title: Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.
abstract: OBJECTIVE
  We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas.
  
  
  METHODS
  Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals.
  
  
  RESULTS
  Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug.
  
  
  CONCLUSIONS
  These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.
authors: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. quinn008@mc.duke.edu
authors: Jennifer A
authors: JA
authors: Quinn
authors: James
authors: J
authors: Pluda
authors: M Eileen
authors: ME
authors: Dolan
authors: Shannon
authors: S
authors: Delaney
authors: Richard
authors: R
authors: Kaplan
authors: Jeremy N
authors: JN
authors: Rich
authors: Allan H
authors: AH
authors: Friedman
authors: David A
authors: DA
authors: Reardon
authors: John H
authors: JH
authors: Sampson
authors: O Michael
authors: OM
authors: Colvin
authors: Michael M
authors: MM
authors: Haglund
authors: Anthony E
authors: AE
authors: Pegg
authors: Robert C
authors: RC
authors: Moschel
authors: Roger E
authors: RE
authors: McLendon
authors: James M
authors: JM
authors: Provenzale
authors: Sridharan
authors: S
authors: Gururangan
authors: Sandra
authors: S
authors: Tourt-Uhlig
authors: James E
authors: JE
authors: Herndon
authors: Darell D
authors: DD
authors: Bigner
authors: Henry S
authors: HS
authors: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006147:Guanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D009607:Nitrosourea Compounds; C064976:O(6)-benzylguanine; D006147:Guanine; D002330:Carmustine