Radical cystectomy has long been the standard of care for muscle-invasive bladder cancer (MIBC), an aggressive cancer with a high risk of progression to recurrent or metastatic disease. Systemic therapy has improved survival outcomes for these patients, with administration in neoadjuvant, adjuvant, and, more recently, "sandwich" perioperative settings. Cisplatin-based therapies have been the mainstay of neoadjuvant treatment for patients without comorbidities who are considered eligible for this chemotherapy. Immune checkpoint inhibition has more recently shown promise not only in prospective single-arm neoadjuvant clinical trials, but also in demonstrating significant improvement in disease-free survival when administered adjuvantly in patients at high risk of recurrence based on residual disease at the time of cystectomy. Furthermore, a biomarker-adapted approach in which patients with detectable postoperative circulating tumor DNA (ctDNA) are selected appears to enhance identification of those most likely to benefit from adjuvant immune checkpoint inhibition. Alternatively, a novel paradigm adopting a combination of preoperative and postoperative therapy sandwiched around cystectomy has been adopted in contemporary clinical trials. Two of these perioperative regimens-cisplatin/gemcitabine/durvalumab and enfortumab vedotin/pembrolizumab-have yielded significant improvements in survival for patients with MIBC and appear poised to become the dominant systemic therapy paradigm for those with MIBC undergoing radical cystectomy. With these advances, opportunities remain to further improve patient outcomes and potentially synthesize these response-adaptive and perioperative approaches. Future studies will address the contribution of postoperative therapy and may ultimately identify patients for whom cystectomy can be deferred altogether.
Journal of the National Comprehensive Cancer Network : JNCCN. 2026 May [Epub]
Jason R Brown, Mamta Parikh
1University Hospitals Seidman Cancer Center, Cleveland, OH., 3UC Davis Comprehensive Cancer Center, Sacramento, CA.