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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
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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
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.
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
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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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)
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.
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
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
Randomized
19
Retrospective
105
51
11.3 11.1
72 31
Retrospective
569
155
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
Prospective Retrospective
31 68
28 65
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.
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Acknowledgment
We thank Balasubramanian Narasimhan, Ph.D., for his assistance with the project.
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