Testing if High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus is Better at Preventing Loss of Memory and Thinking Ability

PRIMARY OBJECTIVE: I. Determine whether stereotactic radiosurgery (SRS) relative to whole brain radiotherapy with hippocampal avoidance (HA-WBRT) plus memantine hydrochloride (memantine) for brain metastases from small cell lung cancer (SCLC) prevents cognitive function failure as measured by cognitive decline on a battery of tests: the Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT). SECONDARY OBJECTIVES: I. Determine whether SRS relative to HA-WBRT plus memantine for brain metastases from SCLC preserves cognitive function as separately measured by the HVLT-R, COWA, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP). II. Assess perceived difficulties in cognitive abilities using Patient Reported Outcomes Measurement Information System (PROMIS) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. III. Assess symptom burden using the MD Anderson Symptom Inventory for brain tumor (MDASI-BT) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. IV. Compare cumulative incidence of intracranial disease progression after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. V. Compare overall survival after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VI. Compare cumulative incidence of neurologic death after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VII. Compare the number of salvage procedures used to manage recurrent intracranial disease following SRS relative to HA-WBRT plus memantine for SCLC brain metastases. VIII. Compare adverse events between the treatment arms according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria. IX. Compare the risk of developing cerebral necrosis between SRS and HA-WBRT plus memantine in patients receiving concurrent immunotherapy. EXPLORATORY OBJECTIVES: I. Compare cumulative incidence of local brain recurrence, distant brain relapse, and leptomeningeal dissemination after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. II. Compare the cost of brain-related therapies and quality-adjusted life years in patients who receive SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. III. Evaluate the time delay to salvage WBRT or HA-WBRT in patients enrolled on the SRS arm. IV. Evaluate whether a time delay for chemotherapy has an effect on overall survival in patients receiving HA WBRT plus memantine relative to SRS for brain metastases from SCLC. V. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VI. Evaluate the correlation between neurocognitive functioning and patient-reported outcomes. VII. Collect serum, plasma and imaging studies for future translational research analyses. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo SRS over 1 day (in some cases several days). ARM II: Patients undergo HA-WBRT once daily (QD) for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive memantine orally (PO) QD or twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and magnetic resonance imaging (MRI) throughout the study. After completion of study treatment, patients are followed up every 2-3 months for 1 year, and then every 6 months thereafter.