Glyburide vs Placebo as Prophylaxis Against Cerebral Edema in Patients Receiving Radiosurgery for Brain Metastases (RAD 1502/UAB 1593)

Inclusion Criteria: * Patients with newly diagnosed brain metastases deemed to be eligible for radiosurgery. * Subject must have cytologically or histologically confirmed malignancy (this is the original malignancy, not the brain metastases). * A diagnostic contrast-enhanced MRI of the brain must be performed within 60 days prior to registration. The contrast-enhancing intraparenchymal brain tumor must be well visualized. * History and physical with neurological examination, height, and weight within 14 days prior to registration * No dexamethasone use (or any other corticosteroid use with the purpose of treating cerebral edema) starting 5 days prior to SRS. Patients may be tapered to meet this criterion if deemed safe by the treating physician. * Women of child-bearing potential (e.g. not post-menopausal or permanently sterilized women) must have a negative pregnancy test obtained within 14 days prior to registration. This is to prevent potential harm to the fetus by glyburide and radiotherapy. * CBC with differential and CMP including Liver Function Tests (LFTs) obtained within 14 days prior to registration and meeting the following requirements: * Creatinine Clearance ≥ 50 mL/min. * Total Bilirubin \< 1.5 x the upper limit of normal (ULN). * ALT and AST ≤ 2.5 x ULN. * Glucose ≥ 80 mg/dL. * Hemoglobin ≥ 7 mg/dL. * Absolute Neutrophil Count \> 100 cells/mm3. * For the Randomized Portion only: Subject must have at least 2 of the following risk factors: {For the Pilot Portion, it is not required that patients have the risk factors mentioned in Inclusion Criteria 9.} * Pretreatment Edema/Tumor ratio (≥ 35:1) as contoured on a baseline MRI obtained at most 60 days prior to registration. Patients are allowed to have Whole Brain Radiotherapy (WBRT) or corticosteroid use between the time of pretreatment MRI and SRS (as long as the corticosteroids can be safely tapered at least 5 days prior to the treatment planning MRI and WBRT is at least 4 days prior to registration). * Greater than 40 pack year history of smoking cigarettes. * Whole Brain Radiotherapy at least 4 days and no more than 1 year prior to registration. * RPA Class III. Exclusion Criteria: * Known sulfonylurea treatment within 7 days prior to registration. Sulfonylureas include glyburide/glibenclamide (Diabeta, Glynase); glyburide plus metformin (Glucovance); glimepiride (Amaryl); repaglinide (Prandin); nateglinide (Starlix); glipizide (Glucotrol, GlibeneseR, MinodiabR); gliclazide (DiamicronR); tolbutamide (Orinase, Tolinase); and glibornuride (Glutril). * Diffuse Leptomeningeal metastases. * Known allergy to sulfa or specific allergy to sulfonylurea drugs. * Use of VEGF inhibitors within 10 days prior to registration. * Allergy to gadolinium. * Type 1 diabetes mellitus or Type 2 diabetes mellitus actively receiving treatment. * Cognitive impairment that precludes a patient from acting as his or her own agent to provide informed consent. * Concurrent use of Bosentan. * Any major medical illnesses or psychiatric impairments that in the treating physician's opinion will prevent administration or completion of protocol therapy ( which may include patients who are elderly, debilitated, or malnourished persons and/or those with renal, hepatic or adrenal insufficiency). * Pregnant or breast feeding women due potential damage to the fetus * Inability to undergo MRI or SRS (e.g. due to safety reasons such as presence of a pacemaker). * Deemed by the treating physician to be unable to eat regular meals. * Patients currently on beta blockers. * Patients with a known diagnosis of ongoing alcoholism/alcohol abuse.