title: Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.
abstract: OBJECTIVE
  This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy.
  
  
  METHODS
  This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS.
  
  
  RESULTS
  Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%).
  
  
  CONCLUSIONS
  The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.
authors.affiliation: Department of Surgery, Pathology, Biostatistics, and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA. seagr003@mc.duke.edu
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: Sara Xiaoyin
authors.initials: SX
authors.lastname: Jiang
authors.forename: James
authors.initials: J
authors.lastname: Carter
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Stevie
authors.initials: S
authors.lastname: Threatt
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002330:Carmustine; D003652:Decanoic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011091:Polyesters / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D003652:Decanoic Acids; D011091:Polyesters; C064976:O(6)-benzylguanine; D006147:Guanine; C055401:decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine