Radiosurgery is the use of a focal high dose of radiation therapy to ablate or kill a tumor. This trial will enroll patients with brain metastases 4 cm or less in greatest diameter and will compare 0mm margin to a 2mm margin for treatment.

Without a stereotactic frame there is considerable variation in practice in the use of planning target volume (PTV) margins for linac radiosurgery. In particular, the use of a single isocenter for multiple targets geometrically increases the risk that rotational errors will result in significant dosimetric errors, and many centers have considered adding margin. A recent AAPM task group survey has found that ~90% of centers worldwide add a PTV margin to account for error and that 8% add more than 2 mm. The most common margin is 2 mm. Other potential reasons to add a margin include spacial MRI error, couch walkout, CBCT to linac isocenter mismatch, and undetected intrafraction motion. Treatment volume is the greatest predictor of radiation toxicity associated with radiosurgery and potentially unnecessary margins will lead to increased risk to the patient. This trial will incorporate a composite endpoint that includes control of the tumor and toxicity.

Uncomplicated tumor control probability (UTCP) is defined as the chance the tumor is locally controlled (TCP) without grade 3 or greater CNS toxicity (1-NTCP). The investigators hypothesize a 2 mm margin will worsen uncomplicated control compared to a 0 mm PTV margin in the treatment multiple metastases in a single fraction.

This trial will inform the standard of care margin (0 mm vs 2 mm) for single isocenter treatment of multiple targets.

Inclusion Criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study
2. Male or female, aged 19 and older
3. Brain metastases diagnosis not requiring retreatment to the same tumor
4. For females of reproductive potential should undergo pregnancy testing as per UAB Radiation Oncology standard policies
5. Ability of subject or Legally Authorized Representative (LAR)) to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Current use of cytotoxic chemotherapy within 3 days of treatment. There are no restrictions on the use of immunotherapy during treatment. TKIs known to be radiation sensitizers such as BRAF should be held at least 24 hours prior to treatment.
2. Inability to have MRI imaging
3. Pregnancy
4. Treatment with another investigational drug 14 days of enrollment
5. Radiosurgery planned for post-operative adjuvant cavity only. Patients with any gross residual after surgery are eligible. Patients with at least one intact metastasis may enroll but adjuvant cavity will not be evaluable.
6. At the time of Radiation Oncology consultation more than twenty targets are identified. Note that it is common that a few additional metastases may be identified during the treatment planning or peer review processes. More than twenty targets may be included if this number is found after the initial clinical review of the treatment planning MRI.
7. Tumor maximal diameter > 4 cm.
8. Prior SBRT or SRS to a lesion planned for retreatment. Note that patients with prior whole brain radiation alone are eligible.
9. Patients with diffuse leptomeningeal tumor are not eligible. Patients with a focal dural or pachymeningeal tumor are eligible if other intra-axial tumors are planned to be treated. Similar to postoperative cavities, the pachymeningeal tumor deposit will be treated but not evaluable for the assessment of local control or toxicity.

INCLUSION OF VULNERABLE PARTICIPANTS Vulnerable populations as defined by the NIH including children, prisoners, and adult subjects who lack capacity to consent to research participation are not eligible.

The patients will be blinded but the treating team will not be blinded after both plans are generated and clinically reviewed.