Brain Metastases in Greater Size - Hypofractionated Options Trial (BIGSHOT)

Inclusion Criteria:

1. The patient or a legally authorized representative must be able and willing to provide study-specific informed consent prior to study entry.
2. Patient must be willing to comply with all study procedures and available for the duration of the study
3. Male or female, aged ≥ 18 years
4. Karnofsky Performance Status (KPS) ≥ 60 within 7 days prior to registration
5. Radiographic confirmation of brain metastasis measuring ≥2 cm and ≤ 5 cm in maximum diameter

   1. Multiple metastases are allowed. Additional metastases will be treated with single fraction SRS as per standard of care. Up to 10 additional smaller metastases are allowed on protocol. All additional smaller metastases must be less than 2 cm.
   2. If a patient has more than one large metastasis (measuring between 2 and 5 cm as above), up to two can be treated on study protocol
   3. All tumors must be ≥ 5mm from the optic chiasm and optic nerves.
6. Known active or history of invasive non-CNS primary cancer based on documented pathologic diagnosis within the past 3 years
7. Patient is able to medically tolerate SRS
8. Patient is neurologically stable (immediate surgery not necessary or not recommended)
9. A negative urine or serum pregnancy test (in persons of childbearing potential) within 7 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
10. Women who are sexually active must agree to use medically acceptable forms of contraception during treatment on this study to prevent pregnancy.

Exclusion Criteria:

1. Prior cranial radiotherapy, including whole brain radiotherapy (WBRT), or SRS in the area of the large metastasis to be treated on study.
2. Evidence of leptomeningeal disease (LMD) Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In such cases, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.
3. Inability to undergo MRI with contrast
4. Planned administration of systemic therapy (chemotherapy or immunotherapy) within 3 days prior to, the day of, or 3 days after completion of SRS.