Neoadjuvant Intravesical Mitomycin C for NMIBC: A Phase III Single-Center, Open-Label Randomized Clinical Trial

Background and Objective: Transurethral resection of bladder tumor (TURBT) is the standard for non-muscle-invasive bladder cancer (NMIBC), yet recurrence rates remain high. This study evaluates the safety, tolerability, and efficacy of neoadjuvant intravesical mitomycin C (neoMMC) before TURBT in reducing recurrence and improving surgical outcomes. Methods: This randomized phase III trial enrolled patients with primary or recurrent NMIBC. Participants were randomized 1:1 to a neoadjuvant group receiving two instillations of MMC (day −14 and −7) before TURBT, or a control group undergoing standard TURBT without neoadjuvant treatment. The primary endpoint was 12-month recurrence-free survival (RFS). Secondary endpoints included surgical quality (complete resection, cauterization only, absence of residual tumor) and safety. Exploratory endpoints included histopathologic response and time to recurrence. Key Findings and Limitations: Among 95 patients (48 neoMMC, 47 controls), baseline characteristics were balanced. After a median follow-up of 19.4 months, recurrences occurred in 9 StA and 4 NeoA patients, with one progression to MIBC in the NeoA arm. RFS did not differ significantly between groups at 12 or 18 months. Neoadjuvant MMC was well tolerated, with only grade 1–2 AEs. Exploratory microbiota analyses suggested that neoadjuvant MMC modulated urinary microbial diversity and was associated with a microbiota profile more similar to that observed in non-recurrent patients. Limitations include single-center design and relatively short follow-up. Conclusions and Clinical Implications: Neoadjuvant intravesical MMC before TURBT was feasible and well tolerated in patients with NMIBC, with no unexpected safety signals. In this prematurely terminated and underpowered trial, no significant improvement in RFS was observed. Larger adequately powered studies are needed to clarify the oncologic efficacy of this approach.