Phase III Trial of Anaplastic Glioma Without 1p/19q Loss of Heterozygosity (LOH)

OBJECTIVES:

Primary

• To assess whether concurrent radiotherapy with daily temozolomide improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma.
• To assess whether adjuvant temozolomide improves survival as compared to no adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma.

Secondary

• To assess whether concurrent and adjuvant temozolomide prolongs progression-free survival and neurological deterioration-free survival in patients with non-1p/19q deleted anaplastic glioma.
• To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma, including late effects on cognition.
• To assess the impact of concurrent and adjuvant temozolomide on the quality of life of patients with non-1p/19q deleted anaplastic glioma.

OUTLINE: This is a multicenter study. Patients are stratified according to institution, World Health Organization (WHO) performance status (0 vs > 0), age (≤ 50 vs > 50), presence of 1p LOH only (yes vs no), presence of oligodendroglial elements (yes vs no), and O6-methylguanine-DNA methyltransferase promoter methylation status (methylated vs unmethylated vs indeterminate). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients undergo radiotherapy* once daily, 5 days a week, for 6.5 weeks (total of 33 fractions).
• Arm II: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy).
• Arm III: Patients undergo radiotherapy* once daily, 5 days a week for 6.5 weeks (total of 33 fractions). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses.
• Arm IV: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses.
• Patients must begin radiotherapy within 8 days after randomization and within 7 weeks after surgery.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients complete quality-of-life questionnaires, including EORTC core quality of life questionnaire (QLQ-C30) version 3, EORTC brain cancer module (BCM20), and the Mini Mental Status Exam at baseline, 4 weeks after the completion of radiotherapy, and then every 3 months for 5 years.

Tissue samples are collected at baseline for histology review, 1p/19q analysis, methylation status of the O6-methylguanine-DNA methyltransferase promoter, and isocitrate dehydrogenase mutation analysis.

After completion of study treatment, patients are followed every 3 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Anaplastic oligodendroglioma
• Anaplastic oligoastrocytoma
• Anaplastic astrocytoma
• Newly diagnosed disease
• Prior surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression
• Absence of combined 1p/19q loss
• Tumor material available for central 1p/19q assessment, central O6-methylguanine-DNA methyltransferase promoter methylation status assessment, isocitrate dehydrogenase mutation analysis, and central pathology review
• Patients must be on a stable or decreasing dose of steroids for at least two weeks prior to randomization

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9 cells/L
• Platelet count ≥ 100 x 10^9 cells/L
• Bilirubin < 1.5 x upper limit of normal (ULN)
• Alkaline phosphatase < 2.5 x ULN
• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 x ULN
• Serum creatinine < 1.5 x ULN
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No known HIV infection or chronic hepatitis B or hepatitis C infection
• No other serious medical condition that would interfere with follow-up
• No medical condition that could interfere with oral medication intake (e.g., frequent vomiting or partial bowel obstruction)
• No other prior malignancies except for any malignancy which was treated with curative intent more than 5 years prior to registration and adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix
• No prior or concurrent malignancies at other sites except for surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer
• No psychological, familial, sociological, or geographical condition that would potentially hamper compliance with the study protocol and follow-up schedule

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy, including carmustine-containing wafers (Gliadel®)
• No prior radiotherapy to the brain
• No concurrent growth factors unless vital for the patient
• No other concurrent investigational treatment
• No other concurrent anticancer agents