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Phase II study of salvage therapy with high-dose tamoxifen and oral etoposide for recurrent malignant glioma

Susan M Chang, Kathleen R Lamborn, Mary Malec, Jane Rabbitt, Margaretta Page and Michael D Prados

Background: Salvage chemotherapy regimens for patients with recurrent glioma are limited in their efficacy. Reports of antitumor activity of the oral agents etoposide (VP-16^®, Immunex Corporation) and high-dose tamoxifen (Nolvadex^®, AstraZeneca) prompted this Phase II study. Tamoxifen and etoposide may be synergistic in their antitumor effects. Both agents are administered orally, are well tolerated individually and do not have overlapping toxicities. We report the results of a Phase II study of this combination as salvage therapy for patients with recurrent glioma. Methods: Patients received tamoxifen at an escalating dose from 120 mg/day to 240 mg/day over a 1-week period, after which time etoposide 50 mg/m2/day for 3 weeks was added to the regimen. Patients remained on tamoxifen continuously and the etoposide was repeated after a 2-week break. This 10-week cycle was repeated until tumor progression or unacceptable toxicity occurred. Response assessments using neuroradiographic imaging and clinical evaluation were performed every 10 weeks. Results: A group of 40 patients (31 males) were treated with this protocol. The median age was 45 years (range 17–71 years) and the median Karnofsky performance status was 80. Of these patients, 17 had glioblastoma multiforme, 14 had a Grade 3 tumor, eight had a Grade 2 tumor and one patient’s tumor type was not specified. Patients represented a heavily pretreated group, with 35% having received two prior chemotherapy regimens and 60% having received at least three prior regimens. There was one complete, three partial and seven stable disease responses (total 27%). Median time to tumor progression was 2 months (approximately 1.4–2.3) and median survival for the cohort was 5 months (approximately 4.4–8.8). Three patients were alive at last contact beyond 3 years (two anaplastic astrocytoma and one oligoastrocytoma). The 6-month progression-free survival was 10%. Treatment was well tolerated, with no Grade 3 or 4 hematologic toxicities observed. Conclusion: This drug combination was well tolerated but had limited efficacy in this group of heavily pretreated patients with recurrent glioma.