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

Marco Bandini, Alberto Briganti, Elizabeth R. Plimack, Günter Niegisch, Evan Y. Yu, Aristotelis Bamias, Neeraj Agarwal, Srikala S. Sridhar, Cora N. Sternberg, Ulka Vaishampayan, Christine Théodore, Jonathan E. Rosenberg, Joaquim Bellmunt, Matthew D. Galsky, Francesco Montorsi, Andrea Necchi

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish
Pages (from-to)248-256
Number of pages9
JournalEuropean urology oncology
Issue number3
StatePublished - May 2019


  • Bladder cancer
  • Nomogram
  • Perioperative chemotherapy
  • Relapse-free survival
  • Urothelial carcinoma


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