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 the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were ≥ 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KIPS) ≥ 60%. Methods and Materials: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m²) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m²) given at 6-week intervals or 6- mercaptopurine (6-MP, 750 mg/m² 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-four received ERT alone, and 163 received ERT + Mito [average age 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS ≥ 90%]. Step- wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age ≥ 45 years (b) KIPS < 90%; (c) GBM/Gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 93 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). Conclusions: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit in the addition of 6-MP to BCNU.