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First-Line Chemotherapy With Cisplatin Plus Fractionated Temozolomide in Recurrent Glioblastoma Multiforme: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

From the Departments of Medical Oncology and Neurological Sciences, Azienda Ospedale-University Hospital, Padova; the Department of Radiochemotherapy, San Raffaele Hospital, Milan; and the Department of Medical Oncology, Bellaria Hospital, Bologna, Italy.

Address reprint requests to Alba A. Brandes, MD, Department of Medical Oncology-Direzione, Azienda Ospedale-Università Ospedale Busonera, Via Gattamelata 64, 35100 Padova, Italy; e-mail: aabrandes{at}unipd.it

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 O⁶-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/m² on day 1, TMZ 130 mg/m² bolus followed by nine doses of 70 mg/m² 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/m² 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% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 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% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%).

CONCLUSION: The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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