|Year : 2012 | Volume
| Issue : 2 | Page : 215-221
Linear accelerator based stereotactic radiosurgery for melanoma brain metastases
Mark E Bernard1, Rodney E Wegner1, Katharine Reineman2, Dwight E Heron1, John Kirkwood3, Steven A Burton1, Arlan H Mintz4
1 Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
2 Neurological Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
3 Department of Medicine, Division of Medical Oncology, Melanoma Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
4 Department of Radiation Oncology and Neurological Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
|Date of Web Publication||26-Jul-2012|
Arlan H Mintz
Department of Neurological Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Suite 400, Pittsburgh, PA 15213
Source of Support: None, Conflict of Interest: None
Purpose: Melanoma is one of the most common malignancies to metastasize to the brain. Many patients with this disease will succumb to central nervous system (CNS) disease, highlighting the importance of effective local treatment of brain metastases for both palliation and survival of the disease. Our objective was to evaluate the outcomes associated with stereotactic radiosurgery (SRS) in the treatment of melanoma brain metastases.
Materials and Methods: We retrospectively reviewed 54 patients with a total of 103 tumors treated with SRS. Twenty patients had prior surgical resection and nine patients underwent prior whole brain radiation therapy (WBRT). 71% of patients had active extracranial disease at the time of SRS. Median number of tumors treated with SRS was 1(range: 1-6) with median radiosurgery tumor volume 2.1 cm 3 (range: 0.05-59.7 cm 3 ). The median dose delivered to the 80% isodose line was 24 Gy in a single fraction.
Results: The median follow-up from SRS was five months (range:1-30 months). Sixty-five percent of patients had a follow-up MRI available for review. Actuarial local control at six months and 12 months was 87 and 68%, respectively. Eighty-one percent of patients developed new distant brain metastases at a median time of two months. The six-month and 12-month actuarial overall survival rates were 50 and 25%, respectively. The only significant predictor of overall survival was surgical resection prior to SRS. Post-SRS bleeding occurred in 18% of patients and at a median interval of 1.5 months. There was only one episode of radiation necrosis with no other treatment-related toxicity.
Conclusion: SRS for brain metastases from melanoma is safe and achieves acceptable local control.
Keywords: Brain metastases, melanoma, radiation therapy
|How to cite this article:|
Bernard ME, Wegner RE, Reineman K, Heron DE, Kirkwood J, Burton SA, Mintz AH. Linear accelerator based stereotactic radiosurgery for melanoma brain metastases. J Can Res Ther 2012;8:215-21
|How to cite this URL:|
Bernard ME, Wegner RE, Reineman K, Heron DE, Kirkwood J, Burton SA, Mintz AH. Linear accelerator based stereotactic radiosurgery for melanoma brain metastases. J Can Res Ther [serial online] 2012 [cited 2019 Dec 11];8:215-21. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/215/98973
| > Introduction|| |
Brain metastases are the most common intracranial neoplasm and affect up to 30% of all cancer patients. , Melanoma is one of the most common malignancies to spread to the brain and will do so in 10-40% of patients with stage IV disease. , Treatment options include surgery followed by some form of radiation therapy (whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), SRS alone, WBRT alone, or SRS plus WBRT. ,,,,, Despite aggressive treatment, many of these patients will still develop local progression and succumb to their CNS disease, highlighting the importance of effective local treatment. Several series have documented the efficacy and safety of SRS for patients with brain metastases from melanoma. ,,, This paper reviews our experience using SRS for such patients.
