Summary

This randomized phase III trial compares giving radiation therapy alone or temozolomide together with radiation therapy and to see which works best in treating patients with newly diagnosed anaplastic glioma or low grade glioma. Radiation therapy uses high-energy x-rays to kill tumor cells. 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. It is not yet known whether giving radiation therapy alone or temozolomide together with radiation therapy is better in treating anaplastic glioma or low grade glioma.

Objectives

PRIMARY OBJECTIVES:
I. To determine whether patients who receive radiotherapy with concomitant temozolomide followed by adjuvant temozolomide (radiation therapy [RT] + temozolomide [TMZ] ? TMZ) (ARM B) have a marginally better progression free survival (PFS) as compared with patients who receive radiotherapy followed by adjuvant procarbazine hydrochloride, lomustine, vincristine sulfate (PCV) chemotherapy (RT ? PCV) (ARM A).

SECONDARY OBJECTIVES:
I. To determine whether patients who receive RT + TMZ ? TMZ have a longer time to progression (clinical or radiographic progression) as compared with patients who receive radiotherapy followed by adjuvant PCV chemotherapy (RT ? PCV).
II. To determine whether there is a difference in survival based on (1;19)(q10,p10) translocation status and MGMT promoter hypermethylation status.
III. To perform descriptive comparisons of additional secondary outcome endpoints, including overall survival, objective tumor response, prognostic factor analysis and quality of life, including comparisons between photon and proton radiotherapy.
IV. To determine the toxicity of the treatment in each arm and perform descriptive comparisons as well as comparisons between photon and proton radiotherapy.
V. To determine the neurocognitive and quality of life (QOL) effects in patients treated on this protocol and correlate these results with outcome endpoints as well as comparisons between photon and proton radiotherapy.
VI. To store biospecimens (plasma or serum, deoxyribonucleic acid [DNA] from tumor and peripheral blood mononuclear cells DNA, tumor tissue, and magnetic resonance imaging [MRI]/ computed tomography [CT] images) for future correlative scientific investigations which explore the scientific relationships of any known and yet-to-be developed markers to clinical outcome and imaging data.

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

ARM A: Patients undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) on days 1-5 for 5-7 weeks. Patients also receive procarbazine hydrochloride orally (PO) on days 8-21, lomustine PO on day 1 and vincristine sulfate intravenously (IV) on days 8 and 29 of courses 3-8. Treatment repeats every 6-7 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans throughout the trial as well as chest x-ray and collection of blood samples on trial.

ARM B: Patients undergo RT as in Arm A and receive temozolomide PO once daily (QD) on days 1-5 for 5-7 weeks. Beginning 4 weeks after completion of concurrent chemoradiotherapy, patients receive adjuvant temozolomide PO QD on days 1-5. Treatment with adjuvant temozolomide repeats every 4 weeks for 6-12 courses in the absence of disease progression and unacceptable toxicity. Patients also undergo CT or MRI scans throughout the trial and collection of blood samples on trial.

After completion of study therapy, patients are followed up every 12 weeks for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

Eligibility

1. PRE-REGISTRATION INCLUSION CRITERIA:
2. United States (US) and Canadian sites: * This review is mandatory prior to registration to confirm eligibility; patients must be willing to submit tissue samples for mandatory central pathology review submission; it should be initiated as soon after surgery as possible
3. Tissue must have been determined to have local 1p/19q co-deletion and IDH mutation prior to submission for central path review * Tumor tissue must show co-deletion of chromosomes 1p and 19q; for eligibility, the 1p/19q analysis results will be accepted from the local site, as determined by either a locally available or reference laboratory (for US, must be Clinical Laboratory Improvement Act [CLIA] certified); acceptable methods for determination of 1p/19q loss include fluorescent in-situ hybridization (FISH), by genomic sequencing or methylomic analyses; US and Canadian sites must send a copy of the official report to the pathology coordinator and upload it in Rave * Tumor must also show evidence of IDH mutation by immunohistochemistry or genomic analyses; this should be performed at the local site (US: performed in a CLIA certified laboratory); the site must send a copy of the official report to the pathology coordinator and upload it in Rave
4. REGISTRATION INCLUSION CRITERIA:
5. Age >= 18 years of age
6. Newly diagnosed and =< 3 months from surgical diagnosis. Patients not recently diagnosed (i.e. patients who had surgical procedure > 3 months earlier) with grade 2 or 3 gliomas are eligible if the patient has not received prior radiation or prior chemotherapy. Patients cannot have received prior treatment directed at this neoplasm with the exception of prior surgery
7. Histologic evidence of WHO grade 2 or 3 oligodendroglioma, defined as a glioma with 1p/19q codeletion in combination with any IDH1 or IDH2 mutation. Codeletion and IDH status should be determined at the referring site’s local or reference laboratory
8. Patients with codeleted low grade gliomas must also be considered “high risk” by exhibiting one or more of the following characteristics: * Age >= 40 and any surgical therapy * Age < 40 with prior and subtotal resection or biopsy (i.e., anything less than gross total resection) * Documented growth following prior surgery (NOTE: patients with prior surgery cannot have received prior radiation, chemotherapy or targeted therapy) * Intractable seizures
9. Surgery (partial or gross total resection or biopsy) must be performed >= 2 weeks prior to registration; patient must have recovered adequately from the effects of surgery
10. Absolute neutrophil count (ANC) >= 1,500/mm^3 (obtained =< 21 days prior to registration)
11. Platelet (PLTs) count >= 100,000/mm^3 (obtained =< 21 days prior to registration)
12. Hemoglobin (Hgb) > 9.0 g/dL (obtained =< 21 days prior to registration)
13. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained =< 21 days prior to registration)
14. Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN (obtained =< 21 days prior to registration)
15. Creatinine =< 1.5 x ULN obtained =< 21 days prior to registration
16. Negative serum or urine pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
17. Willingness and ability to personally complete neurocognitive testing (without assistance) and willingness to complete the QOL testing, (either personally or with assistance)
18. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2
19. Written informed consent
20. Willingness to return to enrolling institution for follow-up during the active monitoring phase (that is, the active treatment and observation portion) of the study); patients who have been formally transferred to another active and approved site participating in this study would not need to return to the enrolling institution for this purpose
21. Willingness to allow the provision of tissue samples for correlative research, as long as adequate tissues are available; patients will not be excluded from participation in the study, if they are willing to allow provision of tissues for the correlative research, but there are insufficient quantities of tissue for the correlative analyses (e.g., a patient otherwise eligible and willing who had biopsy only) Willingness to allow the provision of blood samples for correlative research; patients are not excluded from participation in the study, if they are willing to provide the mandatory biospecimens for translational/correlative research, but for logistical reasons the specimens(s) were not obtainable or if the volume collected was insufficient
22. Ability to read and comprehend English (or French for Canadian sites)

Treatment Sites in Georgia