INTRACRANIAL RADIOSURGERY

Wendy Hara, M.D.

Department of Radiation Oncology, Stanford University, Stanford, California

Phuoc Tran, M.D., Ph.D.

Department of Radiation Oncology, Stanford University, Stanford, California

CYBERKNIFE FOR BRAIN METASTASES OF MALIGNANT MELANOMA AND RENAL CELL CARCINOMA
OBJECTIVE: To evaluate the efcacy of CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS) for patients with brain metastases of malignant melanoma and renal cell carcinoma. METHODS: We conducted a retrospective review of all patients treated by image-guided radiosurgery at our institution between March 1999 and December 2005. Sixty-two patients with 145 brain metastases of renal cell carcinoma or melanoma were identied. RESULTS: The median follow-up period was 10.5 months. Forty-four patients had malignant melanoma, and 18 patients had renal cell carcinoma. The median age was 57 years, and patients were classied as recursive partitioning analysis Class 1 (6 patients), 2 (52 patients) or 3 (4 patients). Thirty-three patients had been treated systemically with either chemotherapy or immunotherapy, and 33 patients were taking corticosteroids at the time of treatment. The mean tumor volume was 1.47 mL (range, 0.0235.7 mL), and the mean prescribed dose was 20 Gy (range, 1424 Gy). The median survival after SRS was 8.3 months. Actuarial survival at 6 and 12 months was 57 and 37%, respectively. On multivariate analysis, Karnofsky Performance Scale score (P 0.01) and previous immunotherapy/clinical trial (P 0.01) signicantly affected overall survival. One-year intracranial progression-free survival was 38%, and local control was 87%. Intracranial control was impacted by whole-brain radiotherapy (P 0.01), previous chemotherapy (P 0.01), and control of the primary at the time of SRS (P 0.02). Surgical resection had no effect on intracranial or local control. Radiographic evidence of radiation necrosis developed in 4 patients (6%). CONCLUSION: CyberKnife radiosurgery provided excellent local control with acceptable toxicity in patients with melanoma or renal cell brain metastases. Initial SRS alone appeared to be a reasonable option, as survival was dictated by systemic disease.
KEY WORDS: Brain metastases, Melanoma, Radiosurgery, Renal cell carcinoma
Neurosurgery 64:A26A32, 2009
DOI: 10.1227/01.NEU.0000339118.55334.EA

Gordon Li, M.D.

Department of Neurosurgery, Stanford University, Stanford, California

Zheng Su, Ph.D.

Department of Applied Mathematics and Statistics, State University of New York at Stony Brook, New York, New York

Putipun Puataweepong, M.D.

Department of Radiology, Ramathibodi Hospital, Bangkok, Thailand

John R. Adler, Jr., M.D.

Department of Neurosurgery, Stanford University, Stanford, California

Scott G. Soltys, M.D.

Department of Radiation Oncology, Stanford University, Stanford, California

Steven D. Chang, M.D.

Department of Neurosurgery, Stanford University, Stanford, California

www.neurosurgery-online.com

Iris C. Gibbs, M.D.

Department of Radiation Oncology, Stanford University, Stanford, California Reprint requests: Wendy Hara, M.D., Department of Radiation Oncology, Stanford University, Stanford Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847. Email: wendy.hara@stanford.edu Received, May 23, 2008. Accepted, October 13, 2008. Copyright 2009 by the Congress of Neurological Surgeons

n estimated 170 000 new brain metastases are diagnosed in the United States every year (29). Brain metastases occur in approximately 10% of patients with renal cell carcinoma (RCC) and 9% of patients with melanoma (16, 26). The incidence may increase with improved magnetic resonance imaging (MRI) and longer survival of cancer patients (26). Historically, these histologies have been considered somewhat radioresistant, with mixed clinical support for this observation (10, 17, 24, 42). Stereotactic radiosurgery (SRS) is a radia-

tion therapy technique characterized by a high level of accuracy and rapid dose falloff at the target edge. This technique is one of the effective treatment modalities for brain metastases. SRS alone, with whole-brain radiotherapy (WBRT) being reserved for salvage in case of progression, has been shown to be an acceptable treatment option for patients with brain metastases, as compared with up-front SRS and WBRT in both retrospective and randomized studies (4, 7, 8, 20, 40). Results of trials evaluating WBRT alone for these histologies have been

