Stage III Bladder Cancer
A larger, randomized study, conducted by the Medical Research Council and the European Organization for Research and Treatment of Cancer, evaluated three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate administered prior to cystectomy or radiation therapy in 976 patients with stage T2 grade 3, stage T3, or stage T4a disease. Although this study demonstrated an improvement in 3-year survival from 50% in patients who received no neoadjuvant chemotherapy to 55.5% in those who had, this difference was not statistically significant (P = .075) because the study had been originally powered to detect a 10% absolute difference in survival.[Level of evidence: 1iiA] A meta-analysis of 10 randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that platinum-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P = .016). Neoadjuvant single-agent cisplatin was not associated with any such survival benefit in the meta-analysis. Based on these findings, it is reasonable to offer neoadjuvant platinum-based combination chemotherapy prior to cystectomy in patients with muscle-invasive bladder cancer. The two regimens that have been most extensively studied and show the strongest evidence of benefit in this setting are MVAC and CMV. There is no data from clinical trials demonstrating equivalent effectiveness with newer regimens such as gemcitabine and cisplatin or high-dose MVAC.
In an effort to reduce the toxic effects of platinum-based regimens given in the perioperative setting, a German multicenter study randomly assigned 327 patients with pathologic T3a-T4a and/or N+ disease after radical cystectomy to 3 cycles of cisplatin and methotrexate (CM) or three cycles of methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC). The median progression-free survival was 43.4 months in the CM arm and 49.7 months in the M-VEC arm, yielding a hazard ratio [HR] for disease progression of 1.13 (90% confidence interval [CI], 0.86–1.48). The median overall survival (OS) was 47.1 months in the CM arm and 51.8 months in the M-VEC arm, yielding an HR for death of 1.10 (90% CI, 0.88–1.44). Leukopenia was more common with the four-drug regimen, but the rates of febrile neutropenia, infection, and treatment-related deaths were the same with both regimens. This study was powered to accept as much as a 50% increase in progression-free survival as being noninferior.[Level of evidence: 1iiA]