Cyberknife Treatment of Brain Metastases of Malignant Melanoma and Renal Cell Carcinoma

A26 | VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT www.neurosurgery-online.com

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

Gordon Li, M.D.Department of Neurosurgery,Stanford University,Stanford, California

Zheng Su, Ph.D.Department of Applied Mathematicsand Statistics,State University of New Yorkat 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

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: [email protected]

Received, May 23, 2008.

Accepted, October 13, 2008.

Copyright 2009 by theCongress of Neurological Surgeons

An estimated 170 000 new brain metastasesare diagnosed in the United States everyyear (29). Brain metastases occur inapproximately 10% of patients with renal cellcarcinoma (RCC) and 9% of patients withmelanoma (16, 26). The incidence may increasewith improved magnetic resonance imaging(MRI) and longer survival of cancer patients(26). Historically, these histologies have beenconsidered somewhat radioresistant, with mixedclinical support for this observation (10, 17, 24,42). Stereotactic radiosurgery (SRS) is a radia-

tion therapy technique characterized by a highlevel of accuracy and rapid dose falloff at thetarget edge. This technique is one of the effectivetreatment modalities for brain metastases.

SRS alone, with whole-brain radiotherapy(WBRT) being reserved for salvage in case ofprogression, has been shown to be an accept-able treatment option for patients with brainmetastases, as compared with up-front SRS andWBRT in both retrospective and randomizedstudies (4, 7, 8, 20, 40). Results of trials evaluat-ing WBRT alone for these histologies have been

CYBERKNIFE FOR BRAIN METASTASES OF MALIGNANTMELANOMA AND RENAL CELL CARCINOMA

OBJECTIVE: To evaluate the efficacy of CyberKnife (Accuray, Inc., Sunnyvale, CA) stereo-tactic radiosurgery (SRS) for patients with brain metastases of malignant melanoma andrenal cell carcinoma.METHODS: We conducted a retrospective review of all patients treated by image-guidedradiosurgery at our institution between March 1999 and December 2005. Sixty-twopatients with 145 brain metastases of renal cell carcinoma or melanoma were identified.RESULTS: The median follow-up period was 10.5 months. Forty-four patients had malig-nant melanoma, and 18 patients had renal cell carcinoma. The median age was 57years, and patients were classified as recursive partitioning analysis Class 1 (6 patients),2 (52 patients) or 3 (4 patients). Thirty-three patients had been treated systemically witheither chemotherapy or immunotherapy, and 33 patients were taking corticosteroidsat 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 afterSRS was 8.3 months. Actuarial survival at 6 and 12 months was 57 and 37%, respec-tively. On multivariate analysis, Karnofsky Performance Scale score (P 0.01) and pre-vious immunotherapy/clinical trial (P 0.01) significantly 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), previouschemotherapy (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 evidenceof radiation necrosis developed in 4 patients (6%).CONCLUSION: CyberKnife radiosurgery provided excellent local control with accept-able toxicity in patients with melanoma or renal cell brain metastases. Initial SRS aloneappeared 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 www.neurosurgery- online.com

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 carci-noma; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy

disappointing, and WBRT may confer long-term neurocognitiverisk (9, 42). Thus, we have favored SRS alone with close follow-up for our patients with newly diagnosed brain metastases ofmalignant melanoma or RCC histologies. Recent reviews havequestioned the omission of up-front WBRT with SRS; thus, we setout to evaluate the efficacy of SRS using the CyberKnife (Accuray,Inc., Sunnyvale, CA) for patients with brain metastases of malig-nant melanoma and RCC at our institution (15, 18).

PATIENTS AND METHODS

We conducted a retrospective review of all patients with brain metas-tases of melanoma or RCC treated by image-guided radiosurgery withthe CyberKnife at Stanford University between March 1999 andDecember 2005. Informed consent was obtained from all patients. Sixty-two patients with 145 brain metastases of RCC or melanoma histologieswere identified. Patients were followed clinically and radiographicallywith MRI. The following information was obtained through chartreview: age, performance status, histology, date of primary diagnosis,control of the primary site at the time of radiosurgery, locations of othermetastatic sites, recursive partitioning analysis class, previous chemo -therapy treatment, previous immunotherapy treatment, previous clini-cal trial participation, corticosteroid use at time of treatment, neurosur-gical resection, WBRT, neurological symptoms at presentation, numberof metastatic brain lesions, location of brain metastases, SRS date, treat-ment volume, prescribed dose, maximum dose, conformality index,progression of the treated lesion, cause and date of death, occurrence ofradiation 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-resolu-tion computed tomographic scans were obtained with 1.25-mm slice thick-ness and fused with an MRI. Target volumes were outlined, and criticalstructures including the eyes, lens, optic nerves, optic chiasm, brainstem,and spinal cord were contoured as avoidance structures. Plans were gen-erated with the CyberKnife inverse treatment planning algorithm (1).

