This randomized phase III trial studies temozolomide (TMZ) and radiation therapy (RT) to compare how well they work with or without bevacizumab in treating patients with newly diagnosed glioblastoma or gliosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as bevacizumab, may find tumor cells and help kill them. It is not yet known whether temozolomide and radiation therapy are more effective when given together with or without bevacizumab in treating glioblastoma or gliosarcoma.

PRIMARY OBJECTIVES:

I. To determine whether the addition of bevacizumab to temozolomide and radiation improves efficacy as measured by progression-free and/or overall survival.

II. To assess the association between overall survival and K^trans change from T1 to T2. (ACRIN 6686) III. To assess the association between overall survival and spin echo cerebral blood volume (CBV) change from T1 to T2. (ACRIN 6686)

SECONDARY OBJECTIVES:

I. To determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit, as measured by either overall survival or progression-free survival, from the addition of bevacizumab.

II. To compare and record the toxicities of the conventional and bevacizumab-containing regimens.

III. To assess the association between progression-free survival and K^trans change from T1 to T2. (ACRIN 6686) IV. To assess the association between progression-free survival and spin echo CBV change from T1 to T2. (ACRIN 6686) V. To assess the association between values of K^trans and spin echo CBV measured separately at T0 and at T1, and overall and progression-free survival. (ACRIN 6686) VI. To assess the association between overall survival and K^trans changes from T0 to T1 and from T2 to T3. (ACRIN 6686) VII. To assess the association between overall survival and spin echo CBV changes from T0 to T1 and from T2 to T3. (ACRIN 6686) VIII. To assess the association between overall survival and apparent diffusion coefficient (ADC) change from T0 to T1. (ACRIN 6686) IX. To assess the association between overall survival and ADC change from T1 to T2. (ACRIN 6686) X. To assess the association between progression-free survival and ADC change from T0 to T1. (ACRIN 6686) XI. To assess the association between progression-free survival and ADC change from T1 to T2. (ACRIN 6686) XII. To assess the association between T1 values of ADC and overall and progression-free survival. (ACRIN 6686) XIII. To assess the association between change in lesion size between T1 and T3, as measured by advanced magnetic resonance imaging (MRI), and overall and progression-free survival. (ACRIN 6686)

TERTIARY OBJECTIVES:

I. To determine the differential acute effects associated with the addition of bevacizumab to temozolomide and radiation, as compared to the conventional arm, on measures of neurocognitive function, health-related quality of life, and symptoms during radiation and across the longitudinal progression-free interval.

II. To determine the relationship of neurocognitive function, health-related quality of life, and symptoms, with progression-free and overall survival.

III. To determine the association between tumor molecular profile (i.e., mesenchymal/angiogenic phenotype and proneural phenotype) and neurocognitive function, health-related quality of life, and symptoms.

IV. To describe the association between health-related quality of life as measured by the European Organization for Research and Treatment Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QL30/BCM20) and mean symptom severity as measured by the M. D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) in patients enrolled in this study.

V. To evaluate the relationship between self-reported neurocognitive function and objectively measured tests of neurocognitive function (NCF).

VI. To assess the association between measures of change in enhancing tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

VII. To assess the association between measures of change in T2-based tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

VIII. To assess the association between changes in ADC values and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms (there are also two registration steps prior to randomization which are labeled as "arms" in ClinicalTrials.gov to facilitate entry of results into the website).

ARM I: Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks and receive temozolomide orally (PO) once daily (QD) for up to 7 weeks. Beginning 4 weeks after completion of chemotherapy and radiation therapy, patients receive temozolomide PO QD on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive placebo IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemotherapy and radiation therapy and continuing until the completion of temozolomide.

ARM II: Patients undergo radiation therapy and receive temozolomide as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemoradiotherapy and continuing until the completion of adjuvant temozolomide.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or gliosarcoma (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 size for analysis of O-6-methylguanine-DNA methyltransferase (MGMT) and determination of molecular profile

  • 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
  • CUSA (Cavitron ultrasonic aspirator)-derived material is not allowed; fresh frozen tumor tissue acquisition is encouraged
  • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis
  • The tumor tissue should be sent as soon as possible to maximize the likelihood of eligibility; tumor tissue should be submitted by 4 weeks after the surgical procedure so that the study registration and treatment can commence by the mandatory 5 week post-surgery outer limit
  • Sites must submit tissue fir central review in order to obtain the MGMT analysis; patients from sites not following protocol-specified process for obtaining MGMT results will be made ineligible

• The tumor must have a supratentorial component

• History/physical examination within 14 days prior to step 2 registration

• The patient must have recovered from the effects of surgery, postoperative infection, and other complications before step 2 registration

• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy; the postoperative scan must be performed within 28 days prior to step 1 registration

  • An MRI or computed tomography (CT) scan (potentially in addition to the postoperative scan) must be obtained within 10 days prior to the start of radiation therapy and must not demonstrate significant postoperative hemorrhage defined as > 1 cm diameter of blood; if > 1 cm of acute blood is detected, the patient will be ineligible for this trial; the radiation planning MRI or CT scan may be used to determine presence of hemorrhage
  • Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and postoperative contrast-enhanced CT scans are obtained and are of sufficient quality; preoperative and postoperative scans must be the same type; such patients cannot be enrolled into the advanced imaging component

• Documentation of steroid doses within 14 days prior to step 2 registration

• Karnofsky performance status >= 70

• 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)

• Blood urea nitrogen (BUN) =< 30 mg/dL within 14 days prior to step 2 registration

• Creatinine =< 1.7 mg/dl within 14 days prior to step 2 registration

• Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg

• Bilirubin =< 2.0 mg/dl within 14 days prior to step 2 registration

• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x normal range within 14 days prior to step 2 registration

• Systolic blood pressure =< 160 mg Hg or diastolic pressure =< 90 mm Hg within 14 days prior to step 2 registration

• Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior to step 2 registration

• Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria:

  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of LMW heparin

• Patient must provide study specific informed consent prior to study entry

• Women of childbearing potential and male participants must practice adequate contraception

• For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

• Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for >= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible)

• Recurrent or multifocal malignant gliomas

• Metastases detected below the tentorium or beyond the cranial vault

• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or bevacizumab; 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 and/or congestive heart failure within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • 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 14 days of step 2 registration
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months
  • Serious and inadequately controlled cardiac arrhythmia
  • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for tumor resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  • Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive
  • 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
  • Any other major medical illnesses or psychiatric impairments 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

• Pregnant or lactating women

• Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study

• For American College of Radiology Imaging Network (ACRIN) 6686 Advanced Imaging: inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker)