Radiosurgery: 6th International Stereotactic Radiosurgery Society Meeting, Kyoto, June 22-26, 2003

Radiosurgery

Radiosurgery Vol. 5

Series Editors

D. Kondziolka Pittsburgh, Pa. M. McDermott San Francisco, Calif. J. Régis Marseille R. Smee Sydney J.C. Flickinger Pittsburgh, Pa.

6th International Stereotactic Radiosurgery Society Meeting, Kyoto, June 22–26, 2003

Radiosurgery Volume Editor

D. Kondziolka

Pittsburgh, Pa.

123 figures, 17 in color, and 45 tables, 2004

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

Douglas Kondziolka, MD, MSc, FRCS(C), FACS Departments of Neurological Surgery and Radiation Oncology Center for Image-Guided Neurosurgery UPMC Presbyterian Hospital University of Pittsburgh Pittsburgh, Pa., USA

Library of Congress Cataloging-in-Publication Data 䊏䊏䊏

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. 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 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 1024–2651 ISBN 3–8055–7717–6

Contents

IX Preface XI The Jacob I. Fabrikant Award The Jacob I. Fabrikant Memorial Address 1 A Strategy for Treating Sellar-Parasellar Tumors Based on Long-Term Results of Microsurgery and Gamma Knife Radiosurgery Kobayashi, T. (Nagoya) Radiobiology 13 What Can We Learn from Pathology? From the Beginnings towards Radiosurgical Pathology Szeifert, G.T. (Budapest); Kondziolka, D.; Lunsford, L.D. (Pittsburgh, Pa.); Hanzély, Z.; Nyáry, I. (Budapest); Salmon, I.; Levivier, M. (Brussels) 22 Radiation Tolerance of the Spinal Cord to Staged Radiosurgery Gibbs, I.C.; Chang, S.D.; Pham, C.; Adler, J.R. (Stanford, Calif.) 29 Construction and Verification of STI Device for Cat Model Hosono, M.N.; Tanaka, K.; Sahara, T.; Nishikawa, M.; Ishii, K.; Kondo, S.; Takada, Y.; Fukuda, H.; Hara, M.; Inoue, Y. (Osaka) Malignant Tumors 38 Acute Sequelae of Stereotactic Radiosurgery Hong, T.S.; Tomé, W.A.; Hayes, L.; Yuan, Z.; Badie, B. (Madison, Wisc.); Rao, R. (Rochester, Minn.); Mehta, M.P. (Madison, Wisc.)

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46 Stereotactic Radiosurgery for Brain Metastases and Cerebral FDG Positron Emission Tomography Golish, S.R.; De Salles, A.A.F.; Yap, C.; Solberg, T.D. (Los Angeles, Calif.) 51 Comparison of MR Spectroscopy and MR Perfusion in Benign and Malignant Infiltrative Brain Tumors Asavaphatiboon, S.; Sinlapawongsa, T.; Laothamatas, J.; Dhanachai, M.; Theerapancharoen, V.; Putthicharoenrat, S. (Bangkok) 66 Tumor Control Probability Predicts the Fate of Multiple Metastatic Brain Tumors Nagano, H.; Nakayama, S.; Asada, H.; Syutou, T.; Tanahata, K.; Inomori, S. (Yokohama) 77 Dose Absorbed by Normal Brainstem and Optic Apparatus in Gamma Knife Surgery for Ten or More Metastases Kamiryo, T.; Yamamoto, M.; Barfod, B.E.; Urakawa, Y. (Ibaraki) 82 Preliminary Novalis Experience in the Treatment of Skull Base Chordomas with Stereotactic Radiosurgery and Stereotactic Radiotherapy Pedroso, A.G.; De Salles, A.A.F.; Frighetto, L.; Torres, R.C.; Solberg, T.D.; Medin, P.; Cabatan-Awang, C.; Selch, M. (Los Angeles, Calif.) 91 Results Following Stereotactic Radiosurgery for Patients with Glioblastoma multiforme Nagai, H.; Kondziolka, D.; Niranjan, A.; Flickinger, J.C.; Lunsford, L.D. (Pittsburgh, Pa.)

Benign Tumors 100 Gamma Knife Stereotactic Radiosurgery for Type 2 Neurofibromatosis Acoustic Neuromas Rowe, J.; Radatz, M.; Walton, L.; Kemeny, A. (Sheffield) 107 Hearing Preservation after Radiosurgery Combined With or Without Microsurgery for Large Vestibular Schwannomas: Preliminary Results Inoue, H.K.; Nishi, H.; Shibazaki, T.; Ono, N. (Ohta) 115 Long-Term Follow-Up Using Linac Radiosurgery and Stereotactic Radiotherapy as a Minimally Invasive Treatment for Intracranial Meningiomas Torres, R.C.; De Salles, A.A.F.; Frighetto, L.; Gravori, T.; Pedroso, A.G.; Goss, B.; Medin, P.; Solberg, T.D.; Ford, J.M.; Selch, M. (Los Angeles, Calif.)

Contents

VI

124 Preservation of Olfaction in Olfactory Groove Meningiomas with Stereotactic Radiosurgery. Report of Three Cases and Review of the Literature Azmi-Ghadimi, H.; Jacobs, A.; Cathcart, C.; Schulder, M. (Newark, N.J.) 134 Gamma Knife Radiosurgery for Pituitary Adenoma Gaur, M.S.; Misra, J.; Banerji, A.K.; Bajaj, N.; Pathak, V.K. (New Delhi) 143 Metabolic Course of Low-Grade Gliomas after Gamma Knife Radiosurgery Evaluated by PET Scan with Methionine Massager, N.; Tang, T.; Goldman, S.; Wikler, D.; Gonzalez, S.R.; Devriendt, D.; Lorenzoni, J.; David, P.; Van Houtte, P.; Brotchi, J.; Levivier, M. (Brussels) Vascular Malformations 153 Radiosurgery for Cavernous Malformations: Results of Long-Term Follow-Up Kida, Y.; Hasegawa, T. (Aichi) Functional Disorders 161 Role of Pituitary Radiosurgery for Management of Intractable Pain and Potential for Future Work Hayashi, M.; Taira, T.; Chernov, M.; Izawa, M. (Tokyo); Lis¤ c¤ák, R. (Prague); Yu, C.P.; Ho, R.T.K. (Hong Kong); Tomita, M.; Katayama, Y.; Kouyama, N.; Kawakami, Y.; Hori, T.; Takakura, K. (Tokyo) 171 Treatment of Trigeminal Neuralgia Using Linear Accelerator-Based Radiosurgery Bradley, K.A.; Tomé, W.A.; Resnick, D.K.; Mehta, M.P. (Madison, Wisc.) 181 Temporal Pattern of Pain Relief Using CyberKnife Radiosurgery for Trigeminal Neuralgia: A Preliminary Report Romanelli, P.; Chang, S.; Gibbs, I.C.; Heit, G.; Adler, J.R. (Stanford, Calif.) 190 Trigeminal Nerve Radiosurgical Treatment in Intractable Chronic Cluster Headache: Preliminary Results Donnet, A. (Marseille); Valade, D. (Paris); Régis, J. (Marseille) Physics and Imaging 197 Measurements of Extracranial Doses in Patients Treated with Leksell Gamma Knife C De Smedt, F.; Vanderlinden, B.; Simon, S.; Paesmans, M.; Devriendt, D.; Massager, N.; Ruiz, S.; Lorenzoni, J.; Van Houtte, P.; Brotchi, J.; Levivier, M. (Brussels)

Contents

VII

213 MAGIC – Normoxic Polymer Gel Dosimetry in Radiosurgery Scheib, S.G. (Zürich); Vogelsanger, W. (Schaffhausen) 225 Measurement of Relative Dose Distributions in Stereotactic Radiosurgery by the Polymer-Gel Dosimeter Novotný, J., Jr.; Spe¤vác¤ek, V.; Hrbác¤ek, J.; Judas, L.; Novotný, J.; .Dvor¤ák, P; Tlachác¤ová, D.; Schmitt, M.; Tinte¤ra, J.; Vymazal, J.; C¤echák, T.; Michálek, J.; Pr¤ádný, M.; Lišc¤ák, R. (Prague) 236 A System for Quality Assurance in Radiosurgery Mack, A. (Frankfurt); Scheib, S.G. (Zürich); Rieker, M.; Weltz, D.; Mack, G. (Tübingen); Czempiel, H.; Kreiner, H.J. (München); Boettcher, H.D.; Seifert, V. (Frankfurt) 247 Clinical Validation Methodology for the Use of Frameless PET in Leksell Gamma Knife® Radiosurgery Wikler, D.; Sadeghi, N.; Goldman, S.; Massager, N.; Levivier, M. (Brussels) 255 Quality Assurance of the Cyberknife Fiducial and Skull Tracking Systems Ho, A.; Cotrutz, C.; Chang, S.D.; Adler, J.R.; Gibbs, I.C. (Stanford, Calif.) 260 Clinical Evaluation of a Gamma Knife Inverse Planning System Wu, Q.J.; Jitprapaikulsarn, S.; Mathayomchan, B.; Einstein, D.; Maciunas, R.J.; Pillai, K.; Wessels, B.W.; Kinsella, T.J.; Chankong, V. (Cleveland, Ohio) 267 MR Spectroscopy and MR Perfusion of Brain Tumors Before and After Radiation Therapy: Preliminary Results Laothamatas, J.; Asavaphatiboon, S.; Sinlapawongsa, T.; Dhanachai, M.; Yongvithisatid, P.; Theerapancharoen, V. (Bangkok) 278 Author Index 280 Subject Index

Contents

VIII

Preface

The International Stereotactic Radiosurgery Society represents a community of colleagues across the world. The 6th meeting of the society was held in Kyoto, Japan, under the stewardship of Prof. Kintomo Takakura and Dr. Masaaki Yamamoto. Dr. David Larson ended his two-year term as ISRS President. The meeting included attendees from all over the world and represented the disciplines of neurosurgery, radiation oncology, medical physics, radiology, oncology, and neurology. The tranquil setting of the Kyoto Conference Center provided a forum for collegiality, discussion, and debate. The 2005 meeting will be held in Brussels, Belgium. This fifth volume includes evaluations of skull base tumor radiosurgery, evaluation of new imaging techniques for radiosurgery, complication management and avoidance, new device evaluations, and extracranial approaches. The multidisciplinary nature of the field remains strong as society members continue to evaluate and share their results. The ISRS remains the only society to embrace all of the different aspects of clinical and research radiosurgery. We remain indebted to our publisher, S. Karger AG, and in particular Angela Weber, for their work on this volume. Douglas Kondziolka

IX

The Jacob I. Fabrikant Award

a

b Dr. David Larson, President of the International Stereotactic Radiosurgery Society, presents the Jacob I. Fabrikant Awards to Dr. John Flickinger (a) and Dr. Tatsuya Kobayashi (b).

XI

The Jacob I. Fabrikant Memorial Address Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 1–12

A Strategy for Treating Sellar-Parasellar Tumors Based on Long-Term Results of Microsurgery and Gamma Knife Radiosurgery1 Tatsuya Kobayashi Department of Neurosurgery, Gamma Knife Center, Komaki City Hospital, Jobushi, Komaki City and Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital, Nakagawa-ku, Nagoya, Japan

Abstract One hundred and three cases with sellar-parasellar tumors were treated using microsurgery and gamma knife radiosurgery, and followed up for more than 5 years. The sellarparasellar area is the most critical eloquent region not only in microsurgery but also in radiosurgery. The tumor volume and the distance from the tumor to the optic nerve are the most important dose-planning factors for these tumors, followed by the radiosensitivity of the tumor. Although the distance to critical structures is short and the marginal dose is limited in cases with suprasellar germinoma, optic glioma or craniopharyngioma, excellent results can be obtained due to the relatively high radiosensitivity of these tumors. When the tumor volume is large and radiosensitivity is low in cases with non-functioning pituitary adenoma or meningioma, surgical debulking of the tumor and decompression of and detachment from the optic pathways (3D strategy) are necessary prior to radiosurgery. As to functioning adenomas, when the tumor is small and the distance is large, a higher radiation dose can be given and favorable results obtained. There is no deterioration of neuroendocrinological functions despite the low radiosensitivity. Copyright © 2004 S. Karger AG, Basel

1 The main part of this paper was presented as a Memorial Lecture for the Fabrikant Award at the 6th Meeting of the International Stereotactic Radiosurgery Society, Kyoto, June 25, 2003.

Over the past 12 years, more than 4,400 patients have been undergone gamma knife radiosurgery at Komaki City Hospital; 1,160 of these cases had pituitary adenomas, meningiomas, craniopharyngiomas, gliomas or pineal and related tumors. Among them, 103 cases were treated for sellar-parasellar tumors and then followed for more than 5 years. In this report, treatment strategies for these tumors are re-evaluated based on the long-term results of microsurgery and stereotactic gamma knife radiosurgery.

Materials and Methods The 103 sellar-parasellar tumor cases included in this study consisted of 30 with pituitary adenomas (PA), of which 12 were non-functioning and 18 were functioning adenomas, 33 with craniopharyngiomas (CRAN), 27 with cavernous sinus meningiomas (CSM), 10 with hypothalamic or optic nerve gliomas (ONG), and 3 with suprasellar germinomas (SSG). Case Characteristics The mean ages of the cases with non-functioning and functioning PA were 50.4 and 40.4 years, respectively. In each group, the majority of cases were female. Eleven of the 12 cases with non-functioning PA had previously undergone surgery, and 2 had received conventional irradiation. Gamma knife radiosurgery was used as the initial treatment in only 1 case. Nine of the 18 cases with functioning PA had undergone surgery, and 4 had received medications or irradiation prior to radiosurgery. Gamma knife radiosurgery was the initial treatment in 4 cases. The CRAN cases were divided into two age groups: 10 children and 23 adults, of which the mean ages were 9.7 and 43.9 years, respectively. The overall male:female ratio was 16:17. Thirty-one patients had undergone surgical treatments prior to radiosurgery; gamma knife radiosurgery was used as the initial treatment in only 2 cases. The mean age of the CSM cases was 52.0 years, and the male:female ratio was 6:21. Seventeen patients had received surgical treatments prior to radiosurgery. Ten patients had not undergone surgery. The mean age of those with hypothalamic gliomas or ONG was 13.5 years, and the male:female ratio was 5:5. All 10 patients had undergone surgical treatment, allowing a pathological diagnosis of astrocytoma G-I or pilocytic astrocytoma to be made. The mean age of the SSG cases was 16.3 years, and all were male. Gamma knife radiosurgery was indicated only for tumors resistant to or which recurred after conventional chemoradiation therapy. Dosimetry The largest mean diameter of tumors treated using gamma knife radiosurgery was 28.2 mm in non-functioning PA, followed by ONG, CSM, and functioning PA, while SSG had the smallest mean diameter of 11 mm. In general, the marginal dose was limited mainly by the size and location of the tumor. The largest marginal dose (25.7 Gy) was given to those with functioning PA because of the relatively small tumor size and sufficient distance between the tumor and the optic nerve in these cases. The marginal dose was limited to 12 Gy in cases with CRAN, ONG and SSG because of optic nerve tumor involvement. The marginal dose was also limited in cases with CSM and non-functioning PA because of the larger tumor size and critical location (table 1).

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Table 1. Characteristics and relative responses to gamma knife radiosurgery of sellarparasellar tumors (n ⫽ 103, follow-up ⬎5 years) Tumors

Case No.

Diam. mm

Marginal dose, Gy

CR rate, %

Response rate, %

Control rate, %

PG rate, %

PA non-funct. PA funct. CRAN CSM ONG SSG

12 18 33 27 10 3

28.2 20.5 20.1 27.4 28.1 1.7

14.3 25.7 12.0 13.6 12.5 12.2

0 16.6 30.3 0 10.0 66.7

58.3 66.6 81.8 44.4 70.0 100

83.3 100 84.8 88.9 90.0 100

16.6 0 15.2 11.1 10.0 0

CR ⫽ Complete response; PG ⫽ progression.

Evaluation of Radiosurgery Efficacy The effects of gamma knife radiosurgery were mainly evaluated by examining changes in tumor size, as shown by MRI examinations performed every 3–6 months after treatment. The changes in tumor volume were expressed using the grading system proposed by the Committee of the Japan Brain Tumor Registry [1] which consists of the following classifications: CR (disappeared), PR (decreased by ⱖ25% of volume), NC (decreased by ⬍25% or unchanged) and PG (enlarged). From these values, the CR, response, control, and PG rates were calculated and compared among the tumor groups. The radiosensitivity of a tumor can be expressed as the relative percentage of CR and/or the response rate. Other evaluations were also made based on changes in neurological and endocrinological signs, as well as the patient’s general condition, every 6 months.

Results

After a long-term follow-up period of at least 5 years (mean 7 years), a CR was obtained in 2 of 3 SSG cases (66.7%), 10 of 33 CRAN cases (30.3%), 3 of 18 functioning PA cases (16.6%), and 1 of 10 ONG cases (10%). The SSG cases had the highest response rate (100%), followed by CRAN (81.8%), ONG (70%), functioning PA (66.7%) and non-functioning PA (58.3%). The response rate was only 44.4% for the CSM cases. However, the control rate was 100% for the functioning PA and SSG cases, and higher than 83.3% for all other tumor groups. Tumor progression occurred in 2 of 12 non-functioning PA cases (16.6%), 5 out of 33 CRAN cases (15.2%), 3 of 27 CSM cases (11.1%) and 1 of 10 ONG cases (10%). PG has not been obtained in any SSG or functioning PA case, to date. Thus, germinoma, CRAN and OPG tumors apparently have relatively high radiosensitivity, while PA tumors and meningiomas have lower radiosensitivity (table 1).

Strategy for Treating Sellar-Parasellar Tumors

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a

b

c

d

Fig. 1. Follow-up MRIs of a craniopharyngioma case: A suprasellar tumor compressing the optic nerves was identified before surgery (a). After subtotal removal, a small residual tumor (13.6 mm in diameter) at the optic nerve and stalk was treated with gamma knife radiosurgery (RS) using a marginal dose of 15 Gy (b). The tumor had nearly disappeared at 12 months (c) and has been stable for more than 116 months, to date (d) without neurological deficit.

The outcomes of our patients, with regard to their neuroendocrinological and general status, correlated well with the degree of tumor regression or progression. Ten of 12 non-functioning PA cases were evaluated as having an excellent outcome after gamma knife radiosurgery, with no side effects, but the remaining 2 cases experienced re-growth of the tumor and deterioration of visual function. Fourteen of 18 cases with functioning PA were evaluated as having an excellent or good outcome with decreasing hormone levels. The outcome was excellent in 16 (48.8%), good to fair in 12 (36%), poor in 3 (9.1%), and death in 2 of 33 CRAN cases (6%). Tumor progression, resulting from cyst enlargement, was observed in 5 cases (15.1%). Hypopituitarism was recognized in 3 cases, increased intracranial pressure in 1, and a visual field defect in 1. The outcome of CSM cases was rated as excellent except for 3 in whom tumor re-growth occurred and 1 case each with epilepsy and visual acuity deterioration as side effects. The outcome was excellent or good in 9 of 10 ONG cases, but there was tumor progression in 1 case. All SSG cases had excellent outcomes without worsening of neuroendocrinological symptoms.

Kobayashi

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84/50

RS

8M

a

b '96.4

'96.9

Fig. 2. Follow-up MRIs and changes in symptoms of Cushing disease associated with microadenoma: A microadenoma measuring 5 mm in diameter was detected in the pituitary gland and was initially treated with gamma knife radiosurgery using a marginal dose of 50 Gy (RS), with the optic nerve receiving ⬍8.4 Gy. The tumor disappeared and the diaphragma sellae was in a lower position at 8 months (8 M). These findings were unchanged for 7 years after treatment. The moon face and obesity (a) had disappeared by 5 months with normalization of ACTH and cortisol levels (b).

Case Presentations Case 1 (fig. 1): A 9-year-old boy with a CRAN presented with headaches and visual disturbances. MRI examination revealed a large mass at the suprasellar region (a). The mass was subtotally removed and a small residual tumor (mean diameter 13.6 mm) attached to the optic nerve and stalk was treated with gamma knife radiosurgery (RS) using a marginal dose of 15 Gy (b). Twelve months after treatment, the tumor had almost completely disappeared (c), and has been stable for more than 116 months to date (d). The patient graduated from university and has been living normally with no neuroendocrinological deficits. Case 2 (fig. 2): An 11-year-old girl exhibited a moon face and obesity (a). MRI examination revealed an intrasellar microadenoma with a diameter of 5 mm

Strategy for Treating Sellar-Parasellar Tumors

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b

a

c

Fig. 3. Follow-up MRIs of a huge suprasellar extension of a non-functioning adenoma: The enormous suprasellar mass (a), associated with visual disturbances (PRE OP), was initially treated by transsphenoidal debulking of the tumor and decompression of the optic nerves. After improvement of visual function and detachment of the optic nerve from the tumor, a residual tumor (b) was treated with gamma knife radiosurgery using a marginal dose of 13 Gy (GK). The tumor showed a PR at 12 months (c) after treatment.

(RS). Cushing disease was diagnosed but transsphenoidal surgery was contraindicated because she had a concha type of sella turcica. The tumor was initially treated using gamma knife radiosurgery with a marginal dose of 50 Gy, with the optic nerve receiving ⬍8.4 Gy. Her symptoms disappeared in 5 months (b), followed by disappearance of the tumor at 8 months (8 M) and normalization of serum hormone levels at 12 months after the procedure. She is currently attending high school and has no endocrinological deficits, 7 years after treatment. Case 3 (fig. 3): A 69-year-old woman complained of visual disturbances and a headache of 6 months’ duration. MRI examination revealed a huge suprasellar mass (PRE OP) resulting in visual acuity loss and bitemporal hemianopsia (a). Transsphenoidal debulking of the tumor and decompression of the optic nerve were performed under a diagnosis of non-functioning PA. After visual function improvement and detachment of the tumor from the optic nerve had been confirmed (3D strategy), gamma knife radiosurgery (GK) was employed for the residual tumor using a marginal dose of 13 Gy (b). The tumor showed a partial response at 12 months (c). Case 4 (fig. 4): A 63-year-old woman complained of double vision, and MRI examination showed a mass (mean diameter 20.2 mm) in her right cavernous sinus. An open tumor biopsy yielded a diagnosis of intracavernous meningioma (a). The tumor was treated with gamma knife radiosurgery using a marginal dose of 13 Gy. The tumor showed a partial response (PR) after 42 months (b) with amelioration of the diplopia. Case 5 (fig. 5): A 4-year-old boy complained of visual loss involving the right eye. MRI examination showed a chiasmal mass with a cyst (mean diameter 19.2 mm), and open biopsy confirmed the diagnosis of pilocytic astrocytoma (a).

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a

b Fig. 4. Follow-up MRIs of intrinsic cavernous sinus meningioma: After biopsy, a mass in the right cavernous sinus was treated with gamma knife radiosurgery using a marginal dose of 13 Gy (a), with the optic nerve receiving ⬍7.8 Gy. The tumor showed a PR at 42 months (b) with amelioration of diplopia.

a

b Fig. 5. Follow-up MRIs of optic nerve glioma: A chiasmal mass including a cyst was treated with gamma knife radiosurgery using a marginal dose of 11 Gy (a) after open biopsy. The pilocytic astrocytoma had nearly disappeared at 30 months (30 M) without deterioration of left eye visual function. The normalized anatomies of optic nerves and stalk are apparent (b).

Strategy for Treating Sellar-Parasellar Tumors

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b

a

c

Fig. 6. Follow-up MRIs of suprasellar germinoma: A solid chiasmal mass, clinically diagnosis as a germinoma, was treated with cisplatin and etoposide chemotherapy, followed by fractionated irradiation of 24 Gy (a). The tumor showed a marked response but a residual tumor (b) required gamma knife irradiation (GK) with a marginal dose of 11 Gy. The tumor had disappeared 16 months (16 M) after radiosurgery (c).

The tumor was treated with gamma knife radiosurgery using a marginal dose of 11 Gy (11 G). At 30 months after treatment (30 M), the tumor had nearly disappeared (b) without visual function deterioration in his left eye. Case 6 (fig. 6): A 15-year-old boy began to experience visual disturbances and developed diabetes insipidus. MRI showed a solid suprasellar mass, leading to a clinical diagnosis of suprasellar germinoma (a). The patient received 8 courses of chemotherapy with carboplatin and etoposide followed by focal irradiation with 24 Gy. The small residual, resistant tumor in the chiasmal portion was treated using gamma knife radiosurgery with a marginal dose of 11 Gy (b). Sixteen months later (16 M), the tumor had completely disappeared (c) without changes in neuroendocrinological signs.

Discussion

In parallel with the development of imaging technology over the past 15 years, stereotactic radiosurgery has been widely introduced and advanced in the field of neurosurgery as a novel radiation therapy modality. Stereotactic gamma knife radiosurgery has been proven to be safe and effective not only for vascular diseases, such as AVM, and various brain tumors, but also for functional conditions, including trigeminal neuralgia, Parkinson disease and epileptic disorders. However, there are a few locations in the brain in which the use of radiosurgery is limited because of the risk of exposing critical structures to radiation. These sites include the optic pathways, as well as cochlear and other cranial nerves, for which tolerable radiation doses have been determined to be

Kobayashi

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low as 10, 14 and 16 Gy, respectively [2]. These locations have been defined as ‘radiosurgical eloquent areas’ and the sellar-parasllar region is the most eloquent area [3]. The treatment dose for sellar-parasellar tumors is limited mainly by the volume and location of the tumor [4], which is represented by the distance between the tumor and the optic pathways. The radiosensitivity of a particular tumor appears to be the third most important factor. The relative sensitivities to radiosurgery of the five tumor groups examined in this study were compared. The radiosensitivity of CRAN, ONG and SSG tumors was somewhat higher than that of PA tumors and meningiomas. A higher response rate and control of residual or recurrent tumors can be expected using gamma knife radiosurgery even with a relatively low marginal dose if the radiosensitivity of the tumor is high, as in SSG, CRAN and ONG tumors. When the radiosensitivity of a large tumor compressing the optic pathway is low, as in non-functioning PA and meningiomas, surgical removal using a 3D strategy is necessary prior to radiosurgery. Therefore, it is important to devise a strategy, assuring a good quality of life, which is specific to and effective for each tumor group or tumor state. This is done by using a combination of different treatment modalities such as microsurgery, stereotactic radiosurgery, fractionated irradiation and chemotherapy. The treatment strategy for PA was formerly a combination of surgical removal with fractionated irradiation [5]; but the response to this protocol was low, and the potential side effects of radiation to the optic nerve, pituitary gland or hypothalamus could not be overlooked [6]. Recent studies [7–9] using stereotactic radiosurgery for the treatment of PA have shown that the effects to be definite and safe without the major complications associated with conventional irradiation. Intrasellar micro- or small adenomas can be safely treated with higher marginal doses because the distance between the tumor and optic pathway is large enough to allow the use of a high dose [9] without the risk of side effects, as in our case 2. As a result, functional PA showed a CR rate of 16.6% without tumor progression, while CR was not obtained and the PG rate was 16.6% in non-functioning PA because the marginal dose was limited by tumor size. Thus, a proposed treatment for large PA involves a combination of surgical removal using a 3D strategy and stereotactic radiosurgery for the remnant tumor. Functioning PA can be treated with gamma knife radiosurgery alone if the tumor is small and confined to the sellae or cavernous sinus [9]. The treatment strategy for CRAN has long been a topic of controversy. Total removal without severe neurological deficits and recurrence has been difficult [10], while partial removal with fractionated irradiation has presented problems with tumor control and hypopituitarism [11]. CRAN tumors have been considered to be radiosensitive, not only with conventional irradiation but

Strategy for Treating Sellar-Parasellar Tumors

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also stereotactic radiosurgery. The results of stereotactic radiosurgery have been excellent [12], and the CR rate in this study was 30.3% while the response rate was 81.8% [13]. Recently repeated long-term results showed the effects of radiosurgery to be dose-dependent and that patient age and the nature of the tumor are significant prognostic factors [14]. However, cyst enlargement was found to be common and was the main cause of tumor progression [13, 14]. Therefore, cystic tumors should generally be surgically treated by aspiration or removal of the cyst prior to radiosurgery [14]. Extensive removal of solid or mixed tumors without deterioration of neuroendocrinological functions followed by radiosurgery for small residual tumors in critical locations should be the treatment of choice as in our case 1. The idea of treating benign meningiomas using irradiation could not be realized until the advent of gamma knife radiosurgery [15]. CSM, which is representative of skull base meningiomas, has a higher response rate than other meningiomas [16, 17]. However, the response rate was only 44.4%, despite the control rate being 90%. In other words, tumor re-growth was identified in about 10% of our cases and was thought to be dose-dependent [18]. CSM has been a challenging tumor for neurosurgeons; total removal is difficult to achieve without severe neurological deficits and recurrence [19]. The reported results of gamma knife radiosurgery included a high control rate for a prolonged period without deterioration, and even some improvement in cranial nerve signs [16, 17]. Partial removal, except for the cavernous portion, using a 3D strategy followed by radiosurgery should also be applied to large tumors. ONG is a type of hypothalamic glioma, with common characteristics, frequently seen in younger children. It is pathologically benign. Treatment for this tumor has been controversial. The results of conventional irradiation are equivocal [20], and surgical removal is often accompanied by functional deterioration [21, 22]. Recent reports suggest chemotherapy to be effective in some cases, although longer follow-up is necessary [23]. In this study, gamma knife radiosurgery for the treatment of ONG resulted in high response and control rates, with a CR rate of 10% and no deterioration in optic function [24]. The treatment of first choice for ONG should therefore be gamma knife radiosurgery with a low marginal dose after the tumor has been biopsied. The treatment strategy for intracranial germinoma has been generally accepted in Japan to consist of cisplatin and etoposide chemotherapy, with lowdose conventional irradiation. This strategy results in a cure rate of more than 90% [25]. However, the treatment of recurrent or resistant tumors after initial therapy was the object of this study. Since germinomas are highly radiosensitive, gamma knife radiosurgery of the tumor using even a low marginal dose can result in high response and control rates [26].

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Conclusion

The volume and location of a tumor, in terms of the distance from the tumor to the optic nerve, and its radiosensitivity are important factors in considering dosimetry for sellar-parasellar tumors. Following biopsy and partial removal, small residual or recurrent CRAN and optic gliomas, even when located near critical organs, can be treated safely and effectively with gamma knife radiosurgery using a relatively low marginal dose. Debulking of the tumor, decompression of the optic nerve and detachment of the tumor from the optic nerve (3D strategy) are necessary before gamma knife radiosurgery to treat large tumors with relatively low radiosensitivity, such as non-functioning PA and meningiomas. Microadenomas and small functioning PA can be diagnosed clinically and treated with gamma knife radiosurgery alone, using a high marginal dose of radiation, without side effects. Intracranial germinomas have been successfully treated by a combination of chemotherapy using cisplatin and etoposide, with low-dose fractionated irradiation. Gamma knife radiosurgery is indicated for previously treated residual or resistant tumors.

References 1 2 3

4 5 6 7

8 9 10

Committee of Brain Tumor Registry of Japan: The Criteria for Evaluation of the Effects of Brain Tumor Treatments (in Japanese). Tokyo, Kanehara, 1995. Leber KA, Bergloef J, Pendle G: Dose-response tolerance of the visual pathways cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998;88:43–50. Kobayashi T, Kida Y, Tanaka T, Yoshida K, Mori Y, Ohsuka K, Hasegawa T, Kondo T: Eloquent areas in the gamma knife treatment of arteriovenous malformations of the brain (in Japanese). Jpn J Neurosurg (Tokyo) 1999;8:385–394. Marks LB, Spencer DP: The influence of volume on the tolerance of the brain to radiosurgery. J Neurosurg 1991;75:177–180. Flickinger JC, Nelson PB, Martinez AJ, Deutsch M, Taylor F: Radiotherapy of non-functional adenomas of the pituitary gland. Cancer 1989;63:2409–2414. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML: Hypopituitarism following external radiotherapy for pituitary tumors in adults. Am J Med 1989;70:145–160. Landolt AM, Haller D, Lomax N, Scheib S, Schubiger D, Siegfried J, Wellis G: Stereotactic radiosurgery for recurrent surgically treated acromegaly: A comparison with fractionated radiotherapy. J Neurosurg 1998;88:1002–1008. Landolt AM, Lomax N: Gamma knife radiosurgery for prolactinomas. J Neurosurg 2000;93 (suppl 3):14–18. Kobayashi T, Kida Y, Mori Y: Gamma knife radiosurgery in the treatment of Cushing disease: Long-term results. J Neurosurg 2000;97(suppl 5):422–428. Hoffman HJ, DeSilva M, Humphreys RP, Drake JM, Smith ML, Blaser SI: Aggressive surgical management of craniopharyngioma in children. J Neurosurg 1992;76:47–52.

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14 15 16 17 18

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20 21

22 23 24 25

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Thomsett MJ, Conte FA, Kaplan SL, Grumbach MM: Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effects of treatment in 42 patients. J Pediatr 1980;97: 728–735. Kobayashi T, Tanaka T, Kida Y: Stereotactic gamma radiosurgery of craniopharyngiomas. Pediatr Neurosurg 1994;21(suppl 1):69–74. 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. Kobayashi T, Kida Y, Hasegawa T: Long-term results of gamma knife surgery for craniopharyngioma. Neurosurg Focus 2003;14:1–6. Kondziolka D, Lunsford LD, Coffey RJ, Flickinger JC: Stereotactic radiosurgery of meningiomas. J Neurosurg 1991;74:552–559. Kobayashi T, Kida Y, Mori Y: Long-term results of stereotactic gamma radiosurgery of meningiomas. Surg Neurol 2001;55:325–331. 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. 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 Neurosurg 2001;95:435–439. Sekhar LN, Patel S, Cusimano M, Wright DC, Sen CN, Bank WO: Surgical treatment of meningiomas involving the cavernous sinus: Evolving ideas based on a ten-year experience. Acta Neurochir Suppl (Wien) 1996;65:58–62. Pierce SM, Barnes PD, Loeffler JS, McGinn C, Tarbel NJ: Definitive radiation therapy in the management of symptomatic patients. Survival and long-term effects. Cancer 1990;65:45–52. Sutton LN, Molloy PT, Sernyak H, Goldwein J, Phillips PL, Roarke 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. Tenny RT, Laws ER, Younge BR, Rush JA: The neurosurgical management of optic glioma: Results in 104 patients. J Neurosurg 1982;57:452–458. Brown MT, Friedman HS, Oakes WJ, Boyko OB, Hockenberger B, Schold CS: Chemotherapy for pilocytic astrocytoma. Cancer 1993;71:3165–3172. Kida Y, Kobayashi T, Mori Y: Gamma knife radiosurgery for low-grade astrocytoma: Results of long-term follow-up. J Neurosurg 2000;93:42–46. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O: Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Childs Nerv Syst 1998;14: 55–62. Kobayashi T, Kida Y, Mori Y: Stereotactic gamma radiosurgery for pineal and related tumors. J Neurooncol 2001;54:301–309.

Tatsuya Kobayashi, MD, PhD, Chairman Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital 1-172 Hokke, Nakagawa, Nagoya, Aichi 454-0933 (Japan) Tel. ⫹81 52 3625151, Fax ⫹81 52 3539126, E-Mail [email protected]

Kobayashi

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Radiobiology Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 13–21

What Can We Learn from Pathology? From the Beginnings towards Radiosurgical Pathology1

György T. Szeiferta, Douglas Kondziolkab, L. Dade Lunsford b, Zoltán Hanzélya, István Nyárya, Isabelle Salmonc, Marc Levivierc a

National Institute of Neurosurgery, Budapest, Hungary; bCenter for Image Guided Neurosurgery, Presbyterian University Hospital, Pittsburgh, Pa., USA and c Centre Gamma Knife, Université Libre de Bruxells, Hôpital Académique Erasme, Brussels, Belgium

Abstract The term of radiosurgery signifies any kind of single application of ionizing radiation energy, in experimental biology or clinical medicine, aiming at the precise and complete destruction of chosen target structures containing healthy and/or pathological cells, without significant concomitant or late radiation damage to adjacent tissues. The goal of this radiosurgical pathology study is to explore the short- and long-term effects of high-dose ionizing radiation on neural tissue and its pathologies with histological, electron-microscopical, tissue culture and biological-biochemical methods. Radiosurgical pathology focuses its scope and microscope for histological, cell, genetic and molecular changes in the human body and experimental animals, or in tissue cultures and other in vitro experiments, generated by the ionizing radiation delivered from radiosurgical devices. Copyright © 2004 S. Karger AG, Basel

Background

Radiosurgery, invented by Prof. Lars Leksell [1], has become a successful treatment modality in the neurosurgical realm during the past three decades. Since 1968, when the first patient was treated in Stockholm with the prototype Gamma Knife, more than two hundred thousand cases have already been operated on worldwide with the Gamma Knife. In addition to this, many patients were treated with other radiosurgical methods like linear accelerators or charged 1This paper is dedicated in honor of Professor Szabolcs Gomba, Department of Pathology,

University Medical School of Debrecen, Hungary, for his 70th birthday.

particle devices. Although the treatment indications and the number of treated patients has been increasing continuously, we know relatively little about pathological background of radiosurgery explaining radiobiology and pathophysiological mechanisms leading to therapeutic or undesired side effects. The future of radiosurgery beyond technical advancements will be built on better understanding of the biological basis of radiation, which will enable treatment of new disorders [2]. Regarding that huge clinical experience has already been accumulated in radiosurgery during the past three decades, it would be timely to process out systematically pathological fundamentals of the effect of single high-dose irradiation, to understand better radiobiology for radiosurgically treatable diseases. Medicine has been built from experience. As it had happened in the ancient times, clinical studies progressed much more ahead than the exploration of pathological-pathophysiological mechanisms of radiosurgical disorders. The father of pathological anatomy, Giovanni Battista Morgagni (1682–1771), had started his regular autopsy studies because he was not happy with the unexplainable physical signs and symptoms, and wanted to reveal the overlying biological process leading to disturbance of the human organism. Although anatomical lessons had been performed before Morgagni as well, the systematic comparison of clinical symptoms with morphological findings graduated him as a dedicated master of clinical pathology. The term of radiosurgery signifies any kind of single application of ionizing radiation energy, in experimental biology or clinical medicine, aiming at the precise and complete destruction of chosen target structures containing healthy and/or pathological cells, without significant concomitant or late radiation damage to adjacent tissues [3]. Therefore, the goal of radiosurgical pathology should be to study the short- and long-term effects of high-dose ionizing radiation on neural tissue and its pathologies with histological, electron-microscopical, tissue culture and biological-biochemical methods. Radiosurgical pathology focuses its scope and microscope for histological, cell, genetic and molecular changes in the human body and experimental animals, or in tissue cultures and other in vitro experiments, generated by the ionizing radiation delivered from radiosurgical devices.

Historical Antecedents

The first human anatomical image collection was created by the great humanist, artist and scientist Leonardo da Vinci (1452–1519) as early as the 15th century (fig. 1a, b). However, from a medical point of view, systematic anatomical lessons were performed by Andreas Vesalius (1514–1564) one century later. His experience was based totally on human autopsy studies and collected it in the book ‘De humani corporis fabrica libri septem’ published in

Szeifert/Kondziolka/Lunsford/Hanzély/Nyáry/Salmon/Levivier

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a

b Fig. 1. a Portrait of Leonardo da Vinci (1452–1519). b Skull delineation from Leonardo’s anatomical image collection.

1543 (fig. 2). In this way the anatomical teachings of Galenos, which came mainly from animal investigations, was developed. Another century ahead, and Giovanni Battista Morgagni (1682–1771), professor of medicine in Padova, Italy, started to collate on a regular basis clinical symptoms and signs with anatomical alterations in the human organism. He explained different disorders as consequences of morphological disturbances in the structure of organs therefore we can regard him as the founder of clinical pathology (fig. 3). His fundamental work ‘De sedibus et causis morborum per anatomen indagatis libri quinque’ was published in 1761. Antonie van Leeuwenhoek (1632–1723) did a meaningful contribution by the use of microscope for scientific investigations. The pioneer of microscopic anatomy was Marcello Malpighi (1628–1694) with regular histological examinations of various organs. Different tissue elements of the organism were discovered by Marie Françoise Xavier Bichat (1771–1802). He suggested that diseases propagate along tissues and established modern histology. An outstanding observation in structural research came from Mathias Jakob Schleiden (1804–1881) and Theodor Schwann (1810–1882). They realized that the cell is the basic unit of every living organism in 1838. Since then, the humoral pathophysiological theory was changed for the cellular approach.

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Fig. 2. The front page of Vesalius’ anatomical book (1543).

The earliest Japanese anatomical studies were found in the books of Zoshi (1754) and the Kaitai Shinsho (1774). Two centuries later, in 1958, and the basic histopathological lesion in radiosurgery was published by Larsson and Leksell’s group [4] in Nature. In that landmark paper they stated that in animal experiments ‘with high-energy protons a sharply delimited lesion can be made at any desired site in the central nervous system.’ Pathological Fundamentals

The basic histopathological radiolesion created by high-energy ionizing radiation in neural tissue is a coagulation necrosis (fig. 4). This can be found

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Fig. 3. Giovanni Battista Morgagni, the father of pathology (1682–1771).

within the target volume, it did not change in time, and the boundary between the necrosis and the surrounding structures is distinct, according to the sharp radiation fall-off [4–8]. Lesions appeared in the spinal cord following irradiation with doses of 400 and 200 Gy on the 3rd and 9th day respectively. They were sharply defined and had about the same width as the beam. In the cerebral hemispheres the earliest lesions were observed 14 days after irradiation with 200 Gy, and the changes between 2 and 8 weeks were similar. Macroscopically, corresponding to the path of the beam, a groove appeared on the upper surface, and a sharply defined narrow band of discoloration was seen beneath the hemispheres. Histologically, within the lesion necrosis of nerve cells, myelin sheaths and axons occurred. Small perivenous hemorrhages were present at the margin of the lesions, and occasionally in the center of the damaged tissue, particularly in the gray matter. Collections of lymphocytes were seen in the necrotic zone and around it proliferation of astrocytes. These were the early experimental pathological changes following high-dose irradiation. In human brain the morphology of radiolesions were similar. The late histological changes were characterized by macrophages and calcium concrements in the necrotic centers of gamma radiolesions, surrounded by a wall with astrocytic proliferation. There were also round cell infiltration and congested capillaries around the lesion. Steiner et al. [9] have demonstrated that at least 140 Gy was necessary to produce a lesion in the human brain after radiosurgery.

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Fig. 4. Sharply demarcated gamma-radiolesion (i.e. coagulation necrosis) towards surrounding tissue. HE. ⫻200.

With more than 160 Gy the lesions were consistently observed, and the optimal dose appeared to be around 170–180 Gy. Higher doses, up to 250 Gy, did not change the physical characteristics of the lesion, which was due to the sharp dose gradient. The pathological effect of radiosurgical interventions on the central nervous system tissue can reflect in degenerative and proliferative changes as well. Endothelial cell injury, apoptosis, coagulation necrosis and hyaline degeneration are the most frequent degenerative processes. These might be the result of cytotoxic effect of radiosurgery. They play important role in the destruction of malignant tumors, or normal tissue structures in functional neurosurgery [10, 11]. On the other hand, granulation tissue formation, proliferation of fibrocytes, fibroblasts, myofibroblasts, capillaries or other vascular elements, inflammatory cells and production of collagen fibers appear as commonest proliferative responses after radiosurgery. This is the pathological situation mostly in the obliteration process of arteriovenous malformations [12–17]. Radiosurgery seems to cause a proliferative vasculopathy within the blood vessels of an AVM that begins with endothelial cell injury [18]. It appears that the abnormal vessels of neoplasms or vascular malformations have a relative sensitivity to radiosurgery in comparison to normal surrounding vessels [19]. Kondziolka et al. [20] believe that the radiobiological effect on meningiomas, schwannomas, pituitary tumors, and other benign neoplasms is a combination of both cytotoxic and delayed vascular effects. This observation was supported by further investigations [21].

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Quo vadis?

Is radiosurgical pathology a new subspeciality? Do we need it? We think that we are at the beginning of a long and interesting road. Our purpose is to collect and process systematically potential radiosurgical pathology cases. That is, to follow all those cases where a radiosurgical intervention had been done as a first step, then the patient underwent an open conventional craniotomy-related operation or autopsy for some reason. We have to compare imaging data, treatment parameters, modern functional methods [22, 23], follow-up material with surgical pathology or autopsy macroscopical and histological findings. Results of experimental pathology should be included and considered as well [24–28]. In this way, systematic comprehensive and comparative investigations could become part of the broader radiobiology concept that would draw our attention and direct our activity towards radiosurgical pathology.

Conclusions

‘Mortui vivos docent’ was the original intention of pathology. Our hope is that radiosurgical pathology will promote better understanding of morphological changes, biological and pathophysiological mechanisms behind therapeutic radiosurgical interventions. In this way it would serve more sophisticated treatment planning of current and future potential radiosurgical disorders for the benefit of our patients in need.

Acknowledgments Dr. Szeifert was supported by the Hungarian Health Scientific Society (ETT) grant 12980-9/2003-1018EKU; 395/KO/03. Parts of this study were funded by a grant from Congress of Neurological Surgeons and Elekta Instruments, Inc.

References 1 2 3 4

Leksell L: Cerebral radiosurgery. I. Gammathalamotomy in two cases of intractable pain. Acta Chir Scand 1968;134:585–595. Kondziolka D, Lunsford LD, Witt TC, Flickinger JC: The future of radiosurgery: Radiobiology, technology and applications. Surg Neurol 2000;54:406–414. Larsson B: Radiobiological fundamentals in radiosurgery; in Steiner L, Lindquist C, Forster D, Backlund EO (eds): Radiosurgery: Baseline and Trends. New York, Raven Press, 1992. Larsson B, Leksell L, Rexed B, Sourander P, Mair W, Andersson B: The high-energy proton beam as a neurosurgical tool. Nature 1958;182:1222–1223.

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5 6 7 8

9 10

11 12

13

14

15 16

17

18 19 20 21

22

23

24

25

Leksell L, Larsson B, Andersson B, Rexed B, Sourander P, Mair W: Lesions in the depth of the brain produced by a beam of high-energy protons. Acta Radiol 1960;54:251–264. Larsson B, Leksell L, Rexed B: The use of high-energy protons for cerebral surgery in man. Acta Chir Scand 1963;125:1–7. Wennerstrand J, Ungerstedt U: Cerebral radiosurgery. II. An anatomical study of gamma radiolesions. Acta Chir Scand 1970;136:133–137. Andersson B, Larsson B, Leksell L, Mair W, Rexed B, Sourander P, Wennerstrand J: Histopathology of late local radiolesions in the goat brain. Acta Radiol Ther Phys Biol 1970;9: 385–394. Steiner L, Forster D, Leksell L, Meyerson BA, Boëthius J: Gammathalamotomy in intractable pain. Acta Neurochir 1980;52:173–184. Szeifert GT, Salmon I, David P, Devriendt D, De Smedt F, Rorive S, Brotchi J, Levivier M: Tumor control and growth in a patient with two cerebral metastases treated with the Leksell Gamma Knife; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 152–161. Szeifert GT, Massager N, Brotchi J, Levivier M: Morphological redifferentiation in a malignant astrocytic tumor after gamma knife radiosurgery. J Neurosurg 2002;97(suppl 5):627–630. Yamamoto M, Jimbo M, Kobayashi M, Toyoda C, Ide M, Tanaka N, Lindquist C, Steiner L: Long-term results of radiosurgery for arteriovenous malformation: Neurodiagnostic imaging and histological studies of angiographically confirmed nidus obliteration. Surg Neurol 1992;37:219–230. Yamamoto M, Jimbo M, Ide M, Kobayashi M, Toyoda C, Lindquist C, Karlson B: Gamma knife radiosurgery for cerebral arteriovenous malformations: An autopsy report focusing on irradiationinduced changes observed in nidus-unrelated arteries. Surg Neurol 1995;44:421–427. Szeifert GT, Kemeny AA, Major O, Timperley WR, Forster DMC: Histopathological changes in cerebral arteriovenous malformations following stereotactic irradiation with the gamma knife; in Kondziolka D (ed): Radiosurgery 1997. Basel, Karger, 1998, vol 2, pp 129–136. Szeifert GT, Kemeny AA, Timperley WR, Forster DMC: The potential role of myofibroblasts in the obliteration of arteriovenous malformations after radiosurgery. Neurosurgery 1997;40:61–66. Szeifert GT, Vandersmissen B, Taib NOB, Balériaux D, Rodesch G, Salmon I, Brotchi J, Levivier M: Recurrent hemorrhage in a radiosurgically obliterated cerebral arteriovenous malformation; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 34–41. Szeifert GT, Salmon I, Balériaux D, Brotchi J, Levivier M: Immunohistochemical analysis of a cerebral arteriovenous malformation obliterated by radiosurgery and presenting with re-bleeding. Case report. Neurol Res 2003;25:718–721. Schneider BF, Eberhard DA, Steiner LE: Histopathology of arteriovenous malformations after gamma knife radiosurgery. J Neurosurg 1997;87:352–357. Szeifert GT, Major O, Fazekas I, Nagy Z: Effects of radiation on cerebral vasculature: A review. Neurosurgery 2001;48:452. Kondziolka D, Lunsford LD, Flickinger JC: The radiobiology of radiosurgery. Neurosurg Clin North Am 1999;10:157–166. Szeifert GT, Massager N, Devriendt D, David P, De Smedt F, Rorive S, Salmon I, Brotchi J, Levivier M: Observation of intracranial neoplasms treated with gamma knife radiosurgery. J Neurosurg 2002;97(suppl 5):623–626. Levivier M, Wikler D, Goldman S, David P, Metens T, Massager N, Gerosa M, Devriendt D, Desmedt F, Simon S, Van Houtte P, Brotchi J: Integration of the metabolic data of positron emission tomography in the dosimetry planning of radiosurgery with the gamma knife: Early experience with brain tumors. J Neurosurg 2000;93(suppl 3):233–238. Levivier M, Wikler D, Goldman S, Massager N, Szeifert GT, David P, Devriendt D, Desmedt F, Simon S, Van Houtte P, Brotchi J: Positron emission tomography-guided radiosurgery: Early experience with the integration of metabolic data in the dosimetry planning with the Leksell Gamma Knife; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 123–133. Major O, Kemeny AA, Forster DMC, Walton L, Szeifert GT: Time modulation effect of taxol on vasoreactivity of rat middle cerebral artery after single dose gamma irradiation; in Kondziolka D (ed): Radiosurgery 1997. Basel, Karger, 1998, vol 2, pp183–196. Kondziolka D, Couce M, Niranjan A, Maesawa S, Fellows W: Histology of the 100-Gy thalamotomy in the baboon; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 279–284.

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Liscak R, Vladyka V, Novotny J Jr, Brozek G, Namestkova K, Mares V, Herynek V, Jirak D, Hayek M, Sykova E: Leksell gamma knife lesioning of the rat hippocampus: The relationship between radiation dose and functional and structural damage. J Neurosurg 2002;97(suppl 5): 666–673. Major O, Szeifert GT, Radatz MWR, Walton L, Kemeny AA: Experimental stereotactic gamma knife radiosurgery. Vascular contractility studies of the rat middle cerebral artery after chronic survival. Neurol Res 2002;24:191–198. Major O, Szeifert GT, Fazekas I, Dusan V, Csonka É, Kocsis B, Bori Z, Kemeny AA, Nagy Z: Effect of a single high-dose gamma irradiation on cultured cells in human cerebral arteriovenous malformation. J Neurosurg 2002;97(suppl 5):459–463.

Marc Levivier, MD, PhD Centre Gamma Knife, Université Libre de Bruxelles Hôpital Erasme, Route de Lennik 808 BE–1070 Brussels (Belgium) Tel. ⫹32 2 5553174, Fax ⫹32 2 5553176, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 22–28

Radiation Tolerance of the Spinal Cord to Staged Radiosurgery Iris C. Gibbs, Steven D. Chang, Christopher Pham, John R. Adler Departments of Radiation Oncology and Neurosurgery, Stanford University Medical Center, Stanford, Calif., USA

Abstract Dose-volume effects on radiation tolerance of the spinal cord require investigation to be revisited. The purpose of this study was to present the early clinical results of patients treated by staged spinal radiosurgery who achieved at least 2 years of follow-up. Our results show that staged spinal radiosurgery is safe and feasible. While dose-volume effects for the spinal cord remain speculative, staged radiosurgery offers an excellent tool to explore further. Copyright © 2004 S. Karger AG, Basel

Tolerance dose is the dose of radiation that produces an acceptable probability of a treatment complication [1, 2]. Inherent in this definition are subjective (acceptable probability) as well as objective (treatment complication) criteria. The sensitivity of the spinal cord to radiotherapy is well established [3, 4]. Objective signs of spinal cord injury are mainly seen as either early transient myelopathy (L’Hermitte’s sign) or delayed radiation myelopathy [5]. Early transient myelopathy is usually self-limiting and requires no specific therapy. On the other hand, delayed radiation myelopathy is a much more serious condition associated with significant functional neurological deficits which may present several months to several years following radiotherapy. Since the first classic publication describing radiation myelopathy of the cervical spinal cord by Boden in 1948, the radiation factors that affect clinical spinal cord injury have been fairly well characterized for conventional radiotherapy [3, 6]. These factors include radiation fraction size, total radiation dose, and interfraction interval [5]. It appears that the effects of volume of spinal cord irradiated on radiation tolerance are much more complex. While some clinical

Table 1. Lesions treated Type of lesion

Location C

T

L/S

total

Intraspinal AVM Hemangioblastoma Cavernous angioma

2 1 1

0 1 0

1 0 0

3 2 1

Extramedullary Meningioma Schwannoma Chordoma

0 1 1

1 1 0

0 0 0

1 2 1

Vertebral body Myeloma

0

1

0

1

evidence supports an inverse relation between the volume of spinal cord irradiated and radiation dose to produce objective spinal cord injury, others show no such effect [7, 8]. Though mathematical models have been devised to predict the probability of spinal cord injury with respect to volume and dose, the effect of volume on the tolerance dose at very low probability is difficult to detect [9]. With the advent of conformal radiation techniques, the ability to limit the volume of spinal cord in the irradiated volume is now feasible. Moreover, with the precision of spinal radiosurgery, these volumes may be ⬍1 cm3. In light of these technological advances in radiation therapy, issues of dose-volume effects on radiation tolerance of the spinal cord need to be revisited. Hence, in order to shed additional light on the issues of radiation tolerance, we present here the early clinical results of patients treated by spinal radiosurgery at our institution who achieved at least 2 years of clinical follow-up.

Materials and Methods Since the inception of the extracranial radiosurgery program at our institution, 53 spinal lesions have been treated using Cyberknife image-guided radiosurgery (Accuray, Inc., Sunnyvale, Calif., USA) on protocol. Of these patients, 11 were identified who have been followed for at least 2 years. The treated lesions include 4 intraspinal, intramedullary lesions, 6 intraspinal, extramedullary lesions, and 1 vertebral body lesion (table 1). The lesions were located from C2 to L1 (6 cervical, 4 thoracic, and 1 lumbar). No patient had prior radiotherapy.

Radiation Tolerance of the Spinal Cord

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For treatment planning, computed tomography images were obtained at 1.25 mm slice thickness through the region of interest. The target lesion as well as the spinal cord and/or cauda equina were contoured on post-contrast axial CT images. To minimize variability, contours were entered by the neurosurgeon such that there was no more than 1–2 mm distance between the visible edges of the spinal cord/cauda equina. Digitally reconstructed radiographs were generated. Dose-volume histograms (DVH) for the target, spinal cord, and non-target tissue were generated based on the CT datasets. Patients were treated using one of two image tracking techniques previously described, (1) anatomical tracking of bony anatomy or, (2) implanted fiducial tracking, respectively [10]. A mean target total dose prescribed to the periphery of the lesion was 19.9 Gy (range 16–25) delivered in 1–5 fractions with a 24-hour interfraction interval. Patients were followed radiographically and clinically every 3–6 months. Clinical and radiographic responses as well as acute and subacute complications were assessed.

Results

The mean follow-up of the 11 patients was 31 months (range 24–50). The mean total dose of 19.9 Gy (16–25) was delivered to the target lesion with dose prescribed to 70–90% isodose curve, normalized to the maximum dose. The mean target volume was 2.56 cm3 (range 0.5–14.1). Target coverage ranged from 79 to 100%. The maximum dose to the spinal cord/cauda equina was determined directly based on the DVH for vertebral body and extra-axial lesions. Because all AVMs were contained within the intraspinal component, the maximum spinal cord dose to these lesions was assumed to be represented by the maximum dose delivered by the treatment plan. Complete dosimetric and volumetric data were available for 8 of 11 patients. Conformal avoidance of radiation dose spread to the spinal cord was largely achievable with vertebral body and extra-axial lesions (fig. 1). Thus, the largest lesion, a vertebral body metastasis, delivered the lowest dose to the spinal cord. On the other hand, due to the location of AVMs within the spinal cord, conformal avoidance of the spinal cord was not generally possible (fig. 2). All arteriovenous malformations were ⬍1 cm3. The maximum total dose to the spinal cord in these patients was 13–27 Gy; the maximum dose per stage to the spinal cord was 4.6–8.5 Gy (table 2). We used the volume of spinal cord contained within the 80% isodose curve to estimate the volume of spinal cord irradiated in the relevant high-dose field. The volume of spinal cord irradiated to the 80% isodose curve was determined based on the DVH and ranged from 0.0 to 1.6 cm3 (table 2). The maximum total dose and the maximum dose per stage to this volume of spinal cord were 3.7–7 and 10.4–24 Gy, respectively. At last follow-up, there were no radiographic or clinical signs of myelopathy in this cohort of patients.

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Fig. 1. Conformal avoidance of the spinal cord in radiosurgery treatment plan of a thoracic vertebral body metastatic tumor.

Fig. 2. Cervical spinal AVM with a compact nidus.

Discussion

In their landmark publications of tolerance dose in the 1970s, Rubin and Casarett [2] opened with the phrase, ‘Dominant thoughts in medical science are rarely allowed to die. They persist even when overthrown and fade slowly from our corporate memory’. Quantifying tolerance of normal tissues as a probability

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Table 2. Spinal cord (SC) dose-volume data Target volume cm3

Target dose Gy

Stages n

Maximum SC dose Gy

Maximum SC dose/ stage

Volume of SC to prescribed dose, cm3

Volume of SC at dmax cm3

Volume of Type of SC at 80% lesion iso-dose, cm3

0.79 0.68 3.08 0.53 0.63 14.10 0.95 1.71

21 20 25 16 21 16 21 18

3 3 5 2 4 2 3 3

23.4 20.8 26.9 17 29.9 13.1 26.5 13.1

7.8 6.9 5.4 8.5 7.5 6.5 8.8 4.6

0.59 0.1 0.075 0.004 0.60 0.001 0.64 0

0.08 0.002 0 0 0.002 0 0.08 0

0.79 0.116 0.100 0.09 0.5 0.002 1.657 0

AVM Sch Men cAg AVM Myel AVM Sch

of complication is attributed to Rubin and Casarett who first described the concepts of TD5/5 and TD50/5 in the 1970s. These values represented the radiation dose that yields a 5 or 50% risk of a particular complication, respectively, within 5 years of treatment. These values represented the accepted estimates of minimal and maximal tissue tolerance as derived from collections of observed tissue complications. Based on the emergence of increasing understanding of the biology of radiation and the appreciation of how organizational structure of tissues influence radiation response, Rubin and Casarett challenged the previously held principle of the Strandqvist line that related varying dose-time schedules by an isoeffect line to provide a guideline of radiation tolerance. Now some three decades later, we are prompted to also challenge previously held notions of radiation tolerance based on technological advances that allow for more precise radiation delivery and more accurate evaluation of volumetric data. With the feasibility of non-invasively performing spinal radiosurgery, exciting discoveries and challenges lie ahead. As we embark upon these relatively unchartered grounds, fundamental radiobiologic determinants of tissue tolerance need to be re-examined. Because radiation myelopathy is such a devastating outcome, it is generally hoped that predictors of radiation risks to the spinal cord are reliable enough to avoid spinal cord injury in any patient. Knowledge of principal determinants of radiation spinal injury is derived from clinical observational experience, animal models, and theoretical modeling. Much of this knowledge was generated during the eras of conventional, widefield irradiation when conservative estimates of spinal cord tolerance were observed. Issues of total radiation dose, fractionation schedules, and tissue repair kinetics dominate the importance of volume effects in the era of conventional irradiation. These concepts are not in question as the differential response of

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Table 3. Normal tissue tolerance to therapeutic irradiation [data from 3, with permission] Organ

Kidney Brain Cord Intestine

TD5/5, cGy Organ volume

TD50/5, cGy Organ volume

Objective clinical endpoint

1/3

2/3

3/3

1/3

2/3

3/3

5,000 6,000 5,000 5,000

3,000 5,000 5,000 –

2,300 4,500 4,700 4,000

– 7,500 7,000 6,000

4,000 6,500 7,000 –

2,800 6,000 – 5,500

Nephritis Necrosis Myelitis, necrosis Obstruction/ perforation/fistula

early and late responding tissue to radiation continues to be supported by clinical data. It is with respect to dose-volume effects, particularly for very small volumes of spinal cord, that the reevaluation of radiobiologic concepts is most relevant. While it has been long speculated that volume effects may exist for spinal cord radiation therapy, due to the organizational structure of the spinal cord as a series organ with functional subunits inter-related, there appeared to be no significant clinical support of this notion within the relevant range of irradiated volumes for conventional radiotherapy, which typically involves volumes of more than one-third of the spinal cord [3, 11]. This can be appreciated by the fact that the observational data of complications risks exhibits a threshold effect within a narrow range of conventionally delivered doses. Tolerance dose as estimated by dose-volume effects have been compiled based on observations of clinical complications in a variety of tissues [3] (table 3). As illustrated, the range of tolerable spinal cord conventional radiation doses is very narrow whether one-third or the entire cord is irradiated. Based on these and similar data, 45 Gy in 22–25 fractions has been the suggested guideline for spinal cord tolerance, yielding a probability of radiation-induced myelopathy of ⬍0.2% [4]. While clinical data are inconclusive on the presence of dose-volume effects for spinal cord injury, some animal experiments in canines support dose-volume effects for pathologic and clinical spinal cord injury. In these experiments, the ED50, the dose required to produce a 50% risk of specific pathologic injuries such as hemorrhage and white matter loss, was shown to be 8.3–15 Gy higher when a 4-cm length of spinal cord was irradiated as compared to a 20-cm length [9]. Despite these findings, however, the authors concluded that the issue of dose-volume effects remains unanswered since a change in the slope of the dose-response curve was no different between the lengths of spinal cord irradiated (i.e. 4 and 20 cm).

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Presentation of the clinical data above is not meant to generate a conclusion about the absolute radiation tolerance of the spinal cord, but rather to contribute to the ongoing debate about potential dose-volume effects of spinal irradiation. In our series, up to 1.6 cm3 of spinal cord were irradiated doses of 10.4–24 Gy, receiving 3.7–7 Gy per stage. Our results show that staged spinal radiosurgery is technically feasible and safe thus far. No patient in this cohort who were followed for at least 2 years, developed serious neurologic sequelae. We conclude that while dose-volume effects for the spinal cord remain speculative, staged radiosurgery offers an excellent tool to explore these issues further.

References 1 2 3 4 5 6 7 8 9

10 11

Withers HR, Thames HD: Dose fractionation and volume effects in normal tissues and tumors. Am J Clin Oncol 1988;11:313–329. Rubin P, Casarett G: A direction for clinical radiation pathology: The tolerance dose. Front Radiat Ther Oncol 1972;6:1–16. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109–122. Schultheiss TE, Kun LE, Ang KK, Stephens LC: Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 1995;31:1093–1112. Rampling R, Symonds P: Radiation myelopathy. Curr Opin Neurol 1998;11:627–632. Boden G: Radiation myelitis of the cervical spinal cord. Br J Radiol 1948;21:464–469. Abbatucci JS, Delozier T, Quint R, Roussel A, Brune D: Radiation myelopathy of the cervical spinal cord: Time, dose and volume factors. Int J Radiat Oncol Biol Phys 1978;4:239–248. Marcus RB Jr, Million RR: The incidence of myelitis after irradiation of the cervical spinal cord. Int J Radiat Oncol Biol Phys 1990;19:3–8. Powers BE, Thames HD, Gillette SM, Smith C, Beck ER, Gillette EL: Volume effects in the irradiated canine spinal cord: Do they exist when the probability of injury is low? Radiother Oncol 1998;46:297–306. Murphy MJ, Adler JR Jr, Bodduluri M, Dooley J, Forster K, Hai J, Le Q, Luxton G, Martin D, Poen J: Image-guided radiosurgery for the spine and pancreas. Comput Aided Surg 2000;5:278–288. Withers HR: Predicting late normal tissue responses. Int J Radiat Oncol Biol Phys 1986;12:693–698.

Iris C. Gibbs, MD Department of Radiation Oncology, Stanford University Medical Center 300 Pasteur Drive, Rm A0–95, Stanford, CA 94305–5302 (USA) Tel. ⫹1 650 7361480, Fax ⫹1 650 7258231, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 29–37

Construction and Verification of STI Device for Cat Model Masako N. Hosono a, Kiyoaki Tanaka b, Tomohiro Sahara a, Misao Nishikawa b, Kentarou Ishii a, Satoko Kondo a, Yoshie Takada a, Haruyuki Fukuda a, Mitsuhiro Hara b, Yuichi Inoue a Departments of aRadiology and bNeurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan

Abstract In order to investigate the radiobiological effects of stereotactic irradiation (STI) on humans, the experimental STI with the similar dose to clinical practices and long-term follow-up would be essential, and the accuracy for the STI system should be well assured. Therefore we constructed the experimental STI system, which gave the instrumental accuracy similar to that required for patients. In the present study, we performed experimental stereotactic radiosurgery (SRS) with the same procedure as the clinical practices using the planning software: X-Knife®. As an initial study, verification tests were performed by dosimetry in a phantom using a film technique. Copyright © 2004 S. Karger AG, Basel

Introduction

Stereotactic irradiation (STI) is already a well-established method and applied to brain tumors, vascular malformations and functional disorders. Many clinical data of STI have been reported about the eligibility and also the brain damage due to STI. While its clinical use is increasing rapidly, the radiobiology of STI is still poorly understood. The experimental STI system for radiobiological studies using animals was constructed which was composed of a specially designed STI device and of the STI dose planning software: X-Knife® version 4.0 (Radionics Inc. USA). This device, modeled by K. Tanaka with Prof. Friedman’s approval, after the system produced in the University of Florida, consists of a platform for animal fixation and a mechanism producing arcs [1]. As an initial study, verification tests were performed by dosimetry in a phantom using a film technique.

b

a Fig. 1. The STI device was set up for irradiation for the phantom (a). The platform was locked at 30⬚, which indicated the couch angle on X-Knife® (b).

Materials and Methods STI Device Our STI device consists of two parts: the platform to fix an animal and the motorized part which creates the non-coplanar arcs (fig. 1). The animal was tightly fixed in the platform using ear-bars and a holding hook for maxilla. The location of the animal head can be expressed by the coordinates of the platform. The platform can be mechanically rotated around its anteroposterior axis through an arc of 180⬚ and locked by the holding pin through the semicircular disk. Bilateral side pillars support the platform which is appropriately aligned into the direction of the collimator connected to the gantry head. A motorized pendular movement of the platform can create described radiation arcs. Sphere Phantom Specially Designed for the Verification The plastic phantom is sphere-shaped, 10 cm in diameter and consists of the 4 slices which are fixed by two penetrating bolts (Taisei Medical, Japan) (fig. 2). All parts of the phantom are made of polyethylene. This material has water-equivalent radiation absorbance and is widely used in verification studies of STI and IMRT in clinical practices [2]. In the center of each slice, there is a gap for insertion of Gafchromic® densitometry media type MD-55 (GAF chromic films) (Nuclear Associates, N.Y., USA) [3]. The sensor of GAF chromic films is a thin-coated, transparent polymeric film which is colorless before irradiation and turns into deep blue after irradiation without physical, chemical, or thermal processing, and can be handled in room light [4, 5]. The phantom has two shallow small holes for fixation by two ear-bars of the platform. The phantom is firmly placed in the platform by the ear-bars and locked by a holding device made of acryl. The location of the phantom was described as the coordinates of the platform. The phantom can be adjusted to an appropriate position according to the scale on the platform.

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a

b Fig. 2. The sphere phantom opened for film insertion (a). The arrow shows the gap for film. The phantom was fixed by the ear-bars and the holding device made of acryl (b).

a

b Fig. 3. The setting inside the gantry of CT. The phantom was placed in the localizer for X-Knife®, and sustained by foamed plastics (a). The slice line of the phantom was aligned to the horizontal line of the laser marker of CT. 3-D image of the planning on X-Knife® (b). The isocenter was set in the center of the gap.

SRS Procedure SRS was performed in simulating clinical practices (fig. 3). At first, CT scan (Asteion, Toshiba, Japan) of the phantom was obtained. The images were acquired with technical parameters of 120 kV, 180 mAs, 1-mm beam collimation, 3.5-mm incrementation, 1.0 s per revolution and reconstruction interval of 2.0 mm. The phantom was kept horizontally against the laser marker of the scanner. With the CT data, SRS was planned by X-Knife® version 4.0. In the present study, SRS was designed as 5 arcs. The isocenter of the dose planning was placed in the center of the spherical phantom, which was also the center of the GAF chromic film placed in the gap. The GAF chromic film was irradiated at the

Construction and Verification of STI Device for Cat Model

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a

b Fig. 4. For plotting a calibration curve, the absorbed doses on the films were measured by the cylindrical ion chamber at several dose points, from 5 to 50 Gy. The linearity was well preserved in this range (a). The result calculated by DD-System (b). The area of 15 Gy was indicated by the arrow.

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dose of 20 Gy at its center. The collimator size was 1 cm in diameter. The setup sheets were rearranged in order to be adapted to our STI system. In short, the gantry angle on X-Knife® was changed to the pendular-movement angle of the platform, and the couch angle was also changed to the locked rotation angle of the platform. Irradiation was performed using 4 MV Linac X-ray (ML-6M Mitsubishi, Japan). Film Dosimetry The GAF chromic films were analyzed 24 h after SRS [5]. At first, the irradiated film was scanned as the file size of 150 dpi by the Esper-Scanner ES-8500 (Seiko-Epson, Japan). The densitometry and absorbed dose conversion of the GAF chromic film were performed by DD-System (R-Tech, Japan) [6]. The absorbed dose distributions were given as radiographic images using calibrated GAF chromic films. The isodose curves were calculated on the basis of the optical density against absorbed dose curve which was obtained previously. In the calibration curve, the absorbed doses of the films were measured by the cylindrical ion chamber at several dose points, from 5 to 50 Gy. The linearity was well preserved in this range. By DD-System, the areas of 15- and 18-Gy isodose curves were calculated (fig. 4). Comparison of the Film Dosimetry and the Planning by X-Knife® To compare the results of the film dosimetry with the planned dose distribution on X-Knife®, the isodose curves of 15 and 18 Gy were captured and the areas were also calculated on the software Photoshop® version 6.0 (Adobe Systems, Calif., USA). Shortly, pixels inside each isodose curve were counted and next, pixels of the gap were also counted. Since the gap was designed as 4 cm2, we could calculate the area inside the each isodose curve (fig. 5).

Results

SRS on the phantom was performed 5 times. Our instruments were easily set up for SRS and the geometry of the phantom and the device was well reproducible as estimated by the coordinates of the platform. The shape of each isodose curve obtained by DD-System was visually consistent with the dose distribution calculated by X-Knife® (fig. 6). Table 1 shows the comparison of the planning results and the film dosimetry. The relative errors of the areas between the planning calculated by Photoshop® and the film dosimetry were 11.93 ⫾ 3.92 and 16.11 ⫾ 4.02% in 15 and 18 Gy, respectively. Discussion

STI has already proved to be effective for the treatment of brain tumors, vascular malformation and functional disorders [7–12]. Substantial data of clinical STI have been reported about the eligibility and also the brain tissue damage accompanied with STI [13, 14]. While its clinical use is increasing rapidly, the radiobiology of STI is still poorly understood. Some investigators tried experimental studies in which animals were treated with relatively

Construction and Verification of STI Device for Cat Model

33

Fig. 5. A 15-Gy isodose curve was shown. Since the gap was designed as 4 cm2, we could calculate the area of each isodose curve by measuring the ratio of the pixels inside the isodose curve to those of the gap.

high-dose STI [15–17]. In order to investigate the radiobiological effects of STI on human, the experimental STI with the similar dose to clinical practices and long-term follow-up would be essential, and the accuracy for the STI system should be well assured. Therefore we constructed the experimental STI system, which gave the instrumental accuracy similar to that required for patients. In the present study, we performed experimental SRS with the same procedure as the clinical practices using the planning software: X-Knife®. Furthermore, we verified this system by conducting SRS and film dosimetry for the phantom. The relative errors of the areas between the film dosimetry and the planning calculated by Photoshop® were 11.93 ⫾ 3.92 and 16.11 ⫾ 4.02% in 15 and 18 Gy, respectively. These results show that the data analysis itself includes several errors. In addition to setting errors of the phantom, the captured data from X-Knife® includes errors of detection of the film gap center, because of the thickness of CT slices. And also marking errors of a film gap and isodose curves did exist. There is a difference of electron density between the calculation on X-Knife® and the actual plastic phantom. Nevertheless, the accuracy of this experimental STI system was well preserved, and SRS for the specially designed phantom was well reproducible. This experimental STI system enables the accurate STI for cats. As the next

Hosono/Tanaka/Sahara/Nishikawa/Ishii/Kondo/ Takada/Fukuda/Hara/Inoue

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a

b Fig. 6. The dose distribution analyzed by DD-System (a) was visually consistent with that of the planning on X-Knife® (b).

Construction and Verification of STI Device for Cat Model

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Table 1. Comparison of the planning results and the film dosimetry

Planning on X-Knife® Dosimetry 1Maximum

Maximum dose1 cGy

15-Gy area cm2

18-Gy area cm2

2,010 2,023 ⫾ 71

0.662 0.583 ⫾ 0.026

0.422 0.354 ⫾ 0.017

doses within the planned fields.

step, we are now constructing the fixation device for CT scan to keep the same geometry as on the platform of our STI device. Since follow-up CT can be performed in the same scan angle with that fixation device, we will be able to compare the follow-up CT with that used for planning.

Acknowledgements We greatly appreciate kind considerations of Prof. Friedman and his colleagues. We also special thank Mr. Onishi (Taisei Medical, Japan), Mr. Yasui and Mr. Takahashi (Toyo Medic Co., Japan). This study was partially supported by the grant of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

References 1 2

3 4

5 6 7 8

9

Bova F, Spiegelmann R, Friedman WA: A device for experimental radiosurgery. Stereotact Funct Neurosurg 1991;56:213–219. Abe T, Miyauchi K, Mori T, Ozamoto Y, Kosoto T, Hattori K, Ohnishi N: Development and evaluation of a new water equivalent phantom in photon beams. Jpn J Radiat Technol 1997;53: 236. Humpherys KC, Kantz AD: Radiochromic-A radiation monitoring system. Radiat Phys Chem 1977;9:737–747. McLaughlin WL, Soares CG, Sayeg JA, McCullough EC, Kline RW, Wu A, Maitz AH: The use of a radiochromic detector for the determination of stereotactic radiosurgery dose characteristics. Med Phys 1994;21:379–387. Yamamoto Y, Takahashi S, Komatsu A, Uchida N, Kato H: Evaluation of GAF chromic dosimetry and its application to PDD and OCR curves. Jpn J Radiat Technol 2001;57:1357–1364. Nakashima T, Yamada K, Ohno Y, Kushima T, Hirokawa Y, Miyazawa M: Usefulness of a dose distribution analysis system with a common scanner. Jpn J Radiat Technol 2002;58:833–839. Fiedman WA, Bova FJ, Mendenhall WM: Linear accelerator radiosurgery for arteriovenous malformations; the relationship of size to outcome. J Neurosurg 1995;82:180–189. Flickinger JC, Pollock BE, Kondziolka D, Lunsford LD: A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys 1996;36: 873–879. Patchell RA: The management of brain metastases. Cancer Treatment Rev 2003;20:1–8.

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10 11

12

13 14

15 16 17

Kondziolka D, Lunsford LD, Coffey RJ, Flickinger JC: Stereotactic radiosurgery of meningiomas. J Neurosurg 1991;74:552–559. Shrieve DC, Alexander E III, Black PM, Wen PY, Fine AH, Kooy HM, Loeffler JS: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: Prognostic factors and long-term outcome. J Neurosurg 1999;90:72–77. Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL: Gamma knife radiosurgery for trigeminal neuralgia: The initial experience of the Barrow Neurological Institute. Int J Radiat Oncol Biol Phys 2000;47:1013–1019. Flickinger JC, Kondziolka D, Pollock BE: Complication from arteriovenous malformation radiosurgery: Multivariate analysis an risk modeling. Int J Radiat Oncol Biol Phys 1997;38:485–490. Ito K, Shin M, Matsuzaki M, Sugasawa K, Sasaki T: Risk factors for neurological complications after acoustic neurinoma radiosurgery: Refinement from further experiences. Int J Radiat Oncol Biol Phys 2000;48:75–80. Spiegelmann R, Fiedman WA, Bova FA, Theele DP, Mickle JP: Linac radiosurgery: An animal model. J Neurosurg 1993;78:638–644. Blatt DR, Fiedman WA, Bova FA, Theele DP, Mickle JP: Temporal characteristics of radiosurgical lesions in an animal model. J Neurosurg 1994;80:1046–1055. Karger CP, Hartmann GH, Hoffmann U, Lorenz WJ: A system for stereotactic irradiation and magnetic resonance evaluations in the rat brain. Int J Radiat Oncol Biol Phys 1995;33:485–492.

Masako N. Hosono, MD, PhD Department of Radiology, Osaka City University Graduate School of Medicine 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan) Tel. ⫹81 6 6645 3831, Fax ⫹81 6 6646 6655, E-Mail [email protected]

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Malignant Tumors Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 38–45

Acute Sequelae of Stereotactic Radiosurgery Theodore S. Hong a, Wolfgang A. Toméa, Lori Hayesa, Zhilong Yuanb, Benham Badiec, Ravi Raod, Minesh P. Mehtaa Departments of Human aOncology, bBiostatistics and cNeurosurgery, University of Wisconsin Medical School, Madison, Wisc. and d Department of Medical Oncology, Mayo Clinic, Rochester, Minn., USA

Abstract Background: Over the last decade, the application of stereotactic radiosurgery has expanded significantly for several clinical indications including benign and malignant tumors, vascular malformations, and functional disorders. Acute complications following stereotactic radiosurgery are generally believed to be uncommon, and relatively minor in grade and severity. Few reports, however, have specifically analyzed or focused on the immediate sequelae following radiosurgery. Material and Methods: 279 consecutive radiosurgery procedures were reviewed in 253 patients (359 lesions) at our institution, specifically evaluating the incidence of sequelae in the first 30 days post-treatment. Patients were evaluated before the procedure, during and immediately after radiosurgery and also at 1 month post-procedure. Based on clinical need, individual patients were followed with greater frequency. In the absence of sequelae, the follow-up frequency was determined by the diagnosis. Results: 52% (132) of patients were treated for brain metastasis, 16% (41) for glioma, and 32% (80) for benign processes. Median age was 52 years (range 18–89 years). Acute sequelae (ⱕ30 days) after radiosurgery occurred in 34.1% (n ⫽ 95) of cases. Most of these were mild to moderate in severity (95.4%). The most common sequelae in descending frequency were headache (17), seizures (11), fluid retention and other steroid side effects (7 each) and neurologic change (7). Multivariate analysis did not show any single factor to predict for increased risk of sequelae. Conclusions: Approximately one-third of patients experience acute sequelae following radiosurgery, most of which are mild to moderate. Severe side effects are uncommon. None of the studied risk factors were predictive for increased sequelae. Copyright © 2004 S. Karger AG, Basel

Radiosurgery is a procedure in which multiple precisely-aimed radiation beams are used to deposit an appropriately large dose of radiation within a discrete lesion while limiting dose to normal tissue. Recently, application of radiosurgery has increased dramatically [1]. The most common indication for radiosurgery is for brain metastasis [2]. Radiosurgery can increase median survival in patients with 1–3 brain metastasis [3, 4]. Furthermore, there is increasing interest in offering radiosurgery in selected patients in lieu of whole-brain radiation therapy (WBRT) to putatively spare patients the late toxicities of WBRT [5]. The role of radiotherapy has also been explored in gliomas in the upfront as well as recurrent setting. Benign lesions and processes such as vestibular schwannomas [6], arteriovenous malformations (AVMs) [7], meningiomas [8], pituitary adenomas [9], and trigeminal neuralgia [10] have also been effectively treated with radiosurgery. There are several techniques for delivering radiosurgery. Gamma knife and modified linear accelerator (Linac)-based radiosurgery are the two most commonly used systems. The gamma knife uses multiple cobalt sources geometrically arranged to deliver dose precisely with a sharp dose fall off. Linacbased radiosurgery employs multiple beam angles and arcs, precisely aimed to produce a high dose in the target with rapid fall off in normal tissue. Acute complications and sequelae of radiosurgery are believed to be uncommon. However few studies have specifically addressed this issue. Large studies on patients treated with gamma knife have been reported, but not necessarily with a focus on acute sequelae. One study of 651 patients by Nakamura et al. [11] demonstrated that less than 5% of patients had grade 3 or greater toxicity; the focus was on long-term toxicities. This study did not specifically address acute toxicities. Another study by Chin et al. [12] demonstrated that acute toxicity occurred in less than 5% of 835 consecutive cases treated with gamma knife. However, these focused only on acute, severe neurological events, rather than the entire spectrum of acute sequelae. To date, the largest published report (n ⫽ 78) analyzing and focusing on all acute sequelae, by Werner-Wasik et al. [13], showed that 35% of patients developed immediate side effects, 87% of which were mild. All patients were treated on a linear accelerator. In this study, we reviewed 279 consecutive radiosurgery procedures in 253 patients (359 lesions) at our institution, specifically evaluating the incidence of sequelae in the first 30 days following radiosurgery. These were classified into three grades, using the previously described methodology of Werner-Wasik et al. [13]. Materials and Methods Intracranial lesions in 279 consecutive radiosurgery procedures were treated in 253 patients in the 5-year period from 1997 to 2001. All patients were treated on a linear

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accelerator modified to perform radiosurgery. A Brown-Robert-Wells invasive frame was used for immobilization for radiosurgery. Dose and treatment volume were based on diagnosis. Patients were evaluated before the procedure, during and immediately after stereotactic radiosurgery. They were re-evaluated for sequelae immediately after frame removal, in the first post-treatment week, and at 1 month, and followed at varying frequency thereafter, depending on clinical parameters. Acute sequelae were defined as any event in a 30-day period, even if unrelated to radiosurgery, following the traditional surgical paradigm of evaluating 30-day post-procedure event rates, without specific causal attribution. Acute sequelae were recorded and scored using a scoring system similar to the one used by Werner-Wasik. We defined mild toxicities as requiring 0–1 episode of intervention or communication during the first 30 days. Mild toxicities included vertigo/dizziness, nausea, vomiting, headache, rash, new or worsening seizures, fatigue or hair loss. Moderate toxicities required either multiple communications (phone calls) or medical intervention and included gait/balance changes, steroid side effects, fluid retention, general weakness, anorexia, local pain, other pain (not local/headache), numbness/tingling, decreased hearing, periorbital edema, infection, bleeding from pin sites, and worsening neurological symptoms. Severe toxicities were those that required hospitalization and included cerebrospinal fluid (CSF) extravasation, new cranial nerve palsy, aphasia, or hemiparesis. Patient parameters as well as radiosurgery characteristics were recorded. Patient parameters included age, gender, diagnosis, prior cranial irradiation, and prior whole-brain radiation. Radiosurgery characteristics included target volume, location, prescription dose, maximum dose, number of lesions treated in a procedure, and number of isocenters used per lesion. A multivariate analysis was then performed on potential prognostic factors. A logistic model was used to determine the probability of experiencing any sequela relative to the study variable. Regression coefficients and their p values were then calculated.

Results

279 procedures were performed in 253 patients (359 lesions). Patient characteristics are listed in table 1. Median age was 55 years (range 18–89 years). Brain metastasis represents the most frequently treated diagnosis, representing over half the patients. Over half of all patients had prior cranial radiotherapy. Over a third of these patients had prior whole-brain radiotherapy. Radiosurgery treatment characteristics are listed in table 2. Mean tumor volume was 4.69 cm3 (range 0.03–33.9 cm3). Mean prescription dose was 15.5 Gy (range 6–80 Gy). Mean maximum dose was 22.8 Gy (range 10.1–80 Gy). The mean number of isocenters treated was 2.53 with a maximum of 17 isocenters. In over 79% of the procedures, a single lesion was treated; the maximum number of lesions treated in a single procedure was 7. Acute sequelae of any grade occurred in 95 of the 279 procedures (34.1%). Some patients experienced more than one side effect (13 patients). The vast majority of sequelae (95.3%) were mild or moderate. Severe sequelae requiring hospitalization occurred in less than 2% of procedures. Table 3 lists the sequelae

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Table 1. Patient characteristics Characteristic

Age ⱕ50 ⬎50 Diagnosis Metastatic Glioma Meningioma AVM Acoustic neuroma Other Prior radiotherapy Any Whole brain Partial brain

Patients (n ⫽ 253) n

%

98 155

38.7 61.3

132 41 13 29 26 12

52.2 16.2 5.1 11.5 10.3 4.7

133 101 32

52.6 39.9 12.7

Table 2. Radiosurgery treatment parameters Parameter

Procedurea

Parameter

n

%

Tumor volumeb ⬍1 cm2 1–3.9 cm2 ⱖ4 cm2

63 120 94

22.6 43.0 33.7

Prescription dose 6–14.9 Gy 15–17.9 Gy ⱖ18 Gy

118 74 87

42.3 26.5 31.2

54 50 94 71

19.4 17.9 33.7 25.4

Maximum dose ⬍18 Gy 18–20.9 Gy 21–25 Gy ⬎25 Gy

Procedurea n

%

Targets, n 1 2 3 4 or more

221 44 10 4

79.2 15.8 3.6 1.4

Isocenters, n 1 2 3 4 or more

141 40 35 63

50.5 14.3 12.5 22.6

a

For procedures with multiple lesions treated, parameters for largest lesion treated is listed. All lesions are included in multivariate analysis. b Volume data not available for two procedures.

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Table 3. Side effects by severity Severity

Side effect

Occurrencesa, n (279 procedures)

Mild

Vertigo/dizzy Nausea Vomiting Headache Rash Seizure Fatigue Hair loss Total Gait/balance change Steroid side effect Fluid retention General weakness Anorexia Pain – other Numbness/tingling Decreased hearing Periorbital edema Infection Bleeding Local pain Neurologic changes Total CSF extravasation Facial nerve palsy Aphasia Hemiparesis Total

6 7 2 17 2 11 6 1 52 1 7 7 2 2 2 1 2 8 5 1 6 7 51 2 1 1 1 5

Moderate

Severe

aSide

effects occurred in 95 out of 279 procedures (34.1%). 2–3 side effects noted after 13 procedures.

by frequency. The most frequently reported sequelae were headache (6.1% of procedures), seizure (3.9%), and periorbital edema (2.9%). Multivariate analysis was performed on these variables [14]. A logistic model was fitted to the data and no variable was found to be significant. Table 4 demonstrates the results of the multivariate analysis and the risk of developing sequelae of any grade. Table 5 demonstrates the results of the multivariate analysis on risk of developing either moderate to severe sequelae. Neither analysis identified a predictive variable for the development of acute sequelae of any grade.

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Table 4. Multivariate analysis – risk of any side effect Variable

Estimate coefficient

Standard error

p value

Age Gender Glioma Meningioma AVM Acoustic neuroma Other (non-metastatic) Targets, n Total volume treated Prescription dose Prescription isodose Prior XRT (Y or N) Prior whole-brain RT (Y or N)

0.002 0.327 0.193 ⫺0.443 0.443 ⫺0.578 0.131 0.138 ⫺0.006 ⫺0.042 0.007 ⫺0.268 ⫺0.299

0.011 0.262 0.428 0.720 0.542 0.596 0.630 0.190 0.024 0.038 0.012 0.442 0.479

0.441 0.211 0.651 0.539 0.414 0.332 0.835 0.467 0.818 0.276 0.568 0.544 0.532

Table 5. Multivariate analysis – moderate to severe side effects Variable

Estimate coefficient

Standard error

p value

Age Gender Glioma Meningioma AVM Acoustic neuroma Other (non-metastatic) Targets, n Total volume treated Prescription dose Prescription isodose Prior XRT (Y or N) Prior whole-brain RT (Y or N)

0.009 0.309 0.184 ⫺1.109 0.155 ⫺0.405 0.003 ⫺0.316 0.003 ⫺0.033 0.002 0.025 ⫺0.731

0.012 0.300 0.468 0.890 0.605 0.641 0.726 0.311 0.027 0.043 0.014 0.482 0.535

0.460 0.303 0.695 0.213 0.798 0.527 0.997 0.308 0.914 0.448 0.890 0.959 0.172

Discussion

Stereotactic radiosurgery is generally regarded as a safe procedure. The number of diagnoses as well as the number of centers performing radiosurgery has increased. Because of its efficacy, radiosurgery offers an attractive alternative

Acute Sequelae of Stereotactic Radiosurgery

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to more invasive procedures. Our study confirms that radiosurgery is a safe procedure, with a serious adverse event rate of less than 5% at 30 days. Few previous studies have focused on the adverse acute events following radiosurgery. Several studies have examined complications following radiosurgery but have not specifically addressed the acute adverse events. WernerWasik et al. [13] reported on 78 patients retrospectively analyzed. These patients were treated with Linac-based radiosurgery. This study demonstrated that 35% developed immediate sequelae 93% of these sequelae were mild to moderate. Increased risk of immediate sequelae was associated with the diagnosis of acoustic neuroma, edema seen on CT scan, dose to margin (prescription dose), and maximum dose. Another study by Majhail et al. [15] prospectively examined side effects occurring in the first 3 months after gamma knife treatment in previously unirradiated patients. Side effects were classified as immediate (first 24 h) or acute (first 3 months). This study found that up to one-fourth of patients experienced self-limiting early toxicities, with no severe toxicities recorded. Multivariate analysis showed that maximum target diameter ⬎25 mm or prescription dose ⬎20 Gy were associated with more early toxicity. One parameter that our study did not address is dose conformality. Nakamura et al. [11] from UCSF correlated toxicity to conformality of dose delivered. In this study, 651 evaluable patients were retrospectively analyzed. Dose conformality was then calculated and compared with the literature on Linac-based radiosurgery. Increasing dose conformality appeared to be correlated with less toxicity. However, the median time to toxicity ranged from 4 to 12.8 months (depending on grade), suggesting that the study analyzed many late toxicities and not exclusively acute toxicities. In our study, we chose to record all adverse events reported in the first 30 days, even if the events appeared to be unrelated to the procedure. This method follows the surgical paradigm for analysis of acute toxicities. Although a significant proportion of patients (34.1%) develop some sequelae, these are predominantly mild or moderate (95.1%). Our study confirms that radiosurgery is safe and associated with few severe side effects. These potential toxicities should be communicated to patients before they elect to undergo this procedure.

Conclusions

Acute adverse events (first 30 days) can occur in approximately one-third of patients. The vast majority of these are mild to moderate. Physicians should communicate the risk of early sequelae to patients.

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References 1 2 3

4

5

6 7 8 9 10 11 12 13 14 15

Boyd TS, Mehta MP: Radiosurgery for brain metastasis. Neurosurg Clin North Am 1999;10: 337–350. Weil MD: Stereotactic radiosurgery for brain tumors. Hematol Oncol Clin North Am 2001;15: 1017–1026. 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 1998;45:427–434. Sperduto PW, Scott C, Andrews D, et al: Preliminary report of RTOG 9508: A phase III trial comparing whole brain irradiation alone versus whole brain irradiation plus stereotactic radiosurgery for patients with two to three unresected brain metastasis. Int J Radiat Oncol Biol Phys 2000; 48:13. 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. Linskey ME, Lunsford LD, Flickinger JC: Radiosurgery for acoustic neuromas: Early experience. Neurosurgery 1995;36:275–284. Maesawa S, Flickinger JC, Kondziolka D, et al: Repeated radiosurgery for incompletely obliterated arteriovenous malformations. J Neurosurg 2000;92:961–270. Valentino V, Schinaia G, Raimondi AJ: The results of radiosurgical management of 72 middle fossa meningiomas. Acta Neurochir 1993;122:60–70. Jackson IM, Noren G: Role of gamma knife therapy in the management of pituitary tumors. Endocrinol Metab Clin North Am 1999;73:23–30. Kondziolka D, Lunsford LD, Flickinger JC, et al: Stereotactic radiosurgery for trigeminal neuralgia: A multi-institutional study using the gamma unit. J Neurosurg 1996;84:940–945. Nakamura JL, Verhey LJ, Smith V, et al: Dose conformity of gamma knife radiosurgery and risk factors for complications. Int J Radiol Oncol Biol Phys 2001;51:1313–1319. Chin LS, Lazio BE, Biggins T, et al: Acute complications following gamma knife radiosurgery are rare. Surg Neurol 2000;53:398–502. Werner-Wasik M, Rudoler S, Preston PE, et al: Immediate side effects of stereotactic radiotherapy and radiosurgery. Int J Radiol Oncol Biol Phys 1999;43:299–304. Cook DR, Weisberg S: Applied Regression Including Computing and Graphics. Chichester, Wiley, 1999. Majhail NS, Chander S, Mehta VS, et al: Factors influencing early complications following gamma knife radiosurgery – A prospective study. Stereotact Funct Neurosurg 2001;76:36–46.

Minesh P. Mehta, MD University of Wisconsin Medical School Department of Human Oncology, K4/310 Clinical Science Center 600 Highland Ave, Madison, WI 53792 (USA) Tel. ⫹1 608 2635009, Fax ⫹1 608 2639947, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 46–50

Stereotactic Radiosurgery for Brain Metastases and Cerebral FDG Positron Emission Tomography S. Raymond Golish a, Antonio A.F. De Sallesb, Cecilia Yap c, Timothy D. Solberg d a b c d

School of Medicine, University of California, Los Angeles (UCLA); Division of Neurosurgery, Department of Surgery UCLA; Department of Nuclear Medicine, UCLA and Department of Radiation Oncology, UCLA, Los Angeles, Calif., USA

Abstract Introduction: Cerebral fluorodeoxyglucose positron emission tomography (FDG PET) has the potential to be useful in planning stereotactic radiosurgery (SRS) for metastatic brain disease. The purpose of this chart review is to investigate the current utilization of PET in management of SRS patients at our center. Methods: Charts were reviewed for all patients treated for metastases to the brain with SRS who had at least one cerebral FDG PET scan in the period 1997 to the present. From each chart, we recorded the dates of PET scans and SRS and compared lesions on scans to lesions treated. Results: Of 402 patients treated with SRS for brain metastases, 77 (19%) had at least one cerebral FDG PET scan during treatment. Of 77 SRS patients receiving a PET scan, 59 (77%) had one PET scan and 18 (23%) had more than one scan for a total of 119 scans. Of 119 total scans, 40 scans from 38 patients preceded SRS by 6 months or less. A total of 66 lesions were treated by SRS following these scans. The sensitivity of PET for treated lesions was 49%. Of 119 total scans, 32 scans from 31 patients preceded SRS by 2 months or less. A total of 57 lesions were treated by SRS following these scans. The sensitivity of PET for treated lesions was 54%. Among all PET scans, 10 scans were indicated for evaluating radiation necrosis or post-surgical changes versus residual tumor, regardless of the follow-up treatment. Conclusions: The sensitivity of PET for treated lesions is mitigated by the time at which the scan was ordered, the multimodal nature of treatment decisions, the presence of patients receiving other treatment, and many other factors. A common indication for PET ordered by the neurosurgical service is to distinguish radiation necrosis from residual/recurrent tumor in the context of an ambiguous MRI after SRS treatment. This indication merits a prospective study. Copyright © 2004 S. Karger AG, Basel

Positron emission tomography (PET) is a functional imaging modality that allows visualization of a variety of biological processes in vivo. PET imaging begins when a tracer or drug is labeled with a positron emitting nucleus. The key to PET is that such tracers and drugs distribute and bind to receptors in a biologically specific way. Bound drugs and tracers spontaneously emit positrons which are collected by a scanner and reconstructed into a PET image. Due to the biologic specificity of PET tracers, the PET image reveals biological function in addition to anatomy. Though dozens of PET tracers have been used for different purposes, the most common tracer is F-18 fluorodeoxyglucose, a glucose analog that is used to image neoplasms, cerebral metabolism, and cardiac metabolism. The use of fluorodeoxyglucose (FDG) PET in oncology is rapidly increasing. The growing utilization of PET has been recognized by the United States Centers for Medicare and Medicaid Reimbursement (CMS). In December of 2000, CMS issued a press release announcing coverage of FDG PET for the diagnosis, staging, and restaging of lung, colorectal, lymphoma, melanoma, esophageal, and head and neck cancer [1]. This coverage is broad-based for these indications, whereas previous coverage focused on specific indications and settings. Some indications are covered for breast and thyroid cancer as well [2]. FDG PET has the potential to be useful in managing SRS patients and is used currently on a case-by-case basis. The purpose of this chart review is to investigate the current utilization of PET in management of SRS patients at our center.

Methods Charts were reviewed for all patients treated for metastases to the brain with SRS who had at least one cerebral FDG PET scan in the period 1997 to the present. The standard scanning protocol involves multiple 5-min static acquisitions following injection of 5–15 mCi of F-18 FDG. No patient was excluded based on other clinical history (e.g. prior whole-brain radiation, prior surgical resection). For SRS, the Novalis system was used (BrainLab AG, Heimstetten, Germany). For PET, scanners from CTI systems were used including the models 851, Exact, and Exact HR⫹ (CTI Molecular Imaging Inc., Knoxville, Tenn., USA). For each patient chart, the dates of all PET scans and the number of lesions identified on each scan were recorded. SRS treatments with a PET scan in the prior 6 months were correlated to determine matching PET lesions. For each chart, we recorded specific indications for ordering PET scans as stated in the notes of the neurosurgical service, and we noted if the PET was noted to be correlated with a specific CT/MRI as stated in the notes of the nuclear medicine service.

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SRS patients

450 400 350 300 250 200 150 100 50 0

402

77

No PET

PET

Fig. 1. Patients treated with SRS who received cerebral FDG PET.

Number of patients (77 total)

70 60

59

50 40 30 20 7

10

6 2

1

1

0

0

1

4

5

6

7

8

9

0 1

2

3

Number of PET scans

Fig. 2. Number of cerebral FDG PET scans received by SRS patients.

Results

Of 402 patients treated with SRS for brain metastases, 77 (19%) had at least one cerebral FDG PET scan during treatment (fig. 1). Of 77 SRS patients receiving a PET scan, 59 (77%) had one PET scan and 18 (23%) had more than one scan for a total of 119 scans (fig. 2). The most common primaries were lung, melanoma, breast and renal cell; a wide variety of other primaries were also present (fig. 3). Of 119 total scans, 40 scans from 38 patients preceded SRS by 6 months or less. A total of 66 lesions were treated by SRS following these scans. The

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30

28

Number of patients

25 20

17 15

15 12 10 5 5 0 Lung

Other

Melanoma

Breast

Renal cell

Fig. 3. Types of primaries in patients who received SRS and cerebral FDG PET.

sensitivity of PET for treated lesions was 49%. Of 119 total scans, 32 scans from 31 patients preceded SRS by 2 months or less. A total of 57 lesions were treated by SRS following these scans. The sensitivity of PET for treated lesions was 54%. Among PETs that did not preceded SRS, 6 aided in the decision to refer patients to surgery. Among all PET scans, 10 scans were instrumental in evaluating radiation necrosis or post-surgical changes versus residual tumor, regardless of the follow-up treatment. Of 119 total scans, 25% were noted by the nuclear medicine service to have been correlated with a specific CT/MRI at the time of being read. Though it is standard practice to correlate anatomical imaging, the specific films used for correlation are not always noted.

Conclusion

The sensitivity of PET for treated lesions is a combination of many factors. The decision to treat a lesion by SRS is multimodal and includes anatomic imaging, clinical status, and previous treatment. No one modality such as PET can be expected to correlate completely with treatment decisions. In addition, the current study examines the sensitivity of PET for treated lesions irrespective of many other variables such as previous treatment with whole-brain radiation therapy or surgical resection; here, previous treatment was not controlled for due to sample size considerations. This study retrospectively examined all PET scans ordered by all services for all indications. Most of these scans were part of a general workup and were

PET and Radiosurgery of Brain Metastases

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ordered by services other than neurosurgery. The lack of specific neurosurgical indications for these scans and the variable durations from scan to lesion treatment are likely major factors mitigating the sensitivity of PET in this study. Anecdotes from the notes indicate that the most common reason the neurosurgical service ordered PET scans was to distinguish radiation necrosis from residual/recurrent tumor in the context of an ambiguous MRI after SRS treatment. PET may also be useful for helping to delineate the boundaries for treatment of residual/recurrent lesions, which are difficult to determine due to the presence of edema and necrosis. These specific neurosurgical indications for PET merit a prospective study which includes lesion sensitivity analysis as well as lesion geometry and region-of-interest analysis.

References 1 2

Centers for Medicare and Medicaid Services Office of Public Affairs: Medicare Expands Coverage of PET Scans. Medicare News, Dec 15, 2000. Centers for Medicare and Medicaid Services Office of Public Affairs: Medicare Expands Coverage for PET Scans. Medicare News, April 16, 2003.

Antonio A. F. De Salles UCLA Surg-Neuro Box 957182, 200 Medical Plaza, Suite 504 Los Angeles, CA 90095–7182 (USA) Tel. ⫹1 310 7941221, Fax ⫹1 310 7941848, E-Mail [email protected]

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Comparison of MR Spectroscopy and MR Perfusion in Benign and Malignant Infiltrative Brain Tumors S. Asavaphatiboon a, T. Sinlapawongsa a, J. Laothamatas a, M. Dhanachai a, V. Theerapancharoen b, S. Putthicharoenrat c Departments of aRadiology and bNeurosurgery, Faculty of Medicine, Ramathibodi Hospital and cDepartment of Pathology, Prasart Neurological Institute, Bangkok, Thailand

Abstract Purpose: To compare the choline/creatine (Cho/Cr), N-acetylaspartase/creatine (NAA/Cr) ratios, and tumor perfusion between benign and malignant infiltrative brain tumors. Methods and Materials: Magnetic resonance spectroscopy (MRS) and magnetic resonance (MR) perfusion of 9 patients with histological diagnosis of benign (2 astrocytomas, 1 oligodendroglioma) and malignant (3 anaplastic astrocytomas, 1 malignant astrocytoma, 1 malignant mixed oligoastrocytoma, 1 glioblastoma multiforme) infiltrative brain tumors were retrospectively reviewed. Four areas of interest were analyzed including normal brain (area 1), normal brain adjacent to the lesions (area 2), non-enhancing hypersignal T2 area (area 3) and solid enhancing area (area 4). Results: The perfusion ratios of malignant and benign tumors were 100% and 100% for area 1, 119.7 ⫾ 46.53% and 90.67 ⫾ 18.01% for area 2, 128.33 ⫾ 70.16% and 70.67 ⫾ 70.69% for area 3, and 308 ⫾ 194.81% and 235 ⫾ 37.32% for area 4. Cho/Cr ratios were 1.23 ⫾ 0.29 and 0.90 ⫾ 0.13 for area 1, 1.26 ⫾ 0.22 and 1.45 ⫾ 0.78 for area 2, 1.89 ⫾ 0.61 and 1.93 ⫾ 0.31 for area 3, and 4.26 ⫾ 2.10 and 2.97 ⫾ 1.66 for area 4. NAA/Cr ratios were 1.69 ⫾ 0.36 and 1.56 ⫾ 0.19 for area 1, 1.61 ⫾ 0.24 and 1.83 ⫾ 0.60 for area 2, 1.3 ⫾ 0.39 and 1.35 ⫾ 0.28 for area 3, and 1.0 ⫾ 0.31 and 0.88 ⫾ 0.51 for area 4. Conclusions: Increased Cho/Cr ratio and decreased NAA/creatine ratio indicates the presence of tumor. The perfusion value in the tumor area is higher than that of normal white matter. Differentiating benign from malignant gliomas by using in vivo proton MRS and perfusion MRI is challenging. Copyright © 2004 S. Karger AG, Basel

The strategies for management of various types of brain tumors depend greatly on histological findings, which can only be determined after surgery or biopsy. If the aggressiveness or grading of the tumor can be predicted when the patient is sent for preoperative imaging evaluation, treatment planning such as surgical and radiation therapy planning could be done more appropriately. In some particular cases, such as deep-seated tumor that cannot be operated, the attempt to get as much information as possible can be critical for further treatment and prognostic prediction. In this situation, a magnetic resonance imaging (MRI) study is possibly the only source of information guiding further therapy. Nowadays, the diagnosis of intracranial neoplasm greatly depends on MRI. In particular, the introduction of new MRI techniques combined with conventional MRI improves diagnostic potential. One of the most widely accepted valuable diagnostic methods for evaluation of many types of brain lesions is in vivo proton magnetic resonance spectroscopy (MRS). This modality provides the ability for characterizing the metabolic changes in different pathologic conditions [1–19], in addition to morphological changes given by conventional MRI [20–22]. The main benefit from applying MRS in brain tumor evaluation includes differentiating non-neoplastic from neoplastic conditions in undiagnosed brain lesions [8, 23–26], and differentiating residual/recurrent tumor from radiation necrosis [27–35]. Furthermore, there are many authors using MRS examinations to determine how spectral patterns are related to tumor grade and progression [4–5, 10–12, 36, 37]. Recent MRS data provide unique information that when combined with high-quality anatomical MRI have implications for identification of tumor type and grade, directing biopsy or surgical resection, planning focal radiation or biological therapies, and understanding the mechanisms of success and failure of new treatments [1–4, 23–24, 27, 38–55]. Pattern analysis of proton MRS data obtained from single-voxel spectroscopy or multi-voxel spectroscopy can be used to detect metabolic signatures of glial brain tumors [9, 56–58]. In a number of studies, there is definite clinical value of proton single-voxel MRS [10, 59–61] and multi-voxel spectroscopy [58] for the management of patients with brain pathologies suspicious for malignant tumors. Dynamic contrast agent-enhanced perfusion MRI is another new MR technique providing additional physiologic information that complements the anatomic information available with conventional MRI. The application of perfusion MRI in research centers and in clinical practice is increasing because it provides maps of the regional variations in cerebral microvasculature of normal and diseased brains [62–66]. Data from perfusion MRI reflects the underlying microvasculature and angiogenesis [67]. This is leading to the application of perfusion MRI to evaluate tumor angiogenesis. The tumor angiogenesis was recently described based on the finding that tumor can induce new capillary

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vessels [68]. Furthermore, the degree of angiogenesis was found correlated to tumor grade in human glioma, with higher grade lesions showing increased angiogenetic factors [69–71]. Therefore, the established role of perfusion MRI in preoperative assessment of glioma vascularity is for determining malignant potential and, therefore, potentially in alteration of therapeutic management [67]. The purpose of this study is (1) to characterize metabolite ratio (choline/creatine (Cho/Cr) and N-acetylaspartase/creatine (NAA/Cr)) and perfusion character in areas of different MRI characters in benign and malignant glioma and (2) to determine how parameters at different areas are related to aggressiveness (benignity and malignancy) of the tumors.

Materials and Methods Patient and Histopathologic Diagnosis Nine patients (5 men, 3 women and 1 girl; age range 6–68 years) with a histopathologic diagnosis of benign (2 astrocytomas, 1 oligodendroglioma) and malignant (3 anaplastic astrocytomas, 1 malignant astrocytoma, 1 mixed oligoastrocytoma, 1 glioblastoma multiforme) infiltrative brain tumors (table 1) underwent MRI, MRS and perfusion MRI. MRS and MR Perfusion All patients were screened on a 1.5-T superconductive scanner unit (model CV&NV/i, software version 9.1, General Electric Medical System, Milwaukee, Wisc., USA) using a head coil. MRS was acquired using 2D multi-voxel spectroscopy study with a point-resolved spectroscopic (PRESS) sequence with parameters of TR/TE (1,600/144 ms, 16 ⫻ 16 phase encoding, 160 ⫻ 160 mm field of view). MR perfusion was obtained in the axial plane with a spin-echo echo planar (SE-EPI) technique with TR/TE (2,000/80 ms, field of view 28 ⫻ 28 cm, matrix size 128 ⫻ 128, scan time 1.42 m), after injection of 0.05 mmol/kg of contrast media to minimize the effect of T1 shortening from enhancing lesions. Series of images (10 slices, 50 images/s) were obtained before, during and after bolus injection of 0.4 mmol/kg contrast media with an injector (Spectrist, Medrad) with a flow rate 5 ml/s, followed by a 30-ml normal saline flush with the same rate. Analysis of MRS and MR Perfusion MRS and MR perfusion data were analyzed on an Advantage workstation using Functool 2000 software (General Electric Medical System). The spectra were post-processed with spectroscopy 2D brain software, the automatic fitting in the frequency domain. The relative intensities of the signal caused by NAA, Cho and creatine (Cr) were calculated for NAA/Cr and Cho/Cr ratios. MR perfusion data were post-processed with standard MR software. The percentage of the perfusion value in each area was compared with normal parenchyma tissue. Area of Interest of MRS and MR Perfusion For MRS and MR perfusion, four areas of interest were analyzed including normal brain (area 1), normal brain adjacent to the lesions (area 2), non-enhancing hypersignal T2 area (area 3) and solid enhancing area (area 4) (fig. 1).

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53

Table 1. List of patient history, histopathological diagnosis and the values of Cho/Cr, NAA/Cr and perfusion ratios of each patient Asavaphatiboon/Sinlapawongsa/Laothamatas/Dhanachai/ Theerapancharoen/Putthicharoenrat

Patient Sex Age Pathological years diagnosis

NAA/Cr

Cho/Cr

Perfusion

area 1 area 2 area 3 area 4 area 1 area 2 area 3 area 4 area 1 area 2 area 3 area 4 1

F

51

2

F

3

Anaplastic mixed oligoastrocytoma

1.517

1.353

2.707

4.119

1.403

1.364

1.782

0.823

100

141

163

655

6

Anaplastic astrocytoma

1.641

1.313

1.286

5.323

2.149

1.419

1.402

1.319

100

75

88

125

M

68

Glioblastoma multiforme

1.168

1.187

2.44

7.78

1.301

1.622

1.635

1.399

100

164

257

373

4

M

47

Anaplastic astrocytoma grade III

1.072

1.168

1.678

2.048

1.403

1.826

0.79

0.903

100

77

98

145

5

M

31

Anaplastic astrocytoma

0.869

0.939

1.194

2.403

1.936

1.946

1.267

0.562

100

82

78

313

6

F

36

Malignant astrocytoma

1.125

1.589

2.047

3.86

1.966

1.46

0.939

1.019

100

176

86

237

7

F

35

Oligodendroglioma 0.939

1.044

1.878

4.872

1.559

2.389

1.312

0.517

100

99

151

276

8

M

56

Astrocytoma

0.719

0.958

1.649

1.884

1.753

1.198

1.09

0.661

100

103

43

226

9

M

32

Astrocytoma

1.038

2.354

2.258

2.143

1.37

1.896

1.642

1.459

100

70

18

203

54

a

b Fig. 1. a Measurement areas of MRS of the patient. b Measurement areas of MR perfusion.

Results

Thirty-six MRS spectra from 9 patients (4 male, 5 female; age range 6–68 years) with cerebral gliomas were obtained and analyzed. These demographic data of all patients are presented in table 1. The data from the 9 patients were divided into two different categories – 3 benign tumors and 6 malignant tumors. Pathological diagnosis includes 2 astrocytomas, 1 oligodendroglioma (which are considered as benign tumors), 3 anaplastic astrocytomas, 1 anaplastic mixed oligoastrocytoma, 1 malignant astrocytoma and 1 glioblastoma (which are considered as malignant tumors). Cho/Cr, NAA/Cr and relative perfusion value from area 1 (normal brain remote to the lesion), area 2 (normal-appearing brain adjacent to the lesion), area 3 (non-enhancing hypersignal T2 area or peritumoral area) and area 4 (solid enhancing tumor) of each patient are presented in table 1. These values from all malignant and benign group patients are calculated separately and presented as mean and standard deviation for each area (table 2). The mean NAA/Cr ratios from both groups obtained from area 1 show a slightly higher ratio value in the malignant group. For area 2, the NAA/Cr ratio of the benign group is higher than that of the malignant group. For area 3, the NAA/Cr ratios of both groups are almost identical. For area 4, the NAA/Cr ratio of the malignant group is slightly higher than that of the benign group. From area 1 to area 4, the trend of mean NAA/Cr ratios is gradually decreased for both groups (table 2). The mean Cho/Cr ratio of the malignant group obtained from area 1 is slightly higher than that of the benign group (1.23 and 0.9, respectively). The mean Cho/Cr ratios obtained from area 2 in both groups are higher than that

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Table 2. Mean and SD values of Cho/Cr, NAA/Cr and perfusion ratios of each area of malignant and benign tumors Ratio

Malignant area 1

Benign area 2

area 3

area 4

area 1

area 2

area 3

area 4

Cho/Cr 1.23–0.29 1.26–0.22 1.89–0.61 4.26–2.10 0.90–0.13 1.45–0.78 1.93–0.31 2.97–1.66 NAA/Cr 1.69–0.36 1.61–0.24 1.3–0.39 1.00–0.31 1.56–0.19 1.83–0.60 1.35–0.28 0.88–0.51 Perfusion 100–0 119.17–46.53 128.33–70.16 308–194.81 100–0 90.67–18.01 70.67–70.69 235–37.32

from area 1 and the values of the malignant group are mildly lower than that of the benign group (1.26 and 1.45, respectively). The mean Cho/Cr ratios obtained from area 3 in both groups are higher than that from area 2 and the value of the malignant group is slightly lower than that of the benign group (1.89 and 1.93, respectively). The mean Cho/Cr ratios obtained from area 4 in both groups are higher than that from area 3 and the value of the malignant group is higher than that of the benign group (4.26 and 2.97, respectively). The spectrum of lactate could be detected in some cases of both groups. Some selected cases are shown in figures 2–4. The relative perfusion values were obtained from areas 2–4 using area 1 as a reference, because area 1 represents most normal-looking brain far from the lesion. There is mild hypoperfusion at area 2 for the benign group (90.67%) and mild hyperperfusion for the malignant group (119.17%). For area 3, there is mild hyperperfusion (128.33%) for the malignant group but hypoperfusion (70.67%) for the benign group. For area 4, there is hyperperfusion for both groups but it is more obvious in the malignant group (308% malignant group, 235.32% benign group).

Discussion

The role of MRS in the differential diagnosis of brain tumors and in characterization of metabolic changes associated with tumor progression, degree of malignancy and response to treatment is an interesting topic for many physicians working in the neurological field [1–4, 23, 24, 27, 38–54]. It represents an intrinsic multiparameter, yielding simultaneous information about a variety of metabolites. Results from in vitro experiments have demonstrated unequivocally that the MRS chemical profile is different for different tissues and for different cell types [72–75]. Therefore, with sufficient spatial and spectral

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a

d

b

c

e

f

Fig. 2. A 36-year-old woman, a case of malignant astrocytoma at the left temporoparietal region. a Coronal T2-weighted MR image shows left temporoparietal mass with heterogeneous hypersignal T2 change. b Coronal contrast-enhanced T1-weighted MR image shows enhancement along the medial part of the tumor. c MR spectra obtained from four different regions: area 1 representing normal-appearing brain shows normal spectral pattern; area 2 representing normal T2 signal brain adjacent to the tumor shows decreased NAA, Cho, Cr peaks with slightly increased Cho/Cr ratio; area 3 representing non-enhancing hypersignal T2 area shows markedly decreased NAA peak and markedly increased Cho peak with presence of lactate peak (inverse peak); area 4 representing solid enhancing area shows spectral pattern almost similar to area 3 (d–f). Perfusion MRI shows hyperperfusion of area 4.

resolution, all tissue types can be localized spatially and identified unambiguously. In in vivo MRS studies, the metabolites that can be identified with long TE MRS are NAA, Cho, creatine/phosphocreatine (Cr) and possibly lactate. NAA is a marker of neuronal integrity in which its reduction signifies neuronal damage. Cho is a substance found in cell membrane, and an elevation of Cho reflects increased membrane turnover or cell proliferation [76]. Thus, an increase in Cho may indicate either rapid cell division in a growing tumor or cell destruction from radiation and an influx of inflammatory cells. Creatine indicates energy stored in the brain and lactate peak can be found in condition that results in anaerobic glycolysis. There are many previous MRS studies where in virtually all untreated tumors an increase of Cho and a decrease of NAA are observed. These results are similar to our study. In the solid enhancing area representing the tumor core,

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a

b

c

d Fig. 3. A 31-year-old man, a case of anaplastic astrocytoma at the right temporoparietal region. a Axial T2-weighted MR image. b Axial contrast-enhanced T1-weighted MR image. c MR spectra obtained from four different regions. d Perfusion MRI.

an increased Cho/Cr ratio and decreased NAA/Cr ratio are detected as compared to normal-appearing brain, findings that are found both in benign and malignant tumors. In malignant tumors, the Cho/Cr ratio tends to rise more than that of benign tumors whereas the reduction of the NAA/Cr ratio is not significantly different between benign and malignant tumors. However, a larger number of the patients are needed for the study in order to identify statistical significance of this parameter for differentiating benign from malignant glioma. There are several authors studying the potential of MRS in grading of brain tumors. The study of Bulakbasi et al. [77] found that MRS is not effective in grading malignant tumors (all grades of glioma are considered malignant). On the other hand, Meyerand et al. [42] successfully use Cho and lactate ratios to separate the high-grade from the low-grade tumors, whereas Castillo et al. [48]

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a

b

c

d Fig. 4. A 32-year-old man, a case of astrocytoma at the brainstem region. a Axial contrast-enhanced T1-weighted MR image. b Axial T2-weighted MR image. c MR spectra obtained from four different regions. d Perfusion MRI.

used the level of myoinositol for tumor-grading evaluation. Moller-Hartmann et al. [24] demonstrate a higher Cho and lipid level in higher-grade astrocytoma. In another study, high-grade tumors can show as much as a fourfold increase in Cho signal [78]. The NAA level was decreased in both malignant and benign tumors. In astrocytomas, the NAA level was reduced to 40–70% of its normal value [3–4, 24, 40, 44]. There was a trend of a decrease in NAA level with the advanced tumor grade [24], but there is no statistically significant relation between the decrease in NAA level and tumor grade [77]. In our study, we could not find the difference in NAA reduction between the different tumor grades. In our study we tried to sample and collect MR spectra from different areas including normal brain remote to the lesion (area 1), normal-appearing brain adjacent to the lesion (area 2), non-enhancing hypersignal T2 area or

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peritumoral area (area 3) and solid enhancing tumor (area 4) because we wanted to define the extent of abnormal metabolic changes correlated to tumor aggressiveness. Key areas are area 3 and area 2 because they are both in the border zone that should be clarified for the presence of tumor. Even though the mean value of each parameter could be calculated and identified, it cannot be applied in real-life practice because the small sample size would not be representative. Furthermore, a variety of pathologies exist in the non-enhancing hypersignal T2 region (area 3) that should be pathologically proven area by area. However, when looking at each patient’s details, there is some important information that has to be kept in mind, for example, 1 case has a significantly high Cho/Cr ratio in area 2 – a finding which reflects that tumor infiltration into the normal signal brain adjacent to the tumor could be found. Concerning the MRS technique, the optimal pulse sequence parameters for tumor grading are still an issue of debate. We used long TE spectra because of less baseline distortion and easier quantification (simpler line shapes and fewer resonances). As a result, data acquired using this technique will have less variability induced by collection and analysis factors. MR spectra were obtained before administration of contrast medium to avoid the effect of contrast agent that induced a decrease of the Cho signal intensity [79]. However, the voxel localization in pre-contrast MR images can be problematic and the most enhancing area could be in the region not included in the voxel. Concerning spatial resolution of MRS, an important consideration in interpreting metabolite levels is the reference value. One of the approaches is to determine the metabolic concentrations in units of mmol/l or weight of brain [79–80], but absolute quantification of the metabolite in vivo MRS is difficult [81, 82]. In most MRS studies, the metabolite levels are reported relative to Cr peak, either from the same voxel or from a voxel containing only normal tissue [2, 9, 16]. Utilization of perfusion MRI can help in the evaluation of various intracranial lesions, including assessment of the degree of neovascularization in brain tumors, evaluating tumor grading and malignancy, and identifying tumor-mimicking lesions. There are several parameters which are derived from dynamic contrast agent-enhanced perfusion MRI such as cerebral blood volume (CBV), cerebral blood flow, and mean transit time. However, the most useful parameter in the evaluation of intracranial mass lesions is CBV [67]. In our study we reported the tumor perfusion in terms of relative value compared to the normal white matter because of limitation in software calculating other perfusion parameters. In the solid enhancing tumor region (area 4) of benign and malignant tumors, there is a marked hyperperfusion of at least twofold compared to the normal white matter (area 1). The relative perfusion value of the malignant tumor group is higher than that of the benign group.

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In addition, mild hyperperfusion of the surrounding brain in area 3 and area 2 was found in the malignant group but mild hypoperfusion of these areas was observed in the benign group. Glioma grading is important for determination of both prognosis and therapy. Hence, perfusion MRI can assess tumor vascularity which further correlates to angiogenesis and the degree of angiogenesis was found to be correlated to the tumor grade in human glioma, with higher-grade lesions showing increased angiogenetic factors [69–71]. Perfusion MRI could be used for grading glioma. The study of Aronen et al. [83] concluded that tumors with any rCBV value more than twice that of white matter have a high likelihood of having a high-grade component while tumors with maximum rCBV values less than 1.5 times white matter are usually low grade. Other authors [62, 63] also reported statistically significant correlations between tumor rCBV and glioma grade. Our results point in the same direction, and although rCBV cannot be calculated, hyperperfusion was found in malignant gliomas and less hyperperfusion was found in benign gliomas. The applications of perfusion MRI in the future tend to be more widespread, especially assessment of glioma vascularity determining malignant potential and therefore potentially in alteration of therapeutic management. In addition, perfusion MRI can be used for a non-invasive assessment of changes in tumor rCBV during treatment by antiangiogenic therapy and thus for monitoring the effectiveness of therapy [67].

Conclusion

Together with conventional MRI, in vivo proton MRS and perfusion MRI provide additional useful information for evaluation of primary glioma. An increased Cho/Cr ratio and decreased NAA/Cr ratio indicates the presence of tumor. The perfusion value in the tumor area is higher than that of normal white matter. Differentiating benign from malignant gliomas by using in vivo proton MRS and perfusion MRI is challenging. However, the small number of patients is a limiting factor in this study. References 1

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Sawwanee Asavaphatiboon Diagnostic Division, Department of Radiology MRI Room, Ramathibodi Hospital 270 Rama VI Road, Phyathai, Bangkok (Thailand) Tel. ⫹662 201 22301, Fax ⫹662 2461176, E-Mail [email protected] or [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 66–76

Tumor Control Probability Predicts the Fate of Multiple Metastatic Brain Tumors Hisato Naganoa, Satoshi Nakayamac, Hiroyuki Asadab, Takashi Syutoub, Kazunori Tanahataa, Shigeo Inomori b Departments of aRadiology and bNeurosurgery, Yokohama Rosai Hospital and c Department of Neurosurgery, Yokohama Citizens’ Medical Center, Yokohama, Japan

Abstract Over 50,000 cases of metastatic brain tumors (MBTs) have been treated with gamma knife (GK) radiosurgery. However, optimal patient selection and treatment factors are still controversial in the cases with over five lesions. Tumor control probability (TCP) may be useful in these situations. From 1992 to 1999, 284 patients with metastatic brain tumor were treated by GK. Within that group, 32 patients (18 male, 14 female) had over five lesions. Their ages ranged from 26 to 77 years with a median age of 56 years. The number of lesions per patient ranged from 5 to 56 (average 11.5). The total volume of the lesions ranged from 1.8 to 111.8 cm3 (average 21.8 cm3). Marginal dose ranged from 8 to 22 Gy (average 15.3 Gy). Normal tissue complication probability (NTCP) ranged from 0.0 to 31% (average 8.7%) and TCP ranged from 0.0 to 83% (average 19.6%). Eleven patients had undergone previous craniotomy. Three were irradiated previously and 6 were given concomitant whole-brain irradiation. Eleven patients had additional extracranial metastatic lesions. Survival period ranged from 0.2 to 26.2 months (median 5 months). Using Cox’s proportional hazard model, only TCP correlated with the survival times (STs) (p ⫽ 0.007). Two patients whose TCP values were over 75% but NTCP values were over 18% survived 5 and 10 months, respectively. These values were very low compared to the expected STs estimated from very high TCP values. The equation, ST ⫽ 118.5⭈(0.3 ⫺ NTCP)⭈TCP ⫹ 3.2, may explain this phenomenon. ST and (0.3 ⫺ NTCP)⭈TCP were somewhat well correlated (R ⫽ 0.67, p ⬍ 0.001). In conclusion, TCP may predict STs of multiple (over five) BT patients. NTCP should also be calculated to avoid excessive irradiation dose. The hyperbolic formula we propose may indicate an appropriate dosimetric solution for each patient with multiple MBTs. Copyright © 2004 S. Karger AG, Basel

TCP ⫽ ∫

SFi ⫽ ∫

2   ind   1  SF 2 ⫺ 0.51  exp ⫺    ⭈ exp ⫺19,108 ⭈   2 0 15 . 2␲ ⭈ 0.15       

1



∑ v i ⭈ SFi  dSF 2 i

ind



2 1   ind ind ind ∑ n j ⭈ d j ⭈ (10 ⫹ d j ) 2 ⭈ ( 10⫹2 ) j  1  SF ⫺ SF 2   exp ⫺  2 dSF2ind   ⭈ SF2   0.05 2␲ ⭈ 0.05  2   

1

(

 2   ∑ 0.526 ⭈ n j ⭈ d j j NTCP ⫽ 1 ⫺ ∏   72.19 i   

)    

12.2

⫺v i / 1,367

  ⫹ 1  

Fig. 1. TCP formula depended upon the distribution of radiosensitivity (SF2ind, ␴ ⫽ 0.05) of clonogens (19,108/mm3) within each subvolume (vi) and the distribution among patients with the same kind of tumor (mean ⫽ 0.51, ␴ ⫽ 0.15). Colombo’s formula was extended to be able to evaluate multiple radiological procedures including WBI (⌺j). Flickinger’s NTCP integrated logistic formula was transformed not to include days per fractions component.

Worldwide, over 50,000 patients with metastatic brain tumors (MBTs) have been treated with gamma knife (GK). It is said that the survival and morbidity results of radiosurgery for one to four brain metastases are equal or superior to those of surgical resection followed by whole-brain irradiation (WBI). However, optimal patient selection and treatment factors are still controversial in cases with over five lesions. Pertaining to the care of patients with four or fewer metastatic brain tumors, many clinical works have been published [1–12]. Stereotactic irradiation (STI) has been considered to be a reasonable treatment for these patients. But for patients with over five lesions, some have claimed that they were not candidates for STI and others have said that these patients were safely and effectively treated by STI [13–17]. Controversy cannot be avoided when debating clinical issues of great importance. Several years ago, Colombo et al. [18] reported a formula to calculate an optimal dose for the STI treatment of intracranial lesions using 6MVX Linac. They defined TGF (therapeutic gain factor) as the ratio of TCP (tumor control probability) to NTCP (normal tissue complication probability) at different levels of dose and then used TGF as a score for the analysis of optimal irradiation technique. Their TCP formula depended upon the difference in radiosensitivity (represented by the variation in survival fraction at a dose of 2 Gy; SF2) of clonogens within the tumors and the difference between patients with the same kind of tumor. We extended that formula to be able to evaluate multiple radiological procedures including WBI (fig. 1). With these biophysical parameters

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Table 1. Characteristics of patients, tumors and treatments

Age, years KPS Tumors, n Total tumor volume, cm3 TCP NTCP Marginal dose, Gy

Minimum

Maximum

Mean

SD

26 60 5 1.8 0.000 0.000 8.0

77 80 56 111.8 0.831 0.312 22.0

56.4 76 11.5 21.8 0.196 0.087 15.3

14.1 10 12.1 26.0 0.235 0.084 3.9

(NTCP and TCP), optimal candidates for the treatment and the dose to be irradiated may be estimated. We retrospectively analyzed those patients with metastatic brain tumors with over five lesions and will demonstrate that NTCP and TCP are useful in predicting the survival time (ST). If the ST of each patient can be estimated, we can better decide whether or not a treatment will be beneficial to our patients.

Patients Thirty-two patients (18 male, 14 female) with over five lesions were irradiated between 1992 and 1999 in our institution. These represent about 10% of patients with MBTs treated in the same period. The median age was 56 years (range 26–77). Karnofsky Performance Score (KPS) was over 60. Total number of the tumors was 331 (median 7, range 5–56). A median total volume of each patient’s tumors was 12.9 cm3 (range 1.8–111.8 cm3) (table 1). In 15 cases, the tumors originated in the lung. The breast was the origin of tumors in 8 cases. Three patients had previously undergone WBI. Six patients were given concomitant WBI. Eleven patients had additional extracranial metastatic lesions. Marginal dose ranged from 8 to 22 Gy (median 15.0 Gy). TCP ranged from 0.0 to 83% (median 8.9%). NTCP ranged from 0.0 to 31% (median 6.1%) (table 1). Follow-up time ranged from 0.2 to 26.2 months, with a median of 5.2 months. Methods of Analysis In our analysis, two statistical methods were used. ST was calculated using the KaplanMeier method. Cox’s hazard model was used to evaluate correlations between some variables and the ST. Evaluated independent variables were patient factors (years of age and performance status), tumor factors [origin of tumors (lung, breast or others), total volume and number of tumors in each patient], and treatment factors (TCP, NTCP and marginal dose). Commercial software, Statistica, was used for these statistics calculations. TCP and NTCP were calculated using Excel add-in software. TCP was estimated using Colombo’s formula, which takes into account both the heterogeneity of tumors and dose

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1.0 0.9

Survival fraction

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0

5

10

a

15

20

1.0

30

Breast Others Lung p⫽ 0.65

0.9 0.8 Survival fraction

25

Time (months)

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0

b

5

10

15

20

25

30

Time (months)

Fig. 2. Survival curves obtained using Kaplan-Meier Product-Limit method. a Survival function of all patients (n ⫽ 32). b Patients were divided into three groups according to the origin of tumors. No difference was statistically signified among these three groups.

distribution [18]. We extended the equation to be able to integrate multiple radiological treatments, including WBI. NTCP was estimated using the integrated logistic formula proposed by Flickinger et al. [19]. The days-per-fractions component, which was intended to compensate overall treatment time, was neglected (fig. 1).

Results

Fifty percent of patients survived for over 5 months. About 20% of patients survived for over 1 year. Multiple-sample test showed no difference in survival with reference to the origin of the tumors (p ⫽ 0.65) (fig. 2).

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TCP p ⫽0.007 Origin p⫽ 0.089 NTCP p⫽ 0.109 Marginal dose p ⫽ 0.161 PS p⫽ 0.574 Total volume p ⫽ 0.741 Age p⫽ 0.886 Tumors, n p⫽ 0.956 ⫺15.0

0.0

15.0

95% CI of ␤

Fig. 3. Cox’s hazard rates of several covariates. Only TCP was significantly covariate statistically.

