First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: A phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

Purpose Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O-6-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. Patients and Methods Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. Results A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% Cl, 23% to 50%), and PFS-12 was 40%. (95% Cl, 0.3% to 16%). Median PFS was 18.4 weeks (95% Cl, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% Cl, 7.7% to 33%). Among 203 treatment cycles delivered, the most common cradle 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (16%). Conclusion The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.