This clinical study is a parallel, prospective observational single-centre trial in patients presenting with 5 to 30 brain metastases. Patients to receive either stereotactic radiosurgery (SRS) alone or SRS plus whole brain radiation (WBRT) will be enrolled.

The current standard of care for patients with limited brain metastases (1 to 4) is stereotactic radiosurgery (SRS) alone. This has evolved from the traditional standard of care in treating patients with whole brain radiation (WBRT). Studies in patients with limited (less than 5) brain metastases have shown that WBRT is harmful with respect to neurocognition and does not improve patient survival compared to SRS alone. As a result, SRS alone now is considered the standard of care treatment for patients with limited metastases. However, there is a lack of high quality prospective randomized evidence on the role of SRS in patients with 5 or more brain metastases to guide treatment.

Therefore, this study seeks to prospectively compare SRS alone versus SRS plus WBRT in patients with 5 to 30 brain metastases.

Inclusion Criteria:

• Histologic or cytologic diagnosis of non-hematopoietic malignancy (excluding germ cell malignancies and small cell carcinoma).
• Patients with ≥ 5 but ≤ 30 de novo brain metastases seen on a diagnostic-quality contrast-enhanced MRI obtained within 30 days prior to enrollment (or randomization if previously randomized). Patients who are found to have 31-50 metastatic lesions at the time of treatment planning may still participate in the study. Disease progression such that > 50 brain metastases are detected after initial MRI prior to enrollment but before SRS will be treated off-protocol as per discretion of the treating physician.
• Patients with ≥ 5 but ≤ 30 new brain metastases who have undergone prior SRS for 4 or less brain metastases with stable intracranial disease as per diagnostic MRI for at least 6 months post last course of SRS. Patients who are found to have 31-50 new metastatic lesions at the time of treatment planning may still participate in the study. Disease progression such that > 50 new brain metastases are detected after initial MRI prior to enrollment but before SRS will be treated off-protocol as per discretion of the treating physician.
• Age ≥ 18.
• Karnofsky Performance Status (KPS) ≥ 70.
• Baseline HVLT-R above ≥ 6
• Patients must be able to tolerate WBRT, and all brain lesions must be eligible for treatment with SRS as determined by the radiation oncologist.
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
• Patient is able to read, speak, and understand (i.e. sufficiently fluent) English in order to allow completion and meaningful analyses of the neurocognitive tests and quality of life questionnaires.
• Patients must be accessible for treatment and follow up. Investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• Patients who are on immunotherapy must have immunotherapy held at least 1 week before and after completion of radiotherapy. Other targeted agents/therapy must be held at least 1 day before and after SRS. Systemic chemotherapy must be held one week prior to treatment and re-started one week after treatment is complete.
• Protocol treatment is to begin within 4 weeks of patient enrollment (or randomization if previously randomized).

Exclusion Criteria:

• Patients with brain metastases resulting from germ cell malignancies, small cell carcinoma, or hematologic malignancies.
• Prior SRS for 5 or more brain metastases or any SRS for brain metastases within the last 6 months.
• Any prior WBRT or radiotherapy for brain metastases such that the study interventions cannot be delivered.
• Prior surgical resection of metastatic cancer from the brain.
• Patients with evidence of leptomeningeal disease.
• Patients who have a pacemaker or other contraindications, such that gadolinium-enhanced MRI cannot be performed or treatment cannot be delivered safely.
• Patients who have received chemotherapy or immunotherapy within 1 week prior to administration of protocol radiotherapy or who are expected / planned to receive chemotherapy within one week of completing protocol radiotherapy.
• Patients with < 5 or > 30 de novo or new brain metastases at time of enrollment, or > 50 brain metastases at time of treatment planning.
• Patients who are pregnant (women of child-bearing age must have negative pregnancy urine test within 7 days of enrollment or randomization).

The participant population will be patients who have MRI-documented 5 to 30, inclusive, brain metastases at time of enrollment and who are suitable for receiving stereotactic radiosurgery (SRS) and whole brain radiation (WBRT), with or without hippocampal-avoidance.