title: Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.
abstract: Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.
authors.affiliation: Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gururangan
authors.forename: L
authors.initials: L
authors.lastname: Cokgor
authors.forename: J N
authors.initials: JN
authors.lastname: Rich
authors.forename: S
authors.initials: S
authors.lastname: Edwards
authors.forename: M L
authors.initials: ML
authors.lastname: Affronti
authors.forename: J A
authors.initials: JA
authors.lastname: Quinn
authors.forename: J E
authors.initials: JE
authors.lastname: Herndon
authors.forename: J M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: R E
authors.initials: RE
authors.lastname: McLendon
authors.forename: S
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: J H
authors.initials: JH
authors.lastname: Sampson
authors.forename: V
authors.initials: V
authors.lastname: Stafford-Fox
authors.forename: S
authors.initials: S
authors.lastname: Zaknoen
authors.forename: M
authors.initials: M
authors.lastname: Early
authors.forename: A H
authors.initials: AH
authors.lastname: Friedman
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage* / Q000009:adverse effects; D015331:Cohort Studies; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012449:Safety; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D004343:Drug Implants; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide