Conditions: Brain and Central Nervous System Tumors
Keywords: adult glioblastoma adult giant cell glioblastoma adult gliosarcoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1173
Healthy volunteers: no

Brief summary:
RATIONALE: 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 or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known which schedule of temozolomide when given together with radiation therapy is more effective in treating glioblastoma or gliosarcoma.

PURPOSE: This randomized phase III trial is studying two different schedules of temozolomide to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed glioblastoma or gliosarcoma.

Detailed description:
OBJECTIVES:

Primary

* Determine if dose-intensifying (increasing the "dose-density") the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival of patients with newly diagnosed glioblastoma or gliosarcoma.

Secondary

* Determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.
* Determine in patients with unmethylated MGMT (O-6-methylguanine-DNA methyltransferase) if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
* Determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
* Determine if there is an association between tumor MGMT gene methylation status and treatment response.
* Compare and record the toxicities of the conventional and dose-intense chemotherapy regimens.
* Evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to recursive partitioning analysis class (III vs IV vs V), MGMT gene methylation status (methylated vs nonmethylated vs indeterminate), and radiotherapy criteria used (standard vs revised European).

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

Arms:
arm 1: Concurrent radiation therapy with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle. arm 2: Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle. arm 3: Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Not randomized to either adjuvant TMZ arm.

Interventions: intervention 1: Concurrent temozolomide intervention 2: Concurrent radiation therapy intervention 3: 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle intervention 4: 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle
Intervention descriptions: intervention 1: Daily oral temozolomide (75 mg/m2) up to 49 doses. intervention 2: 60 Gy in 2 Gy fractions intervention 3: Oral temozolomide on days 1-5 of a 28-day cycle. Dose starts at 150mg/m2 for first cycle, increases to 200mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide. intervention 4: Oral temozolomide on days 1-21 of a 28-day cycle. Dose starts at 75mg/m2 for first cycle, increases to 100mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.

Protocol document: