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Objectives  To assess the impact of two cycles of neoadjuvant chemotherapy (NAC) in patients who underwent nephroureterectomy for high‐risk cN0M0 upper tract urothelial carcinoma (UTUC), and to evaluate the efficacy of NAC in patients with localised disease (≤cT2).    Patients and Methods  We retrospectively analysed patients with high‐risk cN0M0 UTUC who received NAC followed by surgery, compared with a matched cohort who underwent initial surgery at Fujita Health University during 2005–2019. Baseline and tumour characteristics, overall survival (OS), cancer‐specific survival (CSS), and recurrence‐free survival (RFS) were compared between the cohorts. Cox proportional hazards models were used to identify predictors of survival.    Results  There were 117 and 67 patients in the study group and the control group, respectively. Significantly higher pathological downstaging (pDS) and lower lymphovascular invasion (LVI) were observed in the study group than in the control group (48% vs 22%,  P  = 0.008 and 29% vs 46%,  P  = 0.045, respectively). The NAC group had significantly better 5‐year OS (79% vs 53%,  P  = 0.003), 5‐year CSS (84% vs 66%,  P  = 0.008), and 5‐year RFS (80% vs 61%,  P  = 0.001) than the control group. The OS benefit of NAC was observed even in patients with localised (≤cT2) disease ( P  = 0.019). Patients with LVI showed significantly worse CSS both in pathologically locally advanced (≥pT3) and in localised (≤pT2) tumours ( P  = 0.048 and  P  = 0.018, respectively). Multivariate analysis identified LVI, NAC, and pDS as independent predictors of OS. Male sex and post‐NAC LVI were identified as predictors of worse survival in patients who underwent NAC.    Conclusions  Two cycles of NAC improved the survival of patients with high‐risk UTUC, even in patients with localised disease. Although two cycles of NAC appear to be effective in cN0M0 high‐risk UTUC including localised disease, additional larger sample size multicentre prospective studies comparing short‐course NAC regimens followed by surgery and surgery alone are required.

Two cycles of neoadjuvant chemotherapy improves survival in patients with high‐risk upper tract urothelial carcinoma