Preoperative intravesical mitomycin C to reduce bladder recurrence in upper tract urothelial carcinoma – Insights from the landmark REBACARE trial

SUMMARY Bladder recurrence is one of the most common and frustrating complications after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), with recurrence rates reported as high as 22%–47%. Current European Association of Urology (EAU) guidelines recommend a single postoperative intravesical instillation of chemotherapy within 48 h of RNU,[1] based on evidence from landmark trials such as ODMIT-C and the THP monotherapy trial.[2,3] The REBACARE trial was designed to test an innovative yet pragmatic solution: Preoperative intravesical instillation of mitomycin C (MMC)[4] before surgery. Conducted from 2017 to 2020 across 18 hospitals in the Netherlands, the study enrolled 190 patients with nonmetastatic UTUC undergoing RNU or partial ureterectomy. Patients received MMC (40 mg) within 3 h before surgery, retained for 1–2 h, and then irrigated out before the operation commenced. The rationale was that preoperative MMC creates a cytotoxic environment in the bladder urothelium before surgical manipulation, preventing implantation and growth of tumor cells that will be shed during ureteral handling and specimen extraction. In contrast, postoperative MMC targets tumor cells that have already been implanted into the bladder during surgery, acting by chemical eradication of freshly contaminated urothelium before cells can adhere and establish recurrence. The trial further reinforces the recommendation to minimize the use of diagnostic ureteroscopy (d-URS), reserving it only for cases where noninvasive diagnostics (imaging plus cytology) are inconclusive, as per EAU guidance.[5] The trial’s primary endpoint was a 2-year intravesical recurrence (IVR) rate. Historically set at 33.2%, the study aimed to demonstrate a reduction to below 20%. Overall, the observed 2-year IVR rate was 24%. While this narrowly missed the predefined efficacy target, subgroup analysis revealed a clear benefit in patients who had not undergone d-URS prior to surgery, with a threefold reduction in risk (hazard ratio 0.33). In contrast, patients who underwent d-URS did not benefit, likely due to tumor cell implantation during ureteroscopic manipulation. Secondary outcomes such as metastasis-free survival, cancer-specific survival, and overall survival were unaffected, indicating no adverse oncologic consequences of the intervention. Importantly, compliance with MMC administration was very high (96%), surpassing rates achieved with postoperative instillation, and no severe chemotherapy-related toxicity was noted. COMMENTS The REBACARE trial is a strong and timely contribution that addresses a clear gap between guideline recommendations and real-world practice. Postoperative instillation, while recommended, is often underutilized due to safety concerns, and MMC instillation can be delivered safely before surgery without compromising operative outcomes. REBACARE opens a new pathway for perioperative chemotherapy that may be more effective, especially in resource-constrained settings. From a methodological standpoint, the trial has notable strengths. It was a prospective, multicenter study with clear eligibility criteria, thereby enhancing its external validity. The study question was clinically relevant and practical, focusing on feasibility, safety, compliance, and early oncologic outcomes. Compliance rates were nearly universal, indicating that a preoperative instillation approach may overcome the most significant barrier encountered in postoperative practice. Furthermore, the biologic plausibility of the differential effect according to d-URS status supports the internal validity of the findings. However, the study has limitations. First, the absence of a randomized control arm limits causal inference, as historical comparisons may be subject to selection bias and temporal changes in practice. Second, while the overall IVR rate decreased, the primary endpoint of <20% recurrence at 2 years was narrowly missed (24% observed). Third, the trial was conducted primarily in high-volume European centers with standardized surgical protocols, which may limit generalizability to community practice settings. Clinically, the findings emphasize two critical actionable insights. First, d-URS should be avoided, as it is associated with increased IVR and negates the benefit of preoperative chemotherapy. Second, preoperative MMC may provide a viable alternative for centers struggling with postoperative instillation. Lower recurrence rates without major toxicity suggest this could be a practical and cost-effective addition to routine UTUC care. Looking forward, randomized trials comparing preoperative and postoperative instillation head-to-head are necessary before guidelines change. Health-economic and cost-effectiveness analyses would be particularly valuable in resource-limited countries. Additionally, strategies incorporating combined instillation protocols for very high-risk patients or the development of predictive markers to identify who benefits most from preoperative MMC would be valuable. For now, the take-home message is clear: Standardize surgical technique, limit the use of d-URS, and consider preoperative MMC instillation as an emerging, low-cost option to meaningfully reduce bladder recurrence after UTUC surgery. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.