The biologic landscape and therapeutic implications of upper tract urothelial cancer

Management of upper tract urothelial cancer (UTUC) has been largely extrapolated from bladder cancer due to its rarity; however, unique biological and clinical differences between UTUC and bladder cancer have been uncovered. The purpose of this review is to present the current therapeutic landscape of UTUC with an emphasis on biologically driven rationale.

Prospective trials for patients with high-risk localized UTUC have shown improved outcomes with adjuvant and neoadjuvant platinum-based chemotherapy. However, the timing of therapy relative to nephroureterectomy may impact platinum eligibility due to renal functional decline following surgery. In recent years, emerging therapeutic classes including immune checkpoint inhibition, antibody drug conjugates, and targeted therapies have emerged as tolerable alternatives to platinum-based chemotherapy in treating metastatic disease. Biomarker-selected therapies, including those targeting HER2 and FGFR3, have shown encouraging results and are relevant to UTUC based on increased expressions of these targets; however, no prospective study to date has been powered to assess the effect of these modern treatments on patients with UTUC specifically.

Unique biological insights into UTUC pathogenesis and risk factors have expanded the therapeutic landscape for these patients beyond conventional platinum-based chemotherapeutic approaches. Novel therapeutic classes have emerged to guide more precise approaches in treating patients with urothelial cancer, with a need for further trials powered specifically to the UTUC population.