Biologically-based Target Volumes to Treat Newly Diagnosed Glioblastoma

Inclusion Criteria:

* Ability to understand and willingness to provide informed consent
* Newly diagnosed, histologically-confirmed supratentorial WHO grade IV gliomas including glioblastoma (all variants) and gliosarcoma.
* Patients must be 18 years of age or older.≥
* Karnofsky performance status ≥ 70
* Minimal life expectancy of 12 weeks.
* Maximal contiguous volume of tumor based on high b-value diffusion MRI and perfusion MRI \< 1/3 volume of brain
* Patients must be treated within 6 weeks of most recent resection

Within 21 days of radiation fraction 1, the following blood test parameters must be met:

* Hemoglobin ≥ 10 g/dL (transfusion is acceptable)
* absolute neutrophils ≥ 1500/mm3
* platelet count ≥ 100,000/mm3
* total bilirubin ≤ 2 x upper limit of normal (ULN) (unless elevated bilirubin is related to Gilbert syndrome)
* ALT and AST ≤ 5 x ULN
* serum creatinine ≤ 2.0 mg/dL

Exclusion Criteria:

* Recurrent glioma, or tumor involving the brainstem or cerebellum. Prior low-grade glioma without prior RT, now with malignant progression are eligible.
* Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment is not permitted. Prior chemotherapy for a different cancer is allowable if interval since last treatment cycle completion is \>3 years.
* Evidence of CSF dissemination (positive CSF cytology for malignancy or MRI findings consistent with CSF dissemination).
* Multifocal disease (\>1 lobe of involvement) of discontiguous, contrast enhancing disease as seen on conventional MRI
* Evidence of severe concurrent disease requiring treatment
* Known active malignancy as determined by treating medical and radiation oncologist
* Patients unable to undergo MRI exams
* Patients treated with previous cranial or head/neck radiotherapy leading to significant radiation field overlap.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring inpatient hospitalization or delay treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or compromise subject safety.
* Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects.
* Nursing mothers declining to discontinue breastfeeding are excluded because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide.
* Patients with reproductive potential declining to use an effective contraceptive method during treatment are excluded from this study.