Radiation Therapy Combined With Chemotherapy in Treating Patients With Anaplastic Astrocytoma or Mixed Gliomas

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as temozolomide, carmustine, and lomustine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy may kill more tumor cells. PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared to radiation therapy and carmustine or lomustine in treating patients with anaplastic astrocytoma or mixed gliomas.

Detailed Description
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OBJECTIVES: Compare the overall survival and time to tumor progression in patients with anaplastic astrocytoma or mixed gliomas treated with radiotherapy combined with temozolomide vs carmustine or lomustine vs temozolomide and carmustine (arm discontinued as of 8/15/02). Compare the relative toxic effects of these regimens in these patients. Correlate molecular analyses with overall survival and time to tumor progression in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 50 vs 50 and over), Karnofsky performance status (60-80% vs 90-100%), and prior surgery (biopsy only vs resection). Phase I Pilot Arms I and II: Prior to initiating the randomization to 1 of 3 treatment arms in phase III, Patients are accrued to Arm III regimen to determine tolerability. Phase III Patients are randomized to 1 of 2 treatment arms (3rd arm was dropped). Arm I: Patients undergo radiotherapy 5 days a week for 6 weeks. Patients receive oral temozolomide on days 1-5 of the first week of radiotherapy. Chemotherapy repeats every 4 weeks for a total of 12 courses. Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 1-2 hours on days 1-3 of the first week of radiotherapy and a second course on days 56-58. Chemotherapy repeats every 8 weeks for a total of 6 courses. Arm III (dropped, did not open): Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 3 hours on day 5 and oral temozolomide (2 hours after completion of carmustine or lomustine infusion) on days 1-5 of the first week of radiotherapy. Combination chemotherapy repeats every 8 weeks for 6 courses. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: Phase I: 30 patients; Phase III: 454 patients (227 per treatment arm) within 4 years.

Official Title
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A Phase III Randomized Study (Phase I Closed) of Radiation Therapy and Temozolomide Versus Radiation Therapy and Nitrosourea for Anaplastic Astrocytoma And Mixed Anaplastic Oligoastrocytoma (Astrocytoma Dominant)

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: BCNU 80mg/m2
* Drug: TMZ 200mg/m2
* Radiation: radiation therapy
* Drug: CCNU
* Drug: BCNU 150mg/m2
* Drug: BCNU 200mg/m2
* Drug: TMZ 150mg/m2 six 6-week cycles
* Drug: TMZ 150mg/m2 six 8-week cycles


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven unifocal anaplastic astrocytoma or mixed gliomas, including the following: Anaplastic astrocytoma Mixed oligodendroglial/astrocytic tumors Oligodendroglial component must be no greater than 25% No vascular proliferation and necrosis Increased cellularity, pleomorphism, and nuclear atypia allowed No tumor predominantly located in the posterior fossa (i.e., brainstem or cerebellum) Patients with prior biopsy proven low grade astrocytoma who now have anaplastic astrocytoma and have had no prior radiotherapy or chemotherapy also eligible Study therapy must begin within 6 weeks of diagnosis No spinal cord tumors, spinal drop metastases, or metastases to noncontiguous meninges Pathologic evidence of local meningeal infiltration by underlying tumor allowed PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 60-100% Life expectancy: At least 1 year Hematopoietic: Hemoglobin at least 10 g/dL Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 150,000/mm^3 Hepatic: Bilirubin less than 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) less than 2 times ULN Alkaline phosphatase less than 2 times ULN Renal: Blood urea nitrogen no greater than 25 mg/dL Creatinine less than 1.5 times normal Pulmonary: No pre-existing lung disease that, in the investigator's opinion, would preclude administration of carmustine or lomustine or completion of therapy Other: No other major medical illness or psychiatric impairment that would preclude study compliance No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix No known hypersensitivity to 1 of the components of carmustine, lomustine, temozolomide, dacarbazine, or any other nitrosourea No active infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: No prior biologic therapy Chemotherapy: See Disease Characteristics No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: See Disease Characteristics No prior radiotherapy to brain or head and neck Surgery: Not specified Other: No other concurrent anticancer treatment for anaplastic astrocytoma until a recurrence is detected

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase I (sequential) followed by phase III (parallel)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation therapy + temozolomide (TMZ)<br>Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles | Drug: TMZ 200mg/m2<br>* 200 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat every 28 days for a total of 12 cycles.<br>Radiation: radiation therapy<br>* 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.<br>|
| Active Comparator: RT + BCNU/CCNU<br>Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles | Drug: BCNU 80mg/m2<br>* BCNU 80 mg/m2 will be administered as an intravenous infusion on days 1, 2, and 3 of the first week of radiotherapy and on days 56, 57, and 58, then every eight weeks for four more cycles for a total of 6 cycles (maximum BCNU dose 1440 mg/m2).<br>Radiation: radiation therapy<br>* 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.<br>Drug: CCNU<br>* CCNU at 130 mg/m2 orally every 8 weeks for a total of 6 cycles. Administered on day 1 of the first week of radiotherapy and on day 56, then administered every 8 weeks for four more cycles for a total of 6 cycles.<br>|
| Experimental: Pilot Arm #1: RT+TMZ+BCNU<br>Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles | Radiation: radiation therapy<br>* 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.<br>Drug: BCNU 200mg/m2<br>* BCNU 200 mg/m2 will be administered as an intravenous infusion on day 1 of radiotherapy and will be repeated every six weeks for a total of 6 cycles (maximum BCNU dose 1200 mg/m2).<br>Drug: TMZ 150mg/m2 six 6-week cycles<br>* 150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 6-week cycles<br>|
| Experimental: Pilot Arm #2: RT+TMZ+BCNU<br>Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles | Radiation: radiation therapy<br>* 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.<br>Drug: BCNU 150mg/m2<br>* BCNU 150 mg/m2 will be administered as an intravenous infusion on day 5 of radiotherapy, and it will be repeated every eight weeks for a total of six cycles (maximum total BCNU dose 900 mg/m2).<br>Drug: TMZ 150mg/m2 six 8-week cycles<br>* 150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 8-week cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase III) Overall Survival (OS) | Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Per the protocol, the pilot arms were not included in the Phase III analyses. | From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. | 
| (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the adverse event (AE). The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Dose limiting toxicity (DLT) was defined as grade 3+ pulmonary toxicity, grade 4+ thrombocytopenia (< 25,000 for 5 days), neutropenia (< 500/microl for 7 days), or neutropenia of any duration with fever requiring hospital admission after one dose reduction of 50% in BCNU. A 20% rate of grade 3+ pulmonary toxicities or a 40% rate of grade 4+ thrombocytopenia and neutropenia was considered unacceptable for a treatment arm combining RT, TMZ, and BCNU. | From start of treatment to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase III) Time to Tumor Progression (TTP) | Three-year rate is reported. Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Time to tumor progression was estimated using the cumulative incidence function (CIF) on tumor progression, with death as a competing risk. Per the protocol, the pilot arms were not included in the Phase III analyses. | From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. | 
| (Phase III) Number of Patients With Grade 3 or Higher Toxicity | Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the AE. The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The number of patients with grade or higher toxicity was calculated overall and for non-hematologic toxicity only. Per the protocol, the pilot arms were not included in the Phase III analyses. | From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. | 
| (Phase III) Survival Time by MGMT Status | Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated. | From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. | 
| (Phase III) Progression-free Survival by MGMT Status | Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Progression-free survival time is defined as time from randomization to date of progression or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated. | From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult anaplastic astrocytoma, adult mixed glioma