Impact of tumor location on oncological and perioperative outcomes after robot-assisted radical nephroureterectomy for upper tract urothelial carcinoma

Mahmoud Farzat; Ibrahim Altaie; Sami-Ramzi Leyh-Bannurah; Mykyta Kachanov; Florian M Wagenlehner

doi:10.1371/journal.pone.0341638

. 2026 Jan 30;21(1):e0341638. doi: 10.1371/journal.pone.0341638

Impact of tumor location on oncological and perioperative outcomes after robot-assisted radical nephroureterectomy for upper tract urothelial carcinoma

Mahmoud Farzat ^1,^2,^*, Ibrahim Altaie ², Sami-Ramzi Leyh-Bannurah ³, Mykyta Kachanov ⁴, Florian M Wagenlehner ¹

Editor: Yudai Ishiyama⁵

PMCID: PMC12857952 PMID: 41615910

Abstract

Objective

to investigate the effect of tumor location on oncological outcomes in patients receiving robot-assisted radical nephroureterectomy (RANU) for upper urinary tract carcinoma (UTUC).

Methods

A retrospective single-center cohort study of 54 patients with UTUC who underwent RANU by a single surgeon between July 2019 and July 2025, without neoadjuvant chemotherapy or previous or simultaneous cystectomy, were included. Patients were divided into two groups based on tumor location: 18 patients (33%) with ureteral tumors (Group 1) and 36 patients (67%) with renal pelvis tumors (Group 2). Demographics, perioperative data, and pathological results were analyzed. The primary endpoints Cancer-specific survival (CSS) and overall survival (OS) were estimated using Kaplan–Meier and univariable log-rank test.

Results

Console time, blood transfusion, complications, and readmission were comparable in both groups. Group 1 experienced longer hospital stays (8 days vs. 6.5 days, p = 0.03). 48% of patients had ≥ pT2 disease, with a similar T-stage distribution across groups. Of 26 candidates for adjuvant therapy, 10 received chemotherapy with gemcitabine/cisplatin, 2 received nivolumab, and one patient received enfortumab vedotin with pembrolizumab. During a median 26.5-month follow-up, six patients developed bladder recurrence, (median 9 months) after RANU (p = 0.10), and four developed distant metastases (median 4 months) (p = 0.72), resulting in a disease-free survival of 81% (p = 0.08)Cancer-specific survival was 94%, overall survival 89%, with no significant group differences (p = 0.24 and 0.49).

Conclusion

In our series, we observed that tumor location does not impact postoperative and oncological outcomes after RANU for UTUC, regardless of adjuvant therapy. However, further studies are needed to explore this proposed hypothesis.

Introduction

Regarding oncological outcomes, ureteral tumors demonstrate notably higher recurrence rates than tumors that originate in the renal pelvicalyceal system [1]. Krajewski et al. found in their meta-analysis involving 16836 patients that the location of UTUC in the ureter is associated with significantly poorer long-term oncological outcomes [2]. They even spoke in favor of neoadjuvant chemotherapy in ureteral UTUC patients [2]. On the other hand, Joshi and colleagues found that tumor size, rather than location, was associated with worse survival outcomes [3]. In their analysis involving 637 patients across multiple institutions, Yafi et al. found that the location of ureteral tumors, especially when combined with the multifocal disease in the renal pelvis, acts as an independent prognostic factor for increased recurrence of disease and cancer-specific mortality [4]. Other authors reported that the ureteral location is associated with a shorter metastasis-free survival [5]. Interestingly, Tanaka et al. found that ureter tumors, especially in the lower two-thirds, had a higher rate of local recurrence. In contrast, renal pelvic tumors had a higher prevalence of distant relapse in the lungs [6]. Additionally, multifocal presentation of ureteral tumors is a significant prognostic factor of the disease’s progression-free survival [7]. Another study showed a link between tumor location and the occurrence of positive surgical margins [8]. Others suggest that tumor locations within the lower ureter are correlated with less favorable oncological outcomes [9]. Liu et al. reported a trend toward distal ureteral UTUC developing bladder recurrence, but not local recurrence or distant metastasis [10]. Moreover, two meta-analyses revealed a link between tumor location and intravesical recurrence [11,12]. However, Favaretto et al. found that tumor location did not predict bladder recurrence or cancer-specific survival [13]. Shibing et al. proved in their large multi-institutional cohort that tumor size over 3 cm correlated with worse recurrence-free, cancer-specific, and overall survival [14]. These findings were corroborated by subsequent case series [15]. Overall, most current research indicates that the location of ureteral tumors correlates with worse oncological results. This study examines the influence of tumor location on surgical and oncological outcomes in a contemporary, homogeneous cohort of patients undergoing robot-assisted nephroureterectomy (RANU) at a single center, performed by a single surgeon, and offers insights based on real-world clinical data.

Methods

Participants, exclusion criteria and study design

Between July 2019 and July 2025, 85 patients underwent UTUC surgery. In this retrospective context, we used non-probability sampling—specifically, convenience sampling. To achieve a more homogenous cohort, eight patients who underwent segmental ureterectomy, 15 who underwent simultaneous cystectomy, four who underwent prior cystectomies, two who underwent surgery in palliative settings, and two who underwent surgery after neoadjuvant chemotherapy for locally advanced cancer were excluded. This left 54 patients in our analysis, all undergoing surgery with curative intent (See Fig 1). Patients’ data were assessed on the first of September 2025, to conduct a retrospective single-center cohort study. Based on tumor location, a total of 54 patients were divided into two groups: Group 1 included 18 patients with ureteral tumors, and Group 2 included 36 patients with renal pelvis tumors. Based on the final pathological results, patients with non-muscle-invasive UTUC (Ta, Tis, T1) were followed up according to EAU guidelines [16]. Patients with pT2 (tumor invades muscularis), or advanced disease pT3 (tumor beyond muscularis), or T4 (tumor invades adjacent organs or through the kidney into perinephric fat), or N+ (lymph node involvement) were offered adjuvant platinum-based chemotherapy. Those who were ineligible for platinum therapy were given nivolumab.

Preoperative diagnostic and surgical technique

Patients presenting with painless hematuria received a standardized diagnostic assessment, which included sonography, laboratory tests, and urethrocystoscopy. If bladder cancer was ruled out or found near the ureteral orifice, or if an upper urinary tract tumor was suspected, additionally, a retrograde pyelography and renal pelvic urine cytology were conducted. In those with tumor suspicion, a CT scan with a urinary phase was performed in all patients to facilitate better planning of the surgical intervention. Ureterorenoscopy (URS) with biopsy was performed in all patients when the diagnosis was undetermined via retrograde ureteropyelography and CT scan. Patients with locally advanced carcinoma who were eligible for adjuvant chemotherapy and willing to receive these treatments received their treatment before surgery.

All surgeries were performed by a single experienced robotic surgeon (>2,500 robotic procedures) using the Da Vinci X® system (Intuitive Surgical, Sunnyvale, CA, USA). All RANU patients were placed in a lateral position. An 8 mm/Hg Capnoperitoneum was created via a pararectal mini-laparotomy, which was later used to extract the specimen. Four robotic arms were employed. After completing the kidney procedure, the robotic instruments were redeployed for the ureteral part without requiring re-docking or repositioning of the patient. Patients with high-grade cytology or biopsy, evidence of local invasion on CT, variant histology, multifocal disease, tumor size ≥2 cm, or hydronephrosis were classified as high-risk UTUC and received Lymphadenectomy (LAD): ipsilateral iliac nodes in ureteral tumors and hilar, paraaortic, and interaortocaval nodes in renal pelvis tumors. All patients who consented received immediate intravesical instillation therapy with mitomycin 40 mg before transurethral catheter removal.

Variables and statistical analysis

Clinical and oncological variables were prospectively collected in an institutional database and subsequently analyzed retrospectively after full anonymization. Demographic and perioperative data were analyzed, and postoperative complications within 90 days after surgery were classified according to the Clavien-Dindo classification [17]. Follow-ups were performed regularly according to EAU guidelines [16]. Data were analyzed with SPSS® v29. Categorical variables were reported as frequencies and percentages and compared using the Chi-square or Fisher’s exact test, as appropriate. The Kolmogorov-Smirnov test was utilized to assess normal distribution. The independent T-test and Mann-Whitney U tests were applied to parametric and non-parametric variables. A p-value of < 0.05 was considered statistically significant. All p-values listed are two-tailed. Recurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and univariable long-rank tests. The primary endpoint of the study was to assess how UTUC tumor location affects disease-free survival and overall survival. The research adhered to the ethical guidelines specified in the Declaration of Helsinki and received approval from the ethics committees of the Westfalen-Lippe Medical Association and the University of Muenster (2023–500-f-S). The need for patient consent is waived by the ethical committee since this is a retrospective analysis of existing patients’ data. Nonetheless, all patients provided verbal informed consent for data from their medical records to be used in research for educational purposes.

Results

Baseline parameters

The median age of the patients was 73 years. Patients in the ureteral tumor group were more obese with a median BMI of 30.5 kg/m² versus a BMI of 27 kg/m² for the renal pelvis group (p = 0.04). 65% of patients were males. Patients presented with multiple comorbidities; however, ASA scores were comparable across groups. 39% of patients had cardiovascular disease, while Diabetes mellitus and COPD were less frequent. Anticoagulant use was more frequent in Group 1 (44%) than in Group 2 (22%) (p = 0.31). Preoperative ureterorenoscopic definitive histological diagnosis was achieved in 55% of cases in the ureteral tumors group, compared with only 22% in the renal pelvis group (p = 0.01). While the overall hemoglobin values were normal in both groups, renal function showed relative deterioration, with a median value of 58 mL/min/1.73 m² (p = 0.3 and 0.4, respectively). Details are given in Table 1.

