Randomized Phase II Study: Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases

• Pre-Registration Eligibility Criteria:

• Patients who present with symptomatic brain radionecrosis after they have received radiosurgery for brain metastases from primary solid tumor including but not limited to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal cell carcinoma or gliomas

• Patients at institutions that elect to utilize central imaging review to confirm eligibility must be pre-registered prior to submission of these images; images should be submitted as soon as possible after the pre-registration magnetic resonance imaging (MRI) is obtained; turnaround time for this review will be =\< 72 business hours after receipt of images by the Imaging and Radiation Oncology Core (IROC)

• Patients at institutions that elect to confirm eligibility locally may be pre-registered at the same time as they are randomized

• Registration/Randomization Eligibility Criteria:

• A diagnosis of radionecrosis will be based on a clinical onset of symptoms and radiological findings of radionecrosis at 3-24 months following radiosurgery, with or without pathological confirmation.

‣ 1 'Symptomatic' brain radionecrosis to at least one lesion following radiosurgery treatment for brain metastases where 'symptomatic' is defined as:

‣ 1.1 New or increasing headache associated with mass effect, sensory or motor abnormality, cognitive changes, speech difficulty, balance or coordination difficulty, cranial nerve deficits

‣ 1.2 Symptoms are persistent or worsening despite administration of at least dexamethasone 4 mg (or equivalent corticosteroid) daily for 1 week

‣ 2 Clinical eligibility supported by central imaging real-time review. The presence of at least the following conventional MR image characteristic:

‣ 2.1 Conventional MR - Lesion quotient of \< 0.3, where lesion quotient is defined as the proportional value of the maximum axial cross-sectional area of the T2-weighted defined lesion over the maximum axial cross-sectional area of the contrast-enhancing lesion on the T1-weighted post-gadolinium sequence on a comparable axial slice. If the conventional MR findings are not seen, the following dynamic susceptibility-contrast (DSC) MR characteristics may be used to meet eligibility for this study.

‣ 2.2 DSC MR - The cut-offs below will be based on GRE EPI DSC perfusion images, acquired without using a gadolinium pre-load:

‣ 2.2.1 Relative cerebral blood volume (rCBV) \<1.5 in the enhancing- lesion relative to normal-appearing white matter (NAWM)

‣ 2.2.2. Percentage of signal recovery (PSR) \> 76%, where PSR is determined by comparing the lower signal intensity during passage of the contrast bolus with the post-contrast signal intensity on the signal intensity-time curve

‣ 2.3 Centers that standardly use PET or MRS to determine a diagnosis of radionecrosis are permitted to use these modalities to assist in their patient selection; however the criteria described for conventional MR and/or DSC should also be met for study eligibility. Both PET and MRS are not mandatory for study eligibility.

• Prior to start of treatment

‣ 1 Must have been taking a stable dose of corticosteroids for symptom management for at least 1 week before baseline MRI.

‣ 2 No systemic therapy within 2 weeks prior to registration or plan for systemic therapy within the first 8 weeks after study registration. The protocol provides a list of 'approved systemic' therapies that are allowed for concurrent use with bevacizumab.

‣ 3 No bevacizumab ≤ 3 months of study registration.

‣ 4 Central imaging real-time review (72 hour turn around) to confirm eligibility.

• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 14 days prior to registration and confirmation they are not nursing is required.

• Age ≥ 18 years

• Karnofsky Performance Status ≥ 60%

• Required Initial Laboratory Values ≤14 days of registration:

‣ 1 Absolute Neutrophil Count (ANC) ≥ 1,500/mm\^3

‣ 2 Platelet Count ≥ 100,000/mm3

‣ 3 Hemoglobin ≥ 10 g/dL\*

‣ 3.1 allowing transfusion or other intervention to achieve this minimum hemoglobin

‣ 4 BUN \< 30 mg/dL

‣ 5 Creatinine \< 1.7 mg/dL

‣ 6 Bilirubin ≤ 2.0 mg/dL

‣ 7 ALT ≤ 3.0 x upper limits of normal (ULN)

‣ 8 AST ≤ 3.0 x ULN

‣ 9 INR \<1.5 x ULN\*\*

‣ 9.1 unless patients are receiving anti-coagulation therapy. Patients receiving anti-coagulation therapy with an agent such warfarin or heparin are allowed to participate if INR ≤ 3.0.\*\*

‣ 10 UPC Ratio \<0.5 or if ≥ 0.5

‣ 10.1 24-hour urine protein must be \<1000 mg

• Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA) questionnaires.

• Assistance by research personnel is acceptable if participant has disabilities that make reading or writing difficult.

• No evidence of recent hemorrhage at pre-registration MRI of the brain, however the following are permitted: presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumor.

• No excess risk of bleeding (any of the following):

‣ 1 Bleeding diathesis or coagulopathy

‣ 2 Thrombocytopenia

‣ 3 Major surgical procedure, open biopsy, or significant traumatic injury within the past 28 days or anticipation of need for major surgical procedure during the course of the study.

‣ 4 Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy within the past 7 days.

⁃ No clinically significant cardiovascular disease.

∙ 1 No uncontrolled hypertension (systolic blood pressure ≤ 160 mm Hg or diastolic ≤ 100 mm Hg). Patients with hypertension must be adequately controlled with appropriate anti-hypertensive therapy or diet.

∙ 2 No history of arterial thrombotic events within the past 6 months, including:

∙ 2.1 transient ischemic attack (TIA)

∙ 2.2 cerebrovascular accident (CVA)

∙ 2.3 peripheral arterial thrombus

∙ 2.4 unstable angina or angina requiring surgical or medial intervention

∙ 2.5 myocardial infarction (MI)

∙ 2.6 significant peripheral artery disease (i.e., claudication on less than one block)

∙ 2.7 significant vascular disease (i.e., aortic aneurysm, history of aortic dissection)

∙ 3 Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 months are eligible if they are on stable therapeutic anticoagulation.

∙ 4 No current New York Heart Association classification II, III, or IV congestive heart failure.

⁃ No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within past 12 months.

⁃ No central lung metastases with excessive active bleeding.

⁃ No uncontrolled intercurrent illness including, but not limited to any of the following:

⁃ ongoing or active infection requiring IV antibiotics, cardiac arrhythmia, or psychiatric illness and/or social situations that would limit compliance with study requirements.

⁃ No history of serious non-healing wound, ulcer, or bone fractures.