| > Materials and Methods|| |
We were able to identify 54 melanoma patients with 103 brain metastases treated with SRS between 2004 and 2010. Twenty-two patients (40%) were females and 32 patients (60%) were males. The median age was 58 years (range: 21-83). The median Karnofsky performance status (KPS) at the time of treatment was 90 (range: 60-100). Thirty-nine patients (71%) had active systemic disease at the time of SRS. The median total number of metastases per patient was 1 (range: 1-6). The median graded prognostic assessment (GPA) score was 2.5 (range: 0.5-3.5). Six patients (14%) were asymptomatic at the time of brain metastasis diagnosis, 12 patients (28%) had headaches, 15 patients (35%) had ataxia, 4 patients (9%) had generalized confusion, and 5 patients (12%) had unilateral weakness (some patients had multiple symptoms). Nine patients (17%) had previously undergone WBRT to a median dose of 30 Gy in 10 fractions. The median time from WBRT to SRS was two months (range: 0.5-3 months). Twenty patients (37%) had previously undergone resection of at least one metastatic lesion prior to SRS. The median time from resection to SRS was one month (range: 0.5-18 months). Patients with previous surgical resection had a median age of 56 (range: 21-76) a median KPS of 90, 60% (12 of 20) had active extracranial disease, and the median number of total metastases was 1 (range: 1-4). For those patients who did not have resection, the median age was 60 (range: 29-83), median KPS was 80, 76% (26/34) had active extracranial disease, and the median number of metastases was two (range: 1-6).
Simulation and planning
Each patient was comfortably positioned on the CT simulation table and a custom mask was fabricated. A thin-slice high resolution CT with intravenous contrast was then obtained while the patient was immobilized. The acquired images were then transferred to the treatment planning workstation and fused with pre-treatment thin-slice (1.2 mm) contrast enhanced spoiled gradient (SPGR) recalled acquisition in steady state sequence MRI utilizing commercially available fusion software. The tumor volume and any surrounding critical structures were manually delineated by a team including a radiation oncologist, a medical physicist, and a neurosurgeon. For patients with intact metastases, the planning target volume was defined as the contrast-enhancing tumor with no margin. For patients being treated post-resection, the planning target volume was the resection cavity with a 1 mm margin. Dose volume histograms were calculated for the target volume and nearby critical structures and were utilized to select the optimal treatment plan. An ideal SRS plan provided 95% of the prescription dose to the PTV while sparing surrounding organs at risk. If surrounding organs at risk were deemed to be at excess risk for toxicity, a plan with lower PTV coverage was accepted. All patients were treated using the Cyber Knife TM Robotic Radiosurgery System (Accuray, Sunnyvale, CA).
Follow up neurologic exam and MRI scanning (or CT if ineligible for MRI) were performed at two months after SRS, every two to three months for the first year, and at three to six monthly intervals thereafter. Imaging was performed to assess changes in tumor size, to identify the development of any new tumors, and to evaluate the risk of peritumoral reactive swelling. A significant change in tumor size was defined as either an increase or decrease of 2 mm in the contrast enhancing dimensions in any single plane of the tumor. Distant failure was defined as the development of new brain metastases outside the original SRS treatment volume.
Survival time was computed from the time of SRS. Survival curves and median survival were calculated using the Kaplan-Meier method.  Factors affecting survival from the time of brain metastasis diagnosis were determined using the Cox proportional hazards model.  All statistical tests were carried out using SPSS Version 15.0 (SPSS, Chicago, IL). The project was reviewed and approved by the University of Pittsburgh institutional review board (#0503211).
| > Results|| |
Patient characteristics are described in [Table 1]. A total of 103 tumors were treated in these 54 patients. The median number of tumors treated with SRS was 1 (range: 1-6). The median radiosurgery tumor volume was 2.1 cm 3 (range 0.05-59.7cm 3 ). The median total tumor volume (the sum of all treated tumors) was 5.6 cm 3 (range: 0.2-59.7 cm 3 ). The median prescription dose was 24 Gy (range: 12-40 Gy) delivered in 1 fraction (range: 1-5 fractions) to the 80% isodose line. Ninety-nine tumors (89%) were treated in a single fraction, 1 (1%) in 2 fractions, 10 (9%) in 3 fractions, and 1 (1%) in 5 fractions. Dose selection was based on various factors including tumor volume, location, and timing and total dose of prior radiation therapy. The median minimum dose was 22 Gy (range: 8.3-34.8 Gy) and the median tumor coverage was 97% (range: 70-100%). [Figure 1] shows a typical SRS plan for a patient with an intact brain metastasis from melanoma.
