Impact of Adjuvant Immune Checkpoint Inhibitors and Chemotherapy on Survival Outcomes in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study

Impact of Adjuvant Immune Checkpoint Inhibitors and Chemotherapy on Survival Outcomes in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Adjuvant Immune Checkpoint Inhibitors and Chemotherapy on Survival Outcomes in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study Satoshi Washino, Go Kaneko, Tomokazu Sazuka, Shoichi Nagamoto, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9298500/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives The efficacy of adjuvant immune checkpoint inhibitors (ICIs) compared with observation or adjuvant chemotherapy in patients with upper tract urothelial carcinoma (UTUC) at high risk of recurrence remains uncertain. We conducted a retrospective, multi-institutional study to evaluate the impact of adjuvant ICIs and chemotherapy on survival outcomes in patients with high-risk UTUC. Patients and Methods A total of 243 patients with high-risk UTUC were included in the analysis. Patients were categorized into three groups: no adjuvant therapy (n = 151), adjuvant chemotherapy (n = 59), and adjuvant ICI (n = 33). Multivariate Cox proportional hazards regression analysis was performed to identify factors independently associated with DFS. Results The median age was 76 years, and 67.9% of patients were male. Baseline characteristics and pathological findings were largely comparable among the groups, except for differences in the frequency of neoadjuvant therapy and lymph node dissection. Adjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy and no adjuvant therapy (ICI vs. no adjuvant: HR: 0.350, 95% CI: 0.203–0.604; chemotherapy vs. no adjuvant: HR: 0.690, 95% CI: 0.444–1.072; ICI vs. chemotherapy: HR: 0.448, 95% CI: 0.216–0.928,). In multivariate analysis, adjuvant ICI and adjuvant chemotherapy were identified as independent predictors of prolonged DFS, while positive surgical margins were independently associated with shorter DFS. Conclusions Adjuvant ICIs and chemotherapy may reduce disease recurrence following radical nephroureterectomy in patients with high-risk UTUC. Adjuvant ICI may confer greater benefit than chemotherapy. Prospective studies are warranted to validate these findings. Immune check inhibitor chemotherapy adjuvant therapy upper tract urothelial carcinoma survival Figures Figure 1 Figure 2 Figure 3 Introduction Upper tract urothelial carcinoma (UTUC) is an uncommon malignancy, accounting for only 5–10% of all urothelial cancers [ 1 ]. It has been estimated that approximately 60% of UTUCs are invasive at the time of diagnosis (compared to 15–25% of bladder cancers) [ 2 ], and 7% present with metastatic disease [ 3 ]. Given that definitive surgical management in the form of radical nephroureterectomy (RNU) is relatively well-standardized, it has been suggested that further improvements in survival outcomes may be achieved through the use of perioperative chemotherapy or immunotherapy [ 4 ]. The POUT trial demonstrated that patients with UTUC staged as ≥ pT2 and/or pN+ derived benefit from adjuvant chemotherapy [ 5 ]. However, the universal administration of cytotoxic chemotherapy to all UTUC patients with ≥ pT2 stage is impractical, as advanced age and impaired renal function may constitute contraindications to such treatment. The role of adjuvant immune checkpoint inhibitors (ICIs) in UTUC has evolved over the past decade. The CheckMate 274 and AMBASSADOR trials predominantly enrolled patients with bladder cancer; nevertheless, their findings have been extrapolated to UTUC populations [ 6 – 8 ]. These studies included patients who had received neoadjuvant chemotherapy and had ≥ ypT2 and/or ypN+ tumors following cystectomy or nephroureterectomy, as well as those who had not received neoadjuvant chemotherapy and had ≥ pT3 and/or pN+ tumors. However, only 6.7–22% of the study populations comprised UTUC patients. Both CheckMate 274 and AMBASSADOR demonstrated prolonged disease-free survival (DFS) with adjuvant ICIs. However, in subset analyses, the effect of adjuvant ICIs on DFS was less pronounced among UTUC patients. To date, only a limited number of studies have evaluated the efficacy of adjuvant ICIs compared with observation or adjuvant chemotherapy in patients with high-risk UTUC [ 9 – 11 ], and the therapeutic benefit of adjuvant ICIs in this setting remains to be definitively established. In the present multicenter retrospective study, we assessed the impact of adjuvant ICIs and chemotherapy on survival outcomes in patients with high-risk UTUC. Specifically, we aimed to compare DFS among patients who received no adjuvant therapy, adjuvant chemotherapy, or adjuvant ICIs. Patients and Methods Patients The Musashino-Study Group for UTUC database included 612 patients who underwent RNU for UTUC across six academic centers between January 2020 and December 2024. A total of 45 patients were excluded for the following reasons: non-urothelial carcinoma on histology (n = 22), concurrent RNU and radical cystectomy (n = 16), metastatic disease (n = 5), and other reasons (n = 2) (Fig. 1). Among the remaining 567 eligible patients, 243 with high-risk UTUC were included in the present study. High-risk UTUC was defined as pathological evidence of urothelial carcinoma originating in the ureter or renal pelvis with a high risk of recurrence, specifically a pathological stage of ≥ pT3 or pN + in patients who had not received neoadjuvant therapy, and ≥ ypT2 or ypN + in those who had received neoadjuvant therapy. Patients were categorized into three groups: no adjuvant therapy (n = 151), adjuvant chemotherapy (n = 59), and adjuvant ICI (n = 33). In the adjuvant chemotherapy group, gemcitabine plus cisplatin was administered to patients with adequate renal function, whereas gemcitabine plus carboplatin was administered to those with impaired renal function. Chemotherapy was given every 3 weeks for a maximum of three to five cycles, according to each institution’s protocol. In the adjuvant ICI group, nivolumab 240 mg (or 480 mg) was administered every 2 (or 4) weeks, or pembrolizumab 300 mg was administered every 3 weeks, for up to 1 year. This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review board of Jichi Medical University Saitama Medical Centre (No. RinS25-049) and the review boards of the other participating centers. Study objectives The primary objective was to compare DFS among the three groups. DFS was defined as the time from the date of RNU to the date of first recurrence (local recurrence within the urothelial tract, local recurrence outside the urothelial tract, or distant recurrence) or death. Multivariate analyses were performed to evaluate the impact of perioperative therapies and pathological findings on DFS. We also evaluated survival free from recurrence outside the urothelial tract and survival free from local recurrence within the urothelial tract. Survival free from recurrence outside the urothelial tract (non-urothelial tract recurrence-free survival) was defined as the time from the date of RNU to the date of first local recurrence outside the urothelial tract, distant recurrence, or death. Survival free from local recurrence within the urothelial tract (urothelial tract recurrence-free survival) was defined as the time from the date of RNU to the date of first local recurrence within the urothelial tract. A 2-month landmark analysis was conducted for survival analyses to minimize lead-time bias in the adjuvant therapy groups. Safety analyses were performed in both the adjuvant chemotherapy and adjuvant ICI groups. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [ 12 ]. Statistical analysis Data were presented as medians and interquartile ranges (IQRs) or as numbers and percentages, as appropriate. Variables were compared using one-way analysis of variance or chi-square tests. Kaplan-Meier curves were generated to estimate survival outcomes, and comparisons were performed using the log-rank test. Cox proportional hazards models were applied to identify factors associated with DFS. All analyses were performed using GraphPad Prism (version 10.6.1), and p -values < 0.05 were considered statistically significant. Results Patients’ backgrounds and pathological findings The median (IQR) age of the overall population was 76 (70–80) years, and 67.9% of the patients were males (Table 1). The primary tumors were located in the renal pelvis in 114 patients (46.9%) and in the ureter in 129 patients (53.1%). Baseline characteristics, including age, sex, performance status, tumor location, and postoperative renal function, were largely comparable among the three groups, with the exception of the frequency of neoadjuvant therapy and lymph node dissection. Platinum-based neoadjuvant chemotherapy was administered most frequently in the adjuvant ICI group (54.5%), followed by the no-adjuvant group (21.9%), whereas no patients in the adjuvant chemotherapy group received neoadjuvant therapy ( p < 0.0001). Limited and template lymph node dissections were performed in 37 (24.5%) and 7 (4.6%) patients in the no-adjuvant group, 8 (13.6%) and 5 (8.5%) patients in the adjuvant chemotherapy group, and 6 (18.2%) and 6 (18.2%) patients in the adjuvant ICI group, respectively ( p = 0.0040). The median follow-up durations were 12.3 (5.1–32.8), 23.7 (5.1–32.8), and 16.8 (11.1–24.0) months in the no-adjuvant, adjuvant chemotherapy, and adjuvant ICI groups, respectively. Pathological findings, including tumor histology, pathological tumor stage, nodal stage, and resection margin status, did not differ significantly among the three groups (Table 2). Adjuvant chemotherapy and ICI In the adjuvant chemotherapy group, 16 patients (27.1%) received gemcitabine plus cisplatin as the initial regimen; among these patients, treatment was switched to gemcitabine plus carboplatin in two patients due to adverse events. The remaining 43 patients initiated treatment with gemcitabine plus carboplatin. The median time to initiation of adjuvant chemotherapy was 1.8 months (IQR: 1.5–2.2), and the median number of administered cycles was 3 (IQR: 2–4). Among 56 patients with available follow-up data, 41 (73.2%) completed the planned course of adjuvant chemotherapy. Treatment discontinuation occurred in 9 (16.1%), 2 (3.6%), and 4 (7.1%) patients due to treatment-related adverse events (TRAEs), disease progression, and other reasons, respectively. In the adjuvant ICI group, 32 patients received nivolumab and one patient received pembrolizumab. The median time to initiation of adjuvant ICI was 2.1 months (IQR 1.8–2.6). At the time of assessment, 31 patients had either completed or discontinued ICI therapy, whereas two patients were still undergoing treatment. Among patients who completed or discontinued ICI therapy, the median duration of exposure was 5.6 months (IQR: 3.7–11.0). The median cumulative dose of nivolumab was 2400 mg (IQR: 1440–4080). Among 29 evaluable patients, 10 (34.5%) completed adjuvant ICI therapy, whereas 12 (41.4%) and 7 (24.1%) discontinued treatment due to TRAEs and disease progression, respectively. Survival outcomes Adjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy and no adjuvant therapy. The median DFS was not reached (NR) in the adjuvant ICI group, 14.0 months (95% confidence interval [CI]: 10.6–33.7) in the adjuvant chemotherapy group, and 11.9 months (95% CI: 9.2–14.4) in the no-adjuvant group (Fig. 2A). The 12-month DFS rates were 80.2%, 59.4%, and 49.4% in the adjuvant ICI, adjuvant chemotherapy, and no-adjuvant groups, respectively. Adjuvant ICI significantly improved DFS compared to no adjuvant therapy (hazard ratio [HR]: 0.350, 95% CI: 0.203–0.604, p = 0.0083). Adjuvant chemotherapy demonstrated a trend toward improved DFS (HR: 0.690, 95% CI: 0.444–1.072, p = 0.095). A trend favoring adjuvant ICI over adjuvant chemotherapy was also observed (HR: 0.448, 95% CI: 0.216–0.928, p = 0.055). Both adjuvant ICI and adjuvant chemotherapy were associated with prolonged non-urothelial tract recurrence-free survival (Fig. 2B). The median non-urothelial tract recurrence-free survival was 34.3 months (95% CI: 23.2–NR) in the adjuvant ICI group, 19.8 months (95% CI: 12.2–NR) in the adjuvant chemotherapy group, and 15.8 months (95% CI: 10.5–21.0) in the no-adjuvant group. No significant differences were observed in urothelial tract recurrence-free survival among the three groups ( p = 0.144) (Fig. 2C). The most common site of recurrence in the no-adjuvant group was the regional lymph nodes (27.8%), followed by intravesical recurrence (25.2%), lungs (20.5%), and liver (9.3%) (Fig. 2D). Compared to the no-adjuvant group, adjuvant chemotherapy reduced recurrences in the lungs (8.5%, p = 0.042) and liver (1.7%, p = 0.073). Adjuvant ICI reduced recurrences in the regional lymph nodes (9.1%, p = 0.025) and was not associated with any recurrences in the lungs, liver, or bone. Multivariate Cox regression analysis identified adjuvant ICI (HR: 0.313, 95% CI: 0.134–0.639, p = 0.0009) and adjuvant chemotherapy (HR: 0.624, 95% CI: 0.388–0.980, p = 0.041) as independent predictors of prolonged DFS, whereas positive surgical margins were independently associated with shorter DFS (HR: 2.586, 95% CI: 1.493–4.361, p = 0.0009) (Table 3). Overall survival (OS) was longest in the adjuvant chemotherapy group, followed by the adjuvant ICI group, compared to the no-adjuvant group (HR: 0.407, 95% CI: 0.243–0.903, p = 0.0467 for chemotherapy vs. no adjuvant therapy; HR: 0.470, 95% CI: 0.192–1.148, p = 0.185 for ICI vs. no adjuvant therapy; HR: 1.117, 95% CI: 0.286–4.362, p = 0.864 for ICI vs. chemotherapy) (Fig. 3). TRAEs with adjuvant chemotherapy and ICI TRAEs of any grade occurred in 87.0% of the patients receiving adjuvant chemotherapy and in 63.6% of those receiving adjuvant ICIs; TRAEs of grade ≥ 3 occurred in 61.1% and 24.2% of patients in the respective groups (Table 4). The most common TRAEs of any grade in the adjuvant chemotherapy group were neutropenia (87.0%), anemia (87.0%), and thrombocytopenia (87.0%), whereas in the adjuvant ICI group, the most common were fatigue (12.1%) and adrenal insufficiency (12.1%). The most frequent grade ≥ 3 TRAEs in the adjuvant chemotherapy group were neutropenia (61.1%), thrombocytopenia (35.2%), and anemia (11.1%), whereas in the adjuvant ICI group, they were adrenal insufficiency (9.1%) and hyperglycemia (6.1%). One patient (3.0%) in the adjuvant ICI group required high-dose glucocorticoids (≥ 40 mg prednisone) for the treatment of colitis, and corticosteroid replacement therapy for adrenal insufficiency was required in four patients (12.1%). No treatment-related deaths occurred in either group. Discussion The present study demonstrated that adjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy, compared with no adjuvant therapy in patients with UTUC at high risk of recurrence following RNU. In multivariate analysis, both adjuvant ICI and adjuvant chemotherapy were identified as independent predictors of prolonged DFS. In addition, both treatment modalities were associated with improved survival, free from recurrence outside the urothelial tract, compared with the no-adjuvant group, whereas neither significantly reduced local recurrences within the urothelial tract. Efficacy of adjuvant therapies The relative rarity of UTUC has raised substantial concerns regarding the feasibility of conducting adequately powered randomized trials in this population. Consequently, for many years, perioperative chemotherapy for UTUC was largely guided by extrapolation from data derived from bladder cancer studies or from single-arm studies with inherent limitations [ 13 ]. The POUT trial has provided the most robust evidence to date in favor of adjuvant chemotherapy. Demonstrating a 55% reduction in the risk of disease recurrence or death (HR: 0.45; 95% CI: 0.30–0.68) [ 5 ], it represents level 1 evidence supporting the use of adjuvant chemotherapy over RNU alone. In the updated analysis of POUT, the 5-year DFS rates were 62% and 45% in the chemotherapy and surveillance groups, respectively (HR: 0.55; 95% CI: 0.38–0.80). Moreover, a trend toward improved OS was observed in the chemotherapy group (multivariable HR: 0.76; 95% CI: 0.51–1.12) [ 14 ]. In the present study, adjuvant chemotherapy was also associated with improved DFS (HR: 0.448, 95% CI: 0.216–0.928 vs. no-adjuvant group) and OS (HR: 0.407, 95% CI: 0.243–0.903 vs. no-adjuvant group) (Fig. 2A, Fig. 3), further supporting the use of adjuvant chemotherapy over observation in high-risk UTUC. A major limitation of adjuvant chemotherapy was the potential deterioration of renal function after RNU, which may preclude the use of cisplatin in patients who would otherwise benefit from it [ 15 , 16 ]. Indeed, in the present cohort, only 15.6% of patients had an estimated glomerular filtration rate of ≥ 50 mL/min/1.73 m 2 after RNU (Table 1), and gemcitabine plus carboplatin was, therefore, the predominant adjuvant regimen. The CheckMate 274 trial randomized patients who underwent radical extirpative surgery for urothelial carcinoma to receive adjuvant nivolumab or placebo for up to 1 year following RNU or cystectomy [ 6 ]. The trial met its primary endpoint of improved DFS (HR: 0.70; 98.22% CI: 0.55–0.90). However, in the subgroup analysis of patients with UTUC (21% of the overall population), the benefit of adjuvant nivolumab was less apparent. The HR for DFS was not statistically significant for renal pelvic tumors (HR: 1.23; 95% CI: 0.67–2.23) or ureteral tumors (HR: 1.56; 95% CI: 0.70–3.48). The AMBASSADOR trial randomized patients to receive adjuvant pembrolizumab after extirpative surgery for UTUC or bladder cancer [ 7 ], including 22% of patients with UTUC. In the overall cohort, the median DFS more than doubled in the pembrolizumab group (29 vs. 14 months); however, subgroup analysis did not demonstrate a statistically significant difference in DFS among patients with UTUC. Similarly, the IMvigor010 trial evaluating atezolizumab (anti-PD-L1) versus observation in patients with high-risk muscle-invasive urothelial carcinoma failed to meet its primary endpoint of DFS benefit (HR: 0.89; 95% CI: 0.74–1.08) [ 17 ]. In the UTUC subgroup, DFS was not significantly improved (HR: 1.25; 95% CI: 0.57–2.74). Despite the lack of definitive evidence, the use of adjuvant ICIs has increased in real-world practice among patients with high-risk UTUC and, since 2022, the predominant adjuvant regimen has shifted from chemotherapy to ICIs in some settings [ 9 ]. Real-world data on the efficacy of adjuvant ICIs have yielded mixed results. Otiato M et al. evaluated the prognostic impact of adjuvant immunotherapy in high-risk UTUC using a United States-based international multi-institutional database and reported that adjuvant ICI was not associated with improved oncologic outcomes; the 1-year non-urinary tract recurrence-free survival rate was 18% in the adjuvant ICI group versus 30% in the non-ICI group ( p = 0.14) [ 10 ]. In contrast, studies from East Asian countries have reported more favorable outcomes. Chen YC et al. investigated the effectiveness of adjuvant nivolumab in Taiwanese patients with urothelial carcinoma, predominantly UTUC (85.7%), in a single-center study and demonstrated a favorable 24-month DFS rate among patients with UTUC (73.1%) compared to those with bladder urothelial carcinoma (66.7%) [ 18 ]. Nakagawa R et al. reported significantly improved DFS in Japanese patients with UTUC treated with adjuvant nivolumab compared with a control group receiving either no adjuvant therapy or adjuvant chemotherapy (HR: 0.21; 95% CI: 0.10–0.42), and the DFS benefit remained significant when compared directly with the adjuvant chemotherapy group (HR: 0.21; 95% CI: 0.09–0.49) [ 11 ]. Hatakeyama S et al. examined trends in perioperative therapy and the efficacy of adjuvant immunotherapy using a multi-institutional Japanese database of patients with muscle-invasive urothelial carcinoma and UTUC. They reported a trend toward improved DFS and OS with adjuvant ICIs in muscle-invasive bladder cancer. In UTUC, DFS with adjuvant ICIs was comparable to that with adjuvant chemotherapy, whereas OS showed a trend toward improvement with ICIs [ 9 ]. The oncologic outcomes observed in the present study were consistent with those reported in East Asian cohorts. Adjuvant ICI was associated with improved DFS compared with both the no-adjuvant group (HR: 0.350; 95% CI: 0.203–0.604) and the adjuvant chemotherapy group (HR: 0.448; 95% CI: 0.216–0.928) (Fig. 2A). Furthermore, both adjuvant ICI and adjuvant chemotherapy significantly reduced non-urothelial tract recurrences compared to no adjuvant therapy, with adjuvant ICI demonstrating a non-significant trend toward longer survival than chemotherapy (Fig. 2B). In contrast, neither modality significantly reduced recurrence within the urothelial tract compared to observation (Fig. 2C). Altogether, these findings suggest that adjuvant ICIs may preferentially reduce recurrences outside the urothelial tract compared to observation and potentially even compared with adjuvant chemotherapy in high-risk UTUC. Although both adjuvant chemotherapy and adjuvant ICI showed trends toward improved OS compared to observation in the present study, these data remain immature due to the relatively short follow-up duration. Exposure and treatment-related adverse events In the POUT trial, 75% of patients in the chemotherapy group received four cycles of treatment, and 44% experienced grade ≥ 3 acute TRAEs; no treatment-related deaths were reported [ 5 ]. In the CheckMate 274 trial, the median duration of nivolumab exposure was 8.8 months, whereas in the AMBASSADOR trial, the mean number of pembrolizumab cycles administered was 11 (61% of the planned 18 cycles) [ 6 ]. Overall, adjuvant ICIs appear to be associated with fewer TRAEs compared to chemotherapy. In CheckMate 274, grade ≥ 3 TRAEs occurred in 17.9% of patients in the nivolumab group, while in the AMBASSADOR trial, grade ≥ 3 TRAEs occurred in 26.4% of patients in the pembrolizumab group. However, treatment-related deaths were reported in 0.9–1.5% of patients across these trials. In real-world settings, treatment exposure appears to be lower than that observed in phase 3 clinical trials. In a retrospective study by Lee J et al., the median number of cycles of gemcitabine plus cisplatin was 3 (range: 1–4), and the frequencies of grade ≥ 3 TRAEs were 6.7% for neutropenia and 2.2% each for anemia, vomiting, and azotemia [ 19 ]. Chen YC et al. reported that the median number of nivolumab cycles was 8.5 (35.4% of the planned 24 cycles), and 61.9% of patients received fewer than 12 cycles (corresponding to < 6 months of treatment) [ 18 ]. Grade ≥ 3 adverse events related to adjuvant nivolumab occurred in 2.4% of patients. Nakagawa R et al. reported no grade ≥ 3 adverse events in the adjuvant nivolumab group [ 11 ]. The exposure observed in the present study was consistent with these real-world reports, with a median of 3 chemotherapy cycles and a median ICI exposure duration of 5.6 months. Grade ≥ 3 TRAEs occurred in 61.1% of patients receiving adjuvant chemotherapy, compared to 24.2% of those receiving adjuvant ICIs. Completion rates of adjuvant therapy were approximately twice as high in the chemotherapy group as in the ICI group (73.2% vs. 34.5%), whereas discontinuation due to TRAEs was less than half as frequent in the chemotherapy group (16.1% vs. 41.4%). No treatment-related deaths occurred in either group. Collectively, these findings suggest that treatment exposure to both chemotherapy and immunotherapy tends to be lower in real-world practice than in clinical trials. Although both adjuvant chemotherapy and ICIs were administered safely, adjuvant ICI was more frequently discontinued due to TRAEs compared with adjuvant chemotherapy. This study had several limitations. First, its retrospective design introduces the potential for selection bias and unmeasured confounding. Second, the use of neoadjuvant therapy and the extent of lymph node dissection varied among treatment groups. Although these factors were not independently associated with DFS in multivariate analysis, residual confounding cannot be completely excluded. Third, the sample sizes of the adjuvant treatment cohorts were modest. Finally, the follow-up duration was relatively short, particularly for the assessment of OS. Conclusions Adjuvant ICI and chemotherapy may reduce disease recurrence following RNU compared with observation in patients with UTUC at high risk of recurrence. The efficacy of adjuvant ICI may confer greater benefit than that of adjuvant chemotherapy. These findings warrant validation in prospective studies. Declarations Author contributions: Satoshi Washino had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Satoshi Washino. Acquisition of data: Satoshi Washino, Go Kaneko, Tomokazu Sazuka, Shoichi Nagamoto, Yuki Nakamura, Akinori Nakayama, Kohei Mito, Kosuke Kazashi, Kimitoshi Saito, Sumire Takeuchi Analysis and interpretation of data: Satoshi Washino Drafting of the manuscript: Satoshi Washino Critical revision of the manuscript for important intellectual content: Go Kaneko, Tomokazu Sazuka, Shoichi Nagamoto, Yuki Nakamura, Akinori Nakayama Statistical analysis: Satoshi Washino Administrative, technical, or material support: None. Supervision: Tomoaki Miyagawa. Other: None. Acknowledgements: We thank Yoshiko Yonejima for their support with the data collection at Toranomon Hospital. Funding None of the authors of this manuscript received any type of support, benefits, or funding from a commercial party related directly or indirectly to the subject of this article. Authors and affiliations Satoshi Washino 1# , Go Kaneko 2 , Tomokazu Sazuka 3 , Shoichi Nagamoto 4 , Yuki Nakamura 5 , Akinari Nakayama 6 , Kohei Mito 1 , Kosuke Kazashi 1 , Kimitoshi Saito 1 , Sumire Takeuchi 1 , Tomoaki Miyagawa 1 Department of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan Department of Uro-Oncology, Saitama Medical University International Medical Center , 1397-1, Yamane, Hidaka, Saitama , 350-1298, Japan. Department of Urology, Chiba University Graduate School of Medicine, 1 Chome-8-1 Inohana, Chuo Ward, Chiba, 260-8677, Japan Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan. Department of Urology, Saitama Cancer Center, 790, Komuro, Ina-machi, Kitaadati-gun, Saitama 362-0806, Japan. Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Saitama, 343-0845, Japan. Corresponding author Corresponding to Satoshi Washino Ethics statement This study was approved by the institutional review board of each study institution and carried out according to the Declaration of Helsinki and its amendments. Informed consent was obtained from all patients via posters and/or websites using the opt-out method. Satoshi Washino received lecture fees from Ono Pharmaceutical. Go Kaneko received lecture fees from Bristol Meyers Squibb and Ono Pharmaceutical. The other authors have no conflicts of interest to declare. References Gontero P (2023) Guidelines on mon-muscle-invasive bladder cancer (Ta, T1 and CIS). EAU Guidelines published at the 38th Annual Congress Milan; Arnhem, the Netherlands. European Associaton of Urology Guidelines Office Margulis V, Shariat SF, Matin SF et al (2009) Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 115:1224–1233. https://doi.org/10.1002/cncr.24135 Soria F, Shariat SF, Lerner SP et al (2017) Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol 35:379–387. https://doi.org/10.1007/s00345-016-1928-x Leow JJ, Liu Z, Tan TW et al (2020) Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives. OTT Volume 13:1–15. https://doi.org/10.2147/OTT.S225301 Birtle A, Johnson M, Chester J et al (2020) Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 395:1268–1277. https://doi.org/10.1016/S0140-6736(20)30415-3 Bajorin DF, Witjes JA, Gschwend JE et al (2021) Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 384:2102–2114. https://doi.org/10.1056/NEJMoa2034442 Apolo AB, Ballman KV, Sonpavde G et al (2025) Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 392:45–55. https://doi.org/10.1056/NEJMoa2401726 Bellmunt J, Hussain M, Gschwend JE et al (2021) Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22:525–537. https://doi.org/10.1016/S1470-2045(21)00004-8 Hatakeyama S, Fujita N, Kobayashi M et al (2025) Trends in the use and efficacy of adjuvant immunotherapy in muscle-invasive urothelial carcinoma. Sci Rep 15:25247. https://doi.org/10.1038/s41598-025-11319-w Otiato M, Moghaddam FS, Ghoreifi A et al (2025) Prognostic Impact of Adjuvant Immunotherapy in