Sri Saran Manivasagam, Jay D Raman
UTUC management is evolving towards stage-specific strategies integrating chemoablation, systemic therapy, and molecularly guided approaches. Future priorities include randomized trials, optimized drug delivery, and long-term safety evaluation.
BACKGROUND: Upper tract urothelial carcinoma (UTUC) is an uncommon genitourinary malignancy with distinct anatomical and clinical challenges. Historically, treatment strategies have been extrapolated from bladder cancer, leaving gaps in evidence for UTUC-specific management. Recent advances in intraluminal drug delivery and systemic therapy have presented new options across localized, locally advanced, and metastatic disease.
METHODS: We reviewed prospective trials, retrospective cohort studies, and ongoing studies evaluating intraluminal chemo-ablative agents, perioperative chemotherapy, immunotherapy, and targeted therapies for UTUC. Outcomes of efficacy, safety, and innovation in drug delivery systems were synthesized.
RESULTS: Kidney-sparing approaches for localized UTUC have advanced with intraluminal chemoablation. UGN-101, a mitomycin-C containing reverse-thermal gel, demonstrated meaningful complete response rates and durable remission, while mitomycin-C (aqueous) and Bacillus Calmette-Guérin-based regimens showed variable efficacy. Novel delivery systems, including reverse-thermal gels and biodegradable drug-eluting stents, aim to improve drug dwell time and reduce recurrence. For high-risk localized disease, adjuvant platinum-based chemotherapy significantly improved disease-free survival and is now standard of care. Neoadjuvant chemotherapy offers long-term survival benefits and preserves eligibility for cisplatin. Immunotherapy has emerged perioperatively, with adjuvant checkpoint inhibitors improving disease-free survival and ongoing trials exploring chemo-immunotherapy combinations. In metastatic UTUC, antibody-drug conjugates combined with immunotherapy have demonstrated superior progression-free and overall survival compared with chemotherapy. Targeted therapies, such as FGFR inhibitors, provide additional options for biomarker-selected patients.
CONCLUSIONS: UTUC management is evolving towards stage-specific strategies integrating chemoablation, systemic therapy, and molecularly guided approaches. Future priorities include randomized trials, optimized drug delivery, and long-term safety evaluation.