This randomized phase II clinical trial studies the side effects and how well proton beam or intensity-modulated radiation therapy works in preserving brain function in patients with IDH mutant grade II or III glioma. Proton beam radiation therapy uses tiny charged particles to deliver radiation directly to the tumor and may cause less damage to normal tissue. Intensity-modulated or photon beam radiation therapy uses high-energy x-ray beams shaped to treat the tumor and may also cause less damage to normal tissue. It is not yet known if proton beam radiation therapy is more effective than photon-based beam intensity-modulated radiation therapy in treating patients with glioma.

PRIMARY OBJECTIVES:

I. To determine whether proton therapy, compared to intensity-modulated radiation therapy (IMRT), preserves cognitive outcomes over time as measured by the Clinical Trial Battery Composite (CTB COMP) score (calculated from the Hopkins Verbal Learning Test Revised [HVLT-R]) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Controlled Oral Word Association (COWA) test, Trail Making Test (TMT) part A and part B.

SECONDARY OBJECTIVES:

I. To assess whether treatment with proton therapy preserves neurocognitive function as measured separately by each test, HVLT-R, TMT parts A & B, and COWA.

II. To document and compare treatment related symptoms, overall symptom impact, and disease related factor groupings, utilizing the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT), for both treatment arms.

III. To assess whether treatment with proton therapy, compared to IMRT, results in superior quality of life as measured by the Linear Analog Scale Assessment (LASA) scale.

IV. To compare local control patterns of failure and overall and progression-free survival between the two treatment arms.

V. To assess adverse events. VI. To compare Illumnia MethylationEPIC beadchip array-derived IDH and 1p19q status determined centrally to that submitted by enrolling sites.

TERTIARY OBJECTIVES:

I. To assess the impact of chemotherapy use on cognitive outcomes, symptom outcomes and quality of life.

II. To assess dose-response relationships between neuro-anatomic dosimetry and cognitive outcomes within and between treatment arms.

III. To evaluate the association between tumor molecular status and cognition at baseline and within and between treatment arms over time.

IV. To assess patterns of failure and pseudo progression as a function of radiation delivery type and dose received.

V. To assess local control, overall survival and, progression free survival in IDH mutant grade II and III tumors.

VI. To collect blood samples for future studies seeking to correlate changes in peripheral blood biomarkers (genes, micro ribonucleic acid [RNA], proteins, lymphocyte count, melatonin, etc) and the study endpoints.

VII. To document and compare the impact of low to intermediate gliomas and therapy on patients' work and activity participation (The Work Productivity and Activity Impairment [WPAI:GH] Questionnaire: General Health version 2.0) as well as the relationship between changes in patients' work and activity participation and neurocognitive function and patient reported symptoms and interference.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo photon-based IMRT once daily (QD), 5 days a week for 6 weeks for a total of 30 fractions. Beginning 28 days after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) and collection of blood samples throughout the trial.

ARM II: Patients undergo proton beam radiation therapy QD, 5 days a week for 6 weeks for a total of 30 fractions. Beginning 28 days after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity. Patients undergo MRI and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 6 and 12 months and then yearly for 10 years.

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION
• Tumor tissue must be available for submission for central pathology review
• Grade II and III gliomas IDH mutant gliomas including; diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma
• Documentation from the enrolling site confirming the presence of IDH mutation and 1p/19q status; the provided information must document assays performed in clinical laboratory improvement amendments (CLIA)-approved laboratories and be uploaded prior to Step 2 registration
• Age >= 18
• The trial is open to both genders
• Only English or French speaking patients are eligible to participate as the cognitive assessments are only available in these languages
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• History and physical exam, and Karnofsky performance status of >= 70 within 30 days prior to registration
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 60 days prior to registration)
• Platelets >= 100,000 cells/mm^3 (within 60 days prior to registration)
• Hemoglobin >= 10.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable) (within 60 days prior to registration)
• Bilirubin =< 1.5 upper limit of normal (ULN) (within 60 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within 60 days prior to registration)
• Blood urea nitrogen (BUN) < 30 mg/dl (within 60 days prior to registration)
• Serum creatinine < 1.5 mg/dl (within 60 days prior to registration)
• Pre-operative MRI imaging of the brain available for radiation planning
• Post-operative MRI imaging with contrast is mandatory obtained for radiation therapy planning; enrolling sites are not mandated although highly encouraged to obtain thin-slice (< 1.5 mm) 3 dimensional (D) pre and post contrast and axial T2/FLAIR sequences for planning purposes
• Patients must be able to swallow capsules
• PRIOR TO STEP 2 REGISTRATION
• Histologically proven diagnosis of supratentorial, World Health Organization (WHO) grade II or III astrocytoma, oligodendroglioma or oligoastrocytoma, with IDH mutation confirmed by central review
• The following baseline neurocognitive assessments must be completed and uploaded prior to Step 2 registration: HVLT-R (recall, delayed recall, and recognition), TMT Parts A and B, and COWA; the neurocognitive assessment will be uploaded into a folder in the NRG Medidata RAVE System for central evaluation; once the upload and scoring of the tools are complete, a notification will be sent within 3 business days to the Research Associate (RA) to proceed to Step 2; in order for the patient to be eligible, at least 5 of the 6 neurocognitive assessments must be able to be scored (i.e. free of any errors)
• Completion of all items on the following baseline quality of life forms: MDASI-BT, LASA QOL, WPAI-GH and Employment Questionnaire; these quality of life forms will be required and data entered at step 2 registration
• Financial clearance for proton therapy treatment prior step 2 registration
• Women of childbearing age must have a negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease; if applicable

• 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 permissible)

• Prior cranial radiotherapy or radiotherapy to the head and neck where potential field overlaps would exist

• Prior chemotherapy or radiotherapy for any brain tumor

• Histologic diagnosis of glioblastoma (WHO grade IV) or pilocytic astrocytoma (WHO grade I)

• Definitive evidence of multifocal disease

• Planned use of cytotoxic chemotherapy during radiation (only adjuvant temozolomide therapy will be used on this protocol)

• Patients with infra-tentorial tumors are not eligible

• Prior history of neurologic or psychiatric disease believed to impact cognitive function

• The use of memantine during or following radiation is NOT allowed

• Severe, active co-morbidity defined as follows:

  • Unstable angina or congestive heart failure requiring hospitalization within 6 months prior to enrollment
  • Transmural myocardial infarction within the last 6 months prior to 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 registration (Note: EKG to be performed only if clinical suspicion of cardiac issue)
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to 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 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 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 registration
  • Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter; acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that 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 (i.e., 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

• Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, gadolinium allergy or renal dysfunction preventing the patient from receiving gadolinium- institutional guidelines should be used to determine if patients are at risk for renal dysfunction); note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia

• Patients known to have hypersensitivity to dacarbazine (DTIC) are not eligible

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