Melanoma brain metastases are the third most common type of brain metastasis after lung and breast cancer. They develop in a high proportion of advanced melanoma cases; they are clinically seen in 10 to 30 percent of patients with systemic melanoma, and in one autopsy series, incidence was as high as 50 to 73 percent. The median time to development of brain metastasis from the time of initial diagnosis is approximately 3.5 years.¹

Types of Treatment

Melanoma brain metastases exert a profound effect on the quality and length of survival, and despite the best current management, they represent the direct cause of death in 60 to 70 percent of affected patients.

The treatment options for these patients include best supportive care, whole brain radiation therapy, stereotactic radiosurgery, conventional surgery, chemotherapy, or a combination of the above. Because a majority of the patients have or will soon develop widely disseminated disease, treatment is dictated by the need to achieve immediate short-term palliation and the desire for durable symptom-free remission. The median survival of patients with symptomatic brain metastases is approximately one month without treatment and two months with corticosteroid administration (Table 1).²

Surgery is generally used to establish the diagnosis of metastatic disease when it is uncertain and as a treatment for large solitary symptomatic metastases. Patients who are under 60 years old, with controlled extracranial disease, a good performance status (Karnofsky Performance Scale score), and a life expectancy of at least three months are most likely to benefit from surgery. However, only around 10 percent of patients in general are ideal candidates for surgical extirpation. In a large retrospective series of 147 patients treated with surgery, improved neurological status was seen in 78 percent, with 2 percent surgical mortality. Local recurrence occurred in 55 percent of patients, and 26 percent died of intracranial disease. Median survival was 8.5 months with a three-year survival of 9 percent.³

Whole brain radiotherapy (WBRT) is the most commonly used option for most patients with brain metastases. The standard approach is to treat the whole brain up to 30–37.5 Gy in 10–15 daily fractions of 2.5–3 Gy each over 2–3 weeks. The advantages of WBRT include simple clinical set-up, ease of delivery as an outpatient, low cost and minimal disruption of quality of life. Unfortunately, median survival with WBRT alone in the three largest published trials has been only 3.5–4 months.⁴ Patient selection factors would have certainly influenced these poor results. However, the radiological response remains less than 25 percent in melanoma with WBRT, compared to 70–90 percent for other cancers, which indicates resistance to conventional melanoma therapy. Similarly, neurological function is improved in less than 25 percent of patients in melanoma, compared to 50 percent or more for other cancers. Patients with melanoma are less likely to have a radiographic response to WBRT even when there is a clinical response. However, WBRT may be more effective after surgical resection of metastatic tumor, as this may decrease relapse both at the site of surgical removal and elsewhere in the brain.⁵

In a retrospective study from Cleveland Clinic, overall survival with surgery alone was 4.8 months compared to 8.8 months with surgery and WBRT.⁵ Three large retrospective series using WBRT following surgery showed a median survival of 8.9 months.⁴ To date, no prospective trials exist confirming WBRT results in the postoperative setting in melanoma.

Randomized studies have found that different radiation schedules using WBRT did not make an appreciable difference. The Radiation Therapy Oncology Group (RTOG) has tried five schedules of fractionation varying from 20 Gy in one week to 40 Gy in 4 weeks in three randomized trials using WBRT for brain metastases. All the regimens were similar in improvement in neurological function (50 percent), duration of improvement (9–12 weeks), time to progression (10 weeks), survival (15–18 weeks), and/or the quality of palliation.¹ However, no sub-group analysis was done based on the site of primary disease, so the benefit of WBRT fractionation in melanoma remains unclear.

Stereotactic radiosurgery (SRS), a targeted therapy procedure that uses special equipment to position the patient and precisely deliver a large radiation dose to a tumor but not to normal tissue, is an alternative to surgery for patients with limited brain metastases. The rationale for SRS in brain metastases includes the spherical shape of most small (<3cm) lesions, which allows for conformal dose distribution; pseudocapsule of the lesions, which allows tight margins; and location predominantly at the gray-white matter junction, a relatively non-eloquent region that can permit delivery of single large doses. Generally a dose of 15–22 Gy at the 50–80 percent isodose line is administered in a single session to the contrast-enhancing lesion.

Results of large SRS studies have shown a radiological response rate of 80 to 90 percent in all metastases and median survival of 9–12 months, indicating the effectiveness of this therapy. However, the treatment result in melanoma is less encouraging than for other cancers. In a series of 106 patients with 221 melanoma metastases treated with SRS alone in Marseille, France, the median survival was 5.1 months, with metastasis-free survival of 3.7 months. The radiological responses were complete in 14 percent and partial in 42 percent of the cases.⁶ In another series of 103 patients with 151 metastases treated with SRS alone or in addition to WBRT at M.D. Anderson Cancer Center (MDACC) in Houston, the one-year local control and overall survival were 49 percent and 25 percent respectively.⁷ Eighty-five percent of all patients developed new brain metastases at 1 year. At Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, the median survival in 49 patients with 92 melanoma brain metastases treated with SRS alone was 6 months. The prognosis was better in those with a solitary lesion, lesions smaller than 2 cm, and those who received ≥18 Gy; however, even these patients fared worse compared to those with other cancers, indicating a less than satisfactory response to single fraction radiation.⁸

Hypofractionated stereotactic radiotherapy: Patients with limited brain metastases who are not suitable candidates for either surgical resection or SRS due to the lesions’ location or size can be treated with hypofractionated stereotactic radiotherapy while avoiding WBRT up front. At MSKCC, 20 patients were treated with a dose of 30 Gy in 5 fractions using 2 fractions per week to the lesion alone with a tight margin. The one-year control rate was 70 percent and the median overall survival was 8.5 months. The complete response, partial response, and stable disease were 15, 30, and 45 percent respectively in this study, with 15 percent steroid dependency, indicating a new option for these patients (Fig 1).⁹

(a)	(b)
Figure 1. Radiological response of a melanoma brain metastasis located in the midbrain region to hypofractionated stereotactic radiosurgery (a) before therapy and (b) three months after therapy.

Chemotherapy: The role of chemotherapy has traditionally been minimal in the treatment of melanoma brain metastases. However, over the last few years, Temozolomide has shown some activity among the agents that have been studied. In a small phase II trial from the Cytokine Working Group, 31 patients, mostly asymptomatic and chemo-naïve with a good performance status, were treated with WBRT and Temozolomide. In this study, three radiological responses were seen, including one complete response. Median survival was 6 months.¹⁰ The role of Temozolomide with SRS alone in melanoma is now being addressed in clinical trials.

Conclusion

The results of therapy for melanoma brain metastases remain unsatisfactory when compared to other cancers. A small but selective group of patients do benefit from aggressive therapy with surgery or SRS. The role of WBRT either as adjuvant or as the only treatment at this time is not clear. The preliminary results of hypofractionated SRS seem to be comparable to both surgery and SRS in terms of local control and morbidity; the technique merits further trials. Better systemic control still remains the optimal way to prevent brain metastases at this time.

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