Multimodal Kidney-Sparing Strategy for High-Risk Upper Tract Urothelial Carcinoma

Overview

UTUC is a cancer that develops in the lining of the kidney or ureter. The standard treatment is radical nephroureterectomy, which removes the kidney and ureter. Although this surgery can control the cancer, it permanently reduces kidney function. Endoscopic treatment can serve as a kidney-sparing approach for low-risk UTUC; however, in high-risk patients, the high rate of upper tract local recurrence after endoscopic treatment remains the primary failure pattern. This study aims to evaluate the efficacy and safety of radiotherapy-involved kidney-sparing treatment for UTUC. The main questions this study aims to answer are: Can this multimodal kidney-sparing strategy reduce local recurrence of UTUC compared with endoscopic treatment alone? Participants in the kidney-sparing group will: Undergo endoscopic surgery to remove the tumor; Receive systemic therapy with disitamab vedotin and toripalimab; Receive targeted radiotherapy after surgery. Participants will undergo regular follow-up visits, including imaging examinations and endoscopic evaluations, to monitor for recurrence or disease progression. The results of this study may help determine whether a multimodal kidney-sparing treatment strategy could become a safe and effective option for selected patients with high-risk UTUC.

Upper tract urothelial carcinoma (UTUC) is an uncommon malignancy arising from the urothelial lining of the renal pelvis or ureter. Radical nephroureterectomy (RNU) remains the standard treatment for high-risk disease. However, removal of the entire kidney and ureter leads to permanent loss of renal function and may negatively affect long-term quality of life and eligibility for future systemic therapies. Although kidney-sparing treatment is well established for low-risk UTUC, its role in patients with high-risk disease remains uncertain. Recent advances in systemic therapy and radiotherapy have created opportunities to explore multimodal treatment strategies aimed at improving oncological control while preserving renal function. HER2 expression appears to be relatively frequent in UTUC, and HER2-targeted antibody-drug conjugates such as disitamab vedotin have demonstrated promising activity in urothelial carcinoma. In addition, immune checkpoint inhibitors have improved outcomes in advanced urothelial malignancies. Radiotherapy has also been reported to improve locoregional tumor control in selected patients. These developments provide the rationale for integrating endoscopic tumor management with systemic therapy and selective radiotherapy as part of a comprehensive kidney-sparing strategy. This prospective multicenter study is designed to evaluate the feasibility, safety, and preliminary oncological outcomes of a multimodal kidney-sparing treatment pathway in patients with high-risk UTUC. The findings of this study are expected to provide prospective evidence regarding the feasibility of a multimodal kidney-sparing strategy for selected patients with high-risk UTUC and may inform the design of future confirmatory clinical trials. Sample size considerations Given the low incidence of UTUC and the fact that kidney-sparing treatment has not yet been established as a standard-of-care for high-risk disease, the sample size calculation was primarily based on a benchmark comparison against previously published outcomes from kidney-sparing treatment cohorts. According to available literature, the reported 1-year DFS rate following endoscopic tumor ablation combined with systemic therapy was approximately 58.82% \[Chen Z, Ye J, Tu X, et al. Comprehensive modalities of kidney-sparing treatment in a carefully selected cohort of localized high-risk upper tract urothelial carcinoma: a potential paradigm shift. J Clin Oncol. 2025;43(5\_suppl):794-794. doi:10.1200/JCO.2025.43.5\_suppl.794\]. In this study, we hypothesized that the incorporation of radiotherapy into a comprehensive kidney-sparing strategy would increase the 1-year DFS to 85%. Assuming a two-sided significance level of 0.05 and a statistical power of 80%, and accounting for a 20% dropout rate due to potential loss to follow-up and pathological heterogeneity at enrollment, the required sample size was estimated at 36 patients in the kidney-sparing group.