Perioperative Management of Upper Tract Urothelial Carcinoma: Current Evidence and Future Directions

Upper tract urothelial carcinoma (UTUC) is a rare but aggressive malignancy characterized by high rates of muscle-invasive and non-organ-confined disease at diagnosis, substantial postoperative renal function decline, and frequent intravesical recurrence. These clinical features complicate the use of cisplatin-based chemotherapy and limit the development of robust, disease-specific evidence. Most perioperative recommendations remain extrapolated from bladder cancer, and considerable uncertainty persists regarding the optimal integration of chemotherapy, immunotherapy, and emerging biomarkers. This review aims to synthesize contemporary evidence on neoadjuvant and adjuvant systemic therapy in UTUC, identify persistent gaps in clinical practice, and outline future research priorities in the era of biomarker-driven treatment.

Neoadjuvant platinum-based chemotherapy has been evaluated in prospective phase II studies, which suggest potential benefits in terms of pathological downstaging and survival, with manageable toxicity profiles. Observational and propensity-adjusted studies reinforce these benefits, particularly in responders, and real-world data confirm expanding adoption in advanced and node-positive disease. Neoadjuvant immunotherapy as monotherapy has shown limited activity, while recent data from the iNDUCT trial indicate that early chemo-immunotherapy combinations are feasible but have not yet met primary efficacy endpoints. Findings from the POUT trial show a significant improvement in disease-free survival with adjuvant chemotherapy; however, overall survival data remain immature at the time of premature study closure. Adjuvant immunotherapy trials, including IMvigor010, CheckMate 274, and AMBASSADOR, have not shown a definitive benefit in UTUC subgroup analyses, a finding that may reflect limited statistical power. Persistent challenges include inaccurate preoperative staging, limited use of lymphadenectomy, uncertain management of variant histology and clinically node-positive disease, and the unresolved role of carboplatin. Emerging biomarkers such as circulating tumor DNA and urine tumor DNA show promise for refining risk stratification and minimal residual disease assessment but remain investigational and require UTUC-specific prospective validation.

Neoadjuvant platinum-based chemotherapy is gaining acceptance as a perioperative strategy in UTUC, supported by prospective phase II data demonstrating pathological downstaging and manageable safety profiles. Neoadjuvant immunotherapy as monotherapy has demonstrated limited activity to date, whereas chemo-immunotherapy combinations remain under evaluation, with early feasibility but immature efficacy results. Adjuvant chemotherapy, as shown in the POUT trial, significantly improves disease-free survival; however, overall survival benefit remains uncertain due to premature study closure and immature follow-up. Evidence for adjuvant immunotherapy in UTUC remains inconclusive as subgroup analyses from IMvigor010, CheckMate 274, and AMBASSADOR have not demonstrated clear benefit (likely influenced by limited statistical power) highlighting the need for UTUC-specific randomized trials. Emerging biomarkers, including predictive models and circulating tumor DNA, may help refine perioperative treatment selection and guide future individualized strategies.