BACKGROUND: Radical cystectomy (RC) is indicated in primary or secondary muscle-invasive bladder cancer (primMIBC, secMIBC) and in primary or recurrent high- or very high-risk non-muscle-invasive bladder cancer (primHR-NMIBC, recHR-NMIBC). The optimal timing for RC along the disease spectrum of nonmetastatic urothelial carcinoma remains unclear. OBJECTIVE: To compare outcomes after RC between patients with primHR-NMIBC, recHR-NMIBC, primMIBC, and secMIBC. DESIGN SETTING AND PARTICIPANTS: This retrospective, multicenter study included patients with clinically nonmetastatic bladder cancer (BC) treated with RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed oncological outcomes for patients who underwent RC according to the natural history of their BC. primHR-NMIBC and primMIBC were defined as no prior history of BC, and recHR-NMIBC and secMIBC as previously treated NMIBC that recurred or progressed to MIBC, respectively. Log-rank analysis was used to compare survival outcomes, and univariable and multivariable Cox and logistic regression analyses were used to identify predictors for survival. RESULTS AND LIMITATIONS: Among the 908 patients included, 211 (23%) had primHR-NMIBC, 125 (14%) had recHR-NMIBC, 404 (44%) had primMIBC, and 168 (19%) had secMIBC. Lymph node involvement and pathological upstaging were more frequent in the secMIBC group than in the other groups (p < 0.001). The median follow-up was 37 mo. The 5-year recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were 77.9%, 83.2%, and 72.7% in primHR-NMIBC, 60.0%, 59%, and 48.9% in recHR-NMIBC, 60.9%, 64.5%, and 54.8% in primMIBC, and 41.3%, 46.5%, and 39% in secMIBC, respectively, with statistically significant differences across all survival outcomes except between recHR-NMIBC and primMIBC. On multivariable Cox regression, recHR-NMIBC was independently associated with shorter RFS (hazard ratio [HR] 1.64; p = 0.03), CSS (HR 1.79; p = 0.01), and OS (HR 1.45; p = 0.03), and secMIBC was associated with shorter CSS (HR 1.77; p = 0.01) and OS (HR 1.57; p = 0.006). Limitations include the biases inherent to the retrospective study design. CONCLUSIONS: Patients with recHR-NMIBC and primHR-MIBC had similar survival outcomes, while those with sec-MIBC had the worst outcomes. Therefore, early radical intervention may be indicated in selected patients, and potentially neoadjuvant systemic therapies in some patients with recHR-NMIBC. PATIENT SUMMARY: We compared cancer outcomes in different bladder cancer scenarios in a large, multinational series of patients who underwent removal of the bladder with curative intent. We found that patients who experienced recurrence of non-muscle-invasive bladder cancer (NMIBC) had similar survival outcomes to those with initial muscle-invasive bladder cancer (MIBC), while patients who experienced progression of NMIBC to MIBC had the worst outcomes. Selected patients with non-muscle-invasive disease may benefit from early radical surgery or from perioperative chemotherapy or immunotherapy.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Centre Montreal Canada

Department of Pathology Medical University Vienna Vienna General Hospital Vienna Austria

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

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

Department of Urology IRCCS San Raffaele Hospital and Vita Salute San Raffaele University Milan Italy

Department of Urology Jagiellonian University Krakow Poland

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Zurich Zurich Switzerland

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Men's Health and Reproductive Health Research Center Shahid Beheshti University of Medical Sciences Tehran Iran

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

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

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