TCP was significantly influential on ST with a very small hazard rate (p ⫽ 0.007, ␤ ⫽ –4.5, 95% confidence interval (CI) –7.9 to –1.2). Other covariates such as years of age, performance status of patients, origin of tumors, total volume and number of tumors in each patient and marginal dose had no significant influence on the ST. The hazard rate of the NTCP was large but not significant (p ⫽ 0.107, ␤ ⫽ 5.2, 95% CI –1.2 to 11.6) (fig. 3). Due to the short life expectancies of these patients, follow-up images were scarcely available. About one-third of the tumors could undergo volumetric consideration (12 patients, 103 lesions). When V/V0 (V was tumor volume at the investigation and V0 was tumor volume at the treatment) was plotted against TCP, the estimation to the model (V/V0 ⫽ a⭈lnTCP ⫹ b) revealed statistically significant (a ⫽ –0.24 ⫾ 0.06 (95% CI), b ⫽ 0.19 ⫾ 0.08, R ⫽ 0.6, p ⬍ 0.001). V/V0 did not exceed one in 95% of these 103 tumors. That means that 97 tumors were controlled (fig. 4). Shown in the analysis using Cox’s model, NTCP was not a significant covariate but had great ␤ value. Three-dimensional representation of ST, TCP and NTCP illustrates the role of NTCP in dose optimization. In general, TCP and NTCP will increase at the same time radiation dose is increased. Increased NTCP will cancel out the effect of TCP on ST (fig. 5). We proposed the following regression equation: ST ⫽ a⭈[(0.3 ⫺ NTCP)⭈TCP] ⫹ b

The slope [a ⫽ 118.5 ⫾ 62.0 (95% CI)] and the intercept (b ⫽ 3.2 ⫾ 2.8) are statistically significant (p ⬍ 0.05). R2, or the coefficient of determination, is only 0.32. If this equation was applied separately according to the origin of the tumors, the slope of breast cases were markedly large (a ⫽ 295 ⫾ 313), but the value was not statistically significant (p ⫽ 0.11) (fig. 6).

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2.5

2.0 y⫽ ⫺0.24 ln(x) ⫹ 0.19 R2 ⫽ 0.36 1.5 V/V0

p⬍ 0.001

1.0

0.5

0.0 0.00

0.01

0.10

1.00

TCP

Fig. 4. V/V0 (V: tumor volume at the investigation; V0: tumor volume at the treatment) plotted against TCP. The estimation to the model (V/V0 ⫽ a⭈lnTCP ⫹ b) was statistically significant (a ⫽ ⫺0.24 ⫾ 0.06 (95% CI), b ⫽ 0.19 ⫾ 0.08, R ⫽ 0.6, p ⬍ 0.001).

5 10 15 20 25 30 Above

Survival

30

20

10

1.00

0.0 0.75

0.1

0.50

0.2 NTCP

0.3

0.25

TCP

0.00

Fig. 5. Survival time was plotted three-dimensionally against NTCP and TCP. As dose increases, NTCP will get close to increased TCP, and wipe out the outcome of dose escalation.

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30 Breast: y⫽ 294.9x ⫹ 2.7 R2 ⫽ 0.36, p⫽ 0.11

Survival time (months)

25

20

15 Lung: y ⫽ 121.0x ⫹1.1 R2 ⫽ 0.75, p ⬍0.003

10

Others Breast Lung

5

0 0

0.05

0.1

0.15

0.2

(0.3 ⫺ NTCP)·TCP

Fig. 6. Survival time was a function of (0.3 ⫺ NTCP) ⭈ TCP; ST ⫽ a ⭈ [(0.3 ⫺ NTCP)⭈TCP] ⫹ b. If all patients were concerned, the slope (a ⫽ 118.5 ⫾ 62.0 (95% CI)) and the intercept (b ⫽ 3.2 ⫾ 2.8) are statistically significant (R2 ⫽ 0.32, p ⬍ 0.05). If the fitting to the equation was performed separately according to the origin of the tumors, the slope of breast cases were markedly large (a ⫽ 295 ⫾ 313), but the value was not statistically significant (p ⫽ 0.11).

Discussion

For a solitary BT of appropriate size, SRI has been recognized as an equal or superior procedure for surgical resection followed by WBI. Several authors have reported an 80–90% local control rate of the tumor with a minimal dose of 15–30 Gy. Median ST was about 12 months and the incidence of brain necrosis was under 5% [1–3]. For those patients with two to four brain metastases, combined WBI and STI or fractionated STI achieved 80–90% local control with fewer than 5% incidence of radiation-induced brain necrosis. Median survival was reported to be around 6–11 months. This is superior to WBI alone to achieve control of brain disease [4–12] (table 2). Because GK has multiple portals structurally, if the lesions are spherical and do not exceed collimator size, it is not difficult to irradiate ten or more lesions in several hours [14, 15]. Some authors have reported several cases of numerous brain metastases that had good outcomes and may be said to be

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Table 2. Summary of reports referring to SRI arranged in ascending order of tumor numbers per patient Reference (first author)

Patients with metastases

Dmin Gy (median)

% local control

% necrosis

Median survival months

Solitary 1 Auchter 2 Flickinger 3 Shirato

122/122 116/116 44/44

17 ⫾ WBI 16 ⫾ WBI 20,24/8 fxs

86 85 92

0 4 0

12 11 8.6

Up to four 4 Nieder 5 Mehta 6 Kihlstrom 7 Engenhart 8 Fuller 9 Alexander 10 Moriarty 11 Aoyama 12 Shiau

31/25 58/40 235/160 102/69 52/33 421/248 643/353 159/87 261/119

10 ⫹ WBI 18 ⫹ WBI 27 ⫾ WBI 17 ⫾ WBI 25 ⫾ WBI 15 ⫹ WBI 15 ⫹ WBI 35/4 fxs 18.5 ⫾ WBI

52 82 94 94 94 83 75 (at 2 yrs) 69 (at 2 yrs) 93

Over five 13 Serizawa 14 Suzuki 15 Yamamoto M

639/62 480/24 115/3

21.8 21.1 10.9, 10.6, 8.9

94.8

0 3 4 3 2.7 4

2.3 6.5 7 6 7.9 9 10.5 8.7 11 12.4 2.6 4.5–5.5

comparable to WBI [13–15]. Dosimetric considerations revealed that the cumulative irradiation doses with numerous STI targets did not exceed the threshold level of normal brain damage [16, 17]. According to the autopsy study by Pickren et al. [20], about 27% of patients with metastatic brain tumor had five or more lesions. In our study, the percentage of patients in this category was 10% of the metastatic brain tumor patients. This might mean that about one-third of these patients with five or more lesions were treated by STI. The others may be treated by WBI. If STI for the patients with five or more lesions proves to be superior to WBI and the procedure is standardized, two or three times more patients may receive STI. The Kaplan-Meier Product-Limit method indicated that median ST was about 5 months (fig. 2). This value might be comparable to WBI [13, 21, 22]. Cox’s Hazard Model analysis showed that TCP significantly influenced ST with a very small hazard rate (fig. 3). The formula described by Colombo et al. [18] took into account the heterogeneity of tumors, radiosensitivity and radiation dose distribution. In the case of treatment of multiple lesions, the maximum doses for every lesion were often different, even though peripheral minimal

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doses were equally arranged. In these situations, radiobiological analysis concerning only peripheral dose might miss the problem. NTCP should also integrate every complication probability for each subvolume of the brain [19], because radiation-induced damage will occur at the relatively high dose area close to the tumors, not at the normal brain area far from the targets. Few follow-up images were available because of the patient’s short ST. About one-third of the tumors underwent volumetric assessment. Despite the wide variety in the intervals between the day of treatment and the day follow-up images were taken, the estimation of the following regression equation was statistically significant (p ⬍ 0.001): V/V0 ⫽ a⭈ln(TCP) ⫹ b

[a ⫽ ⫺0.24 ⫾ 0.06 (95% CI), b ⫽ 0.19 ⫾ 0.08]

The correlation coefficient was 0.60 (fig. 4). It is not surprising that tumor control rate greatly influenced the survival in these cases with multiple tumors. Three-dimensional representation of ST, TCP and NTCP demonstrates how NTCP can affect dose optimization. In general, TCP and NTCP will increase as radiation dose increases; however, increased NTCP will cancel out the effects of TCP on ST. Two patients, whose TCP were over 75% but NTCP were over 18%, survived 5 and 10 months. These values were very low compared to the expected STs calculated from very high TCP values (fig. 5). This phenomenon is easily explained with a hyperbolic formula (ST ⫽ a⭈(0.3 – NTCP)⭈TCP ⫹ b). Tumors originating from the breast had a steep slope compared to the others, but the regression was not statistically significant (p ⫽ 0.117) (fig. 6). As mentioned by Nieder et al. [4], effective local control of brain metastases is the prerequisite for long-term survival. However, simple dose escalation should not lengthen STs, as forecasted by the hyperbolic formula. As dose increases, NTCP will get close to increased TCP, and wipe out the outcome of dose escalation. Fractionated STI or GK boost following WBI may be a way of overcoming this [23, 24]. In cases of numerous numbers of tumors, fractionation will not be practical [15]. Our extension of Colombo’s formula to be able to evaluate multiple radiological procedures including WBI will work well in these situations. We may be able to achieve lengthened STs without increasing NTCP. Conclusions

TCP predicts ST of multiple metastatic BT patients. Increased NTCP may cancel out the effect of TCP on survival in some cases. Pretreatment calculation of TCP and NTCP with the hyperbolic formula we propose will help to optimize treatment outcomes for these patients.

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References 1

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12

13

14 15

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17

Auchter RM, Lamond JP, Alexander EA, Buatti JM, Chappell R, Friedman WA, Kinsella TJ, Levin AB, Noyes WR, Schultz CJ, Loeffler JS, Mehta MP: A multi-institutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996;35:27–36. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, Hudgins WR, Weiner R, Harsh GR, Sneed PK, Larson DA: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28:797–802. Shirato H, Takamura A, Tomita M, Suzuki K, Nishioka T, Isu T, Kato T, Sawamura Y, Miyamachi K, Abe H, Miyasaka K: Stereotactic irradiation without whole-brain irradiation for single brain metastasis. Int J Radiat Oncol Biol Phys 1997;37:385–391. Nieder C, Nestle U, Walter K, Niewald M, Schnabel K: Dose-response relationships for radiotherapy of brain metastases: Role of intermediate-dose stereotactic radiosurgery plus whole-brain radiotherapy. Am J Clin Oncol 2000;23:584–588. Mehta MP, Rozental JM, Levin AB, Mackie TR, Kubsad SS, Gehring MA, Kinsella TJ: Defining the rote of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 1992;24:619–625. Kihlstrom L, Karlsson B, Lindquist C: Gamma knife surgery for cerebral metastasis: Implications for survival based on 16 years’ experience. Stereotact Funct Neurosurg 1993;61(suppl):45–50. Engenhart R, Kjmmig BN, Hover KH, Wowra B, Romahn J, Lorenz WJ, Gehard VK, Wannenmacher M: Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation. Cancer 1993;71:1353–1361. Fuller BG, Kaplan ID, Adler J, Cox RS, Bagshaw MA: Stereotaxic radiosurgery for brain metastases: The importance of adjuvant whole-brain irradiation. Int J Radial Oncol Biol Phys 1992;23:413–418. Alexander E III, Moriarty TM, Davis RB, Wen PY, Fine HA, Black PM, Kooy HM, Loeffler JS: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995;87:34–40. Moriarty TM, Loefflet JS, Black PM, Shrieve DC, Wen PY, Fine HA, Kooy HM, Alexander E III: Long-term follow-up of patients treated with stereotactic radiosurgery for single or multiple brain metastases; in Kondziolka D (ed): Radiosurgery 1995. Radiosurgery. Basel, Karger, 1996, vol 1, pp 88–91. Aoyama H, Shirato H, Onimaru R, Kagei K, Ikeda J, Ishii N, Sawamura Y, Miyasaka K: Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull. Int J Radiat Oncol Biol Phys 2003;56:793–800. Shiau CY, Sneed PK, Shu HK, Lamborn KR, McDermott MW, Chang S, Nowak P, Petti PL, Smith V, Verhey LJ, Ho M, Park E, Wara WM, Gutin PH, Larson DA: Radiosurgery for brain metastases: Relationship of dose and pattern of enhancement to local tumor control. Int J Radiat Oncol Biol Phys 1997;37:385–391. Serizawa T, Iuchi T, Ono J, Saeki N, Osato K, Odaki 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. Suzuki S, Omagari J, Nishio S, Nishiye E, Fukui M: Gamma knife radiosurgery for simultaneous multiple metastatic tumors. J Neurosurg 2000;93(suppl 3):30–31. Yamamoto M, Ide M, Jimbo M, Aiba M, Ito M, Hirai T, Usukura M: 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, vol 2, pp 94–109. Yang CCJ, Ting J, Wu X, Markoe A: Dose volume histogram analysis of the gamma knife radiosurgery treating twenty-five metastatic intracranial tumors. Stereotact Funct Neurosurg 1998; 70(suppl):41–49. 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.

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19 20 21

22 23 24

Colombo F, Francescon P, Cora S, Testolin A, Chierego G: 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, Maitz AH, Kalend AM: Treatment planning for gamma knife radiosurgery with multiple isocenters. Int J Radiat Oncol Biol Phys 1990;18:1495–1501. Pickren JW, Lopez G, Tzukada Y, Lane WW: Brain metastases. An autopsy study. Cancer Treat Symp 1983;2:295–313. Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, Perez CA, Hendrickson FR: The palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1–9. Larson DA, Flickinger JC, Loeffier JS: The radiobiology of radiosurgery. Int J Radiat Oncol Biol Phys 1993;25:557–561. Kondziolka D, Lunsford LD, Flickinger JC: The radiobiology of radiosurgery. Neurosurg Clin North Am 1999;10:157–166. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC: Stereotactic radiosurgery plus whole-brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427–434.

Dr. Hisato Nagano Department of Radiology, Yokohama Rosai Hospital 3211 Kozukue, Houhoku-ku Yokohama 222-0036 (Japan) Tel. ⫹81 4748111, Fax ⫹81 4748686, E-Mail [email protected]

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Dose Absorbed by Normal Brainstem and Optic Apparatus in Gamma Knife Surgery for Ten or More Metastases Toshifumi Kamiryo, Masaaki Yamamoto, Bierta E. Barfod, Yoichi Urakawa Mito GammaHouse, Katsuta Hospital, Nakane, Hitachi’naka, Ibaraki, Japan

Abstract Purpose: Gamma knife (GK) surgery has recently been carried out on patients with ten or more intracranial metastases. However, cumulative irradiation doses to critical brain structures remain unknown. We calculated the doses absorbed by the brainstem and the optic apparatus. Method and Material: Among a consecutive series of 308 patients who underwent GK surgery for brain metastases at our facility during the period between December 1998 and December 2000, 58 patients (72 procedures) who had ten or more lesions were studied. We excluded subjects with one or more lesions involving either the brainstem or the optic apparatus. The cumulative irradiation doses to the brainstem and optic apparatus were computed using a GammaPlan (Elekta AB, Sweden) and a personal computer. Results: The mean integral dose to the brainstem was 84.3 mJ (range 9.5–766.0). The mean integral dose to the optic apparatus was 3.88 mJ (range 0.3–12.2). The mean cumulative irradiation dose to the brainstem was 3.62 Gy (range 0.56–7.57). The mean cumulative irradiation dose to the optic apparatus was 2.97 Gy (range 1.12–7.03). Conclusion: Cumulative irradiation doses to the brainstem and optic apparatus for patients undergoing GK treatment using numerous radiosurgical targets do not appear to exceed the threshold level of necrosis for critical brain structures. Copyright © 2004 S. Karger AG, Basel

Purpose

The gamma knife (GK) is now widely used to treat metastatic brain tumors. Recently, it has been shown that more than ten lesions can be treated as effectively as a solitary lesion. With such treatment, however, the integral dose delivered to

the normal brain is unknown. Yamamoto et al. [1] reported the treatment of multiple lesions to be safe for the whole normal brain. However, controversy persists as to whether such treatment adversely affects critical brain structures. We analyzed the doses absorbed by the brainstem (BS) and optic apparatus (OA) in patients with 10 or more brain metastases irradiated in a single GK session. The results are presented herein and safety issues are discussed. Methods and Materials Among our consecutive series of 308 patients treated between December 1998 and December 2000, 58 patients (72 procedures) with ten or more lesions were studied. Age ranged from 35 to 83, the mean age being 61.5. We excluded patients who had undergone procedures in which one or more lesions involved either the BS or the OA. The computer system for GK treatment, the Leksell GammaPlan (Elekta AB, Sweden), was used to determine the mean dose absorbed by an area of interest as previously described in detail [1]. The areas of interest, i.e. the BS and OA, were delineated manually in axial views (fig. 1). In order to outline the BS, either the medulla or midbrain was drawn first because these structures were easily observed, then the pons was delineated with reference to a dotted line generated automatically by the GammaPlan which interpolates the structures. The optic nerve, chiasm and optic tract were identified employing the continuity of these structures. The optic tract was delineated within the basal cistern (fig. 2).

Results

The mean follow-up period for our 58 patients was 80 months (range 69–93). There were no OA-related complications. The mean integral dose to the BS was 84.3 mJ (range 9.5–766.0). The mean integral dose to the OA was 3.88 mJ (range 0.3–12.2). The mean dose absorbed by the BS was 3.62 Gy (range 0.56–7.57). The mean dose to the OA was 2.97 Gy (range 1.12–7.03). The maximum absorbed dose for both structures was no more than 7–8 Gy (table 1). Discussion

Recommended doses for stereotactic radiosurgery for BS lesions have been established. Most practitioners will reduce the dose 10–20% if a large volume of the eloquent area is involved in the treatment planning. The dose of fractionated irradiation is reportedly 54–60 Gy at 1.8–2.0 Gy in a text [2]. Stereotactic radiosurgery generally employs 14–24 Gy at other locations. However, the dose will be reduced in the BS depending on the history of previous radiation (location, volume, dose, form, interval, mechanical distortion, etc.). Most neurosurgeons use 16 Gy as the prescription dose, according to the

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Fig. 1. Important structures are outlined in different colors (brainstem (BS) is pink, optic apparatus (OA) is olive), whereas the whole brain is outlined in red. The absorbed dose is calculated at the outlined area using GammaPlan and spreadsheet.

Fig. 2. Three-dimensional picture of the marking to understand each relationship. No shots were confirmed at BS or OA directly or next to them.

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Table 1. Calculated doses to various structures

Structure

Mean dose, Gy

Whole brain Brainstem Optic apparatus

4.69 (2.13–8.51) 3.63 (0.56–7.57) 2.97 (1.12–7.03)

GK literature [3–7]. Recently, based on more than 10 years’ experience treating vestibular schwannoma by GK, approximately 10 Gy delivered to a small part of the BS was found to have no discernible effects on the normal brain. The OA is a highly radiosensitive structure as compared to other cranial nerves which are reportedly unaffected by up to 30–40 Gy (maximum dose) delivered to the cavernous sinus [8–10]. In an effort to prevent cataract formation, a dose below 1.7–1.8 Gy is used for benign lesions and this is usually achieved by plugging the collimators [10]. For other optic structures, keeping radiation below 8 Gy is recommended [11] for preserving visual function. According to our present results, both BS and OA doses (even the maximum) were lower than the threshold for necrosis and therefore not harmful to normal brain structures. Overall, the whole brain receives about 5 Gy per GK treatment and this too must be considered. This may be important in eloquent tissues such as the BS and OA. Our results demonstrate GK treatment of multiple brain metastases to not directly harm important brain tissues. However, dose planning for the second treatment should take cumulative doses absorbed by critical brain structures into consideration.

Conclusions

The cumulative doses absorbed by the BS and OA in patients with ten or more metastases do not appear to exceed the threshold level for necrosis of these critical brain structures.

References 1 2 3

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. Rivet D, Chicoine M, Simpson J, Arquette MA: Central Nervous System. Philadelphia, Lippincott Williams & Wilkins, 2002. Yang CC, Ting J, Wu X, Markoe A: Dose volume histogram analysis of the gamma knife radiosurgery treating twenty-five metastatic intracranial tumors. Stereotact Funct Neurosurg 1998; 70(suppl 1):41–49.

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5 6

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Shu HKG, Sneed PK, Shiau CY, McDermott MW, Lamborn KR, Park E, Ho M, Petti PL, Smith VV, Verhey LJ, Wara WM, Gutin PH, Larson DA: Factors influencing survival after gamma knife radiosurgery for patients with single and multiple brain metastases. Cancer J Sci Am 1996;2:335. Yamanaka K: Prognostic factors for brain metastasis from lung cancer after gamma knife radiosurgery. Osaka City Med J 1999;45:45–59. Muacevic A, Kreth FW, Horstmann GA, Schmid-Elsaesser 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. Suzuki S, Omagari J, Nishio S, Nishiye E, Fukui M: Gamma knife radiosurgery for simultaneous multiple metastatic brain tumors. J Neurosurg 2000;93(suppl 3):30–31. Leber KA, Bergloff J, Langmann G, Mokry M, Schrottner O, Pendl G: Radiation sensitivity of visual and oculomotor pathways. Stereotact Funct Neurosurg 1995;64(suppl 1):233–238. 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. Tishler RB, Loeffler JS, Lunsford LD, Duma C, Alexander E III, Kooy HM, Flickinger JC: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 1993;27:215–221. Hempel M, Hinkelbein W: Eye sequelae following external irradiation. Recent Results Cancer Res 1993;130:231–236.

Masaaki Yamamoto, MD Katsuta Hospital, 5125-2 Nakane Hitachi’naka, Ibaraki 312-0011 (Japan) Tel. ⫹81 29 2710011, Fax ⫹81 29 2741475, E-Mail [email protected]

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Preliminary Novalis Experience in the Treatment of Skull Base Chordomas with Stereotactic Radiosurgery and Stereotactic Radiotherapy A.G. Pedrosoa, A.A.F. De Sallesa,b, L. Frighettoa, R.C. Torresa, T.D. Solbergb, P. Medinb, C. Cabatan-Awanga,b, M. Selchb a

Division of Neurosurgery and bDepartment of Radiation Oncology, University of California at Los Angeles (UCLA), Los Angeles, Calif., USA

Abstract Purpose: The treatment of chordomas is challenging. The role of radiation therapy in addition to surgery is well established. Different techniques have been applied aiming to improve tumor local control. This is the first report using shaped beam and intensity modulation radiotherapy (IMRT) with Novalis. The purpose of this new technique is to allow higher doses to be delivered to the tumor without damaging vital structures close to the lesion. Materials and Methods: Eight patients with histologically confirmed diagnosis of chordoma were treated with Novalis in a single dose or in a fractionated regimen. Three patients were treated with stereotactic radiosurgery (SRS), 1 with hypofractionated radiotherapy (HSRT) and 4 were treated with fractionated radiotherapy (FSRT). There were 5 males and 3 females, median age was 60 year. Median follow-up for SRS cases was 30 months, 28 months for HSRT and 24 months for FSRT. Volumes and dose range for optic apparatus and brainstem were evaluated. Results: Local tumor control was achieved in all cases. Chordomas remained stable with SRS and HSRT. In the FSRT group, two lesions disappeared, one decreased in size and the other was stable. Same volume tumors submitted either to SRS or fractionation presented different responses. Also tumors receiving the same radiation dose but with different volumes showed different behavior. Doses delivered to eloquent structures were superior to tolerable doses described in the literature. No complications due to high doses of radiation were detected. Conclusion: All three methods offered satisfactory local control. Fractionated schemes seem to provide better tumor response since disappearance and decrease in tumor size were only observed in this group. Shaped beam and IMRT techniques allowed a higher dose to the tumor than conventionally given and still sparing damage to adjacent structures. Copyright © 2004 S. Karger AG, Basel

Chordomas are relatively rare tumors derived from remnants of the notochord. These tumors correspond to 3–4% of primary bone tumors [3, 12, 27, 28]. Despite all improvements in surgical techniques, it is rare to achieve complete surgical resection due to the tumor invasive nature. Initial aggressive surgical removal is correlated to less recurrence and better survival rates [1, 7–9, 11, 12, 16, 17, 19, 21, 25, 33, 34, 36–38]. Adjuvant radiation of the residual lesion has an important role improving the outcome [2, 4–7, 10, 17, 22, 33]. Initial encouraging results were achieved with heavy charged particles irradiation [5, 30, 31]. Chordomas are well known to be radioresistant to standard radiotherapy. The Boston group advised the importance of an escalated dose [5]. Only doses higher than 6,000 cGy would be efficient to achieve local tumor control. Nevertheless, the proximity of the tumor to eloquent structures limits the amount of radiation to be delivered. Proton beam radiotherapy offers a unique advantage due to Bragg peak distribution [30] when compared to traditional photon radiotherapy. However, availability of proton beam facilities is still limited. The stereotactic radiosurgery (SRS) technique also fills the necessary requirements. It provides the accurate delivery of high doses of radiation to the lesion with a steep falloff in the peripheral field. However, tumor volume is an important restrictive factor. Fractionated stereotactic radiotherapy (SRT) constitutes an alternative approach for tumors with a volume ⱖ10 cm3 and involving sensitive structures [13]. Linac devices have developed immensely during recent years. Precision and accuracy has equated to that of gamma-knife units [18, 35]. The creation of dedicated devices led to the development of advanced methods to perform SRS/SRT. Novalis is the last generation device developed by BrainLab (Heimstetten, Germany). This device has been used at UCLA since 1997. Novalis performs SRS/SRT using dynamic non-coplanar arcs or multipleshaped beams. Shaped beam radiosurgery arose from the need of delivering high radiation dose to irregular targets avoiding to irradiate normal brain structures [32]. Intensity modulated radiotherapy (IMRT) is one more tool that aims to create a non-uniform radiation beam to achieve a superior dose distribution [14]. Chordomas are tumors that usually spread in an irregular shape close to vital structures in which radiation tolerance is low. Novalis allows the increase of the dose to the tumor without increasing risk of complications. Herein is the preliminary experience with these new techniques in the treatment of skull base chordomas. Materials and Methods Between August 1998 and October 2002, 8 patients with histological diagnosis of chordoma were treated at UCLA Center for Health Sciences. There were 5 males and 3 females,

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Table 1. Treatment characteristics

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Treatment

Dose, cGy Fractions n

Total dose cGy

IDL prescribed isodose line

Margin mm

Tumor Previous volume, cm3 surgery

Follow-up months

Outcome

1 2 3 4 5 6 7 8

SRS SRS SRS HSRT FSRT FSRT FSRT FSRT

1,600 1,800 2,000 1,400 180 170 180 120

1,600 1,800 2,000 4,200 4,500 5,100 7,560 6,480

90 90 90 90 90 85 90 90

0 0 2 1.5 1.4 3 2 3

10.3 0.85 13.1 28.9 13.32 71.75 23.78 8.64

60 8 30 12 28 12 24 8

Stable Stable Stable Stable Disappeared Stable Disappeared Decreased

1 1 1 3 25 30 42 54

1 3 5 3 1 2 2 2

Table 2. Maximal and minimal radiation dose and volume of sensitive structures evaluated using segmentation of the targets and histograms Patient

1 2 3 4 5 6

Right optic nerve

Left optic nerve

Optic tract

Chiasm

Brainstem

max

min

vol

max

min

vol

max

min

vol

max

min

vol

max

min

vol

622 7,308 1,550 5,820 180 2,427

89 1,092 100 360 0 372

0.42 0.34 0.37 0.36 0.89 0.65

1,666 5,040 4,150 5,640 260 1,539

67 336 100 660 0 389

0.29 0.54 0.26 0.24 0.84 0.31

844 2,520 2,400 5,820 360 4,059

156 672 1,200 4,680 80 372

0.42 0.22 0.07 0.17 0.13 0.27

356 1,512 4,500 5,700 520 NV

200 336 1,650 1,800 40 NV

0.09 0.16 0.07 0.17 0.38 NV

1,222 5,628 4,250 5,820 1,800 4,200

44 168 150 420 0 606

19.42 27.36 24,58 32.08 24.65 22.06

84

NV ⫽ Not visualized; max ⫽ maximal dose (cGy); min ⫽ minimal dose; vol ⫽ volume (cm3) of the structure receiving the range between min and max dose.

median age was 60 years (range 38–72). Three patients were treated with SRS, 1 with hypofractionated radiotherapy (HSRT) and 4 with fractionated radiotherapy (FSRT). The mean interval between diagnosis and treatment with SRS or SRT was 54.25 months (range 5–132). All chordomas were located at the clivus. Four presented with cavernous sinus extension while 3 extended to posterior/temporal fossa and 2 to optic apparatus. In the SRS group, mean tumor volume was 8.08 cm3 (range 0.85–13.1 cm3). The patient treated with HSRT had a tumor volume of 28.9 cm3. The FSRT group had a mean tumor volume of 18.55 cm3 (range 8.64–71.75 cm3) All patients underwent surgery previous to SRS/SRT. Only 2 patients presented to treatment after primary surgery. The other 6 cases were treated after being submitted to 2–5 surgeries. One patient had received conventional radiotherapy while 2 others had received gamma-knife SRS. Treatment characteristics are described in table 1. Follow-up for SRS patients ranged from 7 to 70 months (median 30). In the FSRT group median follow-up was 24 months (range 8–31) and the HSRT patient has been followed for 21 months. Follow-up consisted of MRI and clinical examination every 6 months. Maximal and minimal doses prescribed to eloquent structures were available for analysis in 6 cases. The volume of the structure and the doses were extracted from the histograms (table 2). All but one plan was obtained with shaped static beams. The unique exception was planned with IMRT. Treatment Planning and Delivery All 8 patients underwent CT (General Electric, Milwaukee, Wisc., USA) with a stereotactic localization system and 1.5 T MRI scan (Siemens, Erlangen, Germany). The images were transferred to the workstation after being processed in the Digital Imaging and Communications in Medicine (DICOM). Identification of fiducial markers was performed on the BrainScan planning system (versions 3.5 and 5.0, BrainLab, Heimstetten, Germany). The target was drawn based on three planes since coronal and sagittal reconstructions could be displayed in smaller windows in the same screen. CT view was also available. CT and MRI images fusion was achieved, as well as sagittal and coronal images, which were compared with the reconstructions (fig. 1–3). Patients treated with SRS underwent CRW™ (Radionics, Burlington, Mass., USA) or SRS frame (BrainLab) placement under local anesthesia. The group submitted to SRT was placed in a facial manufactured mask. The frame and the fiducials were applied to the mask allowing stereotactic localization when performing the CT. After conclusion of the planning, the patient was attached to Novalis couch. Treatment on Novalis used mMLC for shaped beam or IMRT. The mMLC was mounted on a mobile trolley and the leaf positions were downloaded from the planning. Between each beam, there was checking and positioning of the couch and the gantry. When IMRT was applied, the mMLC was used to shape and modulate the beam at the same time that the Linac source rotated over the patient [14]. At the end of the treatment, the frame and the facial mask were removed. Detailed description of the technique was reported elsewhere [32].

Results

Local tumor control was achieved in all 8 cases. MRI follow-up showed that the three tumors treated with SRS and the one with HSRT remained stable. In the FSRT group, two tumors disappeared, one decreased and one continued stable (table 1).

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a

b

c

d Fig. 1. MRI, T1 post-gadolinium, sagittal view. a Before FSRT (180 cGy, 42 fractions): chordoma located at the superior part of the clivus extending to the pre-pontine cistern. b 12 months follow-up: tumor decreasing in size. c 24 months follow-up: further decrease in size. d 36 months after FSRT: chordoma disappeared.

All lesions treated with SRS showed local control with a median follow-up of 30 months. The tumor treated with hypofractionated SRT also showed the same behavior despite presenting a volume superior to those tumors treated with SRS. Patients submitted to fractionated SRT presented more than local tumor control. In 1 case the tumor decreased while in the other 2 the lesion disappeared. Tumors that disappeared had a similar volume as those treated with SRS and HSRT. The largest tumor in the FSRT group (71.75 cm3) was the only one that remained stable.

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a

b Fig. 2. MRI, T1 post-gadolinium, axial view. a Lesion before treatment with FSRT (180 cGy, 25 fractions). b 30 months after FSRT: complete disappearance of the tumor.

a

b Fig. 3. MRI, T1 post-gadolinium, coronal view. a Chordoma treated with SRS (1,800 cGy). This is the smallest tumor of this series (0.85 cm3). b No tumor growth was observed after 18 months of follow-up.

Maximal and minimal radiation dose and volume of sensitive structures were evaluated using segmentation of the targets and histograms. Results are presented in table 2. Some critical structures such as the optic nerves received higher doses of irradiation than conventionally delivered [20]. However, the volume of the segmented structures receiving a high dose was small.

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No acute toxicity was noticed. Delayed toxicity due to SRS was observed in 1 patient who received 2,000 cGy. He presented hypersignal at the mesial temporal region bilaterally which responded to steroids. No case required surgery after treatment either for tumor growth or radiation necrosis. No metastasis was observed in this group. Discussion

Tumor growth was not observed in any case. Three methods for radiation delivery were applied: SRS, HSRT and FSRT. All methods were effective in achieving tumor control. Interestingly, only tumors in the FSRT group decreased in size or disappeared. In the literature, high doses of proton beam radiotherapy provided satisfactory local tumor control [5]. One should strive for doses ⱖ6,000 cGy, in conventional fractionated schemes or equivalent in single dose [26]. In this small sample the conventional fractionation scheme was the best predictor of tumor response. Although critical structures close to the tumors received higher dose of radiation than the safely recommended in the literature [20], no undue effects of radiation were noticed. This observation is explained by the small volume of these structures receiving the high dose. In the recent past the unique solution would be to deliver a low dose to a specific region of the tumor aiming to preserve the eloquent structure involved. Shaped beam and IMRT provides technical background to increase the equivalent dose to the tumor touching such structures, either by modulating the beam or fractionating the dose. Several techniques have been applied in the treatment of chordomas. This is the first report using shaped beam stereotactic radiation (Novalis). The largest series were reported with proton beam radiation [5, 17]. Smaller series were reported using either gamma-knife SRS [24, 29] or Linac SRT [13]. Chordomas often recur. Median follow-up for SRS patients was 30 months (range 7–70), slightly longer than the median 24 months for FSRT patients (range 8–31). This follow-up period is not long enough for conclusions regarding recurrence. In the literature, recurrence interval varies from 1 month to 17 years [15, 33] with a mean of 32 months. Future follow-up of these patients is necessary to define the success rate of shaped beams or IMRT Novalis technology for the treatment of chordomas. Conclusion

This study suggests that a high dose of radiation can be safely given using shaped beam technology. The high control rate safely achieved in this study

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suggests that an escalation of dose should be tried. Conventional fractionation schemes are likely to achieve better tumor response than single dose or hypofractionation.

References 1 2 3 4

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8 9 10 11 12 13

14

15

16 17

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Al-Mefty O, Borba LAB: Skull base chordomas: A management challenge. J Neurosurg 1997;86: 182–189. Amendola BE, Amendola MA, Olivier E, et al: Chordoma: Role of radiation therapy. Radiology 1986;158:839–843. Arnold H, Herrmann HD: Skull base chordoma with cavernous sinus involvement: Partial or radical tumour removal? Acta Neurochir 1986;83:31–37. Austin JP, Urie MM, Cardenosa G, et al: Probable causes of recurrence in patients with chordoma and chondrosarcoma of the base of skull and cervical spine. Int J Radiat Oncol Biol Phys 1993;25: 439–444. Austin-Seymour M, Munzenrider J, Goitein M, et al: Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the case of the skull. J Neurosurg 1989;70:13–17. Benk V, Liebsch NJ, Munzenrider JE, et al: Base of skull and cervical spine chordomas in children treated by high-dose irradiation. Int J Rad Oncol Biol Phys 1995;31:577–581. Berson AM, Castro JR, Petti P, et al: Charged particle irradiation of chordoma and chondrosarcoma of the base of the skull and cervical spine: The Lawrence Berkeley Laboratory experience. Int J Radiat Oncol Biol Phys 1988;15:559–565. Borba LAB, Al-Mefty O, Mrak RE, Suen J: Cranial chordomas in children and adolescents. J Neurosurg 1996;84:584–591. Carpentier A, Polivka M, Blanquet A, Lot G, George B: Suboccipital and cervical chordomas: The value of aggressive treatment at first presentation of the disease. J Neurosurg 2002;97:1070–1077. Castro JR, Lindstadt DE, Bahary JP, et al: Experience in charged particle irradiation of tumors of the skull base: 1977–1992. Int J Radiat Oncol Biol Phys 1994;29:647–655. Crockard HA, Steel T, Plowman N, Singh A, Crossman J, Revesz T, Holton JL, Cheeseman A: A multidisciplinary team approach to skull base chordomas. J Neurosurg 2001;95:175–183. Dahlin DC, MacCarty CS: Chordoma: A study of 59 cases. Cancer 1952;5:1170–1178. Debus J, Schulz-Ertner D, Schad L, Essig M, Rhein B, Thillmann CO, Wannenmacher M: Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Neurosurgery 2000;47:591–596. De Salles AAF, Solberg T: Stereotactic radiosurgery and intensity modulation radiotherapy; in Schulder M (ed): Handbook of Stereotactic and Functional Neurosurgery. New York, Dekker, 2003. Fagundes MA, Hug EB, Liebsch NJ, Daly W, Efird J, Munzenrider JE: Radiation therapy for chordomas of the base of the skull and cervical spine: Patterns of failure and outcome after relapse. Int J Radiat Oncol Biol Phys 1995;33:579–584. Finn DG, Goeffer HG, Batsakis JG: Chondosarcoma of the head and neck. Laryngocospe 1984;94:1539–1543. Forsyth PA, Cascino TL, Shaw EG, Scheithauer BW, O’Fallon JR, Dozier JC, Piepgras DG: Intracranial chordomas: A clinicopathological and prognostic study of 51 cases. J Neurosurg 1993;78:741–947. Friedman WA, Bova FJ: The University of Florida Radiosurgery System. Surg Neurol 1989;32: 334–342. Gay E, Sekhar LN, Rubinstein E, Wright DC, Sen C, Janecka IP, Snyderman CH: Chordomas and chondrosarcomas of the cranial base: Results and follow-up of 60 patients. Neurosurgery 1995;36: 887–897. Harris R, Levene MB: Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976;120:167–171.

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Hassounah M, Al-Mefty O, Akhtar M, Jinkins JR, Fox JL: Primary cranial and intracranial chondrosarcoma: A survey. Acta Neurochir (Wein) 1985;78:123–132. Hug EB, Fitzek MM, Liebsch NJ, et al: Locally challenging osteo- and chondrogenic tumors of the axial skeleton: Results of combined proton and photon radiation therapy using three-dimensional treatment planning. Int J Radiat Oncol Biol Phys 1995;31:467–476. Hug EB, Loredo LN, Slater JD, DeVries A, Grove RI, Schaefer RA, Rosenberg AE, Slater JM: Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg 1999;91:432–439. Kondziolka D, Lunsford LD, Flickinger JC: The role of radiosurgery in the management of chordoma and chondrosarcoma of the cranial base. Neurosurgery 1991;29:38–46. Kveton JF, Brackmann DE, Glasscock ME, House WF, Hitselberg WE: Chondrosarcoma of the skull base. Otolaryngol Head Neck Surg 1986;94:23–32. Lee SP, Taylor JMG, McBride WH, Withers HR: The radiobiology of stereotactic radiosurgery and radiotherapy; in De Salles AAF, Goetsch SJ (eds): Stereotactic Surgery and Radiosurgery. Madison, Medical Physics Publishing, 1993. Mindell ER: Chordoma. J Bone Joint Surg Am 1981;63:501–505. Mirra JM: Bone Tumors: Diagnosis and Treatment. Philadelphia, Lippincott, 1980, pp 243–252. Muthukumar N, Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for chordoma and chondrosarcoma: Further experiences. Int J Radiat Oncol Biol Phys 1998;41:387–392. Noel G, Habrand JL, Hamid M, Pontvert D, Haie-Meder C, Hasboun D, Moisson P, Ferrand R, Beaudre A, Boisserie G, Gaboriaud G, Mazal A, Kerody K, Schlienger M, Mazeron JJ: Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: The Centre de Protontherapie d’Orsay experience. Int J Radiat Oncol Biol Phys 2001;51:392–398. Pearlman AW, Friedman M: Radical radiation therapy of chordoma. AJR 1970;108:333–341. Pfeffer MR, Spiegelman R: Stereotactic radiosurgery with the BrainLab system; in Schulder M (ed): Handbook of Stereotactic and Functional Neurosurgery. New York, Dekker, 2003. Raffel C, Wright DC, Gutin PH, Wilson CB: Cranial chordomas: Clinical presentation and results of operative and radiation therapy in twenty-six patients. Neurosurgery 1985;17:703–710. Sen CN, Sekhar LN, Schramm VL, et al: Chordoma and chondrosarcoma of the cranial base: An 8-year experience. Neurosurgery 1989;25:931–941. Solberg TD, Medin P, DeMarco J, De Salles AAF, Selch MT: Technical aspects of Linac radiosurgery for functional disorders. J Radiosurg 1998;1:115–127. Volpe R, Mazabraud A: A clinicopathologic review of 25 cases of chordoma. Am J Surg Pathol 1983;7:161–170. Watkins L, Khudados ES, Kaleoglu M, et al: Skull base chordomas: A review of 38 patients, 1958–1988. Br J Neurosurg 1993;7:241–248. Zorlu F, Gurkaynak M, Yildiz F, Oge K, Atahan L: Conventional external radiotherapy in the management of clivus chordomas with overt residual disease. Neurol Sci 2000;21:203–207.

Antonio A. F. De Salles UCLA Surg-Neuro Box 957182, 200 Medical Plaza, Suite 504 Los Angeles, CA 90095–7182 (USA) Tel. ⫹1 310 7941221, Fax ⫹1 310 7941848, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 91–99

Results Following Stereotactic Radiosurgery for Patients with Glioblastoma multiforme Hidemasa Nagai, Douglas Kondziolka, Ajay Niranjan, John C. Flickinger, L. Dade Lunsford Departments of Neurological Surgery and Radiation Oncology, Center for Image-Guided Neurosurgery, UPMC Presbyterian Hospital, University of Pittsburgh, Pittsburgh, Pa., USA

Abstract Objective: During a 15-year interval we evaluated the clinical results following stereo tactic radiosurgery as part of multimodality management in 180 patients with glioblastoma multiforme (GBM). Methods: Adjuvant radiosurgery was performed either prior to disease progression or for recurrent tumor at the time of disease progression. The mean age was 56 years, the mean Karnofsky performance score at radiosurgery was 90, and the median RTOG grade was 4. Tumor location was lobar in 137, deep in 13, and both in 30 patients. Results: Median survival for GBM patients after initial diagnosis in the entire series was 18 months (95% CI 16–20). The median survival after radiosurgery was 10 months. The 2-year survival rate was 34%, and the 5-year survival, 14%. Prolonged survival was related to use of chemotherapy (p ⬍ 0.001), presentation with seizures (p ⬍ 0.001), younger age (p ⬍ 0.0001), prior resection (p ⫽ 0.007), but not use of radiation therapy, tumor location, or gender. Eleven patients had an adverse radiation effect (5.8%). Thirteen patients underwent repeat radiosurgery and 46 had a repeat resection. Patients with tumor regression after radiosurgery lived a median of 33 months, whereas patients with a tumor enlargement lived a median of 17 months (p ⫽ 0.006). Conclusions: Radiosurgery may provide a survival benefit for patients with GBM as part of multimodality management. This benefit may be related to patient selection although an imaging defined tumor response correlated with improved survival. Radiosurgery is safe and well tolerated. Copyright © 2004 S. Karger AG, Basel

Glioblastoma multiforme (GBM) of the brain is a cancer that causes significant patient disability and mortality. Multimodality management including surgery, radiation therapy, boost irradiation techniques and chemotherapy may enhance survival and quality of life in appropriate patients [6, 16, 19]. Despite improvements in each of these treatments, many patients eventually die within 1 year of diagnosis. Factors that influence outcome include histologic grade (glioblastoma vs. anaplastic astrocytoma), patient age, brain location, radiation dose, Karnofsky performance status, and surgical resectability [4, 23]. In 1987 we initiated an evaluation of stereotactic radiosurgery as a less invasive method to boost the standard fractionated radiation dose [5, 15]. Initial criticisms of the use of radiosurgery for malignant gliomas included its focal radiation delivery [10], and the fact that because it was performed in a single session, the potential advantage of radiation delivery over multiple cell-cycle times (as achieved in brachytherapy) was not provided. However, the intense radiobiologic effect of single-session radiation cell kill, regardless of mitotic phase, argued for its consideration. In addition, all patients were recommended to receive standard fractionated local field radiation therapy.

Clinical Methods and Materials Gamma knife radiosurgery was performed in 180 GBM patients using the following entry criteria: mean tumor contrast-enhanced tumor diameter ⬍3.5 cm, age ⬍85 years, Karnofsky performance status ⱖ50, any brain location, and proven histologic diagnosis. Patients were informed that conformal radiosurgery used the contrast-enhancing portion of the tumor as the target, and not presumed tumor infiltration beyond that border at the same dose. However, lower dose radiation also was delivered to a brain volume surrounding the active tumor growth, unless radiosurgery was performed for recurrence. Informed consent was obtained from all patients. Patient Clinical Information For initial histologic diagnosis, 109 patients underwent craniotomy and resection (61%), and 71 had a stereotactic biopsy. The mean patient age was 56 years (range 3–85), and the mean Karnofsky performance score was 90 (range 50–100) at the time of radiosurgery. The typical management strategy included post-diagnosis conventional fractionated radiation therapy (60 Gy) followed by radiosurgery, and oral or intravenous chemotherapy. Radiation therapy (tumor plus 3 cm) was given to 170 (94%) patients, and chemotherapy to 126 patients (70%). The mean tumor volume (calculated by the dose-volume histogram) at radiosurgery was 14.8 ml (range 0.58–84). The 50% isodose line was used to cover the tumor margin in ⬎90% of patients (range 30–90%). The mean dose delivered to the tumor margin was 15 Gy (range 10–20), and the mean maximum dose 30 Gy (range 20–50). The tumors were located in hemispheric (lobar) locations in 137 patients (76%), and deep (non-lobar) locations in 43 patients.

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1.0

Probability

0.8

0.6

0.4

0.2

0.0 0

24

48 72 96 Months following diagnosis

120

Fig. 1. Kaplan-Meier curve of patient survival after initial diagnosis when radiosurgery was part of management. Technique of Radiosurgery All patients had stereotactic radiosurgery under local anesthesia except children younger than 14 years of age who had radiosurgery under general anesthesia. Between 1987 and 1991, patients had stereotactic computed tomography imaging for tumor localization. Patients managed since 1991 underwent stereotactic magnetic resonance imaging for tumor definition. The edge of the contrast-enhanced portion of the mass was used to identify the desired tumor volume for radiosurgical targeting. The isodose configuration was made such that the selected treatment isodose enclosed the margin of contrast uptake. The Leksell Gamma Knife® (model U, B, or C) was used for radiosurgery (Elekta Instruments, Atlanta, Ga., USA). All patients were discharged from hospital within 24 h of treatment and maintained on unchanged preoperative regimens of corticosteroid or anticonvulsant therapy. Initial imaging follow-up was performed 2 months after radiosurgery and then at 3- to 6-month intervals thereafter. Statistical Analysis The product limit method of Kaplan and Meier was used to calculate actuarial rates of tumor control [12]. Univariate comparisons of survival between patient groups were performed with the log rank test [3, 18].

Results

Glioblastoma multiforme At the time of analysis, 147 patients had died and 33 (18%) were alive. Median survival after initial diagnosis was 18 months (95% CI 16–20 months, mean survival 34 months) (fig. 1). The median survival after radiosurgery was 10 months. The 2-year survival rate from diagnosis for the overall series was

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1.0

Probability

0.8

0.6

Chemo (⫹)

0.4

0.2 Chemo (⫺) 0.0 0

24

48

72

96

120

Months following diagnosis

Fig. 2. Survival curves for patients with glioblastoma and radiosurgery stratified by the use or non-use of chemotherapy.

34%, and the 5-year survival, 14%. The 2-year survival rate from radiosurgery was 24%, and the 5-year survival, 10%. Prolonged survival was related to use of chemotherapy (p ⬍ 0.001), presentation with seizures (p ⬍ 0.001), younger age (p ⬍ 0.0001), prior resection (p ⫽ 0.007), but not use of radiation therapy, tumor location, or gender (fig. 2–4). In this radiosurgery population, median survival was 11 months without chemotherapy (n ⫽ 54), and 21 months with chemotherapy (n ⫽ 126). Median survival was 16 months without epilepsy and 21 months in patients who presented with seizures. Median survival was 43 months in patients less than 19 years old (n ⫽ 3), 21 months in those age 20–64 years (n ⫽ 121), and 13 months for those over 65 years (n ⫽ 56). Median survival was 15 months in patients who had a stereotactic biopsy (n ⫽ 71) and 19 months in those who had a resection (n ⫽ 109). Patients with tumor regression after radiosurgery lived a median of 33 months, whereas patients with a tumor enlargement lived a median of 17 months (p ⫽ 0.006). Morbidity No patient suffered acute neurologic morbidity after radiosurgery and no patient suffered seizures after treatment. Eleven patients had evidence of an adverse radiation effect after radiosurgery (5.8%). Tumor hemorrhage occurred in 4 patients (2.2%), and hydrocephalus was seen in 4 patients (2.2%), with 2 patients requiring a shunt. Because of tumor progression, 13 patients underwent

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1.0

Probability

0.8

0.6

0.4

Epilepsy (⫹)

0.2 Epilepsy (⫺) 0.0 0

24

48

72

96

120

Months following diagnosis

Fig. 3. Survival curves for patients with glioblastoma and radiosurgery based on their initial presentation with a seizure disorder.

1.0

Probability

0.8

0.6

0.4

Craniotomy 0.2 Biopsy 0.0 0

24

48

72

96

120

Months following diagnosis

Fig. 4. Survival curves for patients with glioblastoma and radiosurgery based on whether or not initial diagnosis was at craniotomy or stereotactic biopsy.

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repeat radiosurgery, 46 had a repeat resection, and 59 patients received additional chemotherapy.

Discussion

Radiobiology of Radiosurgery for Glial Tumors During radiosurgery a focused volume of radiation is delivered to a sharp bordered intracranial target in a single treatment session. Although radiosurgery is most applicable for histologically benign targets, or well-circumscribed malignant targets such as metastases, adjunct radiosurgery is potentially valuable infiltrating glioblastomas. Although the contrast-enhanced tumor volume identified on imaging can be irradiated by a conformal margin isodose during radiosurgery, the malignant tumor cells beyond that identified by contrast enhancement remain ‘outside’ the full-dose radiosurgery treatment volume [13]. The performance of a focused surgical procedure to the volume of contrast enhancement, whether through craniotomy and tumor resection or radiosurgery, can provide potential benefits to the patient by improving the likelihood of local control [7, 9, 11, 24]. Since treatment failure usually occurs at the tumor resection margin [2], a local boost treatment might be expected to provide benefit [22]. We can compare radiosurgery outcomes to a large series of patients from the University of California, San Francisco, who had fractionated radiation therapy (60 Gy) for adjuvant management of GBM. Median survival in this series was 11.2 months with a 2-year survival rate of 16% [1]. This series of results after radiation therapy alone for glioblastoma is valuable as a historical control to compare the potential benefits of boost radiosurgery. We evaluated the effects of 35 Gy radiosurgery on the rat C6 glioma and a 10-fraction, 85-Gy fractionated dose calculated to be of biological equivalence [14]. In this controlled study, animal survival and reduction in tumor size were identical. However, more pronounced histologic effects were seen in the radiosurgery group when a high maximum dose was delivered. Cytotoxicl effects indicated an early and more direct effect of radiation in this malignant tumor model. Thus, in an experimental model, radiosurgery was found to provide a positive clinical and histologic benefit for a malignant glial tumor [14]. Patient Selection The evaluation of selection bias is necessary prior to understanding the results after radiosurgery or any therapeutic tool used in the management of patients with malignant gliomas. Selection bias was found to be an important factor predicting outcomes for patients suitable for brachytherapy [8]. In the present study, patients undergoing radiosurgery had tumor diameters generally

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⬍3.5 cm in average diameter (smaller than what we would consider acceptable for brachytherapy), had Karnofsky performance scores ⬎50 and had histologic confirmation of tumor type. However, adverse brain location was not an exclusion factor. Thus the present series included patients with such potentially adverse prognostic factors as deep location (brainstem, diencephalon) or subependymal tumor involvement. Effect on Survival One randomized trial has been conducted to evaluate the role of up-front radiosurgery in the management of patients with glioblastoma. Although the results of this study have not been published, the timing of radiosurgery (before radiotherapy) is not typical of clinical practice. Any results from this study may not be generalizable. Recently, Nwokedi et al. [20] reviewed the University of Maryland experience in gamma knife radiosurgery for patients with glioblastoma. The median survival was 13 months in patients who had radiotherapy alone (n ⫽ 33), and 25 months in those who had radiosurgery as a boost therapy (n ⫽ 31). Age, Karnofsky score, and use of radiosurgery were significant predictors of extended survival. Shrieve et al. [22] reported results from the Harvard Joint Center in 78 patients who had glioblastoma radiosurgery. The median survival was 20 months, and half of the patients underwent later surgery for symptomatic necrosis or recurrent tumor. They concluded that the addition of a radiosurgery boost conferred a survival advantage to selected patients. In the current study, we did not compare survival to a cohort of patients who did not have radiosurgery. The main factors for patient selection in our series were tumor volume and performance score. In most patients, radiosurgery remained part of an aggressive multimodality treatment approach. In the earlier years of our experience, many patients were managed without chemotherapy. In more recent years, an array of chemotherapeutic regimens has been used for both up-front and recurrent tumor management, with radiosurgery used when such regimens fail. At present, this has often meant a patient who is further out from their initial diagnosis. Radiosurgery for Tumor Progression When clinical and imaging evidence of tumor progression is documented, management options for many patients are limited. When a lobar tumor progresses, craniotomy and resection are often possible. Further fractionated radiation therapy cannot be administered without high risk to the surrounding brain. The safety of radiosurgery has been documented both for primary or secondary malignant brain tumors [21]. Chemotherapy can be used, depending on the patient’s medical condition and hematologic status.

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When an infiltrative malignant neoplasm is progressing, is a focused therapy such as radiosurgery appropriate? Because most tumor growth is due to local progression, we hypothesized that a specific radiosurgical boost could provide a significant survival benefit for malignant glioma patients, similar to repeat resection. As a well-tolerated, low-morbidity procedure with a less than 24-hour hospital stay, we believe that radiosurgery provided a high level of expected palliation with minimal detrimental effect on quality of life. Thus, for selected patients with progressive small-volume malignant glial tumors after prior therapy, radiosurgery potentially provides safe and effective palliation with enhanced local growth control. At present, we believe that boost stereotactic radiosurgery is a safe and potentially effective adjuvant treatment for patients with newly diagnosed or progressive malignant gliomas. Prior reports have provided data on the use of radiosurgery in selected patient groups. Together with this analysis, we believe there is now impetus for a properly randomized prospective trial that evaluates the use of radiosurgery following radiotherapy in patients with small volume tumors.

References 1

2 3 4 5

6

7 8 9

10 11

Barker F, Prados MD, Chang SM, Gutin P, Lamborn K, Larson D, Malec MK, McDermott M, Sneed PK, Wara W, Wilson CB: Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg 1996;84:442–448. Bashir R, Hochberg F, Oot R: Regrowth patterns of glioblastoma multiforme related to planning of interstitial brachytherapy radiation fields. Neurosurgery 1988;23:27–30. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 1982; 38:29–41. Coffey RJ, Lunsford DL, Taylor FH: Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 1988;22:465–473. Dempsey RK, Kondziolka D, Lunsford LD, Flickinger JC: The role of stereotactic radiosurgery in the treatment of glial tumors; in Lunsford LD (ed): Stereotactic Radiosurgery Update. Amsterdam, Elsevier Science, 1992, pp 407–410. Deutsch M, Green SB, Strike TA, et al: Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma. Int J Radiat Oncol Biol Phys 1989;16:1389–1396. Devaux BC, O’Fallon JR, Kelly PJ: Resection, biopsy and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy and outcome. J Neurosurg 1993;78:767–775. Florell RC, Macdonald DR, Irish WD, Bernstein M, Leibel S, Gutin P, Cairncross JG: Selection bias, survival and brachytherapy for glioma. J Neurosurg 1992;76:179–182. Gutin PH, Leibel SA, Wara WM, Choucair A, Levin VA, Phillips T, Silver P, Da Silva V, Edwards MSB, Davis RL, Weaver KA, Lamb S: Recurrent malignant gliomas: Survival following interstitial brachytherapy with high-activity iodine-125 sources. J Neurosurg 1987;67:864–873. Halperin EC, Burger PC, Bullard DE: The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 1988;15:505–509. Harsh GR, Levin VA, Gutin PH, Seager M, Silver P, Wilson CB: Re-operation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery 1987;21:615–621.

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12 13 14

15 16 17 18 19 20 21

22

23 24

Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. Kondziolka D, Lunsford LD, Claassen D, Pandalai S, Maitz A, Flickinger JC: Radiobiology of radiosurgery. II. The rat C6 glioma model. Neurosurgery 1992;31:280–288. Kondziolka D, Somaza S, Comey C, Lunsford LD, Claassen D, Pandalai S, Maitz A, Flickinger JC: Radiosurgery and fractionated radiation therapy: Comparison of techniques in an in vivo rat glioma model. J Neurosurg 1996;84:1033–1038. 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. Leibel SA, Sheline GE: Radiation therapy for neoplasms of the brain. J Neurosurg 1987;66:1–22. Loeffler JS, Alexander E III, Shea WM, Wen P, Fine HA, Kooy H, Black PM: Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 1992;10:1379–1385. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–170. Nazzaro JM, Neuwelt EA: The role of surgery in the management of supratentorial intermediate and high-grade astrocytomas in adults. J Neurosurg 1990;73:331–344. Nwokedi E, DiBiase S, Jabbour S, Herman J, Amin P, Chin L: Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 2002;50:41–47. Shaw E, Scott C, Souhami L, Dinapoli R, Bahary JP, Kline R, Wharam M, Schultz C, Davey P, Loeffler JS, Del Rowe J, Marks L, Fisher B, Shin K: Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: Initial report of radiation therapy oncology group protocol 90-05. Int J Radiat Oncol Biol Phys 1996;34:647–654. Shrieve DC, Alexander E III, Black PM, Wen P, Fine H, Kooy H, Loeffler JS: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: Prognostic factors and long-term outcome. J Neurosurg 1999;90:72–77. Walker MD, Strike TA, Sheline GE: An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5:1725–1731. Wilson CB: Glioblastoma: The past, the present and the future. Clin Neurosurg 1992;38:32–48.

Douglas Kondziolka, MD, MC, FRCS(C), FACS Professor of Neurological Surgery and Radiation Oncology UPMC, Suite B–400, 200 Lothrop Street Pittsburgh, PA 15213–2582 (USA) Tel. ⫹1 412 6476782, Fax ⫹1 412 6470989, E-Mail [email protected]

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Benign Tumors Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 100–106

Gamma Knife Stereotactic Radiosurgery for Type 2 Neurofibromatosis Acoustic Neuromas Jeremy Rowe, Matthias Radatz, Lee Walton, Andras Kemeny National Centre for Stereotactic Radiosurgery, Royal Hallamshire Hospital, Sheffield, UK

Abstract To evaluate the use of radiosurgery in managing NF2 acoustic neuromas, we retrospectively reviewed 122 tumours treated consecutively in 96 patients. Using current dose protocols we estimate that eight years after radiosurgery, 20% of patients have undergone surgery, 50% are radiologically controlled, and in 30% there will have been variable concerns about control, but they will have been managed conservatively. Forty percent of patients retain their functional level of hearing. Persisting facial and trigeminal neuropathy rates were 5% and 2%. Size constraints applying to NF2 differ from unilateral sporadic tumours, tumours greater than 10 cm3 in volume rarely having good outcomes. Whilst poorer than our results with sporadic tumours, given the dilemmas inherent in NF2, we believe that radiosurgery is a useful treatment strategy in selected patients. Copyright © 2004 S. Karger AG, Basel

The management of bilateral NF2 (type 2 neurofibromatosis) acoustic neuromas presents clinical dilemmas because there is no ideal treatment option. The choices are between observation, surgery and stereotactic radiation treatments. The limitations of observation are reflected in the natural history of NF2: these patients go deaf with tumours which present earlier and grow more rapidly than their sporadic counterparts. The limitations of surgery are reflected by the increasing emphasis placed on conservative management strategies. The published radiosurgical series are limited both in patient numbers and follow-up, and have reported variable results [1–3]. As with time these patients generally develop other tumours and increasing disabilities, they frequently withdraw from clinical follow-up. Duration of follow-up is therefore of

paramount importance in evaluating management strategies for NF2. These considerations prompted this systematic review of our clinical experience. Patient Details From July 1986 to December 2000, 123 treatments were undertaken for 122 acoustic neuromas in 96 patients with NF2. Four families contributed 10 patients and 17 tumours to the series. The sex distribution of patients was equal. The mean age at treatment was 29 ⫾ 11 years (range 11–59), and at presentation 24 ⫾ 11 years (range 7–53). Twenty-eight percent of patients had the severe Wishart phenotype. Radiosurgery was performed as the initial treatment for 97 tumours, 25 tumours being recurrences after previous surgery. All treatments used the Leksell gamma knife. During the time encompassed by this study, there were significant advances in imaging, treatment planning and dose protocols. To address this, tumours were considered in three groups: an early group (n ⫽ 13), treated in 1986–1987 with 25 Gy; an intermediate group (n ⫽ 17), from 1984 to 1994 with 17.5–20 Gy, and a late group (n ⫽ 92) since 1993, with a mean marginal dose of 13.4 ⫾ 1.6 Gy and 5.4 ⫾ 2.5 isocentres. The numerical results quoted in this paper refer to this last group as it most closely reflects current practice.

Outcome Measures Tumour control is difficult to define, hence three measures of this were considered: the rate at which surgical resection was undertaken, the results of serial imaging combined with clinical information, and where applicable relative growth ratios. Relative growth ratios (fig. 1) require an untreated acoustic neuroma on the contralateral side to act as an internal control, and are simply the volume of the treated tumour as a proportion of the opposite control tumour divided by the same fraction calculated a period of time later [4]. A value greater than 100% suggests that radiosurgery is having a beneficial effect shrinking the tumour or slowing its growth relative to the opposite side, whereas a value less than 100% suggests no beneficial effect. Hearing was classified using Gardner-Robertson grades and pure tone audiograms. Facial weakness was graded with the House-Brackmann scale. Any subjective sensory change was classed as trigeminal neuropathy. Values are mean ⫾ SD. Comparisons use paired and unpaired t tests, and ␹2 tests as appropriate. Control rates were calculated as Kaplan-Meier plots. In addition, tumour outcomes were classified as poor, fair or good – poor being a failure within 2 years, fair a failure between 2 and 5 years, and good a tumour controlled for more than 5 years. A regression analysis was run examining the effect of radiation dose, tumour volume, and patient phenotype on outcome.

Results

There were no statistical differences between the Kaplan-Meier tumour control plots for the different dose protocol groups. Figure 2 illustrates the

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Baseline

05/08/97

Treatment

26/10/98

V0

C0

Follow-up

07/03/00

Vt

Ct

Fig. 1. The notion of relative growth ratios derived from patients such as illustrated here. There is a baseline scan showing bilateral acoustic neuromas. Subsequently, at treatment, both tumours have enlarged. V0 is the volume of the tumour being irradiated at the time of treatment and C0 is the volume of the opposite untreated control tumour. At follow-up, the treated side has decreased in size, whilst the untreated tumour continues to grow, their respective volumes being Vt and Ct. The ratio is simply the relative proportions: Relative growth ratio ⫽ V0 /C0 ⫼ Vt /Ct. A value greater than 100% suggests that radiosurgery is having a beneficial effect, shrinking the tumour or slowing its growth relative to the opposite side. Calculating these ratios for all patients with untreated contralateral tumours to act as internal controls, values were significantly elevated 1 and 2 years after radiosurgery, demonstrating that radiosurgery has a beneficial effect. Thereafter, data are limited because of the need to intervene and treat the contralateral tumour.

results for the current low-dose group: 8 years after radiosurgery, 21% of patients have undergone surgery, 79% being managed conservatively. Recalculating this curve, but combining patients undergoing surgery with those whose imaging showed tumour growth, and those in whom there was clinical concern about a loss of control, gave a final control rate of 52% at 8 years.

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100

Control (%)

80 60 40 20 0 0

24

48 72 Time (months)

96

120

Fig. 2. Kaplan-Meier plots illustrating the rate at which surgery is undertaken (solid line), and control defined by surgical intervention, radiological growth, or clinical concern (broken line). Results are for patients treated since 1993 with lower radiation doses, this reflecting our current practice.

Relative growth ratios were significantly elevated (151 ⫾ 72%, p ⫽ 0.01) 1 year after radiosurgery indicating a beneficial effect of radiosurgery. There was a further rise (205 ⫾ 120%, p ⫽ 0.01) at 2 years, the increase from year 1 to year 2 also being significant (p ⫽ 0.02). This trend continued into the third year, but statistical significance was lost because more than half of the patients underwent radiosurgery to the contralateral control tumour on average 27 ⫾ 14 months after the first side. Treating these tumours removes these patients from the analysis, hence numbers and statistical significance are lost. Of those patients in the current low-dose group with discernible hearing (grade I–IV) before radiosurgery, 40% had unchanged grades, 40% having some decrease in grade, and 20% became completely deaf (mean follow-up 3 years). The pure tone audiograms reveal very variable individual responses. Whilst we have seen hearing preservation for 10 years and even recovery, other patients have progressive deterioration despite treatment. Statistically deterioration is also seen before treatment, which is expected as hearing loss is an important factor in deciding to treat. With the current low-dose protocol, the incidence of persisting facial weakness was less than 5%. Excluding patients with trigeminal neuromas, only 2% developed new sensory symptoms. Six percent of patients reported nonspecific vestibular symptoms. There were no brain stem complications related to radiosurgery. One patient, reported in detail elsewhere [5], developed a malignant tumour. This tumour was however behaving atypically, with a 15-fold increase in volume in the 2 years before the radiosurgery, suggesting that radiosurgery did not cause the rapid growth.

