Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for muscle-invasive bladder cancer (MIBC): Japan Clinical Oncology Group study, JCOG0209

4526 Background: Cisplatin-based NAC for patients (pts) with MIBC is considered to provide a 5–8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, MIBC (T2-4aN0M0) within 8 weeks from TURBT, PS 0-1, and age 20-75 years old. Patients were randomized to receive 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), surgery-related complications, adverse events during NAC, the percent with no residual tumor in the RC specimens (pT0), and QOL. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a 7% difference in 5-year OS, 45% in the RC arm, and 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n=64) and RC arm (n=66). Fifty-nine patients in the NAC arm and 65 in the RC arm underwent cystectomy. The patient registration was terminated early because of slow accrual. At the 2nd interim analysis conducted after the completion of patient accrual, OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19-2.18; one-sided log-rank p = 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. PFS of the NAC arm was better than that of the RC arm (HR, 0.61; 95% CI, 0.35-1.06, one-sided log-rank p=0.04). No differences in perioperative complications, other than lymph leakage, were observed between the arms. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (p