Radiation Therapy With or Without Temozolomide in Treating Older Patients With Newly Diagnosed Glioblastoma Multiforme

Study Overview
=================
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 whether radiation therapy and temozolomide are more effective than radiation therapy alone in treating glioblastoma multiforme. PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared with radiation therapy alone in treating patients with newly diagnosed glioblastoma multiforme.

Detailed Description
-----------------
OBJECTIVES: Primary Compare overall survival rates in older patients with newly diagnosed glioblastoma multiforme treated with short-course radiotherapy with or without temozolomide. Secondary Compare progression-free survival of patients treated with these regimens. Compare the nature, severity, and frequency of adverse events in patients treated with these regimens. Compare the quality of life of patient treated with these regimens. Determine the methylation status of the O6-methylguanine-DNA methyltransferase promoter. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to center, age (65-70 years vs 71-75 years vs ≥ 76 years), ECOG performance status (0-1 vs 2), and extent of resection at surgery (biopsy only vs complete or incomplete resection). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo radiotherapy once daily on days 1-5, 8-12, and 15-19 in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo radiotherapy as in arm I and receive oral temozolomide once daily on days 1-25. Beginning 4 weeks after completion of radiotherapy and temozolomide, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with temozolomide alone repeats every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients complete quality of life questionnaires at baseline and periodically during study treatment. Tissue samples are collected at baseline and analyzed for methylation status of the O6-methylguanine-DNA methyltransferase promoter. After completion of study treatment, patients are followed every 3 months.

Official Title
-----------------
A Randomized Phase III Study of Temozolomide and Short-Course Radiation Versus Short-Course Radiation Alone In The Treatment of Newly Diagnosed Glioblastoma Multiforme in Elderly Patients

Conditions
-----------------
Brain and Central Nervous System Tumors

Intervention / Treatment
-----------------
* Drug: temozolomide
* Genetic: DNA methylation analysis
* Procedure: quality-of-life assessment
* Radiation: Radiation


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histopathologically confirmed glioblastoma multiforme Grade IV disease by WHO classification Newly diagnosed disease Initial diagnostic surgery or biopsy performed within the past 4 weeks Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute granulocyte count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN ALT and AST < 2.5 times ULN No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment No other condition (e.g., psychological or geographical) that would preclude study compliance PRIOR CONCURRENT THERAPY: No prior chemotherapy No prior radiotherapy No prior or concurrent investigational therapy No concurrent surgical procedures for tumor debulking No concurrent stereotactic boost radiotherapy No other concurrent chemotherapy, immunotherapy, or biological therapy No concurrent epoetin alfa Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days

Ages Eligible for Study
-----------------
Minimum Age: 65 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Temozolomide<br>Temozolomide and short course radiation | Drug: temozolomide<br>* Temozolomide (concurrent with radiation) 75 mg/m2 PO 3 weeks once a day, daily, from the first day to the last day of radiotherapy, but for no longer than 28 days, and then adjuvantly for up to 12 cycles (150 mg/m2 for the first 5 days of each cycle). Adjuvant TMZ may be escalated to 200mg/m2 in C2 onward if appropriate.<br>Genetic: DNA methylation analysis<br>* A stratified log-rank test, adjusting for the stratification factors (except centre) plus MGMT promoter methylation status, will be used as the primary method to compare the overall survival between the two arms<br>Procedure: quality-of-life assessment<br>* prior to randomization until end of study<br>|
| Active Comparator: Radiation<br>Short course radiation alone | Genetic: DNA methylation analysis<br>* A stratified log-rank test, adjusting for the stratification factors (except centre) plus MGMT promoter methylation status, will be used as the primary method to compare the overall survival between the two arms<br>Procedure: quality-of-life assessment<br>* prior to randomization until end of study<br>Radiation: Radiation<br>* Short course radiotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from date of randomization to the date of death of any causes, or censored at last known alive date. | 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Time from date of randomization to the date of disease progression or death whichever came first, or censored at last disease assessment date. | 7 years | 
| Adverse Events | Evaluated according to CTCAE V3.0 | 7 years | 
| Methylation Status of the O6-methylguanine-DNA Methyltransferase Promoter | Overall survival for patients by Methylation status of the O6-methylguanine-DNA methyltransferase promoter | 7 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma