Survival Outcomes of BCG Only, BCG Plus EMDA-MMC or Upfront Radical Cystectomy in High-Risk Non-Muscle Invasive Bladder Cancers (NMIBCs): A Multicentre, International, Collaborative Study from Tertiary Referral Institutions

<b>Introduction</b>: Conservative or upfront radical management for high- and very high-risk non-muscle-invasive bladder cancer continues to be debated, particularly for cases with adverse pathological features. We aimed to compare survival outcomes among NMIBC patients treated with transurethral resection of bladder tumour (TURBT) followed by either Bacillus Calmette-Guérin (BCG), sequential BCG plus electromotive administration of mitomycin C (EMDA-MMC), or upfront radical cystectomy (RC). <b>Materials and Methods</b>: High- and- very high-risk NMIBC cases undergoing TURBT followed by BCG, BCG plus EMDA-MMC, or RC at two international tertiary referral centres between 2009 and 2024 were retrospectively reviewed. Recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier methods. Multivariable Cox regression models were applied to identify factors independently associated with survival outcomes. <b>Results</b>: A total of 1178 patients were included: 852 received BCG, 249 received BCG/EMDA-MMC, and 77 underwent upfront RC. Kaplan-Meier analysis revealed no significant differences in RFS or PFS between the BCG and BCG/EMDA-MMC groups, nor in OS between the three treatment strategies. According to multivariable analysis, concomitant carcinoma in situ (CIS) and increasing T stage at TURBT were independently associated with poorer RFS (HR 1.39; 95% CI 1.05-1.85), PFS (HR 1.95; 95% CI 1.36-2.82), and OS (HR 2.28; 95% CI 1.60-3.25). A second resection conferred a protective effect on PFS (HR 0.72; 95% CI 0.54-0.95). Treatment modality (BCG, BCG/EMDA-MMC, or upfront RC) was not significantly associated with any survival endpoint. <b>Conclusions</b>: In this large multicentre series of patients with high- and very high-risk NMIBC undergoing TURBT, survival outcomes were primarily influenced by clinical-pathological characteristics rather than the adjuvant treatment of choice.