Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer

Overview

About two-thirds of newly diagnosed cases of bladder cancer are non-muscle-invasive bladder cancer (NMIBC). It is advocated that patients with high-risk NMIBC receive an adjuvant course of intravesical Bacille Calmette-Guerin (BCG) as first-line treatment. However, a substantial proportion of patients will 'fail' BCG. Radical cystectomy remains the treatment of choice for NMIBC who have failed intravesical therapy, but there are situations when surgery is not feasible due to competing co-morbidities or a patient's desire for bladder preservation. For these patients, the potential options available are limited. In MIBC, radiotherapy (RT) in association with chemotherapy, has been shown to produce 10-year overall survival rates comparable to those of radical cystectomy in selected cases. At the opposite, results from trials assessing radiotherapy with or without chemotherapy in patients with NMIBC are less documented and discordant. Immunotherapy with immune-checkpoint blockade therapies is increasing as an option and has shown very promising results for several cancers, including bladder carcinoma. An established body of published work has shown that radiation enhances many of the steps needed for the generation of antigen-specific immune responses, including inflammatory tumor-cell death, dendritic cell activation, and antigen cross-presentation. Several groups have reported improved local control when checkpoint blockade immunotherapy is added to radiation in different tumor types. On the one hand, radiotherapy might stimulate the induction of local endogenous immune responses by anti-PD-1 treatment. On the other hand, active immune stimulation by anti-PD-1 treatment within the tumor microenvironment might maximize radiation-induced antitumor immunity. Combination immunoradiotherapy using PD-1/PD-L1 signaling blockade could therefore offer an interesting strategy in bladder tumors, especially as an optional bladder preservation treatment for BCG unresponsive NMIBC. The originality of the therapeutic strategy is the use of radiation (local treatment) combined with checkpoint blockade immunotherapy (systemic treatment). Radiotherapy might increase response rates by creating a more permissive tumor microenvironment through increasing PD-L1 expression on tumor cells and stimulating the accumulation and activation of CD8+ T cells. Avelumab seems to have a specific cytotoxic activity suggesting its interest in local control of the disease, especially in association with radiotherapy.