Oncological Outcomes in Bacillus Calmette-Guérin–naïve High-risk Non–muscle-invasive Bladder Cancer Patients: A Systematic Review on Current Treatment Strategies and Future Perspectives

Background and objective: Bacillus Calmette-Guérin (BCG) is the standard treatment in patients harboring high-risk (HR) non-muscle-invasive bladder cancer (NMIBC). However, BCG therapy faces frequent adverse events (AEs), limited efficacy, and ongoing shortages, leading to a low completion rate, access challenges, and high recurrence. In consequence, there is a growing interest in exploring alternative treatments, including immune checkpoint inhibitors, chemotherapy combinations, and novel intravesical therapies. This systematic review summarizes current prospective evidence on BCG and alternative treatment options for BCG-naïve HR-NMIBC patients (PROSPERO: CRD42024564900). Methods: A systematic search in MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library retrieved 1042 studies, of which 17 met the inclusion criteria (following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines). Key findings and limitations: In 12 studies on BCG-treated patients (n = 1418), recurrence-free survival (RFS) rates were 66-96% at 1-yr, 63-96% at 2-yr, and 39-66% at 5-yr follow-up. Progression-free survival (PFS) rates were 81-98% at 1-yr, 70-96% at 2-yr, and 70-84% at 5-yr follow-up. In nine studies focusing on patients treated with alternative strategies (n = 657), RFS rates were 51-99% at 1-yr, 48-88% at 2-yr, and 47-55% at 5-yr follow-up. PFS was 90-100% at 1-yr, 88-96% at 2-yr, and 84-93% at 5-yr follow-up. AE rates varied widely across studies, for both BCG and alternative treatments. Unfortunately, studies heterogeneity and a small sample sizes limit statistically meaningful conclusions. Twelve clinical trials are currently investigating new strategies for BCG-naïve HR NMIBC patients. Conclusions and clinical implications: Alternative therapies for BCG-naïve HR NMIBC patients are emerging but need further validation. As challenges such as toxicity, cost, and long-term efficacy persist, ongoing trial results will be crucial in determining their role in future clinical practice.