Bladder-sparing combination treatments for muscle-invasive bladder cancer: A plea for standardized assessment and definition of clinical trials endpoints

Radical cystectomy is the standard of care for muscle invasive bladder cancer, although it represents a surgical procedure with high complication and mortality burden. Thus, more and more emphasis has been placed in favor of alternative treatments especially for patients who are unfit for or aim to avoid radical cystectomy. In this context, preclinical studies highlighted that chemoradiation therapy (CRT) may have immunomodulatory properties on tumor microenvironment with a consequent increase in immune biomarkers. Thus, following the encouraging results reached by immune checkpoint inhibitors (ICIs) in both metastatic and localized disease, CRT and ICIs combination treatment gained momentum as bladder-sparing option and several clinical trials were recently launched both as concurrent and sequential treatments. A narrative review of the literature was performed to summarize the rationale and clinical outcomes of trials testing CRT and ICIs combination. Promising results were recently released mainly from phase II trials reporting clinal complete response rates from 48% to 83%. Moreover, combination treatment, both as concurrent and sequential schedules, appeared to be quite tolerable. However, interpretation of preliminary findings is made difficult due to the heterogeneity of clinical endpoints among trials, patient population included and different measurement of response to treatment. Novel bladder-sparing strategies are finally gaining momentum in bladder cancer treatment. Despite preliminary findings are encouraging, harmonization of terminology and definition of clinical endpoints among trials will be mandatory to correctly assess the potential role of CRT and immunotherapy combination as bladder-sparing solution in routine clinical practice.