Increasing Rates of Perioperative Chemotherapy are Associated with Improved Survival in Men with Urothelial Bladder Cancer with Prostatic Stromal Invasion - Beyond the Abstract

The use of perioperative chemotherapy (CHT) has received little attention in patients with pT4a urothelial bladder cancer (UCUB). Despite international guidelines recommending the use of either neoadjuvant or adjuvant chemotherapy, if no neoadjuvant chemotherapy has been given1,2 before or after radical cystectomy3 and several studies showing its benefit on survival in predominantly pT2-3 patients,4-10 the effect of perioperative CHT on overall survival (OS) and cancer-specific survival (CSS) in patients with prostatic stromal invasion is based on very limited number of observations and therefore lacks robustness. In consequence, we examined this relationship in a contemporary cohort of patients with UCUB and prostatic stromal invasion identified within the Surveillance, Epidemiology and End Results (SEER) database (2004-2016).

Within the SEER database, we identified 1,513 men with pT4aN0-3M0 UCUB treated with radical cystectomy with or without perioperative CHT administration. First, we relied on estimated annual percentage changes to examine the rates of CHT administration over time in this patient population. Second, we tested the effect of CHT on OS and CSS using Kaplan-Meier analyses and Cox-regression models, which allowed us to adjust our results for multiple confounders. Third, to further validate our analyses, we relied on the inverse probability of treatment-weighting (IPTW) to maximally reduce the differences between CHT and no CHT patients. Moreover, landmark analyses were performed at three months after surgery, to address the potential effect of immortal time bias. Finally, we performed subgroup analyses according to median patient age (69 years).

Overall, 1,513 non-metastatic pT4aN0-3 UCUB patients underwent radical cystectomy with lymph node dissection between 2004 and 2016 and CHT was administrated in 732 (48.4%) patients. CHT administration rates increased from 29.0% in 2004 to 64.8% in 2016. The use of CHT was associated with increased OS (45.0% vs. 38.7% at five-year), as well as with increased CSS (50.5% vs. 48.6% at five-year). Moreover, CHT administration independently predicted lower overall mortality (hazard ratio [HR]: 0.62), as well as lower cancer-specific mortality (HR: 0.66). These results were confirmed even after IPTW-adjusted analyses and stratification according to median age. Finally, landmark analyses confirmed a beneficial effect of CHT on OS and CSS after three months from surgery.

Several noteworthy observations may be derived from our study. First, lower increase of CHT use in pT4a patients, relative to pT2 patients, may be interpreted as a limitation in patient’s eligibility in the most recent years, that may be related to patient’s age, performance status, renal function or presence of ototoxicity, but also to lack of confidence in CHT use based on few data supporting its benefit in pT4a patients. Second, the use of CHT confers overall and cancer-specific survival benefits in patients with UCUB with prostatic stromal invasion, even after adjusting for several confounders and using multiple statistical methodology, such as IPTW or landmark analyses. These observations are particularly important since our study represents the largest report, which addressed the role of CHT administration on survival in UCUB patients with prostatic stromal invasion. Finally, our analyses also revealed that the use of CHT may confer survival benefits, regardless of patient age.

In conclusion, our findings should sensitize the urologic community to the importance of considering and providing CHT in UCUB patients with prostatic stromal invasion based on its impressive reduction in overall mortality (OM) as well as in cancer-specific mortality (CSM), using ideally the most modern criteria that do not rely on a specific chronologic age cut-off and provide flexibility11 with respect to other classic exclusion criteria, such as glomerular filtration rate (GFR).12

Written by: Giuseppe Rosiello, Sophie Knipper, Carlotta Palumbo, Angela Pecoraro, Stefano Luzzago, Marina Deuker, Zhe Tian, Giorgio Gandaglia, Andrea Gallina, Francesco Montorsi, Shahrokh F Shariat, Fred Saad, Alberto Briganti, Pierre I Karakiewicz

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Urology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Italy., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Urology, European Institute of Oncology, Milan, Italy., Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada., Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute of Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.

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