Brain and Central Nervous System Tumors
Conditions
Keywords
adult anaplastic astrocytoma, adult mixed glioma
Brief summary
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
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.
Interventions
DRUGBCNU 80mg/m2
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).
DRUGTMZ 200mg/m2
200 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat every 28 days for a total of 12 cycles.
RADIATIONradiation therapy
1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.
DRUGCCNU
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.
DRUGBCNU 150mg/m2
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).
DRUGBCNU 200mg/m2
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).
DRUGTMZ 150mg/m2 six 6-week cycles
150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 6-week cycles
DRUGTMZ 150mg/m2 six 8-week cycles
150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 8-week cycles
Sponsors
National Cancer Institute (NCI)
North Central Cancer Treatment Group
Eastern Cooperative Oncology Group
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I (sequential) followed by phase III (parallel)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| (Phase III) Overall Survival (OS) | 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. | 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. |
| (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | From start of treatment to 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (Phase III) Time to Tumor Progression (TTP) | 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. | 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. |
| (Phase III) Number of Patients With Grade 3 or Higher Toxicity | 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. | 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. |
| (Phase III) Survival Time by MGMT Status | 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. | 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. |
| (Phase III) Progression-free Survival by MGMT Status | 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. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radiation Therapy + Temozolomide (TMZ) Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles | 97 |
| RT + BCNU/CCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles | 99 |
| Pilot Arm #1: RT+TMZ+BCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles | 15 |
| Pilot Arm #2: RT+TMZ+BCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles | 14 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Radiation Therapy + Temozolomide (TMZ) | RT + BCNU/CCNU | Pilot Arm #1: RT+TMZ+BCNU | Pilot Arm #2: RT+TMZ+BCNU | Total |
|---|---|---|---|---|---|
| Age, Continuous | 42 years | 43 years | 48 years | 41 years | 43 years |
| Sex: Female, Male Female | 42 Participants | 47 Participants | 5 Participants | 6 Participants | 100 Participants |
| Sex: Female, Male Male | 55 Participants | 52 Participants | 10 Participants | 8 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 94 / 96 | 95 / 99 | 14 / 15 | 13 / 13 |
| serious Total, serious adverse events | 43 / 96 | 72 / 99 | 8 / 15 | 11 / 13 |
Outcome results
Primary
(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.
Time frame: 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.
Population: Eligible randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Overall Survival (OS) | 3.9 years |
| RT + BCNU/CCNU | (Phase III) Overall Survival (OS) | 3.8 years |
Comparison: The hypothesized median survival time was 36 months for the RT+BCNU/CCNU arm and 54 months for the RT+TMZ arm, corresponding to a hazard ratio (HR) of 0.67. A sample size of 216 evaluable patients per arm would provide 90% power with a one-sided significance level of 0.05. The final analysis was planned after 155 deaths were observed. Interim efficacy analyses were planned after 52 and 104 deaths, with an interim futility analysis planned at 128 deaths.p-value: 0.3695% CI: [0.67, 1.32]Log Rank
Primary
(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.
Time frame: From start of treatment to 3 months
Population: Eligible patients who started study treatment on Pilot Arms 1 and 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | Subjects with Pulmonary DLT | 1 Participants |
| Radiation Therapy + Temozolomide (TMZ) | (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | Subjects with Hematologic DLT | 4 Participants |
| RT + BCNU/CCNU | (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | Subjects with Pulmonary DLT | 0 Participants |
| RT + BCNU/CCNU | (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms | Subjects with Hematologic DLT | 3 Participants |
Secondary
(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.
Time frame: 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.
Population: Eligible randomized patients who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Number of Patients With Grade 3 or Higher Toxicity | Non-hematologic toxicity | 31 participants |
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Number of Patients With Grade 3 or Higher Toxicity | Overall toxicity | 46 participants |
| RT + BCNU/CCNU | (Phase III) Number of Patients With Grade 3 or Higher Toxicity | Non-hematologic toxicity | 34 participants |
| RT + BCNU/CCNU | (Phase III) Number of Patients With Grade 3 or Higher Toxicity | Overall toxicity | 75 participants |
Comparison: Overall toxicityp-value: <0.001Chi-squared
Comparison: Non-hematologic toxicityp-value: 0.76Chi-squared
Secondary
(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.
Time frame: 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.
Population: Eligible patients with MGMT data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Progression-free Survival by MGMT Status | 4.0 years |
| RT + BCNU/CCNU | (Phase III) Progression-free Survival by MGMT Status | 2.1 years |
p-value: 0.4195% CI: [0.7, 2.35]Log Rank
Secondary
(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.
Time frame: 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.
Population: Eligible patients with MGMT data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Survival Time by MGMT Status | 7.2 years |
| RT + BCNU/CCNU | (Phase III) Survival Time by MGMT Status | 3.1 years |
p-value: 0.0895% CI: [0.93, 3.4]Log Rank
Secondary
(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.
Time frame: 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.
Population: Eligible randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation Therapy + Temozolomide (TMZ) | (Phase III) Time to Tumor Progression (TTP) | 45.4 months |
| RT + BCNU/CCNU | (Phase III) Time to Tumor Progression (TTP) | 54.7 months |
p-value: 0.4695% CI: [0.55, 1.16]Gray's test