Neoadjuvant Chemotherapy Produces Long-Term Survival Benefits in High-Risk UTUC

Patients with high-risk localized upper tract urothelial carcinoma (UTUC) who responded to neoadjuvant chemotherapy with gemcitabine and split-dose cisplatin experienced long-term survival benefits compared with nonresponders, according to data from a phase 2 trial (NCT01261728) published in European Urology.¹

At a median follow-up of 5.4 years (IQR, 4.6-7.5) among surviving trial patients (n = 57), the estimated 7-year disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates were 60% (95% CI, 46%-77%), 77% (95% CI, 65%-93%), and 72% (95% CI, 59%-88%), respectively. Compared with nonresponders (n = 21), patients who responded to neoadjuvant chemotherapy (n = 36) achieved superior 7-year DFS (78% vs 31%; HR, 0.15; 95% CI, 0.06-0.39; P < .001), CSS (90% vs 56%; HR, 0.16; 95% CI, 0.04-0.60; P = .002), and OS rates (90% vs 56%; HR, 0.18; 95% CI, 0.06-0.50; P < .001).

“These data support incorporation of [neoadjuvant chemotherapy] in the treatment paradigm for high-risk nonmetastatic UTUC,” Viranda Jayalath, MD, MSc, FRCSC, a urology fellow at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, and his coauthors wrote in the publication.

How was the phase 2 study designed?

The prospective, multicenter study enrolled patients with high-risk nonmetastatic (cN0 M0) UTUC between 2011 and 2019. Patients also needed to be candidates for radical nephroureterectomy or ureterectomy per MSKCC or a participating site attending urologic oncologist, have a Karnofsky performance status of at least 70%, be at least 18 years old, and have the required initial laboratory values.²

Patients received 4 cycles of gemcitabine at 1000 mg/m² in combination with split-dose cisplatin at 35 mg/m² once daily on days 1 and 8 of a 21-day cycle followed by definitive surgery within 12 weeks of completing neoadjuvant chemotherapy.¹ Definitive surgery consisted of radical nephroureterectomy with lymphadenectomy of renal hilar and ipsilateral nodes lateral to the great vessels or ureterectomy with lymphadenectomy of the periureteric/adjacent pelvic nodes.

The publication also included a retrospective cohort of patients with high-risk nonmetastatic UTUC who underwent radical nephroureterectomy within 16 weeks of completing up to 4 cycles of neoadjuvant chemotherapy between 2000 and 2024 (n = 69).

The primary end point was pathologic response rate.² Secondary end points included time to disease progression, OS, and safety and tolerability.

At baseline, the median age in the phase 2 and independent cohorts was 66 years (IQR, 58-71) and 70 years (IQR, 62-73), respectively.¹ Most patients in both cohorts had urothelial cell carcinoma histology alone (91% vs 100%), positive cytology (67% vs 64%), tumors located in the renal pelvis (54% vs 51%), clinical stage cT2-4a disease (91% vs 90%), and received 3 or more chemotherapy cycles (91% vs 90%). The median times from chemotherapy to surgery were 6 weeks (IQR, 5-8) and 7 weeks (IQR, 5-8), respectively.

What were the additional data that were shared in the publication?

At a median follow-up of 4.3 years (IQR, 1.6-5.5) in the expanded cohort (n = 126), the estimated 5-year bladder recurrence-free survival (B-RFS), DFS, CSS, and OS rates were 55% (95% CI, 47%-66%), 71% (95% CI, 62%-81%), 90% (95% CI, 84%-96%), and 82% (95% CI, 75%-91%), respectively. Responders (n = 85) experienced superior 5-year DFS (81% vs 49%; HR, 0.19; 95% CI, 0.09-0.42; P < .001), CSS (96% vs 78%; HR, 0.14; 95% CI, 0.04-0.51; P = .003), and OS (88% vs 71%; HR, 0.35; 95% CI, 0.15-0.79; P = .011) rates compared with nonresponders (n = 41). There was no association between response to neoadjuvant chemotherapy and B-RFS.

“Guideline recommendations for [neoadjuvant chemotherapy] in UTUC vary, largely owing to the lack of level 1 evidence. While the American Urological Association endorses [neoadjuvant chemotherapy] for all patients with high-risk nonmetastatic UTUC, the National Comprehensive Cancer Network offers weaker support, recommending its use in selected high-risk cases,” Jayalath and his coauthors wrote. “Our findings offer the only long-term prospective data on the efficacy of standard-of-care [neoadjuvant chemotherapy] in high-risk nonmetastatic UTUC.”

References

1. 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(2):108-113. doi:10.1016/j.eururo.2025.08.012
2. Gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma. ClinicalTrials.gov. Updated August 8, 2025. Accessed April 20, 2026. https://clinicaltrials.gov/study/NCT01261728