We analyzed the data for overall survival (OS), neurological specificsurvival (NSS), local failure of the treated lesion, intracranial failure (anyfailure in the brain), and failure elsewhere (failure in the brain outside thetreated volume). Patients were considered dead from neurological causesif: 1) there was clinical or radiographic evidence of neurological progres-sion near the time of death, 2) both neurological and systemic progressionexisted, or 3) the patient was lost to follow-up with suspicion of recur-rence. Otherwise, they were censored at the date of the last follow-upevaluation. Local and intracranial failure was determined through clini-cal observations, MRI findings, or clinical/neurological deterioration.

Survival time in years was calculated from the day of SRS by theKaplan-Meier method. Survival, NSS, local control (LC), and intracra-nial control (IC) were analyzed by the Cox proportional hazards model.All factors with a P value of 0.20 or less on univariate analysis wereentered 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).

RESULTS

Patient CharacteristicsPatient characteristics are listed in Table 1. The median follow-

up period was 10.5 months (range, 0.565.3 months). Forty-

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CYBERKNIFE FOR BRAIN METASTASES

four patients had melanoma, and 18 patients had RCC. Eighty-four percent of the patients were recursive partitioning analy-sis Class 2. Twenty-four patients had a single treated brainmetastasis, 26 patients were treated for 2 to 3 metastases, and12 patients were treated for 4 or more metastases; a total of 145lesions were treated. Nine patients did not have their primarysite of cancer controlled at the time of SRS. Patients withextracranial metastatic disease had a median of 2 other sys-temic sites. Fifty-three percent of patients were receiving corti-costeroids at the time of SRS, and 53% had been treated withchemotherapy or immunotherapy for their systemic disease.Twenty-seven percent of patients had been treated with WBRTbefore SRS, and 8% had their treatment planned from thebeginning as a combination of WBRT and SRS. Eleven percentof the lesions were treated with surgical resection followed bya radiosurgical boost without planned WBRT.

Radiosurgery Treatment PlanThe 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 theremainder in 2 (n 8), 3 (n 4), or 5 (n 1) sessions.

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

TABLE 1. Patient and treatment characteristicsa

Characteristics No.

Melanoma (no.) 44

Renal cell (no.) 18

Median age, y (range) 57 (2589)

Median KPS score (range) 80 (60100)

RPA class, no. (%)

1 6 (10)

2 52 (84)

3 4 (6)

Systemic treatment (chemo-/ 33immunotherapy) (no.)

Brain metastases (no.)

1 24

23 26

4 12

Median no. of other systemic sites 2of metastases

Corticosteroids (no.) 33

Neurological symptoms at 43presentation (no.)

Surgery (no.) 26

WBRT (no.) 17


HARA ET AL.

OS and NSSThe 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 agreater OS than patients with melanoma (14.2 versus 5.6months). On multivariate analysis, Karnofsky PerformanceScale score (P 0.01) and previous immunotherapy or clinicaltrial (hazard ratio [HR], 2.55; 95% confidence interval [CI],1.374.75) significantly affected OS (Table 3). NSS was onlyaffected by failure elsewhere in the brain (HR, 3.82; 95% CI,1.0613.76). WBRT did not affect OS or NSS. Although failureelsewhere negatively impacted NSS (P 0.04), it did not signif-icantly affect OS in this cohort (P 0.37).

ICOne-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 con-trolled primary site (HR, 0.41; 95% CI, 0.190.89) significantlyimpacted IC (Table 4). Patients with melanoma had poorer IC(HR, 2.84; 95% CI, 1.455.55). WBRT did not affect LC or failureelsewhere. Surgical resection had no effect on IC or LC.Treatment with corticosteroids (HR, 0.55; 95% CI, 0.301.00) and

