INTRODUCTION: The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. PATIENTS AND METHODS: We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. RESULTS: Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. CONCLUSIONS: Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.

Department of Medicine Division of Hematology and Oncology Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY

Department of Urology and Oncological Urology Wroclaw Medical University Wrocław Poland

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna General Hospital Vienna Austria; Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia; Department of Urology Weill Cornell Medical College New York Presbyterian Hospital New York NY; Department of Urology University of Texas Southwestern Medical Center Dallas TX; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology La Croix du Sud Hospital Institut Universitaire du Cancer Toulouse Oncopole Toulose France

Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Department of Urology Regina Elena National Cancer Institute Rome Italy

Department of Urology Spedali Civili of Brescia Brescia Italy

Department of Urology Spedali Civili of Brescia Brescia Italy; Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Division of Oncology Unit of Urology URI IRCCS Ospedale San Raffaele Milan Italy

Division of Oncology Unit of Urology URI IRCCS Ospedale San Raffaele Milan Italy; Department of Urology La Croix du Sud Hospital Institut Universitaire du Cancer Toulouse Oncopole Toulose France

Division of Oncology Unit of Urology URI IRCCS Ospedale San Raffaele Milan Italy; Department of Urology Luzerner Kantonsspital Lucerne Switzerland

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