ABBREVIATIONS: CI, confidence interval; HR, hazard ratio; IC, intracranial control; LC, local control; MRI, magnetic resonance imaging; NSS, neurological specific survival; OS, overall survival; RCC, renal cell carcinoma; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy

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disappointing, and WBRT may confer long-term neurocognitive risk (9, 42). Thus, we have favored SRS alone with close followup for our patients with newly diagnosed brain metastases of malignant melanoma or RCC histologies. Recent reviews have questioned the omission of up-front WBRT with SRS; thus, we set out to evaluate the efficacy of SRS using the CyberKnife (Accuray, Inc., Sunnyvale, CA) for patients with brain metastases of malignant melanoma and RCC at our institution (15, 18).

TABLE 1. Patient and treatment characteristicsa Characteristics Melanoma (no.) Renal cell (no.) Median age, y (range) Median KPS score (range) RPA class, no. (%) No. 44 18 57 (2589) 80 (60100) 6 (10) 52 (84) 4 (6) 33

PATIENTS AND METHODS

We conducted a retrospective review of all patients with brain metastases of melanoma or RCC treated by image-guided radiosurgery with the CyberKnife at Stanford University between March 1999 and December 2005. Informed consent was obtained from all patients. Sixtytwo patients with 145 brain metastases of RCC or melanoma histologies were identified. Patients were followed clinically and radiographically with MRI. The following information was obtained through chart review: age, performance status, histology, date of primary diagnosis, control of the primary site at the time of radiosurgery, locations of other metastatic sites, recursive partitioning analysis class, previous chemotherapy treatment, previous immunotherapy treatment, previous clinical trial participation, corticosteroid use at time of treatment, neurosurgical resection, WBRT, neurological symptoms at presentation, number of metastatic brain lesions, location of brain metastases, SRS date, treatment volume, prescribed dose, maximum dose, conformality index, progression of the treated lesion, cause and date of death, occurrence of radiation necrosis, and type and date of salvage treatments (12, 14). All patients were simulated supine with an Aquaplast mask (WFR/Aquaplast Corp., Wyckoff, NJ) for immobilization. High-resolution computed tomographic scans were obtained with 1.25-mm slice thickness and fused with an MRI. Target volumes were outlined, and critical structures including the eyes, lens, optic nerves, optic chiasm, brainstem, and spinal cord were contoured as avoidance structures. Plans were generated with the CyberKnife inverse treatment planning algorithm (1). We analyzed the data for overall survival (OS), neurological specific survival (NSS), local failure of the treated lesion, intracranial failure (any failure in the brain), and failure elsewhere (failure in the brain outside the treated volume). Patients were considered dead from neurological causes if: 1) there was clinical or radiographic evidence of neurological progression near the time of death, 2) both neurological and systemic progression existed, or 3) the patient was lost to follow-up with suspicion of recurrence. Otherwise, they were censored at the date of the last follow-up evaluation. Local and intracranial failure was determined through clinical observations, MRI findings, or clinical/neurological deterioration. Survival time in years was calculated from the day of SRS by the Kaplan-Meier method. Survival, NSS, local control (LC), and intracranial control (IC) were analyzed by the Cox proportional hazards model. All factors with a P value of 0.20 or less on univariate analysis were entered into the model, and backward elimination was carried out. Statistical significance was defined as a P value of less than 0.05. Statistical calculations were performed using the R freeware and Prism (Version 4.0; GraphPad Software, Inc., La Jolla, CA).

1 2 3
Systemic treatment (chemo-/ immunotherapy) (no.) Brain metastases (no.)

1 23
4 Median no. of other systemic sites of metastases Corticosteroids (no.) Neurological symptoms at presentation (no.) Surgery (no.) WBRT (no.)
a

24 26 12 2 33 43 26 17

KPS, Karnofsky Performance Scale; RPA, recursive partitioning analysis; WBRT, whole-brain radiotherapy.

four patients had melanoma, and 18 patients had RCC. Eightyfour percent of the patients were recursive partitioning analysis Class 2. Twenty-four patients had a single treated brain metastasis, 26 patients were treated for 2 to 3 metastases, and 12 patients were treated for 4 or more metastases; a total of 145 lesions were treated. Nine patients did not have their primary site of cancer controlled at the time of SRS. Patients with extracranial metastatic disease had a median of 2 other systemic sites. Fifty-three percent of patients were receiving corticosteroids at the time of SRS, and 53% had been treated with chemotherapy or immunotherapy for their systemic disease. Twenty-seven percent of patients had been treated with WBRT before SRS, and 8% had their treatment planned from the beginning as a combination of WBRT and SRS. Eleven percent of the lesions were treated with surgical resection followed by a radiosurgical boost without planned WBRT.

Radiosurgery Treatment Plan

The median tumor volume was 1.47 mL (range, 0.0235.69 mL), the median prescribed dose was 20 Gy (range, 1424 Gy), the median maximum dose was 25.9 Gy (range, 14.438.0 Gy), and the median conformality index was 1.35 (range, 1.013.34). The median prescribed isodose line was 80% (range, 6598%). Most lesions were treated in a single session (n 132), with the remainder in 2 (n 8), 3 (n 4), or 5 (n 1) sessions.

RESULTS
Patient Characteristics
Patient characteristics are listed in Table 1. The median followup period was 10.5 months (range, 0.565.3 months). Forty-

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OS and NSS
The median OS was 8.3 months (range, 0.565.3 months), and the median NSS was 22.3 months (range, 2.165.3 months) (Table 2). At 1 year, the OS was 37%. Patients with RCC had a greater OS than patients with melanoma (14.2 versus 5.6 months). On multivariate analysis, Karnofsky Performance Scale score (P 0.01) and previous immunotherapy or clinical trial (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.374.75) significantly affected OS (Table 3). NSS was only affected by failure elsewhere in the brain (HR, 3.82; 95% CI, 1.0613.76). WBRT did not affect OS or NSS. Although failure elsewhere negatively impacted NSS (P 0.04), it did not significantly affect OS in this cohort (P 0.37).
TABLE 2. Median survivala Overall survival Whole cohort Melanoma RCC WBRT Without WBRT With planned WBRT Without planned WBRT Surgery Without surgery Local failure No local failure Brain failure elsewhere No failure elsewhere Any intracranial failure No intracranial failure
a b

Neurological specic survival 22.3 14.2b 22.4b 14.2 22.3 14.2 22.4 14.2 22.3 10.1 22.4 15.7b Not reachedb 15.72b Not reachedb

8.3 5.6 14.2 8.6 8.0 6.7 8.6 8.9 7.3 10.8 8.6 11.6 3.8 10.8 3.6

IC
One-year actuarial LC of metastases treated with SRS was 87%. One-year intracranial progression-free survival was 38%. On multivariate analysis, WBRT (HR, 0.43; 95% CI, 0.230.80), previous chemotherapy (HR, 2.76; 95% CI, 1.515.05), and controlled primary site (HR, 0.41; 95% CI, 0.190.89) significantly impacted IC (Table 4). Patients with melanoma had poorer IC (HR, 2.84; 95% CI, 1.455.55). WBRT did not affect LC or failure elsewhere. Surgical resection had no effect on IC or LC. Treatment with corticosteroids (HR, 0.55; 95% CI, 0.301.00) and

RCC, renal cell carcinoma; WBRT, whole-brain radiotherapy. P 0.05.

TABLE 3. Overall survival and neurological specic survival analysisa

P value
Characteristic Univariate Age Sex KPS Melanoma Renal cell Primary controlled No. of systemic metastatic sites Previous immunotherapy or clinical trial Previous chemotherapy Any previous WBRT Planned WBRT with SRS Corticosteroid treatment Neurological symptoms at presentation No. of metastases Local failure in treated lesions Failure elsewhere 0.65 0.24 0.04 0.06 0.06 0.37 0.24 0.09 0.65 0.80 0.48 0.08 0.32 0.18 0.48 0.37 Overall survival Multivariate NS NS 0.01 0.01 (HR, 4.06; 95% CI, 1.928.56) NS NS NS 0.01 (HR, 2.55; 95% CI, 1.374.75) NS NS NS NS NS NS NS NS Neurological specic survival Univariate 0.41 0.15 0.61 0.06 0.06 0.80 0.62 0.35 0.94 0.35 0.12 0.38 0.35 0.99 0.17 0.04 Multivariate NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.04 (HR, 3.82; 95% CI, 1.0613.76)

NS, not signicant; KPS, Karnofsky Performance Scale; HR, hazard ratio; CI, condence interval; WBRT, whole-brain radiotherapy; SRS, stereotactic radiosurgery.

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TABLE 4. Local and intracranial controla

P value
Characteristic Melanoma Primary controlled Previous chemotherapy Previous immunotherapy Previous clinical trial Previous WBRT Corticosteroid treatment Neurological symptoms at presentation Surgery Total dose Tumor volume 0.03 0.19 0.01 0.47 0.55 0.17 0.05 0.01 0.54 0.29 0.06 Intracranial control Univariate Multivariate 0.01 (HR, 2.84; 95% CI, 1.455.55) 0.02 (HR, 0.41; 95% CI, 0.190.89) 0.01 (HR, 2.76; 95% CI, 1.515.05) NS NS 0.01 (HR, 0.43; 95% CI, 0.230.80) NS NS NS NS NS 0.20 0.29 0.55 0.39 0.52 0.15 0.91 0.01 0.97 0.95 0.82 Local control Univariate Multivariate NS NS NS NS NS NS NS 0.01 (HR, 0.16; 95% CI, 0.040.62) NS NS NS 0.08 0.06 0.01 0.46 0.39 0.48 0.03 0.02 0.52 0.22 0.05 Control elsewhere Univariate Multivariate 0.04 (HR, 2.03; 95% CI, 1.024.06) 0.01 (HR, 0.27; 95% CI, 0.120.60) 0.01 (HR, 2.88; 95% CI, 1.555.37) NS NS NS 0.05 (HR, 0.55; 95% CI, 0.301.00) NS NS NS 0.01 (HR, 1.09; 95% CI, 1.031.16)

HR, hazard ratio; CI, condence interval; NS, not signicant.

controlled primary site (HR, 0.27; 95% CI, 0.120.60) improved control elsewhere in the brain. Larger tumor volumes (continuous variable) (HR, 1.09; 95% CI, 1.031.16), previous chemotherapy (HR, 2.88; 95% CI, 1.555.37), and melanoma histology (HR, 2.03; 95% CI, 1.024.06) were associated with decreased control.

Toxicity and Salvage

The 29 patients with intracranial failures received salvage treatment with SRS (n 13), surgery plus SRS (n 1), WBRT plus surgery (n 2), WBRT plus SRS (n 1), surgery alone (n 2), or supportive care (n 10). Of the 9 patients who had progression in the treated lesion, salvage therapies included SRS (n 2), WBRT plus surgery (n 1), SRS plus surgery (n 1), surgery (n 2), and supportive care (n 3). Four of these 9 patients died from neurological causes. In the cohort, 4 patients (6%) developed radiation necrosis.

DISCUSSION
Melanoma and RCC have historically been thought to be somewhat radioresistant; however, clinical and in vitro data appear to demonstrate the effectiveness of radiotherapy and individual response variability (17, 25, 33, 37). After WBRT, LC rates of melanoma and RCC tumors range from 0 to 80% (6, 11, 23). These rates compare with an actuarial LC at 1 year of 87% and a crude rate of 94% (136 of 145 lesions) in the present

series, which are similar to reported crude LC rates of 68 to 96% with SRS (5, 17, 21, 22, 30, 37). Surgical resection did not improve LC or OS. Toxicity mainly consisted of radionecrosis (6%), which was acceptable and comparable to other studies (35). WBRT did not improve NSS or OS. Many of our patients had uncontrolled systemic disease, with 10 patients having 4 or more other systemic sites of metastases; thus, the lack of survival difference was not surprising, perhaps partly because of reseeding after treatment (41). An Eastern Cooperative Oncology Group Phase II study (E 6397) (17) that enrolled 36 patients with 1 to 3 brain metastases from melanoma, RCC, or sarcoma found a 6month intracranial progression of 48.3% and a median survival of 8.3 months at a median follow-up duration of 32.7 months. Up-front SRS alone appeared to be reasonable, based on survival. Similar to our analysis, other studies, both randomized and retrospective, have also found no difference in survival, neurological survival, or neurological function preservation with the addition of up-front WBRT to SRS (Table 5) (4, 8, 17, 28, 31, 34, 39, 40). A survival benefit from the addition of WBRT to SRS could be found only in a subset of patients without extracranial disease (15.4 versus 8.3 months) in 1 retrospective study (28). Given the inferior LC reported with WBRT, we favor SRS for treatment of melanoma and RCC metastases. The association of WBRT with long-term risk of neurocognitive deficits is a deterrent to its use, but this risk is clouded by the

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TABLE 5. Studies comparing stereotactic radiosurgery versus stereotactic radiosurgery plus whole-brain radiotherapya Series (ref. no.) Aoyama et al., 2006 (4) Study design Randomized No. of patients 132 No. of melanoma or RCC patients 15 Treatment SRS SRS WBRT Survival (mo) 8 7.5 IC failure (%) 76 47 Outcome 14 metastases, 3 cm No survival or neurological survival difference, no difference in preservation of neurological function Mostly NSCLC, 3 metastases, 50% had surgical resection No survival difference 6.2 9.2 78 30 Solitary metastasis No survival or neurological survival difference, no difference in QOL or neurological function No difference in survival or IC control with salvage treatment 62% after salvage No survival difference

Chougule et al., 2000 (8)

Randomized

109

11

SRS WBRT SRS WBRT Surgery or SRS Surgery/ SRS WBRT SRS SRS WBRT SRS SRS WBRT SRS SRS WBRT

7 5 9

43 19 23

Roos et al., 2006 (34)

Randomized

19

Sneed et al., 1999 (39)

Retrospective

105

51

11.3 11.1

72 31

Sneed et al., 2002 (40) Pirzkall et al., 1998 (28)

Retrospective

569

155

8.2 8.6 5.5 overall 34 23

Retrospective

236

100

13 metastases, no survival difference Survival difference for WBRT in subset without extracranial disease (15.4 versus 8.3 mo) 13 metastases No difference with WBRT or surgery

Manon et al., 2005 (17) Rao et al., 2006 (31)

Prospective Retrospective

31 68

28 65

SRS SRS SRS WBRT

8.3 14.9 12.8

48

RCC, renal cell carcinoma; IC, intracranial control; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy; NSCLC, non-small cell lung cancer; QOL, quality of life.

fact that many patients with brain metastases have neurocognitive deficits at baseline (19). There is a real risk of leukoencephalopathy associated with large fraction sizes (3 Gy) and concurrent chemotherapy (9, 13, 27). Conversely, the issue of patient quality of life impacted by a brain recurrence has also been examined. In a retrospective study of symptomatic brain recurrences, intracranial failure after SRS alone was symptomatic in 12 (71%) of 17 patients and associated with a neurological deficit in 10 (59%) of 17 patients, and, thus, the authors argued for the use of WBRT for patients with potentially long survival

(32). However, in a Japanese prospective randomized trial, when the preservation of neurological function was examined, there was no difference between the group receiving SRS, as compared with those patients treated with up-front WBRT with SRS (4). For these patients, quality of life is a crucial consideration that we could not accurately gauge in this retrospective study; however, we agree that this will become an even greater issue as treatment advances prolong survival. Currently, the ongoing European Organization for Research and Treatment of Cancer 22952 trial investigates the addition of

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WBRT to SRS or surgery in patients with 1 to 3 metastases. A second trial, North Central Cancer Treatment Group 0574, compares SRS with or without WBRT in patients with 1 to 3 metastases. We await the neurocognitive and quality-of-life results from this trial. New areas of study include the combination of radiation with agents such as motexafin gadolinium, efaproxaril, temozolamide, or gefitinib (2, 3, 19, 36, 38). In summary, CyberKnife radiosurgery provided excellent LC with acceptable toxicity in our patients with melanoma or RCC brain metastases. Although WBRT improved overall IC, neither WBRT nor surgery improved OS or NSS. We conclude that initial SRS alone appears reasonable, as survival was dictated by systemic disease. Better systemic therapies are needed, and as systemic control improves, SRS with up-front WBRT should be considered.

