Abstract
Background:
Contralateral recurrence of upper-tract urothelial carcinoma (UTUC) presents a clinical challenge, with limited evidence regarding optimal surgical management.
Objective:
To compare oncological outcomes among patients with contralateral UTUC recurrence managed by second nephroureterectomy (NUR) or nephron-sparing surgery (NSS), relative to those undergoing primary NUR.
Design:
A multicentre retrospective cohort study.
Methods:
In this multicentre retrospective cohort, 3159 patients diagnosed with UTUC between 2018 and 2024 in the Taiwanese UTUC Registry were analysed. Patients undergoing curative-intent surgery were grouped as follows: unilateral UTUC treated with primary NUR; contralateral recurrence treated with a second NUR; and contralateral recurrence managed with nephron-sparing surgery (NSS; segmental ureterectomy or endoscopic ablation). NUR was performed via open, laparoscopic, or robotic-assisted approaches. Outcomes included overall survival (OS), cancer-specific survival (CSS) and bladder recurrence-free survival (BRFS). Propensity score-based overlap weighting adjusted for baseline differences.
Results:
After adjustment, both second NUR and NSS achieved OS, CSS, and BRFS comparable to primary NUR. Tumour biology, including stage, lymphovascular invasion and multifocality, exerted greater prognostic impact than contralateral recurrence status or surgical modality. While the rarity of contralateral recurrence limited statistical power, particularly for CSS and in the NSS subgroup, the consistency of effect estimates supports the robustness of the observed trends.
Conclusion:
In this multicentre real-world cohort, second NUR and NSS for contralateral UTUC recurrence demonstrated broadly comparable survival outcomes to primary NUR, though the limited number of NSS cases and corresponding statistical power preclude firm conclusions.
Keywords: cancer-specific survival, contralateral recurrence, nephron-sparing surgery, nephroureterectomy, real-world evidence, upper-tract urothelial carcinoma
Plain language summary
Treatment outcomes when cancer returns in the opposite kidney tube after curative surgery: results from a large multi-hospital study
Why was the study done? Cancers of the upper urinary tract, which includes the kidney’s drainage tube, can sometimes come back on the opposite side after the first cancer is removed. When this happens, patients and doctors face difficult treatment choices. It is not clear whether another major surgery or a smaller kidney-sparing operation is better. Until now, there has been little research to guide these decisions.
What did the researchers do? The research team used data from the Taiwanese Upper Tract Urothelial Carcinoma Registry, which combines information from many hospitals. They studied more than 3,000 people diagnosed between 2018 and 2024. The team compared three groups: patients who had one cancer removed, those who later developed cancer on the opposite side and had another full removal (nephroureterectomy), and those who had a kidney-sparing procedure instead.
What did the researchers find? Patients who had a second nephroureterectomy, and some carefully selected patients who received a kidney-sparing surgery, showed survival outcomes that were broadly similar to those treated for a single cancer. Their chances of avoiding cancer in the bladder were also generally comparable. Overall, survival was mainly influenced by the cancer’s characteristics – such as its stage or spread into blood vessels – rather than by whether the cancer was new or a recurrence on the opposite side.
What do the findings mean? These results show that surgery can still work well for carefully chosen patients even when cancer returns on the opposite side. This should reassure both patients and doctors when discussing treatment options. However, because this type of recurrence is rare, larger studies are needed to confirm these findings.
Introduction
Urothelial carcinoma is known for its multifocal potential and may arise anywhere along the urinary tract. 1 Tumours of the upper urinary tract account for 5%–10% of all urothelial malignancies. 2 Radical nephroureterectomy (NUR) remains the standard curative treatment for localised upper-tract urothelial carcinoma (UTUC). 3 Nevertheless, 3%–5% of patients experience metachronous contralateral recurrence during follow-up despite initial definitive surgery.2,4
Managing contralateral recurrence is particularly challenging in patients with a solitary kidney after prior NUR. Surgical options include repeat NUR or nephron-sparing surgery (NSS), yet concerns remain regarding feasibility, preservation of renal function and long-term oncological control. Evidence in this setting is scarce, and most available studies are hampered by small sample sizes, heterogeneous patient characteristics, and limited clinical detail, reducing the reliability of survival outcome estimates.5–7
Using a large, real-world, multicentre registry from Taiwan, we evaluated the oncological outcomes of surgical management for metachronous contralateral UTUC recurrence. This study addresses a rare but clinically relevant scenario and aims to provide evidence to support risk-adapted, individualized surgical decision-making in urological practice.
Methods
Overview
This retrospective, multicentre cohort study used data from the Taiwanese UTUC Registry. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, 8 and the completed STROBE checklist is provided in Supplemental Table 1.
Setting
The UTUC Registry, coordinated by the Urology Research Study Group at Taipei Tzu Chi Hospital, collects clinical and pathological data from 19 hospitals across Taiwan, including academic medical centres and regional hospitals (full list in Supplemental Table 1). The registry contains cases diagnosed between July 1988 and July 2023. We included patients who underwent curative-intent radical NUR or NSS between 8 February 2018 and 10 May 2024. Contralateral recurrence was defined as a newly detected lesion in the opposite upper urinary tract, initially identified by imaging and subsequently confirmed by histopathological examination. Baseline variables were age at diagnosis, sex, Eastern Cooperative Oncology Group (ECOG) performance status, known UTUC risk factors, and comorbidities. Pathological parameters included tumour grade, pathological stage, lymphovascular invasion (LVI), and margin status.
Exclusions
Patients without surgical treatment, with incomplete clinical data, or with concomitant cystectomy were excluded to avoid potential confounding effects on oncological outcomes. Eligible patients were grouped as follows:
Unilateral UTUC treated with a primary NUR
Contralateral recurrence treated with a second NUR
Contralateral recurrence managed with NSS after prior NUR
Primary outcomes
Overall survival (OS) and cancer-specific survival (CSS).
Secondary outcomes
Bladder recurrence-free survival (BRFS).
Statistical analysis
We performed analyses using IBM SPSS Statistics, version 26 (IBM Corp., Armonk, NY, USA). Missing values were addressed with complete-case analysis. Categorical variables were compared using Pearson’s chi-squared test; continuous variables using one-way ANOVA. Univariable and multivariable logistic regression identified factors associated with recurrence. Survival was estimated with Kaplan–Meier curves and compared using the stratified log-rank test. To adjust for baseline differences, we applied overlap weighting based on propensity scores (Supplemental Tables 2 and 3 and Supplemental Figures 1 and 2).9,10 We used Cox proportional hazards models, with and without adjustment for confounders, to assess the effect of surgical modality on survival. Statistical significance was set at p < 0.05 (two-sided). Sample size was justified by a power analysis using minimal detectable hazard ratios (MDHRs) at 80% power and α = 0.05.
Results
A total of 3159 patients were analysed, including 3041 who underwent unilateral NUR for primary UTUC, 90 who received a second NUR for contralateral recurrence, and 28 who underwent NSS as a second procedure (Table 1). In the NSS group, 20 patients underwent segmental ureterectomy, and 8 underwent endoscopic ablation using a semirigid ureteroscope. The mean age was lower in the second NUR group than in the primary NUR and second NSS groups (65.7 ± 9.9 vs 69.3 ± 10.3 and 70.0 ± 8.6 years, p = 0.004). End-stage renal disease (ESRD) before surgery was more common in the second NUR group (71.1%) than in the primary NUR (12.1%) and second NSS groups (10.7%; p < 0.001). Concomitant bladder urothelial carcinoma was also more frequent in the second NUR group (41.1%) compared with the other groups (p < 0.001). Patients undergoing second NSS were more likely to have tumours <2 cm (71.4%) and less likely to have tumour necrosis or LVI than those in the other groups (both p < 0.01).
Table 1.
Baseline characteristics of patients with unilateral upper-tract urothelial carcinoma treated with primary nephroureterectomy and those with contralateral recurrence managed by second nephroureterectomy or nephron-sparing surgery.
| Variable | Primary NUR | NUR in CR | NSS in CR | p |
|---|---|---|---|---|
| Patient number, n (%) | 3041 | 90 | 28 | |
| Male: Female | 1281:1760 | 32:58 | 12:16 | 0.459 |
| Age, mean (SD) | 69.3 (10.3) | 65.7 (9.9) | 70.0 (8.6) | 0.004 |
| ECOG, 0–1 | 2788 (91.7) | 82 (91.1) | 27 (96.4) | 0.649 |
| ECOG, 2–4 | 253 (8.3) | 8 (8.9) | 1 (3.6) | |
| HTN (%) | 1722 (56.6) | 62 (68.9) | 17 (60.7) | 0.063 |
| DM (%) | 817 (26.9) | 21 (23.3) | 7 (25.0) | 0.74 |
| ESRD, n (%) | 369 (12.1) | 64 (71.1) | 3 (10.7) | <0.001 |
| Smoking, n (%) | 575 (18.9) | 7 (7.8) | 3 (10.7) | 0.016 |
| Concomitant bladder UC, n (%) | 741 (24.4) | 37 (41.1) | 3 (10.7) | <0.001 |
| Pre-operative hydronephrosis (%) | 1904 (62.6) | 45 (50.0) | 13 (46.4) | 0.012 |
| Pre-operation malignant urine cytology (%) | 828 (27.2) | 26 (28.9) | 7 (25.0) | 0.6 |
| Tumor location, n (%) | ||||
| Renal pelvis | 1287 (42.3) | 25 (27.8) | 3 (10.7) | <0.001 |
| Ureter | 983 (32.3) | 31 (34.4) | 17 (60.7) | |
| Bladder cuff | 4 (0.1) | 0 (0.0) | 3 (10.7) | |
| Multiple locations | 767 (25.2) | 34 (37.8) | 5 (17.9) | |
| Tumor size (%) | ||||
| <2 cm | 785 (25.8) | 37 (41.1) | 20 (71.4) | <0.001 |
| ≥2 cm | 2256 (74.2) | 53 (58.9) | 8 (28.6) | |
| Grade (%) | ||||
| Low grade | 361 (11.9) | 8 (8.9) | 4 (14.3) | 0.633 |
| High grade | 2680 (88.1) | 82 (91.1) | 24 (85.7) | |
| Pathological stage, n(%) | ||||
| Stage 0a/0is/I | 1212 (39.9) | 29 (32.2) | 10 (35.7) | 0.461 |
| Stage II | 589 (19.4) | 20 (22.2) | 8 (28.6) | |
| Stage III/IV | 1240 (40.8) | 41 (45.6) | 10 (35.7) | |
| Tumour necrosis (%) | 498 (16.4) | 6 (6.7) | 0 (0.0) | 0.003 |
| LVI (%) | 659 (21.7) | 9 (10.0) | 2 (7.1) | 0.005 |
| Positive surgical margin (%) | 153 (5.0) | 3 (3.3) | 2 (7.1) | 0.669 |
CR, contralateral recurrence; ECOG, Eastern Cooperative Oncology Group; ESRD, end-stage renal disease; HTN, hypertension; LVI, lymphovascular invasion; NSS, nephron-sparing surgery; NUR, nephroureterectomy; SD, standard deviation; UC, urothelial carcinoma.
Primary outcomes
The mean follow-up duration was similar across groups (p = 0.751). There were no significant differences in OS or CSS between patients treated with primary NUR and those with contralateral recurrence treated with either second NUR or second NSS (Figure 1 and Table 2). Kaplan–Meier analysis confirmed comparable OS (p = 0.97) and CSS (p = 0.29) among the three surgical groups. After overlap weighting to adjust for baseline differences (Supplemental Table 2 and Supplemental Figure 1), adjusted OS and CSS remained similar between the primary UTUC and contralateral recurrence groups, consistent with the unadjusted results (Figure 1).
Figure 1.
Survival curve among patients with unilateral upper-tract urothelial carcinoma after primary nephroureterectomy and those with contralateral recurrence receiving secondary nephroureterectomy or nephron-sparing surgery.
Kaplan–Meier curves for OS (upper panels) and CSS (lower panels) among patients with unilateral UTUC treated with primary NUR and those with CR managed by a second NUR or NSS. “All group” panels show unadjusted analyses, while “Primary NUR vs NUR in CR” and “NUR in CR vs NSS in CR” panels depict overlap-weighted comparisons. Shaded areas represent 95% confidence intervals. Numbers at risk at each time point (in months) are shown below each plot. Log-rank p-values compare survival distributions across groups.
CR, contralateral recurrence; CSS, cancer-specific survival; NSS, nephron-sparing surgery; NUR, nephroureterectomy; OS, overall survival; UTUC, upper-tract urothelial carcinoma.
Table 2.
Oncological outcomes of patients with unilateral upper tract urothelial carcinoma treated with primary nephroureterectomy and those with contralateral recurrence managed by second nephroureterectomy or nephron-sparing surgery.
| Variable | Primary NUR N = 3041 | NUR in CR N = 90 |
NSS in CR N = 28 |
p |
|---|---|---|---|---|
| Follow-up period, mean (SD) months | 57.77 (42.94) | 55.82 (41.21) | 52.60 (43.87) | 0.751 |
| Death during follow-up, n (%) | 1199 (39.4) | 35 (38.9) | 11 (39.3) | 0.995 |
| Death related to UC, n (%) | 516 (17.0) | 11 (12.2) | 2 (7.1) | 0.194 |
| Intravesical recurrence (%) | 725 (23.8) | 16 (17.8) | 9 (32.1) | 0.224 |
CR, contralateral recurrence; LVI, lymphovascular invasion; NSS, nephron-sparing surgery; NUR, nephroureterectomy; SD, standard deviation; UC, urothelial carcinoma.
Secondary outcomes
The incidence of intravesical recurrence was 23.8% for primary NUR, 17.8% for second NUR, and 32.1% for second NSS (p = 0.224). Kaplan–Meier analysis showed no significant differences in BRFS among the three groups (log-rank p = 0.38). After overlap-weighted adjustment, BRFS between the primary UTUC and contralateral recurrence groups remained non-significant (Figure 2).
Figure 2.
Bladder recurrence-free survival among patients with unilateral upper-tract urothelial carcinoma after primary nephroureterectomy and those with contralateral recurrence receiving secondary nephreurstersstomy or nephron-sparing surgery,
Kaplan–Meier curves for BRFS among patients with unilateral UTUC treated with primary NUR and those with CR managed by a second NUR or NSS. “All group” panels show unadjusted analyses, while “Primary NUR vs NUR in CR” and “NUR in CR vs NSS in CR” panels depict overlap-weighted comparisons. Shaded areas represent 95% confidence intervals. Numbers at risk at each time point (in months) are shown below each plot. Log-rank p-values compare BRFS distributions across groups.
BRFS, bladder recurrence-free survival; CR, contralateral recurrence; NSS, nephron-sparing surgery; NUR, nephroureterectomy; UTUC, upper-tract urothelial carcinoma.
Multivariate analysis
In Cox regression (Table 3), neither second NUR nor second NSS was independently associated with OS or CSS compared with primary NUR. Worse OS was independently predicted by older age, higher ECOG score, ESRD, variant or non-urothelial histology, multifocal tumours, tumour size ⩾2 cm, higher pathological stage, LVI, positive margin, and tumour necrosis. Intravesical recurrence was independently associated with female sex, concomitant bladder cancer, LVI and positive margin.
Table 3.
Multivariate analyses of factors associated with oncological outcomes in upper-tract urothelial carcinoma.
| Variables | OS | CSS | BRFS |
|---|---|---|---|
| NUR in CR (vs unilateral) | 0.87 (0.61, 1.25) | 1.00 (0.53, 1.89) | 0.75 (0.45, 1.25) |
| NSS in CR (vs unilateral) | 1.27 (0.69, 2.33) | 0.65 (0.16, 2.65) | 1.38 (0.70, 2.71) |
| Cell type (vs Urothelial) | |||
| UC with variants | 1.14 (0.95, 1.36) | 1.18 (0.92, 1.51) | |
| Others | 1.82 (1.16, 2.85)* | 2.41 (1.43, 4.06)** | |
| Tumour location (vs renal pelvis) | |||
| Ureter | 1.14 (0.98, 1.33) | 1.18 (0.93, 1.51) | 1.21 (1.00, 1.46) |
| Bladder cuff | 1.98 (0.72, 5.43) | 0.90 (0.12, 6.67) | 2.07 (0.74, 5.79) |
| Multiple locations | 1.21 (0.98, 1.50) | 1.00 (0.74, 1.35) | 1.38 (1.05, 1.81)* |
| Multifocal | 1.03 (0.85, 1.24) | 1.46 (1.11, 1.93)** | 1.13 (0.88, 1.44) |
| Tumour size (≥2 cm) | 1.21 (1.04, 1.41)* | 1.81 (1.34, 2.43)** | 1.07 (0.90, 1.28) |
| Pathological stage II | 1.18 (0.99, 1.42) | 2.21 (1.51, 3.22)** | 1.23 (1.02, 1.50)* |
| Pathological stage III/IV | 2.07 (1.76, 2.44)** | 5.35 (3.81, 7.52)** | 1.46 (1.21, 1.75)** |
| High grade | 1.10 (0.89, 1.36) | 2.24 (1.24, 4.05)** | |
| Concomitant bladder cancer | 1.24 (1.08, 1.42)* | 1.50 (1.22, 1.84)** | 1.68 (1.42, 1.98)** |
| LVI | 1.58 (1.39, 1.81)** | 1.64 (1.36, 1.98)** | 1.28 (1.05, 1.56)* |
| Surgical margin | 1.92 (1.57, 2.35)** | 2.04 (1.57, 2.64)** | 1.12 (0.76, 1.65) |
| Pre-operative hydronephrosis | 1.21 (1.06, 1.37)** | 1.14 (0.93, 1.40) | 1.06 (0.90, 1.24) |
| Tumor necrosis | 1.20 (1.03, 1.38)* | 1.11 (0.90, 1.37) | |
| Adjuvant chemotherapy for UTUC | 0.77 (0.65, 0.92)* | 1.06 (0.83, 1.34) | |
Model adjusted for age, sex, ECOG performance status, hypertension, diabetes, ESRD, smoking.
p < 0.05. **p < 0.005.
BRFS, bladder recurrence-free survival; CI, confidence interval; CIS, carcinoma in situ; CR, contralateral recurrence; CSS, cancer-specific survival; ECOG, Eastern Cooperative Oncology Group; ESRD, end-stage renal disease; HR, hazard ratio; HTN, hypertension; LVI, lymphovascular invasion; NSS, nephron-sparing surgery; NUR, nephroureterectomy; OS, overall survival; UTUC, upper-tract urothelial carcinoma.
Discussion
In this multicentre real-world cohort, we compared oncologic outcomes in patients with metachronous contralateral UTUC – previously treated with NUR for primary disease – who underwent either a second NUR or NSS with a reference group of patients with unilateral UTUC treated by primary NUR. After appropriate patient selection, both second NUR and NSS achieved OS, CSS and BRFS outcomes comparable to primary UTUC, and these findings persisted after adjustment for baseline differences using overlap weighting. While the rarity of contralateral recurrence, and particularly the small number of NSS cases, necessitates cautious interpretation, the consistent survival patterns observed suggest that both surgical approaches can achieve favourable oncological outcomes in appropriately selected patients.
Surgical outcomes for contralateral recurrence UTUC have been rarely reported in the literature. In an early study by Holmäng et al., 11 poor cancer-specific outcomes were observed. However, subsequent studies involving limited numbers of metachronous UTUC cases have reported more favourable outcomes.4,12 More recently, population-based data from the SEER registry, focusing primarily on patients with localised UTUC, suggested that metachronous contralateral UTUC does not necessarily confer a worse prognosis compared to primary UTUC; rather, tumour stage appears to be the primary determinant of oncologic outcomes. 7 These findings are consistent with our observations in a multicenter cohort comprising both localised and advanced disease cases. Furthermore, after adjustment for confounding variables in multivariate analysis, metachronous contralateral upper-tract urothelial carcinoma was still not associated with significant differences in OS, CSS or compared to unilateral UTUC (Figure 1).
In our cohort, patients with metachronous contralateral UTUC exhibited several clinical and pathological differences compared to those with primary disease. Although they were, on average, younger, they had a higher prevalence of hypertension and ESRD, likely reflecting the impact of prior NUR. With respect to tumour characteristics, contralateral recurrence UTUC was more frequently associated with concomitant bladder cancer and multifocal tumour presentation at the time of diagnosis, but was less likely to involve tumours ⩾2 cm in size or to demonstrate tumour necrosis. Given these features – along with a higher likelihood of multifocal tumours and concurrent bladder cancer in this group – it is plausible that the underlying tumourigenic mechanism might be more consistent with a field cancerisation effect and a multiclonal origin,13,14 rather than intraluminal seeding with monoclonal tumour cell dissemination. 15 Some molecular studies have provided additional support for this hypothesis. A small but significant proportion of urothelial carcinomas appear to originate from distinct clones within the same urinary tract, a phenomenon that seems more frequent in precursor lesions (such as dysplasia and carcinoma in situ (CIS)) and in early-stage tumours compared with advanced cancers.16,17 These findings reinforce the concept that widespread urothelial exposure to carcinogens may lead to field cancerisation, predisposing to independent tumour development in both the bladder and the upper tract. However, due to the lack of relevant clinical information – such as the presence of vesicoureteral reflux, history of ureteroscopy or exposure to carcinogenic toxins – as well as the absence of molecular or genetic profiling, this hypothesis cannot be definitively confirmed.
Bladder recurrence following treatment for UTUC has been reported in approximately 22%–47% of cases. 18 In our cohort, the incidence of bladder recurrence was 23.8% among patients with primary UTUC and 21.2% among those with contralateral recurrence disease. Due to the limited number of patients with metachronous contralateral UTUC, few studies have directly compared bladder recurrence risk in this specific subgroup. Interestingly, in our Kaplan–Meier analysis, the type of surgical intervention – either NUR or NSS – for metachronous contralateral UTUC did not significantly impact BRFS when compared to the primary NUR (Figure 2). This finding remained consistent after adjusting for baseline differences using the overlap weighting method (Figure 2). In fact, the primary predictors of bladder recurrence identified in the multivariate analysis were features suggestive of extensive urothelial susceptibility, including a concomitant bladder cancer (HR = 1.68, 95% CI: 1.42–1.98), and tumours involving multiple anatomical sites (HR = 1.38, 95% CI: 1.05–1.81). Additionally, adverse pathological features such as pathological stage II (HR = 1.23, 95% CI: 1.02–1.50) and stage III/IV disease (HR = 1.46, 95% CI: 1.21–1.75), positive lymphovascular invasion (LVI; HR = 1.28, 95% CI: 1.05–1.56) were also associated with increased risk. These findings suggest that the risk of bladder recurrence is driven more by intrinsic tumour biology and prior urothelial involvement than by the status of contralateral recurrence UTUC.
With careful patient selection, NSS is increasingly considered an alternative treatment option for UTUC. In our cohort, patients who underwent NSS as a second procedure for contralateral recurrence tended to have more favourable baseline characteristics, including better preoperative ECOG performance status and lower rates of ESRD, preoperative hydronephrosis, and concomitant bladder cancer. Their tumours were also generally smaller and less likely to be multifocal, suggesting a degree of selection for less aggressive disease. Postoperative pathology further supported this, with fewer instances of tumour necrosis and lymphovascular invasion observed in the NSS group. Through this clinical selection process, patients undergoing NSS for contralateral recurrence achieved oncologic outcomes – namely OS, CSS and BRFS – that were comparable to those of patients with primary UTUC treated with standard NUR. These findings align with recent large-scale retrospective studies demonstrating equivalent oncologic outcomes between NSS and NUR,19,20 further supporting the applicability of NSS in the context of contralateral recurrence.
This study has several noteworthy strengths. First, it is a multicentre analysis that includes a relatively large sample of patients with contralateral recurrent UTUC compared with previous reports.11,21 Second, it provides detailed information on perioperative management and adjuvant therapy, which is often lacking in similar retrospective datasets. 7 Third, the inclusion of patients with primary UTUC as a comparative reference group, together with the application of overlap weighting to adjust for baseline differences between subgroups, enabled a more objective assessment of treatment. Currently, the major urological guidelines do not specifically address the management of contralateral recurrence, leaving both patients and clinicians uncertain about the optimal treatment approach in this scenario.22,23 From a clinical perspective, our results support the role of a second NUR as a curative option for appropriately selected patients with contralateral recurrence, offering oncological control comparable to that of primary surgery. This finding may reassure surgeons that repeat NUR remains a viable treatment strategy when oncological control takes precedence over renal preservation. In contrast, for patients with less aggressive tumours and a strong desire to preserve renal function, NSS may be considered in exceptional, carefully selected cases, provided that patients are counselled regarding the limited evidence base and the need for close post-operative surveillance. Overall, these findings align with current guideline recommendations for the management of primary UTUC and underscore the importance of a risk-adapted, individualized approach to surgical decision-making in UTUC management.
This study also has certain limitations. First, as a retrospective study, the potential for residual confounding cannot be excluded despite statistical adjustment. Patients selected for NSS generally presented with more favourable baseline tumour characteristics – such as smaller tumour size, lower multifocality, and less lymphovascular invasion – which may have contributed to the comparable survival outcomes observed. Second, the epidemiology of UTUC in East Asia differs from that in Western populations. In regions such as Taiwan, environmental exposures to arsenic and aristolochic acid-containing herbal medicines are important etiological factors, associated with higher incidences of multifocal, bilateral and low-stage tumours, as well as a distinct mutational signature characterised by A > T transversions. Although stage-adjusted cancer-specific survival appears comparable between Asian and Western cohorts, recurrence – particularly bladder and contralateral recurrence – tends to occur more frequently in East Asia.7,24,25 Therefore, while our findings from this Taiwanese cohort are likely generalisable in terms of oncological outcomes after curative surgery, caution is warranted when extrapolating recurrence patterns and tumour biology to non-endemic populations. Third, the rarity of contralateral recurrence – and the particularly small number of patients undergoing NSS – resulted in few survival events, which directly affected statistical power. In the overlap-weighted analysis, the primary NUR versus NUR-in-contralateral-recurrence comparison achieved adequate power for OS and BRFS but was borderline for CSS, while the NUR-in-contralateral-recurrence versus NSS comparison showed suboptimal power for all endpoints due to fewer events (Supplemental Table 4). These constraints limit the ability to formally confirm equivalence and underscore the need for larger, multi-institutional prospective studies to validate and extend these results. Finally, renal functional outcomes were not available in the registry database and could not be assessed. This limitation precludes evaluation of the effectiveness of NSS in renal function preservation.
Conclusion
Our multicentre analysis found that both second NUR and NSS for contralateral UTUC recurrence showed no statistically significant differences in OS, CSS, or BRFS compared with primary NUR for unilateral UTUC. Although the rarity of contralateral recurrence – particularly cases managed with NSS – limits the statistical power to definitively confirm equivalence, the consistent survival patterns observed, especially after overlap-weighted adjustment, support the potential for curative surgery to achieve favourable oncological outcomes in appropriately selected patients. These findings provide encouraging real-world evidence to guide individualized, risk-adapted surgical planning, while highlighting the need for larger, adequately powered studies to confirm and expand upon these results.
