Modeling 1-year Relapse-free Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients with Clinical T2–4N0M0 Urothelial Bladder Carcinoma: Endpoints for Phase 2 Trials

Background: Several ongoing phase 2 trials are evaluating new neoadjuvant therapy regimens in patients with muscle-invasive bladder cancer (MIBC). The 1-yr recurrence-free survival (RFS) after radical cystectomy (RC), with or without perioperative chemotherapy, can be used to model statistical assumptions and interpret outcomes from these studies. Objective: To provide a benchmark for predicting 1-yr RFS in patients with cT2–4N0 MIBC. Design, setting, and participants: We identified 950 patients with clinical stage T2–4N0 MIBC undergoing RC at 27 centers between 1990 and 2016. We assessed 1-yr RFS rates for patients managed with no perioperative chemotherapy, neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), or NAC followed by AC. Cox regression analyses tested for 1-yr postsurgical RFS predictors. A Cox-based nomogram was developed to estimate 1-yr RFS and its accuracy was assessed in terms of Harrell's c-index, a calibration plot, and decision curve analysis. We report 1-yr RFS rates across the nomogram tertiles. Results and limitations: The 1-yr RFS rates were 67.9% (95% confidence interval [CI] 64–72) after no perioperative chemotherapy, 76.9% (95% CI 72–83%) after NAC, 77.8% (95% CI 71–85%) after AC, and 57% (95% CI 37–87) after NAC + AC. On multivariable analysis, positive surgical margins (p = 0.002), pT stage (p < 0.0001), and pN stage (p<.0001) were significantly associated with RFS, while NAC was not (p = 0.6). The model including all these factors yielded a c-index of 0.76 (95% CI 0.72-0.79), good calibration, and a high net benefit. The 1-yr RFS rates across nomogram tertiles were 90.5% (95% CI 87–94%), 73.4% (95% CI 68–79%), and 51.1% (95% CI 45–58%), respectively. The results lack external validation. Conclusions: Benchmark 1-yr RFS estimates for phase 2 design of new neoadjuvant trials are proposed and can be used for statistical assumptions, pending external validation. Patient summary: Our prognostic model predicting 1-yr survival free from recurrence of bladder cancer after radical cystectomy, with or without standard chemotherapy, could provide an improvement to the quality of phase 2 clinical trial designs and interpretation of their results. To overcome the limitations of pathologic complete response as the endpoint for phase 2 trials of neoadjuvant new drugs for T2-4N0M0 muscle-invasive bladder cancer we developed a model for prediction of 1-yr recurrence-free survival. The model could help in the design of single-arm phase 2 trials of novel agents and in comparison of findings across studies.