A PHASE-III RANDOMIZED PROSPECTIVE TRIAL OF EXTERNAL-BEAM RADIOTHERAPY, MITOMYCIN-C, CARMUSTINE, AND 6-MERCAPTOPURINE FOR THE TREATMENT OF ADULTS WITH ANAPLASTIC GLIOMA OF THE BRAIN

Purpose: This study was designed to evaluate strategies to overcome th e resistance of anaplastic gliomas of the brain to external beam radio therapy (ERT) plus carmustine (BCNU). Patients were greater than or eq ual to 15 years of age, had a histologic diagnosis of malignant glioma , and a Karnofsky performance status (KPS) greater than or equal to 60 %. Methods and Materials: In Randomization 1, patients were assigned t o receive either ERT alone (61.2 Gy) or ERT plus mitomycin C(Mito, IV 125 mg/m(2)) during the first and fourth week of ERT. After this treat ment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6 -mercaptopurine (6-MP, 750 mg/m(2) IV daily for 3 days every 6 weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-fo ur received ERT alone, and 163 received ERT + Mito [average age 52.7 S ears; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection ; 56% KPS greater than or equal to 90%]. Step-wise analysis of surviva l from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age greater than or equal to 45 years (b) KPS < 90% ; (C) GBM/Gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in bot h arms (ERT + Mito) was 10.8 months. Median survival from Randomizatio n 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histol ogies other than GBM/GS. Two hundred and thirty-three patients underwe nt Randomization 2. The proportion of patients in the ERT group who te rminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). Conclu sions: (a) The addition of Mito to ERT had no impart on survival; (b) patients treated with ERT + Mito were at greater risk of terminating t herapy prior to Randomization 2; (c) there was not a significant survi val benefit to the addition of 6-MP to BCNU.