Perioperative Chemotherapy in Bladder and Upper Tract Urothelial Carcinoma: Outcomes by Nodal Status and Lymphovascular Invasion

<b>Background/Objectives:</b> Optimal selection for perioperative therapy in urothelial carcinoma (UC) remains uncertain. We evaluated the efficacy of neoadjuvant and/or adjuvant chemotherapy (NAC/AC) for patients with bladder cancer (BC) and upper tract UC (UTUC), examined the role of lymphovascular invasion (LVI), and considered the implications for adjuvant nivolumab. <b>Methods:</b> We retrospectively analyzed consecutive patients who underwent radical cystectomy or radical nephroureterectomy at a single center (July 1998-April 2021; observation to 31 March 2025). After exclusions, 252 BC and 153 UTUC patients were included. Endpoints were cancer-specific survival, progression-free survival (PFS; BC), non-urinary-tract recurrence-free survival (NUTRFS; UTUC), and overall survival (OS). Survival was estimated by Kaplan-Meier analysis and compared by log-rank tests. <b>Results:</b> For BC, AC did not improve the PFS or OS in the overall pT ≥ 2 population, whereas node-positive (pN+) disease derived significant benefits in both endpoints among NAC-naïve patients (PFS and OS, <i>p</i> = 0.002 and <i>p</i> = 0.008). For UTUC, AC conferred no advantage in NUTRFS or OS for the overall pT ≥ 2 population. However, NUTRFS benefits emerged in the pN+ subset (<i>p</i> = 0.049), although the OS was not improved. Among NAC-treated BC, the outcomes were poorest for ≥ypT3 and ypN+, whereas ypT ≤ 2 fared better. LVI was associated with adverse outcomes and was borderline higher in pN+ versus pT ≥ 2/pN- for BC (<i>p</i> = 0.056) and significantly higher for UTUC (<i>p</i> = 0.012). <b>Conclusions:</b> In this retrospective, single-center cohort, our exploratory analyses suggest that perioperative benefit is largely node-dependent, supporting prioritizing systemic therapy for pN+ disease and cautioning against routine AC for pT2/ypT2 without nodal involvement. After NAC, adjuvant therapy appeared most justified for ≥ypT3/ypN+. Prospective biomarker-integrated validation is warranted and, given the small and underpowered subgroups and the potential for selection and immortal time biases, these observations should be interpreted as hypothesis-generating rather than causal.