Bladder cancer "adjuvant-lite": tastes great (works as well) and less filling (less toxic)?

In this issue, Lehmann et al 1 report that cisplatin plus methotrexate (CM) is not inferior to methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC) in the adjuvant treatment of patients with locally advanced bladder cancer after surgery. The report suggests a possible new standard of care. Do the data support this conclusion? To answer that question, a short review of pre-existing data and statistics is needed. One prerequisite for evaluating treatments in the perioperative setting is the demonstration of efficacy in advanced disease. The rationale has been that regimens meeting such a milestone may be incrementally more effective when the tumor is microscopic, exploiting the enhanced sensitivity of rapidly proliferating cells. This has been the evolution of treatment for transitional-cell carcinoma (TCC) of the bladder. In advanced disease, carefully conducted phase II studies showed transient partial responses with single agents in the 1970s; durable complete remissions were demonstrated when effective agents were combined in three- and four-drug combinations in the 1980s; and prospective randomized comparisons of these combinations provided evidence for survival benefits in the 1990s. In individual trials, methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) conferred a survival benefit compared with single-agent cisplatin and cisplatin, doxorubicin, and cyclophosphamide 2,3 ; and cisplatin, methotrexate, and vinblastine (CMV) demonstrated a survival benefit compared with methotrexate and vinblastine. 4 These results established M-VAC and CMV as treatment standards for patients with metastatic disease. In the new millennium, adequately powered prospective randomized trials with sufficient follow-up of M-VAC and CMV as neoadjuvant therapy were reported, demonstrating survival benefits compared with no chemotherapy and establishing neoadjuvant chemotherapy as the standard management for patients with muscle-invasive disease. In the largest trial of neoadjuvant chemotherapy in TCC, 976 patients with clinical T2-4a disease were randomly assigned to neoadjuvant CMV versus no chemotherapy, combined with cystectomy, radiation therapy, or both as management of the primary tumor. The trial, which was powered to detect an absolute improvement in survival of 10% (from 50% to 60%), was initially reported as negative. 5 However, with 7 years of follow-up, a significant reduction in the hazard ratio for death was observed for the chemotherapy-treated patients (hazard ratio 0.85; 95% CI, 0.72 to 1.0;P .048). 6 In the second trial, INT 0080, 317 patients with clinical stage T2-4a TCC were randomly assigned to receive three cycles of neoadjuvant M-VAC followed by radical cystectomy or radical cystectomy alone. 7 This trial was powered to detect a 50% improvement in median survival with the combined approach. With a median follow-up of almost 9 years, a 21-month difference was observed for chemotherapy-treated patients versus patients who did not receive chemotherapy (77v 46 months, respectively; P .06). The absolute survival benefit at 5 years was 14%, and the hazard ratio for survival was 0.75 (95% CI, 0.57 to 1.0), favoring the neoadjuvant arm. Given these results, why isn’t the neoadjuvant approach practiced more widely? There are several reasons. First, the inaccuracies of clinical staging make the assessment of which patients are destined to metastasize and who, thus, need systemic therapy to achieve cure less precise. Second, the delay in definitive therapy in patients who do not respond to treatment raises concerns regarding compromise of curability. Third, the development of internal urinary reservoirs makes the objective of bladder preservation less tenable for the majority of patients. These factors have led many urologists and urologic oncologists to adopt a treatment policy in which the recommendation for