PHILADELPHIATemozolomide (Temodar) appears to be an effective, well-tolerated oral agent in the setting of recurrent malignant glioma. Further testing is clearly warranted in this patient population, and it is an attractive candidate to be evaluated in the adjuvant setting for newly diagnosed patients, said Michael D. Prados, MD, of the Brain Tumor Research Center, University of California, San Francisco.
Speaking at the 90th annual meeting of the American Association for Cancer Research, Dr. Prados reported the results of two major US phase II multicenter clinical trials. Temozolomide, he said, is a new orally administered second-generation imidazotetrazine prodrug with essentially 100% bioavailability. In preclinical testing, a broad spectrum of activity was noted that was schedule dependent, with little toxicity.
The studies, Dr. Prados said, enrolled patients with glioblastoma multiforme or anaplastic astrocytoma at the time of initial relapse following standard treatment with surgery and external beam radiotherapy. The primary objective was to evaluate progression-free survival at 6 months and the safety of the drug given over 5 days every 4 weeks, he said. Both studies had quality of life assessments that included the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the Brain Cancer Module 20 (BCM20).
Study C94-091, a multicenter, randomized, open-label phase II study, compared temozolomide(Drug information on temozolomide) and procarbazine(Drug information on procarbazine) (Matulane) in the treatment of patients with glioblastoma multiforme at first relapse. It included 225 patients with glioblastoma multiforme who were randomized to temozolomide or procarbazine. Temozolomide was given orally at 200 mg/m²/day or 150 mg/m²/day if prior chemotherapy had been given, for 5 days every 28 days. Procarbazine was given orally at 150 mg/m²/day or 125 mg/m²/day if prior chemotherapy had been given, for 28 days every 56 days.
The results favored temozolomide, Dr. Prados said. Six-month progression-free survival was significantly higher for patients who received temozolomide (21%) than for those who received procarbazine (8%) (P = .008). Median progression-free survival was 12.4 weeks for temozolomide vs 8.32 weeks for procarbazine (P = .0063). The 6-month overall survival rate also favored temozolomide (60% vs 44%, P = .019).
Study CI94-123 was a single-arm, multicenter, open-label phase II trial of temozolomide in patients with anaplastic astrocytoma at first relapse. Temozolo-mide was given orally at 200 mg/m²/day or 150 mg/m²/day if prior chemotherapy had been given, for 5 days every 28 days. The intent-to-treat analysis included 162 patients, and the results include all patients enrolled. After central pathology review, 111 patients were confirmed to have the correct histology.
Progression-free survival at 6 months, was 46%. Median progression-free survival was 5.4 months, and 24% of patients remained progression free at 12 months. The objective response rate was 35% (8% complete response, 27% partial response), with 27% of patients achieving a stable disease classification.
In both studies, temozolomide toxicity was acceptable, with only mild to moderate degrees of severity, Dr. Prados said. In addition, the maintenance of progression-free survival and objective response was associated with stable or improved quality of life as measured by the EORTC QLC-C30 and BCM20 questionnaires.
Ongoing or planned studies of temozolomide in patients with recurrent malignant gliomas are using the agent in combination with nitrosoureas, platinum, and other agents. In addition, there are plans to bring the drug up front in the adjuvant setting with a large phase III study in newly diagnosed anaplastic astrocytomas, Dr. Prados said.