Lessons learned from the POUT trial: Adjuvant chemotherapy does improve the outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma

Abstract

Introduction: The management of patients with upper tract urothelial carcinoma (UTUC) is challenging, with radical nephroureterectomy (RNU) being the gold standard of treatment for high-risk disease. The role of chemotherapy is unclear. The POUT trial is a multicenter UK effort that addresses whether adjuvant chemotherapy improves disease-free survival (DFS) in patients with locally advanced and/or node-positive UTUC. Methods: The POUT trial enrolled 262 patients with UTUC (pT2-T4, N0-3, and M0) between 2012 and 2017. The patients were randomized (1:1) to four cycles of adjuvant gemcitabine–cisplatine (gemcitabine–carboplatin if GFR 30–49 ml/s) or surveillance following RNU. The patients were followed with cross-sectional imaging and cystoscopy every 6 months for the first 2 years and then annually for 5 years. The primary end point was DFS, whereas recurrence-free survival (RFS), overall survival (OS), toxicity, and quality of life (QoL) were the secondary end points. Results: The intent-to-treat analysis was conducted in 262 patients (131 chemotherapy and 131 surveillance). Among the patients treated with chemotherapy, 66% were offered gem-cis, while 68% completed successfully the four planned chemotherapy cycles. Approximately 50% of the patients undergoing chemotherapy developed Grade 3 or greater adverse events. A significant improvement in DFS (hazard ratio [HR]: 0.49 [confidence interval (CI): 0.31–0.76], P = 0.001) was observed at a median follow-up of 17.3 months. Considering the secondary end points, adjuvant chemotherapy was also associated with an improvement in RFS (HR: 0.49 [CI: 0.30–0.78], P = 0.02). Following adjustment for nodal involvement, the difference was more pronounced with a HR: 0.47 (CI: 0.30–0.74), P = 0.001. A difference in the OS curves favoring the adjuvant chemotherapy arm was noticed, but the difference remained nonsignificant due to short follow-up. Conclusions: The POUT trial provides exciting and convincing Level I evidence on the benefit associated with adjuvant chemotherapy administration in patients with locally invasive or node-positive UTUC.