Table 1. Baseline characteristics and preoperative clinical and oncological parameters.

	Total (N = 54)	Ureter (N = 18)	Kidney Pelvis (N = 36)	p-Value
Age (years), median (IQR)	73 (65 - 80)	71 (63 - 78)	74 (66 - 81)	0.5
Gender (Male), n (%)	35 (64.8%)	13 (72.2%)	22 (61.1%)	0.56
BMI (kg/m²), median (IQR)	28.0 (24.8 - 33.3)	30.5 (26.6 - 37.8)	27.0 (24.0 - 31.0)	0.04
ASA Score, n (%)				0.93
1	14 (25.9%)	5 (27.8%)	9 (25.0%)
2	14 (25.9%)	4 (22.2%)	10 (27.8%)
3	26 (48.1%)	9 (50.0%)	17 (47.2%)
Preoperative Histology (URS), n (%)				0.01
No Biopsy/ negative histology	36 (66.7%)	8 (44.4%)	28 (77.8%)
Ta/ G1	11 (20.4%)	6 (33.3%)	5 (13.9%)
T1/ G2	4 (7.4%)	3 (16.7%)	1 (2.8%)
T1/ G3	2 (3.7%)	1 (5.6%)	1 (2.8%)
CIS (Tis)	1 (1.9%)	0 (0%)	1 (2.8%)
Cardiovascular Disease	21 (38.9%)	6 (33.3%)	15 (41.7%)	0.70
Diabetes Mellitus II	5 (9.3%)	1 (5.6%)	4 (11.1%)	0.62
COPD	3 (5.6%)	1 (5.6%)	2 (5.6%)	0.91
Anticoagulation, n (%)	16 (29.6%)	8 (44.4%)	8 (22.2%)	0.31
Aspirin (ASS)	12 (22.2%)	6 (33.3%)	6 (16.7%)
NOAC	4 (7.4%)	2 (11.1%)	2 (5.6%)
Preop. Hb (g/dL), median (IQR)	13.1 (11.0 - 14.4)	13.4 (12.2 - 14.4)	12.9 (9.9 - 14.3)	0.33
Preop. GFR (ml/min), median (IQR)	58 (42 - 70)	62 (48 - 70)	55 (41 - 70)	0.48

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Categorical data are presented as numbers %, BMI: body mass index, ASA: American association of Anesthesiologists, COPD: chronic obstructive pulmonary disease, NOAK: new oral anticoagulant, HB: hemoglobin, GFR: glomerular filtration rate.

Intra- and postoperative data

Console time was, on average, 10 minutes longer in Group 2. While Group 1 patients had a significantly longer mean hospital stay (8 days vs. 6.5 days), the median duration was 5 days across both groups (p 0 = .77). Overall, 52% of patients presented with non-muscle-invasive disease, 14.8% with pT2, and 33.3% with locally advanced tumors pT3-4, N + , exhibiting comparable distributions across the study groups (p = 0.39). High-grade tumors were observed more often in Group 2 (64%) (p = 0.17). Overall, n = 34/54 (63%) of patients in our cohort received immediate single-dose intravesical instillation of mitomycin, with a similar instillation rate across study groups (p = 0.33).

Out of 26 patients with muscle-invasive and locally advanced cancer, 13 received adjuvant therapy. Of them, 10 patients received three cycles of polychemotherapy gemcitabine/cisplatin. When renal function didn’t allow a full dose, patients received a 60% or 80% reduction in cisplatin dose to improve tolerability, and in such cases, the dose was split over two days. 2 patients received Nivolumab for 1 year (4 weeks schema), and one patient was planned for adjuvant therapy with nivolumab, yet in the subsequent staging, new metastases were found and he received Enfortumab Vedotin in combination with Pembrolizumab.

All patients had negative surgical margins. LAD was performed in 35% of patients, with a median of 5 lymph nodes removed, and there was no significant group difference (p = 0.56). Only one patient in group 2 had lymph node metastasis. Four patients (7.4%) required perioperative transfusions.The overall median differences in hemoglobin and GFR of 2.1 g/dL and 9 mL/min/1.73² were similar across study groups (p = 0.82 and 0.91, respectively). Further details in Table 2.

Table 2. Intra- and postoperative results and pathological outcomes.

	Total (N = 54)	Ureter (N = 18)	Kidney Pelvis (N = 36)	p-Value
Console Time (min), median (IQR)	70 (50 - 90)	65 (41 - 85)	75 (55 - 90)	0.39
Hospital Stay (days), mean (IQR), median	7 (5 - 9) 5	8 (6 - 10) 5	6.5 (5 - 8) 5	0.77
Pathological T Stage, n (%)				0.39
Ta/T1/Tis	28 (51.9%)	11 (61.1%)	17 (47.2%)
T2	8 (14.8%)	1 (5.6%)	7 (19.4%)
T3/T4	18 (33.3%)	6 (33.3%)	12 (33.3%)
Tumor Grade, n (%)				0.17
Low Grade (1/2)	23 (42.6%)	10 (55.6%)	13 (36.1%)
High Grade (3)	31 (57.4%)	8 (44.4%)	23 (63.9%)
Lymphadenectomy performed, n (%)	19 (35.2%)	6 (33.3%)	13 (36.1%)	0.90
Lymph nodes removed, median (IQR)	5 (2 - 10)	7.5 (2 - 13)	5 (2 - 9)	0.56
Lymph Node Metastasis, n (%)	1 (1.9%)	0 (0%)	1 (2.8%)	0.99
Positive Surgical Margins	0 (0%)	0 (0%)	0 (0%)
Transfusion, n (%)	4 (7.4%)	1 (5.6%)	3 (8.3%)	0.50
Intravesicale instillation therapy (single dose mitomycin 40 mg)	34 (63%)	13 (72%)	21 (58%)	0.33
Adjuvant Therapy, n (%)	13 (24.1%)	4 (22.2%)	9 (25.0%)	0.99
Gemcitabine/Cisplatin	10 (18.5%)	3 (16.7%)	7 (19.4%)
Immunotherapy	3 (5.6%)	1 (5.6%)	2 (5.6%)
Postop. Hb (g/dL), median (IQR)	10.9 (9.5 - 12.4)	11.2 (9.8 - 12.5)	10.7 (9.2 - 12.3)	0.40
Δ Hb (g/dL), median (IQR)	−2.1 (−3.4 – −1.0)	−2.2 (−3.2 – −1.4)	−2.0 (−3.5 – −0.8)	0.82
Postop. GFR (ml/min), median (IQR)	49 (37 - 59)	52 (43 - 59)	48 (34 - 59)	0.31
Δ GFR (ml/min), median (IQR)	−9 (−17 – −2)	−8 (−16 – −3)	−9 (−18 – −2)	0.92

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Categorical data are presented as numbers %, UTUC: Upper Urinary Tract Urothelial Cell Carcinoma, RARC: robot-assisted radical cystectomy. SD: standard deviation, CI: Checkpoint inhibitor, * Grade according to WHO classification 1999 (Busch et al.) [18].

Complications, oncological and survival outcomes

The overall 90-day complication rate was 20% (n = 11/54), with no significant difference between the groups (27.8% vs. 16.7%, p = 0.4). Of the 11 complications, three were minor (Clavien-Dindo I-II) and eight were major (Clavien-Dindo III-V). The most common major complication was fascia dehiscence, which happened in 3 obese patients at the pararectal mini-laparotomy site, which was used to retrieve the specimen. One female patient with advanced peripheral artery disease developed an embolism in the iliac external artery on the same side of the RANU and underwent uneventful endovascular embolectomy. One male patient developed bleeding after surgery, necessitating a revision. Another patient with advanced COPD and a long history of constipation was reoperated on for bowel obstruction. We recorded two perioperative fatalities in our series. The first one was a female patient with an undiagnosed coagulation path disorder who died after a long stay in the intensive care unit (ICU). The other perioperative death involved an elderly male with extensive abdominal adhesions from prior colorectal cancer surgery. He underwent bowel resection at RANU start and died in the ICU after prolonged cardiac decompensation. More patients were readmitted in the ureteral tumor group (16.7%) compared to patients in the renal pelvis tumor group (8.3%). Over a median follow-up of 26.5 months, bladder recurrence was observed in 6 patients (11%), with a median time to recurrence of 9 months (p = 0.10). Four patients (7.4%) developed distant metastases (median time 4 months) (p = 0.72). This resulted in a disease-free survival of 81% (Fig 2), a cancer-specific survival of 94% (Fig 3), and, considering the 2 perioperative deaths, an overall survival of 89% (Fig 4). Statistically, both groups showed similar survival rates, p = 0.20, 0.24, and 0.49, respectively (Table 3).

Table 3. Complications, readmission, oncological, and survival outcomes.

	Total (N = 54)	Ureter (N = 18)	Kidney Pelvis (N = 36)	p-Value
Any Complication, n (%)	11 (20.4%)	5 (27.8%)	6 (16.7%)	0.41
Complication Severity (Clavien-Dindo), n (%)				0.64
Minor (Grade I-II)	3 (5.5%)	2 (11.1%)	1 (2.7%)
Major (Grade III-V)	8 (17.0%)	3 (16.7%)	5 (13.8%)
90-Day Readmission, n (%)	6 (11.1%)	3 (16.7%)	3 (8.3%)	0.42
Oncological Outcomes
Bladder Recurrence Median to recurrance 9 months	6 (11%)	1 (5.6%)	5 (14%)	0.10
Distant Metastasis Median to metastasis 4 months	4 (7.4%)	1 (5.5%)	3 (8.3%)	0.72
Survival Outcomes
Disease free Survival	44 (81%)	16 (89%)	28 (77%)	0.08
Cancer-Specific Survival	51 (94.4%)	18 (100%)	33 (92%)	0.24
Overall Survival	48 (89%)	17 (94.4%)	31 (86%)	0.49

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Categorical data are presented as numbers and percentages. CD: Clavien-Dindo [17].

Discussion

Studies investigating tumor location, alongside other clinicopathologic factors influencing survival following RANU for UTUC, primarily focus on long-term outcomes and evaluate tumor location as a prognostic indicator of poorer survival [8,11,12]. However, the impact of tumor location on short-term surgical outcomes has not been thoroughly investigated.

The principal finding of our study is that tumor location (ureteral vs. renal pelvis) did not significantly affect short-term surgical or oncological outcomes following RANU for UTUC. Our observation aligns with findings from prior research [19]. In our cohort, 33% of patients were diagnosed with locally advanced (T3–T4, N+) disease, with exact incidence among study groups. Favaretto et al. (9) conducted a retrospective study involving 234 patients and found that pathological stage and nodal status were the only independent predictors of disease recurrence. Tumor location, on the other hand, did not affect outcomes. Similarly, our study found no significant associations between tumor stage, location, or nodal status and oncological outcomes. Our retrospective analysis included a homogeneous patient group, all of whom underwent the same surgical procedure, with similar rates of lymphadenectomy and adjuvant therapy. Under these conditions, tumor location did not appear to influence survival. However, understanding how chemotherapy or immunotherapy affects survival outcomes remains vital. In our study, 26 of 54 patients (48%) had muscle-invasive and locally advanced disease, with 13 receiving adjuvant therapy. The use of adjuvant systemic therapy was evenly distributed between groups, supporting our preliminary conclusion that tumor location did not impact survival.

Furthermore, no significant differences were observed in bladder recurrence, distant metastasis, or overall survival between the groups. Yet ureteral tumor patients showed a higher disease-free survival rate ( 89%) versus (77%) for the renal pelvis group. Nonetheless, the oncological outcomes within our cohort—comprising a bladder recurrence rate of 11%, a distant metastasis rate of 7.4%, and a cancer-specific survival rate of 94.4%—align with the findings documented in currently available literature [8,20]. Except for the disease-free survival, the similar survival outcomes for our study groups, have to be interpreted with caution since our findings may be inflated due to the limited follow-up. And given our small, simple size, our approach carries a high risk of selection bias. It increases the margin of error of our analysis, limiting the ability to generalize the findings to the broader population due to reduced external validity. As a result, our findings may be biased. Another possible explanation for the low recurrence rates observed in our cohort is the absence of positive surgical margins among all patients. This aligns with findings by Colin et al., who reported significantly lower 5-year CSS and metastasis-free survival in patients with positive surgical margins compared to those with negative margins (59.1% and 51.6% vs. 83.3% and 79.3%, respectively) [8,21].

Despite being more obese (median BMI 30.5 kg/m²), patients with ureteral tumors undergoing RANU had a median console time 10 minutes shorter than those with renal pelvis tumors (65 vs. 75 minutes). Both groups received similar lymphadenectomy rates (33% vs. 36%). Interestingly, our overall median operative time of 70 minutes is significantly lower than the durations reported by others [22]. This shorter operative time likely results from avoiding robot redocking, as well as the efficiency and expertise of our surgical team. Chen et al. examined how BMI influences DFS in UTUC patients and found that younger patients with higher BMI were linked to better DFS [23].

In our study, the transfusion rate was 7.4%, consistent with earlier reports (17). Notably, some patients had surgery after extended periods of gross hematuria and received transfusions because of existing comorbidities and to reduce perioperative risks. The median hospital stay was 5 days among both study groups exceeding durations reported in previous studies [24]. This longer stay may reflect local clinical practices, where patients are typically admitted the day before surgery and discharged only after the urinary catheter is removed. Additionally, many older patients often require more time for discharge planning and arranging home care.

