Multi-Institutional Trial of BID Regimen of Temozolomide for Recurrent Malignant Gliomas.

Casilda Balmaceda, C De Rosa, K Peterson, D Peerboom, J Alavi, M Fetell, H Krouwer, S Panullo, E Bagiella, S Weaver, L McAllister, L Heller, R Fine, Columbia-Presbyterian Medical Center, New York, NY; Stanford University, Stanford, CA; Cleveland Clinic, Cleveland, OH; Hospital of the University of Pennsylvania, Philadelphia, PA; Froedert Memorial Lutheran Hospital, Milwaukee, WI; Staten Island University Hospital, Staten Island, NY; Albany Medical College, Albany, NY; The Neurological Clinic, Portland, OR; Integrated therapeutics, Kenilworth, NJ.

Presented at the American Society Of Clinical Oncology, 2001 Conference

Background: Temozolomide has shown activity against recurrent gliomas. Phase II studies have used 150 - 200 mg/m2/day x 5 days. Toxicity was mild, but responses were short. Alternative dosing schedules are being explored. A mechanism of resistance is elevated levels of O6-alkylguanine alkyltransferase (AGAT). Gerson speculated that a BID regimen could lead to a dose-dependent AGAT depletion and higher drug effectiveness. This is the first BID protocol of Temozolomide for malignant gliomas.
Methods: Eligible pts received an oral bolus of 200 mg/m2 followed by nine doses of 90 mg/m2 every 12 hours. Cycles were repeated every 28 days. Response was assessed by MRI every 2 cycles.
Results: 63 pts (33 M, 30 F) have been enrolled to date; clinical characteristics are available for 56. Median age was 47 years (25 -75). Pathology included: glioblastoma multiforme (GBM = 31), anaplastic oligodendroglioma (13), and anaplastic astrocytoma (AA = 12). 34/56 pts had received prior chemotherapy. Of 170 evaluable cycles, grade III-IV leukopenia and thrombocytopenia were noted in 5% and 9 % of the cycles, respectively. One pt died from staph aureus septicemia. Toxicity ussually resolved following dose reduction. No correlation was found between hematologic toxicity and prior chemotherapy. Of 44 evaluable pts, response at 2 cycles was: CR (5%), PR (20%) and SD (52%). Overall response rate at 2 cycles was 77%. 4% of the pts with GBM and 9% of those with AA had CR. 4 pts had SD on MRI, but MR spectroscopy showed choline peak normalization as compared to baseline. Median progression-free survival was 5.5 months ( 3.18-7.65, 95% CI).
Conclusions: A BID regimen of Temozolomide is tolerated well by most pts. Hematologic toxicity was mild and did not recur following dose reduction. Response rates are promising. MR spectroscopy may provide additional information in the evaluation of response.

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