Impact of adjuvant intraarterial chemotherapy on survival for patients with stage IIIA-IIIB bladder urothelial carcinoma after radical cystectomy: An open-label, prospective, randomized clinical trial.

772 Background: The aim of this trial was to evaluate the survival benefit of adjuvant intraarterial chemotherapy (IAC) in patients who received radical cystectomy (RC) and pathologically confirmed stage IIIA-IIIB bladder urothelial carcinoma. Methods: This was a multicenter, randomized study. Patients with stage IIIA-IIIB (pT3-4 or positive node) disease after RC were randomly assigned (1:1) to the IAC group or the observation group. Adjuvant IAC with cisplatin and gemcitabine (GC) was performed through a percutaneous catheter system. The GC regimen consisted of gemcitabine 800 mg/m² and cisplatin 25 mg/m² on days 1, 8, and 15 every 28 days for three cycles. The primary endpoint was recurrence-free survival (RFS). The secondary endpoint was overall survival (OS). The trial was designed to detect a 20% improvement in 5-year RFS, from 35% to 55% in IAC group (HR: 0.57), with a two-sided significance level of 0.05 and 80% power. Considering a 10% loss to follow-up, the calculated sample size was 212 patients (106 for each arm), to be accrued over 7 years. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Results: The interim analysis was cancelled in the 8th year after enrolling 186 patients due to poor accruals. Based on the actual accrual interval, the sample size was recalculated, reducing the target to 184 patients with approximately 100 events. One hundred eighty-six patients were randomly assigned to two arms (93 in the IAC group and 93 in the observation group). The median age was 63 years (quartiles 57-70), with 169 (91%) of the 186 patients being male. Among the patients, 110 (59%) had pT3 disease, and 51 (27%) had pT4 disease. Lymph node involvement (LNI) was 54.3% in total, and was comparable between the two groups (54% vs. 55%). With a median follow-up of 77.9 months, 106 (57%) patients experienced recurrence (48 in the IAC group and 58 in the observation group). In the intention-to-treat (ITT) population, IAC significantly prolonged RFS (HR: 0.66, 95% CI: 0.45-0.96; p = 0.031), with a 5-year RFS of 47.7% (95% CI: 38.0%-60.0%) in the IAC group and 35.2% (95% CI: 26.5%-46.8%) in the observation group. OS was better in the IAC group as compared with the observation group, although the improvement reaches statistical significance only in per-protocol population (PP) (HR: 0.60, 95% CI: 0.39-0.94; p = 0.025). Grade 3/4 treatment-related adverse events occurred in 34.6% of the patients, and a significantly lower incidence of grade 3/4 leukopenia (9.0%) and thrombocytopenia (3.9%) was observed when compared to intravenous chemotherapy. Conclusions: Adjuvant IAC significantly improved RFS in patients with stage IIIA-IIIB bladder urothelial carcinoma, with a good safety and tolerability profile. OS was also significantly improved in the IAC group among the PP population. Clinical trial information: NCT01627197 .