Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse

Background: Recurrent glioblastoma multiforme (GBM) is resistant to most th erapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. Patients and methods: We report an open-label, uncontrolled, multicenter ph ase II trial of temozolomide in 138 patients (intent-to-treat [ITT] populat ion) with glioblastoma multiforme at first relapse and a Karnofsky performa nce status (KPS) greater than or equal to 70. One hundred twenty-eight pati ents were histologically confirmed with GBM or gliosarcoma (GS) by independ ent central review. Chemotherapy-naive patients were treated with temozolom ide 200 mg/m(2)/day orally for the first five days of a 28-day cycle. Patie nts previously treated with nitrosourea-containing adjuvant chemotherapy re ceived 150 mg/m(2)/day for the first five days of a 28-day cycle. In the ab sence of grade 3 or 4 toxicity, patients on the 150 mg/m(2) dose schedule w ere eligible for a 200 mg/m(2) dose on the next cycle. Results: The primary endpoint was six-month progression-free survival asses sed with strict radiological and clinical criteria. Secondary endpoints inc luded radiological response and Health-related Quality of Life (HQL). Progr ession-free survival at six months was 18% (95% confidence interval (CI): 1 1%-26%) for the eligible-histology population. Median progression-free surv ival and median overall survival were 2.1 months and 5.4 months, respective ly. The six-month survival rate was 46%. The objective response rate (compl ete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for b oth the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively asse ssed response and maintenance of a progression-free status were both associ ated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of th erapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. Conclusions: Temozolomide demonstrated modest clinical efficacy, with an ac ceptable safety profile and measurable improvement in quality of life in pa tients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.