Is More Better? Evaluating Neoadjuvant Chemotherapy Cycles Before Surgery for High-Risk Upper Tract Urothelial Carcinoma

Background and Objectives Recent prospective trials and retrospective studies have supported the use of neoadjuvant chemotherapy (NAC) in upper tract urothelial carcinoma (UTUC); however, the optimal number of NAC cycles remains undefined. We investigated the impact of the number of NAC cycles on pathological response and survival outcomes using a multi-institutional cohort of clinically nonmetastatic high-risk UTUC patients treated surgically. Methods We performed a retrospective analysis of the UTUC Collaborative Network (UCAN) database, comprising 2,276 patients who underwent radical nephroureterectomy (RNU) across seven high-volume tertiary care centers in the United States (2000–2021). We identified patients who received cisplatin-based NAC before surgery. Primary endpoints included pathologic complete response (pCR: ypT0N0) and noninvasive stage (≤ypT1N0) at surgery. Secondary endpoints included bladder cancer-free survival (BCFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Outcomes were assessed using multivariable logistic regression and Cox proportional hazards models. Results Total 187 patients received between 1 and 4 cycles of cisplatin NAC for clinically node-negative (cN0) disease and were eligible for inclusion. 128, 49, and 10 patients received 4, 3, and 1 to 2 cycles of NAC, respectively. No patients who received 1 to 2 cycles achieved pCR, whereas 14% of patients who received 3 to 4 cycles achieved pCR. No significant difference in pCR was observed between 3 and 4 cycles (11% vs. 15%, P = 0.49). On multivariable logistic regression analysis, the number of NAC cycles received was not significantly associated with pCR rates between 3 vs. 4 cycles (OR = 1.38, 95% CI = 0.39–6.51, P = 0.6). In comparing oncologic outcomes on multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with improved OS compared to 3 cycles (HR = 0.34, 95% CI = 0.17–0.69, P = 0.003), but this survival benefit did not extend to MFS, BCFS, or CSS. Conclusions pCR rates and cancer-specific oncologic outcomes are similar between patients receiving 3 versus 4 cycles of cisplatin-based NAC prior to RNU for high-risk, clinically nonmetastatic UTUC. Our findings warrant prospective validation to optimize cisplatin-based NAC regimens for high-risk UTUC, balancing efficacy and toxicity.