A Randomized Phase II and Pharmacokinetic Study of Dacarbazine in Patients with Recurrent Glioma |
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Authors: | Vincent Rajkumar S. Reid Joel M. Novotny Paul J. Safgren Stephanie L. Scheithauer Bernd W. Steven Johnson P. Nair Suresh Morton Roscoe F. Hatfield Alan K. Krook James E. Ames Matthew M. Buckner Jan C. |
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Affiliation: | (1) Mayo Clinic and Mayo Foundation, Rochester, MN, USA;(2) Rapid City Regional Oncology Group, Rapid City, SD, USA;(3) Geisinger Clinical Oncology Program, Danville, PA, USA;(4) Iowa Oncology Research Association CCOP, Des Moines, IA, USA;(5) Carle Cancer Center CCOP, Urbana, IL, USA;(6) Duluth CCOP, USA;(7) North Central Cancer Treatment Group, Duluth MN, USA, USA |
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Abstract: | We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750mg/m2IV day 1 every 28 days (Arm A) or DTIC 200mg/m2IV days 1–5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27–67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1–2 nausea (33%), lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazeno] imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15mMmin, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29mMmin, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule. |
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Keywords: | DTIC dacarbazine recurrent gliomas brain tumors chemotherapy glioblastoma |
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