Disclosures
John R. Adler, Jr., M.D., is on the Board of Directors and a shareholder of Accuray, Inc. Iris C. Gibbs, M.D., serves on the Clinical Advisory Board of Accuray, Inc. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

REFERENCES
1. Adler JR Jr, Murphy MJ, Chang SD, Hancock SL: Image-guided robotic radiosurgery. Neurosurgery 44:12991307, 1999. 2. Agarwala SS, Kirkwood JM, Gore M, Dreno B, Thatcher N, Czarnetski B, Atkins M, Buzaid A, Skarlos D, Rankin EM: Temozolomide for the treatment of brain metastases associated with metastatic melanoma: A phase II study. J Clin Oncol 22:21012107, 2004. 3. Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, Throuvalas N: Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20:36443650, 2002. 4. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G: Stereotactic radiosurgery plus whole-brain radiation therapy vs. stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA 295:24832491, 2006. 5. Brown PD, Brown CA, Pollock BE, Gorman DA, Foote RL: Stereotactic radiosurgery for patients with radioresistant brain metastases. Neurosurgery 51:656667, 2002. 6. Cannady SB, Cavanaugh KA, Lee SY, Bukowski RM, Olencki TE, Stevens GH, Barnett GH, Suh JH: Results of whole brain radiotherapy and recursive partitioning analysis in patients with brain metastases from renal cell carcinoma: A retrospective study. Int J Radiat Oncol Biol Phys 58:253258, 2004. 7. Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF, Barnett GH: Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys 47:993999, 2000. 8. Chougule PB, Burton-Williams M, Saris S, Zheng Z, Ponte B, Noren G, Alderson L, Friehs G, Wazer D, Ebstein M: Randomized treatment of brain metastases with gamma knife, whole brain radiotherapy or both Int J Radiat Oncol Biol Phys 48:114, 2000 (abstr). 9. DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789796, 1989. 10. DiBiase SJ, Valicenti RK, Schultz D, Xie Y, Gomella LG, Corn BW: Palliative irradiation for focally symptomatic metastatic renal cell carcinoma: Support for dose escalation based on a biological model. J Urol 158:746749, 1997. 11. Ellerhorst J, Strom E, Nardone E, McCutcheon I: Whole brain irradiation for patients with metastatic melanoma: A review of 87 cases. Int J Radiat Oncol Biol Phys 49:9397, 2001.