|Figure 1: Treatment planning image for an 83-year-old man with brain metastasis from melanoma. The shaded red volume is the planning target volume and the thick orange line represents the 80% isodose|
line. The prescription was for 24 Gy to the 80% IDL. The two shaded green volumes represent the left eye and optic nerve
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The median follow-up from SRS for the entire cohort was five months (range: 1-30). The median follow-up from primary diagnosis was 40 months (1-286 months). Thirty-six patients (65%) had follow-up scans available for review. The median number of follow-up scans available for review was 3 (range: 1-12). With continued follow-up 10 lesions had a local failure documented by MRI or CT-yielding an actuarial local control at six months and 12 months of 87 and 68%, respectively [Figure 2]. Seven of these 10 lesions were retreated with SRS, two were removed with craniotomy and resection, and the last lesion was treated with palliative WBRT alone. Age, sex, tumor volume, prescription dose, KPS, GPA score, prior surgical resection, and prior WBRT were not found to be statistically significant in predicting local control. On further follow-up, 29 patients (81%) developed new metastases at a median time of two months (range: 1-11 months). Three of these patients (10%) had previous WBRT and 12 (41%) had previous surgical resection. Four patients with local and/or regional failure were treated with salvage WBRT and 22 patients were treated with salvage SRS. Four patients required surgical resection of progressing lesions at a median time of 3.5 months (range: two to eight months), pathology from three operations showed residual active tumor cells and one was radiation necrosis.
|Figure 2: Local control following SRS. Local control at six months and 12 months was 87 and 68%, respectively|
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At the time of this analysis, 42 (78%) patients had died. Seven patients (19%) died from their CNS disease, 11 patients (31%) died from systemic disease, and in 18 patients (50%) we were unable to find a documented cause. In terms of overall survival (OS), the actuarial six month and one year OS rates were 50 and 25% respectively [Figure 3]. Multivariate regression of prior surgical resection predicted for better OS (P<0.05). The median survival for patients who had the lesion resected prior to SRS was 13 months, compared to four months for patients with intact tumors treated with SRS [Figure 4]. There was a trend toward worse OS with increasing number of metastases (P=0.09) [Figure 5]. Age, sex, tumor volume, prescription dose, KPS, GPA score, and prior WBRT were not statistically significant in predicting overall survival on multivariate regression. Ten patients (18%) developed a hemorrhage within the radiosurgical volume. The median time to hemorrhage was 1.5 months (range: 0.5-11 months). Of these 10 patients, 4 (40%) were symptomatic and required surgical intervention for hemorrhage evacuation. No other treatment-related complications were documented in this cohort.
|Figure 3: Overall survival following SRS. The actuarial six month and one year OS rates were 50 and 25%, respectively|
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|Figure 4: Overall survival based on previous surgical resection. For patients who had resection of their metastatic lesion(s), the median OS was 13 months, compared to four months with SRS alone|
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|Figure 5: Overall survival by number of metastases treated. The median OS for patients with a solitary metastasis was eight months compared to four months in patients with two or more lesions|
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| > Discussion|| |
The incidence of brain metastasis occurring in those with cancer is approximately 20 to 40%. , Cutaneous melanoma is one of the most common malignancies to metastasize to the brain, with up to 40% of patients with stage IV disease developing brain lesions. Autopsy reports show an even higher incidence with a prevalence of 55-75% in patients that succumbed to melanoma. , Unlike some malignancies in which patients ultimately succumb to extracranial disease, oftentimes brain metastases from melanoma are the cause of neurological deterioration and death. Without treatment, brain metastases often progress rapidly, leading to death within only a few months. Currently, treatment options for brain metastases range from WBRT, surgery, SRS, or a combined modality approach. ,
Surgical resection is typically limited to patients with a good performance status, limited intracranial and extracranial disease, and/or large symptomatic lesions. Following resection, adjuvant WBRT is often delivered with a typical course being 30 Gy in 10 fractions over two weeks. Results from studies including patients with a solitary brain metastasis from a variety of primary histologies confirmed that the addition of surgical resection to WBRT improved local control and reduced the incidence of death from neurologic causes. , Patchell et al compared surgery followed by WBRT to WBRT alone.  The authors showed that the addition of surgical resection to WBRT reduced local recurrences from 50 to 25% and improved overall survival (40 weeks vs. 15 weeks). In addition, patients in the surgical arm maintained functional independence for a greater duration. A similar study by Patchell et al randomized patients to surgical resection with or without WBRT.  The patients who received adjuvant WBRT had decreased local recurrence (10% vs. 46%) and less chance of dying from neurologic causes (14% vs. 44%), but overall survival was similar between the two groups.