TABLE 2. Median survivala

Overall Neurologicalsurvival specific survival

Whole cohort 8.3 22.3

Melanoma 5.6 14.2b

RCC 14.2 22.4b

WBRT 8.6 14.2

Without WBRT 8.0 22.3

With planned WBRT 6.7 14.2

Without planned WBRT 8.6 22.4

Surgery 8.9 14.2

Without surgery 7.3 22.3

Local failure 10.8 10.1

No local failure 8.6 22.4

Brain failure elsewhere 11.6 15.7b

No failure elsewhere 3.8 Not reachedb

Any intracranial failure 10.8 15.72b

No intracranial failure 3.6 Not reachedb

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

TABLE 3. Overall survival and neurological specific survival analysisa

P value

Overall survival Neurological specific survivalCharacteristic

Univariate Multivariate Univariate Multivariate

Age 0.65 NS 0.41 NS

Sex 0.24 NS 0.15 NS

KPS 0.04 0.01 0.61 NS

Melanoma 0.06 0.01 (HR, 4.06; 0.06 NS95% CI, 1.928.56)

Renal cell 0.06 NS 0.06 NS

Primary controlled 0.37 NS 0.80 NS

No. of systemic metastatic sites 0.24 NS 0.62 NS

Previous immunotherapy or clinical trial 0.09 0.01 (HR, 2.55; 0.35 NS95% CI, 1.374.75)

Previous chemotherapy 0.65 NS 0.94 NS

Any previous WBRT 0.80 NS 0.35 NS

Planned WBRT with SRS 0.48 NS 0.12 NS

Corticosteroid treatment 0.08 NS 0.38 NS

Neurological symptoms at presentation 0.32 NS 0.35 NS

No. of metastases 0.18 NS 0.99 NS

Local failure in treated lesions 0.48 NS 0.17 NS

Failure elsewhere 0.37 NS 0.04 0.04 (HR, 3.82;95% CI, 1.0613.76)

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



controlled primary site (HR, 0.27; 95% CI, 0.120.60) improvedcontrol elsewhere in the brain. Larger tumor volumes (continu-ous variable) (HR, 1.09; 95% CI, 1.031.16), previous chemother-apy (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 SalvageThe 29 patients with intracranial failures received salvage

treatment with SRS (n 13), surgery plus SRS (n 1), WBRTplus surgery (n 2), WBRT plus SRS (n 1), surgery alone (n 2), or supportive care (n 10). Of the 9 patients who hadprogression in the treated lesion, salvage therapies includedSRS (n 2), WBRT plus surgery (n 1), SRS plus surgery (n 1), surgery (n 2), and supportive care (n 3). Four of these9 patients died from neurological causes. In the cohort, 4patients (6%) developed radiation necrosis.

DISCUSSIONMelanoma and RCC have historically been thought to be

somewhat radioresistant; however, clinical and in vitro dataappear to demonstrate the effectiveness of radiotherapy andindividual response variability (17, 25, 33, 37). After WBRT, LCrates 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

a HR, hazard ratio; CI, confidence interval; NS, not significant.

TABLE 4. Local and intracranial controla

P value

Intracranial control Local control Control elsewhere Characteristic

Univariate Multivariate Univariate Multivariate Univariate Multivariate

Melanoma 0.03 0.01 (HR, 2.84; 95% 0.20 NS 0.08 0.04 (HR, 2.03;CI, 1.455.55) 95% CI, 1.024.06)

Primary controlled 0.19 0.02 (HR, 0.41; 95% 0.29 NS 0.06 0.01 (HR, 0.27; CI, 0.190.89) 95% CI, 0.120.60)

Previous chemotherapy 0.01 0.01 (HR, 2.76; 95% 0.55 NS 0.01 0.01 (HR, 2.88;CI, 1.515.05) 95% CI, 1.555.37)

Previous immunotherapy 0.47 NS 0.39 NS 0.46 NS

Previous clinical trial 0.55 NS 0.52 NS 0.39 NS

Previous WBRT 0.17 0.01 (HR, 0.43; 95% 0.15 NS 0.48 NSCI, 0.230.80)

Corticosteroid treatment 0.05 NS 0.91 NS 0.03 0.05 (HR, 0.55; 95% CI, 0.301.00)

Neurological symptoms 0.01 NS 0.01 0.01 (HR, 0.16; 0.02 NSat presentation 95% CI, 0.040.62)

Surgery 0.54 NS 0.97 NS 0.52 NS

Total dose 0.29 NS 0.95 NS 0.22 NS

Tumor volume 0.06 NS 0.82 NS 0.05 0.01 (HR, 1.09;95% CI, 1.031.16)

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 mainlyconsisted of radionecrosis (6%), which was acceptable andcomparable to other studies (35).

WBRT did not improve NSS or OS. Many of our patients haduncontrolled systemic disease, with 10 patients having 4 or moreother systemic sites of metastases; thus, the lack of survival dif-ference was not surprising, perhaps partly because of reseedingafter treatment (41). An Eastern Cooperative Oncology GroupPhase II study (E 6397) (17) that enrolled 36 patients with 1 to 3brain metastases from melanoma, RCC, or sarcoma found a 6-month intracranial progression of 48.3% and a median survivalof 8.3 months at a median follow-up duration of 32.7 months.Up-front SRS alone appeared to be reasonable, based on sur-vival. Similar to our analysis, other studies, both randomizedand retrospective, have also found no difference in survival, neu-rological survival, or neurological function preservation withthe 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 SRScould be found only in a subset of patients without extracranialdisease (15.4 versus 8.3 months) in 1 retrospective study (28).Given the inferior LC reported with WBRT, we favor SRS fortreatment of melanoma and RCC metastases.

The association of WBRT with long-term risk of neurocogni-tive deficits is a deterrent to its use, but this risk is clouded by the


HARA ET AL.

fact that many patients with brain metastases have neurocogni-tive deficits at baseline (19). There is a real risk of leukoen-cephalopathy associated with large fraction sizes (3 Gy) andconcurrent chemotherapy (9, 13, 27). Conversely, the issue ofpatient quality of life impacted by a brain recurrence has alsobeen examined. In a retrospective study of symptomatic brainrecurrences, intracranial failure after SRS alone was symptomaticin 12 (71%) of 17 patients and associated with a neurologicaldeficit in 10 (59%) of 17 patients, and, thus, the authors arguedfor the use of WBRT for patients with potentially long survival

(32). However, in a Japanese prospective randomized trial, whenthe preservation of neurological function was examined, therewas no difference between the group receiving SRS, as com-pared with those patients treated with up-front WBRT with SRS(4). For these patients, quality of life is a crucial considerationthat we could not accurately gauge in this retrospective study;however, we agree that this will become an even greater issue astreatment advances prolong survival.

Currently, the ongoing European Organization for Researchand Treatment of Cancer 22952 trial investigates the addition of

TABLE 5. Studies comparing stereotactic radiosurgery versus stereotactic radiosurgery plus whole-brain radiotherapya

No. of mela- ICSeries (ref. no.) Study design

No. ofnoma or RCC Treatment

Survivalfailure Outcome

patientspatients

(mo)(%)

Aoyama et al., Randomized 132 15 SRS 8 76 14 metastases,2006 (4) SRS 7.5 47 3 cm

WBRT No survival or neurological survival difference, no difference in preservation of neurological function

Chougule et Randomized 109 11 SRS 7 43 Mostly NSCLC, 3 al., 2000 (8) WBRT 5 19 metastases, 50% had

SRS 9 23 surgical resection

WBRT No survival difference

Roos et al., Randomized 19 4 Surgery 6.2 78 Solitary metastasis2006 (34) or SRS 9.2 30 No survival or

Surgery/ neurological survival SRS difference, no difference in

WBRT QOL or neurological function

Sneed et al., Retrospective 105 51 SRS 11.3 72 No difference in survival 1999 (39) SRS 11.1 31 or IC control with salvage

WBRT treatment 62% after salvage

Sneed et al., Retrospective 569 155 SRS 8.2 No survival difference2002 (40) SRS 8.6

WBRT

Pirzkall et al., Retrospective 236 100 SRS 5.5 34 13 metastases, no 1998 (28) SRS over- 23 survival difference

WBRT all Survival difference for WBRT in subset without extracranial disease(15.4 versus 8.3 mo)

Manon et al., Prospective 31 28 SRS 8.3 48 13 metastases2005 (17)

Rao et al., Retrospective 68 65 SRS 14.9 No difference with2006 (31) SRS 12.8 WBRT or surgery

WBRT

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

WBRT to SRS or surgery in patients with 1 to 3 metastases. Asecond trial, North Central Cancer Treatment Group 0574, com-pares SRS with or without WBRT in patients with 1 to 3 metas-tases. We await the neurocognitive and quality-of-life resultsfrom this trial. New areas of study include the combination ofradiation with agents such as motexafin gadolinium, efaprox-aril, temozolamide, or gefitinib (2, 3, 19, 36, 38).

In summary, CyberKnife radiosurgery provided excellent LCwith acceptable toxicity in our patients with melanoma or RCCbrain metastases. Although WBRT improved overall IC, neitherWBRT nor surgery improved OS or NSS. We conclude that ini-tial SRS alone appears reasonable, as survival was dictated bysystemic disease. Better systemic therapies are needed, and assystemic control improves, SRS with up-front WBRT shouldbe considered.

DisclosuresJohn 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 ofAccuray, Inc. The other authors have no personal financial or institutional inter-est in any of the drugs, materials, or devices described in this article.

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

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