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)

Lode J. Swinnen, Cathryn Rankin, Hetty Carraway, Kathy S. Albain, Jeannette J. Townsend, George Thomas Budd, Julie A. Kish, Saul E. Rivkin, Deborah T. Blumenthal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)353-358
Number of pages6
JournalJournal of neuro-oncology
Volume86
Issue number3
DOIs
StatePublished - Feb 2008

Keywords

  • Cisplatin
  • DNA excision repair
  • Drug resistance
  • Glioma

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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