WBRT has been used for decades in patients with brain metastases and is thus very well-studied. The use of WBRT for patients with brain metastases from a variety of primary cancers has been shown to improve existing neurologic symptoms and improve overall survival compared to corticosteroids and best supportive care which has a median survival time of four to five months.  The overall response rates to WBRT have varied from 50 to 85% depending on the series. ,, In more recent years, SRS has been shown to be an effective alternative therapy for patients with brain metastases. It is especially useful in patients with progression of disease following WBRT, for whom treatment-related neurotoxicity is a major concern. SRS allows for the delivery of a highly-focused dose of radiation with rapid fall-off thereby reducing the dose to the surrounding uninvolved brain. This feature should potentially reduce the likelihood of developing late neurocognitive deficits, an issue that becomes of increasing concern in long-term survivors. Furthermore, melanoma is considered resistant to the typical daily doses used with WBRT. , Therefore by using SRS, a higher more effective doses can be safely delivered. SRS has been very well studied in the setting of brain metastasis. In patients with brain metastases, SRS has shown to be both efficacious and safe with local control rates of 65-95% and an adverse radiation effect rate of 5-10%. ,,
SRS has also been well-studied in the setting of brain metastases from malignant melanoma [Table 2]. Mathieu and colleagues initially reported on outcomes following Gamma Knife SRS for malignant melanoma brain metastasis.  This study consisted of 244 patients with 754 metastatic tumors. In 2010, Leiw et al updated this study to 333 patients and 1570 brain metastasis. The median dose delivered to the margin was 18 Gy in a single fraction. The median follow-up was relatively short at 3.8 months, but local control was documented in 73% of the patients. Actuarial six month and 12 month OS rates after SRS were 47 and 25%, respectively. After treatment, 21 patients (7%) had radiation-induced symptomatic effects and 64 (25%) showed evidence of delayed intratumoral hemorrhage.
|Table 2: Summary of the major series presenting outcomes of melanoma brain metastases treated with SRS|
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The Eastern Cooperative Oncology Group performed a phase II trial to evaluate whether SRS alone was a feasible treatment in patients with one to three brain metastasis stemming from radio-resistant primary cancers.  The study consisted of 31 patients receiving 24, 18, or 15 Gy in a single fraction depending on the tumor size. The median follow-up was 32.7 months and the median OS was 8.3 months. In terms of local control, the six-month intracranial failure of patients receiving only radiosurgery was 32%. Radiation toxicity that was grade 3 or higher was recorded in three patients (10%). The authors of this study concluded that although intracranial failure rates remained high, the median survival time for patients treated with radiosurgery alone was comparable to the published surgical and concurrent SRS plus WBRT series. Therefore, delaying WBRT could be appropriate for some subgroups of patients with radio-resistant tumors; however, regular avoidance of WBRT should be judiciously executed.
Another retrospective study reviewed outcomes in patients with brain metastases from melanoma and renal cell carcinoma.  There were a total of 101 patients with 339 brain metastases. Seventy-three patients (72%) had a primary melanoma and accounted for 280 of the lesions. Out of these 101 patients, 71 patients received SRS alone, 17 received SRS combined with WBRT, and 13 received salvage SRS after prior WBRT failure. Patients received SRS doses ranging from 15 to >20Gy, which was again based on the size of the tumor. Follow up took place for a minimum of 12 months in all surviving patients. The median follow-up was not reported, but actuarial local control at one year was 63.6%. Those patients treated with SRS as a primary treatment had a longer progression-free-survival of 12.0 months, compared to 5.4 months if delivered after WBRT failure. The median OS for patients with melanoma was 7.4 months after receiving SRS. The combination of WBRT and SRS did not confer a local control or OS advantage.
