ESCALATED DOSAGES OF METHOTREXATE, VINBLASTINE, DOXORUBICIN, AND CISPLATIN PLUS RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR IN ADVANCED UROTHELIAL CARCINOMA - AN EASTERN-COOPERATIVE-ONCOLOGY-GROUP TRIAL

Purpose: This multicenter cooperative group phase I/II trial evaluated the toxicity and efficacy of escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) with recombinant human granulocyte colony- stimulating factor (rhG-CSF) in patients with advanced urothelial carcinoma. Patients and Methods: From November 1990 through October 1991, 35 patients with advanced urothelial cancer previously untreated with chemotherapy were treated with escalated dosages of M-VAC (M-VAC(II)). In patients with prior pelvic radiotherapy, standard M-VAC (M-VAC(II)) was administered plus rhG- CSF. For other patients, M-VAC(II) dosages were methotrexate 40 mg/m2 (days 1, 15, and 22), vinblastine 4 mg/m2 (days 2, 15, and 22), doxorubicin 40 mg/m2 (day 2), and cisplatin 100 mg/m2 (day 2). In addition, rhG-CSF was administered at a dosage of 300 μg subcutaneously on days 4 to 11. Cycles were repeated every 4 weeks. For patients who tolerated the first course of therapy, subsequent escalation by 25% of all drugs was performed. Results: Six complete responses and 15 partial responses were observed (60%; 95% confidence interval, 42% to 76%). The median duration of response was 4.6 months, and the median survival time was 9.4 months (range, 0.5 to 23.5+). Twenty-eight of 35 patients experienced grade 3 or 4 leukopenia, including 14 patients who developed fever associated with neutropenia. Eight (23%) early deaths were observed. Conclusion: This regimen (M-VAC(II)) with escalated dosages of M-VAC was associated with significant toxicity and had no apparent benefit over M-VAC(I) therapy with regard to complete response rate or survival. Further evaluation of the dose-intensity of the components of this regimen in this disease is likely to be of limited benefit to patients.