title: A phase II study of cisplatin preceded by a 12-h continuous infusion of concurrent hydroxyurea and cytosine arabinoside (Ara-C) for adult patients with malignant gliomas (Southwest Oncology Group S9149).
abstract: Inhibition of DNA excision repair can modulate resistance to cisplatin. Cytosine arabinoside (Ara-C) and hydroxyurea (HU), in combination, inhibit the excision-repair system and removal of platinum-DNA adducts. Marked cytotoxic synergy had been demonstrated in vitro at clinically achievable levels. The three-drug regimen was found to be feasible in clinical pilot studies. A Phase II study in patients with relapsed or progressive anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) was performed in the Southwest Oncology Group. The primary end point was 6 month survival, historically about 42%. A loading dose of HU 1,260 mg/m2 IV over 1 h was followed by Ara-C 1,200 mg/m2 plus HU 5,040 mg/m2 IV over 12 h, followed by cisplatin 100 mg/m2 IV over 1 h. A total of 76 patients were registered. The GBM stratum registered 56 patients in a two-stage accrual. Among 51 eligible GBM patients, the 6-month survival probability was 41% (95% CI 28-55%), and median overall survival was 5 months (95% CI 4-6 months). The 6-month progression-free survival probability was 25% (95% CI 14-37%), and median progression-free survival was 2 months (95% CI 2-4 months). One patient achieved a partial response (2%, 95% CI 0-10%), 13 patients had stable disease (25%, 95% CI 14-39%). Twenty-two patients progressed, and 14 were not assessable for response. The AA stratum was closed early after 20 patients due to slow accrual. Among 19 eligible patients, the 6-month survival probability was 58% (95% CI 36-80%), and median overall survival was 7 months (95% CI 7-14 months). The 6-month progression-free survival probability was 26% (95% CI 6-46%), and median progression-free survival was 3 months (95% CI 2-5 months). No responses were seen. Six patients (32%) had stable disease (95% CI 13-57%), 11 progressed, and 2 were not assessable for response. Of the 70 patients evaluable for toxicity, two died of infection. Twenty-three patients (33%) experienced Grade 4 toxicities, primarily hematological. Cisplatin combined with HU and Ara-C did not improve the 6 month survival rate in patients with relapsed or progressive AA or GBM. Significantly more hematological toxicity was seen than expected from cisplatin alone. Although benefit might be possible in a more platinum-sensitive tumor type, further clinical trials with this regimen for patients with glioblastoma multiforme or anaplastic astrocytoma are not justified.
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, CRB 2M88, 1650 Orleans Street, Baltimore, MD 21231, USA. lswinne1@jhmi.edu
authors.forename: Lode J
authors.initials: LJ
authors.lastname: Swinnen
authors.forename: Cathryn
authors.initials: C
authors.lastname: Rankin
authors.forename: Hetty
authors.initials: H
authors.lastname: Carraway
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Jeannette J
authors.initials: JJ
authors.lastname: Townsend
authors.forename: George Thomas
authors.initials: GT
authors.lastname: Budd
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kish
authors.forename: Saul E
authors.initials: SE
authors.lastname: Rivkin
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Blumenthal
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000627:therapeutic use*; D003561:Cytarabine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D002945:Cisplatin