A similar series published by Hara et al reviewed the outcomes in 62 patients with 145 brain metastases from melanoma or renal cell carcinoma.  Forty-four patients (71%) in this series had a primary melanoma and all were treated using the Cyber Knife TM robotic radiosurgery system. One hundred and thirty-two lesions were treated in a single session and the remaining 13 were treated over two to five sessions. The median follow up was 10.5 months with a 12 month local control rate of 87%. The 12 month intracranial failure rate was 38 and impacted by controlled primary site, previous WBRT, and previous systemic therapy. The median OS for the entire cohort was 8.3 months, and for patients with brain metastases from melanoma it was 5.6 months. Following SRS, four patients (6%) had symptomatic occurrence of radiation necrosis.
A group from Marseille, France reviewed their outcomes following Gamma Knife SRS in patients with brain metastases from melanoma.  This study included a total of 106 patients with 221 lesions, none of which had prior WBRT. All patients were treated to a relatively high margin dose ranging between 20 and 30 Gy in a single fraction (median dose: 25 Gy). The median OS was 5.09 months with an actuarial survival rate of 43.4% at six months and 13.2% at 12 months. Local control was established in 84% of treated tumors. Treatment-related toxicity was minimal with only six patients (5%) developing complications after SRS.
Chemotherapy is another treatment option for patients with brain metastases from melanoma. Its efficacy in the treatment of brain metastases, however, is limited by the blood brain barrier. A small phase II trial compared WBRT (40 Gy in 20 fractions) with and without concurrent temozolomide for patients with brain metastases from various primaries.  The temozolomide group showed a significantly better response rate on follow-up imaging-96%, with 38% of those responding experiencing a complete response. In the WBRT alone group, only 67% of patients had an imaging response. Similarly, the patients receiving temozolomide were more likely to experience neurological improvement and less likely to require corticosteroids. In terms of OS, patients in the temozolomide arm had a slight survival advantage of 1.6 months, but given the small number of patients this did not reach significance. A similar phase II protocol tested the combination of WBRT (30 Gy in 10 fractions) with temozolomide and thalidomide in 39 patients, all with brain metastases from melanoma.  Unfortunately, only three patients showed a response on imaging, and the toxicity of the regimen resulted in only a single patient receiving more than two cycles. Another phase II trial treated 38 patients with stage IV melanoma using temozolomide and high dose interleukin-2.  Ten of the patients in this study had previously treated brain metastases. Of those 10 patients, nine were evaluated, and eight had progression of disease within the central nervous system. Unfortunately, in our series we were unable to get an accurate history of the chemotherapy that the patients were receiving to determine if there was an effect.
All of the above data suggests that SRS alone is safe and efficacious in the treatment of brain metastases from melanoma. Our series using Linac has produced similar results to those for Gamma Knife presented above with 6 and 12 month local control rates of 87 and 68%, respectively, without significant toxicity (2% rate of radiation necrosis). Similar to other series, there was an approximately 20% rate of intratumoral hemorrhage noted on follow-up MRI. In our series, only 17% of patients had previous WBRT. Along these lines, only an additional 7% required WBRT as a salvage therapy for progression. However, we did show a trend toward worse outcome with an increasing number of lesions (P=0.09). In addition, a higher proportion of patients in our series (81%) developed new, distant brain metastases compared to other series. These points highlight the fact that WBRT (either alone or in combination with SRS) may still be warranted in selected patients with brain metastases from melanoma. We also showed an improved outcome in patients who had surgical resection of metastatic lesions prior to SRS. Granted, surgical resection is likely a surrogate for good performance status, younger age, fewer number of metastases, and controlled primary; all of which are associated with an improved outcome.  Also, this finding may be most likely attributed to the small number of patients in our series, especially given no other series shows this to our knowledge. Regardless, surgical resection still remains a standard treatment option for patients with brain metastases, even in the setting of the relatively short OS seen with metastatic melanoma.
Weaknesses of the present study include its retrospective nature and the inherent biases present in such studies. In addition, only 65% of patients in our study had follow-up imaging available for review; although this likely due, in part, to the poor prognosis in this particular group of patients with many being incapacitated before follow-up assessments (median OS: six months). The patients presented here also represent a very heterogeneous group with some patients having prior WBRT, prior surgical resection, or SRS alone, making it difficult to compare the various modalities.
| > Conclusion|| |
SRS for brain metastases from melanoma is safe and achieves acceptable local control. As progress is made with systemic therapy, the importance of intracranial control will become even more important, as currently most patients succumb to systemic disease.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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