Supplemental Material
Supplemental material, sj-docx-1-tau-10.1177_17562872261419593 for Contralateral recurrent upper-tract urothelial carcinoma after curative surgery: a multicentre retrospective cohort study by Yao-Lin Kao, I-Hsuan Alan Chen, Chia-Cheng Yu, Chao-Hsiang Chang, Hsi-Chin Wu, Ching-Chia Li, Wen-Jeng Wu, Yao-Chou Tsai, Chih-Chin Yu, Chung-You Tsai, Pai-Yu Cheng, Chao-Yuan Huang and Chien-Hui Ou in Therapeutic Advances in Urology
Acknowledgments
All members of the Taiwan Upper Tract Urothelial Carcinoma Collaboration group: Allen W. Chiu, Bing-Juin Chiang, Chao-Hsiang Chang, Chao-Yuan Huang, Cheng-Huang Shen, Cheng-Kuang Yang, Cheng-Ling Lee, Chen-Hsun Ho, Che-Wei Chang, Chia-Chang Wu, Chieh-Chun Liao, Chien-Hui Ou, Chih-Chen Hsu, Chih-Chin Yu, Chih-Hung Lin, Chih-Ming Lu, Chih-Yin Yeh, Ching-Chia Li, Chi-Ping Huang, Chi-Rei Yang, Chi-Wen Lo, Chuan-Shu Chen, Chung-Hsin Chen, Chung-You Tsai, Chung-Yu Lin, Chun-Hou Liao, Chun-Kai Hsu, Fang-Yu Ku, Hann-Chorng Kuo, Han-Yu Weng, Hao-Han Chang, Hong-Chiang Chang, Hsiao-Jen Chung, Hsin-Chih Yeh, Hsu-Che Huang, Ian-Seng Cheong, I-Hsuan Alan Chen, Jen-Kai Fang, Jen-Shu Tseng, Jen-Tai Lin, Jian-Hua Hong, Jih-Sheng Chen, Jungle Chi-Hsiang Wu, Kai-Jie Yu, Keng-Kok Tan, Kuan-Hsun Huang, Kun-Lin Hsieh, Lian-Ching Yu, Lun-Hsiang Yuan, Hao-Lun Luo, Marcelo Chen, Min-Hsin Yang, Pai-Yu Cheng, Po-Hung Lin, Richard Chen-Yu Wu, See-Tong Pang, Shin-Hong Chen, Shin-Mei Wong, Shiu-Dong Chung, Shi-Wei Huang, Shuo-Meng Wang, Shu-Yu,Wu, Steven Kuan-Hua Huang, Ta-Yao Tai, Thomas Y. Hsueh, Ting-En Tai, Victor Chia-Hsiang Lin, Wei-Chieh Chen, Wei-Ming Li, Wei-Yu Lin, Wen-Hsin Tseng, Wen-Jeng Wu, Wun-Rong Lin, Yao-Chou Tsai, Yen-Chuan Ou, Yeong-Chin Jou, Yeong-Shiau Pu, Yi-Chia Lin, Yi-Hsuan Wu, Yi-Huei Chang, Yi-sheng Lin, Yi-Sheng Tai, Yu-Khun Lee, Yuan-Hong Jiang, Yu-Che Hsieh, Yu-Chi Chen, Yu-Ching Wen, Yung-Tai Chen, Zhe-Rui Yang.
Footnotes
ORCID iD: Yao-Lin Kao 
https://orcid.org/0000-0002-4147-9041
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Yao-Lin Kao, Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
I-Hsuan Alan Chen, Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Chia-Cheng Yu, Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Chao-Hsiang Chang, Department of Urology, China Medical University and Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan.
Hsi-Chin Wu, Department of Urology, China Medical University and Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Department of Urology, China Medical University Beigang Hospital, Yunlin, Taiwan.
Ching-Chia Li, Department of Urology, Kaohsiung Medical University Gangshan Hospital, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Wen-Jeng Wu, Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yao-Chou Tsai, Department of Surgery, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan; Department of Urology, Taipei Medical University Hospital, Taipei Medical University, Taipei City, Taiwan.
Chih-Chin Yu, School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan; Department of Urology, Taipei Medical University Hospital, Taipei Medical University, Taipei City, Taiwan.
Chung-You Tsai, Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Electrical Engineering, Yuan-Ze University, Taoyuan, Taiwan.
