European Urology

International Collaboration of Trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, the Australian Bladder Cancer Study Group, the National Cancer Institute of Canada Clinical Trials Group, Finnbladder, Norwegian Bladder Cancer Study Group, and Club Urologico Espanol de Tratamiento Oncologico Group
J Clin Oncol 2011;29:2171–7
Experts’ summary:
The impact of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is reported with the long-term results of a previously published phase 3 trial. Between 1985 and 1995, 976 patients were randomized to receive or not receive three cycles of cisplatin, methotrexate, and vinblastine (CMV) neoadjuvant chemotherapy. Definitive local treatment included cystectomy and/or radiotherapy based on patient or physician choice. Patients were stratified by this choice.

With a median follow-up of 8 yr, median overall survival was significantly increased in chemotherapy arm from 37 to 44 mo. A significant risk reduction was reported for death (16%; hazard ratio [HR]: 0.84; 95% confidence interval [CI], 0.72–0.99; p = 0.037), corresponding to an increase in 10-yr survival from 30% to 36%; for metastases or death (23%; HR: 0.77; 95% CI, 0.66–0.90; p = 0.001); and for local disease or death (13%; HR: 0.87; 95% CI, 0.75–1.01; p = 0.067).
Experts’ comments:
Neoadjuvant or adjuvant chemotherapy can be discussed with regard to patients with localized muscle-invasive bladder carcinoma; however, the literature clearly supports the use of preoperative treatment demonstrating a survival benefit compared with surgery alone in two meta-analyses [1] and [2]. Despite these data, neoadjuvant chemotherapy meets resistance in the oncology community. This long-term analysis is one more brick in the edifice supporting this standard of care. Even if definitive treatment was based on local radiotherapy alone in nearly 50% of patients, stratification reduces the risk of bias induced by this nonoptimal local treatment. Moreover, risk reduction of death after chemotherapy was close in both groups: 20% with radiotherapy alone (p = 0.07) and 26% with surgery alone (p = 0.022).

Despite the proven survival benefit, we can ask about the choice of the CMV regimen. In the metastatic setting, the modified dose-dense (DD) methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) regimen resulted in higher response rates and a slightly better overall survival as compared to standard MVAC [3]. The efficacy of CMV and DD MVAC regimens has not been compared directly in a randomized phase 3 trial, but DD MVAC is recognized as the most effective in 2011.

Finally, we still ask the question of the optimal number of cycles: Are three cycles or more needed for the best prevention of metastatic recurrence? Nevertheless, we may assume that a supposedly even more efficient chemotherapy regimen would lead to an even greater benefit and would reinforce the positive conclusions of this trial.

Published data and the presently actualized results support neoadjuvant cisplatin-based chemotherapy before radical cystectomy and complete pelvic lymph node dissection as a standard of care. Conversely, numerous trials tried to assess the benefit of adjuvant therapy in bladder cancer, but methodologic biases do not allow the drawing of a definitive conclusion about its efficiency. However, improvement is necessary in patient selection and chemotherapy efficacy. Accordingly, biomarkers are urgently needed to determine which patients are more likely to benefit from neoadjuvant chemotherapy.

Finally, the French Genito-Urinary Tumor Group is embarking on a randomized trial comparing DD MVAC to gemcitabine and cisplatin to determine the optimal regimen to be given in the perioperative setting.

Conflicts of interest

The authors have nothing to disclose.