Patients with High-Risk Upper Tract Urothelial Cancer: Results from the ROBUUST 2.0 Collaborative Group. Cancers 17:2144. https://doi.org/10.3390/cancers17132144 Nakagawa R, Naito R, Izumi K et al (2025) Real-World Efficacy of Postoperative Adjuvant Nivolumab in High‐Risk Urothelial Carcinoma: A Retrospective Comparative Study in an Asian Population. Asia-Pac J Clncl Oncol ajco 70051. https://doi.org/10.1111/ajco.70051 (2009) Common Terminology Criteria for Adverse Events (CTCAE) Bamias A, Deliveliotis C, Fountzilas G et al (2004) Adjuvant Chemotherapy With Paclitaxel and Carboplatin in Patients With Advanced Carcinoma of the Upper Urinary Tract: A Study by the Hellenic Cooperative Oncology Group. JCO 22:2150–2154. https://doi.org/10.1200/JCO.2004.09.043 Birtle AJ, Jones R, Chester J et al (2024) Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. JCO 42:1466–1471. https://doi.org/10.1200/JCO.23.01659 Xylinas E, Rink M, Margulis V et al (2013) Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 112:453–461. https://doi.org/10.1111/j.1464-410X.2012.11649.x Kaag M, Trost L, Thompson RH et al (2014) Preoperative predictors of renal function decline after radical nephroureterectomy for upper tract urothelial carcinoma. BJU Int 114:674–679. https://doi.org/10.1111/bju.12597 Powles T, Assaf ZJ, Davarpanah N et al (2021) ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595:432–437. https://doi.org/10.1038/s41586-021-03642-9 Chen Y-C, Lai J-I, Chang Y-H et al (2025) Efficacy of adjuvant nivolumab in patients with upper tract predominant urothelial carcinoma: A single-center real-world study. Urologic Oncology: Seminars Original Investigations 43. https://doi.org/10.1016/j.urolonc.2025.07.014 . :697.e11-697.e18 Lee J, Lim SH, Chung JH et al (2024) Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study. Cancer Res Treat 56:871–876. https://doi.org/10.4143/crt.2023.1226 Tables Tables are available in the Supplementary Files section. Supplementary Files Table20260120.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9298500","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620016525,"identity":"3ae5f1b2-5d1f-4649-bcf1-ad0fe5caaca9","order_by":0,"name":"Satoshi Washino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYLACCQMJIMl8gIGxASZCnBa2BBK0QACPAUILPiA/I8fwg0WBhT3/7J5vEj932MgxsB8+wGC5A7cWgxs5xhJAhyXOuHN2m2TvmTRjBp60BAbJM3i0SORuAGlJYLiRu02Ct+1wYoME0IWSbfgclrv5B1CLvfyNnGeSf4nRAjYcqIVxw40cNmmibDE48/6bBcgvG2+kGVvLtqUZswH9cgCfX+Tb05JvS/yps5e7kfzw5ts2Gzl+9sMHH0viCTEQYIZGHAuYZgPiw5IN+LUwfoBq/QAX+UhAyygYBaNgFIwoAAANP0t+tIzWrgAAAABJRU5ErkJggg==","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":true,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Washino","suffix":""},{"id":620016526,"identity":"9e1d2ea2-c05f-4ae2-97c1-36b7374a1efd","order_by":1,"name":"Go Kaneko","email":"","orcid":"","institution":"Saitama Medical University International Medical Center: Saitama Ika Daigaku Kokusai Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Go","middleName":"","lastName":"Kaneko","suffix":""},{"id":620016527,"identity":"10c2ea5e-1b63-4684-a3d3-8dda3bea488d","order_by":2,"name":"Tomokazu Sazuka","email":"","orcid":"","institution":"Chiba University Graduate School of Medicine School of Medicine: Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Tomokazu","middleName":"","lastName":"Sazuka","suffix":""},{"id":620016528,"identity":"77d4e43b-016d-4fd2-b4e6-9d3d0d02675e","order_by":3,"name":"Shoichi Nagamoto","email":"","orcid":"","institution":"Saitama Medical Center Saitama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shoichi","middleName":"","lastName":"Nagamoto","suffix":""},{"id":620016529,"identity":"1251018c-7769-4522-96cf-7d4cc5486efa","order_by":4,"name":"Yuki Nakamura","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Nakamura","suffix":""},{"id":620016530,"identity":"df123b18-271c-41a6-9a56-731e65cdbdf2","order_by":5,"name":"Akinori Nakayama","email":"","orcid":"","institution":"Dokkyo Medical University Saitama Medical Center: Dokkyo Ika Daigaku Saitama Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Akinori","middleName":"","lastName":"Nakayama","suffix":""},{"id":620016531,"identity":"33224a8d-484b-44dc-9399-ac9b715cc69c","order_by":6,"name":"Kohei Mito","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Mito","suffix":""},{"id":620016532,"identity":"c206ba46-5f5b-4273-94b5-a5e888905d86","order_by":7,"name":"Kouske Kazashi","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":false,"prefix":"","firstName":"Kouske","middleName":"","lastName":"Kazashi","suffix":""},{"id":620016533,"identity":"deece330-5c33-49e5-b4ee-db658b3d1aa9","order_by":8,"name":"Kimitoshi Saito","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":false,"prefix":"","firstName":"Kimitoshi","middleName":"","lastName":"Saito","suffix":""},{"id":620016534,"identity":"69a01fdb-cef9-4b4c-9d93-8abdefadb342","order_by":9,"name":"Sumire Takeuchi","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":false,"prefix":"","firstName":"Sumire","middleName":"","lastName":"Takeuchi","suffix":""},{"id":620016535,"identity":"15c9ca2a-7597-40e6-86e8-385a5a4bf6e8","order_by":10,"name":"Akihiro Yano","email":"","orcid":"","institution":"Saitama Medical University Saitama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Yano","suffix":""},{"id":620016536,"identity":"b24532db-39c8-4e13-b388-f6339d2756ca","order_by":11,"name":"Tomoaki Miyagawa","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center Department of Urology: Jichi Ika Daigaku Fuzoku Saitama Iryo Center Hinyokika","correspondingAuthor":false,"prefix":"","firstName":"Tomoaki","middleName":"","lastName":"Miyagawa","suffix":""}],"badges":[],"createdAt":"2026-04-02 05:42:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9298500/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9298500/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107253972,"identity":"954dca50-772b-4c81-aa43-fde8e618de25","added_by":"auto","created_at":"2026-04-19 11:59:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":387673,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection flow diagram\u003c/p\u003e\n\u003cp\u003eUTUC: Upper tract urothelial carcinoma, RNU: radical nephroureterectomy, UC: urothelial carcinoma, adj: adjuvant, chemo: chemotherapy, ICI: immune checkpoint inhibitor\u003c/p\u003e","description":"","filename":"Fig1Patientsflow.png","url":"https://assets-eu.researchsquare.com/files/rs-9298500/v1/ec6eeddf4cb298edcc9263d9.png"},{"id":107253974,"identity":"b025553d-f2b8-4f53-95ae-4f38b17cdcd0","added_by":"auto","created_at":"2026-04-19 11:59:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1625483,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes according to adjuvant treatment\u003c/p\u003e\n\u003cp\u003e(A) Disease-free survival.\u003cbr\u003e\n(B) Non–urothelial tract recurrence-free survival.\u003cbr\u003e\n(C) Urothelial tract recurrence-free survival.\u003cbr\u003e\n(D) Distribution of recurrence sites.\u003c/p\u003e\n\u003cp\u003eSurvival curves were generated using the Kaplan–Meier method and compared using the log-rank test.\u003c/p\u003e\n\u003cp\u003e*, **, ***: p \u0026lt; 0.05, p \u0026lt; 0.01, p \u0026lt; 0.001 versus no adjuvant group, respectively; #: p \u0026lt; 0.05 versus adjuvant chemotherapy group.\u003c/p\u003e\n\u003cp\u003eChemo: chemotherapy, ICI: immune checkpoint inhibitor, Adj: adjuvant.\u003c/p\u003e","description":"","filename":"Fig2DFS20260107.png","url":"https://assets-eu.researchsquare.com/files/rs-9298500/v1/8a385a40c936a2d44f7dadce.png"},{"id":107483779,"identity":"3701189b-8d32-4e1d-835f-9f827476474f","added_by":"auto","created_at":"2026-04-22 02:29:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":518060,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival according to adjuvant treatment\u003c/p\u003e\n\u003cp\u003eOverall survival was estimated using the Ka\\plan–Meier method and compared using the log-rank test.\u003c/p\u003e\n\u003cp\u003e*: p \u0026lt; 0.05 versus no adjuvant group.\u003c/p\u003e\n\u003cp\u003eChemo: chemotherapy, ICI: immune checkpoint inhibitor, Adj: adjuvant.\u003c/p\u003e","description":"","filename":"Fig3OS20260119.png","url":"https://assets-eu.researchsquare.com/files/rs-9298500/v1/43ef47c3d98d5efa954a3d48.png"},{"id":108491823,"identity":"5c33491c-7a79-4787-9f09-1c8347d05608","added_by":"auto","created_at":"2026-05-05 09:55:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2940321,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9298500/v1/0495bbe8-e687-448f-940c-04311e8966f7.pdf"},{"id":107484584,"identity":"94d1a450-a84e-4a13-a37c-e46f11852e7b","added_by":"auto","created_at":"2026-04-22 02:32:26","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34057,"visible":true,"origin":"","legend":"","description":"","filename":"Table20260120.docx","url":"https://assets-eu.researchsquare.com/files/rs-9298500/v1/f7a86e5a7efda224c1bdd898.docx"}],"financialInterests":"","formattedTitle":"Impact of Adjuvant Immune Checkpoint Inhibitors and Chemotherapy on Survival Outcomes in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUpper tract urothelial carcinoma (UTUC) is an uncommon malignancy, accounting for only 5\u0026ndash;10% of all urothelial cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It has been estimated that approximately 60% of UTUCs are invasive at the time of diagnosis (compared to 15\u0026ndash;25% of bladder cancers) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and 7% present with metastatic disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Given that definitive surgical management in the form of radical nephroureterectomy (RNU) is relatively well-standardized, it has been suggested that further improvements in survival outcomes may be achieved through the use of perioperative chemotherapy or immunotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe POUT trial demonstrated that patients with UTUC staged as \u0026ge;\u0026thinsp;pT2 and/or pN+ derived benefit from adjuvant chemotherapy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, the universal administration of cytotoxic chemotherapy to all UTUC patients with \u0026ge;\u0026thinsp;pT2 stage is impractical, as advanced age and impaired renal function may constitute contraindications to such treatment.\u003c/p\u003e \u003cp\u003eThe role of adjuvant immune checkpoint inhibitors (ICIs) in UTUC has evolved over the past decade. The CheckMate 274 and AMBASSADOR trials predominantly enrolled patients with bladder cancer; nevertheless, their findings have been extrapolated to UTUC populations [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These studies included patients who had received neoadjuvant chemotherapy and had\u0026thinsp;\u0026ge;\u0026thinsp;ypT2 and/or ypN+ tumors following cystectomy or nephroureterectomy, as well as those who had not received neoadjuvant chemotherapy and had\u0026thinsp;\u0026ge;\u0026thinsp;pT3 and/or pN+ tumors. However, only 6.7\u0026ndash;22% of the study populations comprised UTUC patients. Both CheckMate 274 and AMBASSADOR demonstrated prolonged disease-free survival (DFS) with adjuvant ICIs. However, in subset analyses, the effect of adjuvant ICIs on DFS was less pronounced among UTUC patients.\u003c/p\u003e \u003cp\u003eTo date, only a limited number of studies have evaluated the efficacy of adjuvant ICIs compared with observation or adjuvant chemotherapy in patients with high-risk UTUC [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and the therapeutic benefit of adjuvant ICIs in this setting remains to be definitively established. In the present multicenter retrospective study, we assessed the impact of adjuvant ICIs and chemotherapy on survival outcomes in patients with high-risk UTUC. Specifically, we aimed to compare DFS among patients who received no adjuvant therapy, adjuvant chemotherapy, or adjuvant ICIs.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThe Musashino-Study Group for UTUC database included 612 patients who underwent RNU for UTUC across six academic centers between January 2020 and December 2024. A total of 45 patients were excluded for the following reasons: non-urothelial carcinoma on histology (n\u0026thinsp;=\u0026thinsp;22), concurrent RNU and radical cystectomy (n\u0026thinsp;=\u0026thinsp;16), metastatic disease (n\u0026thinsp;=\u0026thinsp;5), and other reasons (n\u0026thinsp;=\u0026thinsp;2) (Fig.\u0026nbsp;1). Among the remaining 567 eligible patients, 243 with high-risk UTUC were included in the present study. High-risk UTUC was defined as pathological evidence of urothelial carcinoma originating in the ureter or renal pelvis with a high risk of recurrence, specifically a pathological stage of \u0026ge;\u0026thinsp;pT3 or pN\u0026thinsp;+\u0026thinsp;in patients who had not received neoadjuvant therapy, and \u0026ge;\u0026thinsp;ypT2 or ypN\u0026thinsp;+\u0026thinsp;in those who had received neoadjuvant therapy.\u003c/p\u003e \u003cp\u003ePatients were categorized into three groups: no adjuvant therapy (n\u0026thinsp;=\u0026thinsp;151), adjuvant chemotherapy (n\u0026thinsp;=\u0026thinsp;59), and adjuvant ICI (n\u0026thinsp;=\u0026thinsp;33). In the adjuvant chemotherapy group, gemcitabine plus cisplatin was administered to patients with adequate renal function, whereas gemcitabine plus carboplatin was administered to those with impaired renal function. Chemotherapy was given every 3 weeks for a maximum of three to five cycles, according to each institution\u0026rsquo;s protocol. In the adjuvant ICI group, nivolumab 240 mg (or 480 mg) was administered every 2 (or 4) weeks, or pembrolizumab 300 mg was administered every 3 weeks, for up to 1 year.\u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review board of Jichi Medical University Saitama Medical Centre (No. RinS25-049) and the review boards of the other participating centers.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy objectives\u003c/h3\u003e\n\u003cp\u003eThe primary objective was to compare DFS among the three groups. DFS was defined as the time from the date of RNU to the date of first recurrence (local recurrence within the urothelial tract, local recurrence outside the urothelial tract, or distant recurrence) or death. Multivariate analyses were performed to evaluate the impact of perioperative therapies and pathological findings on DFS.\u003c/p\u003e \u003cp\u003eWe also evaluated survival free from recurrence outside the urothelial tract and survival free from local recurrence within the urothelial tract. Survival free from recurrence outside the urothelial tract (non-urothelial tract recurrence-free survival) was defined as the time from the date of RNU to the date of first local recurrence outside the urothelial tract, distant recurrence, or death. Survival free from local recurrence within the urothelial tract (urothelial tract recurrence-free survival) was defined as the time from the date of RNU to the date of first local recurrence within the urothelial tract. A 2-month landmark analysis was conducted for survival analyses to minimize lead-time bias in the adjuvant therapy groups.\u003c/p\u003e \u003cp\u003eSafety analyses were performed in both the adjuvant chemotherapy and adjuvant ICI groups. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were presented as medians and interquartile ranges (IQRs) or as numbers and percentages, as appropriate. Variables were compared using one-way analysis of variance or chi-square tests. Kaplan-Meier curves were generated to estimate survival outcomes, and comparisons were performed using the log-rank test. Cox proportional hazards models were applied to identify factors associated with DFS. All analyses were performed using GraphPad Prism (version 10.6.1), and \u003cem\u003ep\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; backgrounds and pathological findings\u003c/h2\u003e \u003cp\u003eThe median (IQR) age of the overall population was 76 (70\u0026ndash;80) years, and 67.9% of the patients were males (Table\u0026nbsp;1). The primary tumors were located in the renal pelvis in 114 patients (46.9%) and in the ureter in 129 patients (53.1%). Baseline characteristics, including age, sex, performance status, tumor location, and postoperative renal function, were largely comparable among the three groups, with the exception of the frequency of neoadjuvant therapy and lymph node dissection. Platinum-based neoadjuvant chemotherapy was administered most frequently in the adjuvant ICI group (54.5%), followed by the no-adjuvant group (21.9%), whereas no patients in the adjuvant chemotherapy group received neoadjuvant therapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Limited and template lymph node dissections were performed in 37 (24.5%) and 7 (4.6%) patients in the no-adjuvant group, 8 (13.6%) and 5 (8.5%) patients in the adjuvant chemotherapy group, and 6 (18.2%) and 6 (18.2%) patients in the adjuvant ICI group, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0040). The median follow-up durations were 12.3 (5.1\u0026ndash;32.8), 23.7 (5.1\u0026ndash;32.8), and 16.8 (11.1\u0026ndash;24.0) months in the no-adjuvant, adjuvant chemotherapy, and adjuvant ICI groups, respectively.\u003c/p\u003e \u003cp\u003ePathological findings, including tumor histology, pathological tumor stage, nodal stage, and resection margin status, did not differ significantly among the three groups (Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdjuvant chemotherapy and ICI\u003c/h2\u003e \u003cp\u003eIn the adjuvant chemotherapy group, 16 patients (27.1%) received gemcitabine plus cisplatin as the initial regimen; among these patients, treatment was switched to gemcitabine plus carboplatin in two patients due to adverse events. The remaining 43 patients initiated treatment with gemcitabine plus carboplatin. The median time to initiation of adjuvant chemotherapy was 1.8 months (IQR: 1.5\u0026ndash;2.2), and the median number of administered cycles was 3 (IQR: 2\u0026ndash;4). Among 56 patients with available follow-up data, 41 (73.2%) completed the planned course of adjuvant chemotherapy. Treatment discontinuation occurred in 9 (16.1%), 2 (3.6%), and 4 (7.1%) patients due to treatment-related adverse events (TRAEs), disease progression, and other reasons, respectively.\u003c/p\u003e \u003cp\u003eIn the adjuvant ICI group, 32 patients received nivolumab and one patient received pembrolizumab. The median time to initiation of adjuvant ICI was 2.1 months (IQR 1.8\u0026ndash;2.6). At the time of assessment, 31 patients had either completed or discontinued ICI therapy, whereas two patients were still undergoing treatment. Among patients who completed or discontinued ICI therapy, the median duration of exposure was 5.6 months (IQR: 3.7\u0026ndash;11.0). The median cumulative dose of nivolumab was 2400 mg (IQR: 1440\u0026ndash;4080). Among 29 evaluable patients, 10 (34.5%) completed adjuvant ICI therapy, whereas 12 (41.4%) and 7 (24.1%) discontinued treatment due to TRAEs and disease progression, respectively.