title: A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma.
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 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV 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-triazenol imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, 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.
authors.affiliation: Mayo Clinic and Mayo Founccdation, Rochester, MN 55905, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: J M
authors.initials: JM
authors.lastname: Reid
authors.forename: P J
authors.initials: PJ
authors.lastname: Novotny
authors.forename: S L
authors.initials: SL
authors.lastname: Safgren
authors.forename: B W
authors.initials: BW
authors.lastname: Scheithauer
authors.forename: P S
authors.initials: PS
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Nair
authors.forename: R F
authors.initials: RF
authors.lastname: Morton
authors.forename: A K
authors.initials: AK
authors.lastname: Hatfield
authors.forename: J E
authors.initials: JE
authors.lastname: Krook
authors.forename: M M
authors.initials: MM
authors.lastname: Ames
authors.forename: J C
authors.initials: JC
authors.lastname: Buckner
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine