This phase II trial studies how well stereotactic radiosurgery works in treating patients with melanoma that has spread to more than 3 places in the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue.

PRIMARY OBJECTIVES:

I. To determine local control of brain metastases at 4 months after initial treatment with stereotactic radiosurgery (SRS) in patients with > 3 melanoma brain metastases (MBM).

II. To determine cognitive decline at 4 months defined as a significant decline (>= 5 point decrease from baseline based on the reliable change index) in the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall after initial treatment with SRS versus whole brain radiation therapy (WBRT) in patients with > 3 MBMs.

SECONDARY OBJECTIVES:

I. To determine local tumor control and distal tumor control in the brain at 1, 4, 6, 9 and 12 months post-treatment.

II. To determine overall survival in treated patients. III. To assess the pattern of neurocognitive change in memory at 1, 4, 6, 9, and 12 months post-treatment as well as executive function, attention, processing speed and upper extremity fine motor dexterity.

IV. To evaluate composite neurocognitive function scores in treated patients. V. To assess the pre-treatment factors of age, Karnofsky performance scale (KPS), extra-cranial disease, BRAF-V600E mutation status in the predictive determination of local and distal control and neurocognitive outcome in each treatment arm.

VI. To assess the correlation between number of lesions and total volume of intracranial disease and neurocognitive outcome in each treatment arm.

VII. To document post-treatment adverse side effects in treated patients. VIII. Evaluate the time to initiation of systemic therapy from completion of radiation treatment.

IX. Evaluate the duration/number of cycles of systemic chemotherapy given following radiation treatment.

CORRELATIVE STUDIES:

I. To determine if apolipoprotein E (Apo E) (i.e., Apo E2, Apo E3, and Apo E4) genotyping may prove to be a predictor of radiation induced neurocognitive decline (or neuro-protection).

II. To determine if inflammatory markers (i.e., IL-1, IL-6, and TNF-alpha) may prove to be predictors of radiation induced neurocognitive decline.

III. To determine if hormone and growth factors (i.e., glucocorticoids [e.g., cortisol], gonadal steroids [e.g., estradiol, testosterone, progesterone], growth hormone, human chorionic gonadotropin (hCG), insulin-like growth factor-1 [IGF-1], and neuronal growth factor [NGF]) may prove to be a predictor of radiation induced neurocognitive decline.

IV. To assess whether baseline and post-radiation fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scans can predict for neurocognitive decline.

OUTLINE:

Patients undergo SRS on day 1.

After completion of study treatment, patients are followed up for 12 months.

Inclusion Criteria:

• All patients with histologic proof of malignant melanoma. Histologic confirmation may be from the primary tumor site, or from another metastatic site (systemic lymph node, etc). Cytology-alone is not an acceptable method of diagnosis
• Greater than 3 presumed melanoma brain metastases on contrast-enhanced brain MRI scan obtained no greater than 4 weeks prior to study registration
• Patients must sign informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital
• Patients must have Karnofsky performance status (KPS) >= 70
• Patients must be eligible to have all lesions treated as determined by the study radiation oncologist
• Creatinine clearance > 30 ml/min
• Platelets > 50,000
• Patients should have normal coagulation (international normalized ratio [INR] < 1.3) and be able to withhold anticoagulation/antiplatelet medications a minimum of 24 hours prior to radiosurgery treatment (or until INR normalizes), on the day of treatment and 24 hours after radiosurgery treatment has concluded
• Patients can be undergoing concurrent systemic therapy, such as temozolomide, at the discretion of their treating oncologist

Exclusion Criteria:

• Patients are excluded if they have been treated with whole brain radiotherapy within the prior 3 months
• Patients are excluded if they have a history of metastatic cancer in addition to melanoma or a history of uncontrolled non-metastatic cancer. Patients with localized squamous cell carcinoma and/or basal cell carcinoma are not excluded
• Patients are excluded if there is radiographic or cerebrospinal fluid (CSF) evidence of leptomeningeal disease
• Female patients of childbearing age are excluded if they are pregnant as determined with a serum beta HCG no greater than 14 days prior to study registration, or breast-feeding. (The exclusion is made because gadolinium may be teratogenic in pregnancy)
• Patients are excluded if there is any history of gadolinium allergy
• Patients are excluded if they are unable to obtain a magnetic resonance imaging (MRI) scan for any other reason