CLINICAL TRIAL / NCT02179086

Inclusion Criteria: - PRIOR TO STEP 1 REGISTRATION - A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial - The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed) - Patients must provide study-specific informed consent prior to step 1 registration - PRIOR TO STEP 2 REGISTRATION - Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration - Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of O(6)-methylguanine-DNA-methyltransferase (MGMT) status - Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present - Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed - History/physical examination within 28 days prior to step 2 registration - The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration - Documentation of steroid doses within 28 days prior to step 2 registration - Karnofsky performance status >= 70 within 28 days prior to step 2 registration - Age >= 18 - Absolute neutrophil count (ANC) >= 1,800 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 10.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable) - Bilirubin =< 1.5 upper limit of normal (ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN - Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Recurrent or multifocal malignant gliomas - Any site of distant disease (for example, drop metastases from the GBM tumor site) - Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide) - Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted - Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields - Severe, active co-morbidity, defined as follows: - Unstable angina at step 2 registration - Transmural myocardial infarction within the last 6 months prior to step 2 registration - Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration - New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration - Serious and inadequately controlled arrhythmia at step 2 registration - Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration - Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol - Any other severe immunocompromised condition - Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity - End-stage renal disease (ie, on dialysis or dialysis has been recommended) - Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration - Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia) - Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.