Neoadjuvant chemotherapy (NAC) has become increasingly attractive in UTUC because it leverages a narrow but critical window to deliver cisplatin-based systemic therapy while renal function is still preserved. In fact, a substantial proportion of patients become cisplatin-ineligible after RNU due to a predictable decline in glomerular filtration rate. Despite growing adoption, we still lack UTUC-specific evidence to address how many cycles of NAC should be given before surgery. In routine practice, clinicians often extrapolate from bladder cancer, even though UTUC differs in staging accuracy, biology, and baseline patient comorbidity.
Our multi-institutional study using the UTUC Collaborative Network (UCAN) was designed to directly address this knowledge gap by asking whether de-escalating cisplatin-based NAC from four to three cycles can offer comparable pathological response and oncologic outcomes while reducing toxicity in patients undergoing RNU for high-risk, clinically node-negative UTUC. Importantly, based on the best available real-world data, we found that the incremental benefit of a fourth cycle is limited.
Across seven high-volume academic centers, we identified 187 patients treated with 1–4 cycles of cisplatin-based NAC followed by RNU, with most receiving either three cycles (n=49) or four cycles (n=128). Pathologic outcomes were similar between these two groups. Pathologic complete response rates were comparable at 11% with three cycles and 15% with four cycles, and rates of downstaging to non-muscle invasive disease (≤ypT1N0) likewise did not differ significantly. Long-term oncologic outcomes revealed the same pattern: bladder cancer-free survival and metastasis-free survival were similar, and cancer-specific survival did not differ after multivariable adjustment. Although four cycles were associated with improved overall survival, that signal was not accompanied by improvement in metastasis-related endpoints, suggesting that it may reflect residual confounding or selection of healthier patients able to complete more chemotherapy rather than a true additional anticancer effect.
At the same time, our data suggest that an adequate course of NAC still matters. Patients who received fewer than three cycles experienced inferior pathologic outcomes and no complete responses, albeit in a small subgroup. Taken together, these findings support that in many patients, the oncologic benefit of cisplatin-based NAC in UTUC may largely plateau after three cycles, with limited incremental gains from a fourth cycle.
Therefore, our data has immediate clinical implications. Cisplatin carries cumulative toxicities, including nephrotoxicity, neuropathy, and ototoxicity, that are especially consequential in an older UTUC population with frequent comorbidities and finite renal reserve. If three cycles capture most of the benefit, avoiding a fourth cycle may meaningfully reduce treatment burden without sacrificing cancer-specific outcomes. Duration of NAC also affects time to definitive surgery; prolonged neoadjuvant therapy can delay RNU, and mounting evidence in urothelial carcinoma suggests that excessive delays may compromise outcomes. Finally, clinicians frequently face real-world scenarios in which patients develop dose-limiting toxicity after three cycles. Our findings provide support for proceeding to surgery at that point rather than pushing for an additional cycle based primarily on extrapolation.
Our study also has important caveats. Its retrospective nature introduces an unavoidable risk of selection bias, particularly because patients who completed four cycles may have been fitter or more chemotherapy-tolerant at baseline. The sample size, especially in the three-cycle group, limits statistical power to detect smaller but clinically meaningful differences, and the rarity of pCR events further constrains inference. We also lacked granular toxicity reporting and longitudinal renal function data during NAC, which are central to weighing tradeoffs between additional cycles and perioperative risk. Finally, inter-institutional variation in surgical and lymph node dissection practices may have influenced pathologic staging.
Even with these limitations, our work provides one of the first UTUC-specific evaluations of NAC duration using a large multi-institutional cohort. In a rare disease where prospective trials are difficult, and practice often borrows from bladder cancer by necessity, this dataset offers actionable evidence to guide treatment planning and shared decision-making. More broadly, while prospective validation is needed, our study challenges the assumption that more chemotherapy necessarily improves outcomes and highlights the need to balance toxicity and the timeliness of surgery in choosing NAC duration for UTUC.
Written by:
- Taibo Li, MD, PhD, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
- Nirmish Singla, MD, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, Medical University of Vienna, Vienna, Austria; Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD