ACNU-cisplatin continuous infusion chemotherapy as salvage therapy for recurrent glioblastomas: phase II study

Purpose: To evaluate the activity and the toxicity of ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-cholroethyl)-3-nitrosourea hydrochloride) administered with cisplatin by intravenous infusion for 72 h in select patients with recurrent glioblastoma. Patients and methods: From April 1996 to 2002, 37 patients with histologically proven glioblastoma, who showed recurrence on image study after operation and radiation, met the eligibility criteria of our cohort. The mean time to recurrence was 9.7 +/- 7.0 (1-26 months). Treatment response was evaluated every 6 weeks using magnetic resonance imaging (MRI). Complete blood counts were collected every week to monitor and treat possible bone marrow suppression from the treatment. Survival rates were analyzed using the Kaplan-Meier and log rank test. Results: Post-chemotherapy MRI was available in 36 of 37 patients. Response to treatment was observed in 19 patients (53%) including two cases of complete remission. Six patients (17%) showed progression (PD) and 11 patients (31%) had stable disease (SD). Two or more cycles of chemotherapy was the only factor that predicted response to treatment. The overall median survival for all patients was 17.0 +/- 5.5 months. Age (<40 years) and time to recurrence (>= 1 year) were the clinical factors that predicted improved overall survival. Survival gain after chemotherapy was 9 months. Patients who responded and those with SD after treatment (11 months) had a longer median survival compared to PD (5 months) (P=0.01). Myelosuppression was severe (grade III/IV leukopenia in 15 patients (40%) and grade III/IV thrombocytopenia in 19 patients (52%)) but most recovered more than WHO grade II at the end of the chemotherapy cycles. There was only one fatality due to sepsis from pneumonia during the initial leukopenic state. Conclusion: ACNU and cisplatin chemotherapy can be an effective salvage therapy for recurrent glioblastoma patients. Myelosuppression from the chemotherapy regimen was the greatest side-effect but was manageable.