Our 90-day readmission rate of 11% corresponds with findings by Liedeberg et al. [25], who reported a rate of 8.2%. However, their reported major complication rate was markedly lower (1/146 patients) compared to ours (8/54 patients). This discrepancy may reflect the impact of the surgical learning curve in our setting, as well as different baseline characteristics in our series in contrast to the Swedish series. In our cohort, the 90-day postoperative mortality rate was 3.7% (2 patients), which is slightly higher than the rates reported in a recent meta-analysis comparing robotic and laparoscopic approaches [19,26]. However, although neither of those two patients was operated on with palliative intent, the two deaths observed in our cohort were likely due to pre-existing vulnerabilities in the patients. In our study, 48% of patients were classified as ASA 3. We also reported additional data, including pre-existing cardiovascular diseases and COPD. However, this classification alone does not fully capture their clinical condition. Consequently, our results should be interpreted with caution and viewed as exploratory rather than definitive.

Apart from the point we discussed, this study has more limitations. In addition to its retrospective design, the relatively small patient group may limit the ability to make meaningful comparisons with other data. However, patients with upper urinary tract cancer who are suitable for surgery are not very common, and it took nearly six years for a high-volume urological department, performing more than 400 robot-assisted surgeries annually, to treat 85 such patients. This underscores the importance of sharing these findings to highlight the challenges in diagnosing and managing these cases. Furthermore, the follow-up period of 26.5 months is too short to allow a thorough analysis of clinical outcomes.

Furthermore, because of the limited number of events, the study has a reduced ability to identify meaningful differences between locations. To improve consistency regarding tumor location among similar patients, we excluded those who underwent segmental ureterectomy or neoadjuvant chemotherapy. We also omitted patients with prior or concurrent cystectomy and those operated on palliatively, as bladder cancer heavily influences survival outcomes.

Additionally, understanding the effects of chemotherapy or immunotherapy is a critical and compelling question; however, it should be examined across different settings and ideally through a randomized clinical trial with an adequate patient sample. This was beyond the scope of this analysis. The final point concerns the Single-Surgeon Series. Although this approach ensures technical consistency and reduces variability, it greatly constrains external validity and generalizability. As a result, the exploratory nature of our findings must be acknowledged. Results achieved by a single expert may not be replicable in lower-volume centers or by surgeons with less experience.

Conclusion

In our single-center retrospective study of patients undergoing robot-assisted nephroureterectomy for upper tract urothelial carcinoma, considering the small sample size and short follow-up period, no statistically significant difference in survival was observed between ureteral and renal pelvis tumors. While ureteral tumors have previously been associated with poorer prognosis, our data did not confirm this association. The use of a standardized surgical technique may have contributed to the uniformly favorable outcomes observed across both groups. These findings underscore the need for larger, multicenter prospective studies with extended follow-up to better assess the prognostic significance of tumor location in upper tract urothelial carcinoma and to inform individualized treatment strategies.

Supporting information

S1 File. RANU-20.12.2025.

(SAV)

pone.0341638.s001.sav^{(13.2KB, sav)}

Abbreviations

URS: ureterorenoscopy
EAU: European Association of Urology
CDC: Clavien-Dindo Complication
UTUC: upper urinary tract carcinoma
RANU: robot-assisted radical nephroureterectomy
RARC: robot-assisted radical Cystectomy
LAD: Lymphadenectomy
LN: Lymph nodes
URS: ureterorenoscopy
AC: anticoagulation
NOAC: new oral anticoagulant
ASA: American Association of anesthesiology score
BMI: body mass index
Hgb: hemoglobin
PSM: positive surgical margins
CCS: cancer-specific survival
RFS: recurrence-free survival
OS: overall survival
BR: bladder recurrence
ICU: intensive care unit.

Data Availability

The datasets generated and analyzed during the current study are not publicly available due to national regulations on the protection of sensitive personal information. Data can be requested from the Ethik-Kommission Westfalen-Lippe via email at gutachterkommission@aekwl.de. Data may be made available to eligible researchers upon completion of all required prerequisites, such as a Data Use agreement.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0341638.r001

Decision Letter 0

Yudai Ishiyama

11 Dec 2025

Dear Dr. Farzat,

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Additional Editor Comments:

In addition to the reviewers’ comments, please carefully consider the following points from the Editor and incorporate them into your revision:

1. Scientific soundness and sample size considerations

It is the journal’s policy to consider manuscripts for publication as long as the findings are scientifically sound. I am therefore aiming to make the editorial decision based solely on this criterion. That said, the main finding of the present study—namely, the lack of difference between the two groups—requires careful attention, as underpowered studies often introduce confusion into the scientific literature.

Please review the reviewers’ comments thoroughly, and note that the editorial decision regarding scientific soundness and suitability for publication at this time—especially given the small sample size—will be further considered after your revision.

Additionally, the Introduction requires more context. Many prior studies have evaluated oncological differences between pelvic and ureteral tumors, and this body of evidence should be appropriately summarized.

2. Clarification and standardization of the Methods section

Authors are strongly advised to revise the Methods section using more standardized and conventional descriptions. The current presentation leads to confusion, and clearer methodology will improve the overall readability of the manuscript.

3. Interpretation of non-significant results

As noted by one reviewer, non-significant p-values alone are not valid or clinically meaningful when the sample size is very small. The revised manuscript should avoid overreliance on non-significance and consider alternative approaches to presenting and interpreting the data.

4. Inclusion of figures

Authors are encouraged to provide figures, especially Kaplan–Meier curves. These are essential for adequately presenting survival analyses.

Thank you for your thoughtful revision of the manuscript. I look forward to reviewing your updated submission.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Overall Assessment

This manuscript presents a well-structured retrospective analysis evaluating the impact of tumor location (ureter vs renal pelvis) on perioperative and oncological outcomes following robot-assisted radical nephroureterectomy (RANU). The study population is relatively homogeneous, with all procedures performed by a single experienced surgeon, which strengthens internal validity. The paper is clearly written and provides valuable real-world data regarding surgical outcomes and recurrence patterns.

Importantly, the authors challenge the commonly held view that ureteral tumors carry a worse prognosis, reporting no significant differences between locations in this contemporary RANU cohort. Only minor revisions are required before the manuscript can be considered for publication.

Major Comments

1. The Methods section contains several exclusion criteria (prior cystectomy, segmental ureterectomy, NAC, palliative cases) but the flow of how 85 patients were narrowed to 54 could be more clearly summarized.

Suggestion: Add a short CONSORT-style flow diagram or a clear descriptive paragraph stating the exact numbers excluded for each reason.

2. The manuscript uses the term muscle-invasive (e.g., “15% with muscle-invasive disease”). However, UTUC staging does not commonly use this term (unlike bladder cancer).

Suggestion: Replace with “≥pT2 disease” or specify explicitly that muscle-invasive corresponds to ≥pT2.

3. You state that 33% of patients had “locally advanced disease,” but the staging definition is not provided. Suggestion: Add a definition (e.g., locally advanced = pT3–T4 and/or cN+).

4. It is stated that LAD was performed “in high-risk cases,” but high-risk criteria are not clearly defined.

Suggestion: Specify the criteria (e.g., suspicious nodes on imaging, high-grade tumor, large tumor size).

5. The Results section describes recurrence times, but adding a median time to bladder recurrence—even if the sample is small—would improve clarity.

6. There are several p-values written as “p = 0.9” or “p=0.1” without consistent spacing.

Suggestion: Standardize formatting (e.g., p = 0.90). Also specify whether all p-values are two-sided.

7. CSS is reported as 98.1% and OS as 94.4%, but the follow-up period (median 29 months) is relatively short.

Suggestion: Explicitly highlight in the Results or Discussion that survival estimates may be inflated due to limited follow-up.

8. There are several minor grammatical inconsistencies and spacing issues throughout the manuscript (e.g., “64%%”, “5 lymph nodes”, “10 Adjuvant chemotherapy”).

A light language edit would improve readability.

Reviewer #2: 1. The study is described as a “case-control” study. However, the design is more accurately a retrospective single-center cohort study in which patients are divided into two groups based on tumor location (ureter vs renal pelvis). Please revise the description of the study design throughout the manuscript.

2. The definitions of the survival outcomes and the methods used to assess them are not clearly described. Please explicitly define all primary and secondary endpoints (CSS, OS, RFS).

3. The manuscript states that Kaplan–Meier and Cox regression analyses were used to estimate CSS and OS. However, there is only one cancer-related death and two deaths overall (CSS 98.1%, OS 94.4%). With such a low number of events, Cox regression is statistically unstable and unlikely to yield reliable hazard ratios, and hazard ratios and 95% confidence intervals are not reported. Either present the Cox regression results explicitly (variables included, HRs, 95% CIs) or, if the analysis is not robust, remove Cox regression from the Methods and focus on descriptive Kaplan–Meier curves and univariable log-rank tests. Please clearly state in the Discussion and Limitations that, due to the small number of events, the study has limited power to detect clinically relevant differences between locations.

4. The Methods state that lymphadenectomy was performed in high-risk cases and that all consenting patients received immediate intravesical instillation therapy. In the Results, 26 patients with muscle-invasive or locally advanced disease are reported, of whom 13 received adjuvant therapy (10 chemotherapy, 3 immunotherapy). However, important details are missing: Which agents and doses were used for intravesical instillation? How many patients (overall and by tumor location) actually received it? What were the regimens for adjuvant chemotherapy and immunotherapy? Please provide these details.

5. The median follow-up of 29 months is relatively short for UTUC, particularly for detecting late recurrences and deaths. Nonetheless, the Abstract and Conclusion state that tumor location “does not impact postoperative and oncological outcomes.” Given the small sample and limited follow-up, softening the conclusion is recommended to reflect that no statistically significant differences were observed between ureteral and renal pelvis tumors in this single-center cohort, pending confirmation in larger, multicenter series with longer follow-up.