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eAdjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy and no adjuvant therapy. The median DFS was not reached (NR) in the adjuvant ICI group, 14.0 months (95% confidence interval [CI]: 10.6\u0026ndash;33.7) in the adjuvant chemotherapy group, and 11.9 months (95% CI: 9.2\u0026ndash;14.4) in the no-adjuvant group (Fig.\u0026nbsp;2A). The 12-month DFS rates were 80.2%, 59.4%, and 49.4% in the adjuvant ICI, adjuvant chemotherapy, and no-adjuvant groups, respectively. Adjuvant ICI significantly improved DFS compared to no adjuvant therapy (hazard ratio [HR]: 0.350, 95% CI: 0.203\u0026ndash;0.604, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0083). Adjuvant chemotherapy demonstrated a trend toward improved DFS (HR: 0.690, 95% CI: 0.444\u0026ndash;1.072, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.095). A trend favoring adjuvant ICI over adjuvant chemotherapy was also observed (HR: 0.448, 95% CI: 0.216\u0026ndash;0.928, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.055).\u003c/p\u003e \u003cp\u003eBoth adjuvant ICI and adjuvant chemotherapy were associated with prolonged non-urothelial tract recurrence-free survival (Fig.\u0026nbsp;2B). The median non-urothelial tract recurrence-free survival was 34.3 months (95% CI: 23.2\u0026ndash;NR) in the adjuvant ICI group, 19.8 months (95% CI: 12.2\u0026ndash;NR) in the adjuvant chemotherapy group, and 15.8 months (95% CI: 10.5\u0026ndash;21.0) in the no-adjuvant group. No significant differences were observed in urothelial tract recurrence-free survival among the three groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.144) (Fig.\u0026nbsp;2C). The most common site of recurrence in the no-adjuvant group was the regional lymph nodes (27.8%), followed by intravesical recurrence (25.2%), lungs (20.5%), and liver (9.3%) (Fig.\u0026nbsp;2D). Compared to the no-adjuvant group, adjuvant chemotherapy reduced recurrences in the lungs (8.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042) and liver (1.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.073). Adjuvant ICI reduced recurrences in the regional lymph nodes (9.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025) and was not associated with any recurrences in the lungs, liver, or bone.\u003c/p\u003e \u003cp\u003eMultivariate Cox regression analysis identified adjuvant ICI (HR: 0.313, 95% CI: 0.134\u0026ndash;0.639, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0009) and adjuvant chemotherapy (HR: 0.624, 95% CI: 0.388\u0026ndash;0.980, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041) as independent predictors of prolonged DFS, whereas positive surgical margins were independently associated with shorter DFS (HR: 2.586, 95% CI: 1.493\u0026ndash;4.361, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0009) (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eOverall survival (OS) was longest in the adjuvant chemotherapy group, followed by the adjuvant ICI group, compared to the no-adjuvant group (HR: 0.407, 95% CI: 0.243\u0026ndash;0.903, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0467 for chemotherapy vs. no adjuvant therapy; HR: 0.470, 95% CI: 0.192\u0026ndash;1.148, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.185 for ICI vs. no adjuvant therapy; HR: 1.117, 95% CI: 0.286\u0026ndash;4.362, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.864 for ICI vs. chemotherapy) (Fig.\u0026nbsp;3).\u003c/p\u003e\n\u003ch3\u003eTRAEs with adjuvant chemotherapy and ICI\u003c/h3\u003e\n\u003cp\u003eTRAEs of any grade occurred in 87.0% of the patients receiving adjuvant chemotherapy and in 63.6% of those receiving adjuvant ICIs; TRAEs of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 occurred in 61.1% and 24.2% of patients in the respective groups (Table\u0026nbsp;4). The most common TRAEs of any grade in the adjuvant chemotherapy group were neutropenia (87.0%), anemia (87.0%), and thrombocytopenia (87.0%), whereas in the adjuvant ICI group, the most common were fatigue (12.1%) and adrenal insufficiency (12.1%). The most frequent grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs in the adjuvant chemotherapy group were neutropenia (61.1%), thrombocytopenia (35.2%), and anemia (11.1%), whereas in the adjuvant ICI group, they were adrenal insufficiency (9.1%) and hyperglycemia (6.1%). One patient (3.0%) in the adjuvant ICI group required high-dose glucocorticoids (\u0026ge;\u0026thinsp;40 mg prednisone) for the treatment of colitis, and corticosteroid replacement therapy for adrenal insufficiency was required in four patients (12.1%). No treatment-related deaths occurred in either group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e The present study demonstrated that adjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy, compared with no adjuvant therapy in patients with UTUC at high risk of recurrence following RNU. In multivariate analysis, both adjuvant ICI and adjuvant chemotherapy were identified as independent predictors of prolonged DFS. In addition, both treatment modalities were associated with improved survival, free from recurrence outside the urothelial tract, compared with the no-adjuvant group, whereas neither significantly reduced local recurrences within the urothelial tract.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy of adjuvant therapies\u003c/h2\u003e \u003cp\u003eThe relative rarity of UTUC has raised substantial concerns regarding the feasibility of conducting adequately powered randomized trials in this population. Consequently, for many years, perioperative chemotherapy for UTUC was largely guided by extrapolation from data derived from bladder cancer studies or from single-arm studies with inherent limitations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe POUT trial has provided the most robust evidence to date in favor of adjuvant chemotherapy. Demonstrating a 55% reduction in the risk of disease recurrence or death (HR: 0.45; 95% CI: 0.30\u0026ndash;0.68) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], it represents level 1 evidence supporting the use of adjuvant chemotherapy over RNU alone. In the updated analysis of POUT, the 5-year DFS rates were 62% and 45% in the chemotherapy and surveillance groups, respectively (HR: 0.55; 95% CI: 0.38\u0026ndash;0.80). Moreover, a trend toward improved OS was observed in the chemotherapy group (multivariable HR: 0.76; 95% CI: 0.51\u0026ndash;1.12) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the present study, adjuvant chemotherapy was also associated with improved DFS (HR: 0.448, 95% CI: 0.216\u0026ndash;0.928 vs. no-adjuvant group) and OS (HR: 0.407, 95% CI: 0.243\u0026ndash;0.903 vs. no-adjuvant group) (Fig.\u0026nbsp;2A, Fig.\u0026nbsp;3), further supporting the use of adjuvant chemotherapy over observation in high-risk UTUC. A major limitation of adjuvant chemotherapy was the potential deterioration of renal function after RNU, which may preclude the use of cisplatin in patients who would otherwise benefit from it [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Indeed, in the present cohort, only 15.6% of patients had an estimated glomerular filtration rate of \u0026ge;\u0026thinsp;50 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e after RNU (Table\u0026nbsp;1), and gemcitabine plus carboplatin was, therefore, the predominant adjuvant regimen.\u003c/p\u003e \u003cp\u003eThe CheckMate 274 trial randomized patients who underwent radical extirpative surgery for urothelial carcinoma to receive adjuvant nivolumab or placebo for up to 1 year following RNU or cystectomy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The trial met its primary endpoint of improved DFS (HR: 0.70; 98.22% CI: 0.55\u0026ndash;0.90). However, in the subgroup analysis of patients with UTUC (21% of the overall population), the benefit of adjuvant nivolumab was less apparent. The HR for DFS was not statistically significant for renal pelvic tumors (HR: 1.23; 95% CI: 0.67\u0026ndash;2.23) or ureteral tumors (HR: 1.56; 95% CI: 0.70\u0026ndash;3.48). The AMBASSADOR trial randomized patients to receive adjuvant pembrolizumab after extirpative surgery for UTUC or bladder cancer [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], including 22% of patients with UTUC. In the overall cohort, the median DFS more than doubled in the pembrolizumab group (29 vs. 14 months); however, subgroup analysis did not demonstrate a statistically significant difference in DFS among patients with UTUC. Similarly, the IMvigor010 trial evaluating atezolizumab (anti-PD-L1) versus observation in patients with high-risk muscle-invasive urothelial carcinoma failed to meet its primary endpoint of DFS benefit (HR: 0.89; 95% CI: 0.74\u0026ndash;1.08) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the UTUC subgroup, DFS was not significantly improved (HR: 1.25; 95% CI: 0.57\u0026ndash;2.74).\u003c/p\u003e \u003cp\u003eDespite the lack of definitive evidence, the use of adjuvant ICIs has increased in real-world practice among patients with high-risk UTUC and, since 2022, the predominant adjuvant regimen has shifted from chemotherapy to ICIs in some settings [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Real-world data on the efficacy of adjuvant ICIs have yielded mixed results. Otiato M et al. evaluated the prognostic impact of adjuvant immunotherapy in high-risk UTUC using a United States-based international multi-institutional database and reported that adjuvant ICI was not associated with improved oncologic outcomes; the 1-year non-urinary tract recurrence-free survival rate was 18% in the adjuvant ICI group versus 30% in the non-ICI group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.14) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In contrast, studies from East Asian countries have reported more favorable outcomes. Chen YC et al. investigated the effectiveness of adjuvant nivolumab in Taiwanese patients with urothelial carcinoma, predominantly UTUC (85.7%), in a single-center study and demonstrated a favorable 24-month DFS rate among patients with UTUC (73.1%) compared to those with bladder urothelial carcinoma (66.7%) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nakagawa R et al. reported significantly improved DFS in Japanese patients with UTUC treated with adjuvant nivolumab compared with a control group receiving either no adjuvant therapy or adjuvant chemotherapy (HR: 0.21; 95% CI: 0.10\u0026ndash;0.42), and the DFS benefit remained significant when compared directly with the adjuvant chemotherapy group (HR: 0.21; 95% CI: 0.09\u0026ndash;0.49) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Hatakeyama S et al. examined trends in perioperative therapy and the efficacy of adjuvant immunotherapy using a multi-institutional Japanese database of patients with muscle-invasive urothelial carcinoma and UTUC. They reported a trend toward improved DFS and OS with adjuvant ICIs in muscle-invasive bladder cancer. In UTUC, DFS with adjuvant ICIs was comparable to that with adjuvant chemotherapy, whereas OS showed a trend toward improvement with ICIs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe oncologic outcomes observed in the present study were consistent with those reported in East Asian cohorts. Adjuvant ICI was associated with improved DFS compared with both the no-adjuvant group (HR: 0.350; 95% CI: 0.203\u0026ndash;0.604) and the adjuvant chemotherapy group (HR: 0.448; 95% CI: 0.216\u0026ndash;0.928) (Fig.\u0026nbsp;2A). Furthermore, both adjuvant ICI and adjuvant chemotherapy significantly reduced non-urothelial tract recurrences compared to no adjuvant therapy, with adjuvant ICI demonstrating a non-significant trend toward longer survival than chemotherapy (Fig.\u0026nbsp;2B). In contrast, neither modality significantly reduced recurrence within the urothelial tract compared to observation (Fig.\u0026nbsp;2C). Altogether, these findings suggest that adjuvant ICIs may preferentially reduce recurrences outside the urothelial tract compared to observation and potentially even compared with adjuvant chemotherapy in high-risk UTUC. Although both adjuvant chemotherapy and adjuvant ICI showed trends toward improved OS compared to observation in the present study, these data remain immature due to the relatively short follow-up duration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eExposure and treatment-related adverse events\u003c/h2\u003e \u003cp\u003eIn the POUT trial, 75% of patients in the chemotherapy group received four cycles of treatment, and 44% experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;3 acute TRAEs; no treatment-related deaths were reported [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the CheckMate 274 trial, the median duration of nivolumab exposure was 8.8 months, whereas in the AMBASSADOR trial, the mean number of pembrolizumab cycles administered was 11 (61% of the planned 18 cycles) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Overall, adjuvant ICIs appear to be associated with fewer TRAEs compared to chemotherapy. In CheckMate 274, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs occurred in 17.9% of patients in the nivolumab group, while in the AMBASSADOR trial, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs occurred in 26.4% of patients in the pembrolizumab group. However, treatment-related deaths were reported in 0.9\u0026ndash;1.5% of patients across these trials.\u003c/p\u003e \u003cp\u003eIn real-world settings, treatment exposure appears to be lower than that observed in phase 3 clinical trials. In a retrospective study by Lee J et al., the median number of cycles of gemcitabine plus cisplatin was 3 (range: 1\u0026ndash;4), and the frequencies of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs were 6.7% for neutropenia and 2.2% each for anemia, vomiting, and azotemia [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Chen YC et al. reported that the median number of nivolumab cycles was 8.5 (35.4% of the planned 24 cycles), and 61.9% of patients received fewer than 12 cycles (corresponding to \u0026lt;\u0026thinsp;6 months of treatment) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events related to adjuvant nivolumab occurred in 2.4% of patients. Nakagawa R et al. reported no grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events in the adjuvant nivolumab group [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The exposure observed in the present study was consistent with these real-world reports, with a median of 3 chemotherapy cycles and a median ICI exposure duration of 5.6 months. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs occurred in 61.1% of patients receiving adjuvant chemotherapy, compared to 24.2% of those receiving adjuvant ICIs. Completion rates of adjuvant therapy were approximately twice as high in the chemotherapy group as in the ICI group (73.2% vs. 34.5%), whereas discontinuation due to TRAEs was less than half as frequent in the chemotherapy group (16.1% vs. 41.4%). No treatment-related deaths occurred in either group. Collectively, these findings suggest that treatment exposure to both chemotherapy and immunotherapy tends to be lower in real-world practice than in clinical trials. Although both adjuvant chemotherapy and ICIs were administered safely, adjuvant ICI was more frequently discontinued due to TRAEs compared with adjuvant chemotherapy.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, its retrospective design introduces the potential for selection bias and unmeasured confounding. Second, the use of neoadjuvant therapy and the extent of lymph node dissection varied among treatment groups. Although these factors were not independently associated with DFS in multivariate analysis, residual confounding cannot be completely excluded. Third, the sample sizes of the adjuvant treatment cohorts were modest. Finally, the follow-up duration was relatively short, particularly for the assessment of OS.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAdjuvant ICI and chemotherapy may reduce disease recurrence following RNU compared with observation in patients with UTUC at high risk of recurrence. The efficacy of adjuvant ICI may confer greater benefit than that of adjuvant chemotherapy. These findings warrant validation in prospective studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e Satoshi Washino had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Study concept and design: Satoshi Washino.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcquisition of data: Satoshi Washino, Go Kaneko, Tomokazu Sazuka, Shoichi Nagamoto, Yuki Nakamura, Akinori Nakayama, Kohei Mito, Kosuke Kazashi, Kimitoshi Saito, Sumire Takeuchi\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: Satoshi Washino\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: Satoshi Washino\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectual content: Go Kaneko, Tomokazu Sazuka, Shoichi Nagamoto, Yuki Nakamura, Akinori Nakayama\u003c/p\u003e\n\u003cp\u003eStatistical analysis: Satoshi Washino\u003c/p\u003e\n\n\u003cp\u003eAdministrative, technical, or material support: None.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupervision: Tomoaki Miyagawa.\u003c/p\u003e\n\u003cp\u003eOther: None.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe thank Yoshiko Yonejima for their support with the data collection at Toranomon Hospital.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors of this manuscript received any type of support, benefits, or funding from a commercial party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSatoshi Washino \u003csup\u003e1#\u003c/sup\u003e, Go Kaneko \u003csup\u003e2\u003c/sup\u003e, Tomokazu Sazuka \u003csup\u003e3\u003c/sup\u003e, Shoichi Nagamoto \u003csup\u003e4\u003c/sup\u003e, Yuki Nakamura \u003csup\u003e5\u003c/sup\u003e, Akinari Nakayama \u003csup\u003e6\u003c/sup\u003e, Kohei Mito \u003csup\u003e1\u003c/sup\u003e, Kosuke Kazashi \u003csup\u003e1\u003c/sup\u003e, Kimitoshi Saito \u003csup\u003e1\u003c/sup\u003e, Sumire Takeuchi \u003csup\u003e1\u003c/sup\u003e, Tomoaki Miyagawa \u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eDepartment of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan\u003c/li\u003e\n \u003cli\u003eDepartment of Uro-Oncology, Saitama Medical University International Medical Center\u003cstrong\u003e, \u003cstrong\u003e1397-1, Yamane, Hidaka, Saitama\u003c/strong\u003e,\u0026nbsp;\u003c/strong\u003e350-1298, Japan.\u003c/li\u003e\n \u003cli\u003eDepartment of Urology, Chiba University Graduate School of Medicine, 1 Chome-8-1 Inohana, Chuo Ward, Chiba, 260-8677, Japan\u003c/li\u003e\n \u003cli\u003eDepartment of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan.\u003c/li\u003e\n \u003cli\u003eDepartment of Urology, Saitama Cancer Center, 790, Komuro, Ina-machi, Kitaadati-gun, Saitama 362-0806, Japan.\u003c/li\u003e\n \u003cli\u003eDepartment of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Saitama, 343-0845, Japan.