Immune-checkpoint inhibitors have the potential to induce long-term remission of bladder cancer.

The reasoning underlying the strategy of immunotherapy in the nonmetastatic setting rests on its ability to induce T cell expansion. Better preserved immunity in earlier stages might induce greater utility in this setting.

The promising initial results of immune-checkpoint inhibitors for the treatment of nonmetastatic urothelial carcinoma warrant further evaluation on the potential long-term survival benefits.

Ongoing and future trials of immune-checkpoint inhibitors in the curative setting might identify unique safety concerns in addition to those in the metastatic setting.

The appropriate selection of patients for immune-checkpoint inhibitors using biomarkers, such as tumor mutation burden and Programmed death-ligand 1 expression, is an area of greater interest and active investigation in the nonmetastatic setting.

Non–muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non–muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2–T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4–9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Nonmetastatic urothelial carcinoma

Immunotherapy

Bladder-sparing strategies

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