Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: Results of a randomized, multicenter, phase III trial (AUO-AB 05/95)

Purpose: Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy. Patients and Methods: A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm² on day 1 and methotrexate 40 mg/qm² on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm² on days 1, 15, and 22, vinblastine 3 mg/qm² on days 2, 15, and 22, epirubicin 45 mg/qm ² on day 2, and cisplatin 70 mg/qm² on day 2 of a 28-day cycle (M-VEC). Results: The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (α = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates ± SE) for CM versus M-VEC were 46.3% ± 4.6% v 48.8% ± 4.5%, 52.0% ± 4.6% v 52.3% ± 4.8%, and 46.1% ± 4.3% v 45.1% ± 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001). Conclusion: CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.