Upper tract urothelial carcinoma (UTUC) is a rare but aggressive malignancy with high recurrence risk. While radical nephroureterectomy (RNU) is the standard treatment, the role of perioperative chemotherapy remains debated. The POUT trial supports adjuvant chemotherapy (AC), whereas evidence for neoadjuvant chemotherapy (NAC) comes mainly from retrospective studies. To further assess chemotherapy sequencing, we utilized TriNetx, a real-world database integrating multi-institutional electronic health records, to compare NAC and AC outcomes in UTUC patients undergoing RNU.

Using the TriNetx database, we conducted a retrospective study of UTUC patients receiving either neoadjuvant cisplatin/carboplatin (NAC) or adjuvant cisplatin/carboplatin (AC). After propensity score matching, Kaplan-Meier analysis was performed to compare overall survival (OS) between the cohorts.

After applying inclusion criteria and propensity score matching, a total of 546 patients were included in each cohort. The median OS was 2,764 days in the NAC group, compared to 2,012 days in the AC group, highlighting the potential survival benefit of neoadjuvant chemotherapy. Kaplan-Meier analysis further confirmed a significant survival advantage for the NAC group over the AC group (p = 0.0424, HR = 0.829, 95% CI: 0.692–0.994).

Our real-world analysis using the TriNetx database suggests that NAC is associated with superior overall survival compared to AC in UTUC patients undergoing RNU. These findings support NAC as a potentially preferred perioperative treatment strategy. Future prospective studies are needed to confirm these results and refine treatment guidelines, ultimately improving UTUC patient outcomes.