Real-world outcomes of bladder-sparing strategies for BCG-unresponsive non-muscle-invasive bladder cancer: a multicenter study

Introduction: Patients with BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) face a high risk of disease progression. While radical cystectomy (RC) remains the recommended standard of care, many patients are unfit for or unwilling to undergo radical surgery, leading to bladder-sparing strategies spreading in real-world practice. This study aims to describe the oncological outcomes of patients diagnosed with BCG-unresponsive NMIBC treated with gemcitabine/docetaxel (Gem/Doce), electromotive drug administration of mitomycin C (EMDA/MMC), further BCG, or upfront RC. Methods: We included patients diagnosed with BCG-unresponsive NMIBC treated across 21 European centers (2009–2024) with either intravesical Gem/Doce, EMDA/MMC, further BCG, or upfront RC. Cumulative incidence curves were used to estimate the risk of recurrence, high-grade recurrence, progression, cancer-specific and overall mortality. Multivariable Cox regression models were used to assess the association between treatment type and the risk of recurrence and progression. Results: Of the 361 patients, 104 (28%) received Gem/Doce, 58 (16%) EMDA/MMC, 150 (42%) further BCG, and 49 (14%) underwent RC. Overall median follow-up was 73 months. Recurrence and high-grade recurrence rates were comparable between Gem/Doce and EMDA/MMC (adjusted HR: 1.30 and 0.40, respectively; both p > 0.5). The 2-year risk of progression was 15% with Gem/Doce, 20% with EMDA/MMC, and 30% with further BCG (p < 0.001). In multivariable analysis, Gem/Doce was associated with a significantly lower risk of progression compared to further BCG (adjusted HR: 0.19, 95% CI 0.09–0.43; p < 0.001). The 2-year cancer-specific mortality was 0% for both Gem/Doce and EMDA/MMC, 4% for BCG, and 7% for RC, with corresponding other-cause mortality rates of 3%, 8%, 11%, and 8%, respectively. Conclusions: In real-world practice, our study indicates that both Gem/Doce and EMDA/MMC represent viable treatment bladder-sparing options for patients with BCG-unresponsive NMIBC who refuse or are unfit for RC. For patients eligible and consenting to surgery, RC remains the guideline-endorsed standard. Prospective trials are warranted to define the optimal therapeutic algorithm for this challenging patient population.