma, see Primary central nervous system lymphoma Meningioma, see Skull-base meningioma Metastasis, see Brain metastasis Nonvestibular schwannoma, Gamma knife radiosurgery case presentations 114, 115 outcomes 113, 115, 116 patient characteristics 113 Normal tissue complication probability (NTCP), survival time prediction in brain metastasis 12–18 Parkinson’s disease, see Gamma knife thalamotomy Pituitary adenoma, Gamma knife radiosurgery adrenocorticotropic hormone-producing adenoma 85–88, 91, 92, 93 comparative outcomes 92, 93 growth hormone-producing adenoma 79, 81–83, 90 historical perspective 77, 78 nonfunctioning adenoma 78–80, 89, 90 patient characteristics 78 prolactin-producing adenoma 83–85, 90, 91, 93 Posterior fossa meningioma, see Skull-base meningioma Primary central nervous system lymphoma (PCNSL) epidemiology 137 Gamma knife radiosurgery 137–140 Prolactin-producing pituitary adenoma, Gamma knife radiosurgery 83–85, 90, 91–93 Schwannoma, see Nonvestibular schwannoma; Vestibular schwannoma Skull-base meningioma (SBM) Gamma knife radiosurgery cavernous sinus meningioma 101–105, 108, 109 patient characteristics 97, 98 posterior fossa meningioma 105–107, 109, 110

Subject Index

treatment strategies 98–100 treatment options 96 Survival time (ST), prediction in brain metastasis 12–18 Thalamotomy, see Gamma knife thalamotomy Thalamus cavernous malformation, see Cavernous malformation Tremor, see Gamma knife thalamotomy Trigeminal nerve function, vestibular schwannoma Gamma knife radiosurgery 54 Trigeminal neuralgia (TGN) Gamma knife radiosurgery efficacy 183, 185, 186 elderly patients with intractable neuralgia 188, 189 optimal targeting 187, 188 patient selection 183, 189 prospects 189, 190 treatment planning 183–185 treatment options 182, 183 Tumor control probability (TCP), survival time prediction in brain metastasis 12–18 Vestibular function, vestibular schwannoma Gamma knife radiosurgery 55, 56, 59, 60 Vestibular schwannoma, Gamma knife radiosurgery facial nerve function 45, 53, 54, 58, 59 follow-up 48 hearing preservation 45, 52, 53, 57, 58 hydrocephalus 54, 55 pathological findings 50 patient characteristics 46, 47 single-photon emission computed tomography findings 50, 51 treatment planning 48 trigeminal nerve function 54 tumor control 48, 49, 56, 57 vestibular function 55, 56, 59, 60 Whole brain radiation therapy (WBRT), metastasis management 142, 154, 166, 167

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196