The goal of this clinical research study is to compare IMRT with IMPT in patients with glioblastoma. Researchers want to learn about cognitive side effects (mental status changes) that may occur, such as memory loss and impaired thinking.

IMRT is the delivery of focused radiation therapy using photon beams and advanced computer planning to help shape the dose in order to give the highest possible dose to the tumor with the least dose to surrounding normal tissues.

IMPT is also focused radiation therapy similar to IMRT, but it uses proton particles to deliver the radiation instead of photon beams. IMPT also uses advanced computer planning in order to shape the dose to the target with the least dose to surrounding normal tissues.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group.

If you are in Group 1, you will receive IMRT.

If you are in Group 2, you will receive IMPT.

Radiation Therapy:

In both groups, you will receive radiation treatments each day, Monday-Friday, starting on Day 1. You will continue to receive radiation treatment until you have completed 30 total treatments. This is a total of up to 6 weeks of treatment.

You will sign a separate consent form for the IMRT or IMPT that will explain the procedures and risks in detail.

Study Visits:

Before beginning radiation, you will have what is called a "simulation" to plan your radiation. During the simulation, you will be flat on your back on a computed tomography (CT) table and a soft plastic mask will be made to help hold your head still during treatment. This is the position you will be in when you receive radiation treatment. You will then have a CT scan, which will make computerized images to help plan your treatment.

At Month 2 (+/- 30 days):

• You will have a physical exam, including measurement of your vital signs.
• You will have an MRI to check the status of the disease.
• You will be asked about any drugs you may be taking and side effects you may be having.
• You will complete the thinking skills tests and the questionnaires about your quality of life and symptoms.

Length of Treatment:

You may receive up to 6 weeks of radiation therapy. You will no longer be able to receive radiation therapy if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your active participation on the study will be over after the follow-up visits.

Follow-Up:

At Month 4 (+/- 30 days) and then every 2 months for up to 2 years after radiation therapy:

• You will have a physical exam, including measurement of your vital signs.
• You will be asked about any side effects you may be having.
• You will have an MRI to check the status of the disease.
• You will complete the thinking skills tests and the questionnaires about your quality of life and symptoms.

Starting 2 years after radiation therapy, the study staff will continue checking your medical record to find out about your health status from then on.

This is an investigational study. IMRT is delivered using FDA-approved and commercially available methods. IMPT is investigational.

Up to 90 participants will be enrolled in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Histological diagnosis of: Glioblastoma or Gliosarcoma (WHO Grade IV) adapted RPA class III, IV, or V.
2. All patients must be >/=18 years of age.
3. All patients must sign informed consent verifying that they are aware of the investigational nature of this study in keeping with the rules and policies of MD Anderson Cancer Center. The only acceptable consent form is the one approved by MD Anderson IRB.
4. All patients must have a baseline Mini Mental Status Examination score >/=21.
5. All patients must have a KPS >/=70.
6. All patients must be eligible to have either IMRT or IMPT as determined by the study radiation oncologist.
7. All patients must be able to undergo MRI with and without contrast with a glomerular filtration rate (eGFR) greater than or equal to 30 mg/min/1.72 m2.
8. All patients must have adequate liver, renal, and hematologic function within 14 days of registration as defined by Aspartate Amino Transferase (AST)/Alanine Amino Transferase (ALT)/Alkaline Phosphatase < 3 times normal, creatinine </=1.7 mg/dl, BUN </= 35mg/dl, absolute neutrophil count >/=1,800 cells/mm3, Hemoglobin >/= 10 g/dl, and platelet count > 100,000.
9. All patients must be able to adequately read, write and speak to participate in the cognitive and quality of life assessments. However mild to moderate deficits in these functions due to tumor are allowed.

Exclusion Criteria:

1. Patients will be excluded if they are not planning to receive concurrent temozolomide.
2. Patients will be excluded if they have had prior radiation to the brain.
3. Patients will be excluded if they have had prior surgical resection of brain for other brain tumors.
4. Patients will be excluded if they are pregnant as assessed by serum beta human chorionic gonadotropin (b-HCG). A serum b-HCG test will be performed no greater than 14 days prior to study registration for women of childbearing potential.
5. Patients with gliomatosis will be excluded.
6. Patients with Gliadel bis-chloroethylnitrosourea (BCNU) implanted wafers will be excluded.
7. Patients weighing greater than 136 kilograms will be excluded.

Between June 2013 and March 2016, 90 patients consented to participate and 67 were treated (28 PT, 39 IMRT) with the majority of patients excluded before treatment began due to insurance denial of proton therapy

2 years

During this study, both the Intensity Modulated Radiotherapy (IMRT) and Intensity Modulated Proton Radiotherapy (IMPT) arms reported serious and life-threatening adverse events. Specifically, 2 participants in the IMRT arm and 1 participant in the IMPT arm experienced Grade 4 life-threatening events that required urgent intervention