Hypofractionation Trial of Re-irradiation in Good Prognosis Recurrent Glioblastoma

Background: * Although survival of glioblastoma (GBM) has improved using standard of care chemoradiation, outcomes are still poor. Most patients will recur within months to years, in or adjacent to their previous treatment field. * There is no consensus standard of care for patients with recurrent GBM. Re-resection is recommended, if possible, to improve symptoms and decrease tumor volume. However, this treatment option is possible only in a minority of patients, and for these patients re-irradiation has emerged as a possible treatment. * Modern radiation therapy (RT) techniques allow delivery of re-irradiation while minimizing the dose to previously treated organs at risk (OAR) within the radiation field. * Data from a recently completed clinical trial at our center (16-C-0081, NCT02709226) suggests that the Maximum Tolerated Dose (MTD) of re-irradiation in 350 cGy fractions is 4200 cGy. Objective: -To determine the maximum tolerated dosage of daily re-irradiation in participants with recurrent Grade 4 gliomas Eligibility: * A histologic diagnosis of GBM, gliosarcoma, or transformation, from a lower grade to a grade 4 brain tumor. * Previous glioma irradiation to curative-intent doses. * Age \>= 18. * Karnofsky performance scale (KPS) \>= 70. Design: * This is a single center phase I trial using a '3 + 3' design and a three (3) dose level hypofractionation schema to enroll a maximum of 21 evaluable participants. * Prior to radiation therapy, participants will undergo laboratory evaluations, magnetic resonance imaging (MRI), and a treatment planning computed tomography (CT). * RT will be administered daily 4 days a week for 1, 2, or 3 weeks in the Radiation Oncology Branch, NCI, at NIH. Radiation will be delivered on consecutive days, 4 fractions per week via a linear accelerator using 6 megavoltage (MV) photons or greater. * Follow-up visits following RT are planned at 1 month, every 2 months for years 1-2, and every 3 months for year 3. These visits will be stopped earlier in case of progression. After progression or 3 years of follow-up, participants will be followed remotely for survival until 5 years after treatment completion.