Evanguelos Xylinas1, Luis Kluth2, Niccolo Passoni3, Quoc-Dien Trinh4, Malte Rieken5, Richard K Lee6, Harun Fajkovic7, Giacomo Novara8, Vitaly Margulis9, Jay D Raman10, Yair Lotan9, Morgan Rouprêt11, Atiqullah Aziz12, Hans-Martin Fritsche12, Alon Weizer13, Juan I Martinez-Salamanca14, Kazumasa Matsumoto15, Christian Seitz16, Mesut Remzi16, Thomas Walton17, Pierre I Karakiewicz4, Francesco Montorsi3, Marc Zerbib18, Douglas S Scherr6, Shahrokh F Shariat19. 1. Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France. 2. Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Department of Urology, Vita-Salute University, Milan, Italy. 4. Department of Urology, University of Montreal, Montreal, QC, Canada. 5. Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, University Hospital Basel, Basel, Switzerland. 6. Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA. 7. Department of Urology, Landesklinikum, St. Poelten, St. Poelten, Austria. 8. Department of Surgical, Oncological and Gastroenterologic Sciences, Urology Clinic, University of Padua, Padua, Italy. 9. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 10. Division of Urology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA. 11. Department of Urology, Pitie-Salpetriere Hospital, Assistance Publique Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, University Paris 6, Paris, France. 12. Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany. 13. Department of Urology, University of Michigan, Ann Arbor, MI, USA. 14. Department of Urology, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, Madrid, Spain. 15. Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. 16. Department of Urology, St. John of God Hospital, Teaching Hospital of the Medical University of Vienna, Vienna, Austria. 17. Department of Urology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 18. Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France. 19. Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, St. John of God Hospital, Teaching Hospital of the Medical University of Vienna, Vienna, Austria; Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA. Electronic address: sfshariat@gmail.com.
Abstract
BACKGROUND: Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. OBJECTIVE: The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. INTERVENTIONS: RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. RESULTS AND LIMITATIONS: With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% ± 1%, 78% ± 1%, 68% ± 1%, and 47% ± 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤ 0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. CONCLUSIONS: Intravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU.
BACKGROUND: Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. OBJECTIVE: The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. INTERVENTIONS: RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. RESULTS AND LIMITATIONS: With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% ± 1%, 78% ± 1%, 68% ± 1%, and 47% ± 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤ 0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. CONCLUSIONS: Intravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU.
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