12. Feuvret L, Nol G, Mazeron JJ, Bey P: Conformity index: A review. Int J Radiat Oncol Biol Phys 64:333342, 2006. 13. Fonseca R, ONeill BP, Foote RL, Grill JP, Sloan JA, Frytak S: Cerebral toxicity in patients treated for small cell carcinoma of the lung. Mayo Clin Proc 74:461465, 1999. 14. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745751, 1997. 15. Khuntia D, Brown P, Li J, Mehta MP: Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24:12951304, 2006. 16. Leibel SA (ed): Textbook of Radiation Oncology. Philadelphia, Saunders, 2004, p 934. 17. Manon R, ONeill A, Knisely J, Werner-Wasik M, Lazarus HM, Wagner H, Gilbert M, Mehta M: Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: An Eastern Cooperative Oncology Group study (E 6397). J Clin Oncol 23:88708876, 2005. 18. Mehta MP, Khuntia D: Current strategies in whole-brain radiation therapy for brain metastases. Neurosurgery 57 [Suppl 5]:S33S44, 2005. 19. Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W, Souhami L, Bezjak A, Leibenhaut M, Komaki R, Schultz C, Timmerman R, Curran W, Smith J, Phan SC, Miller RA, Renschler MF: Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 21:25292536, 2003. 20. Mehta MP, Tsao MN, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L: The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 63:3746, 2005. 21. Mori Y, Kondziolka D, Flickinger JC, Kirkwood JM, Agarwala S, Lunsford LD: Stereotactic radiosurgery for cerebral metastatic melanoma: Factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 42:581589, 1998. 22. Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD: Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 83:344353, 1998. 23. Nieder C, Berberich W, Nestle U, Niewald M, Walter K, Schnabel K: Relation between local result and total dose of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 33:349355, 1995. 24. Nieder C, Berberich W, Schnabel K: Tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys 39:2530, 1997. 25. Ning S, Trisler K, Wessels BW, Knox SJ: Radiobiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts. Cancer 80 [Suppl 12]:25192528, 1997. 26. Patchell RA: The management of brain metastases. Cancer Treat Rev 29:533540, 2003. 27. Patchell RA, Regine WF: The rationale for adjuvant whole brain radiation therapy with radiosurgery in the treatment of single brain metastases. Technol Cancer Res Treat 2:111115, 2003. 28. Pirzkall A, Debus J, Lohr F, Fuss M, Rhein B, Engenhart-Cabillic R, Wannenmacher M: Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 16:35633569, 1998. 29. Posner JB: Management of brain metastases. Rev Neurol (Paris) 148:477487, 1992. 30. Radbill AE, Fiveash JF, Falkenberg ET, Guthrie BL, Young PE, Meleth S, Markert JM: Initial treatment of melanoma brain metastases using gamma knife radiosurgery: An evaluation of efficacy and toxicity. Cancer 101:825833, 2004. 31. Rao G, Klimo P Jr, Thompson CJ, Samlowski W, Wang M, Watson G, Shrieve D, Jensen RL: Stereotactic radiosurgery as therapy for melanoma, renal carcinoma, and sarcoma brain metastases: Impact of added surgical resection and whole-brain radiotherapy. Int J Radiat Oncol Biol Phys 66 [Suppl 4]: S20S25, 2006. 32. Regine WF, Huhn JL, Patchell RA, St Clair WH, Strottmann J, Meigooni A, Sanders M, Young AB: Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed

NEUROSURGERY

VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT | A31

HARA ET AL.

33. 34.

35.

36.

37.

38.

brain metastases: Results and implications. Int J Radiat Oncol Biol Phys 52:333338, 2002. Rofstad EK: Radiation biology of malignant melanoma. Acta Radiol Oncol 25:110, 1986. Roos DE, Wirth A, Burmeister BH, Spry NA, Drummond KJ, Beresford JA, McClure BE: Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: Mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05). Radiother Oncol 80:318322, 2006. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291298, 2000. Shaw E, Scott C, Suh J, Kadish S, Stea B, Hackman J, Pearlman A, Murray K, Gaspar L, Mehta M, Curran W, Gerber M: RSR13 plus cranial radiation therapy in patients with brain metastases: Comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database. J Clin Oncol 21:23642371, 2003. Sheehan JP, Sun MH, Kondziolka D, Flickinger J, Lunsford LD: Radiosurgery in patients with renal cell carcinoma metastasis to the brain: Long-term outcomes and prognostic factors influencing survival and local tumor control. J Neurosurg 98:342349, 2003. Shimato S, Mitsudomi T, Kosaka T, Yatabe Y, Wakabayashi T, Mizuno M, Nakahara N, Hatano H, Natsume A, Ishii D, Yoshida J: EGFR mutations in

39.

40.

41.

42.

patients with brain metastases from lung cancer: Association with the efficacy of gefitinib. Neuro Oncol 8:137144, 2006. Sneed PK, Lamborn KR, Forstner JM, McDermott MW, Chang S, Park E, Gutin PH, Phillips TL, Wara WM, Larson DA: Radiosurgery for brain metastases: Is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 43:549558, 1999. Sneed PK, Suh JH, Goetsch SJ, Sanghavi SN, Chappell R, Buatti JM, Regine WF, Weltman E, King VJ, Breneman JC, Sperduto PW, Mehta MP: A multiinstitutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519526, 2002. Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, Tans JT, Lambooij N, Metsaars JA, Wattendorff AR, Brand R, Hermans J: Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol 33:583590, 1993. Wrnski M, Maor MH, Davis BJ, Sawaya R, Levin VA: External radiation of brain metastases from renal carcinoma: A retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:753759, 1997.

Acknowledgment
We thank Balasubramanian Narasimhan, Ph.D., for his assistance with the project.

A32 | VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT

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