Neoadjuvant chemotherapy in upper tract urothelial carcinoma: interpreting durable long-term outcomes in a changing treatment landscape

Upper tract urothelial carcinoma (UTUC) is a rare, clinically aggressive malignancy with an incidence of 4,000–7,000 cases annually in the United States (1). At the time of diagnosis, approximately 50–60% of patients present with muscle-invasive or non-organ confined disease (2), with 5-year cancer-specific mortality rates ranging between 30 and 50% (3). Even among UTUC patients eligible for radical nephroureterectomy (RNU), the 5-year survival rates range between 40% and 60%, suggesting the presence of micrometastatic disease at the time of diagnosis in a subset of such patients (4). These adverse survival outcomes, coupled with an anticipated decline in renal function following RNU, have served as the rationale for evaluating neoadjuvant chemotherapy (NAC) prior to RNU or distal ureterectomy for high-risk UTUC patients.

Jayalath et al. recently reported the final long-term outcomes from a prospective, multicenter phase II trial evaluating gemcitabine and split-dose cisplatin in patients with high-risk, nonmetastatic UTUC, alongside an expanded institutional cohort analysis (5). In the primary trial cohort (n=57), the authors demonstrated a pathologic response rate (< ypT2N0) of 63%, including a complete response rate (i.e., ypT0N0) of 19%. Notably, 91% of patients received at least three cycles of chemotherapy and all proceeded to definitive surgery, underscoring the feasibility of a neoadjuvant approach in appropriately selected patients.

At a median follow-up of 5.4 years among survivors, the 7-year disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates were 60%, 77%, and 72%, respectively. These outcomes compare favorably with those from historical surgical series and represent the most mature prospective data for NAC in high-risk UTUC. Significantly, patients achieving a pathologic response (ypT2N0) were observed to have improved survival outcomes—7-year DFS of 78% versus 31% [hazard ratio (HR) 0.15, P<0.001], CSS of 90% versus 56% (HR 0.16, P=0.002), and OS approaching 90% versus 56% (HR 0.18, P<0.001). These findings were consistent in the expanded cohort (n=126), reinforcing the ‘robustness’ of this association (5).

The results of this phase II trial are consistent with those observed from similar trials in this space. In a phase II trial of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) in 10 patients with either cT204aN0-1 muscle invasive bladder cancer or high-risk UTUC, defined by high-grade disease on biopsy or positive urine cytology, Hoffman-Censits et al. reported pathologic downstaging to < pT2 in 50–60% of patients (6). In 2020, Margulis et al. published the results of a multicenter, prospective phase II trial (EA8141) that aimed to assess four cycles of NAC in patients with high-grade UTUC. Among 29 patients receiving aMVAC, a pathologic complete response was observed in 14% of all patients, and 18/29 (62%) achieved a final pathologic stage of < ypT2 (7).

Overall, these data suggest that up to two-thirds of high-risk UTUC patients achieve pathologic downstaging with cisplatin-based NAC regimens, with pathologic responses associated with improved survival outcomes. These findings support the American Urological Association (AUA) guideline recommendation to offer cisplatin-based NAC to eligible, high-risk UTUC patients planned for RNU or ureterectomy and expected post-operative estimated glomerular filtration rates (eGFR) of <60 mL/min/1.73 m² (8).

These data must be interpreted within the context of a rapidly evolving treatment landscape for urothelial carcinoma. The combination of enfortumab vedotin plus pembrolizumab has emerged as the front-line treatment for patients with locally advanced/metastatic urothelial carcinoma based on the results of the EV-302 trial that demonstrated a median OS of 31.5 months with this combination versus 16.1 months with platinum-based chemotherapy (9). This regimen has been more recently evaluated in the neoadjuvant setting prior to planned radical cystectomy for cisplatin-ineligible or declining bladder cancer patients and demonstrated a pathologic complete response of 57% (10). While these data are derived from bladder cancer cohorts, their biological relevance to UTUC remains significant. The NEPTUNE trial (NCT06356155) is evaluating neoadjuvant enfortumab vedotin and pembrolizumab in cisplatin-eligible UTUC.

Importantly, this combination may be administered to patients with impaired renal function (eGFR <30 mL/min/1.73 m²), which challenges the main argument for neoadjuvant systemic therapy prior to RNU—loss of the ‘window of opportunity’ to administer cisplatin-based chemotherapy prior to the potential development of renal impairment post-RNU. The argument that systemic therapy must be delivered preoperatively to maximize eligibility may no longer uniformly apply, and a strategy of routine NAC for all cisplatin-eligible patients risks overtreatment and toxicity for patients with lower risk pathologic features on their RNU specimen. This is further highlighted by the fact that 93% of patients receiving NAC in this setting experienced treatment-related toxicities, including 74% with grade ≥3 toxicities (11).

An approved alternate approach in this setting remains adjuvant platinum-based chemotherapy, with the randomized phase III POUT trial demonstrating an improvement in 5-year OS from 57% to 66%, compared to surveillance (12). Use of adjuvant therapy spares patients with lower-risk pathologic features unnecessary systemic therapy and avoids surgical delays in non-responders. This inability to prospectively identify responders to NAC remains a central limitation of the current paradigm and highlights the need for improved patient selection strategies.

To this end, prognostic and predictive biomarkers are sorely needed in the neoadjuvant setting. Circulating tumor DNA (ctDNA) has been demonstrated to be an important prognostic biomarker of adverse clinical outcomes in bladder cancer and has been used to guide adjuvant therapy approaches in muscle invasive bladder cancer in the IMvigor011 trial (13). In UTUC, Huelster et al. demonstrated that ctDNA had 71% sensitivity, at a specificity of 94%, to predict muscle invasive and/or non-organ-confined UTUC. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (1-year: 69% vs. 100%, P<0.001) and CSS (1-year: 56% vs. 100%, P=0.016) (14). Perhaps a future treatment algorithm will include routine ctDNA testing for high-risk UTUC patients, with neoadjuvant systemic therapy (e.g., enfortumab vedotin plus pembrolizumab) reserved for patients with a positive ctDNA test and those testing negative for ctDNA proceeding directly to RNU or distal ureterectomy.

Finally, it is important to acknowledge the limitations of the present study by Jayalath et al. As a single-arm phase II trial, it lacks a randomized comparator, and the expanded cohort introduces the potential for selection bias. Nonetheless, in the context of a rare disease where randomized trials are inherently challenging, these data provide important prospective evidence and represent the most mature clinical trial data in this space.

In conclusion, this study provides the most mature prospective evidence to date supporting the use of cisplatin-based NAC in high-risk localized UTUC, with meaningful pathologic responses that translate into improved survival outcomes. The treatment paradigm of high-risk UTUC will likely evolve in the near future with the emergence of enfortumab vedotin plus pembrolizumab and the incorporation of tumor-informed biomarkers for risk-adapted treatment selection.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0426/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0426/coif). R.K.S. reports consulting fees from Johnson & Johnson, and Antheum; and support for attending meetings and/or travel from UroToday. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [Crossref]
2. Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol 2020;9:1794-8. [Crossref] [PubMed]
3. Rouprêt M, Babjuk M, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. Eur Urol 2021;79:62-79. [Crossref] [PubMed]
4. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009;115:1224-33. [Crossref] [PubMed]
5. Jayalath VH, Assel M, Iyer G, et al. Neoadjuvant Chemotherapy for High-risk Localized Upper Tract Urothelial Carcinoma: Final Long-term Outcomes from a Phase 2 Clinical Trial and an Expanded Cohort. Eur Urol 2026;89:108-13. [Crossref] [PubMed]
6. Hoffman-Censits JH, Trabulsi EJ, Chen DYT, et al. Neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in patients with high-grade upper-tract urothelial carcinoma. J Clin Oncol 2014;32:
7. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol 2020;203:690-8. [Crossref] [PubMed]
8. Coleman JA, Clark PE, Bixler BR, et al. Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J Urol 2023;209:1071-81. [Crossref] [PubMed]
9. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875-88. [Crossref] [PubMed]
10. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer. N Engl J Med 2026;394:1257-69. [Crossref] [PubMed]
11. Coleman JA, Yip W, Wong NC, et al. Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma. J Clin Oncol 2023;41:1618-25. [Crossref] [PubMed]
12. Birtle AJ, Jones R, Chester J, et al. Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. J Clin Oncol 2024;42:1466-71. [Crossref] [PubMed]
13. Powles T, Kann AG, Castellano D, et al. ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer. N Engl J Med 2025;393:2395-408. [Crossref] [PubMed]
14. Huelster HL, Gould B, Schiftan EA, et al. Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma. Eur Urol 2024;85:283-92. [Crossref] [PubMed]