This phase III trial studies how well single fraction stereotactic radiosurgery works compared with fractionated stereotactic radiosurgery in treating patients with cancer that has spread to the brain from other parts of the body and has been removed by surgery. Single fraction stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Fractionated stereotactic radiosurgery delivers multiple, smaller doses of radiation therapy over time. This study may help doctors find out if fractionated stereotactic radiosurgery is better or worse than the usual approach with single fraction stereotactic radiosurgery.

PRIMARY OBJECTIVES:

I. To ascertain if time to surgical bed failure is increased with fractionated stereotactic radiosurgery (FSRS) compared to single-fraction stereotactic radiosurgery (SSRS) in patients with resected brain metastasis.

SECONDARY OBJECTIVES:

I. To ascertain if there is better emotional well-being at 9 months as assessed by the Functional Assessment of Cancer Therapy-Brain (FACT-BR) in patients with resected brain metastasis undergoing FSRS compared to SSRS (Primary quality of life [QOL] objective).

II. To ascertain whether there is improved overall survival in patients with resected brain metastases who undergo FSRS compared to patients who receive SSRS.

III. To ascertain in patients with resected brain metastases whether there is improved overall QOL as assessed by the FACT-BR and Linear Analog Self-Assessment (LASA) in patients who receive FSRS compared to patients who receive SSRS (Secondary QOL objective).

IV. To compare the functional independence in patients who receive FSRS to patients who receive SSRS.

V. To tabulate and descriptively compare the post-treatment adverse events associated with the interventions, including the potential impact of immunotherapy and targeted therapy.

VI. To compare rates of radiation necrosis at 12 months in patients who receive FSRS to patients who receive SSRS.

VII. To evaluate if there is any difference in central nervous system (CNS) failure patterns (local, distant brain failure, local leptomeningeal disease, widespread leptomeningeal disease) in patients who receive FSRS compared to patients who receive SSRS after resection of brain metastasis.

VIII. To ascertain in patients with resected brain metastases whether there is increased time to whole-brain radiotherapy (WBRT) in patients who receive FSRS compared to patients who receive SSRS.

IX. To determine in long-term survivors (patients who are alive more than 12 months from time of randomization) whether there is better emotional well-being and overall QOL as assessed by the FACT-BR and LASA in patients who receive FSRS to the surgical bed compared to patients who receive SSRS (Secondary QOL objective).

X. To assess for differences in CNS failure patterns (surgical, local, distant brain failure, leptomeningeal disease) as well as radiation necrosis rates as assessed by central review in patients who receive FSRS compared to patients who receive SSRS after resection of a brain metastasis.

XI. To ascertain in patients with resected brain metastases whether there is improved QOL as assessed by all other total and individual FACT-BR and LASA items and subscale values in patients who receive FSRS compared to patients who receive SSRS (Exploratory QOL objective).

XII. To determine in patients with resected brain metastases whether there is less cognitive progression in patients who receive FSRS to the surgical bed compared to patients who receive SSRS (Exploratory cognitive objective).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo SSRS over 1 session.

ARM II: Patients undergo FSRS over 3 or 5 daily sessions.

After completion of study, patients are followed up at 30 days, at 3, 6, 9, 12, 16, and 24 months, then every 6 months until 5 years from randomization.

Inclusion Criteria:

PRE-REGISTRATION:

• Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.

• Three or fewer (i.e. 0 to 3) unresected brain metastases (as defined on the post operative magnetic resonance imaging [MRI]) at the time of screening.

  o Note: Dural based metastases (e.g. commonly seen in breast cancer) are eligible.

• Unresected lesions must measure < 4.0 cm in maximal extent on the contrasted post-operative treatment MRI brain scan. The unresected lesions will be treated with SRS as outlined in the treatment section of the concept.

  o Note: The metastases size restriction does not apply to the resected brain metastasis.

• One brain metastasis must be completely (gross total resection) resected =< 30 days prior to pre-registration.

  o NOTE: May not have had resection of more than one brain metastasis.

• The resected brain metastasis must measure 2 cm or larger on the pre-operative MRI.

• Resection cavity must measure < 5.0 cm in maximal extent and the resection must be complete (gross total resection) on the post-operative MRI obtained =< 30 days prior to pre-registration.

• Karnofsky performance status of >= 60.

• For women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to pre-registration is required.

  • Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment.
  • A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

• Ability to complete an MRI of the head with contrast.

• The brain metastasis must be located > 5 mm of the optic chiasm; the brain metastasis must be located outside the brainstem (i.e. not inside the brainstem).

• Must not have any prior whole brain radiation therapy.

• Past radiosurgery to other lesions is allowed.

  o NOTE: The surgically resected lesion cannot be the same location treated in the past with radiosurgery (i.e. repeat radiosurgery to the same location/lesion is not allowed on this protocol).

• May not have primary germ cell tumor, small cell carcinoma, or lymphoma.

• No evidence of leptomeningeal metastasis (LMD).

  o NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or equivocal 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, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.

• Must be fluent in English, Spanish, or French.

REGISTRATION:

• Completion of all baseline electronic patient-reported outcome (ePRO) quality of life measures (or booklet quality of life measures) and Montreal Cognitive Assessment (MoCA).