Pai-Yu Cheng, Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Electrical Engineering, Yuan-Ze University, Taoyuan, Taiwan.
Chao-Yuan Huang, Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
Chien-Hui Ou, Department of Urology, Tainan Hospital, Ministry of Health and Welfare, No. 125, Jhongshan Rd., West Central Dist., Tainan City 700, Taiwan (R.O.C.).
Declarations
Ethics approval and consent to participate: This study was approved by the Institutional Review Boards (IRBs) of all 19 participating hospitals in the Taiwanese UTUC Registry. The IRB approval numbers for each institution are listed below: 1. Taipei Tzu Chi Hospital, New Taipei – IRB No. 12-X-004. 2. Hualien Tzu Chi Hospital, Hualien – IRB No. IRB112-257-B. 3. Kaohsiung Medical University Hospital, Kaohsiung – IRB No. KMUHIRB-E(I)-20180214. 4. Ditmanson Chia-Yi Christian Hospital, Chiayi – IRB No. IRB2020103. 5. Kaohsiung Chang Gung Memorial Hospital, Kaohsiung – IRB No. 202401236B0. 6. Linkou Chang Gung Memorial Hospital, Taoyuan – IRB No. 202100079B0. 7. Chiayi Chang Gung Memorial Hospital, Chiayi – IRB No. 202301058B0. 8. Kaohsiung Veterans General Hospital, Kaohsiung – IRB No. KSVGH22-CT13-14. 9. China Medical University Hospital, Taichung – IRB No. CMUH107-REC3-146(FR). 10. Taipei City Hospital, Taipei –N201808014. 11. National Taiwan University Hospital, Taipei – IRB No. 201911084RINC. 12. Shuang Ho Hospital, New Taipei – IRB No. N201808014. 13. Chi Mei Medical Center, Tainan – IRB No. 11006-001. 14. Tai An Hospital, Miaoli – IRB No. 109-E-03. 15. Cardinal Tien Hospital, New Taipei – IRB No. CTH-107-3-5-035. 16. Far Eastern Memorial Hospital, New Taipei – IRB No. 108140-E. 17. National Cheng Kung University Hospital, Tainan – IRB No. A-ER-103-036. 18. Taipei Medical University Hospital, Taipei – IRB No. N201808014. 19. Mackay Memorial Hospital, Taipei – IRB No. 25MMHIS047e. As anonymised data were obtained from electronic health records, written informed consent was waived in accordance with institutional policies and national regulations.
Consent for publication: Not applicable. No identifiable patient data are presented in this study.
Author contributions: Yao-Lin Kao: Conceptualization; Funding acquisition; Methodology; Writing – original draft.
I-Hsuan Alan Chen: Data curation; Methodology; Resources; Writing – original draft.
Chia-Cheng Yu: Data curation; Formal analysis; Resources; Visualization; Writing – original draft.
Chao-Hsiang Chang: Data curation; Supervision; Writing – review & editing.
Hsi-Chin Wu: Investigation; Project administration; Validation; Writing – review & editing.
Ching-Chia Li: Investigation; Validation; Writing – review & editing.
Wen-Jeng Wu: Investigation; Validation; Writing – review & editing.
Yao-Chou Tsai: Formal analysis; Software; Writing – review & editing.
Chih-Chin Yu: Project administration; Validation; Visualization; Writing – review & editing.
Chung-You Tsai: Investigation; Supervision; Validation; Writing – review & editing.
Pai-Yu Cheng: Data curation; Supervision; Writing – review & editing.
Chao-Yuan Huang: Formal analysis; Supervision; Writing – review & editing.
Chien-Hui Ou: Funding acquisition; Methodology; Writing – review & editing.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by grants from the National Cheng Kung University Hospital (NCKUH-11503017) and Tainan Hospital, Ministry of Health and Welfare (PG11306-0018).
The authors declare that there is no conflict of interest.
Availability of data and materials: Data from the Taiwanese UTUC Registry are not publicly available due to ethical and institutional restrictions but may be obtained from the corresponding author upon reasonable request and with appropriate Institutional Review Board approval.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-docx-1-tau-10.1177_17562872261419593 for Contralateral recurrent upper-tract urothelial carcinoma after curative surgery: a multicentre retrospective cohort study by Yao-Lin Kao, I-Hsuan Alan Chen, Chia-Cheng Yu, Chao-Hsiang Chang, Hsi-Chin Wu, Ching-Chia Li, Wen-Jeng Wu, Yao-Chou Tsai, Chih-Chin Yu, Chung-You Tsai, Pai-Yu Cheng, Chao-Yuan Huang and Chien-Hui Ou in Therapeutic Advances in Urology