Bladder-sparing strategies for non-muscle-invasive bladder cancer after bacillus Calmette-Guérin failure: a...

Non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection and intravesical instillation therapy. For patients with high-risk NMIBC after failure of bacillus Calmette-Guérin (BCG) therapy, radical cystectomy and urinary diversion are the standard of care, which can be associated with a high morbidity and impaired quality of life. Developing efficacious bladder-sparing strategies is an unmet need for such patients. We conducted a systematic review of prospective interventional studies on NMIBC after BCG failure.

We comprehensively searched the Cochrane Database, PubMed and ClinicalTrials.gov to identify prospective studies on NMIBC after BCG failure from their inception up to June 2025. Search results were summarised according to types of agents by focusing on efficacy. To assess the risk of bias, the Methodological Index for Non-Randomized Studies was used for single-arm studies, while the Risk of Bias 2.0 tool was applied to randomised controlled trials.

Of 2493 studies screened, 114 studies met the eligibility criteria, of which most were early-phase or single-arm trials. Types of agents or modalities used included immunotherapy and biological response modifiers, cytotoxic anticancer drugs, immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, antibody-drug conjugates, radiotherapy and photodynamic therapy; of these, the former three accounted for more than 80% of the eligible trials. Among 37 published studies, complete response (CR) rates in patients with carcinoma in situ with or without papillary NMIBC ranged from 8% to 84%, and 12-month recurrence-free survival rates ranged from 20% to 86%. Interim reports of several ongoing trials using a novel intravesical drug delivery system of gemcitabine, gene therapy-based biological response modifiers with or without ICI, and a combination of ICI with anticancer agents demonstrated CR rates of 70% or higher.

This systematic review demonstrated the promising efficacy of novel bladder-sparing strategies for NMIBC after BCG failure. This review is limited by the predominance of early-phase trials and a limited number of comparative studies, offering only limited guidance for clinical decision-making.