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

Radiation Therapy Oncology Group

Status and phase: Completed; Phase 3

Conditions: Brain and Central Nervous System Tumors

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

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00004259

NCCTG-RTOG-9813

RTOG-9813

ECOG-R9813

CDR0000067512

Details and patient eligibility

About

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.

Full 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.

Enrollment: 230 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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230 participants in 4 patient groups

Radiation therapy + temozolomide (TMZ)

Experimental group

Description:

Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles

Treatment:

Drug: TMZ 200mg/m2

Radiation: radiation therapy

RT + BCNU/CCNU

Active Comparator group

Description:

Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles

Treatment:

Drug: BCNU 80mg/m2

Drug: CCNU

Radiation: radiation therapy

Pilot Arm #1: RT+TMZ+BCNU

Experimental group

Description:

Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles

Treatment:

Drug: BCNU 200mg/m2

Radiation: radiation therapy

Drug: TMZ 150mg/m2 six 6-week cycles

Pilot Arm #2: RT+TMZ+BCNU

Experimental group

Description:

Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles

Treatment:

Drug: TMZ 150mg/m2 six 8-week cycles

Drug: BCNU 150mg/m2

Radiation: radiation therapy