Comparing Single vs Multiple Dose Radiation for Cancer Patients With Brain Metastasis and Receiving Immunotherapy

Inclusion Criteria: * At least one intact brain metastasis or resection cavity ≥ 2 cm in diameter or ≥ 4 cc volume. * Patients at initial diagnosis of brain metastases and patients with known brain metastasis treated with systemic therapy alone are eligible. * Patients who have previously undergone SRS for brain metastases are eligible if all MRIs and DICOM-RT files from prior SRS courses are available for upload to TRIAD and there are no lesions requiring re-irradiation. Prior SRS data upload is NOT required prior to enrollment and randomization. Both SSRS and FSRS are acceptable. * Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice-by-slice contouring on a treatment planning software package can be used to calculate the total tumor volume. * Any extent of non-CNS disease is allowed. There is no requirement for non-CNS disease to be controlled prior to study entry. * For patients considered to be borderline or potentially eligible by size or volume criteria, sites have the option to send in DICOM films for central review screening. * Age ≥ 18 years at the time of enrollment. * Total number of brain metastases (including resection cavities) ≤ 15 on diagnostic MRI; all lesions must be amenable to SSRS and FSRS as determined by the treating radiation oncologist. Treatment must take place at a facility credentialed by the Imaging and Radiation Oncology Core (IROC) for SRS and that offers both SSRS and FSRS as treatment options. * Total gross tumor volume must be ≤ 30 cc. Lesion volume will be approximated by measuring each lesion's three perpendicular diameters on contrast-enhanced T1 MRI and the product of those diameters will be divided by 2 (V = xyz/2). Direct volumetric measurements by contouring all lesions on all visible slices on treatment planning software is also acceptable. If there is a cavity, only gross residual disease within or adjacent to the cavity is counted toward the 30 cc total volume. * Ability to tolerate MRI brain with gadolinium-based contrast. * Pathologically confirmed melanoma, renal cell carcinoma, non-small cell lung cancer, small cell lung cancer, or breast cancer. * Has received, is currently receiving, or is planned to receive immune checkpoint inhibitor therapy (defined as agent targeted to PD-1/PD-L1 axis) within 30 days of the planned first day of SSRS/FSRS. Dual ICI therapy with PD-1/PD-L1 and CTLA-4 targeted agents are allowed, but patients treated with a single agent CTLA-4 targeted agent only are ineligible. o It is not mandatory to wait for the results of next generation sequencing (NGS) or other molecular tumor testing to determine if the patient is planned to receive ICI if the enrolling physician feels that identification of a mutation that would preclude ICI therapy (such as an EGFR mutation in a patient with NSCLC) is unlikely to be identified. * Karnofsky Performance Status (KPS) ≥ 50. Refer to Appendix A. * Negative serum or urine pregnancy test within 14 days of randomization for women of child-bearing potential. * Ability to understand and the willingness to sign written informed consent. * Patients must be able to provide informed consent. * Must be able to speak, read and understand English or Spanish Exclusion Criteria: * Prior fractionated, whole, or partial brain radiation therapy. Prior fractionated SRS is acceptable. * Prior courses of SRS for benign tumors such as meningiomas, pituitary adenomas, schwannomas may be acceptable if the treatment is \> 2cm away from the site of a metastatic lesion that would be treated on this study. The study PI or a designated co-PI must review this type of case to confirm eligibility prior to enrollment. * Prior diagnosis ARE, including pseudoprogression or radiation necrosis/radionecrosis, or previously treated lesions being actively evaluated for possible ARE or local failure such as concerning imaging findings currently being tracked with short interval MRI. * Leptomeningeal carcinomatosis established by lumbar puncture cytology, or MRI imaging. In the absence of a clinical indication, a lumbar puncture is not required to confirm eligibility. * A brain metastasis that is 5 mm or less from the optic chiasm or optic nerves * Inability to tolerate brain MRI or receive gadolinium-based contrast * Planned or prior therapy with bevacizumab (or bevacizumab biosimilar) within 30 days of the planned first day of SRS as part of a systemic therapy regimen at study enrollment. * Serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines.