BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for cT2-4aN0M0 bladder cancer (BCa) patients candidates for radical cystectomy (RC). This study examines changes in NAC administration over time and its impact on survival within a large, real-world multicenter cohort. METHODS: Our analysis included cT2-4aN0M0 BCa patients from 23 tertiary referral centers who underwent RC and pelvic lymph-node dissection with or without NAC administration between 2004 and 2024. The estimated annual percentage change (EAPC) was used to analyze the temporal trend of NAC administration and pathological complete response rates (pT0) over time. Subsequently, we relied on 1:1 propensity score matching (PSM) for age, sex, cT stage, Charlson Comorbidity Index (CCI), and smoking habit. Multivariable logistic regression (MLR) model addressed the association of pT0 and NAC exposure. Survival analyses consisted of Kaplan-Meier plots (KM) and multivariable Cox regression models (MCR) addressing cancer-specific mortality (CSM) and overall mortality (OM) according to NAC exposure. RESULTS: Overall, 3,138 patients were identified. Of these, 859 (27%) received NAC. NAC implementation increased substantially from 2004 to 2024 (EAPC: + 9.2%, p < 0.001), as well as pT0 rates (EAPC: + 7.6, p < 0.001). After 1:1 PSM (847 NAC + vs. 847 NAC-), MLR showed NAC as the strongest predictor of pT0 (OR: 2.89, p < 0.001). KM estimated 5-year CSM and OM rates of 22.5% versus 31.3% and 23.6 versus 34.5% in NAC + versus NAC-, respectively.At MCR, NAC exposure was associated with lower CSM (HR: 0.90, p = 0.01) and OM (HR:0.85, p = 0.001) rates relative to their unexposed counterparts. CONCLUSIONS: The current study demonstrated a significant increase in NAC administration over time, accompanied by higher rates of pT0 as well as improved survival among NAC-treated patients. The major limitation is represented by the retrospective nature of the study.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Centre Montréal Québec Canada

Departament of Urology Hospital Universitario Ramón y Cajal IRYCIS Universidad de Alcala Madrid Spain

Department of General Oncological and Functional Urology Medical University of Warsaw Warsaw Poland

Department of Maternal Infant and Urologic Sciences Policlinico Umberto 1 Hospital Sapienza University of Rome Rome Italy

Department of Oncology and Hematology Oncology University of Milan Milan Italy

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Azienda Ospedaliera Universitaria Integrata Verona Verona Italy

Department of Urology Clinique Pasteur Toulouse France

Department of Urology Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology European Institute of Oncology IRCCS Milan Italy

Department of Urology Fundacio Puigvert Barcelona Spain

Department of Urology Humanitas Clinical and Research Institute IRCCS Rozzano Milan Italy

Department of Urology IMED Hospital Valencia Spain

Department of Urology Jules Bordet Institute Hôpital Universitaire de Bruxelles Brussels Belgium

Department of Urology La Croix du Sud Hôpital Quint Fonsegrives France

Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Department of Urology Netherlands Cancer Institute Amsterdam The Netherlands

Department of Urology Onze Lieve Vrouwziekenhuis Hospital Aalst Belgium

Department of Urology Ospedale Maggiore Della Carità 28100 Novara Italy

Department of Urology Rangueil Hospital Toulouse France

Department of Urology Regina Elena _National Cancer Institute IRCCS Rome Italy

Department of Urology Spedali Civili of Brescia Brescia Italy

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Zürich Zürich Switzerland

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology University of Tor Vergata Rome Italy

Department of Urology Weill Cornell Medical College New York NY USA

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

Division of Urology Department of Surgical Sciences San Giovanni Battista Hospital University of Studies of Torino Turin Italy

Division of Urology Geneva University Hospitals Geneva Switzerland

Guy's and St Thomas' NHS Foundation Trust Guy's Hospital London UK

Institute of Science Tokyo Hospital Tokyo Japan

München Klinik Bogenhausen Munich Germany

S H Ho Urology Centre Department of Surgery The Chinese University of Hong Kong Hong Kong China

Sorbonne University GRC 5 Predictive Onco Uro AP HP Urology Pitie Salpetriere Hospital 75013 Paris France

St George's University Hospital London UK

Urological Research Institute Unit of Urology IRCCS Ospedale San Raffaele Vita Salute San Raffaele University Milan Italy

Urologische Klinik Und Poliklinik Klinikum Großhadern Der LMU München Marchioninistraße 15 81377 Munich Germany

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