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Performing the regression analysis, tumour size was the major determinant of outcome (p ⬍ 0.001). Whilst 82% of small (⬍2 cm3) tumours had good outcomes, this fell to 46% for tumours ⬎8 cm3. Expressed alternatively, the sensitivity for good outcomes was 0.96 for a 10-cm3 volume limit. In this material we could not relate the radiation dose to tumour control and outcome.

Discussion

Tumour control is difficult to define, and the multifocal nature of NF2 makes patient outcomes harder to evaluate. The simplest definition of tumour control, or loss of it, is the rate at which surgical resection is undertaken after radiosurgery. This is important as it is what patients ask – they do after all undergo radiosurgery with the specific aim of avoiding surgery. In a sense it can be answered precisely: 79% of patients avoid surgery for 8 years. This is falsely simplistic. Whilst surgery is a clearly defined event, the decision to undertake it is anything but. An extreme example of this is afforded by 1 patient who died of pneumonia 14 months after radiosurgery. Factors in his death included end-stage NF2 disease, with hypostasis from tetraparesis and spinal disease and concern about infra- and supratentorial tumours. With increasing disability and decreasing therapeutic options he withdrew from follow-up, and there is no record of his bulbar function. The problem is in classifying his tumour control. In terms of freedom from surgery, he is a success. If his pneumonia was hypostatic, one can also argue that tumour control extended beyond the natural history of the disease. Radiologically he was not imaged as he withdrew from follow-up. If, however, his pneumonia was due to aspiration and bulbar dysfunction, clinically there was a loss of tumour control. To address these uncertainties, we recalculated the Kaplan-Meier plot, but including as uncensored observations, not only patients undergoing surgery but those in whom there was any concern radiologically or clinically about a loss of control. This gave a final control rate of 52%. Importantly, some of these ‘failures’ may be very successful clinical results – another case involves a tumour with modest growth which has subsequently stabilized, in a patient who is otherwise well with preserved hearing. We have interpreted this data to state that 8 years after radiosurgery, 20% of tumours will have undergone surgery, 50% will be well controlled, and in 30% there will have been some variable concern about control but that up to that time they will have been managed conservatively. The relative growth ratios are an attempt to address the natural history of the disease. The use of a contralateral tumour as an internal control can be

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criticized, but any criticism should make it harder to see a statistical benefit. The fact that a benefit is being seen is powerful evidence that radiosurgery is advantageous, and suggests that the poor control rate reflects the different biological behaviour of these NF2 tumours. Hearing preservation rates (defined as unchanged Garner-Robertson grade) of 40% are poor compared with our experience treating unilateral acoustic neuromas, but compares favourably with the results of surgery [6]. Similarly, 5% persisting facial nerve palsy rate is worse than our unilateral experience, but is better than open surgery. Whilst we would not wish to underestimate the risk of malignancy in a disorder with altered tumour suppressor genes, this would appear to be low, in this series less than 1%, and is certainly no worse than the mortality associated with open surgery [6, 7]. Can we improve patient selection? The regression analysis shows that size is the major determinant of outcome. A sensitivity of 0.96 for a 10-cm3 volume limit suggests that if only tumours of 10-cm3 volume or less were treated, then 96% of all patients achieving a good outcome would still be treated. Importantly, the size limits applying to efficacious radiosurgery for NF2 acoustic neuromas may be different from those based on experience with sporadic tumours where good control rates are achieved for tumours ⬎10 cm3.

Conclusions

We estimate that with current techniques 8 years after radiosurgery, 20% of tumours will have undergone surgery, 50% will be well controlled, and in 30% there will have been some variable concern about control but that up to that time they will have been managed conservatively. This is achieved with 40% hearing preservation and a 5% persisting facial palsy rate. We believe that presenting the results in this way is important in reflecting the complexities of the NF2 condition, and that most previous surgical and radiosurgical series have not adequately addressed the issues that surround the long-term morbidity encountered in this disease. Numerical results may be improved by careful patient selection in terms of tumour size.

References 1 2

Subach BR, Kondziolka D, Lunsford LD, et al: Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis type 2. J Neurosurg 1999;90:815–822. Kida Y, Kobayashi T, Tanaka T, et al: Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol 2000;53:383–389.

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3 4

5

6

7

Roche PH, Regis J, Pellet W, et al: Neurofibromatosis type 2. Preliminary results of gamma knife radiosurgery of vestibular schwannomas. Neurochirugie 2000;46:339–353. Rowe JG, Radatz MWR, Walton L, et al: Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry 2003;74:1288–1293. Bari M, Forster D, Kemeny AA, et al: Malignancy in a vestibular schwannoma. Report of a case with central neurofibromatosis treated by stereotactic radiosurgery and surgical excision with a review of the literature. Br J Neurosurg 2002;16:284–289. Samii M, Matthies C, Tatagiba M: Management of vestibular schwannomas (acoustic neuromas): Auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2. Neurosurgery 1997;40:696–706. Samii M, Matthies C: Management of 1,000 vestibular schwannomas (acoustic neuromas): Surgical management and results with an emphasis on complications and how to avoid them. Neurosurgery 1997;40:11–23.

J. Rowe National Centre for Stereotactic Radiosurgery Royal Hallamshire Hospital Glossop Road, Sheffield S10 2JF (UK) Tel. ⫹44 114 2713572, Fax ⫹44 114 2754930, E-Mail [email protected]

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Hearing Preservation after Radiosurgery Combined With or Without Microsurgery for Large Vestibular Schwannomas: Preliminary Results Hiroshi K. Inoue, Hideo Nishi, Tohru Shibazaki, Nobuo Ono Restorative Neurosurgery, Institute of Neural Organization, Fujioka, Numata Neurosurgery and Heart Disease Hospital, Numata, Gamma Knife Center, Hidaka Hospital, Takasaki, and Horie Hospital, Ohta, Japan

Abstract Strategies for hearing preservation of patients with large vestibular schwannomas (VS) are reported based on long-term (10–12 years) results of low-dose radiosurgery for 30 patients with VS. The results showed high tumor control (85.2%) and hearing preservation rates (72.7%). Six large tumors (ⱖ4 cm) including NF-2 also received low-dose radiosurgery. Tumor control was achieved in all (stable 4, decreased 2) during a follow-up period of 5–12 years. Then, 3 patients with large tumors were treated with a combination of microsurgery and radiosurgery. Two of 8 patients with large tumors had functional hearing before treatment and the same level of hearing was preserved in both patients up to 11 years after treatment. Hearing preservation of large VS is possible with low-dose radiosurgery combined with or without microsurgery. Copyright © 2004 S. Karger AG, Basel

Radiosurgery was first used as a less invasive addition to microsurgery for the treatment of vestibular schwannomas and then widely developed as an alternative treatment especially for the functional preservation of cranial nerves [1–3]. Technical developments in radiosurgery for the treatment of vestibular schwannomas have decreased the frequency of adverse effects on facial nerves and increased the likelihood of hearing preservation [4–6]. Facial palsy has not been seen after recent low-dose treatments of less than 12 Gy [4]. However, the

radiosurgical treatment of larger tumors ⬎3 cm in diameter is still difficult and requires special techniques, such as staged or fractionated methods [7–9]. Long-term results for these methods are not yet available [10–12]. Low-dose treatments may be effective for large vestibular schwannomas because fewer adverse effects on surrounding structures, such as cranial nerves and the brainstem, are likely to occur. Technical developments in microsurgery have also decreased the number of complications encountered and increased hearing preservation; however, the rate of facial palsy after microsurgery is not negligible, and the rate of hearing preservation is not satisfactory [13–15]. For large vestibular schwannomas, a translabyrinthine approach is used for the functional preservation of the facial nerve; however, this method sacrifices the labyrinth, causing hearing loss [16–18]. Subcapsular removal using a retrosigmoid or middle fossa approach is one option for hearing preservation, although tumor regrowth may occur without additional treatment [19]. One strategy for preserving hearing using a combination of microsurgery and radiosurgery techniques has been reported to preserve the function of the facial nerve in patients with large tumors [20]. Here, our preliminary results on hearing preservation in patients with large vestibular schwannomas that were treated using low-dose radiosurgery with or without microsurgery are reported and treatment strategies for large vestibular schwannomas are described, based on our long-term results for low-dose radiosurgical treatment.

Patients and Methods Two-hundred and nine vestibular schwannomas were treated using gamma knife radiosurgery between May 1991 and March 2002. Imaging studies used for dose planning included MR images and bone-window CT examinations. The distortion in the MR images was corrected using CT images of the internal auditory canal. The anterior rim of the porus acusticus and the internal auditory canal were defined with axial images of thin-section CT scans and a 50% isodose line representing the tumor margin was carefully applied to this portion for patients with useful hearing. Moreover, the first author decided to use lowdose treatment (12 Gy) as of May 1991, instead of the regular dose, to decrease the adverse effects of treatment on the facial and cochleal nerves. Surgical resection was planned in cases when the low-dose treatment failed to control tumor growth. Six tumors in 5 patients (including one NF-2 patient) with large tumors of a maximum diameter of 4 cm or more were treated using gamma knife radiosurgery. Four of these tumors were recurrent after surgical resection. Three patients with large tumors received a combination of microsurgery and radiosurgery. During microsurgery, subcapsular tumor removal was performed using intraoperative monitoring of the facial and cochleal nerves. Thirty patients (including 4 NF-2 patients) treated with radiosurgery between 1991 and 1993 were analyzed to evaluate the long-term results 10–12 years after low-dose treatment.

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Table 1. Summary of 5 patients with large vestibular schwannomas who underwent radiosurgery Case

Age years

Sex

Side

Tumor

Volume ml

Dose central/ margin, Gy

Follow-up years

1

44

F

2 3 4 5

57 60 66 67

M M F F

Left Right Left Left Right Left

Recurrent New Recurrent Recurrent Recurrent New

20.6 17.3 19.5 24.9 22.4 21.3

25/10 24/12 30/11 24/12 27/12 24/12

12 11 9 9 7 5

a

b Fig. 1. Case 5, a 67-year-old female. a MR image showing a large vestibular schwannoma. The tumor was treated with a marginal dose of 12 Gy. b MR image showing a reduction in the size of the tumor 5 years after radiosurgery. No facial palsy developed after radiosurgery.

Results

Five patients with large tumors who were treated with radiosurgery are listed in table 1. The mean volume of the tumors was 21.0 ml. Tumors were treated with a marginal dose of 10–12 Gy and followed for 12 years. The size of the tumors had remained stable in 4 and decreased in 2 after a follow-up period of 5–12 years (fig. 1). No new persistent trigeminal, facial, or lower

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Table 2. Summary of 3 patients with large vestibular schwannomas who underwent a combination of microsurgery and radiosurgery Case

Age years

Sex

Post-operation months

Volume ml

Dose central/ margin, Gy

Follow-up years

6 7 8

47 41 66

F F M

2 4 5

28.5 20.6 2.2

24/12 22/12 24/12

6 1.5 1

cranial nerve palsies developed after radiosurgery. All patients with recurrent tumors had facial palsies prior to radiosurgery. However, no deterioration appeared after treatment. One patient (case 1) had useful hearing on the right side prior to radiosurgey, though the left side was deaf as a result of a recurrent NF-2 tumor. The patient had the same level of useful hearing on her right side 11 years after radiosurgery and could use the telephone with her ear on her right side. No adverse effects on the cerebellum or brainstem were seen and no further operations were required in any of the patients to date. Three patients with large tumors underwent surgical removal and the residual tumors were treated with radiosurgery 2–5 months after microsurgery (table 2). One patient (case 8) was still able to hear on the affected side prior to microsurgery. The tumor was removed subcapsularly, and the patient’s hearing was preserved (fig. 2). The mean volume of the tumors was 17.1 ml at the time of radiosurgery. The tumors were treated with a marginal dose of 12 Gy and followed for 1–6 years. The size of the tumors was stable in 2 patients and smaller in 1 patient during the follow-up period. No new neuropathies of the cranial nerves developed after radiosurgery. In 1 patient with preserved hearing after microsurgery, the tumor decreased in size 1 year after radiosurgery; this patient’s hearing remained stable (fig. 3). Thirty-one tumors in 30 patients were treated with a marginal dose of 9.9–12 Gy; the volume of the treated tumors ranged from 0.1 to 20.6 ml (mean 4.0). Four patients died during the follow-up period from unrelated disease (stroke, cancer, pneumonia). Twenty-six patients were followed for more than 10 years. Four tumors, including one NF-2 and one cystic tumor, increased in size and were removed. The volume of these tumors was 1.8–6.9 ml (mean 3.3) at the time of radiosurgery. No differences from the controlled tumors were found. Auditory acuity was preserved in 72.7% including 3 patients with NF-2 lesions. Tinnitus improved in 50.0%. Tumor growth control was achieved in 85.2%. No permanent neuropathies of the trigeminal or facial nerves developed after radiosurgery.

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a

b

c

Fig. 2. Case 8, a 66-year-old male. a MR image of a large vestibular schwannoma. The tumor was subcapsularly removed, with hearing preservation. b MR image during radiosurgery 5 months after surgical removal. The tumor was treated with a marginal dose of 12 Gy. c MR image 10 months after radiosurgery. The tumor has decreased in size, and no neuropathies developed after treatment.

a

b Fig. 3. Audiograms for case 8. Dotted lines showing the affected side. a Before removal operation. b One year after radiosurgery. No changes in facial or cochleal nerve functions were observed after treatment.

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Discussion

The treatment of vestibular schwannomas is one of the main topics of interest for neurosurgeons and neuro-otologists. Several microsurgical approaches are used and have been developed for the functional preservation of the facial and cochleal nerves. Preservation rates are high for small tumors with a diameter of up to 3 cm. However, the operative morbidity for large tumors is moderate, and functional preservation of the facial and cochleal nerves remains difficult. A translabyrinthine approach is recommended for the preservation of facial function in large tumors, despite a sacrifice in hearing ability. The preservation rates of facial function (House-Brackmann I or II) for experienced surgeons are between 38% [16] and 45% [18]. The preservation of functional hearing in large tumors of ⬎3 cm in diameter is between 16% [21] and 23.5% [22], depending on the size of the tumor. The preservation of hearing in patients with large tumors ⬎4 cm in diameter has not been achieved [16]. Dissection of the facial and cochleal nerves in large tumors induces functional damage to the nerves in most patients. Intracapsular removal seems to be necessary for the functional preservation of facial and cochleal nerves. Technical developments in radiosurgery have resulted in a very low morbidity rate for neuropathies and a high rate of hearing preservation in patients with small vestibular schwannomas [4–6]. Although radiosurgery has been thought to be contraindicated for large vestibular schwannomas, we started to perform low-dose treatments in selected patients. We demonstrated that large recurrent tumors treated with low-dose radiosurgery were stable or decreased in size 5–12 years after treatment, with no adverse effects seen to date. The preservation of functional hearing was possible in 1 NF-2 patient who had useful hearing prior to radiosurgery. Although the number of cases is limited and the follow-up period is short, low-dose radiosurgery may be an alternative treatment for large vestibular schwannomas, creating the possibility of preserving not only facial nerve function, but useful hearing as well. As we have shown by our long-term follow-up, a craniotomy was required after radiosurgery in several patients, especially for patients with cerebellar or brainstem compression symptoms. A relatively early craniotomy was also required in a patient with a cystic tumor because of cystic enlargement. Other patients with tumor regrowth in this series may be treated with a second radiosurgery because the regrowth occurred 5 years or more after the first radiosurgery and the size of the recurrent tumors was small in all the cases. The rate of hearing preservation may increase with the use of a second radiosurgery. Facial palsy after low-dose radiosurgery did not occur in any of the patients in this series, including patients with large vestibular schwannomas. The radiosurgical morbidity of neuropathies is apparently smaller than that of microsurgery. Hearing

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preservation in large vestibular schwannomas is more likely after radiosurgery than after microsurgery. We chose a combination of microsurgery and radiosurgery for 3 patients in this series with large vestibular schwannomas, depending on the shape (spherical) and type (cystic) of the tumor. Mass effects in the posterior fossa and the compression of the cerebellum and brainstem are greater in large spherical tumors (large volume) than in oval or elongated tumors. Tumor swelling after radiosurgery may easily produce compression symptoms, requiring a craniotomy. Subcapsular tumor removal was performed in patients with these tumors, and the residual tumors were treated with radiosurgery. The follow-up time is still short, but 1 patient with hearing prior to the operation continues to exhibit not only normal facial function, but also the same level of hearing function as possessed prior to radiosurgery. A combination treatment is therefore recommended for patients with large vestibular schwannomas with preserved hearing. It is concluded that low-dose radiosurgery for vestibular schwannomas, including NF-2 lesions, is effective for the functional preservation of cranial nerves as well as tumor control for 10–12 years after treatment. Strategies using radiosurgery with or without microsurgery are recommended for patients with large tumors, especially those with useful cranial nerve functions.

References 1 2 3 4

5

6

7

8

9

Lunsford LD, Linskey ME: Stereotactic radiosurgery in the treatment of patients with acoustic tumors. Otolaryngol Clin North Am 1992;25:471–491. Noren G, Greitz D, Hirsch A, Lax I: Gamma knife surgery in acoustic tumours. Acta Neurochir Suppl (Wien) 1993;58:104–107. Noren G: Long-term complications following gamma knife radiosurgery of vestibular schwannomas. Stereotact Funct Neurosurg 1998;70(suppl 1):65–73. Hirato M, Inoue HK, Zama A, Ohye C, Shibazaki T, Andou Y: Gamma knife radiosurgery for acoustic schwannoma: Effects of low radiation dose and functional prognosis. Stereotact Funct Neurosurg 1996;66:134–141. Regis J, Delsanti C, Roche P, Soumare O, Dufour H, Porcheron D, Peragut JC, Thomassin JM, Pellet W: Preservation of hearing function in the radiosurgical treatment of unilateral vestibular schwannomas. Preliminary results. Neurochirurgie 2002;48:471–478. Fukuoka S, Takanashi M, Hojo A, Konishi M, Nakamura H: Gamma knife radiosurgery for acoustic schwannomas: An analysis of the method of low dose and conformal multiple shots with smaller collimator (English abstract). Jpn J Neurosurg (Tokyo) 2003;12:527–533. Inoue HK, Hayashi S, Ishihara J, Horikoshi S, Zama A, Hirato M, Shibazaki T, Andou Y, Ohye C: Fractionated radiosurgery for malignant gliomas: Neurobiological effects and FDG-PET studies. Stereotact Funct Neurosurg 1995;64(suppl 1):249–257. Lederman G, Lowry J, Wertheim S, Fine M, Lombardi E, Wronski M, Arbit E: Acoustic neuroma: Potential benefits of fractionated stereotactic radiosurgery. Stereotact Funct Neurosurg 1997;69: 175–182. Poen JC, Golby AJ, Forster KM, Martin DP, Chinn DM, Hancock SL, Adler JR Jr: Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: A preliminary report. Neurosurgery 1999;45:1299–1305.

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10 11

12 13 14

15

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18 19 20 21 22

Pendl G, Unger F, Papaefthymiou G, Eustacchio S: Staged radiosurgical treatment for large benign cerebral lesions. J Neurosurg 2000;93(suppl 3):107–112. Andrews DW, Suarez O, Goldman HW, Downes MB, Bednarz G, Corn BW, Werner-Wasik M, Rosenstock J, Curran WJ Jr: Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: Comparative observations of 125 patients treated at one institution. Int J Radiat Oncol Biol Phys 2001;50:1265–1278. Williams JA: Fractionated stereotactic radiotherapy for acoustic neuromas. Stereotact Funct Neurosurg 2002;78:17–28. Samii M, Matthies C: Management of 1,000 vestibular schwannomas (acoustic neuromas): Hearing function in 1,000 tumor resections. Neurosurgery 1997;40:248–260. Schlake HP, Milewski C, Goldbrunner RH, Kindgen A, Riemann R, Helms J, Roosen K: Combined intraoperative monitoring of hearing by means of auditory brainstem responses and transtympanic electrocochleography during surgery of intra- and extrameatal acoustic neurinomas. Acta Neurochir (Wien) 2001;143:985–995. Karpinos M, Teh BS, Zeck O, Carpenter LS, Phan C, Mai WY, Lu HH, Chiu JK, Butler EB, Gormley WB, Woo SY: Treatment of acoustic neuroma: Stereotactic radiosurgery vs. microsurgery. Int J Radiat Oncol Biol Phys 2002;54:1410–1421. Gormley WB, Sekhar LN, Wright DC, Kamerer D, Schessel D: Acoustic neuromas: Results of current surgical management. Neurosurgery 1997;41:50–58. Lanman TH, Brackmann DE, Hitselberger WE, Subin B: Report of 190 consecutive cases of large acoustic tumors (vestibular schwannoma) removed via the translabyrinthine approach. J Neurosurg 1999;90:617–623. Mamikoglu B, Wiet RJ, Esquivel CR: Translabyrinthine approach for the management of large and giant vestibular schwannomas. Otol Neurotol 2002;23:224–227. Lownie SP, Drake CG: Radical intracapsular removal of acoustic neurinomas. Long-term follow-up review of 11 patients. J Neurosurg 1991;74:422–425. Iwai Y, Yamanaka K, Ishiguro T: Surgery combined with radiosurgery of large acoustic neuromas. Surg Neurol 2003;59:283–291. Strauss C, Fahlbusch R, Berg M, Haid T: Function-saving microsurgery in suboccipital removal of large acoustic neuromas (in German) HNO 1989;37:281–286. Fahlbusch R, Neu M, Strauss C: Preservation of hearing in large acoustic neurinomas following removal via suboccipito-lateral approach. Acta Neurochir (Wien) 1998;140:771–777.

Hiroshi K. Inoue, MD Restorative Neurosurgery Institute of Neural Organization Fujioka, Gunma 375-0021 (Japan) Tel. ⫹81 901 4679095, Fax ⫹81 274 233006, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 115–123

Long-Term Follow-Up Using Linac Radiosurgery and Stereotactic Radiotherapy as a Minimally Invasive Treatment for Intracranial Meningiomas Rodrigo Couto Torresa, Antonio A.F. De Sallesa, Leonardo Frighettoa, Tooraj Gravori a, Alessandra G. Pedrosoa, Brian Gossb, Paul Medinb, Timothy D. Solbergb, Judith Marianne Ford b, Michael Selchb a

Division of Neurosurgery and bDepartment of Radiation Oncology, University of California at Los Angeles, Calif., USA

Abstract Purpose: Report of technical aspects, results and strategies of stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT) for treatment of intracranial meningiomas. Methods: A retrospective review of intracranial meningiomas treated at UCLA from May 1991 to July 2003 was performed with emphasis on technical aspects, radiological and clinical results. 161 patients with intracranial meningiomas treated by linear accelerator (Linac) stereotactic radiation were identified. There were 33 meningiomas in 32 patients with follow-up more than 48 months. Mean patient age was 57.2 years (range 19–87). There were 25 females and 7 males. 21 patients had surgical resection prior to radiosurgery. Stereotactic radiation was the primary treatment in 12 patients. Single dose radiation to 26 lesions and 7 were treated with fractionated technique. SRS dose prescribed to the periphery of the tumor ranged from 12 to 22 Gy (mean 15 Gy), SRT dose ranged from 23 to 54 Gy (mean 48 Gy). The prescription isodose ranged from 50 to 90% for the single dose group and from 85 to 90% for the fractionated treatments. Results: Follow-up was available for 32 patients treated between 48 and 125 months (mean 72.5). Tumor growth control was achieved in 30 benign meningiomas treated with SRS (92.3%) and in 7 benign meningiomas treated with SRT (100%). Worsening of previous neurological deficit was identified in 2 patients (7.9%) treated with SRS. No complications were found in SRT patients. Conclusion: Radiosurgery has been an alternative to surgical resection of selected intracranial meningiomas. Patients with tumors not amenable to either surgery or radiosurgery are now candidates for a less

invasive technique than conventional radiotherapy. The need for total/subtotal surgical resection of these tumors is being challenged by superior imaging capabilities that allow for precise and effective stereotactic radiotherapy. Copyright © 2004 S. Karger AG, Basel

Single dose stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) have been an established technique for the treatment of intracranial meningiomas where surgical resection is not indicated. Initially, radiation served in the management of residual tumors after microsurgery. Its appropriate utilization proved to be successful using all the available techniques, including linear accelerators [6, 11, 25, 26], gamma knife [12, 14, 15, 27] proton beam [32], and conventional fractionated external beam radiation [2, 9, 10, 22, 29]. As previously described [31], the high success rate and safety of SRS after the advent of high-definition MRI established radiosurgery as an invaluable tool in the management of intracranial meningiomas. The availability of stereotactic radiation techniques has changed the neurosurgical approach of intracranial meningiomas, especially in relation to complex skull base lesions. These advances include the advent of SRT and the availability of a micro-multileaf collimator capable of performing shaped beam SRS and SRT. This report describes the outcome of patients with intracranial meningiomas who were treated with Linear Accelerator SRS and SRT with more than 48 months’ follow-up. Material and Methods Between 1991 and 2002, 161 patients with 194 intracranial meningiomas underwent SRS or SRT at UCLA Medical Center. All treatments were performed using a Linac-based stereotatic system. Initially, treatments were performed using a Philips SRS 200 adapted into a Clinac 18 (Varian, Palo Alto, Calif., USA) linear accelerator. A dedicated Linac to radiosurgery was first used in 1996, utilizing the Radionics X-Knife system (Radionics, Burlington, Mass., USA). Since 1997, our department has been using the Novalis (BrainLab AG, Heimstetten, Germany) dedicated Linac. A minimum of 48 months of clinical and radiological follow-up were obtained in 32 patients harboring 33 meningiomas. SRS was the modality of choice in 26 meningiomas (78%), while 7 (22%) were treated with the fractionated technique. The overall mean follow-up was 75 months (range 48–125). The mean follow-up for patients treated with SRS was 83.9 months (range 48–125) and for SRT 57.4 months (range 48–62). There were 25 women (78.5%) and 7 men (21.5%) with a mean age of 51.4 years (range 18–87). Stereotactic radiation was the first treatment option in 12 patients (36.4%) and was applied following microsurgery in 21 (63.6%). Patients were routinely submitted to a BRW (Radionics) or a BrainLab (BrainLab AG) stereotactic frame placement under local anesthesia. A stereotactic CT scan was performed

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Table 1. Technical parameters used in the treatment of intracranial meningiomas (n ⫽ 33) Parameter

SRS (n ⫽ 26)

SRT (n ⫽ 7)

Fractions, n Volume, cm3 Isodose, % Prescribed dose, cGy Maximal dose, cGy Dose per fraction, cGy Multiple isocenters Shaped beam CT planning only

1 1.1–43 (16.6) 50–90 (85) 1,200–2,285 (1,567) 1,500–4,000 (2,456) NA 28 8 3

5–30 (26.85) 1.25–57 (10.7) 85–90 (89.27) 2,380–5,400 (4,839) 4,500–6,000 (5,350) 165–500 (183) 1 6 0

SRS ⫽ Stereotactic radiosurgery; SRT ⫽ stereotactic radiotherapy; NA ⫽ not applicable. Mean values are shown in parentheses.

and fused with a previously acquired 3-mm slices MRI scan. Image fusion was performed using a mutual information algorithm, which allows geometric alignment between the two image sets. CT scans were used for the precision of the stereotactic localization while highresolution MRI scans provided the anatomical details necessary for the treatment planning. The same protocol was used for SRT patients; however, a replaceable mask made of thermotransformable material (BrainLab) or a GTC frame (Radionics) was applied. Complex shaped lesions were treated with conformal planning using multiple isocenters, arc selection and weighting to avoid critical structures. Recently a micro-multileaf collimator generating conformal plans has been used, obviating the need for multiple isocenters for dose conformation. The dosimetry characteristics used in this series are presented in table 1. SRT was indicated for tumors involving the optical apparatus, substantially compressing the brainstem or when the tumor was deemed too large for single dose treatment. Patient follow-up was performed with MRI scans every 6 months for the first 3 years and every 12 months thereafter.

Results

The overall tumor growth control rate for the 33 benign meningiomas included in this study was 93.9% (32 patients). Reduction in tumor volume was observed in 11 meningiomas (33.3%), stabilization of the tumor with no evidence of growth in 20 cases (60.6%), and further tumor growth occurred in 2 patients (6.66%). Single fraction SRS provided a treatment success rate of 92.3% (24 patients). Tumor volume reduction occurred in 9 patients (34.3%) and stabilization in 15 patients (56.3%) in the SRS group. Failure was observed in 2 (7.7%) of the

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Overview 10 beams

5,040cGy, 90%

7 months follow-up

Fig. 1. Left: pretreatment planning with 10 beams. Center: preoperative MR image showing isodose lines. Right: control 7 months postoperative MR image demonstrating significant decrease in size of a intracranial meningioma after SRT. A single shaped beam isocenter, 28 fractions of 180 cGy, prescribed to the 90% isodose line, were applied for a total dose of 5,040 cGy.

21 patients treated with this modality. SRT, achieved a treatment success rate of 100% (7 patients). Reduction in tumor volume occurred in 2 patients (33.8%) and stabilization in 5 (63.4%) patients treated with SRT (fig. 1). The tumor growth control for benign intracranial meningiomas after stereotactic radiation is described in table 2. Neurological examination and imaging studies (table 3) were available in 32 patients in a follow-up period ranging from 48 to 125 months after treatment (mean 78.4, median 65). Improvement of the presenting symptoms was observed in 4 patients (15%) treated with SRS and in 3 (42%) submitted to SRT. The overall clinical improvement was 21.2% (7 patients). The clinical status remained unchanged in 20 patients (76.9%) and 4 patients (48%) submitted to SRS and SRT respectively. Worsening of the clinical symptoms was observed in 2 patients (7.7%) treated with SRS due to complications or progression of the diseases.

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Table 2. Tumor growth control after stereotactic radiation of benign meningiomas Tumor size

Decreased No change Increased Total Tumor control

Treatment group, % SRS

SRT

total

9 (34.6) 15 (57.7) 2 (7.7) 26 (100) 24 (92.3)

2 (28.5) 5 (71.5) 0 7 (100) 7 (100)

11 (33) 20 (60.1) 2 (6.6) 33 (100) 31 (93.9)

SRS ⫽ Stereotactic radiosurgery; SRT ⫽ stereotactic radiotherapy.

Table 3. Clinical follow-up results Neurological findings

Improved Unchanged Worse Patients

Treatment group, % SRS

SRT

total

4 (15.4) 20 (76.9) 2 (7.7) 26 (100)

3 (42) 4 (58) 0 7 (100)

7 (21.2) 24 (72.7) 2 (6.1) 33 (100)

SRS ⫽ Stereotactic radiosurgery; SRT ⫽ stereotactic radiotherapy.

The incidence of clinical complications in the SRS group was 7% (2 patients). A slight decrease in visual acuity was observed in 1 patient and another patient developed a decrease in facial sensation. These complications were mild and did not change the activities of daily living of the patients. No complications occurred in the patients treated with SRT.

Discussion

The long-term follow-up demonstrated that both SRS and SRT are effective as adjuvant or as primary treatment, for intracranial meningiomas. As previously demonstrated in the literature, success rates of more than 90% can be achieved

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with few complications when stereotactic radiation techniques are used in the management of intracranial meningiomas [6–8, 11, 12, 14, 15, 27]. The slight difference in tumor outcome observed in this study for patients treated with SRS ⫻ SRT does not reflect advantages of a specific treatment modality. It may be an artifact of the longer follow-up period available for the SRS group, as well as the improvement of imaging and planning over the years. This study also shows that the use of stereotactic radiation can be expanded to larger tumors which were previously not candidates for radiosurgery. Tumors encasing or compressing important structures such as the optic apparatus, cranial nerves and brainstem can also be treated by fractionated stereotactic radiation techniques. The low morbidity and mortality of SRS and SRT, when compared to attempts of complete surgical resection [13, 24] or conventional radiation therapy, have validated the application of stereotactic radiation techniques as a treatment option for intracranial meningiomas [3, 4, 8, 11, 12, 18, 19, 23, 25, 30, 33]. Microsurgery remains the best option for symptomatic intracranial meningiomas when complete surgical resection can be achieved with low morbidity. Depending on the tumor location and complexity of nearby structures, complete resection of intracranial meningiomas including the dural extension may be impossible to achieve without morbidity [5, 16, 17]. In cases of invasive meningiomas associated with brain matter, SRS and SRT are options either as an adjuvant or as the first treatment modality. As previously described by us [31], the use of SRS alone has limitations that may make it unusable for some cases. These limitations relate to tumor size and proximity to eloquent structures such as the optic apparatus. Single fraction SRS can be used for the treatment of meningiomas with ⬍3 cm (20 cm3 in volume) and with a minimal distance from the optic apparatus between 2 and 4 mm [4, 8, 18, 21, 28]. Alternative approaches to overcome such limitations usually result in treatment failure. These include the performance of two-staged procedures [12, 19] or decrease in the ideal peripheral dose [19]. The advent of SRT overcame the single fraction limitations offering the possibility of the use of this modality alone in the management of large intracranial meningiomas. SRT is ideal for tumors that cannot be completely resected or those in which the resection is associated with greater risk of morbidity and mortality. SRT is a treatment option when the risk of radiosurgery is unacceptably high, such as that closely associated with the optic pathways or the brainstem [1, 30]. This is especially important after the observation in the literature of improvement in visual acuity after SRT [1, 31]. The deliberate delivery of toxic radiation doses to the optic structures in order to provide tumor control with the costs of visual loss [23, 33] is not admissible anymore with the availability of safer techniques. Andrews et al. [1] reported their experience with 33 patients treated with a similar treatment paradigm as

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the one used in our institution. In this series, 92% of the patients demonstrated preserved vision and 42% manifested improvement in visual acuity. The data presented in this report, as well as in other reports in the literature, shows that stereotactic radiation alone can provide similar results to microsurgery followed by radiation [2, 6, 8, 9, 12, 14, 15, 26, 29]. This supports the use of SRS or SRT as the first treatment option for the management of intracranial meningiomas. However, the selection of the best treatment option for these lesions should take into account tumor location, severity of the symptoms at presentation and the long-term follow-up of the available modalities. Microsurgery is superior in providing symptomatic relief especially for convexity meningiomas and other locations where a total resection can be achieved. Stereotactic radiation has proven to be a better treatment modality for complex skull base lesions, especially those involving the cavernous sinus, resulting in lower recurrence rates and fewer complications. Moreover, recent advances in stereotactic radiation techniques can further improve treatment outcomes and increase the number of tumors suitable for such treatment. These advances include the advent of SRT and the availability of shaped beam surgery capable of delivering intensity-modulated stereotactic radiosurgery/radiotherapy (IMRS/IMRT). These treatment modalities produce less target dose heterogeneity with the use of a single isocenter and a shorter estimated treatment time. The application of IMRS/IMRT in the treatment of complex skull base lesions provided comparable target coverage and sparing of structures at risk, while improving the conformity index at the prescription isodose contour when compared to the multiple isocenter [20]. Conclusion

Radiosurgery has been an alternative to surgical resection of selected intracranial meningiomas. Patients with tumors not amenable to either surgery or radiosurgery are now candidates for a less invasive technique than conventional radiotherapy. The need for total/subtotal surgical resection of these tumors is being challenged by superior imaging capabilities that allow for precise and effective SRT. References 1

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Rodrigo Couto Torres, MD 200 Medical Plaza, Suite 504 Los Angeles, CA 90095 (USA) Tel. ⫹1 (310) 794 1221, Fax ⫹1 (310) 794 1848, E-Mail [email protected]

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Preservation of Olfaction in Olfactory Groove Meningiomas with Stereotactic Radiosurgery Report of Three Cases and Review of the Literature

Hooman Azmi-Ghadimia, Alexander Jacobsb, Charles Cathcart b, Michael Schulder a a

Department of Neurological Surgery, Neurological Institute of New Jersey, New Jersey Medical School and bDepartment of Radiology, Division of Radiation Oncology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, N.J., USA

Abstract Objective and Importance: Anosmia is a frequent complication of surgical treatment of olfactory groove meningiomas (OGMs). The loss of olfaction can significantly impact on patient quality of life. We present 3 patients with incidentally discovered small OGMs who were treated with stereotactic radiosurgery (SRS). All patients have had tumor control and have not suffered from olfactory loss. This is the first study to elaborate on the safety of SRS in relation to the first cranial nerve. Clinical Case Presentation: Three women, aged 46, 62 and 52 years, presented with incidentally discovered OGMs. They were all asymptomatic from these tumors and had intact olfaction. Intervention: Two patients received single session SRS, 1 with 2,000 cGy to the 85th percentile line, and the other 1,500 cGy to the 85th percentile line. The third patient chose hypofractionated SRS because she was an employee of the hospital and did not wish her colleagues to see her with a frame. She received 2,600 cGy in five daily fractions. All 3 patients have had tumor control with no complications and remain symptom-free with intact olfaction. Conclusion: SRS provides an excellent treatment alternative for a select group of patients with OGMs who wish to maintain their sense of smell. Copyright © 2004 S. Karger AG, Basel

Surgery for olfactory groove meningiomas (OGMs) usually sacrifices the sense of smell [3]. Anosmia is often accepted as an inevitable part of skull base surgery, with significant impact on quality of life [4, 24, 31, 35, 36]. Furthermore,

Table 1. Patient data and summary Patient

Age

Sex

Tumor volume, cm3

Modality

Prescription dose, cGy

Complications

Follow-up months

1 2 3

46 62 52

F F F

1.0 1.2 0.9

SRS SRS Hypofractionated SR

2,000 1,500 5 ⫻ 525

None None None

75 87 56

anosmia can affect patient health, nutrition, safety and even employment [4]. Psychological well-being of patients may also be affected by the loss of ability to smell, and patients may develop depression [10, 12, 35, 36]. Stereotactic radiosurgery (SRS) offers an olfaction-preserving alternative for the treatment of OGMs in a select group of patients. In addition, SRS offers a high likelihood of tumor control, with low risk of morbidity [30]. Radiation tolerance of other cranial nerves has been described [15, 22], but the tolerance of the olfactory nerve and tracts to radiation has not been addressed. We present 3 patients with OGMs treated with SRS. Two patients were treated with single dose SRS, and 1 with hypofractionated SRS. All 3 patients were females (table 1), had tumors ⬍25 mm, and had no symptoms related to their tumors. All have had tumor control without complications from the treatment. They remain symptom-free with intact olfaction. Case Reports Case 1: A 46-year-old female presented with an incidentally discovered OGM. She had had an accident which led to a CT scan of the head, with discovery of the meningioma (fig. 1a). The patient had no loss of taste or smell. On physical exam, she had no cranial nerve or other neurological deficits. The patient was offered the options of observation, surgery, or SRS, and she chose SRS for preservation of olfaction. SRS was performed with the Radionics X-knife system, version 2.0 (Radionics, Burlington, Mass., USA). Imaging and planning were done with a stereotactic CT. A treatment plan of 6 arcs using one 18-mm collimator was generated. A prescription dose of 2,000 cGy to the 85% line was delivered (fig. 1b). At her 6-year follow-up after SRS, she remained asymptomatic and neurologically intact, without any decrease in her sense of taste or smell. Follow-up imaging showed no change in tumor size (fig. 1c). Case 2: A 62-year-old female who developed headaches after being involved in an MVA, presented after an MR of the head revealed a meningioma of the left frontal skull base (fig. 2a). She had no other complaints related to the mass and her sense of smell was intact. On physical exam she had no neurological deficits. The patient was offered both surgery and SRS for the treatment of this mass, and chose the latter option.

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a

b

c Fig. 1. a Patient 1, contrast-enhanced CT. b Radiosurgical treatment plan. c Follow-up MRI showing no tumor growth.

SRS was performed with a technique similar to that described above. The prescription dose was 1,500 cGy to the 85% isodose line (fig. 2b). After 7 years the patient has had no new symptoms and continues to work. There have been no changes in the size of the tumor or the surrounding edema (fig. 2c). She also has had no changes in her sense of smell. Case 3: A 52-year-old female presenting with an incidental OGM, discovered on workup for hearing loss (fig. 3a). She was otherwise intact, including her sense of smell. She opted for hypofractionated SRS for the treatment of her tumor, since she was an employee at the hospital and did not want to be seen with a frame on her head.

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a

b

c Fig. 2. a Patient 2, contrast-enhanced MR at presentation. b Radiosurgical treatment plan. c Follow-up MRI showing no change in tumor.

Localization was done using fused CT and MRI with a Gill-Thomas-Cosman relocatable frame [20]. She received a total of five treatments. On a daily basis she received a dose of 520 cGy to the 80% isodose line which yielded a total dose of 2,600 cGy. There were five beams used to 495 total arc degrees and an 18-mm collimator (fig. 3b). She remains symptomfree to date, with no changes in her sense of smell.

Discussion

Olfactory System Anatomy The detection of odors is carried out by receptors in the olfactory epithelium. These receptors are bipolar neurons with specialized dendrites projecting to the surface mucosa. The ends of these dendrites expand into structures called

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a

b Fig. 3. a Patient 3, CT before treatment. b Treatment plan for hypofractionated SRS.

olfactory knobs which possess receptors for odors. The long process of these cells, the axon, joins the axons of about 10–100 other receptor cells, forming axon bundles that pierce the cribriform plate of the ethmoid bone as the first cranial nerve, and project to the olfactory bulb [6]. Within the olfactory bulb, these axons synapse with second order neurons which then project to the olfactory cortex via the olfactory tract [6]. Olfactory information ultimately is relayed through the thalamus to the neocortex. An important point that distinguishes the olfactory nerves from most other cranial nerves (CN) is that CN I, like CN II, is part of the central nervous system while other CNs are considered peripheral nerves. Importance of the Sense of Smell Olfaction is a poorly understood and often overlooked sense. Most patients do not become aware of the loss of smell because it often occurs gradually [39], and if they do complain, they often complain of an inability to taste rather than loss of smell. Yet anosmia could have a drastic effect on patients, significantly affecting their quality of life [4, 24, 31, 35, 36]. Patients with anosmia lose the ability to appreciate food and drink, leading to a disregard for food and malnutrition, especially in the elderly. In addition, because of the inability to taste food, patients may have a propensity to use excess salt or sugar in an attempt to bring out the flavor of the food which could be detrimental for diabetics or hypertensives [4].

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Anosmia may also affect the safety of patients. The ability to detect warning odors in life-threatening situations is lost with olfactory dysfunction. The inability to detect gas, smoke, and spoiled foods may affect the safety of patients suffering from olfactory loss [5, 9, 36], and leave them with feelings of vulnerability. Indeed, Toller [36] found the feeling of vulnerability as the single most stressful aspect of living with a smell disorder in a survey of patients suffering from this ailment. Anosmia could also raise social concerns for patients especially relating to personal body odor, leading to either poor hygiene or an obsession for cleanliness in fear of avoiding body odor [5]. Employment could also be affected in anosmics. Electricians for example would need to know when and where cables are burning or car mechanics would need to know whether some clear fluid is water or gasoline. Cooks, florists, firemen, plumbers, professional food and beverage tasters, natural gas workers, chemists and a variety of industrial workers could all be affected by the loss of their sense of smell [5, 9, 10]. All these problems could lead to depression in anosmics. Some authors have found that depression frequently accompanies chemosensory distortions [10, 13, 35, 36]. The impact on the quality of life, the feelings of vulnerability, and the social concerns all could undermine the psychological well-being of patients and lead to states of depression. In addition, olfactory dysfunction may play a direct role in depression by allowing disinhibited output of the amygdala, causing intensified feelings of sadness and fear [28]. Olfactory Groove Meningiomas About 8–18% of intracranial meningiomas arise in the olfactory region [7, 26, 35, 39]. In general, they arise from the cribriform plate of the ethmoid bone in the midline between the crista galli and the planum sphenoidale. The olfactory tracts are usually displaced laterally by these tumors and once large enough they push the optic chiasm posteriorly. The A2 segments of the anterior cerebral arteries are also pushed posteriorly by these tumors. The blood supply of the tumor is mainly from the anterior and posterior ethmoidal branches of the ophthalmic artery [37]. Once large enough, these lesions can cause anosmia, headaches, visual and memory disturbances, mental apathy and even dementia [2]. The Foster Kennedy syndrome, which is the triad of anosmia, ipsilateral optic nerve atrophy, and contralateral papilledema, is an uncommon syndrome associated with large OGMs. The first successful surgical resection of an OGM was reported by Francis Durante in 1885 [8]. Harvey Cushing [8] reported a series of 28 patients with OGMs, of whom 3 had subjective hyposmia. Other investigators have also reported on OGMs in large meningioma series, with little elaboration on the sense of smell pre- or post-operatively [7, 23, 26].

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Investigations of olfactory function in larger groups of patients with OGMs are rare. The loss of the sense of smell with surgery for OGMs is generally thought to be inevitable [3]. With the realization that anosmia may be a complication in several different approaches for skull base lesions, attempts were made at salvaging the olfactory tract during these surgeries [16, 31–34]. However, in surgery for patients with OGMs, preservation of olfactory function seems to be extremely difficult irrespective of tumor size or surgical approach. This certainly holds for the ipsilateral olfactory tract [39], and preservation of the contralateral olfactory tract is fair at best [18, 38]. Stereotactic Radiosurgery SRS in recent years has offered an alternative for the primary treatment of patients with skull base meningiomas [17, 21, 29]. Despite the advances in neuroanesthesia and microsurgery, skull base meningiomas still present a challenge to the neurosurgeon. While total surgical resection is ideal it is often not possible because of the proximity of the tumor to vital neurovascular structures [1, 7, 25, 30] and a subsequent high risk of morbidity with surgery [1, 11]. On the other hand, incompletely resected tumors have a high recurrence rate [19]. SRS, as primary treatment for patients with meningiomas, has been shown to provide excellent tumor control, short recuperation times for patients and acceptable rates of morbidity [30]. Meningiomas are ideal for radiosurgery because they are well demarcated, easily visualized on preoperative computed tomography or magnetic resonance imaging and are rarely infiltrative [1, 30, 40]. This mode of treatment is especially attractive for patients with skull base meningiomas because of the high rates of morbidity associated with conventional surgical treatment of these lesions. OGMs may be somewhat different than other skull base meningiomas since they are in the anterior skull base and not immediately adjacent to the brainstem. Nevertheless, surgical resection of these lesions does carry risks of morbidity. These include anosmia, CSF leak and infection, postoperative hematoma, sagittal sinus and anterior cerebral artery injury, hemiparesis, visual loss, and postoperative seizures [14, 18, 27, 37, 39]. In selected patients SRS can offer primary treatment for OGMs with reduced risk of morbidity, and at the same time provide excellent tumor control with preservation of olfactory function. Prior studies have investigated the radiation thresholds for other cranial nerves [15, 22]. However, the safety radiation dose for the olfactory nerves and tracts has not been addressed previously. We have presented 3 patients with small OGMs who were are treated with SRS alone. All 3 had tumors which were ⬍30 mm in diameter, often accepted as the maximum size for SRS [21]. Follow-up has been for up to 7 years, and none of the patients have had an increase in their tumor size to date. They have

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experienced no side effects associated with SRS, and none have suffered from anosmia. It is important to note that these meningiomas are benign lesions that may not grow in size. In addition, treatment of these tumors while they are small increases the safety of SRS and probably increases the chances of preserving olfaction.

Conclusion

OGMs are benign tumors of the anterior skull base which can become large and cause severe symptoms. Surgery is the ideal modality for the treatment of these tumors, but it can lead to morbidities especially to the loss of the sense of smell. In a select group of patients, with small tumors, SRS offers an excellent alternative for treatment of OGMs in patients who wish to maintain their sense of smell.

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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. Babu R, Barton A, Kasoff SS: Resection of olfactory groove meningiomas: Technical note revisited. Surg Neurol 1995;44:567–572. Black PM: Meningiomas. Neurosurgery 1993;32:643–657. Bromley SM: Smell and taste disorders: A primary care approach. Am Fam Physician 2000;61: 427–436, 438. Callahan CD, Hinkebein J: Neuropsychological significance of anosmia following traumatic brain injury. J Head Trauma Rehabil 1999;14:581–587. Castellucci VF: The chemical senses: Taste and smell; in Kandel ER, Schwartz JH, Jessell TM (eds): Principles of Neural Science. New York, Elsevier, 1991. 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. Cushing H, Eisenhardt L: Meningiomas: The olfactory meningiomas with primary anosmia. Springfield, Charles C Thomas, 1938. Dare AO, Balos LL, Grand W: Olfaction preservation in anterior cranial base approaches: An anatomic study. Neurosurgery 2001;48:1142–1146. Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF, Kimmelman CP, Brightman VJ, Snow JB Jr: Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch Otolaryngol Head Neck Surg 1991; 117:519–528. DeMonte F, Smith HK, al-Mefty O: Outcome of aggressive removal of cavernous sinus meningiomas. J Neurosurg 1994;81:245–251. Doty RL, Kimmelman CP: Smell and taste and their disorders; in Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System: Clinical Neurobiology. Philadelphia, Saunders, 1993, pp 390–403.

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Michael Schulder, MD Department of Neurological Surgery, Neurological Institute of New Jersey 90 Bergen Street, Suite 8100, Newark, NJ 07103 (USA) Tel. ⫹1 973 972 2908, Fax ⫹1 973 972 2333, E-Mail [email protected]

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Gamma Knife Radiosurgery for Pituitary Adenoma M.S. Gaur, J. Misra, A.K. Banerji, N. Bajaj, V.K. Pathak Rancan Gamma Knife Centre, Vidyasagar Institute of Mental Health and Neurosciences (Vimhans), New Delhi, India

Abstract In this report we have analyzed 86 patients with whom we had more than 6 months of follow-up to assess the efficacy of gamma knife radiosurgery for tumor growth and endocrinopathy control for this study. Of these 86 patients, 43 had hormone-secreting tumors. All patients were followed with contrast MRI, perimetry and hormone profile every 6 months. The 43 patients with non-functioning pituitary adenoma were treated with an average prescription dose of 10 Gy (6–16) at an average prescription isodose of 44% (28–50%) with an average of 24 Gy (14–35) dose at the maximum. Of the 43 hormone-secreting tumor patients, 29 were suffering from acromegaly with a rise in growth hormone and were treated with an average prescription dose of 17.6 Gy (9–25) at an average prescription isodose of 45.5 Gy (40–50) with an average of 38.5 Gy (20–50) dose at maximum. Eleven had high prolactin levels and they were treated with an average prescription dose of 16 Gy (7–30) at an average prescription isodose of 41% (40–50%) with an average of 34.2 Gy (17.5–75) dose at maximum. Tumor control rate in non-functioning tumor was 93% at 2 years of follow-up. Among acromegaly patients, there was 100% tumor control and 84% normalization at 2 years of follow-up. Among prolactin-secreting adenomas, tumor control was 100% while only 50% normalized. Gamma knife radiosurgery is effective and safe for treatment of primary, recurrent or residual functioning as well as non-functioning adenomas and for pituitary tumor. Acromegaly patients respond better than prolactin-secreting tumors. Good tumor growth and hormonal control can be achieved. The complication rate is low as compared to fractionated radiotherapy. Copyright © 2004 S. Karger AG, Basel

The management of pituitary adenomas saw unprecedented progress in the later half of the 20th century with development of techniques like magnetic resonance imaging (MRI), immunohistochemical stain, radioimmunoassay, newer medication and refinement of surgical techniques with microscopes and

endoscopy. Although there is still considerable lowering in risks of surgery, a recent study from the USA showed the risk of CSF fistula to be 3.9%, new visual damage 1.8%, pituitary insufficiency 19.4% and death 0.9% associated with transsphenoidal surgery [1]. Fractionated radiation therapy has been used for inoperable, residual and recurrent adenomas for a long time and has shown a tumor control rate of 76–97% [2–7], but has complications like hypopituitarism (12–100%) [3–9] and optic neuropathy (1–2%) [2, 3, 7, 9, 10]. Recent reports have shown the efficacy of radiosurgery with fewer chances of complications [11–14]. In the last 4 years we have treated 112 functioning and non-functioning pituitary adenomas. In this report, we have analyzed 86 of the above patients with whom we had more than 6 months of follow-up to assess the efficacy of gamma knife radiosurgery for tumor growth and endocrinopathy control for this study.

Material and Method From April 1998 to April 2002, 101 patients with primary, residual or recurrent functioning and non-functioning adenomas were treated with gamma knife of which 86 were followed for 6 months to 4 years. All patients were evaluated and selected by a board including a microneurosurgeon, neuroradiologist and gamma knife surgeon, and factors considered were age, presence or absence of endocrinopathy, medical therapy history, previous history of surgery, optic and other cranial nerve involvement, previous radiotherapy and risk of anesthesia. All patients were admitted 1 day before treatment and routine hematological investigations were done. Radiological or cardiac examination was done where relevant. Most of the patients were treated under local anesthesia while some needed short general anesthesia for frame fixation. All patients were planned using Gamma Plan®. The treatment dose was prescribed such as not to give more than 8 Gy to optic pathways. Previous irradiation, if administered, was considered and dose corrections made accordingly. All patients were discharged the next morning. Patients were followed every 6 months with contrast MRI, hormone profile and visual acuity and field examination. Of the 86 patients included in this study, 43 patients had a non-functioning adenoma (NFA), 29 had acromegaly (AC), and 11 had prolactin-secreting adenoma (PA). There were 2 patients both suffering from Cushing’s disease and 1 with mixed endocrinopathy who were excluded, as the sample was very small. The mean age was 48 years (range 13–80). There were 54 males and 32 females. Mean tumor volume for the whole sample was 5.3 cm3 (range 0.14–29.80). Among 43 NFA patients, 32 were male and 11 female with a mean age of 56 years (range 15–80). Twenty-two of them presented with a history of visual deficit, 8 with hypopituitarism, while 12 with just headache and 1 with seizures. Twenty-one patients had transsphenoidal or transcranial surgery and had prior radiotherapy. Mean tumor volume was 6.62 cm3 (range 1.8–29.80). All NFA tumors were treated with a mean prescription dose of 10 Gy (range 6–16) at a mean isodose of 44% (range 28–50%) and mean maximum dose of 24 Gy (14–35). Among 29 AC patients, 20 were male and 9 female with a mean age of 43 years (range 24–58). All of them presented with typical acromegaly endocrinopathy. Ten patients had

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transsphenoidal surgery. The growth hormone (GH) level ranged from 5.0 to 153.0 ng/ml. Mean tumor volume was 3 cm3 (range 0.27–4.7). All tumors were treated with a mean prescription dose of 17.95 Gy (range 9–25) at a mean isodose of 45.5% (range 40–50%) and mean maximum dose of 38.5 Gy (20–62.5). All patients were followed with serial GH level. IGF-1 levels were done only in very few patients before and after treatment and thus could not be standardized for follow-up. Among 11 PA patients, 3 were male and 8 female with a mean age of 36 years (range 13–67). Five females presented with amenorrhea-galactorrhea syndrome while among 3 male patients, 2 adults had sexual dysfunction and 1 adolescent patient had growth retardation. Seven patients had transsphenoidal or transcranial surgery. All patients had a prior bromocriptine trial and of these, 6 had escalating bromocriptine dosage with poor control and 5 had intolerance to the drug. Three patients continue to take bromocriptine even after gamma knife treatment. The serum prolactin levels ranged from 9.2 to 277.0 ng/ml. Mean tumor volume was 4.95 cm3 (range 0.36–11.7). All tumors were treated with a mean prescription dose of 16 Gy (range 7–30) at a mean isodose of 41% (range 40–50%) and mean maximum dose of 34.2 Gy (17.5–75).

Results

Tumor Control Among NFA patients, 74% showed reduction in volume (⬍50% of pretreatment volume) at 1 year follow-up, while by the end of 2 years, 93% were reduced in size. On analyzing these patients according to tumor volume, we found that tumors with ⬎6 cm3 volume showed 70% reduction in size as compared to 96% in those with ⬍6 cm3 volume at 2 years of follow-up. Among AC and PA tumors, all achieved tumor control by 2 years (100% reduced). Endocrinological Control Endocrinological control among 29 AC tumors at 6 months to 1 year of follow-up was as follows: 33.3% had normalized, 33.3% were reduced and 33.3% had either the same or increased GH level. At 1–2 years of follow-up, 71.4% had normalized, 14.3% were reduced and 14.3% remained the same or increased. Follow-up patients of more than 2 years had 84% normalized while 16% had a reduced GH level. Endocrinological control among 11 PA tumors at 1–2 years of follow-up revealed 50% were reduced and 50% remained the same or increased. More than 2 years of follow-up patients revealed that 54.6% had normalized, 36.3% were reduced and 9.1% had remained the same or had an increased serum prolactin level. Visual Field Changes All patients with pretreatment visual involvement were among NFA and all showed visual field improvement progressively comparable to reduction in

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a

b

c

d Fig. 1. Patient SSM, 70-year-old male, with ischemic heart disease with right bundle branch block presenting with visual deterioration, refused surgical decompression. Treated with 8 Gy at 40% isodose (9.2 cm3 volume). a–d Treatment plan and follow-up MRI after 12, 24 and 36 months.

size of tumor. One patient from the AC tumor group had deterioration in the visual field after 3 months of gamma knife treatment but improved to normal field by 6 months of follow-up. The optic nerve in this case received 7 Gy at 1% of its volume and the prescription dose was 9 Gy at 45% isodose (fig. 1, 2). Side Effects Two patients, 1 with AC tumor and 1 with NFA, who developed sixth nerve paresis between 3 and 6 months of the posttreatment period had

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Pre-gamma

a 12 months

b 24 months

c 36 months

d Fig. 2. a–d Same patient as in figure 1 showing pre-gamma knife and follow-up perimetry charts after 12, 24 and 36 months. Progressive improvement in visual field can be seen.

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received 20 and 24 Gy in the cavernous sinus. Both improved to normal function by the end of the first year after steroids. Two patients, 1 with AC tumor and 1 with PA tumor, developed hypopituitarism. They had received 50 and 45 Gy dose at maximum. Both were treated with replacement therapy and both normalized by the end of 2 years with discontinuation of replacement therapy. One patient in the nonfunctioning tumor group developed intratumoral bleeding after 2 years of progressive reduction in size. MRI scan showed a mild increase in size of the tumor. Bleeding increased after 2 days with visual deterioration. The patient was operated using the transsphenoidal approach.

Discussion

Tumor Growth Control Recent reports have claimed effective tumor growth control with gamma knife radiosurgery to be between 93 and 100% [4, 6, 14–16]. Tumor control and reduction in volume in our patients have been similar. Better tumor control seen in functioning tumors may be correlated to the high dose delivered to these tumors. In addition, larger tumors in the NFA group had a lower reduction rate due to the lesser dose given pertinent to the adjoining optic nerve. Fractionated radiation studies for pituitary tumors have shown a similar tumor control of 76–97% [3, 4, 6], but associated complications like hypopituitarism and optic nerve changes are not desirable. We have not seen any deterioration in vision in even large tumors (⬎6 cm3) in our group. A progressive improvement in visual field was observed where there was severe visual compromise. Endocrinological Effects In our patients, both AC and PA tumors showed marked improvement in hormone levels. However, changes were more dramatic in AC tumors. Previously published studies have also reported improvement in endocrinopathies after gamma knife radiosurgery in 77–96% of cases [2, 11, 17–20]. Zhang et al. [20] reported hormonal control of 96% in patients followed for more than 24 months after gamma knife given a marginal dose of 18–35 Gy. They also suggest that a dose of 30 Gy or more at the margin can control hyperglycemia more effectively but it is not significant for tumor control. Laws and Vance [17] report 18–25 Gy as a good dose for controlling endocrinopathy in acromegaly and a higher dose is better. The dose rate in our AC tumor group has been 9–25 Gy. All our patients followed for more than 2 years have normalization of GH and IGF-1 (where it could be followed). Even patients receiving only 9 Gy showed tumor reduction starting at 6 months and normalization of hormone levels within 1 year.

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Among PA tumors the response has been less compared to AC tumors. Landot and Lomax [13] separated patients into groups who continued to take bromocriptine and those who stopped medication before gamma knife. In patients without bromocriptine, all 5 patients had normalization while only 3 of 15 on bromocriptine could be normalized and reduce medication. They recommended discontinuing medication before gamma knife treatment. Martinez et al. [18] reported a reduction in hormone levels but no normalization. In our group, only 6 patients normalized while 4 others had reduced levels and 1 patient did not improve. There was no significant correlation with use of bromocriptine as the number was too small. Four of 7 patients without bromocriptine normalized while among the others, 2 showed marginal reduction from the pretreatment level. Hypopituitarism Hypopituitarism with gamma knife is reported to be between 0 and 19% [19, 21, 22] in most series. Fractionated radiotherapy causes hypopituitarism in 13–56% [23]. McCord et al. [15] reported hypopituitarism in 46–93 (49%) patients followed for a long duration after fractionated radiotherapy. In our series, only 2 (2.8%) patients developed hypopituitarism and needed replacement for a few months. Visual Complications Fractionated radiotherapy series [2, 4, 6, 7] report 12–100% visual complications while gamma knife series [7, 14, 15, 17, 22–24] reveal 0–4% visual complications, most of which are transient. Zhang et al. [20] report deterioration in vision in patients given ⬎12 Gy radiation to optic pathways. In our group, only 1 patient developed posttreatment deterioration in vision after 3 months and recovered fully after a course of steroids. The optic nerve received 7 Gy at 1% volume in this case. Two patients in our series developed sixth nerve paresis and diplopia where the cavernous sinus dose was 20 and 24 Gy respectively. Both improved after a course of steroids. Shin et al. [14] reported that only 1 of 16 patients developed transient sixth nerve paresis with cavernous sinus invasion. Chen et al. [25] reported that 1 of 72 patients developed sixth nerve paresis.

Conclusion

Gamma knife radiosurgery is effective and safe for treatment of both functioning and nonfunctioning primary, recurrent or residual pituitary adenomas.

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Acromegaly patients respond better than prolactin-secreting tumors. Good tumor growth and hormonal control can be achieved. The complication rate is low as compared to fractionated radiotherapy.

References 1

2 3

4 5 6

7 8

9 10 11 12

13

14 15 16 17 18 19 20

Ciric I, Ragin A, Baumgartner C, Pierce D: Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225–237. Flickinger JC, Nelson PB, Martinez AJ, Deutsch M, Taylor F: Radiotherapy for non-functional adenomas of pituitary gland. Cancer 1989;63:2409–2414. McCollough WM, Marcus RB Jr, Rhoton AL, Ballinger WE, Million RR: Long-term follow-up for radiation therapy for pituitary adenoma: The absence of late recurrence after ⬎4,500 Gy. Int J Radiat Oncol Biol Phys 1991;21:607–614. Rush C, Cooper PR: Symptom resolution, tumor control and side effects following postoperative radiotherapy for pituitary macroadenomas. Int J Radiat Oncol Biol Phys 1997;37:1031–1034. Salinger DJ, Brady LW, Miyamoto CT: Radiation therapy in the treatment of pituitary adenomas. Am J Clin Oncol 1992;15:467–473. Tsang RW, Brierley JD, Panzarella T, Gospodarowicz MK, Sutcliffe SB, Simpson WJ: Radiation therapy for pituitary adenoma: Treatment outcome and prognostic factors. Int J Radiat Oncol Biol Phys 1994;30:557–565. Zeirhut D, Flentje M, Adolph J, Erdmann J, Raue F, Wannenmacher M: External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33:307–314. Goffman TE, Dewan R, Arakaki R, Oldfield EH, Glatstein E: Persistent or recurrent acromegaly, long-term endocrinological efficacy and neurologic safety of postsurgical radiation therapy. Cancer 1992;69:271–275. Rush SC, Newall J: Pituitary adenomas: The efficacy of radiotherapy as sole treatment. Int J Radiat Oncol Biol Phys 1989;17:165–169. Fisher BJ, Gasper LE, Noone B: Radiation therapy for pituitary adenoma: Delayed sequelae. Radiology 1993;187:843–846. Ganz JC, Backlund EO, Thorsen FA: The effect of gamma knife surgery of pituitary adenomas on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 1993;61(suppl):30–37. Hayashi M, Izawa M, Hiyama H, Nakamura S, Atsuchi S, Sato H, Nakaya K, Sasaki K, Ochiai T, Kubo O, Hori T, Takakura K: Gamma knife radiosurgery for pituitary adenomas. Stereotact Funct Neurosurg 1999;72(suppl):111–118. Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G: Stereotactic radiosurgery for recurrent surgically treated acromegaly: Comparison with fractionated radiotherapy. J Neurosurg 1998;88:1002–1008. Shin M, Hiroki K, Tomio S, Tago M, Morita A, Ueki K, Kirino T: Stereotactic radiosurgery for pituitary adenoma invading cavernous sinus. J Neurosurg 2000;93(suppl 3):2–5. McCord MW, Buatti JM, Fennell EM: Radiotherapy for pituitary adenoma: Long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437–444. Park YG, Chang JW, Kim EY, Chung SS: Gamma knife radiosurgery in pituitary microadenoma. Yonsei Med 1996;37:165–173. Laws ER, Vance ML: Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin North Am 1999;2:157–166. Martinez R, Bravo G, Burzaco J, Rey G: Pituitary tumors and gamma knife surgery. Clinical experience with more than 2 years of follow-up. Stereotact Funct Neurosurg 1998;70(suppl 1):110–118. Salinger DJ, Brady LW, Miyamoto CT: Radiation therapy in the treatment of pituitary adenomas. Am J Clin Oncol 1992;15:467–473. Zhang N, Pan L, Wang EM, Zhong D, Wang BJ, Cai PW: Radiosurgery for growth hormone producing pituitary adenomas. J Neurosurg 2000;93(suppl 3):6–9.

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21

22

23

24 25

Mokry M, Ramschak-Schwarzer S, Simbrunner J, Ganz JC, Pendl G: A six-year experience with the postoperative radiosurgical management of pituitary adenomas. Sterotact Funct Neurosurg 1999;72(suppl 1):88–100. Vladyska V, Liscak R, Simonova G, Marek J, Jezkova J: Radiosurgical treatment of hypophyseal adenomas with gamma knife: Results in a group of 163 patients during 5-year period. Casopis Lekaru Ceskych Cas Lek Cesk 2000;139:757–766. Becker G, Kocher M, Kortmann RD, Paulsen F, Jeremic B, Muller RP, Bamberg M: Radiation therapy in the multimodal treatment approach of pituitary adenoma. Strahlenther Onkol 2002;178:173–186. Ove R, Kelman S, Amin PP, Chin LS: Preservation of visual fields after perisellar gamma knife radiosurgery. Int J Cancer 2000;90:343–350. Chen JC, Giannotta SL, Yu C, Petrovich Z, Levy ML, Apuzzo ML: Radiosurgical management of benign cavernous sinus tumors: Dose profiles and acute complications. Neurosurgery 2001;48:1022–1032.

