{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:56:37Z","timestamp":1776070597305,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Upper-tract urothelial carcinoma (UTUC) represents a biologically distinct and clinically challenging subset of urothelial malignancies, accounting for only 5\u201310% of urothelial cancers but carrying a disproportionately high risk of advanced disease and recurrence. Historically, management strategies for UTUC have been extrapolated from bladder cancer data, with limited prospective evidence specific to the upper urinary tract. However, recent years have witnessed an expanding number of UTUC-focused clinical trials that are reshaping treatment paradigms across localized, locally advanced, and metastatic disease states. This review examines the evolving landscape of clinical trials in UTUC, highlighting pivotal and ongoing studies that will inform contemporary management. We summarize evidence supporting perioperative systemic therapy, including neoadjuvant and adjuvant chemotherapy, and discuss the expanding role of immune checkpoint inhibitors in both perioperative and metastatic settings. Additionally, we review trials evaluating kidney-sparing approaches, intraluminal therapies, and novel drug-delivery platforms aimed at preserving renal function while maintaining oncologic control. Emerging trial designs incorporating molecular profiling, fibroblast growth factor receptor (FGFR)-targeted therapies, and biomarker-driven patient selection are also explored. Despite meaningful progress, significant gaps remain, including the underrepresentation of UTUC patients in large urothelial cancer trials, heterogeneity in risk stratification, and challenges in trial accrual for this rare disease. We conclude by outlining future directions for UTUC-specific clinical research, emphasizing the need for collaborative, multicenter trials, innovative endpoints, and integrated translational studies to further refine personalized treatment strategies. As the clinical trial ecosystem for UTUC continues to mature, these efforts hold promises for improving outcomes while balancing oncologic efficacy with renal preservation.<\/jats:p>","DOI":"10.3390\/cancers18081223","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T07:29:29Z","timestamp":1776065369000},"page":"1223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Trials and Emerging Therapeutic Paradigms in Upper-Tract Urothelial Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Julian","family":"Chavarriaga","sequence":"first","affiliation":[{"name":"Department of Urology, Penn State Health, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6684-0331","authenticated-orcid":false,"given":"Jay D.","family":"Raman","sequence":"additional","affiliation":[{"name":"Department of Urology, Penn State Health, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer Statistics, 2022","volume":"71","author":"Siegel","year":"2022","journal-title":"CA Cancer J. 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