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eCorresponding author\u003c/p\u003e\n\u003cp\u003eCorresponding to Satoshi Washino\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review board of each study institution and carried out according to the Declaration of Helsinki and its amendments. Informed consent was obtained from all patients via posters and/or websites using the opt-out method. Satoshi Washino received lecture fees from Ono Pharmaceutical. Go Kaneko received lecture fees from Bristol Meyers Squibb and Ono Pharmaceutical. The other authors have no conflicts of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGontero P (2023) Guidelines on mon-muscle-invasive bladder cancer (Ta, T1 and CIS). EAU Guidelines published at the 38th Annual Congress Milan; Arnhem, the Netherlands. European Associaton of Urology Guidelines Office\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMargulis V, Shariat SF, Matin SF et al (2009) Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 115:1224\u0026ndash;1233. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cncr.24135\u003c/span\u003e\u003cspan address=\"10.1002/cncr.24135\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoria F, Shariat SF, Lerner SP et al (2017) Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol 35:379\u0026ndash;387. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00345-016-1928-x\u003c/span\u003e\u003cspan address=\"10.1007/s00345-016-1928-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeow JJ, Liu Z, Tan TW et al (2020) Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives. OTT Volume 13:1\u0026ndash;15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/OTT.S225301\u003c/span\u003e\u003cspan address=\"10.2147/OTT.S225301\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBirtle A, Johnson M, Chester J et al (2020) Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 395:1268\u0026ndash;1277. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(20)30415-3\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(20)30415-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBajorin DF, Witjes JA, Gschwend JE et al (2021) Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 384:2102\u0026ndash;2114. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2034442\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2034442\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eApolo AB, Ballman KV, Sonpavde G et al (2025) Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 392:45\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2401726\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2401726\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, Hussain M, Gschwend JE et al (2021) Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22:525\u0026ndash;537. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1470-2045(21)00004-8\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(21)00004-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHatakeyama S, Fujita N, Kobayashi M et al (2025) Trends in the use and efficacy of adjuvant immunotherapy in muscle-invasive urothelial carcinoma. Sci Rep 15:25247. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-025-11319-w\u003c/span\u003e\u003cspan address=\"10.1038/s41598-025-11319-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOtiato M, Moghaddam FS, Ghoreifi A et al (2025) Prognostic Impact of Adjuvant Immunotherapy in Patients with High-Risk Upper Tract Urothelial Cancer: Results from the ROBUUST 2.0 Collaborative Group. Cancers 17:2144. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cancers17132144\u003c/span\u003e\u003cspan address=\"10.3390/cancers17132144\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakagawa R, Naito R, Izumi K et al (2025) Real-World Efficacy of Postoperative Adjuvant Nivolumab in High‐Risk Urothelial Carcinoma: A Retrospective Comparative Study in an Asian Population. Asia-Pac J Clncl Oncol ajco 70051. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/ajco.70051\u003c/span\u003e\u003cspan address=\"10.1111/ajco.70051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(2009) Common Terminology Criteria for Adverse Events (CTCAE)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBamias A, Deliveliotis C, Fountzilas G et al (2004) Adjuvant Chemotherapy With Paclitaxel and Carboplatin in Patients With Advanced Carcinoma of the Upper Urinary Tract: A Study by the Hellenic Cooperative Oncology Group. JCO 22:2150\u0026ndash;2154. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.2004.09.043\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2004.09.043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBirtle AJ, Jones R, Chester J et al (2024) Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. JCO 42:1466\u0026ndash;1471. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.23.01659\u003c/span\u003e\u003cspan address=\"10.1200/JCO.23.01659\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXylinas E, Rink M, Margulis V et al (2013) Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 112:453\u0026ndash;461. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/j.1464-410X.2012.11649.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1464-410X.2012.11649.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaag M, Trost L, Thompson RH et al (2014) Preoperative predictors of renal function decline after radical nephroureterectomy for upper tract urothelial carcinoma. BJU Int 114:674\u0026ndash;679. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/bju.12597\u003c/span\u003e\u003cspan address=\"10.1111/bju.12597\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, Assaf ZJ, Davarpanah N et al (2021) ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595:432\u0026ndash;437. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41586-021-03642-9\u003c/span\u003e\u003cspan address=\"10.1038/s41586-021-03642-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Y-C, Lai J-I, Chang Y-H et al (2025) Efficacy of adjuvant nivolumab in patients with upper tract predominant urothelial carcinoma: A single-center real-world study. Urologic Oncology: Seminars Original Investigations 43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.urolonc.2025.07.014\u003c/span\u003e\u003cspan address=\"10.1016/j.urolonc.2025.07.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. :697.e11-697.e18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee J, Lim SH, Chung JH et al (2024) Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study. Cancer Res Treat 56:871\u0026ndash;876. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4143/crt.2023.1226\u003c/span\u003e\u003cspan address=\"10.4143/crt.2023.1226\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune check inhibitor, chemotherapy, adjuvant therapy, upper tract urothelial carcinoma, survival","lastPublishedDoi":"10.21203/rs.3.rs-9298500/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9298500/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe efficacy of adjuvant immune checkpoint inhibitors (ICIs) compared with observation or adjuvant chemotherapy in patients with upper tract urothelial carcinoma (UTUC) at high risk of recurrence remains uncertain. We conducted a retrospective, multi-institutional study to evaluate the impact of adjuvant ICIs and chemotherapy on survival outcomes in patients with high-risk UTUC.\u003c/p\u003e\u003ch2\u003ePatients and Methods\u003c/h2\u003e \u003cp\u003eA total of 243 patients with high-risk UTUC were included in the analysis. Patients were categorized into three groups: no adjuvant therapy (n\u0026thinsp;=\u0026thinsp;151), adjuvant chemotherapy (n\u0026thinsp;=\u0026thinsp;59), and adjuvant ICI (n\u0026thinsp;=\u0026thinsp;33). Multivariate Cox proportional hazards regression analysis was performed to identify factors independently associated with DFS.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median age was 76 years, and 67.9% of patients were male. Baseline characteristics and pathological findings were largely comparable among the groups, except for differences in the frequency of neoadjuvant therapy and lymph node dissection. Adjuvant ICI was associated with the longest DFS, followed by adjuvant chemotherapy and no adjuvant therapy (ICI vs. no adjuvant: HR: 0.350, 95% CI: 0.203\u0026ndash;0.604; chemotherapy vs. no adjuvant: HR: 0.690, 95% CI: 0.444\u0026ndash;1.072; ICI vs. chemotherapy: HR: 0.448, 95% CI: 0.216\u0026ndash;0.928,). In multivariate analysis, adjuvant ICI and adjuvant chemotherapy were identified as independent predictors of prolonged DFS, while positive surgical margins were independently associated with shorter DFS.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAdjuvant ICIs and chemotherapy may reduce disease recurrence following radical nephroureterectomy in patients with high-risk UTUC. Adjuvant ICI may confer greater benefit than chemotherapy. Prospective studies are warranted to validate these findings.\u003c/p\u003e","manuscriptTitle":"Impact of Adjuvant Immune Checkpoint Inhibitors and Chemotherapy on Survival Outcomes in High-Risk Upper Tract Urothelial Carcinoma: A Multicenter Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 11:58:58","doi":"10.21203/rs.3.rs-9298500/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"591816e9-4ee7-42f8-8d37-de5cbd42bf68","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Reject","date":"2026-05-02T04:25:31+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-02T08:25:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 11:58:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9298500","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9298500","identity":"rs-9298500","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}