Dr. Maheep Singh Gaur, MCh Head, Rancan Gamma Knife Centre Vidyasagar Institute of Mental Health and Neurosciences 1, Institutional Area, Nehru Nagar, New Delhi 110065 (India) Tel. ⫹91 9810072078, Fax ⫹91 11 26314379, E-Mail [email protected]

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Metabolic Course of Low-Grade Gliomas after Gamma Knife Radiosurgery Evaluated by PET Scan with Methionine Nicolas Massager a,b, Thanh Tang c, Serge Goldman c, David Wikler a,c, Salvador Ruiz Gonzalez a, Daniel Devriendt a,e, José Lorenzoni a, Philippe David d, Paul Van Houtte e, Jacques Brotchi a,b, Marc Levivier a,b a

Gamma Knife Center, Université Libre de Bruxelles; bDepartment of Neurosurgery, PET/Biomedical Cyclotron Unit, dDepartment of Neuroradiology, Hôpital Erasme, and eDepartment of Radiation Therapy and Laboratory of Physics, Institut J. Bordet, Brussels, Belgium

c

Abstract In order to characterize modification of the metabolism of low-grade gliomas (LGG) after gamma knife radiosurgery (GKR), we prospectively studied the uptake of [11C]methionine of 7 patients every 3–6 months after GKR treatment for a histologically confirmed, residual or recurrent LGG. We found that the methionine-related metabolism of LGG can increase or decrease significantly in the first months after a GKR procedure; these early PET changes age unrelated with histology and are not predictive of the efficacy of GKR. PET with [11C]methionine performed at ⱖ1 year after GKR seems to be more efficient than MR to assess tumor progression of LGG. Copyright © 2004 S. Karger AG, Basel

Low-grade gliomas (LGG) represent one of the most frequent brain neoplasms [14]. They are histologically separated into two different groups: WHO grade I, or pilocytic astrocytomas, and grade II gliomas. Most LGG are nonevolutive tumors: they are thought to be clinically benign and associated with long survival. They can often be cured by surgery alone; however, these tumors

Table 1. Patients (6 women, 1 man) treated by GKR for a LGG Massager/Tang/Goldman/Wikler/Gonzalez/Devriendt/ Lorenzoni/David/Van Houtte/Brotchi/Levivier

Margin Maximum Follow-up PET on Initial1 dose, Gy dose, Gy duration follow-up, PET-MET months n response to GKR

Delayed2 PET-MET course after GKR

1,300

13

26

36

9

Increase

Decrease

I

Cerebellum Resection 13,600

12

24

3

1

Increase

NA

Fibrillary astrocytoma

II

Brainstem

Resection

2,200

12

24

18

3

Increase

Decrease

4

48, M Fibrillary astrocytoma

II

Temporal

Resection

2,700

15

30

12

2

Decrease

NA

5

19, F

Pilocytic astrocytoma

I

Third ventricle

Resection

667

13

26

24

1

NA

Increase

6

56, F

Fibrillary astrocytoma

II

Frontal

Biopsy

1,900

15

30

24

3

Decrease

Increase

7

44, F

Oligodendrogli II oma

Frontal

Biopsy

4,100

12

24

36

5

Decrease

Increase

No Age sex

Histology

WHO Location grade

Previous surgery

Target volume cm3

1

18, F

Pilocytic astrocytoma

I

Brainstem

Resection

2

14, F

Pilocytic astrocytoma

3

13, F

NA ⫽ Data not available. 1Initial ⫽ within the first 12 months after GKR. 2Delayed ⫽ after 12 months post-GKR.

144

can be located in critical areas that make complete resection a difficult or even impossible challenge. Moreover, some LGG do not have such an indolent behavior and recur or progress despite surgery. For all those cases, radiosurgery may offer an interesting alternative therapeutic option [9, 14, 23]. The radiobiological effect of gamma knife radiosurgery (GKR) on cerebral tumors is not well known [6, 8, 12, 15, 16, 27]. In particular, the radiosurgical treatment of LGG produces metabolic modifications into the tumor that have never been studied in detail. The postoperative evolution of tumors treated by GKR is generally assessed only by serial MRI in order to evaluate progression of the tumor size after treatment, development of a tumoral cyst or a central necrosis, and radiation-induced peritumoral edema [7, 9, 20, 25]. The aim of the present study was to analyze the timing and extent of metabolic changes of LGG after GKR, using serial PET examinations with [11C]methionine (PET-MET) as radiotracer.

Materials and Methods Seven patients (6 women, 1 man) treated by GKR for a LGG were studied (table 1). Age varied from 13 to 56 years (median 19); 2 patients were under 18. All patients had undergone one or several previous surgeries (resection in 5 patients and stereotactic biopsy in 2 patients) in order that all tumors were histologically confirmed before GKR treatment. There were 3 pilocytic astrocytomas (WHO grade I), 3 grade II astrocytomas, and 1 grade II oligodendroglioma. The tumors were located in the frontal lobe (2 patients), temporal lobe (1 patient), third ventricle (1 patient), cerebellum (1 patient) and brainstem (2 patients). Current indications for GKR were histologically confirmed LGG of ⬍3 cm in mean diameter, residual or recurrent after surgery. Initially, all the patients were treated by GKR using combined information of MRI and PET-MET, according to an original procedure described elsewhere [17, 18]. We decided to prospectively follow those patients by serial PET-MET in order to evaluate the metabolic course of LGG after the radiosurgical treatment. Radiosurgical Procedure The stereotactic frame (Leksell G Frame®, Elekta, Stockholm, Sweden) was attached to the patient’s head under local anesthesia with mild sedation in a standard manner. After stereotactic MR and CT images were obtained, the patient was transferred to the PET/ Biomedical Cyclotron Unit connected to the Gamma Knife Center. During PET data acquisition, the stereotactic frame was secured with the Elekta CT bed adapter together with a customized head-holder. The patient was injected intravenously with a bolus of approximately 555 MBq (15 mCi) of [11C]methionine and maintained in a darkened room with no verbal stimulation. Images used for stereotactic calculation were acquired 20 min after injection of the radiotracer. The technical aspects of the integration of PET images in the Leksell GammaPlan software (LGP) have been described in detail elsewhere [17]. Briefly, stereotactic PET

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images are acquired with the Siemens/CTI ECAT 962 (HR⫹) two- and three-dimensional tomography (Knoxville, Tenn., USA) allowing the simultaneous acquisition of 63 planes with a slice thickness of 2.4 mm. Registration fiducials were obtained with a dedicated PET indicator box developed by Elekta. A custom software converting PET data file format to LGP file format is used to import PET data into LGP. The PET volume is then handled as a CT or MR volume in LGP. To visualize PET with a high-contrast pseudocolor lookup table (LUT), we replaced the gray scale LUT file with our own PET color LUT file during the radiosurgical planning. Once defined in LGP, the stereotactic PET images are correlated with the other stereotactic image modalities of the same patient and are used for determination of the target volume. The radiosurgical planning was performed using complementary information from PET and MR studies [18]. The final target volume was defined on the MR taking into account the MR characteristics and the PET-generated metabolic data. Multiple isocenters with collimators of different sizes were used to fit the prescription isodose to the target volume, and the patients were treated by LGK C. Follow-Up and Data Analysis Patients were discharged the day after the radiosurgical procedure. Serial follow-up studies including both PET-MET and MR imaging and clinical examination were performed every 3 months during the first year postoperatively and every 6 months thereafter. MR images were analyzed using standard MR imaging software. When the tumor was enhancing after gadolinium injection, the shape of the tumor was drawn on each slide in order to calculate the volume of the enhancing tumor, and apparition of a loss of contrast enhancement at the center of the lesion was noted. For lesions with no contrast enhancement, the size of the tumor was compared on different sequences (T1, T2, FLAIR) with the previous examination in order to provide information on the evolution of the tumor size. For semiquantitative analysis of PET-MET examinations, the regions of interests (ROI) were set up independently from MR data. PET-MET acquisition was realigned following the canthomeatal line. As normal reference tissue, we chose the temporal cortex at the same location for all the acquisitions, namely 30 slices from the bottom of the cerebellum. An elliptical ROI and its mirror image were placed in the temporal cortex. The mean activity within these ROIs was used for setting the threshold and to normalize the activity detected in the tumors. For the patient who presented a temporal lesion, only the normal temporal side was considered. In the region of the tumors, ROIs covering all voxels with count values above a threshold set at 130% of the mean activity in the temporal cortex were automatically generated. Then, volume and uptake of MET on each slice were recorded. To assess metabolic activity of the whole tumor, a metabolic activity volume index (AVI) was calculated as: ⌺ (tumor volume ⫻ tumor activity/temporal cortex activity).

Results

The median follow-up duration was 24 months (extremes 3–36 months). The number of PET imaging during the follow-up was 1 for 2 patients, 2 for

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Patient 1 Patient 2 Patient 3

800 700 600 500 400 300 200 100 0 0

a

Relative metabolic activity volume index (%)

Relative metabolic activity volume index (%)

900

6

12

18 Months

24

30

36

600

Patient 4 Patient 5 Patient 6 Patient 7

500 400 300 200 100 0 0

6

12

18 Months

24

36

b

Fig. 1. a Initial increase and delayed decrease of tumor metabolism after radiosurgery (3 patients). b Initial decrease and delayed increase of tumor metabolism after radiosurgery (4 patients).

1 patient, 3 for 2 patients, 5 for 1 patient and 9 for 1 patient. The mean number of PET imaging during follow-up was 3.4 (extremes 1–9 imaging). Evolution of the Metabolic Activity of LGG after GKR We identified two different patterns of metabolic modification of LGG after the treatment. For 3 patients (1 with 9 PET, 1 with 3 PET and 1 with 1 PET during follow-up) we found a significant increase of the metabolic activity of the tumor as the initial response to GKR (fig. 1a). This hypermetabolic reaction was maximal in the first 1–6 months after treatment, and decreased thereafter. Computer-assisted measurement of the methionine-related tumoral metabolism shows a maximum increase of 810, 234 and 201% for the 3 patients. For 2 patients with a longer follow-up with PET-MET (18 and 36 months), we observed a progressive reduction of this acute tumoral hypermetabolism, that continues to decrease below the preoperative metabolism of the tumor, until absence of any methionine-related metabolic activity on the area targeted by GKR (fig. 2). For 3 other patients (1 with 1 PET, 1 with 2 PET, 1 with 3 PET and 1 with 5 PET during follow-up), metabolic activity of the tumor reduces in the early stages after GKR (fig. 1b); for the last patient, PET-MET was not performed early after the GKR procedure. Three patients of this group had a follow-up longer than 12 months; all of these patients presented a delayed increase of tumor metabolism that fits with tumor progression both clinically and on MRI (fig. 3).

LGG after GKR Evaluated by PET Scan with Methionine

30

147

0

3

6

9

12

24

36

(Months after GK)

Fig. 2. Patient 1: pilocytic astrocytoma. Initial increase and delayed prolonged reduction of tumor metabolism on serial PET-MET after radiosurgery.

0

6

12

(Months after GK)

Fig. 3. Patient 6: grade II astrocytoma. Initial decrease and delayed recurrence of tumor metabolism on serial PET-MET after radiosurgery.

Correlation between PET-MET and MRI during Follow-Up Thorough analysis of the radiological tumor characteristics on MRI performed serially after GKR shows that MRI modifications appeared some months after the change in metabolic activity assessed by PET-MET. Either apparition of central tumoral necrosis or tumor proliferation on MRI has been preceded by metabolic modifications on PET-MET in the same way. An example of this statement is provided in figure 2, where significant reduction of the methionine metabolism into the tumor on the MRI performed 6 months after the GKR may be related to the apparition of central loss of gadolinium enhancement on MRI performed at 9 months post-GKR.

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Influence of Histology and GKR Dosimetry on the Metabolic Course of LGG after GKR We have not found any correlation between the metabolic course of the tumor after GKR and histology. For patients in the group with initial increase of PET-MET activity and delayed reduction of tumoral metabolism, we have 2 grade I pilocytic astrocytomas and 1 grade II fibrillary astrocytoma; in the second group, we have 1 grade I pilocytic astrocytoma, 2 grade II fibrillary astrocytomas and 1 grade II oligodendroglioma. The following parameters of GKR dosimetry have been correlated with PET-MET course after treatment: target volume, irradiated volume, percent of coverage, ratio, conformity index, margin dose, maximum dose, irradiation time. We have not found any correlation between these dosimetry parameters and the metabolic response of the tumor after GKR.

Discussion

In the present study we describe the PET-MET metabolic course of 7 patients with a LGG treated by GKR with PET guidance [17, 18] and we found that the tumoral metabolism can increase or decrease initially after the treatment, and that the initial metabolic response of the tumor after GKR seems to be inversely proportional to long-term evolution of the tumor metabolism. The metabolic pattern of LGG can easily be assessed in vivo using PET scan imaging [3, 22]. Until now, studies of the metabolism of low-grade tumors have mainly relied on the glycolytic pathway using fluorodeoxyglucose [3, 4] or on the amino acid uptake using methionine [3, 5]. PET can also be used for serial in vivo metabolic analysis of a tumor in a repeat manner during follow-up after some treatments addressed to the tumor [2, 3], as GKR. Some groups have reported the use of PET to help in the differential diagnosis between radiation necrosis and tumor recurrence after radiosurgical treatment [1, 6, 21]. Other groups have used PET to evaluate the response to GKR; however, those studies addressed to arteriovenous malformations [8] or malignant tumors [12, 27]. To the best of our knowledge, no previous study has reported results of the in vivo metabolic response of low-grade tumors to GKR. Initially, we developed an original technique to include PET-related metabolic information of cerebral tumors in the planning of GKR [17, 18]. Actually, most LGG show no gadolinium enhancement on MRI, which makes delineation of the tumor to be treated for GKR treatment a challenge on MRI sequences only. Information provided by PET-MET may optimize target selection of such ill-defined lesions. At the current time, we have treated more than 50 patients with this technique, including some patients with a LGG, although

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GKR in this indication remains a controversial issue. Moreover, we have decided to prospectively follow those patients with combination of serial PET and MRI, in order to determine the metabolic course of these tumors after GKR treatment and the potential benefit of a PET-MET follow-up on MRI for LGG treated by GKR. Thorough analysis of the metabolic course of our population suggests that two different evolutions on PET-MET may occur after GKR of LGG. Some patients present a hypermetabolic reaction in the first months after GKR; later on, this tumoral hypermetabolism decreases slowly, and can become hypometabolic in the long-term course assessed by PET-MET. Some other patients had an initial decrease of methionine activity after GKR, which do not sustain with time. In other words, the initial response to GKR seems to be inversely correlated to the long-term efficacy of GKR for LGG: an acute hypermetabolic reaction after GKR seems to predict long-term tumor control. These two opposing metabolic courses after GKR are not correlated with histology or any of the different parameters of dosimetry. PET-MET modifications after GKR have preceded MR changes for all patients of our study. In particular, tumor progression has always been assessed first on PET examination only, several months before it appeared on MRI of the next follow-up imaging. Few studies have evaluated the radiobiological effects of radiosurgery, especially for benign tumor [11, 16, 25]. Two different mechanisms have been proposed to explain tumor control after radiosurgery: a cytotoxic effect and/or a vascular effect [11, 15, 16, 19, 25]. Tsuzuki et al. [24] assessed that tumor shrinkage is mainly due to apoptosis and not to a vascular effect. However, their results are mainly found for malignant lymphoma and only partially for benign tumors, and their follow-up duration is too short to judge the full effect of GKR for those LGG. Some recent studies have shown that vascular response to focal irradiation may play an important role in the mechanism of tumor control after radiosurgery [13, 26]. Kondziolka et al. [15] postulated that the loss of contrast enhancement that appears inside the tumor several months after GKR is due to a delayed vascular effect. Other authors have postulated that apoptosis may play a significant role in the early effects of radiosurgery for benign tumors [25]. The mechanism and biological significance of an initial increased uptake of methionine in LGG are still not well understood [10]. It has been postulated that this increased uptake is due to activation of carrier-mediated transport at the blood-brain barrier, rather than increased diffusion [10]. The increase of amino acids transport could be due to beginning angiogenesis. Therefore, we think that the initial modifications in methionine uptake early after GKR found in the present study reinforces the theory that modifications of the vasculature of the neoplasm happens in the early stages after radiosurgery [13, 26]. The loss

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of contrast enhancement within the central area of the tumor occurring several months after GKR may be the consequence of this vascular effect. Therefore, a more routine integration of PET-MET metabolic images in the follow-up of patients with LGG undergoing GKR may help to better understand the radiobiological course of these tumors.

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13 14 15

Chao ST, Suh JH, Raja S, Lee SY, Barnett G: The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery. Int J Cancer (Radiat Oncol Invest) 2001;96:191–197. Coleman RE, Hoffman JM, Hanson MW: Clinical application of PET for the evaluation of brain tumors. J Nucl Med 1991;32:616–622. Derlon JM, Petit-Taboué M, Chapon F, Beaudouin V, Noël MH, Creveuil C, Courtheoux P, Houtteville JP: The in vivo metabolic pattern of low-grade brain gliomas: A positron emission tomographic study using 18F-fluorodeoxyglucose and 11C-L-methylmethionine. Neurosurgery 1997; 40:276–288. De Witte O, Levivier M, Violon P, Salmon I, Damhaut P, Wikler D, Hildebrand J, Brotchi J, Goldman S: Prognostic value of positron emission tomography with [18F]fluoro-2-deoxy-D-glucose in the low-grade glioma. Neurosurgery 1996;39:470–476. De Witte O, Goldberg I, Wikler D, Rorive S, Damhaut P, Monclus M, Salmon I, Brotchi J, Goldman S: Positron emission tomography with injection of methionine as a prognostic factor in glioma. J Neurosurg 2001;95:746–750. Ericson K, Kihlström L, Mogard J, Karlsson B, Lindquist C, Widen L, Collins VP, Stone-Elander S: Positron emission tomography using 18F-fluorodeoxyglucose in patients with stereotactically irradiated brain metastases. Stereotact Funct Neurosurg 1996;66(suppl 1):214–224. Friedman DP, Morales RE, Goldman HW: MR imaging findings after stereotactic radiosurgery using the gamma knife. AJR 2001;176:1589–1595. Guo WY, Pan DHC, Liu S, Chung WY, Shiau CY, Cheng SS, Chang CY, Chen KY, Yeh SH, Lee LS: Early irradiation effects observed on magnetic resonance imaging and angiography, and positron emission tomography for arteriovenous malformations treated by gamma knife radiosurgery. Stereotact Funct Neurosurg 1995;64(suppl 1):258–269. Hadjipanayis CG, Kondziolka D, Gardner P, Niranjan A, Dagam S, Flickinger JC, Lunsford LD: Stereotactic radiosurgery for pilocytic astrocytomas when multimodal therapy is necessary. J Neurosurg 2002;97:56–64. Herholz K, Hölzer T, Bauer B, Schröder R, Voges J, Ermestus RI, Mendoza G, Weber-Luxenburger G, Löttgen J, Thiel A, Wienhard K, Heiss WD: 11C-methionine PET for differential diagnosis of lowgrade gliomas. Neurology 1998;50:1316–1322. Hirato M, Hirato J, Zama A, Inoue H, Ohye C, Shibazaki T, Andou Y: Radiobiological effects of gamma knife radiosurgery on brain tumors studied in autopsy and surgical specimens. Stereotact Funct Neurosurg 1996;66(suppl 1):4–16. Inoue HK, Hayashi S, Ishihara J, Horikoshi S, Zama A, Hirato M, Shibazaki T, Andou Y, Ohye C: Fractionated gamma knife radiosurgery for malignant gliomas: Neurobiological effects and FDGPET studies. Stereotact Funct Neurosurg 1995;64(suppl 1):249–257. Kamiryo T, Lopes MBS, Kassell NF, Steiner L, Lee KS: Radiosurgery-induced microvascular alterations precede necrosis of the brain neutropil. Neurosurgery 2001;49:409–415. Kida Y, Kobayashi T, Mori Y: Gamma knife radiosurgery for low-grade astrocytomas: Results of long-term follow-up. J Neurosurg 2000;93(suppl 3):42–46. Kondziolka D, Lunsford LD, Maitz A, Flickinger JC: Radiobiologic considerations in gamma knife radiosurgery; in Lunsford LD, Kondziolka D, Flickinger JC (eds): Gamma Knife Brain Surgery. Progr Neurol Surg. Basel, Karger, 1998, vol 14, pp 21–38.

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Kondziolka D, Lunsford LD, Flickinger JC: The radiobiology of radiosurgery. Neurosurg Clin North Am 1999;10:157–166. Levivier M, Wikler D, Goldman S, David P, Metens T, Massager N, Gerosa M, Devriendt D, Desmedt F, Simon S, Van Houtte P, Brotchi J: Integration of the metabolic data of positron emission tomography in the dosimetry planning of radiosurgery with the Leksell gamma knife: Early experience with brain tumors. J Neurosurg 2000;93(suppl 3):233–238. Levivier M, Wikler D, Goldman S, Massager N, Szeifert GT, David P, Devriendt D, Desmedt F, Simon S, Van Houtte P, Brotchi J: Positron emission tomography-guided radiosurgery: Early experience with the integration of metabolic data in the dosimetry planning with the Leksell gamma knife; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 123–133. Linksey 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. Lunsford LD, Kondziolka D, Maitz A, Flickinger JC: Black holes, white dwarfs and supernovas: Imaging after radiosurgery. Stereotact Funct Neurosurg 1998;70(suppl 1):2–10. Mogard J, Kihlström L, Ericson K, Karlsson B, Guo WY, Stone-Elander S: Recurrent tumor vs. radiation effects after gamma knife radiosurgery of intracerebral metastases: Diagnosis with PETFDG. J Comput Assist Tomogr 1994;18:177–181. Roelcke U, Radu EW, Hausmass O: Tracer transport and metabolism in a patient with juvenile pilocytic astrocytoma. A PET study. J Neurooncol 1998;36:279–283. Somaza SC, Kondziolka D, Lunsford LD, Flickinger JC, Bissonette DJ, Albright AL: Early outcomes after stereotactic radiosurgery for growing pilocytic astrocytomas in children. Pediatr Neurosurg 1996;25:109–115. Tsuzuki T, Tsunoda S, Sakaki T, Konishi N, Hiasa Y, Nakamura M, Yoshino E: Tumor cell proliferation and apoptosis associated with the gamma knife effect. Stereotact Funct Neurosurg 1996; 66(suppl 1):39–48. Uematsu Y, Fujita K, Tanaka Y, Shimizu M, Cobayashi S, Itakura T, Kubo K: Gamma knife radiosurgery for neuroepithelial tumors: Radiological and histological changes. Neuropathology 2001; 21:298–306. Yang T, Wu SL, Liang JC, Rao ZR, Ju G: Time-dependant changes after gamma knife radiosurgery in the rat forebrain. Neurosurgery 2000;47:407–416. Yoshino E, Ohmori Y, Imahori Y, Higuchi T, Furuya S, Naruse S, Mori T, Suzuki K, Yamaki T, Ueda S, Tsuzuki T, Takai S: Irradiation effects observed on the metabolism of metastatic brain tumors: Analysis by positron emission tomography and 1H-magnetic resonance spectroscopy. Stereotact Funct Neurosurg 1996;66(suppl 1):240–259.

Nicolas Massager, MD Gamma Knife Center, University Hospital Erasme Route de Lennik 808, BE–1070 Brussels (Belgium) Tel. ⫹32 2 555 31 74, Fax ⫹32 2 555 31 76, E-Mail [email protected]

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Radiosurgery for Cavernous Malformations: Results of Long-Term Follow-Up Yoshihisa Kida, Toshinori Hasegawa Department of Neurosurgery, Komaki City Hospital, Aichi, Japan

Abstract The long-term results of radiosurgery for cavernous malformations (CMs) are reported. 152 cases (mean age 37.2 years) of symptomatic CMs have been treated with a gamma knife. The majority of them were located in eloquent areas like the brainstem or basal ganglia, followed by lobar and cerebellar lesions. With the mean maximum and marginal dose of 26.4 and 14.9 Gy respectively, 30% showed a shrinkage and the others were unchanged in the mean follow-up of 55.4 months. The hemorrhage rate after radiosurgery considerably decreased to 3.2%/year/case, which is almost one-tenth of that 5 years before gamma knife treatment (31.8%). In fact, the hemorrhage rate was 8% in the first year, then apparently and subsequently decreased to less than 5% and finally reached 0% in the seventh year. Complications were chiefly related to radiation-induced edema in 11.2%. Because of the significantly decreased rate of hemorrhage and acceptable rate of complications, radiosurgery for CM is apparently useful. Copyright © 2004 S. Karger AG, Basel

With modern technology it is not difficult to detect the lesions of cavernous malformations (CMs) and very often they are found incidentally with MRI. Although the natural history is not always clear, it is well known that these lesions are essentially silent and rarely cause intracranial hemorrhage or convulsive seizure. However, it is also well known that these incidents may recur repetitively and rather frequently [1–3]. Therefore, it is important to develop effective treatment methods for such symptomatic lesions to prevent such incidents [4]. Because of a great success in the treatment of AVM, radiosurgery has been applied to CMs by several investigators [5–8]. Because of insufficient data

Table 1. Characteristics of the cases with CMs – all are symptomatic, presenting with hemorrhage, seizure or neurological deficits Sex

Male Female

86 66

Age, years

Range Mean

9–71 37.2

Onset

Hemorrhage Seizure Neurological deficits

121 (79.6%) 23 (15.1%) 5 (3.3%)

70 60 50 40 30 20 10 0 Cerebellum

BG

Brainstem

Lobar

Fig. 1. Locations of CMs treated with gamma knife. BG ⫽ Basal ganglia.

and relatively frequent complications, radiosurgery of CMs has always been controversial. We have studied the long-term results of radiosurgery for CMs and discussed the role of radiosurgery in comparison with other treatment modalities like operative resection. Materials and Methods Current indications for radiosurgery of CMs are as follows: (1) symptomatic lesions with single or repeated hemorrhage or frequent seizures; (2) lesions located in deep and eloquent areas like the brainstem or basal ganglia, where surgery is very difficult and often harmful; (3) those cases with high risks like elderly patients, and (4) lesions are desirable ⬍30 mm in mean diameter. Following radiological studies with MRI and cerebral angiography if required, radiosurgery is scheduled for symptomatic CMs. At least 1 month is required after the final hemorrhage with gamma knife treatment.

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Table 2. Radiosurgery of CMs (152 cases treated at Komaki City Hospital)

Radiosurgery

Range

Mean

Lesion size, mm Maximum dose, Gy Marginal dose, Gy

5–32.8 13.5–44 10–25.2

15.2 26.4 14.9

Since the installation of a gamma knife in 1991, we have treated 152 cases of CM using this method and have a sufficient follow-up period of more than 24 months. There were 86 males and 66 females, with ages ranging from 9 to 71 (mean 37.2) years. All of the cases are symptomatic ones, presenting hemorrhage (121), seizure [23] and neurological deficits [5] (table 1). The locations of CMs are most popular in the brainstem, followed by the cerebral hemisphere, basal ganglia and cerebellum (fig. 1). After radiosurgery, follow-up studies are performed every 3 months in the first year, every 6 months thereafter and every 12 months after 5 years. Neurological changes with radiological findings are studied and recorded. Mean lesion sizes are compared with the ones at radiosurgery and recorded in terms of CR (complete remission), PR (partial remission), MR (minor response), NC (no change) and PG (progression).

Results

Radiosurgical Dose. Lesion size, maximum dose and marginal dose at radiosurgery are demonstrated in table 2. The mean lesion size is 15.2 mm and treated with gamma knife with mean maximum and marginal doses of 26.4 and 14.9 Gy respectively. Our strategy is to give ⬎15 Gy for cerebral and cerebellar lesions, but ⬍13 Gy for brainstem and basal ganglia lesions in order to prevent complications. Radiological Response. With a mean follow-up of 55.4 (12–120) months, radiological response and control rates are shown in figure 2. There is no significant difference in response in each location. In fact, 30% of lesions demonstrated a shrinkage, but the other 70% showed no obvious change in size. More than 95% of them showed the lesional control (fig. 3). Hemorrhage Rate. The overall hemorrhage rate 5 years before radiosurgery was 31.8%. In contrast, it decreased to 3.2% during the whole follow-up period after radiosurgery. The hemorrhage rate each year after radiosurgery was 8% in the first year, and less than 5% from the second year and reached 0% in the seventh year (fig. 4). The hemorrhage rate after radiosurgery in relation to the frequency of previous hemorrhage is demonstrated in table 3. After one and two hemorrhages, the hemorrhage rate after radiosurgery was 3.6 and 4.6%/year respectively. However, when bleeding occurred more than three times before radiosurgery, it apparently decreased to 1.0%/year of the hemorrhage rate after radiosurgery.

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70 60 50 40 30 20 10 0 CR

PR

MR

NC

PG

Response

2

Control

100 80 60 40 20 0 BG

BS

Cerebellum

Cerebral

3

35 30 25 20 15 10 5 Y h 7t

Y 6t h

Y 5t h

Y 4t h

Y d 3r

Y d 2n

1s tY

Be

fo r

e

0

4

Fig. 2. Radiological responses following radiosurgery (mean follow-up: 55.4 months). Response rate: 29.6%; control rate: 95.4%. CR ⫽ Complete remission, PR ⫽ partial remission, MR ⫽ minor response, NC ⫽ no change, PG ⫽ progression. Fig. 3. Radiological responses related to each location (mean follow-up: 55 months). There is no big difference in response or control. BG ⫽ Basal ganglia, BS ⫽ brainstem. Fig. 4. Actuarial rate of hemorrhage following radiosurgery (RS). Hemorrhage rate before and after radiosurgery are 31.8 and 3.2%/year/case respectively.

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Table 3. Hemorrhage rate after radiosurgery (RS) in relation to hemorrhagic incidents before Hemorrhage before RS

n

Mean follow-up months

Bleeding after RS

Rate (%/year/ case)

Once Twice More than 3 times

65 37 21

61 50 55

12 7 1

3.6 4.6 1.0

8 7 6 5 4 3 2 1 0 CR

PR

MR

NC

unknown

Fig. 5. Outcome of seizures following radiosurgery. Seizures are controlled well among more than half of the cases (n ⫽ 23, mean age 31.3 years). For abbreviations, see figure 2.

Outcome of Seizures. There are 23 cases of CM presenting with intractable seizures. All of them are supratentorial in location. After radiosurgery, seizures disappeared in 4, considerably decreased in 8, moderately decreased in 2 and were unchanged in 7 (fig. 5). It generally took a relatively longer time for the cessation of seizure and the results were not consistent. Complications. As described before, rebleeding after radiosurgery occurred in 21 cases (13.3%). Radiation-induced edema did not infrequently occur (11.2%). In the mean follow-up of 55.4 months, death occurred in 5, of which 3 were by progression of CM, and the others were by unrelated causes. New lesions were confirmed in 3 (2%) during the whole follow-up period (table 4).

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Table 4. Overall complications after radiosurgery of CMs Complication

n

%

Rebleeding Edema Death

21 17 5

New lesion

3

13.3 11.2 3.2 (progression of AOVM (2); brain tumor (1); sudden death (1); lung abscess (1)) 2.0

Discussion

Natural History. It is clear that the majority of CMs are silent in clinical behavior. In fact, Curling et al. [9] reported that the annual risk of hemorrhage from CMs is quite low, indicating less than 0.25%/year/patient. Likewise, Robinson et al. [10] and Zabramski et al. [11] reported a similar incidence of hemorrhage. However, it is totally different once the hemorrhage occurs and the subsequent risk of hemorrhage or seizure is extremely high. Recently, Kondziolka et al. [12] reported that the overall hemorrhage risk from CM is 2.6%/year and 0.6% without prior hemorrhage. However, the risk jumped up to 4.5% after a single hemorrhage and surprisingly 32% after two or more hemorrhages. This number is extremely higher in incidence when compared with the cases associated with one, two or more frequent hemorrhages. Results of Radiosurgery. The results of radiosurgery for the treatment of CMs have been reported by several investigators, in which several authors demonstrated a remarkable response [5–8] and a few showed unsatisfactory results [13]. In our series it is apparent that the hemorrhage rate is considerably decreased, even though subsequent hemorrhage occurred in a few cases. The hemorrhage risk in the first year after radiosurgery is not sufficiently low, but it decreased tremendously following the third year and was almost none after 7 years. Similar results were reported by Kondziolka et al. [8] in which the incidence of hemorrhage during first 2 years and the subsequent 10 years are 12.3 and 0.76% respectively. In our series some of the cases presented very intractable seizures, especially when the lesions were in the temporal lobe. Radiosurgery has certainly worked for the seizure control, but the effects were not always consistent. Also it has taken a long time for the control of seizures following radiosurgery. Therefore, radical resection of CMs seems to be adequate in the supratentorial lesions with intractable seizures since early seizure control can be reportedly achieved [14, 15].

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Complications. In the early cases there were many complications after radiosurgery of CM, mostly related to radiation-induced edema. The incidence of radiation injury has been reported as 26% by Kondziolka et al. [7], 26.5% by Amin-Hanjani et al. [5] and 10.5% by Chang et al. [6]. Although symptoms and signs were relatively mild, complications may be troublesome when the radiation injury occurs in the vital structures like the brainstem. After decreasing the marginal dose below 13 Gy for brainstem CMs and 15 Gy for cerebral CMs, the complication rate is greatly decreased in our experience. This is much better than the results reported by several investigators and by us in the past. Surgery for Brainstem Lesions. Recently, surgical resection of CM in the brainstem has been reported by a couple of investigators [16, 17] in which excellent resection of the lesion and the favorable outcome have been documented [18]. Wang et al. [19] reported the operative results of 137 brainstem CMs, in which there were no operative mortalities with 72% improved or stable and 28% deteriorated cases. A selection bias for operation is apparent since only exophytic or shallow brainstem lesions have been indicated for the operative procedure. Moreover, it is very important that the surgical procedure of the brainstem should be performed by only truly skillful surgeons because unskillful surgery might cause a devastating sequela for the patients.

Conclusion

Because of the decreased incidence of hemorrhage, radiosurgery of CM is justified for the treatment of symptomatic CMs in the brainstem and basal ganglia. Those lesions in the cerebral hemisphere, which are apparently resectable, should be treated by operation.

References 1

2

3

4 5

Awad IA, Robinson JR: Cavernous malformations and epilepsy; in Awad IA, Barrow DL (eds): Cavernous malformations. Park Ridge/Ill, American Association of Neurological Surgeons, 1991, pp 49–63. Duffau H, Sichez CJP, Faillot T, Bitar A, Arthuis F, Effenterre RV, 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. 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. Maraire JN, Awad IA: Intracranial cavernous malformations: Lesion behavior and management strategies. Neurosurgery 1995;37:591–605. 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.

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Chang SD, Levy RP, Adler JR, Martin DP, Krakovitz PR, Steinberg GK: Stereotactic radiosurgery of angiographically occult vascular malformations: 14-year experience. Neurosurgery 1998;43: 213–221. 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. Kondziolka D, Lunsford D, Flickinger JC, Kestle JRW: Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995;83:825–831. Curling OD, Kelly DL, Elster AD, et al: An analysis of the natural history of cavernous angioma. J Neurosurg 1991;75:702–708. Robinson JR, Awad IA, Little JR: Natural history of the cavernous angioma. J Neurosurg 1991; 75:709–714. 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. Kondziolka D, Lunsford LD, Kestle JRW: The natural history of cerebral cavernous malformations. J Neurosurg 1995;83:820–824. Weil S, Tew JM, Steiner L: Comparison of radiosurgery and microsurgery for treatment of cavernous malformations of the brain stem. J Neurosurg 1990;72:336, abstr 1990. 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. Cohen DS, Zubay GP, Goodman RR: Seizure outcome after lesionectomy for cavernous malformations. J Neurosurg 1995;83:237–242. Amin-Hanjani, Ogilvy CS, Ojemann RG, Crowell RM: Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 1998;42:1220–1228. Cantore G, Missori P, Santoro A: Cavernous angiomas of the brainstem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol 1999;52:84–94. 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. 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.

Yoshihisa Kida, MD Department of Neurosurgery, Komaki City Hospital 1-20, Jhobusi, Komaki City, Aichi 485 (Japan) Tel. ⫹81 568 764131, Fax ⫹81 568 764145, E-Mail [email protected]

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Functional Disorders Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 161–170

Role of Pituitary Radiosurgery for Management of Intractable Pain and Potential for Future Work Motohiro Hayashi a,b, Takaomi Taira a, Mikhail Chernov a, Masahiro Izawa a, Roman Lis¤ c¤ákc, Chung Ping Yu d, Robert T.K. Ho d, Mihoko Tomitae, Yoko Katayama e, Nobuo Kouyama e, Yoriko Kawakami e, Tomokatsu Hori a, Kintomo Takakura a,b a

Department of Neurosurgery, Neurological Institute, and bGraduate School of Medicine, Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan; cDepartment of Stereotactic and Radiation Neurosurgery, Hospital Na Homolce, Prague, Czech Republic; dGamma Knife Centre, Canossa Hospital, Hong Kong, SAR, and eDepartment of Physiology, Tokyo Women’s Medical University, Tokyo, Japan

Abstract Rationale: Up until two or three decades ago, cancer pain had been treated with surgical/chemical hypophysectomy, and there was a report that central pain (thalamic pain syndrome) had also been tried to be controlled with chemical hypophysectomy. The clinical results showed that hypophysectomy provided most of the patients relief from severe pain. However, severe accompanying adverse effects (panhypopituitarism, diabetes insipidus, and visual dysfunction) were found in almost all patients. This historical evidence prompted us to perform gamma knife surgery (GKS) for control of this kind of severe intractable pain with a high irradiation dose to the pituitary stalk/gland as an alternative hypophysectomy. This method has provided the majority of patients relief from severe pain, and surprisingly without any of the above-mentioned complications. Material and Methods: We have been carrying out a prospective collaborative study in Prague, Hong Kong, and our institute (Tokyo) for this treatment to evaluate the efficacy and safety of this method. Indications for this treatment are: (1) no other effective treatment prior to GKS; (2) general condition is considered good (KPS ⬎ 40%); (3) morphine is effective for pain control (for cancer pain), and (4) no previous treatment with radiation (GKS/conventional radiotherapy) for brain metastasis. In our institutional experience, in Tokyo, we have treated 10 patients who suffered from severe cancer pain due to bone metastasis with GKS, and 15 patients who suffered from post-stroke thalamic pain syndrome. The target was just the border in between the pituitary stalk and gland.

Maximum dose was 160 Gy for cancer pain and 140 Gy for central pain. We could follow up all patients (⬎1 month) with cancer pain and 8 patients (⬎6 months) with thalamic pain syndrome. Results: All patients (10/10) with cancer pain experienced significant pain reduction, and 87.5% (7/8) of the cases with thalamic pain syndrome initially experienced significant pain reduction. Some of patients felt reduced pain within several hours. Pain reduction was apparent within 7 days (median 2 days). No recurrence was observed in the patients with cancer pain; on the other hand, real recurrence was seen in 71.4% (5/7) of the cases with thalamic pain syndrome over 6 months of follow-up. No other complication has been observed in any of the cases up to now. Conclusions: Our clinical study protocol is not mandatory and still insufficient. In particular, much more investigation for clinical results of GKS in patients with thalamic pain syndrome is needed to optimize this treatment protocol. However, efficacy and safety have been shown in all of our cases. We believe that this treatment has a potential to control severe pain well, and that GKS plays a very important role in the field of intractable pain management. Copyright © 2004 S. Karger AG, Basel

Gamma knife surgery (GKS) has been widely used in the treatment for brain diseases, not only tumors and vascular anomalies, but also functional disorders such as epilepsy, movement disorder, and intractable pain. Cancer pain is represented by severe intractable pain which has been difficult to cure. This severe intractable pain has been tried to be controlled with various protocols such as focal irradiation, functional surgery, and medication (morphine, etc.), but no sufficient pain control has been observed. Up until two or three decades ago, cancer pain had been tried to be controlled with hypophysectomy. In 1953, Luft and Olivecrona [13] reported the first experience of control of cancer pain with surgical hypophysectomy for the patients with breast cancer. Certainly, they only wanted to suppress the activity of hormonal cancer with hypophysectomy. Otherwise a surprising clinical result, they had experienced complete pain relief. Surgical hypophysectomy had been extensively used worldwide as radiofrequency coagulation [18], direct ablation with transsphenoidal approach [7], and radioactive implantation [2]. Subsequently, chemical hypophysectomy which was direct pituitary ablation using alcohol injection had been developed as an alternative and lesser invasive treatment [3, 8, 11, 14]. The overall clinical results of surgical/chemical hypophysectomy had achieved in 64.4% a complete pain relief in 1,101 reported cases [2, 3, 7–9, 11, 14, 18]. However, significant adverse effects had appeared in the majority after hypophysectomy; panhypopituitarism had been observed in all of the cases. Severe diabetes insipidus had also been observed in half of the cases. Eye movement disorder, visual field defect, hypothalamic insult, and meningitis had also been observed in some. These complications were much more important for

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such end-stage patients. However, the efficacy of hypophysectomy had been shown to have a potential to control cancer pain, although the action mechanism had not yet been elucidated. Historically, intractable pain was also been tried to be treated with GKS. In 1968, Leksell [9] treated 2 patients with cancer pain by GKS, whose target was the thalamic nucleus, as centrum medianum thalamotomy, with 200–250 Gy at maximum dose. Steiner et al. [15] and Young et al. [16, 17] also treated intractable pain in a similar way. Young et al. reported that good clinical response (more than 50% pain reduction) was observed in 65% of the patients [16]. On the other hand, Buckland et al. [1] tried to treat cancer pain using GKS, targeted to the pituitary gland with 200–250 Gy. This report was the first series of pituitary ablation by GKS to show this efficacy. Subsequently, we have reported that pituitary radiosurgery with highresolution MRI/CT could control this kind of intractable pain well, whose target was the pituitary stalk/gland with 150–200 (median 160) Gy at maximum dose as an alternative treatment to surgical/chemical hypophysectomy [4–6, 11, 12]. Our experience was still limited. However, all of the patients with cancer pain experienced significant pain relief with or without medication, and surprisingly, no significant complication was observed within 1–24 months of follow-up [4–6, 11, 12]. The action mechanism of this method has remained unclear. However, gamma knife pituitary radiosurgery (GKPR) has a big potential to control cancer pain completely with preservation of the underlying function. Lately we have also treated patients with thalamic pain syndrome with a similar strategy as a future indication. Consequently, we should establish an optimal protocol to provide efficacy and safety for these patients.

Material and Methods Patient eligibility was performed according to the indications listed in table 1 [5]. The most important indication was that morphine was provided to the patients to significantly reduce pain severity, because GKPR is supposed to trigger a morphine-like effect as a similar intrinsic action mechanism of hypophysectomy. At the time of preoperative evaluation we had to check all patients for normal visual and endocrinological functions. The Leksell frame was applied to the head parallel to the optic pathway. We performed MRI (T1WI axial 1.0-mm slices/T2WI coronal 2.0-mm slices/3D heavily T2WI axial 0.5-mm slices) and CT (plain axial 1.0-mm slices/bone 1.0-mm slices). We used Gamma Plan (Elekta Instrument AB, Stockholm, Sweden) to make dose planning for this treatment. A center of the isocenter should be located on the border between the pituitary stalk and the pituitary gland. The 50% isodose area (8-mm collimator) should involve both the lower part of the pituitary stalk and more than half of the pituitary gland. We used 160 Gy at maximum dose for the cases with cancer pain. On the other hand, we used 140 Gy

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Fig. 1. Dose planning using 3D image (50% isodose): this figure shows the target which was 50% isodose area (80 Gy) and the anatomical relationship between the target and the optic pathway, carotid artery, pituitary gland, stalk and brainstem.

Table 1. Indication of GKS targeted to the pituitary gland/stalk 1 Pain should be related to bone metastasis for cancer pain, and should be central pain (thalamic pain syndrome: pain, numbness) 2 General condition was kept in good health (KPS ⬎ 40%) 3 Insufficient effect in spite of previous treatment 4 Pain should be controlled well using morphine 5 No treatment history of GKS and radiation therapy to the intracranial tumors

for the cases with thalamic pain syndrome. Subsequently, we should take into account for the delivered irradiation dose to the optic pathway to be kept to ⬍8 Gy at maximum dose. If the length of the pituitary stalk is too short, we will have to move the isocenter lower in order to reduce the excessive irradiation dose to the optic pathway. We find it better to modify the gamma angle from 90⬚ to 75–85⬚ to make the 8-Gy isodose line parallel to the optic pathway. Also, the beam plugging technique should be used to modify the shape of 8-Gy line to reduce the delivered dose to the optic pathway, without modification of the 50% isodose line. Finally, we have to check the three-dimensional images to confirm the relationship between the target (50% isodose line) and the surrounding vital structures (fig. 1) and to determine the relationship between the 8-Gy line and the optic pathway (fig. 2). In our experience, we treated 10 patients with cancer pain related to bone metastasis and 15 patients with post-stroke thalamic pain syndrome. We could follow up 10 patients with cancer pain for 1–6 months, and 8 patients with thalamic pain syndrome for over 6 months.

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Fig. 2. Dose planning using 3D image (5% isodose): this figure shows the 5% isodose area (8 Gy) to determine the anatomical relationship between the area and the optic pathway. An excessive irradiated dose to the optic pathway has to be avoided.

Results

Clinical Data and Dose/Energy Calculation in Patients with Cancer Pain We have treated 10 patients (5 men, 5 women, average age 58.4 years) with cancer pain related to bone metastasis, and all patients could be followed up for more than 1 month. The origin of cancer was as follows: 4 hormonal cancers (prostate cancer 2, breast cancer 2), 6 non-hormonal cancers (colon cancer 2, lung cancer 1, esophageal cancer 2, unknown 1). Preoperatively the average prescription dose of morphine was ⬎84.5 mg/day. Average Karnofsky performance scale (KPS) at preoperative evaluation was 55.8. Dose/energy calculation was checked in every patient, mean length of the pituitary stalk was 10.3 mm, mean maximum and average dose of the pituitary stalk were 160.0 and 55.3 Gy. Mean unit energy (delivered energy to the target/target volume) of the pituitary stalk was 55.5 mJ/cm3. Mean maximum and average dose of the pituitary gland were 161.2 and 119.5 Gy. Mean unit energy of the pituitary gland was 119.5 mJ/cm3. Clinical Data and Dose/Energy Calculation in Patients with Thalamic Pain Syndrome Of the 15 patients we treated with thalamic pain syndrome, 8 (5 men, 3 women, average age 63.5 years) could be followed up for more than 6 months. All patients suffered from cerebral vascular disease; 6 thalamic hemorrhage

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and 2 thalamic infarction. The mean duration between onset and treatment was 84.0 months. Dose/energy calculation was checked in every patient, mean length of the pituitary stalk was 9.3 mm, mean maximum and average dose of the pituitary stalk were 137.6 and 47.1 Gy. Mean unit energy of the pituitary stalk was 31.0 mJ/cm3. Mean maximum and average dose of the pituitary gland were 140.7 and 106.5 Gy. Mean unit energy of the pituitary gland was 106.7 mJ/cm3. Clinical Results of Patients with Cancer Pain after GKPR Significant pain reduction was observed in all cases within several days after GKPR. Complete pain relief with/without morphine was observed in 80% (8/10), and significant pain reduction was observed in 20% (2/10). The efficacy lasted for their remaining lifetime (1–6 months) without recurrence of the pain related to bone metastasis. There was no significant difference of the effect between hormonal cancer and non-hormonal cancer. No secondary effect of hormonal insufficiency, such as panhypopituitarism and diabetes insipidus, was observed within this limited period. No patient developed visual dysfunction, such as visual acuity loss or visual field defect, and no morphological change on MRI was demonstrated (fig. 3). Clinical Results of Patients with Thalamic Pain Syndrome after GKPR Almost cases have both symptoms of severe pain and numbness at the time of preoperative evaluation. Initially, pain reduction was observed in 87.5% (7/8) within several days after GKPR. One patient experienced complete recurrence of pain immediately (within 2 weeks). In another 6 cases with pain reduction after GKPR, the efficacy could be continued within 6 months. However, complete recurrence of severe pain was observed in 71.4% (5/7) over 6 months later. A long-term effect could only be seen in 2 patients (over 1 year). Severe numbness has never improved since GKPR. One patient felt worsening after GKPR, because the severity of numbness got worse in spite of significant pain reduction. No secondary effect of hormonal insufficiency was observed, and no patient developed visual dysfunction. No morphological change on MRI was demonstrated.

Discussion

Hypophysectomy and b-Endorphin The action mechanism that hypophysectomy caused in complete pain relief has not yet been elucidated. The majority of patients with cancer pain has been treated with morphine and has experienced pain reduction. Therefore, one of

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a

b

d

e

c

Fig. 3. Postoperative changes of MRI findings: these MRI (sagittal T2WI), which were obtained at pre-GKPR (a), 4 days (b), 1 week (c), 1 month (d), and 2 months (e) later, showed no morphological change at the pituitary gland/stalk.

the action mechanisms suggests that hypophysectomy might have triggered an intrinsic morphine-like effect. ␤-Endorphin, whose precursor (preproopiomelanocortin – PPOMC) was localized in the pituitary gland and arcuate nucleus in the hypothalamus, is well known to control this kind of severe pain like morphine. Several studies have reported that the level of ␤-endorphin increased after hypophysectomy in both blood and cerebrospinal fluid. Hypophysectomy, ablation of the pituitary gland and stalk, was supposed to trigger and release an excessive quantity of PPOMC into the blood and cerebrospinal fluid. ␤-Endorphin should be one of the contributions in this action mechanism. What Is the Action Mechanism of GKPR for Cancer Pain? Lately, pituitary gland/stalk irradiation with gamma knife has been applied as a new alternative treatment option for control of cancer pain. GKPR provided surprisingly positive and satisfactory clinical results, i.e. immediate, complete and long-lasting clinical effects in the control of cancer pain without any significant secondary side effects, although we did use an extremely high

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irradiation average dose and unit energy as 119.5 Gy and 119.5 mJ/cm3, comparing with those of tumor/vascular anomaly radiosurgery (20–30 mJ/cm3). We could summarize the effect of GKPR according to our clinical experience as follows: (1) there was no evidence of destructive changes, no dysfunction of endocrinological status and no morphological change of MRI findings [4–6, 11], and (2) clinical symptoms showed hyperfunction of the hypothalamus after GKPR, rapid recovery of appetite loss and general well-being [4–6]. GKPR has provided the same pain reduction as hypophysectomy, however no severe secondary effect was ever seen in the GKPR cases [6]. Therefore, we strongly presume that the action mechanism due to GKPR might have provided something of a ‘stimulating effect’ to the hypothalamus-thalamus instead of the expected ‘destructive effect’ to the pituitary gland/stalk like pituitary ablation. That should be a ‘new neuromodulating effect’ to the central nervous system by radiosurgery [5, 6]. We have just started to investigate MR spectroscopy in the area of hypothalamus and thalamus to try to show the ‘new neuromodulating effect’ as hyperfunction of the hypothalamus-thalamus, especially the level of NAA/Cr ratio, which is related to the activity of neuron cells. Rationale and Future Work of GKPR for Thalamic Pain Syndrome In 1983, Levin et al. [10] already reported their experience of treatment for 3 patients who suffered from thalamic pain syndrome using chemical hypophysectomy. All of them experienced significant pain reduction within 48 h, and finally 2 of them presented complete pain relief and another presented a significant reduction (⬎80%) of pain. All cases had an accompanying temporary secondary effect, panhypopituitarism and diabetes insipidus. The effect lasted from 19 to 58 months. This histological evidence prompted us to develop one idea that thalamic pain syndrome could also be controlled with GKPR like cancer pain treatment. In 2002, we developed a new treatment protocol for thalamic pain syndrome according to our experience with cancer pain [6]. We defined the maximum dose as 140 Gy which was lower than used for cancer pain, because we had to take into account the risk of a secondary effect for those patients who were expected to live longer. According to the clinical results, almost all cases (87.5%) experienced initial pain reduction, however the majority (71.4%) presented real recurrence of pain within 6 months. No secondary effect was observed. Even if GKPR provides a temporary effect, this biological phenomenon prompts us to develop a new treatment indication. The only remaining problem is the duration of the effect. Lately we suppose the maximum dose should be increased from 140 to 160 Gy which is equal to the treatment protocol for cancer pain with GKPR. Much more experience and a longer duration of follow-up are necessary to evaluate the overall efficacy and

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safety. However, GKPR has been shown to provide significant pain reduction in the majority of patients without any secondary effect. We strongly believe GKPR has a possibility to control this kind of medically refractory severe pain in the near future.

Conclusions

In our institutional experience we have treated 25 consecutive patients with intractable pain (10 patients with cancer pain related to bone metastasis and 15 patients with thalamic pain syndrome). Both subgroups had a good indication of the treatment with GKS targeted to the pituitary gland/stalk (GKPR), and were treated safely. The majority have experienced significant pain reduction. Thus far, our experience is still limited. Moreover, some modification is needed, especially for patients with thalamic pain syndrome. However, efficacy and safety were shown in 25 patients. We believe that this treatment has the potential to manage and control severe intractable pain, and that GKPR will play a much more important role in the field of pain control in the future. Before the final evaluation, we need to gain more experience and produce an optimal protocol to evaluate which parameters are the most important, to determine which treatment strategy is the best, to crucially prove the efficacy and safety, and to develop this treatment.

References 1 2 3 4

5 6 7 8 9 10 11

Backlund EO, Rahn T, Sarby B, et al: Closed stereotaxic hypophysectomy by means of 60CO gamma radiation. Acta Radiol Ther Phys Biol 1972;11:545–555. Forrest AP, Blair DW, Brown DA: Radioactive implantation of the pituitary. Br J Surg 1959;47: 61–70. Greco T, Sbaragli S, Cammili L: L’alcoolizatione della ipofisi per via transdenoidale nalla terapia di particoleri tumori malgni. Settimana Med 1957;45:355–356. Hayashi M, Nakaya K, Ochiai T, et al: Gamma knife radiosurgery for cancer pain – New trial method for gamma knife radiosurgical pituitary stalk ablation (in Japanese). Stereotact Radiother 2000;4:1–12. Hayashi M, Taira T, Chernov M, et al: Gamma knife surgery for cancer pain – Pituitary gland/stalk ablation: A multicenter prospective protocol since 2002. J Neurosurg 2002;97(suppl 5):433–437. Hayashi M: Current strategy of gamma knife surgery for intractable pain (in Japanese). Pain Clinic 2003;24:213–231. Hardy J: Transsphenoidal hypophysectomy. J Neurosurg 1971;34:582–594. Katz J, Levin AB: Treatment of diffuse metastatic cancer pain by instillation of alcohol into the sella turcica. Anesthesiology 1977;46:115–121. Leksell L: Cerebral radiosurgery. I. Gamma thalamotomy in two cases of intractable pain. Acta Chir Scand 1968;134:585–595. Levin AB, Ramirez LF, Katz J: The use of stereotaxic chemical hypophysectomy in the treatment of thalamic pain syndrome. J Neurosurg 1983;59:1002–1006. Lipton S, Miles J, Williams N, et al: Pituitary injection of alcohol for widespread cancer pain. Pain 1978;5:73–82.

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Liscak R, Vladyka V: Radiosurgical hypophysectomy in painful bone metastasis from breast cancer. Cas Lék Ces 1998;137:154–157. Luft R, Olivecrona H: Experiences with hypophysectomy. J Neurosurg 1953;10:301–316. Morrica G: Chemical hypophysectomy for cancer pain; in Bonica JJ (ed): Advances in Neurology. 4. Pain. New York, Raven Press, 1974, pp 707–714. Steiner L, Forster D, Leksell L, et al: Gamma thalamotomy in intractable pain. Acta Neurochir (Wien) 1980;52:173–184. Young RF, Jaques DS, Rand RW, et al: Medial thalamotomy with the Leksell gamma knife for treatment of chronic pain. Acta Neurochir Suppl (Wien) 1994;62:105–110. Young RF, Jaques DS, Rand RW, et al: Technique of stereotactic medial thalamotomy with the Leksell gamma knife for treatment of chronic pain. Neurol Res 1995;17:59–65. Zervas N: Stereotaxic radiofrequency surgery of the normal and abnormal pituitary gland. Semin Med Beth Israel Hosp 1969;280:429–437.

Motohiro Hayashi Department of Neurosurgery, Neurological Institute Tokyo Women’s Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo 162-8666 (Japan) Tel. ⫹81 3 3353 8111, Fax ⫹81 3 5269 7438, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 171–180

Treatment of Trigeminal Neuralgia Using Linear Accelerator-Based Radiosurgery Kristin A. Bradleya, Wolfgang A. Toméa, Daniel K. Resnickb, Minesh P. Mehtaa,b Departments of aHuman Oncology and bNeurosurgery, University of Wisconsin, Madison, Wisc., USA

Abstract The successful use of Linac-based radiosurgery for patients with medication refractory trigeminal neuralgia is reported. Since August 2000, 16 patients with medication refractory, idiopathic trigeminal neuralgia have been treated with Linac-based radiosurgery. All patients had at least a 9/10 pain level and at least one neurosurgical intervention had been utilized in 7 patients; 5 patients had more than one intervention. All patients were treated with a single fraction of 80 Gy at a dose rate of 600 MU/min to the trigeminal nerve root. To aid in the visualization and targeting of the trigeminal nerve, a 3D Fast Imaging Employing STeadyState Acquisition (3D-FIESTA) technique can be employed. A 4-mm collimator and a 7-arc technique designed to minimize the dose to the brainstem was used. For treatment delivery, a stereotactic floor stand (Zmed IsoStandTM, Ashland, Mass., USA) was employed. This system has an isocenter stability of 0.15 ⫾ 0.1 mm. Response to treatment was assessed 1, 3 and 6 months after treatment. 10/16 patients achieved either a complete response or a major response within 1 month of treatment, and 2 patients who initially had a minor response experienced a complete or major response by 6 months post-radiosurgery. Thus, 12/16 patients achieved a complete/major response within 6 months of treatment, and 4/16 patients experienced a minor response or no response by the last follow-up visit. 3/16 patients experienced relapse of their trigeminal neuralgia pain at 6, 6.5 and 16 months, respectively. The actuarial 6-month complete/major response rate for patients with primary trigeminal neuralgia was 77.5%, with an actuarial 6-month relapse rate of 21.3%. One patient, who had undergone five prior neurosurgical interventions, developed neuropathic keratopathy at 7 months, and another patient developed increasing facial paresthesia following radiosurgery. No other complications were seen. This preliminary report suggests that, analogous to gamma knife radiosurgery, Linac-based radiosurgery is also a safe and effective management for idiopathic, medication refractory trigeminal neuralgia. Copyright © 2004 S. Karger AG, Basel

Trigeminal neuralgia, which affects approximately 4.3 per 100,000 people per year, is a rare disorder causing facial pain, most commonly in people older than 50 [1]. In some patients, idiopathic trigeminal neuralgia is believed to be due to compression of the trigeminal nerve root by an anomalous blood vessel at its junction with the pons [4]. The initial treatment for trigeminal neuralgia is pharmacologic, with agents such as carbamazepine, baclofen, gabapentin and oxcarbazepine. If medical therapy is unsuccessful or produces intolerable side effects, neurosurgical intervention is often the next approach. Neurosurgical options include microvascular decompression, radiofrequency thermal rhizotomy, glycerol rhizotomy, nerve sectioning, balloon compression, ethanol injection, etc. [2, 5, 11, 17]. Lars Leksell [9] first reported the use of stereotactic radiosurgery to treat trigeminal neuralgia in 1971. Since then, gamma knife radiosurgery has increasingly been used for trigeminal neuralgia, in particular for patients that have persistent or recurrent pain after pharmacologic therapy and traditional neurosurgical interventions [3, 7, 8, 12, 16]. We present the initial experience at the University of Wisconsin using linear accelerator-based radiosurgery and 3D Fast Imaging Employing STeady-State Acquisition (3D-FIESTA) technique to better visualize the trigeminal nerve for treating trigeminal neuralgia.

Material and Methods Patient Population Between August 2000 and December 2002, 16 patients with idiopathic trigeminal neuralgia were treated using linear accelerator-based radiosurgery at the University of Wisconsin. The patient characteristics are listed in table 1. Of the 16 patients, 12 were women and 4 were men. The mean age at radiosurgery was 67 years (range 44–87). All patients had medication refractory trigeminal neuralgia with at least a 9/10 pain level. Seven patients (44%) had undergone at least one prior neurosurgical intervention and 5 of the patients (31%) had undergone two or more neurosurgical interventions. Prior neurosurgical inventions included microvascular decompression, glycerol or radiofrequency rhizotomy, balloon compression and ethanol injection. Radiosurgical Technique All patients were treated uniformly using a Varian Clinac 600 CD linear accelerator (Varian Medical Systems, Inc., Palo Alto, Calif., USA) equipped with a stereotactic floor stand (Zmed IsoStand™, Ashland, Mass., USA). Our linear accelerator radiosurgery system has an isocenter stability of 0.15 ⫾ 0.1 mm for any couch and gantry angle, which is comparable to that of a gamma knife. Prior to the radiosurgical procedure, all patients undergo a thin-slice, volumetric 3D-SPGR gadolinium-enhanced MRI for target delineation, and more recently, a 3D-FIESTA-MRI series has been added to aid in the localization of the trigeminal nerve (fig. 1). On the day of the procedure, a BRW head ring is placed on the patient’s head and a thin-slice, contrast-enhanced treatment planning CT is performed. Using the

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Table 1. Patient characteristics Characteristics

Age, years Mean Range Gender Female Male Patients with one or more prior neurosurgical interventions Patients with more than one prior neurosurgical intervention

Patients (n ⫽ 16)

67 44–87 12 4 7 (44%) 5 (31%)

Fig. 1. Visualization of right trigeminal nerve using FIESTA imaging sequence.

PinnacleTM Treatment Planning System (Philips Medical Systems, Andover, Mass., USA), the T1-MRI and more recently the 3D-FIESTA-MRI is auto-fused with the CT dataset using in-house fusion software, and is independently validated by three investigators (M.M., D.R., W.T.) using multiplanar images and ‘checkerboard’ displays. After fusion validation, the treating neurosurgeon and radiation oncologist jointly contour the trigeminal nerve root target 2–3 mm from its junction with the pons on the fused MRI image sets. A single 4-mm collimator and a multi-arc technique was used in all cases, with the isocenter placement and

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a

b Fig. 2. a Typical 7 arc arrangement for the treatment of right-sided trigeminal neuralgia. b Resulting isodose distribution from this arc arrangement, showing elliptical shape in the superior-inferior axis. The 70-Gy isodose line is shown in dark gray and the 40-Gy isodose line, which represents 50% of the maximum dose, is shown in light gray.

arc pattern chosen to maximize coverage of the targeted trigeminal nerve while minimizing dose to the brainstem (cf. fig. 2a). The mean number of arcs was seven, with individual arc length averaging 90⬚. Each arc was treated 3, 4 or 5 times for a total of 21–36 arcs and 1,890–3,060⬚ of beam delivery per patient. All patients received 80 Gy central dose, resulting in 40 Gy to the 50% isodose surface. The brainstem, a conformal avoidance structure, was constrained to a dose of ⬍20 Gy. A typical isodose distribution resulting from this arc arrangement is shown in figure 2b. As can be seen from figure 2a and b, the resulting dose distribution is elongated in the superior-inferior axis and tilted away from the superior part of the conformal avoidance structure brainstem. In any radiosurgery procedure, the largest positional uncertainty is in the superior-inferior axis because of the finite slice thickness of the imaging modalities. Therefore, an elongated dose distribution in the superior-inferior axis is preferable over

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Table 2. Radiosurgery response categories Category

Description

Complete response

Pain-free, minimal if any use of medications Almost completely pain-free, pain score ⱕ3/10 Pain score ⬎3/10 and ⱕ7/10 Any pain ⬎7/10

Major response Minor response No response

circular dose distributions since it allows one to take this positional uncertainty of the trigeminal nerve explicitly into account. The actual treatment was delivered in less than 55 min for all patients using our floor stand based linear accelerator radiosurgery system. Response Assessment Response to treatment was assessed at 1-, 3-, 6- and 12-month follow-up visits using a questionnaire that included the following: a self-reported 0–10 pain scale; descriptive reporting of pain severity, intensity and frequency; a list of medications with any changes noted, and documentation of any possible side effects of treatment. Each patient’s response to treatment was then categorized as: (a) complete response: pain-free, minimal if any use of medications; (b) major response: almost completely pain-free, pain score ⱕ3/10; (c) minor response: pain score ⬎3/10 and ⱕ7/10; or (d) no response: any pain ⬎7/10 (table 2). Statistical Analysis The actuarial complete/major response rate and actuarial relapse rate were calculated using the Kaplan-Meier product limit method [6]. Time to response or time to relapse for each subject was determined according to the available follow-up information.

Results

Response to Treatment As described above, patients were assessed as having a complete, major, minor or no response to treatment based on a self-reported 0–10 pain scale as well as the individual patient’s description of the severity, intensity and frequency of pain. With a median follow-up of 7.3 months (range 1–24), the 6-month actuarial complete or major response rate was 77.5% (fig. 3). All but 2 of the patients obtaining a complete or major response did so within 1 month of the radiosurgical procedure; these 2 patients obtained a minor response by 1 month and achieved a complete or major response by 3 months. Relapse of Pain Three of the 16 patients had relapsed at 6, 6.5 and 16 months. One of these patients had 5 prior neurosurgical interventions and for the other 2 relapsed

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90

Percent response

80 70 60 50 40 30 20 10 0 0

2

4

6

Months

Fig. 3. Actuarial complete/major response rate vs. time for the idiopathic trigeminal neuralgia patients.

patients, radiosurgery was their first non-pharmacologic treatment. The actuarial 6-month relapse rate was 21.3%. Complications of Radiosurgery Two of 16 patients (12.5%) experienced a complication after radiosurgery. One patient experienced increased facial paresthesia after radiosurgery, and 1 patient developed neuropathic keratopathy 7 months post-radiosurgery. The patient who developed the keratopathy had undergone multiple [5] neurosurgical interventions prior to receiving radiosurgery. No other complications were seen following radiosurgery.

Discussion

Gamma Knife Experience Recently, radiosurgery has been used increasingly for the treatment of medication-refractory trigeminal neuralgia. To date, the experiences reported in the literature have almost exclusively been with gamma knife radiosurgery. Early gamma knife experience, reported by Lars Leksell in 1971, reported success in 2 patients who underwent stereotactically guided irradiation of the trigeminal ganglion [9]. After Leksell’s initial experience, Lindquist et al. [10] and Rand et al. [15] reported that 13/22 and 7/12 patients, respectively, had complete or partial pain relief following radiosurgery that targeted the gasserian ganglion. Following these early gamma knife experiences for trigeminal neuralgia, Kondziolka et al. [8] reported on a prospective, multi-institutional trial that

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treated 50 patients to a maximum dose ranging between 60 and 90 Gy. With a median follow-up of 18 months, 56% of the patients had an excellent response (pain-free) following radiosurgery, 32% had a good response (50–90% relief) and 12% had a poor response (0–50% relief). This trial determined that a maximum dose of ⱖ70 Gy was associated with a significantly greater chance of complete pain relief compared to doses of ⬍70 Gy. The success of this multi-institutional trial has led to the expanded use of radiosurgery for trigeminal neuralgia. The largest reported single-institution experience is from the University of Pittsburgh. In 2001, they reported on 220 patients with idiopathic trigeminal neuralgia, the majority of whom received maximal radiosurgical doses of 70, 75 or 80 Gy [12]. Of the 220 patients, 63.6, 59.2, 56.6 and 37.7% achieved and maintained an excellent or good outcome at 1, 2, 3 and 5 years following radiosurgery. The median time to achieving greater than 50% pain relief was 2 months. Although many of the patients (61.4%) had undergone prior neurosurgical procedures, few complications were seen after treatment with radiosurgery. These results provided further evidence that radiosurgery is a safe and effective treatment strategy for trigeminal neuralgia. Two other institutions recently have published their results using gamma knife radiosurgery for trigeminal neuralgia [14, 16]. The Mayo Clinic reported on 117 patients with idiopathic trigeminal neuralgia who were treated to 70 Gy (23%), 80 Gy (12%) or 90 Gy (44%). With a median follow-up of 26 months and a median time to complete pain relief of 3 weeks, the rate of achieving and maintaining an excellent outcome was 57% at 1 year after radiosurgery [14]. Like the Pittsburgh cohort, the majority (58%) of the patients had undergone prior neurosurgical intervention. At the Barrow Neurological Institute, 35 or 40 Gy, prescribed to the 50% isodose curve, was used to treat 54 patients [16]. Fifty-two of 54 (96%) patients reported improvement in their pain: 35% of patients were pain-free; 6% experienced occasional pain not requiring medication; 48% had pain adequately controlled with the medication; 7% had inadequate pain improvement even with medications, and 4% reported no improvement in their pain following radiosurgery. In both the Mayo and Barrow Institute experiences, new facial numbness after radiosurgery was associated with pain relief. Linear Accelerator Radiosurgery Experience at the University of Wisconsin In our initial experience managing trigeminal neuralgia with linear accelerator-based radiosurgery, with a median follow-up of 7.3 months, we report an actuarial 6-month complete/major (self-reported pain of 0–3/10) response rate of 77.5% in patients with idiopathic trigeminal neuralgia.

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Our results are comparable to the gamma knife results discussed in the preceding section [8, 12, 14, 16]. Similar to the gamma knife experiences, the majority of patients achieve pain relief within the first month following radiosurgery. A small minority of patients, 2/16 in our series, experienced minor relief by 1 month but then achieved a complete or major response by 3 months post-radiosurgery. However, our radiosurgical technique differs from the standard gamma knife technique discussed in the literature [12, 14, 16] in two ways. First, we employ an elliptically elongated dose distribution in the superior-inferior axis. This strategy allows us to account for the positional uncertainty of the trigeminal nerve in the superior-inferior axis that is due to the finite slice thickness of the imaging modalities used for treatment planning. In addition, we recently have added a 3D-FIESTA-MRI series to aid in the localization of the trigeminal nerve. 3D-FIESTA-MRI provides elegant visualization of the trigeminal nerve and hence an enhanced level of confidence in targeting the nerve. Similar to the gamma knife experience, we complete all treatments in less than 1 h. Our 6-month relapse rate of 21.3% is in the range described by institutions performing gamma knife radiosurgery for trigeminal neuralgia [8, 12, 14, 16]. In addition, like the gamma knife experience, we have seen a low complication rate following radiosurgery for trigeminal neuralgia. One patient had increasing facial paresthesia and 1 patient, who had undergone five surgical procedures prior to receiving radiosurgery, developed neuropathic keratopathy. Corneal dryness, analgesia and keratitis after radiosurgery for trigeminal neuralgia have been reported previously by other investigators [13, 14]. Matsuda et al. [13] noted a relationship between the volume of brainstem irradiated and the development of ophthalmic complications. One shortcoming of our experience is that we have a relatively short median follow-up of 7.3 months. Because most patients achieve maximal response within 3 months of radiosurgery, the short follow-up should not impact the 6-month complete/major response rate. The durability and maintenance of our response rates however, will need to be reassessed when longer follow-up is available.

Conclusions

With this report, we present the first successfully published data indicating the effectiveness of linear accelerator-based radiosurgery for idiopathic trigeminal neuralgia that is refractory to pharmacologic therapy. Similar to reports from institutions using gamma knife radiosurgery, we have found that complete or major

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relief from idiopathic trigeminal neuralgia can be expected in approximately three-quarters of patients. In our experience, most patients experience pain relief within 1 month of treatment, although maximal relief may not be obtained until a few months following radiosurgery. Technologic advances such as 3D-FIESTA imaging and careful attention to radiotherapy details, including use of an elliptical dose distribution in the superior-inferior axis and a treatment delivery time of less than 55 min for all patients, have resulted in preliminary results comparable to those achieved by others using gamma knife radiosurgery. Our data need additional time to mature before we can ensure equivalent durability of pain relief.

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5 6 7

8 9 10 11 12 13 14 15

Bowsher D: Trigeminal neuralgia: An anatomically oriented overview. Clin Anat 1997;10: 409–415. Fraioli B, Esposito V, Guidetti B, Cruccu G, Manfredi M: Treatment of trigeminal neuralgia by thermocoagulation, glycerolization and percutaneous compression of the gasserian ganglion and/or retrogasserian rootlets: Long-term results and therapeutic protocol. Neurosurgery 1989; 24:239–245. Flickinger JC, Pollock BE, Kondziolka D, Phuong LK, Foote RL, Stafford SL, Lunsford LD: Does increased nerve length within the treatment volume improve trigeminal neuralgia radiosurgery? A prospective double-blind, randomized study. Int J Radiat Oncol Biol Phys 2001;51: 449–454. Hamlyn PJ: Neurovascular relationships in the posterior cranial fossa, with special reference to trigeminal neuralgia. 1. Review of the literature and development of a new method of vascular injection-filling in cadaveric controls. Clin Anat 1997;10:371–379. Jho HD, Lunsford LD: Percutaneous retrogasserian glycerol rhizotomy. Current technique and results. Neurosurg Clin North Am 1997;8:63–74. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. Kondziolka D, Lunsford LD, Flickinger JC, Young RF, Vermeulen S, Duma CM, Jacques DB, Rand RW, Regis J, Peragut JC, Manera L, Epstein MH, Lindquist C: Stereotactic radiosurgery for trigeminal neuralgia: A multi-institutional study using the gamma unit. J Neurosurg 1996; 84:940–945. Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain 2002;18:42–47. Leksell L: Stereotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand 1971;137:311–314. Lindquist C, Kihlström L, Hellstrand E: Functional neurosurgery – A future for the gamma knife? Stereotact Funct Neurosurg 1991;57:72–81. Lovely TJ, Jannetta PJ: Microvascular decompression for trigeminal neuralgia. Surgical technique and long-term results. Neurosurg Clin North Am 1997;8:11–29. Maesawa S, Salame C, Flickinger JC, Pirris S, Kondziolka D, Lunsford LD: Clinical outcomes after stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2001;94:14–20. Matsuda S, Serizawa T, Sato M, Ono J: Gamma knife radiosurgery for trigeminal neuralgia: The dry-eye complication. J Neurosurg 2002;97(suppl):525–528. Pollock BE, Phuong LK, Gorman DA, Foote RL, Stafford SL: Stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2002;97:347–353. Rand RW, Jacques DB, Melbye RW, Copcutt BG, Levenick MN, Fisher MR: Leksell gamma knife treatment of tic douloureux. Stereotact Funct Neurosurg 1993;61:93–102.

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Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL: Gamma knife radiosurgery for trigeminal neuralgia: The initial experience of The Barrow Neurological Institute. Int J Radiat Oncol Biol Phys 2000;47:1013–1019. Scrivani SJ, Keith DA, Mathews ES, Kaban LB: Percutaneous stereotactic differential radiofrequency thermal rhizotomy for the treatment of trigeminal neuralgia. J Oral Maxillofac Surg 1999;57:104–111.

Minesh P. Mehta, MD Department of Human Oncology, University of Wisconsin 600 Highland Ave, K4/310–3684, Madison, WI 53792 (USA) Tel. ⫹1 608 2635009, Fax ⫹1 608 2626256, E-Mail [email protected]

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Temporal Pattern of Pain Relief Using CyberKnife Radiosurgery for Trigeminal Neuralgia: A Preliminary Report Pantaleo Romanellia, Steve Changa, Iris C. Gibbsb, Gary Heita, John R. Adlera Departments of aNeurosurgery and bRadiation Oncology, Stanford University Medical Center, Stanford, Calif., USA

Abstract Radiosurgery is a non-invasive alternative to treat medically refractory trigeminal neuralgia (TN) in selected patients. Several reports have described outcomes after gamma knife radiosurgery (GKR) for TN. We have recently treated a small cohort of patients with TN using a Linac-based frameless radiosurgical device, the CyberKnife (Accuray Inc., Sunnyvale, Calif., USA). Stereotactic irradiation is delivered by a compact 6-MV x-ray Linac moved and pointed by a precise and highly maneuverable robotic arm. Real-time image guidance using amorphous silicone detectors outlines the contour of the patient’s skull and provides accurate localization without requiring a rigid stereotactic frame. Preliminary results in 13 patients were encouraging; 7 patients (53.8%) developed pain relief within a week, and overall, 8 patients (61.5%) experienced a long-lasting satisfactory outcome. Reduced constraints on treatment planning due to the absence of a stereotactic ring, improved targeting accuracy produced by computed tomographic cisternography, and conformal dosimetry may explain the early onset of analgesia in a large subset of treated patients. These results should be considered preliminary, however, and need to be confirmed by a prospective study on a larger patient sample. Copyright © 2004 S. Karger AG, Basel

Radiosurgery is an effective minimally-invasive therapeutic option for trigeminal neuralgia (TN), and is commonly offered to patients who are considered poor surgical candidates due to age or concomitant medical problems, or to patients who have failed to respond to other procedures. A low incidence

of side effects (mostly related to reduced facial sensory function) accompanies pain relief comparable to that offered by more invasive treatments. The safety and efficacy of gamma knife radiosurgery (GKR) for TN has been reported several times [1–7]. The median time to achieve more than 50% pain relief was about 2 months in one of the largest series published [1]. For this reason, acutely ill patients are rarely treated with GKR when immediate pain relief can be achieved with invasive treatments such as microvascular decompression, radiofrequency rhizotomy, and balloon compression. The CyberKnife, a frameless stereotactic radiosurgery system with an imageguided Linac mounted on a highly maneuverable robotic arm, can deliver conformal irradiation without the rigid frame required for GKR. The CyberKnife has been used in the Department of Neurosurgery at Stanford University to treat patients with medically refractory TN. Here we report on the outcomes of CyberKnife radiosurgery in a group of patients with medically refractory TN, several of whom showed pain relief within hours of surgery. Some of these patients were included in a recent brief report; new patients have been added, longer follow-ups are available, and extensive treatment planning details are provided in this expanded report.

Methods Patient Population CyberKnife radiosurgery was offered to patients with idiopathic TN that was unresponsive to conventional medications, patients that failed or refused surgery or were not suitable candidates for surgery due to age or medical contraindications. Thirteen patients (mean age 66.3 years, range 42–93 years) received CyberKnife radiosurgery for the treatment of medically refractory TN between August 2002 and July 2003. Patient data were entered in a HIPAA-compliant prospective database, and regular clinical follow-ups at approximately 3 and 6 months were scheduled and integrated with telephone interviews. Pain outcome was classified prospectively as satisfactory (complete or almost complete pain relief, with or without meds), fair (more than 50% reduction of pain), poor (less than 50% reduction or no response). Imaging Modality: CT Cisternography To obtain an accurate distortion-free localization of the trigeminal nerve, computed tomographic (CT) cisternography was performed in all patients. CT cisternography has been shown to produce excellent visualization of the structures contained in the posterior fossa, especially the cranial nerves [8]. After the injection of 5.0 cm3 of Omnipaque-300 into the thecal sac by lumbar puncture, the patient was kept in the Trendelenburg position for about 30 min to facilitate the diffusion of the contrast in the basal cisterns. A thin-section CT scan (175 slices, thickness of 1.25 mm) was made through the entire head, showing the anatomy of the basal cisterns and outlining the trigeminal nerve from its origin in the brainstem to its entry into Meckel’s cave (fig. 1).

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Fig. 1. CT cisternography (slice thickness 1.25 mm). The trigeminal nerve (arrow) can be followed bilaterally for its entire cisternal extension from the root entry zone to Meckel’s cave.

Treatment Planning The CT images were networked to the CyberKnife work station where the trigeminal nerve was outlined. The most proximal point of the nerve identified for the purposes of treatment planning was 3 mm away from the brainstem. The length of the nerve outlined was usually around 7 mm. An inverse planning procedure was then performed, optimizing the set of beam directions and delivering homogenous dose distributions that closely conformed to the trigeminal nerve (fig. 2). Image-Guided Radiosurgery A compact 6-MV x-ray LINAC is accurately positioned by a robotic arm that can move and point the Linac with 6 degrees of freedom [9, 10]. Two x-ray imaging devices based on amorphous silicon detectors are positioned on either side of the patient’s anatomy and acquire real-time digital radiographs of the skull at repeated intervals during treatment. The images are automatically registered to digitally reconstructed radiographs derived from the treatment planning CT. This registration process allowed the position of the skull (and thus

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Fig. 2. CyberKnife treatment plan. Axial, sagittal and coronal planes with 80% (inner line) and 50% (outer line) isodose lines are shown. Conformal irradiation is shaped to cover the entire length of nerve while sparing the proximal 3 mm close to the root entry zone in the brainstem.

the treatment site) to be translated to the coordinate frame of the Linac. A control loop between the imaging system and the robotic arm adjusted the pointing of the Linac therapeutic beam to the observed position of the treatment anatomy (target). If the patient moved, the change was detected during the next imaging cycle and the beam was adjusted and realigned with the target. Dose Placement Precision An important performance characteristic of the CyberKnife is the accuracy with which it can place the dose distribution. Application accuracy for the CyberKnife system is based on the accuracy of beam delivery, which combines the robot and the camera image

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tracking system, and the accuracy of target localization, which combines CT imaging and treatment planning [11, 12].

Clinical Outcomes

Thirteen patients with idiopathic TN were treated with CyberKnife radiosurgery. An average 81.5% isodose line (range 79–87) was used to deliver a mean dose of 64.15 Gy (range 60–70). The maximum dose (Dmax) ranged from 72.6 to 86.4 Gy (mean 78.6). The mean length of trigeminal nerve treated was 7.4 mm (range 5–10) with mean volume treated of 0.066 cm3 (range 0.019–0.158). Mean follow-up was 6.4 months (range 1–13). Ten out of 13 patients (76.9%), receiving 63–70 Gy to an isodose ranging form 79 to 87%, developed satisfactory pain relief after radiosurgery, with minimal or no residual pain. These patients received a maximum dose ranging from 74.1 to 86.4 Gy. However, 2 patients who experienced immediate pain relief relapsed about 3 months after the treatment. These 2 patients were prescribed 66 and 70 Gy to the 81% isodose (Dmax 86.4 and 81.9 Gy). Three patients (23.1%) receiving 60 Gy to an isodose ranging from 78 to 80% with a maximum dose ranging from 73.1 to 77 Gy had poor outcome; 2 had no response and 1 developed less than 50% pain relief after a treatment. This last patient was retreated with a higher dose, which again failed to produce satisfactory pain control after 2 months of follow-up. In summary, 8 patients (61.5%) had persistent satisfactory pain relief while 5 (39.5%) experienced a poor outcome due to lack of response (3) or to a relapse (2). Side Effects Related to Radiosurgery Four patients experiencing immediate pain relief developed facial hypoesthesia later on. They received 66–70 Gy to an isodose ranging from 79 to 82% and a maximum dose ranging from 80 to 86.4 Gy. No cases of corneal numbness were detected. Temporal Patterns of Pain Relief So far we have noted three predominant patterns of pain relief: immediate, early, and late. Four patients noticed immediate pain relief, i.e., greater than 50% reduction in pain overnight after surgery, with maximal effect within 48 h. Three patients (25%) had early onset of pain relief, starting about 48 h after the procedure, with complete relief within 72 h. Three patients had late pain relief, developing during the first month after treatment in 2 and after the first month in the other. Thus, 9 of the 10 patients that experienced pain relief did so during the first month after radiosurgery, and the tenth patient developed pain

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relief during the second month. In no case was a response to treatment detected after the first 2 months. Overall, 7 out of 13 patients (53.8%) developed substantial pain relief within 1 week after the treatment. Three of these patients developed contralateral hypoesthesia involving the entire face but not viewed as bothersome, and 1 of them developed bothersome paresthesias requiring medications. These 7 patients received 64–70 Gy (median 66) prescribed to an isodose line ranging from 79 to 87% (median 81%). The 3 patients experiencing late pain relief received 60–65 Gy to an isodose ranging from 78 to 83%. No sensory changes were detected in this group. Two patients receiving 60 Gy to the 80% isodose showed no response and no sensory changes after 6 months’ follow-up. Finally, 1 patient receiving 60 Gy to the 78% isodose developed minor pain relief. This patient was retreated with 66 Gy, but his pain relief 2 months after the second procedure was still less than 50%.

Discussion

The onset of pain relief in this small cohort of TN patients treated with CyberKnife radiosurgery usually occurred with a substantially shorter latency compared to patients undergoing GKR for TN. Patients treated with GKR usually experienced analgesia with a latency of 2–6 months [1–5, 7]. In our group, 7 out of 12 patients developed satisfactory pain relief within the first week after the treatment. The 4 patients with overnight pain relief also developed facial hypoesthesia, 1 with bothersome paresthesias. For this reason, subsequent patients received a reduced dose which did not reproduce the pattern of overnight pain relief seen in the initial patients, but was also not associated with facial hypoesthesia. Currently we prescribe 66 Gy to the 80% isodose. This treatment seems to produce pain relief within a month without side effects. Obviously the small number of patients presented here does not allow us to consider these data as anything more than preliminary. We are currently recruiting patients so that we may study a larger sample. Also, longer followups are necessary to detect delayed relapses or radiation-induced neuropathic changes. Despite these caveats, tentative explanations for the fast onset of pain relief after CyberKnife radiosurgery may be warranted. The main differences between our series and others based on GKR are the imaging modality used to localize the trigeminal nerve, and the frameless, Linac-based radiation delivery system. Our targeting technique is based on positive contrast CT cisternography, which enables very accurate localization [8] and targeting of the trigeminal nerve and, compared to conventional MR-based targeting, is not affected by magnetic field artifacts that may distort the image geometry.

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Clinically relevant accuracy of the CyberKnife radiosurgery system is based on the beam delivery accuracy, which combines the robot and the camera image tracking system, and the target localization accuracy, which combines CT imaging and treatment planning. A phantom study found that mean errors of the second generation CyberKnife currently in use at Stanford ranged from 0.7 mm for a CT slice thickness of 0.625 mm to 1.97 mm for a CT slice thickness of 3.75 mm [12]. An average radial error of 1.14 mm (SD 0.3 mm) was found using CT slice thickness of 1.25 mm. CT-based positive contrast identification of the trigeminal nerve using 1.25-mm slices helps to outline the target along the entire length of the nerve, sparing the proximal 3 mm to reduce brainstem irradiation. MR-based localization the trigeminal nerve may not be as accurate. In a study comparing localization accuracy of MR and CT using a BrownRobert-Wells frame, the average coordinate difference was ⱖ5 mm [13]. An additional factor improving radiation delivery to the nerve is the treatment conformality of CyberKnife radiosurgery. The absence of a rigid frame avoids restrictions to treatment planning and delivery of radiation, thus enhancing the conformal delivery of radiation and allowing a more homogeneous irradiation along the entire length of the trigeminal nerve. The conformal irradiation provided by the CyberKnife is especially convenient for the treatment of an elongated structure such as the TN. To treat non-spherical targets, isocentric radiosurgical methods such as the GKR or conventional Linacs rely on a single isocenter [1–7], which covers only a fraction of the target, or on multiple overlapping isocenters [14, 15], which produce target dose heterogeneity. Enhanced treatment conformality may result in the coverage of the entire target, thus preserving dose homogeneity. The rapid onset of pain relief in some of the patients may reflect an enhanced functional effect of conformal delivery of a higher dose of radiation to an extended length of the nerve. This speculation is supported by the fact that the 4 patients who experienced ‘immediate’ pain relief were also treated with the highest doses early in the series (66–70 Gy to an isodose ranging from 79 to 82%, Dmax 80–86.4 Gy). In addition, these doses are in the low range compared to GKR doses, which are divided conventionally into ‘low’ (70 Gy) and ‘high’ (90 Gy) [15]. GKR experience shows that patients receiving high doses experience better rates of complete pain relief compared to those receiving low doses (61 vs. 41%) with increased incidence of trigeminal nerve dysfunction (54 vs. 15%) [15]. Treatment of a longer segment of the nerve increases the rate of trigeminal nerve dysfunction without improving pain outcomes [14]. Still, fast pain relief after GKR is an uncommon phenomenon regardless of the dose used or the length of nerve segment treated. Our experience suggests that CyberKnife radiosurgery for TN can produce rates of pain relief and trigeminal nerve dysfunction that are roughly comparable to those obtained after high-dose GKR,

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but with substantially lower doses. Immediate relief may be mostly related to the conformal treatment of an extended length of the nerve with prescribed doses of 70 Gy. On the other hand, treating a smaller extent of the nerve may reduce the complication rate. Clearly, more experience is required to optimize the pain outcomes and reduce the rate of trigeminal nerve dysfunction after CyberKnife radiosurgery.

Conclusion

CyberKnife radiosurgery is able to produce immediate pain relief in patients with TN. Larger patient samples are necessary to validate these findings. A combination of conformal irradiation and increased targeting accuracy due to CT cisternography could explain the rapid onset of pain relief. An optimal dose range able to produce pain relief and minimize facial sensory denervation needs to be confirmed.

Acknowledgements The authors wish to thank Marc Levivier, MD, for helpful comments, Beth Hoyte, for help preparing figures, and David Schaal, PhD, for assistance preparing the manuscript.

References 1 2

3 4 5 6

7

8 9

Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain 2002;18:42–47. Kondziolka D, Lunsford LD, Flickinger JC, Young RF, Vermeulen S, Duma CM, Jacques DB, Rand RW, Regis J, Peragut JC, Manera L, Epstein MH, Lindquist C: Stereotactic radiosurgery for trigeminal neuralgia: A multi-institutional study using the gamma unit. J Neurosurg 1996;84: 940–945. Rand RW: Leksell gamma knife treatment of tic douloureux. Neurosurg Clin North 1997;8:75–78. Urgosik D, Vymazal J, Vladyka V, Liscak R: Gamma knife treatment of trigeminal neuralgia: Clinical and electrophysiological study. Stereotact Funct Neurosurg 1998;70(suppl 1):200–209. Young RF: Functional neurosurgery with the Leksell gamma knife. Stereotact Funct Neurosurg 1996;66:19–23. Young RF, Jacques DS, Mark R, Vermeulen S, Coputt B, Li F: Gamma knife treatment of trigeminal neuralgia: Long-term experience. Proc 10th International Meeting of the Leksell Gamma Knife Society, 2000. Regis J, Bartolomei F, Metellus P, Rey M, Genton P, Dravet C, Bureau M, Semah F, Gastaut JL, Peragut JC, Chauvel P: Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin North Am 1999;10:359–377. Mawad ME, Silver AJ, Hilal SK, Ganti SR: Computed tomography of the brain stem with intrathecal metrizamide. I. The normal brain stem. AJR Am J Roentgenol 1983;140:553–563. Murphy MJ: An automatic six-degree-of-freedom image registration algorithm for image-guided frameless stereotaxic radiosurgery. Med Phys 1997;24:857–866.

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10 11 12 13 14

15

Adler JR Jr, Murphy MJ, Chang SD, Hancock SL: Image-guided robotic radiosurgery. Neurosurgery 1999;44:1299–1307. Murphy MJ, Cox RS: The accuracy of dose localization for an image-guided frameless radiosurgery system. Med Phys 1996;23:2043–2049. Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP: An analysis of the accuracy of the CyberKnife: A robotic frameless stereotactic radiosurgical system. Neurosurgery 2003;52:140–147. Heilbrun MP: Image-guided stereotactic surgery: Adjunct technical advances; in Wilkins RH, Rengachary SS (eds): Neurosurgery Update II. New York, McGraw-Hill, 1991, pp 373–378. Flickinger JC, Pollock BE, Kondziolka D, Phuong LK, Foote RL, Stafford SL, Lunsford LD: Does increased nerve length within the treatment volume improve trigeminal neuralgia radiosurgery? A prospective double-blind, randomized study. Int J Radiat Oncol Biol Phys 2001;51:449–454. Pollock BE, Phuong LK, Foote RL, Stafford SL, Gorman DA: High-dose trigeminal neuralgia radiosurgery associated with increased risk of trigeminal nerve dysfunction. Neurosurgery 2001; 49:58–64.

Pantaleo Romanelli, MD Epilepsy Surgery Unit, Neuromed IRCCS Via Atinense 18, IT–86077 Pozzilli/IS (Italy) Tel. ⫹39 0865 9291, Fax ⫹39 0865 925351, E-Mail [email protected]

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Trigeminal Nerve Radiosurgical Treatment in Intractable Chronic Cluster Headache: Preliminary Results Anne Donneta, Dominique Valadeb, Jean Régisa a

Service de Neurochirurgie Fonctionnelle et Stéréotaxique, Hôpital d’adulte de la Timone, Marseille, bCentre Urgence Céphalée, Hôpital Lariboisière, Paris, France

Abstract Purpose: Since the initial report of Ford’s group in 1998, no further studies have attempted to evaluate radiosurgery of the trigeminal nerve in chronic cluster headache (CH). The medical rationale for targeting of the trigeminal nerve is questionable, but due to the severity of the more resistant cases, no potential solution must be neglected. Method: A prospective self-controlled trial was organized. Ten patients presenting with a very severe and drug-resistant chronic CH have been enrolled (9 male, 1 female). Mean age was 49.8 (32–77) years. The mean duration of the CH was 9 (2–33) years. The cisternal portion of the nerve was targeted with a single 4-mm collimator (80–85 Gy max.). Results: The mean follow-up was 6.7 months (more than 3 months for 7 patients). No improvement was observed in 2 patients, in 5 a dramatic improvement or cessation of pain occurred at a mean delay of 14 days. Two of these patients were pain-free for only 1 or 2 weeks and pain recurred on a minor scale, 3 are still pain-free with no medication for the attacks (for 12 and 4 months) and 1 of them is with no chronic treatment. Three patients have developed paresthesia with no hypesthesia, 1 a disabling hypesthesia. Conclusion: The rate and severity of trigeminal nerve injury appears significantly higher than in trigeminal neuralgia. This first prospective evaluation demonstrates the possibility to obtain complete pain cessation during a significant period of time but a long-term evaluation is necessary. Copyright © 2004 S. Karger AG, Basel

Chronic cluster headache (CH) is one of the most severe primary headaches known. Its pathophysiology is not clearly understood [1]. This syndrome can be highly disabling with significant toxicity and huge drug costs (sumatriptan, verapamil). Improvements have been reported with surgical procedures

classically proposed for trigeminal neuralgia (microvascular decompression [2], thermocoagulation [3], trigeminal nerve section [4]). Unfortunately with these procedures the rate of pain cessation was low and the rate of toxicity high. In 1998, Ford et al. [5] reported positive results after radiosurgical targeting of the trigeminal nerve. Since this initial report, no further studies have attempted to evaluate radiosurgery of the trigeminal nerve in chronic CH and no long-term follow-up study has ever been published by this group. In order to strictly evaluate the safety efficacy of trigeminal nerve radiosurgery in chronic CH, we organized a multicentric prospective self-controlled trial. The preliminary results of this study are reported here.

Material and Methods A multicentric prospective self-controlled trial was organized. The procedure of the prospective trial was submitted to the ethic committee and health authorities and modified according to their recommendations. An information brochure and informed consent were proposed and explained to the patients which was then signed by the patient and investigator. The experimental character of this procedure was extensively explained to the patients. Specific risks of failure or side effects and specially the risk of hypesthesia and deafferentation pain were presented to the patients. Each patient was admitted to Marseille Timone University Hospital the day before radiosurgery and underwent radiosurgery the following day (2 nights). Frame application was performed under local anesthesia and after prescription of a mild sedative medication. The frame was positioned in order to make the frame’s base ring parallel to the trigeminal nerve axis [6]. Preoperative stereotactic imaging included systematically an MR and CT scan. The MR (Siemens 1.5) sequences included a T2 high-resolution (0.5 mm) 3D acquisition (CISS) acquired in the axial plan, and a 3D T1 acquisition (MPR) of 1.5 mm thickness. CT scan bone window acquisition served as a part of the quality control to check and eventually correct any MR image distortions [6]. The cisternal portion of the nerve was targeted with a single 4-mm collimator. The target was pushed as anteriorly as possible in the cistern in order to cover the plexus triangularis and to decrease the energy delivered to the brainstem. The dose at the maximum (100%) was defined by the protocol as 80–85 Gy. The maximum dose was 80 Gy in 9 patients and 85 Gy in 1. A model C gamma knife was used for the radiosurgical procedure. No immediate side effects have been reported by the patients.

Results

Between January 2002 and February 2003, 10 patients (9 male, 1 female) (table 1) presenting with a very severe and drug-resistant chronic CH were enrolled. Mean age was 49.8 (32–77) years. The mean duration of CH was 9 (2–33) years. Mean follow-up was 6.7 months (more than 3 months for 7 patients). No improvement was observed in 2 patients, in 5 a dramatic improvement or cessation of pain occurred at a mean delay of 14 days. Two of these

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Table 1. Patient information Name

Age

Sex

Chronic since

GKS date

Evolution of chronic CH

Side effects

QU.JL

47

M

1985

02.01.2002

Complete disappearance in 15 days; since pain attack, less frequent

Hypesthesia; deafferentation pain

DU.Lu

52

M

1992

05.02.2002

June 2002 complete pain cessation, ‘cured’

0

LA.Je

60

M

2000

06.06.2002

Till day 7 no pain; days 7–11 pain recurred; day 37 Arnold infiltration, no more pain, ‘cured’; no more pain, stopped verampamil; Arnold infiltration has never been successful in this patient

Paresthesia; 15.08.2002 no hypesthesia

RO.Yv

43

M

2000

27.06.2002

Improvement of the frequency and severity of the pain attacks and complete stop 1 week then pain recurred (12.2002)

0

RE.Pa

35

M

2000

05.07.2002

Transient improvement at 5 months, at last visit no improvement

Paresthesia without hypesthesia

DA.Wi

62

M

17.10.2002

Complete disappearance of the pain at 5 months, ‘cured’

Hypesthesia; no corneal reflex

SCH.Pa

50

M

1998

05.11.2002

No improvement at 6 months

Paresthesia (chick)

GA.Je

77

F

1970

21.01.2003

No improvement at 1 month

0

GR.Da

32

M

2000

02.2003

?

?

VA.Di

40

M

1995

02.2003

?

?

patients were pain-free for only 1 or 2 weeks and pain recurred on a minor scale, 3 are still pain-free with no medication for the attacks (for 12 and 4 months) and 1 of them is with no chronic treatment. Three patients have developed paresthesia with no hypesthesia, and 1 a disabling hypesthesia. The severity of the deafferentation pain in this last patient has led to us to perform a cortical stimulation. Discussion

CH is one of the most debilitating headache syndromes encountered. CH is characterized by attacks of strictly unilateral, severe pain with orbital,

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Table 2. IHS diagnostic criteria for CH A

At least five attacks fulfilling B through D

B

Severe unilateral orbital, supraorbital and/or temporal pain lasting from 15 to 80 min if untreated

C

Headache is associated with at last one of the following signs, which have to be present on the pain side: 1. Conjunctival injection 2. Lacrimation 3. Nasal congestion 4. Rhinorrhea 5. Forehead and facial sweating 6. Miosis 7. Ptosis 8. Eyelid edema

D

Frequency of attacks from one every other day to eight per day

supraorbital or temporal location. Attacks last 15–180 min and usually occur one or several times per day, especially at night. They are accompanied by ipsilateral conjunctival injection, lacrimation, rhinorrhea or nasal congestion (table 2) [16]. Ninety percent of CH sufferers fall into the episodic syndrome, but 10% suffer chronic CH in which the attacks come closely spaced with no periods of remission lasting longer than 14 days or pain without remission for more than a year. Once the chronic cluster syndrome is established, medical treatment has been of limited success. With failure of medical treatment, it is not surprising that various invasive and surgical procedures have been tried in the hope of providing symptomatic relief. Clinical criteria for surgery in chronic CH are: total resistance to pharmacotherapy, headache located on the same side; pain mainly in the distribution of the ophthalmic division of the trigeminal nerve, and psychologically stable individuals. The response to previous sphenopalatine ganglion blockade was considered as insufficiently specific to serve as an inclusion/exclusion criterion [7]. Many sites have been surgically attacked in an attempt to terminate CH [8]: interruption of the parasympathetic pathways by sectioning the nervus intermedius [9], the greater superficial petrosal nerve or the sphenopalatine ganglion [10], or by lesion of the trigeminal nerve [3, 4, 11]. Anatomy and Pathology of CH There are a number of different sites from where the pain and attacks of CH might originate or be mediated: the regional orbital, internal or external carotid circulation, the cavernous sinus, the trigeminal-vascular nervous

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connections, the sympathetic and parasympathetic nerves and the hypothalamic centers [for review, see 1]. The exact etiology and pathophysiology of CH remain to be fully elucidated, but the three major aspects of this syndrome must be explained. These include the trigeminal distribution of the pain, the ipsilateral autonomic accompaniments and the episodic pattern of attacks. The first being that CH pain is located within the distribution area of the ophthalmic division of the trigeminal nerve, with the maximum pain invariably centered in or around the eye or forehead. The pain threshold is reduced within this area during CH periods. It is logical to believe that pain in the face must reach the central nervous system through the trigeminal sensory nerve fibers and that, just as in trigeminal neuralgia, interruption of some portion of the trigeminal system should prevent the painful impulses reaching the pons. Second, that the ipsilateral autonomic features reflect sympathetic dysfunction. A considerable body of evidence points to the cavernous sinus as the likely site of involvement given the convergence of the trigeminal, parasympathetic and sympathetic fibers of the region. Finally, the episodic and often clockwise consistency and seasonal predilection of attacks have the signature of a dysfunctional central pacemaker which can be situated in the hypothalamus. In fact, trigeminal pathway procedures have been realized: alcohol injection of the gasserian ganglion, root section of the trigeminal nerve [4], glycerol rhizotomy [8], radiofrequency rhizolysis of the trigeminal nerve [3], microvascular decompression of the trigeminal nerve [2] or the nervus intermedius [12]. Gamma knife radiosurgery is the latest technology to be used to interrupt or otherwise interfere with the sensory trigeminal pathway. Originally employed for trigeminal neuralgia, it has been applied in chronic CH [5]. The target was the trigeminal root entry zone in the pons. In these data, 4 males and 2 females with refractory chronic CH were treated with a 70-Gy dose to the isocenter. Four of the 6 patients had excellent relief (defined as CH-free and taking minimal or no medication). One patient had good relief and the final patient’s result was judged to be fair. No serious side effects were reported, but the long-term benefits were not evaluated in this study. Among the proposed neurosurgical techniques, thermocoagulation of the trigeminal nerve or of the sphenopalatine ganglion and microvascular decompression have recently been re-evaluated. In 1987, Sanders and Zuurmond [7] reported a series of 66 patients with refractory CH with a mean follow-up of 2 years. Unfortunately, only 10 were chronic (and 56 episodic). Among the 10 patients with chronic CH, complete pain relief was obtained in 3 (partial relief in 3). In 1995, Taha and Tew [3] reported a series of 7 patients with refractory chronic CH treated by radiofrequency rhizotomy. All the patients were reported to be pain-free immediately after the procedure but at last

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follow-up (median follow-up 5 years; 2–20 years) only 2 were still pain-free (at 7 and 20 years) and 3 have mild recurrence with good drug sensitivity. They reported 1 patient with complications (transient diplopia and keratitis). Finally, Lovely et al. [2] reported a series of 20 patients with chronic CH in whom they performed microvascular decompression of the trigeminal nerve alone (n ⫽ 9) or associated with a microvascular decompression of the nervus intermedius (n ⫽ 3) or with section of the nervus intermedius (n ⫽ 10). At the last followup a reduction of more than 90% of the pain was achieved in 50% of the patients (9) and a reduction of more than 50% of the pain in 6 patients. Complications include 1 infected cranioplasty requiring removal, 1 CSF leakage requiring spinal drainage, and 7 patients with headache requiring a lumbar puncture but no hearing loss or facial palsy being reported. Our experience with radiosurgery does not compare very favorably with these series. However, due to the frequency of recurrences whatever technique was used, no additional option must be neglected. In our experience of gamma knife surgery for trigeminal neuralgia (276 procedures), in spite of the use of the same target and a similar dose, hypesthesia remains rare (5.8%) and we have never encountered severe hypesthesia associated with iatrogenic deafferentation pain [data to be published]. Several hypotheses may be raised to explain this intriguing discrepancy. Perhaps in patients with trigeminal neuralgia who have a structural alteration of their V nerve, this nerve is more resistant to radiosurgery. An alternative hypothesis may be an abnormal sensitivity of the nerve in chronic CH. The quite high toxicity and low efficacy of radiosurgery directed toward the nerve (at least in our hands) indicates the requirement for the development of new therapeutic options. The first published results of posterior hypothalamic stimulation are encouraging [13, 14]. Some authors have proposed to direct radiosurgery toward the sphenopalatine ganglion or both the sphenopalatine ganglion [15] and the trigeminal nerve [Delotbinière, pers. commun.].

Conclusion

The rate and severity of trigeminal nerve injury appears significantly higher than in trigeminal neuralgia. This first prospective evaluation demonstrates the possibility to obtain complete pain cessation during a significant period of time but a long-term evaluation is necessary. This study does not support the positive results of the Ford’s study. We consider the toxicity as significant for a low rate of pain cessation making this procedure less attractive even for the more desperate subgroup of patients. Other approaches are currently being evaluated by our group.

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References 1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16

Schoenen J: Cluster headaches – Central or peripheral in origin? Lancet 1998;352:253–255. Lovely TJ, Kotsiakis X, Jannetta PJ: The surgical management of chronic cluster headache. Headache 1998;38:590–594. Taha JM, Tew JM Jr: Long-term results of radiofrequency rhizotomy in the treatment of cluster headache. Headache 1995;35:193–196. Matharu MS, Goadsby PJ: Persistence of attacks of cluster headache after trigeminal nerve root section. Brain 2002;125:976–984. Ford RG, Ford KT, Swaid S, Young P, Jennelle R: Gamma knife treatment of refractory cluster headache. Headache 1998;38:3–9. Regis J, Bartolomei F, Metellus P, et al: Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin North Am 1999;10:359–377. Sanders M, Zuurmond WW: Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: A 12- to 70-month follow-up evaluation. J Neurosurg 1997;87: 876–880. Rozen TD: Interventional treatment for cluster headache: A review of the options. Curr Pain Headache Rep 2002;6:57–64. Rowed DW: Chronic cluster headache managed by nervus intermedius section. Headache 1990;30:401–406. Meyer JS, Binns PM, Ericsson AD, Vulpe M: Sphenopalatine gangionectomy for cluster headache. Arch Otolaryngol 1970;92:475–484. Green MW: Long-term follow-up of chronic cluster headache treated surgically with trigeminal tractotomy. Headache 2003;43:479–481. Solomon S, Apfelbaum RI: Surgical decompression of the facial nerve in the treatment of chronic cluster headache. Arch Neurol 1986;43:479–482. Franzini A, Ferroli P, Leone M, Broggi G: Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: First reported series. Neurosurgery 2003;52:1095–1101. Leone M, Franzini A, Broggi G, Bussone G: Hypothalamic deep brain stimulation for intractable chronic cluster headache: A 3-year follow-up. Neurol Sci 2003;24(suppl 2):143–145. Pollock BE, Kondziolka D: Stereotactic radiosurgical treatment of sphenopalatine neuralgia. Case report. J Neurosurg 1997;87:450–453. Classification Committee of the IHS: Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain of the headache. Cephalagia 1988;8(suppl 7):1–96.

Prof. Jean Régis Service de Neurochirurgie Fonctionnelle et Stéréotaxique Hôpital d’adulte de la Timone, 264, bvd Saint Pierre FR–13385 Marseille Cedex 05 (France) Tel. ⫹33 4 9138 7058, Fax ⫹33 4 9138 7056, E-Mail [email protected]

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Physics and Imaging Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 197–212

Measurements of Extracranial Doses in Patients Treated with Leksell Gamma Knife C Francoise De Smedt a,b, Bruno Vanderlindena,b, Stephane Simona,b, Marianne Paesmansc, Daniel Devriendt a,b, Nicolas Massager a, Salvador Ruiz a, Jose Lorenzoni a, Paul Van Houtteb, Jacques Brotchi a, Marc Levivier a a b c

Gamma Knife Centre, Université Libre de Bruxelles, Hôpital Erasme; Department of Radiation Therapy and Laboratory of Physics, and Data Centre, Institut Jules Bordet, Brussels, Belgium

Abstract Most of the patients treated with Leksell Gamma Knife® (LGK) present benign lesions, it is thus essential to evaluate extracranial doses. A study of in vivo measurements on 228 unselected patients treated with LGK Model C is presented. Measurements were performed with TL dosimeters which were positioned on the lateral canthus, thyroid, breasts and gonads. Pathology, target maximum dose, reference isodose volume, integral dose, treatment time, distance and influences of plugs on extracranial doses are analyzed. The treatment of some benign pathologies like meningioma can give relatively important extracranial doses (mean dose of 13.3 cGy on thyroid). Surprisingly, no correlation could be shown between maximum dose, reference isodose volume, integral dose and extracranial doses. On the other hand, the total treatment time and the use of plugs have a significant influence on doses received on extracranial sites. Copyright © 2004 S. Karger AG, Basel

The aim of radiosurgery is to cover most accurately lesions with prescribed radiation and to avoid any secondary effects on critical tissues. Intracranial tissues are obviously the most critical but extracranial doses to healthy tissues must also be evaluated. Leksell Gamma Knife® (LGK; Elekta AB, Stockholm, Sweden) is a technique used to perform radiosurgical treatments. A single dose radiation is prescribed and delivered on the target volume. LGK uses

201 60Co sources ranged inside a hemispherical shielding. First, a ‘primary’ collimator defines ␥ beam trajectories emitted by 60Co decay. These 201 ␥ beams are directed towards a common point, called ‘isocenter’ or focus point. Then, a second iron ‘helmet’, containing 201 tungsten collimators and mounted on the patient couch, directs a second time ␥ beams towards the isocenter. These second collimators have variable diameters at the focus point (4, 8, 14 and 18 mm), which allow treatments of targets of different sizes and complexities. A stereotactic frame is put on the patient’s head to establish target coordinates and to position the patient in the gamma knife. Multiple head positions are usually necessary to cover the entire volume of the target. For each position (also called a ‘shot’), the patient, placed on the couch, enters the gamma knife until the second collimators are aligned with the primary (treatment position) and exits the unit after radiation delivering. Since 1967, when LGK was initially developed, many technical improvements were achieved. The first commercial LGKs (Models U and B) have manual systems of patient positioning. Graduated slides bars, called ‘trunnions’, allow adjusting stereotactic coordinates in the three Cartesian axes. Between two manual changes of coordinates, the patient exits the unit until the shielding doors are closed. During these couch movements, the patient is also exposed to radiation and receives a ‘transit dose’ [1, 2]. In the latest version (Model C), installed in our hospital in December 1999, stereotactic coordinates are monitored by an Automatic Positioning System (APS™). Between two shots, the couch moves out from the treatment position and goes to the ‘defocus position’, where automatic adjustments of coordinates are performed, so that the couch transit doses are smaller than those delivered with previous models [3]. As most of the patients treated with LGK present benign lesions, it is important to evaluate extracranial doses and to assess an order of magnitude of the carcinogenic risk. The International Commission on Radiological Protection (ICRP) recommends in its publication 60 to take 50 10⫺3 Sv⫺1 as risk factor for an induced lethal cancer after a low dose and low dose rate population exposure [4]. Several studies on extracranial doses have already been published [2, 5–7]. We propose here a study on 228 unselected patients treated in our center with a LGK Model C. Different parameter influences are analyzed in order to give extracranial doses as small as possible to the patient and therefore optimize treatment from the radioprotection point of view.

Material and Methods Dose measurements were performed with LiF:Mg, Ti and Li2B4O7:Mn (3.2 ⫻ 3.2 ⫻ 0.9 mm). Their effective atomic number, which is the equivalent total atomic number of

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a compound (respectively Zeff ⫽ 8.2 and Zeff ⫽ 7.4) makes them close to the tissue equivalence (Zeff ⫽ 7.42) for the photoelectric effect. The Compton effect component of the mass attenuation coefficient is proportional to the ratio Z/M, where M is the molar mass. This ratio is approximately similar for the different mediums. Thus, for Compton effect, TL dosimeters are also close to the tissue equivalence. Detectors were calibrated in a 60Co beam at the Radiotherapy Department of Bordet Institute in Brussels. The 60Co beam is calibrated once a month with a NE2571 ionization chamber. TL dosimeters were irradiated to 1 Gy and positioned at a depth of 5 mm in a PMMA phantom made of several plates of 20 ⫻ 20 cm2. The irradiation is performed at the distance of 80 cm from the 60Co source within the irradiation field of 10 ⫻ 10 cm2. Two sets of 21 TL dosimeters were irradiated and for each of them calibration and relative sensitivity factors were determined. Calibration factor is defined as the dose (Gy) per mean integrated signal (nC) for the whole batch of TL dosimeters. Relative sensitive factor is the ratio of an individual readout on the mean batch readout. This calibration was repeated every 6 months in order to correct the slight decrease in sensitivity of the detectors. Linearity in dose response was also checked between 0 and 1 Gy. TLD manual Harshaw reader model 3500 was used for readouts. The heating cycle consisted of a preheating at 135⬚C during 12 s, followed by a linear increase of the temperature of 10⬚C/s with a maximum of 270⬚C where the signal was integrated during 16 s. Annealing was performed at 305⬚C during 20 s. The same heating cycle was applied for Fluoride and Borate TL dosimeters because the temperatures of the main peak of Fluoride and Borate TL glow curve are similar (respectively 195 and 200⬚C). Measurements were performed in 228 unselected patients from February 2000 to March 2003. Among these 228 patients, 17% suffered of meningioma, 19% of trigeminal neuralgia, 4% of pituitary adenoma, 20% of schwannoma, 15% of single metastasis, 11% of multiple metastases, 7% of glial tumor, 5% of AVM, 1% of epilepsy and 1% of otherlesions. TL dosimeters were placed within little PMMA holders containing each three detectors. Holders were positioned on the lateral canthus, thyroid, breasts, gonads, and for some patients on the vertex. Distance between helmet and organs was also measured.

Results

Table 1 describes global original results without any analysis. The mean, maximum and minimum doses for all patients and sites of measurements are summarized. As expected, the largest doses are delivered to the vertex (mean dose of 41.7 cGy, maximum dose of 138.3 cGy, measured on 56 patients) and lateral canthus (mean dose of 35.1 cGy, maximum dose of 315.9 cGy, measured on 202 patients) and the smallest ones to the gonads (mean dose of 0.6 cGy, maximum dose of 2.8 cGy, measured on 228 patients). Mean delivered doses on thyroid (measured on 227 patients) and breasts (measured on 227 patients) are respectively 9.6 and 3.8 cGy with a maximum of 58.8 and 19.8 cGy. Table 1 shows that extracranial doses are generally very small. It is thus not to be feared that deterministic effects like epilation on the vertex area or cataract appear. Maximum gonad dose is even so small that it might be quite safe for a hypothetical fetus.

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Table 1. In vivo measurements results (Gy) for all patients (n) and sites of interest

Lateral canthus Thyroid Breasts Gonads Vertex

Mean dose

Standard deviation

Minimum dose

Maximum dose

0.3516 (n ⫽ 202) 0.0966 (n ⫽ 227) 0.0388 (n ⫽ 227) 0.0063 (n ⫽ 228) 0.4170 (n ⫽ 56)

0.4495 0.0658 0.0283 0.0051 0.3332

0.0215 0.0161 0.0065 0.0005 0.0333

3.1589 0.5883 0.1979 0.0286 1.3828

Analysis of Pathology Influence The first parameter analyzed is the possible influence of pathology on delivered extracranial dose. To determine any influence, for each site of interest, the mean dose in Gy is presented in function of each pathology. Figures 1–4 show the mean lateral canthus, thyroid, breast and gonad doses for each pathology treated. For the lateral canthus, multiple metastases treatments give the highest mean dose of 66 cGy, followed by meningioma (53 cGy), AVM (52 cGy) and pituitary adenoma treatments (49 cGy). Single metastasis, glial tumor, schwannoma and trigeminal neuralgia treatments give a mean lateral canthus dose of 31, 30, 20 and 13 cGy. For the other sites of interest, pituitary adenoma treatment gives the highest dose with a value of 18 cGy for thyroid; 9.3 cGy for breasts and 1.1 cGy for gonads. Treatments of meningioma, AVM and multiple metastases give 13.3, 11.5 and 12.3 cGy on thyroid, 5.7, 4.3 and 4.7 cGy on breasts and 0.9, 0.8 and 0.9 cGy on gonads. Figures 2–4 show smaller doses given by the treatments of schwannoma, trigeminal neuralgia, single metastasis and glial tumor with values of respectively 7.4, 8.8, 7 and 5.2 cGy for thyroid; 2.7, 3.6, 2.4 and 2.2 cGy for breasts; 0.4, 0.5, 0.5 and 0.3 cGy for gonads. Two groups of pathologies can be created, one with low extracranial doses (schwannoma, trigeminal neuralgia, single metastasis and glial tumor) and the other one with higher extracranial doses (pituitary adenoma, meningioma, multiple metastases and AVM). A one-way ANOVA test was performed and was followed by a post-hoc Tukey test to determine, for each pathology, what the other pathologies statistically significant different for the mean extracranial dose are. Disease groups with less than 20 observations were excluded from the test. The results of p values are presented in table 2. The treatment of meningiomas gives a significantly higher extracranial dose than of single metastasis for thyroid, breasts and gonads (respectively p ⬍ 0.001,

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0.20 0.66

0.6

0.53

0.16 0.52

0.49 0.5 0.4

0.31

0.30

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0.13

0.133 0.14

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0.12 0.088

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0.070

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Met.

Mets

Trigeminal neuralgia

AVM

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Pituitary adenoma

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Met.

Mets

Trigeminal neuralgia

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AVM

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0.00

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0.012

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0.0112 0.0097

0.08

0.010

0.0089

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0.06

0.047

0.05

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0.04 0.027

0.024 0.022

0.03

Mean gonads dose (Gy)

Mean breasts dose (Gy)

0.180

0.18

Mean thyroid dose (Gy)

Mean lateral canthus dose (Gy)

0.7

0.0085

0.008 0.0054

0.006

0.0049 0.0041 0.0033

0.004

0.02 0.002 0.01 0.00

Fig. 1–4. Pathology influence on (1) mean lateral canthus, (2) mean thyroid, (3) mean breast and (4) mean gonad doses (Gy).

⬍0.001, 0.001) but no significantly higher dose is given to the lateral canthus (p ⫽ 0.234). It gives also higher doses than schwannoma and trigeminal neuralgia for the four sites of interest (p values from 0.011 to ⬍0.001). No significantly different mean doses appear between meningioma and multiple metastases (p values from 0.976 to 0.433) for the lateral canthus, thyroid, breasts and gonads. On the other hand, multiple metastases treatment gives a higher dose than single

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Glial tumor

Met.

Mets

Trigeminal neuralgia

AVM

Schwannoma

4

Meningioma

Pituitary adenoma

Glial tumor

Met.

Mets

Trigeminal neuralgia

AVM

Schwannoma

3

Meningioma

Pituitary adenoma

0.000

Table 2. Probability values after ANOVA and Tukey tests for mean lateral canthus, thyroid, breast and gonad doses Site of interest

Diseases

Meningioma

Metastasis

Multiple metastases

Schwannoma

Trigeminal neuralgia

Lateral canthus

Meningioma Metastasis Multiple metastases Schwannoma Trigeminal neuralgia

– – –

0.234 – –

0.884 0.028 –

0.011 0.84 ⬍0.001

0.001 0.383 ⬍0.001

– –

– –

– –

– –

0.929 –

Meningioma Metastasis Multiple metastases Schwannoma Trigeminal neuralgia

– – –

⬍0.001 – –

0.976 0.009 –

⬍0.001 0.999 0.009

0.004 0.715 0.125

– –

– –

– –

– –

0.801 –

Meningioma Metastasis Multiple metastases Schwannoma Trigeminal neuralgia

– – –

⬍0.001 – –

0.433 ⬍0.001 –

⬍0.001 0.958 0.001

⬍0.001 0.093 0.158

– –

– –

– –

– –

0.279 –

Meningioma Metastasis Multiple metastases Schwannoma Trigeminal neuralgia

– – –

0.001 – –

0.957 ⬍0.001 –

⬍0.001 0.932 ⬍0.001

0.002 0.988 0.001

– –

– –

– –

– –

0.621 –

Thyroid

Breasts

Gonads

metastasis and schwannoma treatment for the four sensitive sites (p values from 0.028 to ⬍0.001). Comparison between mean doses of multiple metastases and trigeminal neuralgia gives more various results. A significantly higher dose is present for the lateral canthus and gonad for multiple metastases treatment (respectively p ⬍ 0.001 and p ⫽ 0.001). Treatment of single metastasis does not give a higher dose than of schwannoma and trigeminal neuralgia for all sites and schwannoma mean dose is not significantly different from trigeminal neuralgia mean dose also for all sites of interest. Generally, if a treatment is more complex the extracranial dose will be higher.

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3.5

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60

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Maximum dose (Gy) 0.035

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0.03 0.2 Gonads dose (Gy)

Breasts dose (Gy)

0.025 0.15

0.1

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0.05 0.005 0

0 0

7

20

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60

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80

100

0

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8

40

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Maximum dose (Gy)

Fig. 5–8. Maximum prescribed dose influence on (5) lateral canthus, (6) thyroid, (7) breast and (8) gonad doses.

Analysis of Target Maximum Dose Influence The second analyzed parameter is the maximum prescribed dose. The range of maximum dose for the 228 treated patients is from 21.8 to 90 Gy but sometimes the maximum dose can reach 140 Gy for functional lesions. Figures 5–8 show the lateral canthus, thyroid, breast and gonad doses as a function of maximum prescribed dose. As shown in these four graphs, no direct correlation could be determined between the maximum target dose and extracranial delivered doses. Maximum dose of 90 Gy, used in trigeminal neuralgia treatment, does not necessarily involve a higher extracranial dose than the 40 or 48 Gy maximum doses prescribed for multiple metastases treatments. The relatively more

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100

scattered results for gonads are probably due to the variation of distance from the helmet to gonads and to the accuracy of small dose measurements. Variations in extracranial doses are very high even for a same maximum dose. For instance, in trigeminal neuralgia treatment, maximum dose is set at 90 Gy but measured extracranial doses for breasts vary from 1.2 to 8.7 cGy. Analysis of Reference Isodose Volume Influence Another interesting parameter to analyze is the reference isodose volume. The reference isodose volume is defined as the volume receiving the therapeutic prescribed dose. This volume can be very small or larger depending on the size of the target. Figures 9–12 show the influence of this volume on extracranially delivered doses. For trigeminal neuralgia, the dose is prescribed at the isocenter, the reference isodose volume is therefore defined as the volume of a 50% isodose line of the 4-mm collimator. No correlation was found between extracranial doses and reference isodose volume. Analysis of Integral Dose Influence In order to assess the importance of total exposure of a patient, one can estimate the total energy deposited in the patient’s body. This total energy is called integral dose. Here the integral dose (mJ) is defined as the product of reference isodose volume by the prescribed dose multiplied by human density. In this manner, comparison of extracranial doses for treatment with the same isodose volume and prescribed dose can be made. For each site of interest, extracranially delivered doses as a function of integral dose are presented in figures 13–16. No correlation between integral dose and delivered dose to sites of interest was found. Analysis of Treatment Time Influence Treatment time is defined as total time of irradiation, i.e. time spent in the gamma knife at the treatment position. Because of decreasing 60Co dose rate with time, results are normalized for a dose rate of 3 Gy/min and presented in figures 17–21. Linear regressions were performed for all sites of interest doses as a function of treatment time. For thyroid and breasts, the relation is almost linear with an R2 value of respectively 0.7056 and 0.7204. The thyroid and breast doses are respectively 2.1 and 0.9 mGy for 1 min of treatment if the dose rate is 3 Gy/min. For gonads and vertex, a linear relation is also found but with a smaller R2 value than for thyroid and breasts (respectively 0.4926 and 0.4324). Lateral canthus doses are almost not correlated with treatment time with an R2 value of 0.1314.

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10,000 15,000 20,000 25,000 30,000 35,000 Reference isodose volume (mm3)

0

5,000

12

10,000 15,000 20,000 25,000 30,000 35,000

Reference isodose volume (mm3)

Fig. 9–12. Reference isodose volume influence on (9) lateral canthus, (10) thyroid, (11) breast and (12) gonad doses.

Analysis of Distance Influence Thyroid dose has been taken as 100% dose. Breast and gonad doses were normalized to thyroid dose by dividing their values (multiplied by 100) by the corresponding thyroid value. These normalized doses were then plotted as a function of measured distances between thyroid, breasts and gonads. A decreasing exponential equation was fit to the data which is in good agreement with experimental points (fig. 22). Linearization of the data (fig. 23) was performed by applying the logarithm on breast and gonad dose divided by thyroid dose. A linear regression was then performed with an R2 value of 0.888.

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Integral dose (mJ)

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200

300

400

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Integral dose (mJ)

Fig. 13–16. Integral dose influence on (13) lateral canthus, (14) thyroid, (15) breast and (16) gonad doses.

Analysis of Plugs’ Influence In the treatment of trigeminal neuralgia, healthy intracranial tissues like the brainstem can be very close to the target and receive a higher dose than allowed. Thus, plugs are used to ‘move’ deposited energy away from healthy tissue while maintaining target conformity. These plugs are in fact beam stoppers and it is interesting to know how they could influence the extracranial dose. This pathology was chosen because of its standardized treatment planning (a 4-mm shot with 90 Gy at maximum). Recurrent trigeminal neuralgias, treated with 70 Gy, were excluded from this analysis. Among patients suffering

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Lateral canthus dose (Gy)

3.5

y⫽ 0.0061x ⫹ 0.0604 2 R ⫽ 0.1314

1.5 1

y ⫽0.0021x R2 ⫽ 0.7056

0.4 0.3 0.2

0.5

0.1

0 0

17

20 40 60 80 100 120 140 160 180 Treatment time (min) Reference dose rate⫽ 3Gy/min

0

18

0

20 40 60 80 100 120 140 160 Treatment time (min) Reference dose rate⫽3 Gy/min

180

0.25 0.035 0.03 y⫽ 0.0009x R2 ⫽ 0.7204

0.15

0.1

Gonads dose (Gy)

Breasts dose (Gy)

0.2

y ⫽0.0001x R2 ⫽ 0.4926

0.025 0.02 0.015 0.01

0.05 0.005 0

0 0

19

20 40 60 80 100 120 140 160 Treatment time (min) Reference dose rate⫽ 3Gy/min

180

0

20

50 100 150 Treatment time (min) Reference dose rate⫽ 3 Gy/min

1.6 1.4

Vertex dose (Gy)

1.2 y⫽ 0.0084x R2 ⫽ 0.4324

1.0 0.8 0.6 0.4 0.2 0.0

21

0

20 40 60 80 100 120 140 160 180 Total treament time (min) Reference dose rate ⫽ 3Gy/min

Fig. 17–21. Lateral canthus (17), thyroid (18), breasts (19), gonads (20) and vertex (21) doses in function of time.

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200

0

90

⫺0.5

80

⫺1

70

⫺1.5 y ⫽ 100e ⫺0.0534x R2 ⫽0.888

60 50

ln (D/Dmax)

Normalized dose (%)

100

40 30

30

40

50

60

70

⫺2

⫺3 y⫽ ⫺0.0534x R2 ⫽0.888

⫺4

10

⫺4.5

0 0

22

20

⫺2.5

⫺3.5

20

10

20

40 Distance (cm)

60

80

23

⫺5

Distance (cm)

Fig. 22, 23. Normalized dose to thyroid in function of (22) distance and (23) distance (ln).

Table 3. Mean dose (Gy) with and without plugs for trigeminal neuralgia treatment

Without plug (n ⫽ 20) With plugs (n ⫽ 13) Unpaired t test

Lateral canthus

Thyroid

Breasts

Gonads

Vertex

0.124 0.174 0.0760

0.076 0.103 0.0003

0.031 0.049 0.0002

0.005 0.009 0.0066

0.270 0.232 0.2842

of this pathology, 20 were treated without plugs and 13 with plugs. The mean number of plugs used was 59 with a range of 1–99. Table 3 shows the mean dose on the lateral canthus, thyroid, breast, gonad and vertex with and without plugs during treatment. An unpaired t test was also performed to determine any significant difference between the two groups. Mean doses delivered to thyroid, breasts and gonads without plugs have a value of 0.076, 0.031 and 0.005 Gy. With the use of plugs, these doses have a higher value of respectively 0.103 Gy (⫹35%), 0.049 Gy (⫹58%) and 0.009 Gy (⫹80%). A significant difference in mean doses is observed between treatments with and without plugs for these three sites of interest (p value of 0.0003, 0.0002 and 0.0066). However, for the lateral canthus and vertex, mean doses without plugs have a value of 0.124 and 0.270 Gy and with plugs of 0.174 Gy (⫹40%) and 0.232 Gy (⫺16%), and no significant difference in mean dose is observed (p value of 0.076 and 0.2842).

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80

100 90 80 70 60 50 40 30 20 10 0

Breasts

Thyroid

2

R ⫽ 0.4051

Dose (mGy)

Scatter 18mm (29.5%)

Dose (mGy)

20

Scatter 18 mm (23.6%)

15 10

Leakage 18mm (70.5%)

Leakage 18 mm (76.4%)

5 0

0

5

24

10 15 Collimator size (mm)

4.5

20

0

5

25

10 15 Collimator size (mm)

20

Gonads

4

R2 ⫽ 0.0168

3.5 Dose (mGy)

25

R2 ⫽0.9552

Scatter 18 mm (5.5%)

3 2.5 2

Leakage 18 mm (94.5%)

1.5 1 0.5 0

26

0

5

10 15 Collimator size (mm)

20

Fig. 24–26. Phantom (24) thyroid, (25) breast and (26) gonad doses in function of collimator size (30 min total treatment time).

Preliminary Data on Anthropomorphic Phantom When the patient enters the gamma knife and spends time in the treatment position, two types of exposure, scattering and leakage, can contribute to extracranial doses. The scatter component is dependent of maximum dose, irradiated volume and distance between the scatter volume and site of measurement. The leakage component is dependent on time spent in the gamma knife and on distance between site of measurement and cobalt sources. From measurements on anthropomorphic phantom, for a same treatment time (30 min, with a dose rate of 3.428 Gy/min) and various sizes of collimator, the contribution of each component can be established. Figures 24–26 represent extracranial doses for thyroid, breasts and gonads, for exposure with 4-, 8-, 14- and 18-mm collimators. Error bars correspond to the range of measured values. If measurements are extrapolated to zero collimator size, the assumption that only the leakage component is present for this value can be made. The leakage component is mainly present for each site of interest. For the thyroid, if a 18-mm collimator is used, the scatter component contributes for 29.5% to extracranial dose and leakage for 70.5%. If a 4-mm collimator is used, the scatter component contributes for 8.5% and leakage for 91.5%. For breasts and a 18-mm collimator,

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scatter contributes for 23.6% to extracranial dose and leakage for 76.4%. For a 4-mm collimator, the proportion is 6.4% for scatter and 93.6% for leakage. For gonads, the scatter component is even negligible with a contribution of 5.5% for a 18-mm collimator and of 1.3% for a 4-mm collimator.

Discussion

The large maximum dose observed in table 1 for the lateral canthus is probably due to direct ␥ beams reaching TL detectors. The vertex and lateral canthus receive doses with the same order of magnitude. Most of the time, these sites of interest are within the helmet and supposed to be exposed to intense scatter, leakage and sometimes primary beams. These are also supposed to be closer to the isocenter than other sites. The large standard deviation for these two sites can be explained by all these factors that can differently influence the delivered dose. Compared to Model U, for which thyroid, sternum and pelvis mean doses of respectively 20.6, 21.4 and 4.1 cGy have been reported [6], we found much smaller mean doses with the new Model C. These lower mean values with Model C have already been published by Yu et al. [5]. In their study, the sternum mean dose (3.3 cGy) is very close to our value for breasts (3.8 cGy) and the pelvis mean dose (0.6 cGy) is identical to our gonads dose (0.6 cGy). A difference in mean thyroid dose can also be noticed (5.8 vs. 9.6 cGy in our study) and is probably due to a difference in the TL dosimeter positioning. Close to isocenter, this factor can have a high influence on the extracranial dose (fig. 22, 23). From table 2, results of p values show that there is a significant difference between extracranial doses given by treatment of multiple metastases and those given by single metastasis. This observation is of course obvious. Multiple metastases treatments give also a significantly higher dose than schwannomas which are usually small lesions and need a smaller therapeutic radiation dose. These factors involve a shorter treatment time and therefore smaller extracranial doses (fig. 17–21). A significantly different dose appears also between multiple metastasis and trigeminal neuralgia for lateral canthus. This can be explained by the fact that multiple metastases are treated with larger collimators and with a larger number of shots than trigeminal neuralgia and therefore are more likely to irradiate TL dosimeters with direct beams. On the other hand, no significantly different doses are observed for thyroid and breast. Meningiomas are usually complex targets and many small shots are used to achieve good conformity. Unfortunately, many shots will increase the total treatment time and extracranial doses are mainly influenced by this factor. Figures 5–8 show that maximum prescribed dose does not influence extracranial doses. The analysis of contribution of scatter and leakage components shows

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that leakage is the major component of the patient exposure for extracranial sites. The minor contribution of the scatter component can give an explanation of the relative independence between extracranial dose and maximum prescribed dose. Usually in external radiotherapy, extracranial doses are reported as a percentage of maximum dose delivered. This method is however not suitable for gamma knife treatments because the target volume is covered by a large number of shots and each shot gives its own leakage exposure. From figures 5–16 no correlation can be made between extracranial doses, reference isodose volume and integral dose. The independence of measured extracranial doses regarding reference isodose volume and integral dose confirms the small scatter contribution. Reference isodose volume is dependent of target size. For larger volumes, 18- or 14-mm collimators are generally used for treatment planning. These treatments are achieved with a smaller total number of shots and within a shorter total treatment time. This gives the explanation why the larger volumes are not correlated with higher extracranial doses. We can even have a ‘treatment volume paradox’: larger treated volumes giving smaller extracranial doses. On the other hand, extracranial doses and total treatment time are well correlated. For the lateral canthus, gonads and vertex, correlation is not as significant as for thyroid and breasts. Direct beams on TL dosimeters for lateral canthus can of course explain a higher variance in results. Gonad doses are usually small, so the variance can also be larger because of measurement uncertainties with TL dosimeters. Their different positioning on the patient can also influence extracranial doses because gonads are not always at the same distance from cobalt sources. As demonstrated by Bradford et al. [8], direct beams that pass through helmet cap hole during couch transit can give significant doses on vertex. From this study, a transit dose of 4.4 cGy/shot at 10 cm from the focus point and of 5.6 cGy/shot at distances ⬎15 cm from this point were measured. This additional factor, the fact that TL dosimeters are not always aligned with the helmet cap hole and the fact that it is difficult to fix them on hairs, can give a high variation in vertex extracranial doses. The relation between distance and normalized doses to thyroid dose shows also clearly the influence of distance between sources and sites of interest on extracranial doses. From these results, a model could be used to determine for example breast and gonad doses from single thyroid dose measurement and measured distances between thyroid and these organs. From table 3, thyroid, breasts and gonads mean doses are significantly different when plugs are used during treatment. For the lateral canthus and vertex, the difference is not so significant, probably due to presence of direct beams on TL dosimeters.

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Conclusions

From this study on 228 treated patients, different analyses give an idea on how to choose a good compromise between conformal treatment and the lowest extracranial doses. The treatment of some pathologies, like meningioma, gives a significantly higher dose due to their complex shape, for instance. It is therefore important to keep in mind, especially for benign lesions, that extracranial sites are exposed and that treatment planning can be optimized to reduce total time. No obvious correlation exists between maximum dose, treated volume, integral dose and extracranial doses. On the other hand, total treatment time has a relatively important influence on extracranial doses and the use of plugs in trigeminal neuralgia treatment can also give a higher dose to extracranial sites. In order to optimize treatment time, it is better to choose larger collimators for large simple targets to minimize the total number of shots and therefore the total treatment time.

References 1 2

3

4 5 6 7 8

Ertl A, Zehetmayer M, Schoggl A, et al: Shuttle dose at the Vienna Leksell gamma knife. Phys Med Biol 1998;43:1567–1578. Novotny J Jr, Novotny J, Hobzova L, Simonova G, Liscak R, Vladyka V: Transportation dose and doses to extracranial sites during stereotactic radiosurgery with the Leksell gamma knife. Stereotact Funct Neurosurg 1996;66:170–183. Horstmann GA, Schöpgens H, Van Eck ATCJ, Kreiner HJ, Hertz W: First clinical experience with the automatic positioning system and Leksell gamma knife model C, Technical note. J Neurosurg 2000;93(suppl 3):193–197. ICRP Publ 60: 1990 Recommendations of the International Commission of Radiological Protection. Annals of the ICRP, vol 21/1–3. Yu C, Jozsef G, Apuzzo MLJ, McPherson D, Petrovich Z: Fetal radiation doses for model C gamma knife radiosurgery. Neurosurgery 2003;52:687–693. Yu C, Jozsef G, Apuzzo MLJ, McPherson D, Petrovich Z: Extracranial radiation doses in patients undergoing gamma knife radiosurgery. Neurosurgery 1997;41:553–560. Berk HW, Larner JM, Spaulding C, Agarwal SK, Scott MR, Steiner L: Extracranial absorbed doses with gamma knife radiosurgery. Stereotact Funct Neurosurg 1993;61(suppl 1):164–172. Bradford CD, Morabito B, Shearer DR, Noren G, Chougule P: Radiation-induced epilation due to couch transit dose for the Leksell gamma knife model C. Int J Radiat Oncol Biol Phys 2002;54: 1134–1139.

Francoise De Smedt Centre Gamma Knife, Hôpital Erasme Route de Lennik, 808, BE–1070 Brussels (Belgium) Tel. ⫹32 2 5553174, Fax ⫹32 2 5553176, E-Mail [email protected]

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Kondziolka D (ed): Radiosurgery. Basel, Karger, 2004, vol 5, pp 213–224

MAGIC – Normoxic Polymer Gel Dosimetry in Radiosurgery Stefan G. Scheiba, Walter Vogelsangerb a b

Klinik Im Park, Department of Medical Radiation Physics, Zürich and Kantonsschule Schaffhausen, Schaffhausen, Switzerland

Abstract Theoretically, gel dosimeters, which change their NMR properties when irradiated, are suitable for narrow photon beam dosimetry in radiosurgery. Recently, the formulation for a new polymer gel (MAGIC), which is made under normal atmospheric conditions, was proposed and investigated. Gel batches have been produced with varying chemical compositions and dose-response curves were measured up to 50 Gy delivered using Gamma Knife® B. A clinical 1.5 T MR scanner was used and two Hahn spin echo pulse sequences with a repetition time of 1 s and echo times of 10 and 40 ms were chosen to calculate the 3D R2 map of the irradiated gel samples. The slope and intercept of the dose-R2 relationship change with the chemical composition of the gel and the curve is linear up to a dose of 50 Gy. Depending on the gel composition, the intercept varies between 3 and 4 s⫺1 and the slope between 0.79 and 0.95 (Gys)⫺1 at room temperature. These preliminary results, together with first dose verifications using Gamma Knife B, are promising, especially considering the ease of MAGIC gel manufacturing in a clinical environment. Copyright © 2004 S. Karger AG, Basel

Theoretically, gel dosimeters, which change their NMR and optical properties when being irradiated, are suitable for narrow photon beam dosimetry in radiosurgery; these dosimeters are tissue equivalent, their response is independent of the dose rate and photon energy applied in clinical situations, the response is directionally independent and they show a linear dose-response relationship [1]. Dosimetry gels act as absorbing medium and are integrating 3D dosimeters with variable isotropic sub-millimeter spatial resolution [2], depending on the method of analyses, for which either MR or optical CT scanning may be chosen [3]. Furthermore, gel dosimeters can also be used for absolute dose verifications in areas where lateral electronic equilibrium does not exist [4].

However, Fricke-based dosimetry gels suffer from diffusion effects thus blurring the measured dose distribution and polymer gels, which do not show such effects, have to be manufactured and used in hypoxic conditions often using toxic components. Currently the most common polymer gels used for clinical dose verifications are BANG-type polymer gels [5–8]. A disadvantage of these gels is the component bisacrylamide, which is toxic. Also, any oxygen contamination during manufacturing and storage of these gels inhibits polymerization, because oxygen acts as a free radical scavenger. Therefore, these gels have to be manufactured in sealed oxygen-free systems and phantom containers which are non-permeable to oxygen must be used, further complicating the use of these gels in a clinical environment. Recently, the formulation for a new polymer gel, which is made under normal atmospheric conditions, has been published [9]. The gel, named MAGIC, which is an acronym, is made of water, hydroquinone (18 mmol/l), Methacrylic (9%) and Ascorbic (2 mmol/l) acid in Gelatin (8%), Initiated by Copper (CuSO4 ⭈ 5H2O, 0.02 mmol/l). The advantage of MAGIC polymer gel is that manufacturing and processing can be performed under normal atmospheric conditions, therefore this gel is also called normoxic [10, 11] and the components of this gel are less toxic than those of BANG-type gels. Only a few accessories for MAGIC gel production are necessary, lowering the investment compared to a sealed gel production system and further facilitating the use of this gel, which can be easily produced in a clinical environment. The purpose of this study was to initiate the production of MAGIC gel on site, to produce several gel batches with varying concentrations of their compounds, to measure dose-response curves, to investigate aging effects and to use this polymer gel in a simple Gamma Knife® dose verification.

Material and Methods For gel manufacture we used a balance (10-mg scale), a thermometer, different vessels and a hotplate including a magnetic stirrer. Starting from Fongs formula [9], we defined our standard gel composition shown in table 1. Gel batches (of 1 kg each) have been produced with different amounts of methacrylic acid (12, 9 and 6% by weight), CuSO4 ⭈5H2O (0.04, 0.02 and 0.01 mmol/l) and hydroquinone (10, 1 and 0 mmol/l). Gelatine (8% by weight) and ascorbic acid (2 mmol/l) concentrations have not been changed in this study. Methacrylic acid, the monomer homogeneously distributed in the gel matrix and containing approximately 250 ppm hydroquinone, was added by the manufacturer in order to prevent polymerization on stock. Ascorbic acid together with copper sulfate builds complexes which act as oxygen scavenger and will bind the oxygen dissolved within the gel, dependent on their concentration, within hours [10]. For the production of 1 kg of gel, 80 g of gelatine were added to 709 g of distilled water. This compound was heated in a water bath to approximately 50⬚C stirring continuously. After

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Table 1. Chemical composition of 1,000 g standard MAGIC gel Compound

Amount

Concentration

Mixed together

Total amount of gel

1,000.4 g

100%

–

Distilled water

830 g

–

709.0 g

Gelatine type A from porcine skin Sigma, 300 Bloom, [9000-70-8]

80 g

8%

80.0 g

Hydroquinone Sigma, 99⫹%, [123-31-9]

1.101 g

10 mmol/l

100.0 g solution

Ascorbic acid Fluka, ⬎99%, [50-81-7]

0.35226 g

2 mmol/l

20.0 g solution

CuSO4 ⭈5H2O Copper (II) sulfate pentahydrate 98⫹%, [7758-99-8]

0.0024968 g

0.01 mmol/l

1.0 g solution

Methacrylic acid Sigma, 99%, [79-41-4]

90 g

9%

90.0 g

the gelatine was completely melted and dissolved the compound was cooled down to approximately 35⬚C. In the meantime three different solutions were produced: 1.10 g of hydroquinone in 100 g water, 0.25 g of copper sulfate in 100 g water and 1.76 g of ascorbic acid in 100 g water. Then 20 g of the ascorbic acid solution and 1 g of the copper sulfate solution were poured into the hydroquinone solution and mixed together. The hydroquinone-copper-sulfate-ascorbic-acid mixture and also 90 g of methacrylic acid are added to the cooled gelatine. The gel was well mixed without creating air bubbles and then filled into small glass vials (diameter ⫽ 23 mm, height ⫽ 45 mm) and larger PVC and PET containers (3 ⫻ 3 cm2, 4.5 cm height and 3.7 ⫻ 3.7 cm2, 6 cm height). The vials and containers were filled up to the top and then closed with a lid in order to prevent additional oxygen diffusion into the gel while solidifying. The gel was kept in the dark at room temperature for approximately 10 h to solidify and then was stored in a refrigerator. The whole manufacturing procedure is very simple, since no glove box or oxygen purging is necessary, and took approximately 2 h per gel batch. The gel samples were allowed to equalize to room temperature for several hours prior to irradiation and were mounted in the center of a tissue equivalent (PMMA), spherical phantom (diameter ⫽ 16 cm). For irradiation a Gamma Knife® B (mean photo energy ⫽ 1.25 MeV) equipped with the 18-mm collimator helmet, delivering a dose rate of 3.5 Gy/min, was used. In order to measure dose-response curves, several gel samples were irradiated up to a maximum of 50 Gy. After irradiation the previously translucent gels become cloudy, dependent on the absorbed dose, so that the gel could also be analyzed by optical CT scanning [3]. In this study we used a clinical whole-body 1.5 T MR scanner (GE Signa 1.5 Echospeed LFX) and the head coil to measure the dose-dependent spin-spin relaxation rate R2. It is well known [1] that the relaxation rate R2 varies linearly with absorbed dose and can be calculated using spin echo imaging. In this study, two single spin echo pulse sequences (Hahn spin echo) with echo times of 10 and 40 ms were applied (details shown in table 2). The two 3D image data sets for the

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Table 2. MR imaging parameters of the applied single spin echo (Hahn spin echo) pulse sequences

Repetition time, TR Echo times, TE Field of view, FOV Bandwidth Slice thickness Number of slices Spacing Frequency direction Phase direction Number of acquisitions Phase field of view Frequency direction Scanning time per TE

1,000 ms 10, 40 ms 33 cm 15.63 MHz 2.0 mm 26 Interleave 256 pixel 256 pixel 4 0.50 L/R 22 min

different echo times were exported to an in-house developed analyses software which calculates the 3D R2 ⫽ 1/T2 distribution according to R2 ⫽

 S (TE1 )  1 ⭈ ln  TE2 ⫺ TE1  S (TE2 ) 

The homogeneous dose plateau region of the 18-mm collimator dose distribution was analyzed for each vial and the dose-dependent mean value and standard deviation of the measured R2 values were calculated using a circular area with a radius of 5 mm. The geometrical resolution chosen was 1.3 ⫻ 1.3 ⫻ 2.0 mm3. In order to measure the temperature dependence of the measured R2 values a standard gel composition was scanned at temperatures from 11 to 29⬚C. The room temperature of the MR suite was 25⬚C. Also a dose-response curve for the standard gel composition was measured for a maximum dose of 5 Gy in order to investigate the potential use of this gel for fractionated treatment regimens. In order to investigate the aging effects of the gel, several samples of the same batch were repeatedly scanned and their dose- and time-dependent R2 values were recorded. To test the stability of the analysis, several samples of the same gel batch were analyzed prior irradiation to measure their R2 values. Finally, an absolute 3D dose verification using the standard gel composition was performed. A gel container (3.7 ⫻ 3.7 cm2, 6 cm height) was mounted in the center of the spherical phantom and was irradiated to a maximum dose of 20 Gy using the 14-mm collimator helmet. Using our gel analyses software, the dose-response curve of this gel composition was used to calculate the measured 3D absolute dose distribution and to compare it with that calculated by the treatment-planning system.

Results

Dependent on the chemical composition, the dose-response curves were linear up to a dose of 50 Gy (fig. 1–3). The indicated error in R2 (range 3–55 s⫺1)

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70

60

R2 (1/s)

50

40

30

20 12% methacrylic acid 9% methacrylic acid 6% methacrylic acid

10

0 0

20

40

60

Dose (Gy)

Fig. 1. Relaxation rate R2 as a function of dose from 0 to 50 Gy for 6, 9 and 12% by weight methacrylic acid for the standard gel composition.

60

50

R2 (1/s)

40

30

20 0.04mmol/l copper sulfate 10

0.02mmol/l copper sulfate 0.01mmol/l copper sulfate

0 0

20

40

60

Dose (Gy)

Fig. 2. Relaxation rate R2 as a function of dose from 0 to 50 Gy for 0.01, 0.02 and 0.04 mmol/l copper sulfate concentration for the standard gel composition.

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60

50

R2 (1/s)

40

30

20 10mmol/l hydroquinone 10

1mmol/l hydroquinone 0mmol/l hydroquinone

0 0

10

20

30 Dose (Gy)

40

50

60

Fig. 3. Relaxation rate R2 as a function of dose from 0 to 50 Gy for 0, 1 and 10 mmol/l hydroquinone concentration for the standard gel composition. Some hydroquinone (250 ppm) is added to the methacrylic acid by the manufacturer in order to prevent polymerization on stock.

increases with increasing dose to a maximum value of 5%. The slope of the dose-response curves varies between 0.79 and 0.95 (Gys)⫺1, the intercept between 3 and 4 s⫺1. For each variation of the chemical compositions, we started from the standard gel composition quoted in table 1. Changing the amount of the monomer, the methacrylic acid, from 6 to 9 and 12% by weight, results in a significant change of the dose-response curve as seen in figure 1. We found a correlation between methacrylic acid amount and linearity and saturation dose of the doseresponse curves. In figure 2 the effect of the variation of the copper sulfate concentration (0.01, 0.02 and 0.04 mmol/l) on the dose-response curve for the standard gel composition is shown. The measured data can be fitted by a linear dose-response relation with increased slope for decreased copper sulfate concentrations. Figure 3 shows the variation of the dose-response curves for the standard composition with varying concentration of hydroquinone (0, 1 and 10 mmol/l), which inhibits autopolymerization. The more hydroquinone is added, the lower the slope will be. As shown in figure 4, the measured relaxation rate and therefore the dose to R2 relationship varies with the temperature of the gel during MR imaging. With decreasing gel temperature the slope of the dose-response curve increases, resulting in an improved sensitivity and dose resolution. Figure 5 is a different plot of the data shown in figure 4. The measured R2 values are

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40

11⬚C 15⬚C 20⬚C 21⬚C 29⬚C

35 30

R2 (1/s)

25 20 15 10 5 0 0

5

10

15

20

25

Dose (Gy)

Fig. 4. Relaxation rate as a function of dose for different gel temperatures from 11 to 29⬚C during MR imaging.

45

20Gy 15Gy 10Gy 5 Gy 2 Gy 1 Gy Linear (20Gy) Linear (5Gy)

40 35

R2 (1/s)

30 25 20 15 10 5 0 0

10

20

30

40

Temperature (⬚C)

Fig. 5. R2 as a function of gel temperature during MR imaging for absorbed doses from 1 to 20 Gy.

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9 8 7

R2 (1/s)

6 5 4 3 2 1 0 0

1

2

3 Dose (Gy)

4

5

6

Fig. 6. R2 as a function of dose from 0 to 5 Gy for the standard gel composition.

plotted against temperature, now with the dose being the parameter for the different curves. For different doses, the linear temperature to R2 fits intersect each other at a temperature of 38⬚C, the melting temperature of the gel. Figure 6 shows the linear dose-response curve for the standard gel composition in the low-dose region as used for fractionated treatment regimens. The maximum error in R2 was 6%. In figure 7 the time-dependent change in R2 after irradiation is shown for a time delay of up to 75 h. It can be clearly seen that the R2 values decrease with increasing time after irradiation, therefore slightly decreasing the slope of the linear dose-response curve and decreasing the dose resolution. Figure 8 shows the variation of the mean R2 values measured for 6 non-irradiated gel samples measured simultaneously at different positions within the head coil. The mean value is 3.08 ⫾ 0.21 1/s. Figure 9 shows a comparison of the calculated (solid line) and measured (broken line) dose profile along the X-axis for the absolute dose distribution using the 14-mm collimator helmet in the center of the sphere.

Discussion

Lowering the monomer concentration causes saturation effects to occur at rather low doses. In order to cover the dose range applied in radiosurgery we recommend 9% by weight of methacrylic acid, since this results in a fairly

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30

0Gy 10Gy 20Gy

25

30Gy

R2 (1/s)

20

15

10

5

0 0

20

40

60

80

Time between irradiation and imaging (h)

Fig. 7. R2 as a function of time between irradiation and MR imaging for various absorbed dose values.

4

R2 (1/s)

3

2

1

0 0

1

2

3 4 Number of vial

5

6

Fig. 8. R2 for six unirradiated gel samples from the same batch coincide within their error bars.

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25

Dose (Gy)

15

10

5

0 70

80

90

100 110 X-axis (mm)

120

130

Fig. 9. Dose profile along the X-axis for an absolute dose verification using a single 14-mm collimator helmet and a spherical tissue equivalent sphere (diameter ⫽ 16 cm) with Gamma Knife® B and a maximum dose of 20 Gy. The solid line represents the calculated dose profile and the broken line represents the measured dose profile.

linear dose-response curve up to 50 Gy. Since copper sulfate acts as an oxygen scavenger, together with ascorbic acid, which was not changed in this study, it has been demonstrated that an increasing concentration of copper sulfate inhibits the radiation-induced polymerization [10]. In order to get a steep doseresponse curve and to scavenge the dissolved oxygen within a reasonable time, a copper sulfate concentration of 0.01 mmol/l is adequate. As mentioned, 250 ppm hydroquinone is already part of the methacrylic acid in order to prevent polymerization on stock. The further the hydroquinone concentration is increased, the more the radiation-induced polymerization will be inhibited, thus decreasing the slope of the dose-response curve. For polymer gels, the dose response is highly dependent on the gel temperature during MR scanning [12]. The lower the temperature, the steeper the dose-response curve will be. Therefore, the readout temperature has to be known in order to extract correction factors if the calibration gels are not scanned together with the verification gel. Aging effects, meaning the decrease of R2 with time, are also demonstrated for polymer gels and can be corrected

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for, if necessary. Alternatively a set of calibration measurements could be done at the same time as the verification experiment for the same gel batch, in order to decrease such uncertainties to an acceptable level. The uncertainty introduced by the analyses of different gel samples of the same batch is in the order of the uncertainty of the measured R2 values, which can be decreased by optimized NMR imaging parameters such as optimized echo times. The first absolute dose verification using the MAGIC gel demonstrated the potential of this new polymer gel in small beam photon dosimetry for radiosurgery. In conclusion it can be pointed out that MAGIC gel dosimetry can be easily introduced in a clinical environment. The accessories and chemicals necessary for gel production are relatively cheap and the manufacturing process under normal oxygenation is very simple. Toxicity of the chemical compounds is not a real problem, however, methacrylic acid and hydroquinone should be handled with care. The calibration and verification gel should be scanned at the same temperature, aging effects should be known and the gel has to kept away from any UV light because of background polymerization. These effects are very similar to polymer gels and well known. The steep and linear dose response up to 50 Gy makes this gel an ideal candidate for 3D dose verifications in radiosurgery.

References 1 2

3 4

5

6

7

8

Maryanski MJ, Ibbott GS, Eastman P, Schulz RJ, Gore JC: Radiation therapy dosimetry using resonance imaging of polymer gels. Med Phys 1996;23:699–705. Ertl A, Berg M, Zehetmayer M, Frigo P: High-resolution dose profile studies based on MR imaging with polymer BANG™ gels in stereotactic radiation techniques. Magn Reson Imaging 2000;18:343–349. Oldham M, Siewerdsen JH, Shetty A, Jaffray DA: High-resolution gel dosimetry by optical CT and MR scanning. Med Phys 2001;28:1436–1445. Mack A, Scheib SG, Major J, Gianolini S, Pazmandi G, Feist H, Czempiel H, Kreiner HJ: Precision dosimetry for narrow photon beams used in radiosurgery – Determination of Gamma Knife® output factors. Med Phys 2002;29:2080–2089. Meeks SL, Bova FJ, Maryanski MJ, Kendrick LA, Ranade MK, Buatti JM, Friedman WA: Image registration of BANG gel dose maps for quantitative dosimetry verification. Int J Radiat Oncol Biol Phys 1999;43:1135–1141. Ibbott GS, Maryanski MJ, Eastman P, Holcomb SD, Zhang Y, Avison RG, Sanders M, Gore JC: Three-dimensional visualization and measurement of conformal dose distributions using magnetic resonance imaging of BANG polymer gel dosimeters. Int J Radiat Oncol Biol Phys 1997;38:1097–1103. Low DA, Dempsey JF, Venkatesan R, Mutic S, Markman J, Mark Haacke E, Purdy JA: Evaluation of polymer gels and MRI as a 3-D dosimeter for intensity-modulated radiation therapy. Med Phys 1999;26:1542–1551. Novotny J Jr, Novotny J, Spevacek V, Dvorak P, Cechak T, Liscak R, Brozek G, Tintera J, Vymazal J: Application of polymer gel dosimetry in gamma knife radiosurgery. J Neurosurg 2002;97: 556–562.

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9 10 11 12

Fong PM, Keil DC, Does MD, Core JC: Polymer gels for magnetic resonance imaging of radiation dose distributions at normal room atmosphere. Phys Med Biol 2001;46:3105–3113. De Deene Y, Hurley C, Venning A, Vergote K, Mather M, Healy BJ, Baldock C: A basic study of some normoxic polymer gel dosimeters. Phys Med Biol 2002;47:3441–3463. De Deene Y, Venning A, Hurley C, Healy BJ, Baldock C: Dose-response stability and integrity of the dose distribution of various polymer gel dosimeters. Phys Med Biol 2002;47:2459–2470. Maryanski MJ, Audet C, Gore JC: Effects of cross-linking and temperature on the dose response of a BANG polymer gel dosimeter. Phys Med Biol 1997;42:303–311.

Stefan G. Scheib, PhD Department of Medical Radiation Physics, Klinik Im Park Seestrasse 220, CH–8027 Zürich (Switzerland) Tel. ⫹41 1 2092216, Fax ⫹41 1 2092011, E-Mail [email protected]

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Measurement of Relative Dose Distributions in Stereotactic Radiosurgery by the Polymer-Gel Dosimeter Josef Novotný, Jr.a,e, Václav Spe¤vác¤ek b, Jan Hrbác¤ek b, Libor Judas c, Josef Novotný a, Pavel Dvor¤ák b, Daniela Tlachác¤ováa, Michal Schmitt a, Jaroslav Tinte¤ra a, Josef Vymazal a, Tomas¤ C¤echák b, Jir¤í Michálek d, Martin Pr¤ádnýd, Roman Lišc¤ák a a Na Homolce Hospital; bCTU in Prague, Faculty of Nuclear Science and Physical Engineering; cGeneral Teaching Hospital, Department of Radiation Protection; dInstitute of Macromolecular Chemistry Academy of Science CR, and eCharles University in Prague, 1st Faculty of Medicine, Institute of Biophysics and Informatics, Prague, Czech Republic

Abstract The purpose of this study was to evaluate relative dose distributions in six various treatment plans (acoustic schwannoma, pituitary adenoma, meningioma, metastasis, uveal melanoma and glaucoma) in the Leksell gamma knife stereotactic radiosurgery procedure by polymer-gel dosimeter. The presented experiment allowed a check of the entire stereotactic procedure including target stereotactic localization on MRI, treatment planning and irradiation. Relatively good agreement between dose profiles calculated and measured in a special head phantom by polymer-gel dosimeter was observed. The maximum observed deviation in the spatial position of the center of measured and calculated dose profiles was 0.9 mm (median 0.3). Maximum observed difference in FWHM of measured and calculated profiles was 3.0 mm (median 1.4). No significant difference was observed in deviations between calculated and measured dose profiles related to different treatments simulated in this experiment. The use of the polymer-gel dosimeter for verification of stereotactic procedures has some unique advantages compared to other dosimetric systems which can be summarized as follows: (1) the dosimeter itself is tissue equivalent, (2) three-dimensional dose distributions can be measured, and (3) the dosimeter allows simulation of the patient’s procedures without any limitations. Copyright © 2004 S. Karger AG, Basel

Three-dimensional dose distributions created in stereotactic radiosurgery or radiotherapy are specifically tailored to individual targets. To assure the quality of the whole treatment procedure, proper phantoms and dosimetric systems are required. Since stereotactic radiosurgery or radiotherapy can create rather complicated three-dimensional dose distributions, the dosimetric system should ideally be able to measure the dose distribution in three-dimensional space as well. The polymer-gel dosimeter is a promising tool to satisfy this requirement [1–6]. Polymer-gel dosimetry is based on radiation-induced polymerization and cross-linking of acrylic monomers. The concentration of radiation produced polymer and the degree of cross-linking in the irradiated regions of the gel (which are proportional to the applied dose) increases the nuclear magnetic resonance (NMR) relaxation rates of neighboring water protons. Consequently, three-dimensional dose distributions can be measured and visualized after dosimeter NMR relaxometry. The purpose of this study was to evaluate relative dose distributions in the Leksell gamma knife (Elekta Instrument AB, Stockholm, Sweden) stereotactic radiosurgery procedure by the polymer-gel dosimeter. Therefore, six various treatment plans were simulated and measured.

Methods and Materials Polymer-Gel Dosimeter Preparation The polymer-gel dosimeter was prepared according to procedures described elsewhere [7, 8]. Fluorescent purity grade N,N⬘-methylene-bisacrylamide obtained from Applichem (Darmstadt, Germany), electrophoresis grade acrylic acid obtained from Riedel-de Haen (Seelze, Germany) and gelatin type A (acid-derived), approximately 300 Bloom obtained from Sigma (Sheboygan, Wisc., USA) were used for the gel preparation. Distilled purified water was always used. Chemical composition of the polymer gel used in this study is given in table 1. The prepared polymer gel was poured into eleven cylindrically shaped glass vessels (inner diameter 15 mm, length 75 mm, wall thickness 2 mm) used for the dosimeter calibration and six spherically shaped glass vessels (inner diameter 46 mm, wall thickness 3 mm) used for the irradiation on the Leksell gamma knife. To assure maximum precision, all samples used in this study originated from the same batch. Polymer-Gel Dosimeter Calibration and Irradiation Calibration of the polymer-gel dosimeter was done on 60Co unit Theratron 1000 (MDS Nordion, Canada). Altogether, nine samples were subsequently fixed in the center of the water-filled cylinder (inner diameter 185 mm, length 240 mm) and irradiated by box technique (field size 100 ⫻ 100 mm2, SSD 1,000 mm) by doses in the range of 2–20 Gy. Two non-irradiated dosimeters were used for background reading. Six spherical test vessels filled with the polymer gel were subsequently fixed in the special holder in the different positions of the water-filled head phantom (fig. 1).

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Table 1. Chemical composition of the polymer-gel dosimeter used in this study Component

Formula

Weight fraction %

N,N⬘-methylene-bisacrylamide Acrylic acid Sodium hydroxide Gelatin Water

(CH2CHCONH)2CH2 CH2CHCOOH NaOH (C17H32N5O6)X H2O

3.0 3.0 0.3 5.0 88.7

a

b Fig. 1. Water-filled head phantom with the special fixation holder. a Spherically shaped glass test vessel filled by the polymer-gel dosimeter was fixed with the use of the special holder. This holder allowed fixation of the test vessel in any position in the head phantom. b Water-filled head phantom was fixed in the Leksell stereotactic frame. A special indicator box was attached to the frame for the NMR stereotactic investigation.

To simulate the patient procedure as closely as possible, the head phantom was then fixed in the stereotactic frame (fig. 1) and underwent stereotactic NMR localization. Treatment plans were calculated for the head phantom using the Leksell GammaPlan (Elekta Instrument AB) treatment planning software. Altogether, six different treatment plans from normal clinical cases were selected and recalculated for the head phantom. Detailed

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Table 2. Some characteristics of different treatments simulated in this study Simulated treatment

Collimator size, mm

Total number of isocenters

Plugging

Acoustic schwannoma Pituitary adenoma Meningioma Metastasis Uveal melanoma Glaucoma

4 8 14 14 8 8

13 5 8 4 1 4

None 51 sources plugged None None None 37 sources plugged

a

b Fig. 2. Irradiation of the head phantom with the polymer-gel dosimeter by the Leksell gamma knife. Irradiation was based on the Leksell GammaPlan treatment planning software. a Phantom was irradiated in the Automatic Positioning System (APS) in the case of acoustic schwannoma, pituitary adenoma, meningioma and metastasis. b In the case of uveal melanoma and glaucoma the head phantom was irradiated in the prone position using trunnions.

description of these plans is given in table 2. All steps during treatment planning were done as usually for an ordinary patient’s treatment. Finally, the head phantom was irradiated in the Leksell gamma knife based on the calculated treatment plans with the maximum dose to the target of 14 Gy. The phantom was irradiated in the Automatic Positioning System (APS) in the case of acoustic schwannoma, pituitary adenoma, meningioma and metastasis. In the case of uveal melanoma and glaucoma, the head phantom was irradiated in the prone position using trunnions (fig. 2). Polymer-Gel Dosimeter Evaluation Evaluation of the polymerized polymer-gel dosimeter was performed on a Siemens Expert 1T scanner in the transmitter/receiver head coil at least 24 h after irradiation.

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A multi-echo sequence with 16 echoes was used for the evaluation of irradiated polymergel dosimeters. The parameters of the sequence were as follows: TR 2,000 ms, TE 22.5, 45.0, 67.5, 90.0, 112.5, 135.0, 157.5, 180.0, 202.5, 225.0, 247.5, 270.0, 292.5, 315.0, 337.5, 360.0 ms, slice thickness 2 mm, FOV 255 mm, matrix size 256 ⫻ 256, pixel size 1.00 ⫻ 1.00 mm2, one acquisition. All NMR measured T2 relaxation data were corrected to one reference temperature of 25.0⬚C using an algorithm described elsewhere [7]. Further details about the evaluation can be found in Novotný et al. [5, 6]. To quantify obtained results, comparison of 50% isodose lines between measured data and calculated ones was carried out. Since the majority of treatment plans are using 50% isodose (or very close to this value), as a typical target peripheral isodose in the case of the Leksell gamma knife, the selected value seems to be optimal. Two parameters that express the difference between calculated and measured dose distributions at the 50% isodose level were used. The first one was defined as a difference in the position between the center of the profile calculated by the treatment planning system and the measured one. The center of the profile was defined as a center of full width in half maximum (FWHM). Values of these differences were calculated for each volume in each of three axes and denoted as ⌬X, ⌬Y, ⌬Z. The second parameter expressed the difference between the size of the calculated and measured 50% isodose curves (difference of FWHMs for evaluated profiles). These differences were calculated for each volume in each of three axes. Values of these differences were denoted as ⌬FWHMX, ⌬FWHMY and ⌬FWHMZ.

Results

Polymerization that occurred in the irradiated samples together with threedimensional views of treatment plans is shown in figure 3. Examples of comparison between measured and calculated dose profiles are given in figure 4. Values of ⌬X, ⌬Y, ⌬Z, ⌬FWHMX, ⌬FWHMY and ⌬FWHMZ for all six evaluated treatments in this study are summarized in table 3.

Discussion

The presented experiment allowed a check of the entire stereotactic procedure with the Leksell gamma knife including target stereotactic localization on NMR, treatment planning and irradiation. Consequently, both mechanical and dosimetric (relative dosimetry) parameters can be evaluated at the same time and the total inaccuracy of the procedure can be assessed. This study is continuation of simpler experiment performed by authors when irradiation of the dosimeter by only one isocenter positioned in the center of the head phantom was subsequently checked for all four different Leksell gamma knife collimator helmets [6]. More complicated treatment plans including multiple isocenters, plugged collimator helmets and eccentric targets were simulated in this study.

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a

b

c

d

e

f

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The presented method has some unique advantages compared to other dosimetric methods. Firstly, the polymer gel is tissue equivalent. That unique property of the dosimeter means that there is no perturbation of the measured dose distribution compared to other dosimetric systems such as ion chamber, semiconductor detector, thermoluminescent dosimeter, film dosimeter, etc. Secondly, the total three-dimensional dose distribution can be obtained. Although only dose profiles in X, Y and Z axes are evaluated in this study it would be possible to obtain and evaluate a dose distribution in any selected plane. Since the total three-dimensional dose distribution can be obtained from the polymer-gel dosimeter it would be possible to check some other parameters (used for the treatment planning optimization) calculated by the treatment planning system such as dose volume histograms. Thirdly, the polymer-gel dosimeter allows simulation of the patient’s treatment procedure without any limitations. The polymer-gel dosimeter can be filled in any anatomical phantom and allows the full three-dimensional dose distribution to be obtained after irradiation. It implies that it is not necessary to do any non-standard steps compared to the patient’s procedure. Thus the polymer-gel dosimeter allows to check the entire treatment chain from the target imaging, treatment planning and irradiation itself. Relatively good agreement between dose profiles calculated and measured was observed. The maximum observed deviation in the spatial position of the center of measured and calculated dose profiles was 0.9 mm (median 0.3). Maximum observed difference in FWHM of measured and calculated profiles was 3.0 mm (median 1.4). A significant difference was not observed in deviations between calculated and measured dose profiles related to different treatments simulated in this experiment. Some discrepancy between profiles measured by the polymer gel and calculated ones was observed mainly in the region of lower percentage dose levels, especially below 20%. The reason for this discrepancy is given probably by increased uncertainty of dose determination by the polymer-gel dosimeter at low doses (⬃2.0 Gy). The median observed deviation in the spatial position of the center of measured and calculated dose profiles was exactly the same as in a simpler experiment performed previously by the current authors [6]. However, the median observed difference in FWHM of measured and calculated profiles was larger in this study than in previous experiment [6] (median 1.4 mm Fig. 3. Three-dimensional views of different treatment plans: a acoustic schwannoma, b pituitary adenoma, c meningioma, d metastasis, e uveal melanoma, f glaucoma. These plans were calculated by the Leksell GammaPlan treatment planning software. Polymerization that occurred in polymer-gel dosimeters irradiated by these plans is shown too.

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10

15

20

30

35

10

15

20

25

30

Z axis gel Z axis LGP

10

15

20

b Z axis gel Z axis LGP

5

110 100 90 80 70 60 50 40 30 20 10 0

40

Meningioma

110 100 90 80 70 60 50 40 30 20 10 0

c

35

40

10

15

20

Y coordinate (mm)

5

10

15

20

25

30

35

110 100 90 80 70 60 50 40 30 20 10 0 5

30

40

40

45

50

X coordinate (mm) Glaucoma

25

35

X axis gel X axis LGP

d

Y axis gel Y axis LGP

5

30

Metastasis

110 100 90 80 70 60 50 40 30 20 10 0

Uveal melanoma

110 100 90 80 70 60 50 40 30 20 10 0

25

Z coordinate (mm)

45

Z coordinate (mm)

Percentage dose

Percentage dose

25

Y coordinate (mm)

Percentage dose

Percentage dose

a

e

Pituitary adenoma Y axis gel Y axis LGP Percentage dose

Percentage dose

Acoustic schwannoma

110 100 90 80 70 60 50 40 30 20 10 0

10

15

f

20 25 30 X coordinate (mm)

X axis gel X axis LGP

35

Fig. 4. Examples of profiles calculated by the Leksell GammaPlan treatment planning software (LGP) and measured by the polymer-gel (gel) for different treatment plans are shown: a acoustic schwannoma, b pituitary adenoma, c meningioma, d metastasis, e uveal melanoma, f glaucoma profiles are presented.

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Table 3. Two parameters that express the difference between calculated and measured dose distributions at the 50% isodose level were used to perform quantitative evaluation of the results obtained in this study Simulated treatment

⌬X mm

⌬Y mm

⌬Z mm

⌬FWHMX mm

⌬FWHMY mm

⌬FWHMZ mm

Acoustic schwannoma Pituitary adenoma Meningioma Metastasis Uveal melanoma Glaucoma

0.1 0.4 0.3 0.4 0.4 0.2

0.1 0.4 0.1 0.2 0.2 0.1

0.2 0.3 0.9 0.8 0.1 0.5

1.6 1.5 2.1 1.5 0.2 0.8

0.9 3.0 1.1 1.9 0.2 2.5

1.4 0.6 0.4 1.3 1.4 1.5

The first one (⌬X, ⌬Y, ⌬Z) shows difference in the position between the center of the profile calculated by the treatment planning system and measured one. The center of the profile was defined as the center of full width in half maximum (FWHM). The second one (⌬FWHMX, ⌬FWHMY, ⌬FWHMZ) shows difference between the size of the 50% isodose curves calculated and measured ones.

compare to 0.3 mm) when only one single isocenter treatment was simulated. This discrepancy can be explained by much higher dose inhomogeneity in the treatments simulated in this study compared to single isocenter treatment. Consequently, small spatial misplacement between evaluated slices from the treatment planning system and polymer gel can create a relatively large discrepancy in dose distribution. Measurements done in this study are extremely sensitive for the correct matching of evaluated slices and profiles since very steep dose gradients are measured. Even a very small spatial difference between selected slices from the treatment planning system and slices from NMR evaluated polymer gel can cause a large deviation in dose distribution. A change of the relative dose even more than 20% per 1 mm was observed for some treatments verified in this study. Consequently, improvement of the spatial localization of evaluated samples could improve reliability and accuracy of the method. A very accurate geometric application of the dose is needed specially when high doses are applied and dose distributions with high gradients are used. Stereotactic radiosurgery with the Leksell gamma knife is a technique where very high biologically effective doses are applied with high precision to the target. The presented study demonstrates an effective technique to assess the entire geometric and dosimetric (relative) inaccuracies of the Leksell gamma knife treatment procedure. As mentioned above, the potential of the polymer-gel dosimeter is not just to measure the three-dimensional

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dose distribution of arbitrary treatment plans, but to check some other parameters such as dose volume histograms too. Additional measurements and comparison with other dosimetric techniques such as film dosimetry should clarify deviations between measured and calculated profiles found in this study.

Conclusions

The dosimetric technique described allows assessment of the entire geometric and dosimetric (relative) inaccuracies of the performed radiosurgical procedure. A reasonable agreement was observed between dose profiles measured and calculated by the treatment planning system for all tested treatment plans. The use of a polymer-gel dosimeter for verification of stereotactic procedures has some unique advantages compared to other dosimetric systems which can be summarized as follows: (1) the dosimeter itself is tissue equivalent, (2) three-dimensional dose distributions can be measured, and (3) the dosimeter allows simulation of the patient’s procedures without any limitations.

Acknowledgement The research presented in this study was supported by IGA MH CR grant NC 7460–3/2003.

References 1

2 3

4 5

6

Maryanski MJ, Schulz RJ, Ibott GS, Gatenby JC, Xie J, Horton D, Gore JC: Magnetic resonance imaging of radiation dose distributions using a polymer-gel dosimeter. Phys Med Biol 1994; 39:1437–1455. Maryanski MJ, Ibbott GS, Eastman P, Schulz RJ, Gore JC: Radiation therapy dosimetry using magnetic resonance imaging of polymer gels. Med Phys 1996;23:699–705. DeDeene Y, DeWagter C, VanDuyse B, Derycke S, DeNeve W, Achten E: Three-dimensional dosimetry using polymer gel and magnetic resonance imaging applied to the verification of conformal radiation therapy in head and neck cancer. Radiother Oncol 1998;48:283–291. Ertl A, Berg A, Zehetmayer M, Frigo P: High-resolution studies based on MR imaging with polymer BANG™ gels in stereotactic radiation techniques. Magn Reson Imaging 2000:18:343–349. Novotný J Jr, Novotný J, Spe¤vác¤ek V, Dvor¤ák P, C¤echák T, Lišc¤ák R, Broz¤ek G, Tinte¤ra J, Vymazal J: Application of polymer gel dosimetry in gamma knife radiosurgery. J Neurosurg 2002;97(suppl 5):556–562. Novotný J Jr, Dvor¤ák P, Spe¤vác¤ek V, Tinte¤ra J, Novotný J, C¤echák T, Lišc¤ák R: Quality control of the stereotactic radiosurgery procedure with the polymer-gel dosimetry. Radiother Oncol 2002;63: 223–230.

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Spe¤vác¤ek V, Novotný J Jr, Dvor¤ák P, Novotný J, Vymazal J, C¤echák T: Temperature dependence of polymer-gel dosimeter nuclear magnetic resonance response. Med Phys 2001;28:2370–2378. Novotný J Jr, Spe¤vác¤ek V, Dvor¤ák P, Novotný J, C¤echák T: Energy and dose rate dependence of BANG-2 polymer-gel dosimeter. Med Phys 2001;28:2379–2386.

Josef Novotný, Jr, MSc, PhD Na Homolce Hospital, Department of Medical Physics Roentgenova 2, Prague 5 150 30 (Czech Republic) Tel. ⫹420 604 203197, Fax ⫹420 257 210688, E-Mail [email protected]

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A System for Quality Assurance in Radiosurgery Andreas Mack b, Stefan G. Scheiba, Markus Rieker c, Dirk Weltzc, Guenther Mack d, Heinz Czempiel e, Hans J. Kreiner e, Heinz D. Boettcherf, Volker Seifert g a

Radiophysics/Gamma Knife, Klinik Im Park, Zürich, Switzerland; Gamma Knife Zentrum, Frankfurt; cPTGR-GmbH, Tübingen; dInstitute for Experimental Physics, Eberhard Karls University, Tübingen; eGKS GmbH, München; Departments of fRadiotherapy and Oncology, and gDepartment of Neurosurgery, Goethe University, Frankfurt, Germany

b

Abstract A quality assurance system has been developed for stereotactic radiosurgery and radiotherapy, to fulfill three goals: first to evaluate the geometrical error within imaging, second to simulate the complete chain of a treatment beginning with the imaging and ending with the application of dose, and third to verify calculated dose distributions in three dimensions with high spatial resolution and accuracy. A water-filled cylindrical imaging phantom has been manufactured in which equally spaced rods are placed. It can be mounted to a stereotactic frame in different orientations to be imaged using CT and MRI. The distances of the rod positions are analyzed and a reference grid can be positioned to calculate displacement vectors according to which e.g. the head coil can be adjusted. The spectral emission of the light and the filters together with the efficiency of the red CCD channel were matched and balanced with the absorption spectra of the radiochromic film used with the adapted drum scanner. Standardized software has been designed for evaluating the film data, for calibration, for correction of temperature and darkening and for test routines. A spherical phantom with shells and inserts of different tissue equivalent materials has been developed to simulate complex treatment situations within the human skull. Copyright © 2004 S. Karger AG, Basel

Concept

For a successful treatment in stereotactic radiotherapy and radiosurgery a thorough quality assurance is necessary [1, 2]. Three main parameters have to

be checked: the imaging quality as the most sensitive parameter [3], the overall uncertainty of a complete treatment, including the imaging, planning, adjusting the parameters and applying the dose [4], and the verification of calculated dose plans in phantoms [5]. QUASIR (quality assurance in radiosurgery/radiotherapy) was developed for these complex tasks. The quality assurance set is composed of different modules which are used to check and verify the most important uncertainties in stereotactic radiotherapy and radiosurgery (SRT/SRS). Standardized test routines can be performed according to E-DIN 6875-1. The components are: TOPAS (tomographic phantom analysis) consists of a phantom for checking the imaging quality of CT and MRI and a software routine for analyzing the scanned sequences and images for the investigation of artifacts and deviations [3]. STERAS (stereotactic radiosurgery/radiotherapy analysis) consists of a precise spherical phantom made up of hemispheres and shells of different materials, which can take inserts for different detectors and especially for radiosensitive Gafchromic® films for measuring dose distributions within the head phantom and a drum scanner with corresponding software for the analysis and evaluation of the irradiated self-developing films. Materials and Methods 1. TOPAS (tomographic phantom analysis) was developed to follow two goals: first to evaluate the magnitude of error within the volume of interest (e.g. head coil) and second, to develop a tool to adjust the fields of the scanners. A sphere cylinder with a diameter of 17.5 cm, filled with distilled water and equipped with 145 equally spaced rods of GFK, was constructed (fig. 1a). It can be mounted to the Leksell frame in different orientations (fig. 1b) to allow measurements in axial or in sagittal directions. The central rod is kept in position 100/100 of the corresponding plane. The images taken with the fiducial box for MRI or CT are evaluated by a software defining the images analog to the planning system (LGP). In a first step, the distances of the fiducials are analyzed, afterwards, a reference grid is positioned to any of the rods (preferably the central one) according to which a displacement vector is read out for each rod in every slice (fig. 1c). The results are shown in color distributions and histograms. Thus different sequences can be analyzed and compared. The set can be used for daily measurements and for adjusting gradient fields of MRI scanners and for balancing x-ray tubes of CT scanners. Furthermore, it can be used to check DSA facilities. 2. STERAS (stereotactic radiosurgery/radiotherapy analysis) was developed to follow three goals: first to determine the overall uncertainty of a complete treatment, including the imaging, planning, adjusting the parameters and applying the dose, second to develop a standard in finding the optimal treatment technique, and third to verify calculated dose distributions in phantoms. Phantom In order to describe dose distributions within small fields where no electron equilibrium exists as in cases for cavities and inhomogeneities (r, Z) and to take into account curved

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b

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c Fig. 1. a Cylinder phantom for determination of imaging artifacts in MRI and CT. The phantom consists of 145 rods which are arranged equidistantly in a quadratic grid. The body is filled with distilled water. b Cylinder phantom within the fiducial box ready for positioning in the head coil of the MR scanner. The phantom can be adjusted in different directions so that either axial or sagittal scans can be performed. c TOPAS main window after the calculations have been completed. The results are shown in the table and are represented in colors according to their magnitude.

surfaces, it is important to have measuring devices which model and simulate these complicated scatter conditions [6]. The spherical phantom suits these demands. The phantom consists of two hemispheres having a cubic clearance with the dimension of (7.2 cm3) (fig. 2b). This cavity can be filled with layers of different materials and thicknesses. Special inserts can house in all currently used stereotactic chambers as well as TLDs, alanine pellets and films (fig. 2c). The phantom can be enclosed in shells of different plastic materials, PMMA for water or Teflon for bone to represent the skull (fig. 2a). The coordinates of the phantom can be determined by using the corresponding fiducial box. For the purpose of verifying a calculated dose plan, the phantom can be adjusted within the stereotactic frame.

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c Fig. 2. a Spherical phantom with inserts for different dose meters (chamber, L-test, TLD) adjusted within the stereotactic frame, in this composition with hemispheres made from Teflon. Hemispheres made of PMMA are seen in the background. b Head phantom opened up with inserts made of different materials to be used for a variety of dosimetric techniques. c Inner hemisphere of the spherical phantom. A layer made of plastic (PMMA) to take TLDs is embedded in the cavity (7.2 cm3) of the hemisphere. There are additional inserts for chambers, films and alanine pellets. Film Dosimetry Radiochromic films are almost tissue equivalent and show hardly any energy dependence, with absorption peaks at 610 and 676 nm. After the dying process caused by irradiation, the sensitive layer of the Gafchromic® film MD-55 II shows the absorption distribution (fig. 3a). The film is self-developing, shows additivity which is important for fractionated techniques, has an excellent resolution and allows absolute dose measurements (fig. 3b). When using Gafchromic® film, several effects have to be taken into account, as for instance the dependence of the light absorption on the temperature, the darkening of the film after irradiation (fig. 3c) and the sensitivity to UV light. These effects are considered by choosing suitable measuring criteria and correction algorithms. A drum scanner is used to analyze the film data. The spectral emission of the light source and the characteristics of the filter

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together with the red channel were determined and superposed to the absorption spectrum of the radiochromic, almost tissue equivalent Gafchromic® film. In addition, a UV foil was mounted above the light source to protect the films from the UV light of the light source. For adaptation and optimization of the filter, light source and CCD channel to the absorption spectrum of the film [7], see figure 3a. Standardized Test Routines System Test This test quantifies the overall accuracy of any stereotactic treatment (SRS/SRT) by simulating a single isocenter irradiation [8]. In addition to other imaging modalities, the MR images are an integral part of the stereotactic system (SRS/SRT) and therefore must be

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c Fig. 4. a Spherical phantom with insert for the system test (capillary cross). b System test in radiosugery: a Gafchromic® film – embedded between the two capillary cross layers of the sphere phantom – runs through all steps of a radiosurgical treatment. The deviation of the coloring on the film to the premarked point in the center is measured. c Positioning of the film: the software recognizes the points and repositions different scans. The film size is 30 ⫻ 30 mm. The coloring in the middle is caused by the irradiation.

tested [9]. In order to evaluate how precisely a target can be irradiated, a Gafchromic® film is embedded between two plates both containing a capillary cross which can be filled with copper sulfate (fig. 4a). The film has marks at the edge so that the different scans can be positioned automatically. The cross or film plane together with the head phantom is adjusted either axially or sagittally within the stereotactic frame (fig. 4b). The position of the target is kept unknown until the dose is applied. After the images have been imported and defined and

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c Fig. 5. a L-test: the given target with the dimensions 12 ⫻ 8 mm and 4 mm in diameter. b Calculation in the planing system. c The experimental verification. The evaluation shows measured absolute dose distributions (isodose lines) and profiles.

the dose planning has been performed, the phantom is irradiated according to the data in the planning protocol. Finally, the film colored by the radiation is evaluated. The deviation from the center of gravity of the colored area to the center point marked at the beginning is measured and displayed (fig. 4c). L-Test In order to model a small irregularly formed target, a visible capillary ‘L’ with the dimension of 8 ⫻ 12 mm and diameter 4 mm is used (fig. 5a). As with the capillary cross, it can be filled with copper sulfate. It is a challenge for every stereotactic device (SRS/SRT), together with the planning system (fig. 5b), to model this artificially complex-shaped lesion as exactly and precisely as possible by using a high-dose gradient creating an optimum of

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c Fig. 6. a Verification of a dose plan for an acoustic neuroma: a stack of films embedded between the inserts of the phantom is irradiated according to the data in the protocol. This figure shows one plate of a stack in which a film can be inserted. b The planning of the acoustic neurinoma was performed, the stack of films irradiated according to protocol. c Analyzation of the stack of films. The screen shot shows the measured absolute dose distributions in different planes, represented as isodose lines.

conformity [10] (fig. 5c). This test is applied to choose the most suitable stereotactic radiation technique, e.g. Linac (arc, MLC) – gamma knife (plug patterns). Simulation Patient Calculated dose distributions (fig. 6b) can be verified by simulating the application of dose in the head phantom. After adjusting the coordinates and applying the dose, a stack of embedded films (fig. 6a) is read in and analyzed. The resulting measured dose distributions (fig. 6c) can be compared to the calculated parameters [11]. Several slab thicknesses can be chosen. The film thickness of 0.3 mm is the limiting parameter of the resolution orthogonal to the film plane. Several plates (1.5, 3.0 and 6 mm) allow any composition of stacks. Furthermore, different materials and dosimetric techniques can be combined.

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Results

The most sensitive technical factor having an influence on the overall precision of radiosurgery is the imaging (mainly MRI) study [12, 13]. The TOPAS set can be used for daily measurements and for adjusting gradient fields of MRI scanners and for balancing x-ray tubes of CT scanners. Furthermore, it can be used to check DSA facilities. The STERAS system allows the complete simulation of the patient treatment. Besides the checking of the overall uncertainty and finding the ideal treatment technique by hitting a target (L) as precise as possible, a stack of films can be used to verify calculated dose distributions in three dimensions delivering a dosemeter accuracy of better than 3% (double irradiation technique), when working carefully. The system allows resolutions down to 1/100 mm in film plane and 1.5 mm for the rectangular plane (slice thickness of film slab sandwich) and the dose range extends from 10 to 65 Gy. The software allows a comfortable handling and includes models to correct for base and fog, temperature and darkening of the film. The scanner satisfies by simple mechanics and is equipped with compartments, which have been optimized concerning the absorption spectra of the radiochromic film, delivering a high efficiency for the small interesting range between 610 and 676 nm. The sphere phantom can be used for any purpose in radiosurgery. Since it can be equipped with slabs of different materials to simulate bone, tissue and air, complicated situations can be modeled. The QA system fulfils the demands and standards of the German DIN and of the IEC.

Discussion

Based on our own experience and that of experts involved in stereotactic radiation procedures, four main areas of radiosurgery physics should be covered by a QA procedure [14]: determination of the imaging quality as the most sensitive parameter [15–21], measurements of the geometrical position accuracy of the total system (integrating system test) [22], measurement of output factors [23] (of intensity variations vs. collimator diameter) and tests and experimental verification of complex, 2- or 3-dimensional dose distributions as applied in real treatments [24–26]. Within this context, a key question is whether the 3-dimensional dose distribution (in regard to position and dose) planned in the dose planning system is congruent with the experimentally realized 3-dimensional dose distribution or the real treatment situation respectively [27–30]. The QA package can be applied for measuring these output factors,

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for verifying dose distributions (single fraction/fractionated) regarding dose and position, to ensure reproducibility of dose and position and for other applications in research (e.g. for checking the precision of planned dose distributions in extreme treatment positions like the treatment of eye tumors (retina melanomas) or for testing the effects of plugging) and QA. Another important aspect of this equipment is that it meets all requirements for QA tools as described in the new German DIN standard for ‘Stereotactic Irradiation’. The system represents a state-of-the-art QA tool for therapy instruments used in radiosurgery such as gamma knives and stereotactic Linacs. The system contains all necessary parts including films, scanner, phantom and software. References 1 2

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Warrington AP, Laing RW, Brada M: Quality assurance in fractionated stereotactic radiotherapy. Radiother Oncol 1994;30:239–246. Landi A, Marina R, DeGrandi C, Crespi A, Montanari G, Sganzerla EP, Gaini SM: Accuracy of stereotactic localisation with magnetic resonance compared to CT scan: Experimental findings. Acta Neurochir (Wien) 2001;143:593–601. Orth RC, Sinha P, Madsen EL, Frank G, Korosec FR, Mackie TR, Mehta MP: Development of a unique phantom to assess the geometric accuracy of magnetic resonance imaging for stereotactic localization. Neurosurgery 1999;45:1423–1431. Choi DR, Ahn YC, Kim DY, Huh SJ, Lee JI: Accuracy in target localization in stereotactic radiosurgery. Med Dosim 1997;22:53–58. Grebe G, Pfaender M, Roll M, Luedemann L, Wurm RE: Dynamic arc radiosurgery and radiotherapy: Commissioning and verification of dose distributions. Int J Radiat Oncol Biol Phys 2001;49:1451–1460 [erratum in Int J Radiat Oncol Biol Phys 2001;51:865]. Ramani R, Ketko MG, O’Brien PF, Schwartz ML: A QA phantom for dynamic stereotactic radiosurgery: Quantitative measurements. Med Phys 1995;22:1343–1346. Mack A, Mack G, Weltz D, Scheib S, Böttcher H, Seifert V: High precision film dosimetry with Gafchromic® films for quality assurance when using small fields. Med Phys 2003;30:2399–2409. Mack A, Czempiel H, Kreiner H, Dürr B, Wowra B: Quality assurance in stereotactic space, a system test for verifying the accuracy of aim in radiosurgery. Med Phys 2002;29:561–568. Lemieux L, Kitchen ND, Hughes SW, Thomas DG: Voxel-based localization in frame-based and frameless stereotaxy and its accuracy. Med Phys 1994;21:1301–1310. Jess A, Kreiner HJ, Heck B, Wowra B, Mack A: Bestrahlungsplanung bei kleinen complex geformten Läsionen und ihre experimentelle Verifikation. Z Med Phys 2003;13:16–21. Mack A, Mack G, Weltz D, Czempiel H, Kreiner HJ: Verification of dose plans using film dosimetry for quality assurance in radiosurgery; in Kondziolka D (ed): Radiosurgery. Basel, Karger, 2002, vol 4, pp 213–227. Kondziolka D, Dempsey PK, Lunsford LD, Kestle JR, Dolan EJ, Kanal E, Tasker RR: A comparison between magnetic resonance imaging and computed tomography for stereotactic coordinate determination. Neurosurgery 1992;30:402–407. Condon B, Hadley D: Errors in MR stereotaxy due to undetected extraneous metal objects. Phys Med Biol 1997;42:1779–1789. Mack A, Mack G, Weltz D, Hönes A, Jess A, Wowra B, Czempiel H, Heck B, Kreiner HJ, Seifert V, Böttcher H: Qualitätssicherung im stereotaktischen Raum. Bestimmung der Genauigkeit von Ort und Dosis bei Einzeit-Bestrahlungen. Strahlentherapie und Onkologie 2003;179: 760–766. Barker GJ, Tofts PS: Semiautomated quality assurance for quantitative magnetic resonance imaging. Magn Reson Imaging 1992;10:585–595.

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Guo WY, Chu WC, Wu MC, Chung WY, Gwan WP, Lee YL, Pan HC, Chang CY: An evaluation of the accuracy of magnetic-resonance-guided gamma knife surgery. Stereotact Funct Neurosurg 1996;66(suppl 1):85–92. Piovan E, Zampieri PG, Alessandrini F, Gerosa MA, Nicolato A, Pasoli A, Foroni R, Giri MG, Bricolo A, Benati A: Quality assessment of magnetic resonance stereotactic localization for gamma knife radiosurgery. Stereotact Funct Neurosurg 1995;64(suppl 1):228–232. Walton L, Hampshire A, Forster DM, Kemeny AA: A phantom study to assess the accuracy of stereotactic localization, using T1-weighted magnetic resonance imaging with the Leksell stereotactic system. Neurosurgery 1996;38:170–178. Wu TH, Lee JS, Wu HM, Chu WF, Guo WY: Evaluating geometric accuracy of multi-platform stereotactic neuroimaging in radiosurgery. Stereotact Funct Neurosurg 2002;78:39–48. Yu C, Apuzzo ML, Zee CS, Petrovich Z: A phantom study of the geometric accuracy of computed tomographic and magnetic resonance imaging stereotactic localization with the Leksell stereotactic system. Neurosurgery 2001;48:1092–1098. Yu C, Petrovich Z, Apuzzo ML, Luxton G: An image fusion study of the geometric accuracy of magnetic resonance imaging with the Leksell stereotactic localization system. J Appl Clin Med Phys 2001;2:42–50. Low DA, Li Z, Drzymala RE: Minimization of target positioning error in accelerator-based radiosurgery. Med Phys 1995;22:443–448. Mack A, Scheib S, Major J, Gianolini S, Pazmandi G, Feist H, Czempiel H, Kreiner H: Precision dosimetry for narrow photon beams used in radiosurgery – Determination of gamma knife output factors. Med Phys 2002;29:2080–2089. Mack A, Weltz D, Czempiel H, Heck B, Kreiner HJ, Wolff R, Mack G: Experimentally determined 3-D dose distributions of small, complex targets. J Neurosurg 2002;97(suppl 5):551–555. Tsai JS, Engler MJ, Rivard MJ, Mahajan A, Borden JA, Zheng Z: A formalism for independent checking of gamma knife dose calculations. Med Phys 2001;28:1842–1849. Welsh KT, Wlodarczyk RA, Reinstein LE: A new geometric and mechanical verification device for medical Linacs. J Appl Clin Med Phys 2002;3:154–161. Walton L, Hampshire A, Brownett C, Soanes T, Vaughan P, Rowe J, Radatz M, Kemeny A: Rotational movements of the automatic positioning system under load and their significance for patient treatments. J Neurosurg 2002;97(suppl):569–573. Tsai JS, Wazer DE, Ling MN, Wu JK, Fagundes M, DiPetrillo T, Kramer B, Koistinen M, Engler MJ: Dosimetric verification of the dynamic intensity-modulated radiation therapy of 92 patients. Int J Radiat Oncol Biol Phys 1998;15:1213–1230. Arjomandy B, Altschuler MD: A quality assurance device for the accuracy of the isocentres of teletherapy and simulation machines. Phys Med Biol 2000;45:2207–2217. Brezovich IA, Pareek PN, Plott WE, Jennelle RL: Quality assurance system to correct for errors arising from couch rotation in Linac-based stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 1997;38:883–890.

Dr. rer. nat. Andreas Mack Gamma Knife Zentrum, Frankfurt Schleusenweg 2–16, Nebengebäude 95 DE–60528 Frankfurt (Germany) Tel. ⫹49 69 6773 5914, E-Mail [email protected]

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Clinical Validation Methodology for the Use of Frameless PET in Leksell Gamma Knife® Radiosurgery D. Wikler a, N. Sadeghi c, S. Goldmana, N. Massager b, M. Levivier b a PET Scan/Biomedical Cyclotron Unit, Departments of bNeurosurgery and Gamma Knife Center, and cNeuroradiology, Université Libre de Bruxelles, Brussels, Belgium

Abstract We previously validated stereotactic PET with adapted fiducials for Leksell Gamma Knife® (LGK) radiosurgery. However, rare availability of PET scanners in LGK centers prevents the wide use of this technology. Frameless registration techniques such as voxelbased similarity features optimization algorithms were validated for image-guided neurosurgery and radiotherapy systems. We present a methodology to clinically validate frameless registration approaches for LGK treatment, which is intrinsically frame-based, to comply with accuracy requirements of single-session high-dose irradiation. An error transformation is computed and used to derive a modified dose plan. The ratio between coverage indexes of modified dose plan and original dose plan is proposed to assess the clinical validity of frameless registered PET for LGK. This methodology can be used to validate integration of various frameless registration algorithms and other modalities in LGK. Copyright © 2004 S. Karger AG, Basel

Gamma knife radiosurgery treatment planning relies critically on medical imaging modalities. Medical images give the ability to define a treatment target volume as well as a geometric transformation from the image space to the stereotactic frame space. Each modality likely to be used for image-guided therapy planning has to be validated for its clinical relevance and accuracy in order to be compatible with the application requirements. Gamma knife radiosurgery presents the highest requirements in terms of imaging and registration accuracy as the treatment is applied in a single high-dose session with no

other spatial control than medical imaging. Until recently, the only proposed and validated imaging modalities for gamma knife radiosurgery treatment planning were 2D or 3D morphological representations of the brain such as x-ray ventriculography, computed tomography (CT), magnetic resonance imaging (MRI) or digital subtraction angiography. The advent of new functional imaging modalities such as positron emission tomography (PET), magnetic resonance spectroscopy, chemical shift imaging, diffusion and perfusion weighted magnetic resonance imaging, task-based activation functional MRI maps, along with the demonstration of their value either for highly specific and prognostic delineation of brain tumors or eloquent functional areas, opens new challenges for gamma knife radiosurgery planning strategies. The successful use of these new modalities depends, however, on the ability to precisely define the localization and extension of the treatment target volume as well as to accurately define the stereotactic transformation to the Leksell frame coordinate system. We will detail these requirements and specifically address them for the use of PET in gamma knife radiosurgery treatment planning. The localization accuracy of a specific imaging modality is linked to its capacity to provide an undistorted representation of the brain anatomical or functional features. These issues have been discussed and addressed for anatomical imaging modalities [1–11] since the early ages of stereotactic neurosurgery aiming at offering localization accuracy compatible with the mechanical accuracy of the treatment devices and the required accuracy of the related clinical procedures. These studies revealed in particular the superiority of CT compared to MRI in terms of accuracy, the importance of imaging equipment quality control, the significance of acquisition parameters tuning and the possible requirement for distortion correction applications or the use of multimodality fusion in the context of image-guided therapy, a generic term for image-guided neurosurgery, radiotherapy and radiosurgery. For functional imaging, the accuracy problem has also been investigated but rarely in the perspective of imageguided therapy. However, PET can be considered as an exact modality for localization of functional features due to both its direct measure of metabolic activity which ensures exact localization of investigated function as well as its low frequency voxel values spatial distribution which reduces the impact of the positron mean course before annihilation and partial volume effects [12]. The exact estimation of the extent of a specific element is related to the resolution of the imaging modality and to the delineation strategy used to define a specific volume of interest within the image dataset. If state-of-the-art anatomical imaging scanners offer great resolution characteristics between 0.5 and 1.5 mm, functional modalities typically present poor resolution around 4–5 mm.

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The quality of brain functional features delineation will then mainly result from the volume of interest definition strategy. This is a very complex and interesting topic, not fully addressed in the current literature but which is beyond the scope of this paper. The last accuracy issue to consider is the computation method and error of the stereotactic transformation that register the images to the Leksell frame [13, 14]. The classical gamma knife registration procedure uses an N-shaped external markers-based registration algorithm. For PET, we previously validated an analog solution producing stereotactic PET images with an adapted fiducials system using a continuous tube filled with [18]F fluorine solution [15, 16]. We showed that PET could be registered to the Leksell frame space with accuracy comparable to CT. However, if the fiducials-based registration system is a very accurate and reliable solution, this method is not always practicable for functional imaging modalities. Issues related to the production of stereotactic PET are, on one hand, the rare availability of PET scanners in Leksell Gamma Knife® (LGK) centers, and on the other hand, the complexity of the fiducials system filling procedure as well as the overhead of an additional modality acquisition to be conducted on the intervention day. These issues prevent the wide use of this technology. Extending this fiducialsbased registration strategy to other functional modalities also present several hitches. The more frequent difficulty is to properly image the fiducials system. One potential solution is the use of registration to one stereotactic anatomical modality using similarity features-based techniques. These algorithms have already been demonstrated to be accurate enough for less demanding stereotactic applications such as image-guided neurosurgery and radiotherapy. Among the various voxel similarity measures used for automatic registration, the mutual information (MI)-based algorithm [17, 18] appeared to be the most accurate and reliable for intermodality registration where there is no linear correlation between the images voxel values. This finding makes the MI algorithm the best candidate for automatic registration between functional modalities and either CT or MRI anatomical modality. Validation methodologies commonly proposed for the assessment of automatic registration accuracy evaluates the distance between the automatically registered volume and the fiducials-based registered volume considered as a gold standard for external or anatomical landmarks [19, 20]. The drawbacks of such methods are the user dependency of the computation as well as the clinical relevance of the evaluation measure. To address the clinical pertinence problem, we propose to add to the classical gold standard comparison, a measure that reflects the impact of the registration error on the treatment quality.

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Material and Methods Frame-based stereotactic high-resolution MRI 3D T1 gradient echo pulse sequence is performed on a Philips 1.5 T MRI scanner (Gyroscan Intera, Best, The Netherlands). These MRI pulse sequences are tuned to minimize spatial distortion and the maximum distortions were assessed to be of the order of 1 mm using an original 3D phantom design [21]. Framebased stereotactic PET-FDG or PET-methionine are acquired on a CTI/Siemens ECAT962 (HR⫹) scanner (CPS, Knoxville, Tenn., USA) using our previously described procedure [15, 16]. Frame-based stereotactic high-resolution CT sequential scans are acquired on a Siemens Somatom Plus 4 with no gantry tilt (Siemens, Erlangen, Germany). MRI, CT and PET modalities are imported in Leksell GammaPlan® (LGP) radiosurgery planning software. PET modality was imported using custom software to convert PET file format to LGP format. Registration to Leksell space is achieved for MRI, CT and PET modalities using the automatic segmentation of fiducials provided into LGP. Computed registration 3D transformations parameters matrices TMRI, TCT and TPET, are extracted with a utility provided by Elekta Research & Development (Elekta AB, Stockholm, Sweden). The gold standard frame-based registration transformations both for PET to MRI and PET to CT can then be computed as: TLGP(MRI) ⫽ Inverse (TMRI)⭈TPET TLGP(CT) ⫽ Inverse (TCT)⭈TPET The same datasets are then used to determine the equivalent registration transformations, TMI(MRI), TMI(CT) using a customized implementation of the MI similarity measure algorithm from the National Library of Medicine Insight Segmentation and Registration Toolkit (ITK) [22]. A pre-release of a similar algorithm implementation in LGP provided by Elekta R&D is also used to determine the same transformation. The parameters for ITK-based MI algorithms are the following: 4 resolution modes, 12,500 iterations (5,000, 2,500, 2,500, 2,500), quaternion gradient descent optimizer with respective steps (10–4, 10–5, 5.10–6, 10–6). The parameters for LGP ␤ release registration algorithm are currently set to default values and not adjustable. After correction for coordinate space discrepancies between both applications, the error between both registration methods either for registration to MRI or CT (TE(MRI), TE(CT)) can then be estimated as a 3D transformation from: TLGP(MRI) ⫽ TMI(MRI) ⭈(TE(MRI)) TLGP(CT) ⫽ TMI(CT) ⭈(TE(CT)) so that: TE(MRI) ⫽ (TMI(MRI))⫺1 ⭈TLGP(MRI) TE(CT) ⫽ (TMI(CT))⫺1 ⭈TLGP(CT) where TE(MRI) and TE(CT) are rigid body transformations presenting translation, rotation components as well as scaling components because of the recalculation of voxel sizes by the LGP fiducials-based registration. To provide a valid measure for error estimation in terms of impact on the radiosurgery treatment, we apply either TE(MRI) or TE(CT) on the gamma knife treatment isocenters. This generates modified dose plans on the planning series (either MRI or CT). These modified dose plans will generate new prescribed isodose volume (PIV) translated, rotated and eventually

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scaled compared to the gold standard PIV that was defined from the target volume (TV). Hence, the conformity ratio PIV/TV [23] could be slightly modified when the TV is only derived from PET modality and probably even more when the TV is derived from a combination of MRI (or CT) and PET information following our regular planning strategy. Moreover, when confronted to translation and rotation errors, it is mandatory to add to the conformity ratio, a term accounting for the possible partial PIV coverage of the TV. Therefore, to assess further the TV that is actually covered by the PIV, we use TVPIV [24], and we compute a conformity index by dividing these two [25]. The actual alteration of the treatment as a result of the registration error can consequently be evaluated by the change of this conformity index: [PIV/TV]/TVPIV. We propose this metric to assess the clinical validity of frameless registered modalities for gamma knife radiosurgery treatments.

Results

We collected 10 of our cases that underwent combined CT, MRI and PET stereotactic planning imaging modalities. We imported and registered the stereotactic PET into LGP according to the method described above. After the gamma knife radiosurgery treatment, we registered the PET datasets to the highest resolution MRI series using both ITK and LGP implementations of the MI algorithm. We computed the error matrices TE (MRI) and selected 1 case with a translation error of 1.5 mm in one direction. This case was a pituitary adenoma with low target volume and low isodose volume. We worked on a sample wizard-based non-optimized planning. The stereotactic PET-based TVPIV was equal to 1 and the frameless PET-based TVPIV was equal to 0.27. The stereotactic PET planning conformity index was equal to 1.41 and the frameless PET planning conformity index was equal to 4.

Discussion

The introduction of frameless imaging modalities into gamma knife radiosurgery treatment planning is a major change of strategy for a fundamentally frame-based procedure. It is important to clearly define the rationale for this proposal. The motivation for such an application is certainly not the reduced resolution of functional imaging techniques as opposed to anatomical imaging. As a matter of fact, we previously demonstrated that resolution issues are not related to localization capabilities and we are expecting that the combination of the functional information with high-resolution morphological images could lead to better definition of functional boundaries. Our goal is also definitely not to advocate the conversion of gamma knife treatment to a frameless procedure,

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as current state-of-the-art frameless image-guided therapy systems do not guarantee the accuracy and reliability of a frame-based approach. This is essentially the reason, along with the fact that the frame is available in the gamma knife procedure workflow, of our preceding development of stereotactic PET integration within gamma knife treatment planning. This is also the basis of our research for a clinically relevant measure for the validation of frameless registration methods. The actual rationale for frameless registration of functional modalities is to overcome such problems as proper fiducials imaging as well as excessive number of imaging examinations. Our developed methodology is aimed at being very restrictive. Preliminary results show how a translation registration error over 1 mm in one direction will change drastically the metric we have chosen for clinical validation. One possible bias of our methodology could be the presence of the imaged fiducials in the source and target modalities used for registration. We believe that the statistical nature of the MI similarity measure should reduce the incidence of this potential bias but we shall test this in the future by masking the images to hide the fiducials for several cases and investigate the impact on the registration outcome. Another potential bias in our study is the similar orientations of the acquired imaging volumes for the multiple modalities. Because of the frame being attached to the scanner couch through the bed adapter and the LGP acquisition recommendations, the rotation component of the computed registration transformation is very small. These particular initial conditions for our study datasets could influence the results of the frameless registration and it will also be our commitment to make sure it is not the case. An option would be to test the possible bias by randomly rotating several volumes before registration. Distinct criteria will have to be taken into account to assess the validity of the use of frameless registration for functional imaging modalities. The impact on the quality of the treatment as represented by the measure we introduced will have to be balanced with the particular indications of the intervention both in terms of damage risk to surrounding brain structures and likelihood of treatment success. Apart from accuracy, the reliability of frameless registration will have to be evaluated according to such factors as registration algorithm parameters, image acquisition characteristics or patient clinical history, for example previous surgery or radiotherapy.

Conclusion

We present a very strict methodology that will allow assessing whether frameless modalities can be used for LGK treatment planning. Preliminary

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results indicate that low inaccuracies can cause high modifications on the planned treatment. We plan to use this method to evaluate in which conditions frameless PET can be used for gamma knife radiosurgery planning. The ability to safely use such registration techniques will depend on the imaging modality characteristics, the acquisition parameters, the registration algorithm implementation and the treatment indication. It is worth mentioning that successful results could offer new opportunities for registration strategy with anatomical imaging modalities. One could imagine such registration scheme to register a high-resolution diagnostic frameless MRI to a frame-based planning CT. Moreover, the use of non-rigid registration techniques along with such a planning strategy could potentially improve the MRI image accuracy through distortion correction using the CT as a reference. Undoubtedly, further results will give evidence that careful tuning and quality control should be addressed when using frameless registration for gamma knife radiosurgery planning. References 1

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Kondziolka D, Dempsey PK, Lunsford LD, Kestle JR, Dolan EJ, Kanal E, et al: A comparison between magnetic resonance imaging and computed tomography for stereotactic coordinate determination. Neurosurgery 1992;30:402–407. Walton L, Hampshire A, Forster DM, Kemeny AA: Accuracy of stereotactic localisation using magnetic resonance imaging: A comparison between two- and three-dimensional studies. Stereotact Funct Neurosurg 1996;66(suppl 1):49–56. Orth RC, Sinha P, Madsen EL, Frank G, Korosec FR, Mackie TR, et al: Development of a unique phantom to assess the geometric accuracy of magnetic resonance imaging for stereotactic localization. Neurosurgery 1999;45:1423–1431. Hariz MI, Bergenheim AT: A comparative study on ventriculographic and computerized tomographyguided determinations of brain targets in functional stereotaxis. J Neurosurg 1990;73:565–571. diPierro CG, Francel PC, Jackson TR, Kamiryo T, Laws ER Jr: Optimizing accuracy in magnetic resonance imaging-guided stereotaxis: A technique with validation based on the anterior commissureposterior commissure line. J Neurosurg 1999;90:94–100. Lunsford LD: Magnetic resonance imaging stereotactic thalamotomy: Report of a case with comparison to computed tomography. Neurosurgery 1988;23:363–367. Alexander E 3rd, Kooy HM, van Herk M, Schwartz M, Barnes PD, Tarbell N, et al: Magnetic resonance image-directed stereotactic neurosurgery: Use of image fusion with computerized tomography to enhance spatial accuracy. J Neurosurg 1995;83:271–276. Lemieux L, Kitchen ND, Hughes SW, Thomas DG: Voxel-based localization in frame-based and frameless stereotaxy and its accuracy. Med Phys 1994;21:1301–1310. Maciunas RJ, Galloway RL Jr, Latimer JW: The application accuracy of stereotactic frames. Neurosurgery 1994;35:682–695. Schad L, Lott S, Schmitt F, Sturm V, Lorenz WJ: Correction of spatial distortion in MR imaging: A prerequisite for accurate stereotaxy. J Comput Assist Tomogr 1987;11:499–505. Sumanaweera TS, Adler JR Jr, Napel S, Glover GH: Characterization of spatial distortion in magnetic resonance imaging and its implications for stereotactic surgery. Neurosurgery 1994;35:696–704. Hoffman E, Phelps M: Positron emission tomography: Principles and quantitation; in Phelps M, Mazziotta J, Schelbert H (eds): Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart. New York, Raven Press, 1986, pp 237–286.

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Fitzpatrick JM, West JB: The distribution of target registration error in rigid-body point-based registration. IEEE Trans Med Imaging 2001;20:917–927. Fitzpatrick JM, West JB, Maurer CR Jr: Predicting error in rigid-body point-based registration. IEEE Trans Med Imaging 1998;17:694–702. Levivier M, Wikler D, Goldman S, David P, Metens T, Massager N, et al: Integration of the metabolic data of positron emission tomography in the dosimetry planning of radiosurgery with the gamma knife: Early experience with brain tumors. Technical note. J Neurosurg 2000;93(suppl 3): 233–238. Wikler D, Levivier M, Damhaut P, Desmedt F, David P, Goldman S: Practical issues and accuracy study to use positron emission tomography as a stereotactic planning modality for gamma knife radiosurgery. Gamma Knife Users’ Society Meeting, Squaw Valley, Calif. 2000. Wells WM 3rd, Viola P, Atsumi H, Nakajima S, Kikinis R: Multi-modal volume registration by maximization of mutual information. Med Image Anal 1996;1:35–51. Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P: Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 1997;16:187–198. West J, Fitzpatrick JM, Wang MY, Dawant BM, Maurer CR Jr, Kessler RM, et al: Comparison and evaluation of retrospective intermodality brain image registration techniques. J Comput Assist Tomogr 1997;21:554–566. West J, Fitzpatrick JM, Wang MY, Dawant BM, Maurer CR Jr, Kessler RM, et al: Retrospective intermodality registration techniques for images of the head: Surface-based versus volume-based. IEEE Trans Med Imaging 1999;18:144–150. Wikler D, Breeuwer M, Levivier M, David P, Metens T: Image-guided surgery clinical validation of phantom-based 3D MR distortion correction; in ISMRM 10th Scientific Meeting & Exhibition, Honolulu, Hawaii 2002. Ibanez L, Schroeder W, Ng L, Cates J: The ITK Software Guide; in The Insight Software Consortium http://www.itk.org; 2003. Shaw E, Kline R, Gillin M, Souhami L, Hirschfeld A, Dinapoli R, et al: Radiation Therapy Oncology Group: Radiosurgery quality assurance guidelines. Int J Radiat Oncol Biol Phys 1993;27:1231–1239. Paddick II: A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 2000;93(suppl 3):219–222. Levivier M, Lorenzoni J, Massager N, Ruiz S, Devriendt D, Brotchi J: Use of the Leksell gamma knife C with automatic positioning system for the treatment of meningioma and vestibular schwannoma. Neurosurg Focus 2003;14(5).

David Wikler Gamma Knife Center, Hôpital Erasme Route de Lennik, 808 BE–1070 Brussels (Belgium) Tel. ⫹32 2 5553174, Fax ⫹32 2 5553176, E-Mail [email protected]

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Quality Assurance of the Cyberknife Fiducial and Skull Tracking Systems Anthony Hoa, Cristian Cotrutz a, Steven D. Changb, John R. Adlerb, Iris C. Gibbsa Departments of aRadiation Oncology and bNeurosurgery, Stanford University Medical Center, Stanford, Calif., USA

Abstract Routine quality assurance (QA) should be performed for any radiosurgery system. Given the complexity of the Cyberknife, QA plays an even more important function. Below we review the suggested daily and monthly QA procedures to test the accuracy of the imageguidance systems and the consistency of the dose profile. Furthermore, we describe a simplified method for ensuring the integrity of the entire system. Copyright © 2004 S. Karger AG, Basel

Image-guided Cyberknife radiosurgery has emerged as a feasible, accurate radiosurgery delivery technique [1]. The Cyberknife system uses a compact X-band 6-MV linear accelerator mounted onto a mobile robotic arm to deliver radiosurgical doses with sub-millimeter accuracy. The dose delivery precision is achieved using a near real-time adjustment of the robot position to compensate for the patient shifts during treatment. Any variation of the patient position is detected by an image-guidance system containing paired cameras, which cast images onto amorphous silicon detectors. These images are compared to the DRRs that are reconstructed from the planning CT images, and any detected displacements are translated into robot position adjustments to compensate for patient movement [2]. The flexibility of the system allows for treatment of both intra- and extracranial lesions in a frameless manner. Unlike conventional radiation therapy, the entire radiation dose is delivered in one or a few treatments. Therefore, reliability of radiation planning system and treatment delivery

system is imperative. While routine quality assurance (QA) is essential for any radiosurgery system, QA plays an even more vital role for Cyberknife radiosurgery system, due to the complexity of the system and the wide range of applications to intra- and extracranial treatments. It is imperative that the accuracy of radiation dose targeting is maintained. We present suggested end-to-end monthly QA tests to verify that the Cyberknife system, which integrates treatment planning, robot movement, image processing and Linac, can deliver the simulated planned treatment.

Material and Methods Monthly QA Test for Fiducial Tracking Accuracy The purpose of this test is to verify the accuracy of dose delivery when the positioning of a phantom in the irradiation position is performed based on the fiducial identification (fiducial tracking) by the Cyberknife imaging system. A 30 ⫻ 30 ⫻ 11 cm rectangular solid water (WT1) phantom containing a planar array of slots for 1 ⫻ 1 ⫻ 1 mm thermoluminescent detectors (TLDs) on a 2-mm grid, plus fiducial markers for the Cyberknife image-guided robot pointing control system was assembled and CT scanned using 1.5-mm CT slices. The CT scans of the phantom were performed for two setups: (1) with the planar array of TLD slots oriented horizontally, and (2) vertically. Approximately 47 TLDs are used for each setup. Both setups allow the dose verification on three perpendicular directions (fig. 1). Treatment plans (TPS) were generated for both setups with the center of the patient dose computation grid moved to the center of the TLD array. The phantom was irradiated according to the patient treatment plan. The Harshaw TLD microchips (1 ⫻ 1 ⫻ 1 mm) were read out to compare measured dose, dose shape and location with TPS calculations. The TLDs were read using a Harshaw automatic TLD reader (model 5500). For TLD calibration, 100 MU is used with a SSD of 78.5 cm at a depth of 1.5 cm using a 60-mm collimator. The TLD supralinearity is being corrected. Monthly QA Test for Skull Tracking Accuracy The purpose of this test is to verify the accuracy of dose delivery when the positioning of a phantom in the irradiation position is performed based on the patient anatomy (skull tracking) by the Cyberknife imaging system. For skull tracking QA test, a GE CIRS head phantom is used. The central cubic insert of the phantom accommodates the TLDs and has the dimension of 6.35 ⫻ 6.35 ⫻ 6.35 cm, with 2-mm thick tissue equivalent slabs. The central plate has 61 holes, diameter 1.5 mm, depth 1 mm, to accommodate the same microchips used for the fiducial tracking test. The spacing of the TLD holes in the cassette is 2 mm center to center. Other plates have a single hole in the center. The CIRS phantom is scanned with a 0.625-mm CT slice thickness. A treatment plan is generated using the OnTarget TPS. The single isocenter treatment plan uses a 5-mm collimator, which aims at the center of the cubic insert. The plan is normalized to deliver 800 cGy to the 90% isodose line.

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Before treatment delivery, 7 TLDs are placed in the central cubic insert. Five TLDs are placed in the central slice (ant., post., right, left and center) and the other 2 in the inferior and superior insert slices. Thus, the accuracy along right-left, anterior-posterior, and superior-inferior directions are checked at the same time. The measurements are performed three times, for three sets of 7 TLDs, and then the readings are averaged to verify that the beams are aiming at the center of the TLD array. For TLD calibration, 800 cGy is delivered with the same phantom setup as used in the fiducial tracking test (fig. 2).

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Fig. 2. Setup for skull tracking using CIRS phantom.

Results

Fiducial Tracking The 2D center of the measured dose distribution deviated from predicted values by 1.1 ⫾ 0.6 mm (range 0.2–2.1), and dose differed by ⫹1.4 ⫾ 4.9% (⫺4.1 to ⫹11.7%). Measured FWHMs of dose peaks differed from predicted values by 0.65 ⫾ 0.74 mm (lateral) and 0.55 ⫾ 0.82 mm (inf-sup). QA results confirm system performance.

Discussion

Routine QA should be performed for any radiosurgery system. Given the complexity of the Cyberknife tracking system, QA plays an even more important function. The entire system requires that all components function properly including treatment planning, the robot, the imaging subsystems, as well as the

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treatment process itself. Though it is possible to use radiochromatic film as a QA tool, the described techniques of using monthly TLD readings provide a simplified reliable method of ensuring the integrity of the entire system [3, 4]. The results show that the beam is delivered to within 1 mm of the TLD array center, indicating that the Cyberknife as well as the TLD system are both stable and consistent.

References 1 2

3 4

Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP: An analysis of the accuracy of the Cyberknife: A robotic frameless stereotactic radiosurgical system. Neurosurgery 2003;52:140–147. Chang SD, Murphy M, Geis P, Martin DP, Hancock SL, Doty JR, Adler JR Jr: Clinical experience with image-guided robotic radiosurgery (the Cyberknife) in the treatment of brain and spinal cord tumors. Neurol Med Chir (Tokyo) 1998;38:780–783. Shiomi H, Inoue T, Nakamura S, Shimamoto S, Adler JR Jr, Bodduluri M: CyberKnife (in Japanese). Igaku Butsuri 2001;21:11–16. Ho A, Luxton G, Hai J, Martin D: Simplification to verify dose delivery accuracy using TLD and a head phantom for the Cyberknife system. 44th Annual Meeting of the American Association of Physicists in Medicine. Med Phys 2002;29:1924.

Iris C. Gibbs, MD Stanford University Medical Center 300 Pasteur Drive, Rm A0-95, MC:5302 Stanford, CA 94305-5302 (USA) Tel. ⫹1 650 7361480, Fax ⫹1 650 7258231, E-Mail [email protected]

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Clinical Evaluation of a Gamma Knife Inverse Planning System Q. Jackie Wua, Suradet Jitprapaikulsarnb, Boonyanit Mathayomchanb, Douglas Einsteina, Robert J. Maciunasc, Kunjun Pillai a, Barry W. Wesselsa, Timothy J. Kinsellaa, Vira Chankong b a

b

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Department of Radiation Oncology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland; Department of Electrical Engineering and Computer Science, Case Western Reserve University School of Engineering, and Department of Neurosurgery, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA

Abstract The clinical evaluation of an in-house developed gamma knife inverse planning system is presented. This system utilizes morphological characteristics (skeleton) of a target to search for optimal shots. The planning process is very efficient and accurate as it determines shot locations and shot sizes (i.e., collimator size and weight combination) simultaneously, taking into consideration the target size as well as its shape. In addition, the process guarantees an optimal spatial arrangement among shots so that excessive ‘hot spots’ are avoided and the global dose distribution conforms to the target shape. Patient cases with different target volumes and shapes were tested retrospectively using this inverse planning system. For the patient cases presented, the number of shots used ranges from 7 to 20, the planning time is in the range of 1–3 min (2-GHz Pentium 4 workstation). The dose conformity indices range from 1.36 to 1.62. Copyright © 2004 S. Karger AG, Basel

The purpose of treatment planning for Gamma Knife™ radiosurgery is to optimally choose the number, locations and sizes of the shots in order to deliver high-dose radiation to the tumor volume while minimizing the dose to surrounding healthy brain tissues [1–3]. Our in-house developed gamma knife inverse planning system utilizes a combinatorial optimization approach of

Tumor contour

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packing non-elastic, solid 3D spheres (i.e. shots) into a target volume such that certain coverage conditions are met [4–10]. This system applies a morphological analysis of the target coupled with strategic fine tuning of the timing parameters to search for an optimal shot configuration. The planning process is very efficient and accurate as it determines shot locations and shot sizes (i.e., collimator size and weight combination) simultaneously, while accounting for both the volume and shape of the target. Once an optimal solution is found, the system translates the 3D spheres used in the packing algorithm into clinical parameters as shot locations, collimator sizes, and weights.

Methods Morphology-Guided Planning Approach During a manual treatment planning process, a planner usually selects a shot’s size and position to ‘match’ a specific part of the target. However, dose overlaps among multiple shots compromise the ideal match, and the shot positions and sizes must be manually adjusted in order to yield a desirable dosimetrical coverage. Several iterations are often needed to achieve an optimal plan. We first introduced the unique approach of skeletonization-based shot placement and plan optimization [8, 9]. The conceptual similarity of the manual planning and skeletonbased planning is illustrated in figure 1. The figure simulates a planner placing the first shot on the target. Ideally, the shot should cover the corner of the target, with the shot centered in the region and the size matching the corner area. In morphological description, the shot is on the skeleton (shown as dashed lines) or ‘bisectors’ of the target volume, and the shot size is the largest among those centered on the local segment of the skeleton that could be inscribed within the target volume. For the second shot, again, either a small shot could be placed to match the lower bottom contour line, or a larger one covering the open area with its boundary matching the target contour on both sides could be used. Both of the potential shots are on the skeleton of the remaining uncovered target. This manual ‘matching’ process has two components, (1) positioning the shot in the center of the region it intends to cover, and (2) using the largest shot size possible to provide high-dose coverage to the target boundary. Skeletonization [11], a special morphological analysis tool, can provide the shots’ isocenter as well as the matching sizes.

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We have developed a morphology-guided planning system to automatically generate such shot configuration. In addition, this process uses linear programming to fine tune the exposure time of each shot as well as an iterative decomposition-based optimization scheme to fine tune the spatial arrangement among shots so that excessive ‘hot spots’ are avoided and the global dose distribution conforms to the target shape as much as possible [4, 10]. Clinical Evaluation of the MGP System A prototype of the morphologically guided treatment planning system (MGP) has been implemented. For clinical validation, a retrospective study on patients treated with gamma knife radiosurgery has been conducted. The MR images were exported to the MGP system. To begin, we match the target outlined in the MGP system to within 2 mm in any dimension of those outlined by the physicians on the Leksell GammaPlan [12]. In addition, we ensure that the volume on both systems cannot differ by more than 5%, recognizing that the two systems may calculate the volume differently. The software also allows us to overlay both volumes for more detailed analysis and to pinpoint the discrepancies. The MGP system generates shot configurations using the target information. After shot configurations are generated, they are transferred to the Leksell GammaPlan for dose calculation and plan evaluation 12. This way, the MGP inverse plan and the manual plan are calculated and compared under the same dosimetry syst em. Currently, neither the gamma angle nor the plugging pattern is modeled in the MGP system. We evaluate clinical dosimetry parameters such as total number of shots, types of collimator used, target coverage (percentage of target covered by prescription isodose line) and the RTOG conformity index PITV (prescription isodose volume over target volume).

Results and Discussion

For all the cases presented, the prescription isodose line (IDL) is the default 50% IDL. Each case is presented in the axial, coronal and sagittal views. Target contours, as well as the 50% and the 30% IDLs are shown on each of the views. In each figure, the manual plan is presented in the upper row and the corresponding MGP plan is presented in the lower row. All the manual plans did not use plugging. Since the MGP system does not model the gamma angles, they are set the same as their corresponding manual plans. Figure 2 shows the manual and the MGP inverse plan for a benign tumor of 2.0 cm3. For the manual plan, ten 8-mm shots were used. The target coverage is 100% and the conformity index is 1.55. The corresponding MGP inverse plan used seven shots (one 14 mm and six 8 mm). The target coverage is 97% and conformity index is 1.47. Similarly, figure 3 shows a meningioma tumor with a volume of 4.7 cm3. The manual plan used nine shots (five 14 mm and four 8 mm) with a PITV of 1.30. The MGP inverse plan used twelve shots (one 18 mm, one 14 mm and ten 8 mm) with a PITV of 1.36. Target coverage is 99% for both plans. Of interest, the manual plan used more shots for the first patient case while the MGP plan used more shots for the second one.

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Fig. 2. Dose distribution of the manual plan (upper row) and the MGP plan.

Fig. 3. Dose distribution of the manual plan (upper row) and the MGP plan (lower row).

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b Fig. 4a, b. Dose distribution of the manual plans and the MGP plans.

Sometimes a human planner may compromise conformity for fewer shots during the planning process, or pack many shots to form a highly conformal plan if the target is adjacent to critical structures. For example, the two cases shown in figure 4 have similar volume (5.1 vs. 5.6 cm3). However, eights shots (four 14 mm and four 8 mm) were used for case (a) while twenty shots

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(one 14 mm and nineteen 8 mm) were used for case (b). The conformity indices for the manual plans are 1.96 (a) and 1.16 (b). The MGP system, using the same planning criteria, generated similar shot configurations for both cases. Thirteen shots were used for case (a) (three 14 mm, ten 8 mm), and fourteen shots for case (b) (five 14 mm, nine 8 mm). For the MGP plan, conformity indices for both cases are similar as well, 1.42 vs. 1.62. For all the cases discussed above, MGP plans have consistent conformity quality in the range of 1.36–1.62, regardless of target size or shape. Future work will include more user specified conformity criteria to allow the choice of fewer shots or higher conformity. The greatest value of the MGP system is the ease with which the planning process is carried out and the considerable saving in planning time. By the time the physician finishes outlining the target, the planning time of each of the above cases is in the range of 30–60 min for manual planning compared with 1–3 min for the MGP system. Therefore, a significant amount of planning time can be saved by using the automated planning process. The MGP technique can be implemented either as a replacement for manual planning, or as a tool to quickly generate an initial plan for subsequent manual fine tuning.

Conclusion

Target volume and shape, as represented by the skeleton, are used to determine optimal shot positions, sizes and number of shots. This planning process has been automated for multi-shot treatment. Clinical cases in 3D demonstrate that this approach is capable of generating high-quality conformal treatment plans quickly. A complete plan can be generated in less than 3 min, making realtime inverse planning a reality.

Acknowledgement This work is supported in part by a grant from the Whitaker Foundation (R-00-0427).

References 1

2 3 4

Shaw E, Kline R, Gillin M, Souhami L, Hirschfeld A, Dinapoli R, et al: Radiation Therapy Oncology Group: Radiosurgery quality assurance guidelines. Int J Radiat Oncol Biol Phys 1993; 27:1231–1239. Flickinger JC, Lunsford LD, Wu A, Maitz AH, Kalend AM: Treatment planning for gamma knife radiosurgery with multiple isocenters. Int J Radiat Oncol Biol Phys 1990;18:1495–1501. Wu A: Physics and dosimetry of the gamma knife. Neurosurg Clin North Am 1992;3:35–50. Chankong V, Jitprapaikulsarn S, Wu QJ: Optimization of gamma knife treatment plans, optimization and engineering on radiation oncology (submitted).

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Wang J: Packing of unequal spheres and automated radiosurgical treatment planning. J Comb Optim 1999;3:453–463. Wang J: Medial axis and optimal locations for min-max sphere packing. J Comb Optim 2000;4: 487–503. Wu Q, Bourland JD, Robb RA: Fast 3D medial axis transformation to reduce computation and complexity in radiosurgery treatment planning. SPIE 1996;2710:562–571. Wu QJ, Bourland JD: Morphology-guided radiosurgery treatment planning and optimization for multiple isocenters. Med Phys 1999;26:2151–2160. Wu QJ, Bourland JD: Three-dimensional skeletonization for computer-assisted treatment planning in radiosurgery. Comput Med Imaging Graph 2000;24:243–251. Wu QJ, Chankong V, Jitprapaikulsarn S, Wessels BW, Einstein DB, Mathayomchan B, et al: Real-time inverse planning for gamma knife radiosurgery. Med Phys (submitted). Serra J: Image Analysis and Mathematical Morphology. New York, Academic Press, 1984. Elekta Instruments Manual – Leksell GammaPlan online reference. Elekta, Stockholm.

Dr. Q. Jackie Wu Department of Radiation Oncology, Lerner Tower B181, 11100 Euclid Avenue Case Western Reserve University School of Medicine and University Hospitals of Cleveland Cleveland, OH 44106 (USA) Tel. ⫹1 440 250 2008, Fax ⫹1 440 250 2877, E-Mail [email protected]

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MR Spectroscopy and MR Perfusion of Brain Tumors Before and After Radiation Therapy: Preliminary Results Jiraporn Laothamatas, Sawwanee Asavaphatiboon, Thanwa Sinlapawongsa, Mantana Dhanachai, Pornpan Yongvithisatid, Veerasak Theerapancharoen Ramathibodi Hospital, Bangkok, Thailand

Abstract Background and Purpose: Our goal was to study the potential roles of magnetic resonance spectroscopy (MRS) and magnetic resonance (MR) perfusion in determining brain tumor response after radiation therapy. Methods: A retrospective analysis of 18 MRI, MRS and MR perfusions of 9 patients with 8 cases of grade 1–4 cerebral glioma and 1 case of neuroblastoma were done by comparing the choline/creatine (Cho/Cr), N-acetylaspatase/ creatine (NAA/Cr) and regional cerebral blood volume (rCBV) before and after radiation therapy. Results: There is no statistically significant difference in Cho/Cr, NAA/Cr and rCBV ratios between the pre- and post-radiation therapy in all areas in both tumor regression and tumor progression groups. However, after radiation therapy there is a tendency to decrease Cho/Cr, NAA/Cr and perfusion of the tumor in the tumor regression group and a tendency to increase Cho/Cr and NAA/Cr of the tumor in the tumor progression group. Conclusion: Even though there is no statistically significant change and difference after radiation therapy between the tumor regression and tumor progression groups, the Cho/Cr, NAA/Cr and semiquantitative rCBV show a tendency to decrease in the tumor regression group and increase in the tumor progression group. They may be used to assess the tumor response to radiation therapy complimentary to the routine brain imaging. An alternative method of tumor perfusion measurement, a permeability map, may correct the error caused by blood-brain barrier breakdown in the enhanced tumor. Copyright © 2004 S. Karger AG, Basel

Choline (Cho) is the metabolite from cell membrane breakdown and synthesis and represents the rate of cell growth and destruction. N-acetylaspartase (NAA) represents neuronal cells. These two metabolites can be obtained in vivo using proton MR spectroscopy (MRS) technique [1]. Magnetic resonance (MR) perfusion, regional cerebral blood volume (rCBV), represents the microvascularity at the region of interest [2–4]. Rapidly grown tumor requires a high blood supply, increased cell destruction and synthesis and loss of normal neurons. Therefore, Cho, NAA and rCBV of the tumors may be used to monitor the tumor response to treatment, both after radiation and chemotherapy [5–15].

Materials and Methods Retrospective analysis of 18 MR images, multivoxel proton MRS and MR perfusion of 9 patients with one grade 1 astrocytoma, 1 grade 2 brainstem astrocytoma, 4 anaplastic astrocytomas, 1 malignant glioma, 1 anaplastic mixed oligoastrocytoma, and 1 neuroblastoma were performed before and after radiation therapy. All of the studies were performed at Ramathibodi Hospital from December 13, 2001 to July 31, 2003, with a 1.5 T superconducting magnet with gradient strength of 40 mT/s (1.5T NVi/Cvi, General Electrics Medical Systems, Milwaukee, Wisc., USA). There were 5 females and 4 males with an age range of 2–64 (mean 35.67) years. The patients were divided into three groups as tumor regression (fig. 1), tumor unchanged (fig. 2) and tumor progression (fig. 3) according to the imaging and clinical criterias. The post-radiation follow-up time was 3–16 (mean 5.33) months. Patient data are shown in table 1. MR perfusion of the tumor was performed with dynamic susceptibility single-shot EPI spin echo T2 technique, bandwidth of 120 MHz, 10 levels with 51 phases/level for a total of 510 frames, FOV 28 cm, matrix 128 ⫻ 128, and TR/TE 2,000/80 ms. Intravenous double dose, 0.2 mmol/kg, gadolinium-based contrast (gadoliniumDTPA, Schering, Germany) was administered at an injection rate of 4–5 ml/s by the power injector followed by 20 ml of saline. Multivoxel proton spectroscopy was performed with PRESS CSI (point resolved spectroscopy with chemical shift imaging) technique, field of view 16 cm, matrix 16 ⫻ 16 and TR/TE 1,600/144 ms. Retrospective analysis of the choline/creatine (Cho/Cr), N-acetylaspatase/creatine (NAA/Cr) and the rCBV ratios were done using Functool 2000 software (General Electrics Medical Systems) at different portions of the tumors, the non-enhancing hypersignal T2 area (area 2), the solid enhancing area (area 3), the tumor necrotic area (area 4), the normal signal brain at the margin of the tumor (area 5) and contralateral normal brain (area 1) (fig. 4). The calculated values before and after radiation therapy of each group were analyzed and compared (tables 2–4).

Results

The mean values of Cho/Cr, NAA/Cr and rCBV ratios before and after radiation therapy of each area are shown in tables 2–4. There is no statistically significant difference in Cho/Cr, NAA/Cr and rCBV ratios between the pre- and

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3d

3e

3f Fig. 2. Axial FLAIR (a, b) and post-gadolinium T1W (c) before and 7 months after (d–f) radiation therapy of a 49-year-old male with grade 3 astrocytoma of the right frontotemporal lobe with a well-defined cystic component in the frontal lobe demonstrating no significant change in size and enhancement of the tumor after radiation therapy. Fig. 3. Axial FLAIR, T1W before and after gadolinium MRI of the brain before (a–c) and 4 months after (d–f) radiation therapy of a 32-year-old male with malignant astrocytoma of the brainstem demonstrating moderate progression in both tumor extension and degree of enhancement.

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4a

4b

4c

4d

4e

4f

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Table 1. Patient data, tumor types and treatment results Case No.

Age/sex

Tumor types and grade

1 2 3 4 5

2/M 48/M 35/M 50/F 36/F

Astrocytoma grade 1 Anaplastic astrocytoma Anaplastic astrocytoma Anaplastic mixed oligoastrocytoma Malignant glioma

Tumor unchanged 6 40/F

Anaplastic astrocytoma

Tumor progression group 7 31/M Brainstem astrocytoma grade 2 8 64/F Anaplastic astrocytoma 9 15/F Neuroblastoma

Table 2. Average Cho/Cr value of the tumor regression and progression groups

Area 1 Area 2 Area 3 Area 4 Area 5

Tumor regression group

Tumor progression group

pre

post

pre

post

1.446 (0.313) 2.697 (1.452) 3.498 (2.699) 3.696 (1.512) 1.217 (0.585)

1.361 (0.322) 1.886 (1.550) 2.142 (0.762) 1.958 (1.183) 1.339 (0.186)

1.497 (0.583) 2.062 (0.305) 2.005 (0.357) 2.021 (0.084) 1.652 (0.624)

1.235 (0.157) 2.839 (0.590) 2.562 (0.392) 3.121 (0.366) 1.610 (0.579)

Hypothesis

p value area 1

area 2

area 3

area 4

area 5

1. Cho/Cr (regression) ⫽ Cho/Cr (progression)

0.837

0.806

0.487

0.749

0.253

2. Pre-RT ⫽ post-RT

0.364

0.918

0.631

0.230

0.822

3. Interaction between groups and time

0.628

0.275

0.344

0.340

0.690

Fig. 4. a–c Axial FSE T2W, post-gadolinium T1W and spectroscopy spectra. d–f Perfusion curve, axial FSE T2W and perfusion image of the normal brain (area 1), non-enhancing hypersignal T2 tumor (area 2), enhancing tumor (area 3), necrotic tumor (area 4) and normal signal brain at the tumor margin (area 5).

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Table 3. Average NAA/Cr value of both the tumor regression and progression groups

Area 1 Area 2 Area 3 Area 4 Area 5

Tumor regression group

Tumor progression group

pre

post

pre

post

1.875 (0.147) 1.259 (0.764) 0.997 (0.507) 1.494 (0.077) 1.230 (0.638)

1.797 (0.441) 0.716 (0.449) 0.928 (0.510) 0.710 (0.429) 1.195 (0.506)

1.873 (0.601) 1.20 (0.300) 0.818 (0.455) 0.903 (0.424) 1.455 (0.385)

1.411 (0.370) 1.735 (1.000) 0.905 (0.303) 1.265 (0.186) 1.396 (0.157)

Hypothesis

p value area 1

area 2

area 3

area 4

area 5

1. Cho/Cr (regression) ⫽ Cho/Cr (progression)

0.435

0.227

0.716

0.934

0.470

2. Pre-RT ⫽ post-RT

0.100

0.893

0.985

0.959

0.844

3. Interaction between groups and time

0.209

0.110

0.716

0.442

0.959

Table 4. Average perfusion value of both the tumor regression and progression groups

Area 1 Area 2 Area 3 Area 4 Area 5

Tumor regression group

Tumor progression group

pre

post

pre

post

1.000 (0.000) 2.184 (1.371) 3.080 (2.397) 0.230 (0.325) 1.766 (0.440)

1.000 (0.000) 2.100 (1.080) 2.870 (3.033) 1.730 (1.457) 1.608 (0.664)

1.000 (0.000) 1.607 (1.298) 2.680 (2.693) 2.060 (3.063) 1.500 (0.508)

1.000 (0.000) 1.840 (1.066) 1.700 (0.947) 0.637 (0.607) 1.060 (0.633)

Hypothesis

p value area 1

area 2

area 3

area 4

area 5

1. Perfusion (regression) ⫽ perfusion (progression)

0.000

0.481

0.655

0.816

0.231

2. Pre-RT ⫽ post-RT

0.000

0.994

0.705

0.681

0.282

3. Interaction between groups and time

0.000

0.748

0.609

0.679

0.657

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post-radiation therapy in all areas in both tumor regression and tumor progression groups. The perfusion of the normal brain away from the tumor (area 1) has been set as a normal reference at 100%. The tumor perfusion is higher than the normal reference white matter, except for the tumor necrotic areas in both groups before and after radiation therapy. For the tumor regression group, there is a tendency to decrease Cho/Cr, NAA/Cr and perfusion in the tumors (areas 2 and 3) after radiation therapy, except for an increased perfusion in the necrotic tumor (area 4). In the normal signal brain area away from the tumor (area 1), the Cho/Cr and NAA/Cr are all decreased. The normal signal brain area adjacent to the tumor margin (area 5) demonstrates increased Cho/Cr, decreased NAA/Cr and rCBV ratios. For the tumor progression group, there is a tendency to increase Cho/Cr and NAA/Cr in the tumor (areas 2 and 3) after radiation therapy, except for the necrotic tumor (area 4) showing decreased NAA/Cr. The tumor perfusion is increased in the non-enhancing hypersignal T2 area (area 2) but decreased in the enhancing (area 3) and necrotic (area 4) areas. The normal signal brain areas (area 5) showed a tendency to decreased Cho/Cr, NAA/Cr and perfusion.

Discussion

MR spectroscopy and MR perfusion of the tumor after radiation are more complicated than those of the non-treated brain. Therefore, for the spectral patterns of tumor metabolite and rCBV to be useful for patients with treated brain tumors, they must be able to distinguish tumor from treatment effects and necrosis [15]. In this study, before radiation therapy all the tumors demonstrated marked elevated Cho/Cr and rCBV and decreased NAA/Cr compared to the normal white matter as is has previously been described that highly elevated Cho and decreased NAA indicate tumor [16–18]. The rCBV above that of normal white matter also corresponds to tumor [19]. After radiation therapy a trend to decrease Cho/Cr, NAA/Cr and perfusion in the tumor regression group and to increase Cho/Cr, NAA/Cr in the tumor progression group is observed, while the tumor perfusion in the tumor progression group is rather inhomogenous with a trend to increase perfusion in the non-enhanced portion and decreased perfusion in the enhanced and necrotic portions. The blood-brain barrier breakdown in the enhanced area can cause an error in rCBV quantification [20] because it will result in underestimated perfusion. It may explain why the perfusion is decreased with tumor progression in this study. This error can be reduced by baseline correction methods, using alternative methods such as measurement of blood flow using arterial input function [4] or using permeability map [21] instead of rCBV. For the necrotic tumor area, the perfusion is

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lower than that of the normal white matter before radiation therapy and is decreased after radiation therapy corresponding to what others have described [19, 22, 23] that there is an association of microvascular density and tumor energy metabolism in most human gliomas. The normal signal brain adjacent to the tumor margin (area 5) shows only minimal change of Cho/Cr, NAA/Cr and slightly decreased perfusion. The normal white matter away from the tumor (area 1) revealed decreased Cho/Cr and NAA/Cr in both tumor regression and progression groups indicating post-radiation change.

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11 12

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15

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Wald LL, Nelson SJ, Day MR, Noworolski SE, Henry RG, Huhn SL, et al: Serial proton magnetic resonance spectroscopy imaging of glioblastoma multiforme after brachytherapy. J Neurosurg 1997;87:525–534. Dowling C, Bollen AW, Noworolski SM, McDermott MW, Barbaro NM, Day MR, et al: Preoperative proton MR spectroscopic imaging of brain tumors: Correlation with histopathologic analysis of resection specimens. AJNR Am J Neuroradiol 2001;22:604–612. Tedeschi G, Lundbom N, Raman R, Bonavita S, Duyn JH, Alger JR, et al: Increased choline signal coinciding with malignant degeneration of cerebral gliomas: A serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 1997;87:516–524. Aronen HJ, Gazit IE, Louis DN, Buchbinder BR, Pardo FS, Weisskoff RM, et al: Cerebral blood volume maps of gliomas: Comparison with tumor grade and histologic findings. Radiology 1994;191:41–51. Cha S, Knopp EA, Johnson G, Litt A, Glass J, Gruber ML, et al: Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin. AJNR Am J Neuroradiol 2000;21:881–890. Li KL, Zhu XP, Checkley DR, Tessier JJ, Hillier VF, Waterton JC, et al: Simultaneous mapping of blood volume and endothelial permeability surface area product in gliomas using iterative analysis of first-pass dynamic contrast enhanced MRI data. Br J Radiol 2003;76:39–50. Kamada K, Houkin K, Abe H, Sawamura Y, Kashiwaba T: Differentiation of cerebral radiation necrosis from tumor recurrence by proton magnetic resonance spectroscopy. Neurol Med Chir (Tokyo) 1997;37:250–256. Aronen HJ, Pardo FS, Kennedy DN, Belliveau JW, Packard SD, Hsu DW, et al: High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas. Clin Cancer Res 2000;6:2189–2200.

Jiraporn Laothamatas, MD Ramathibodi Hospital Bangkok 10400 (Thailand) Tel. ⫹66 2247 97667, Fax ⫹66 2201 1176, E-Mail [email protected]

MRS and MR Perfusion of Brain Tumors Before and After RT

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Author Index

Adler, J.R. 22, 181, 255 Asada, H. 66 Asavaphatiboon, S. 51, 267 Azmi-Ghadimi, H. 124 Badie, B. 38 Bajaj, N. 134 Banerji, A.K. 134 Barfod, B.E. 77 Boettcher, H.D. 236 Bradley, K.A. 171 Brotchi, J. 143, 197 C¤echák, T. 225 Cabatan-Awang, C. 82 Cathcart, C. 124 Chang, S. 181 Chang, S.D. 22, 255 Chankong, V. 260 Chernov, M. 161 Cotrutz, C. 255 Czempiel, H. 236 David, P. 143 De Salles, A.A.F. 46, 82, 115 De Smedt, F. 197 Devriendt, D. 143, 197 Dhanachai, M. 51, 267 Donnet, A. 190 Dvor¤ák, P. 225

Einstein, D. 260 Flickinger, J.C. 91 Ford, J.M. 115 Frighetto, L. 82, 115 Fukuda, H. 29 Gaur, M.S. 134 Gibbs, I.C. 22, 181, 255 Goldman, S. 143, 247 Golish, S.R. 46 Gonzalez, S.R. 143 Goss, B. 115 Gravori, T. 115 Hanzély, Z. 13 Hara, M. 29 Hasegawa, T. 153 Hayashi, M. 161 Hayes, L. 38 Heit, G. 181 Ho, A. 255 Ho, R.T.K. 161 Hong, T.S. 38 Hori, T. 161 Hosono, M.N. 29 Hrbác¤ek, J. 225 Inomori, S. 66 Inoue, H.K. 107 Inoue, Y. 29 Ishii, K. 29 Izawa, M. 161

Jacobs, A. 124 Jitprapaikulsarn, S. 260 Judas, L. 225 Kamiryo, T. 77 Katayama, Y. 161 Kawakami, Y. 161 Kemeny, A. 100 Kida, Y. 153 Kinsella, T.J. 260 Kobayashi, T. 1 Kondo, S. 29 Kondziolka, D. 13, 91 Kouyama, N. 161 Kreiner, H.J. 236 Laothamatas, J. 51, 267 Levivier, M. 13, 143, 197, 247 Lišc¤ák, R. 16, 225 Lorenzoni, J. 143, 197 Lunsford, L.D. 13, 91 Maciunas, R.J. 260 Mack, A. 236 Mack, G. 236 Massager, N. 143, 197, 247 Mathayomchan, B. 260 Medin, P. 82, 115 Mehta, M.P. 38, 171 Michálek, J. 225 Misra, J. 134

278

Nagai, H. 91 Nagano, H. 66 Nakayama, S. 66 Niranjan, A. 91 Nishi, H. 107 Nishikawa, M. 29 Novotný, J. 225 Novotný, J., Jr. 225 Nyáry, I. 13

Rowe, J. 100 Ruiz, S. 197

Paesmans, M. 197 Pathak, V.K. 134 Pedroso, A.G. 82, 115 Pham, C. 22 Pillai, K. 260 Pr¤ádný, M. 225 Putthicharoenrat, S. 51

Sadeghi, N. 247 Sahara, T. 29 Salmon, I. 13 Scheib, S.G. 213, 236 Schmitt, M. 225 Schulder, M. 124 Seifert, V. 236 Selch, M. 82, 115 Shibazaki, T. 107 Simon, S. 197 Sinlapawongsa, T. 51, 267 Solberg, T.D. 46, 82, 115 Spe¤vác¤ek, V. 225 Syutou, T. 66 Szeifert, G.T. 13

Radatz, M. 100 Rao, R. 38 Régis, J. 190 Resnick, D.K. 171 Rieker, M. 236 Romanelli, P. 181

Taira, T. 161 Takada, Y. 29 Takakura, K. 161 Tanahata, K. 66 Tanaka, K. 29 Tang, T. 143

Ono, N. 107

Author Index

Theerapancharoen, V. 51, 267 Tinte¤ra, J. 225 Tlachác¤ová, D. 225 Tomé, W.A. 38, 171 Tomita, M. 161 Torres, R.C. 82, 115 Urakawa, Y. 77 Valade, D. 190 Van Houtte, P. 143, 197 Vanderlinden, B. 197 Vogelsanger, W. 213 Vymazal, J. 225 Walton, L. 100 Weltz, D. 236 Wessels, B.W. 260 Wikler, D. 143, 247 Wu, Q.J. 260 Yamamoto, M. 77 Yap, C. 46 Yongvithisatid, P. 267 Yu, C.P. 161 Yuan, Z. 38

279

Subject Index

Acoustic neuroma, neurofibromatosis type 2 gamma knife radiosurgery complications 103, 105 hearing outcomes 103, 105 outcome measures 101 patient selection 105 study design 101 tumor control 101–105 treatment options 100, 101 Acute complications, radiosurgery grading 42 incidence determination dose conformality effects 44 multivariate analysis 42, 43 patient characteristics 40, 41 radiosurgery treatment parameters 40, 41 side effect types 42 study design 39, 40, 44 patient education 44 Anosmia, see Meningioma Brain tumor metastases gamma knife radiosurgery multiple tumor capabilities 72, 73 ten or more metastases and dose absorption brainstem 78, 80 dose planning 78, 80 optic apparatus 78, 80 study design 78 treatment planning, see Positron emission tomography

tumor control probability, multiple tumor treatment prognosis normal tissue complication probability, effects on survival time 70, 74 study design 68, 69 survival time prediction 68–70, 73, 74 whole-brain irradiation 67, 72, 73 Cancer pain, see Pain Cavernous malformations brainstem lesion surgery 159 gamma knife radiosurgery complications 157, 159 dose 155 hemorrhage rate 155, 158 indications 154 response 155 seizure outcomes 157, 158 study design 155 imaging 153, 154 natural history 158 Chordoma, see Skull base chordoma Cluster headache (CH) diagnostic criteria 192, 193 gamma knife radiosurgery of trigeminal nerve complications 194, 195 outcomes 191, 192, 194, 195 study design 191 pathophysiology 190, 193–195 treatment options 190, 191, 194

280

Complications, see Acute complications, radiosurgery Computed tomography (CT) cisternography for trigeminal neuralgia radiosurgery 182 gamma knife treatment planning accuracy 248, 249 image acquisition 250, 251 overview 247, 248 registration with other imaging techniques 249 validation of frameless positron emission tomography 251–253 stereotactic irradiation device for cat studies 34, 36 Craniopharyngioma, see Sellar-parasellar tumors CyberKnife radiosurgery fiducial and skull tracking accuracy, quality assurance importance 258, 259 monthly test for fiducial tracking accuracy 256 monthly test for skull tracking accuracy 256, 257 outcomes 258 principles 255 trigeminal neuralgia, see Trigeminal neuralgia Dosimetry, see MAGIC; Polymer gel dosimetry Fiducial tracking, see CyberKnife radiosurgery Gamma knife acoustic neuroma management, see Acoustic neuroma, neurofibromatosis type 2 brain tumor metastasis treatment, see Brain tumor metastases cavernous malformation management, see Cavernous malformations cluster headache management, see Cluster headache

Subject Index

development 13 extracranial dose measurement with model C instrument cancer risks 198 distance influence analysis 205, 211 doses by tissue 199, 200, 210 integral dose influence analysis 204, 211 pathology influence analysis 200–202 phantom data 209, 210 plug influence analysis 206, 208, 211 reference isodose volume influence analysis 204, 211 study design 198, 199 target maximum dose influence analysis 203, 204 treatment time influence analysis 204, 212 glioblastoma multiforme treatment, see Glioblastoma multiforme low-grade gliomas, see Glioma pain management, see Pain pituitary adenoma management, see Pituitary adenoma polymer gel dosimetry, see MAGIC; Polymer gel dosimetry principles 39, 197, 198 sellar-parasellar tumor treatment, see Sellar-parasellar tumors treatment planning imaging, see Computed tomography; Magnetic resonance imaging; Positron emission tomography inverse treatment planning advantages 265 clinical evaluation 262, 264, 265 morphology-guided planning approach 261, 262 overview 260, 261 vestibular schwannoma management, see Vestibular schwannoma Gel dosimetry, see Polymer gel dosimetry

281

Glioblastoma multiforme (GBM) gamma knife radiosurgery morbidity 94, 96 patient characteristics 92 patient selection 96, 97 statistical analysis 93 survival outcomes 93, 94 technique 93 tumor progression management 97, 98 prognostic factors 92, 97 radiobiology 96 Glioma, see also Sellar-parasellar tumors methionine uptake positron emission tomography, evaluation of low-grade gliomas after gamma knife surgery dosimetry effects on metabolic course 149 follow-up and data analysis 146 histology 143, 149 magnetic resonance imaging correlation 148–150 metabolic activity evaluation 147, 149–151 patient characteristics 144, 145 radiosurgery 145, 146 optic nerve glioma microsurgery versus gamma knife radiosurgery 10, 11 Hearing preservation acoustic neuroma gamma knife radiosurgery in neurofibromatosis type 2 103, 105 vestibular schwannoma management, see Vestibular schwannoma Hypophysectomy, see Pain Linac radiosurgery, see also CyberKnife radiosurgery Novalis system, treatment of meningiomas combined radiosurgery and radiotherapy 116 complications 119, 120 intensity-modulated stereotactic radiosurgery/radiotherapy 121 neurological outcomes 118 patient selection 120 study design 116, 117

Subject Index

tumor control 117–120 vision outcomes 120, 121 Novalis system, treatment of skull base chordomas combined radiosurgery and radiotherapy 83 outcomes 85–89 patient characteristics 83, 85 toxicity 88 treatment planning and delivery 85 principles 39 trigeminal neuralgia management, see Trigeminal neuralgia MAGIC advantages 214 composition and effects on dose response 214, 215, 218, 220, 222 magnetic resonance imaging of absorbed dose under varying conditions 215, 216, 218, 220 production in the clinic 214, 215, 223 temperature effects on dose response 220, 222, 223 Magnetic resonance imaging (MRI) brain tumor angiogenesis evaluation 52, 53, 61 correlation with methionine uptake positron emission tomography, low-grade gliomas 148–150 gamma knife treatment planning accuracy 248, 249 image acquisition 250, 251 overview 247, 248 registration with other imaging techniques 249 validation of frameless positron emission tomography 251–253 MAGIC gel absorbed dose 215, 216, 218, 220 perfusion evaluation of brain tumors areas of interest analysis 53 hemodynamic parameters 60, 61 perfusion ratios in malignant versus benign tumors 55, 56, 61 principles 268 radiation therapy effects

282

study design 268 tumor progression group 275, 276 tumor regression group 275, 276 study design 53, 54 Magnetic resonance spectroscopy (MRS) brain tumor evaluation advantages 52 areas of interest analysis 53, 59, 60 grading of brain tumors 58, 59 metabolite ratios in malignant versus benign tumors 55–58, 61 principles 268 pulse sequences 60 radiation therapy effects metabolite ratios 268, 275 study design 268 tumor progression group 275, 276 tumor regression group 275, 276 study design 53, 54 pattern analysis 52 spatial resolution 60 Meningioma, see also Sellar-parasellar tumors Novalis system treatment combined radiosurgery and radiotherapy 116 complications 119, 120 intensity-modulated stereotactic radiosurgery/radiotherapy 121 neurological outcomes 118 patient selection 120 study design 116, 117 tumor control 117–120 vision outcomes 120, 121 olfaction preservation in olfactory groove meningiomas, stereotactic radiosurgery anosmia impact on patients 124, 125, 128, 129 case reports 125–127, 130, 131 conventional surgery outcomes 129, 130 olfactory system anatomy 127, 128 rationale 124, 125 Microsurgery sellar-parasellar tumors, see Sellarparasellar tumors

Subject Index

vestibular schwannoma, see Vestibular schwannoma Morphology-guided planning, see Gamma knife Neurofibromatosis type 2 acoustic neuroma, see Acoustic neuroma, neurofibromatosis type 2 vestibular schwannoma, see Vestibular schwannoma Normal tissue complication probability (NTCP) calculation 67, 69 multiple brain tumor metastases prognosis 70, 74 Novalis, see Linac radiosurgery Nuclear magnetic resonance (NMR), polymer gel absorbed dose 228, 229, 233 Olfaction, see Meningioma Olfactory groove meningioma, see Meningioma Pain gamma knife management cancer pain 165–168 dose/energy calculations 165, 166 indications 163, 164 mechanisms of action 167–169 overview 163 radiosurgery 163, 164 thalamic pain syndrome 165, 166, 168, 169 hypophysectomy management of cancer pain 162, 163 mechanism of action 167 thalamic pain syndrome management 163 Pathology, see Radiosurgical pathology Pituitary adenoma, see also Sellar-parasellar tumors fractionated radiotherapy 135 gamma knife radiosurgery advantages 140, 141 endocrinological control 136, 139, 140 hypopituitarism 140 side effects 137, 139 study design 135, 136

283

Pituitary adenoma, see also Sellar-parasellar tumors (continued) gamma knife radiosurgery (continued) tumor control 136, 139 visual field changes 136, 137, 140 surgery risks 135 Polymer gel dosimetry, see also MAGIC applications 213, 226, 233, 234 gamma knife treatment plan evaluation calibration and irradiation 226–228 dose distribution parameters 229, 233 gel preparation 226 nuclear magnetic resonance, absorbed dose 228, 229, 233 observed versus calculated values 231, 233, 234 gel types 214 Positron emission tomography (PET) brain metastasis utility 48, 49 fluorodeoxyglucose as tracer 47 gamma knife treatment planning accuracy 248, 249 image acquisition 250, 251 overview 247, 248 registration with other imaging techniques 249 validation of frameless imaging 251–253 methionine uptake positron emission tomography, evaluation of low-grade gliomas after gamma knife surgery dosimetry effects on metabolic course 149 follow-up and data analysis 146 histology 143, 149 magnetic resonance imaging correlation 148–150 metabolic activity evaluation 147, 149–151 patient characteristics 144, 145 radiosurgery 145, 146 principles 47 radiation necrosis imaging 50 study design 47 Quality assurance CyberKnife fiducial and skull tracking accuracy quality assurance

Subject Index

importance 258, 259 monthly test for fiducial tracking accuracy 256 monthly test for skull tracking accuracy 256, 257 outcomes 258 overview 236, 237, 244 Quality assurance in radiosurgery/ radiotherapy (QUASIR), see Stereotactic radiosurgery/radiotherapy analysis; Tomographic phantom analysis Radiation tolerance definition 22 spinal cord, see Spinal cord radiation tolerance Radiosurgical pathology degenerative and proliferative changes in radiosurgery 18 goals 14 historical perspective 14–16 radiolesion characteristics 16–18 rationale 19 Schwannoma, see Vestibular schwannoma Sellar-parasellar tumors, microsurgery versus gamma knife radiosurgery case characteristics 2 control rates by tumor type 3, 4, 9 craniopharyngioma 5, 9 dosimetry 2, 9 germinoma 10 meningioma 6, 10, 11 optic nerve glioma 10, 11 pilocytic astrocytoma case presentation 6, 8 pituitary adenoma 5, 6, 9 radiosensitivity of tumors 9 radiosurgery efficacy evaluation 3 suprasellar germinoma case presentation 8 Skull base chordoma epidemiology 83 Novalis system treatment combined radiosurgery and radiotherapy 83 outcomes 85–89 patient characteristics 83, 85

284

toxicity 88 treatment planning and delivery 85 radiation tolerance 83 Spinal cord radiation tolerance injury signs 22 modeling 23 radiation parameters in injury 22, 23 treatment planning dose-volume effects 24–28 study design 23, 24 tolerance dose 26, 27 Stereotactic irradiation (STI), experimental device for cat studies computed tomography 34, 36 device features 30 film dosimetry 33 phantom 30 stereotactic radiosurgery 31, 33 X-Knife software, comparison with film dosimetry 29, 33, 34, 36 Stereotactic radiation therapy (SRT) Novalis system, treatment of meningiomas combined radiosurgery and radiotherapy 116 complications 119, 120 intensity-modulated stereotactic radiosurgery/radiotherapy 121 neurological outcomes 118 patient selection 120 study design 116, 117 tumor control 117–120 vision outcomes 120, 121 Novalis system, treatment of skull base chordomas combined radiosurgery and radiotherapy 83 outcomes 85–89 patient characteristics 83, 85 toxicity 88 treatment planning and delivery 85 Stereotactic radiosurgery/radiotherapy analysis (STERAS) applications 244 goals 237 phantom, see Tomographic phantom analysis test routines L-test 242, 243

Subject Index

simulation patient 243 system test 240–242 Thalamic pain syndrome, see Pain Tomographic phantom analysis (TOPAS) applications 244 film dosimetry 239, 240 goals 237 phantom 237, 238 Trigeminal nerve radiosurgery, see Cluster headache; Trigeminal neuralgia Trigeminal neuralgia CyberKnife radiosurgery computed tomographic cisternography 182 dose placement precision 184–187 image-guided radiosurgery 183, 184 pain relief and temporal patterns 185, 186, 188 patient selection 182 side effects 185 treatment planning 183, 187, 188 epidemiology 172 gamma knife radiosurgery 172, 176, 177, 182 Linac radiosurgery complications 176 pain relapse 175, 176 patient selection 172 technique 172–175, 177, 178 response assessment 175 statistical analysis 175 medical therapy 172 Tumor control probability (TCP) formula 67 multiple brain tumor treatment prognosis normal tissue complication probability, effects on survival time 70, 74 study design 68, 69 survival time prediction 68–70, 73, 74 whole-brain irradiation 67, 72, 73 Vestibular schwannoma gamma knife radiosurgery and microsurgery for hearing preservation

285

Vestibular schwannoma gamma knife radiosurgery and microsurgery for hearing preservation (continued) outcomes with and without microsurgery 109, 110, 112, 113 rationale 108 study design 108 large-tumor treatment 107, 108

Subject Index

Vision optic apparatus dose absorption, radiosurgery of multiple brain metastases 78, 80 pituitary adenoma gamma knife radiosurgery effects 136, 137, 140 preservation with meningioma treatment 120, 121 Whole-brain irradiation, multiple brain metastases 67, 72, 73

286