6. The study reports a statistically significant difference in hospital stay (8 days for the ureter group vs. 6.5 days for the renal pelvis group). The Discussion (Page 8, lines 227-230) attributes this generally to local clinical practices and catheter removal. This finding warrants a more specific explanation of why the ureter group specifically required longer stays, rather than a general comment on discharge planning. Was the protocol for catheter removal different between the groups?

7. There appear to be small inconsistencies between the Abstract and the main text regarding the proportions of muscle-invasive vs locally advanced disease (“14% muscle-invasive” vs “15%” in the Results). Please review and harmonize these percentages.

8. In Table 1, the p-value for gender is 0.5; however, in the first sentence of the Results section, it is described as if the p-value for BMI were 0.5 instead of gender, which seems an error.

9. In Table 1, BMI is significantly higher in the ureteral group than in the renal pelvis group (30.5 vs 27.0 kg/m², p = 0.04). Please comment on the observed baseline difference in BMI and its potential relevance.

10. The Methods state that 85 patients underwent UTUC surgery between July 2019 and July 2025, with data assessed on 01.09.2025. The date of data evaluation is written as “01.09.2025.” To ensure it is correctly understood, please revise it, for example, by writing out the month in English.

11. The term “locally advanced disease,” which seems to refer to T3–T4 tumors, is used in the Discussion, but it is not explicitly defined in the Methods or in the Results. Please clearly define “locally advanced” disease in the Methods.

12. In the Discussion, the statement about Colin et al. and positive surgical margins appears to be cited as reference (16). In contrast, the reference list suggests that Colin et al. correspond to reference 5. Please review all in-text citations and reference numbers for accuracy and consistency.

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Reviewer #1: Yes: Fumihiko Urabe

Reviewer #2: No

**********

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PLoS One. 2026 Jan 30;21(1):e0341638. doi: 10.1371/journal.pone.0341638.r002

Author response to Decision Letter 1

22 Dec 2025

Rebuttal letter: Impact of Tumor Location on Oncological and Perioperative Outcomes after Robot-Assisted Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Dear Dr. Ishiyama,

Dear Editorial Board of POLS one,

Here is a point-by-point response to your comments and the reviewers' recommendations.

Editor Comments:

In addition to the reviewers’ comments, please carefully consider the following points from the Editor and incorporate them into your revision:

1. Scientific soundness and sample size considerations: It is the journal’s policy to consider manuscripts for publication as long as the findings are scientifically sound. I am therefore aiming to make the editorial decision based solely on this criterion. That said, the main finding of the present study—namely, the lack of difference between the two groups—requires careful attention, as underpowered studies often introduce confusion into the scientific literature.

We thank you, dear Dr. Ishiyama, for your insightful review and valuable comments.

Regarding sample size and the scientific validity of our study, we clarified in the methods and discussion sections that, in this retrospective context, we used non-probability sampling—specifically, convenience sampling. Given our small, simple size, this approach carries a high risk of selection bias. It increases the margin of error of our analysis, limiting the ability to generalize the findings to the broader population due to reduced external validity. As a result, our findings may be biased. Yet, in this paper, we aimed to reflect our real-world experience with UTUC patients in a high-volume urological department. During a follow-up period of more than 2 years (which is still short for UTUC), we observed no significant differences in survival regarding tumor location in those patients.

First, we revised the introduction and cited an additional four studies to provide more context.

We also conducted a new round of telephone follow-up, repeated the statistical workup, and excluded all patients who died from the calculation of the follow-up period (mean 34 months, median 26,5 months). We rewrote a significant portion of the manuscript. We discovered that two patients had developed distant metastasis, and one of them died due to terminal metastatic disease.

Altogether, in our cohort,

6 patients developed bladder recurrence (median 9 months)

4 patients developed distant metastasis (median 4 months)

2 patients died from surgery-related complications

1 patient died from cancer-unrelated causes

3 patients died from terminal metastatic disease

Changing the survival outcomes into this:

Oncological Outcomes

Bladder Recurrence 6 (11%) 1 (5.6%) 5 (14%) 0.10

Distant Metastasis 4 (7.4 %) 1 (5.5 %) 3 (8.3 %) 0.72

Survival Outcomes

Disease free Survival 44 (81 %) 16 (89 %) 28 (77 %) 0.08

Cancer-Specific Survival 51 (94.4 %) 18 (100%) 33 (92 %) 0.24

Overall Survival 48 (89 %) 17 (94.4 %) 31 (86 %) 0.49

2. Clarification and standardization of the Methods section: Authors are strongly advised to revise the Methods section using more standardized and conventional descriptions. The current presentation leads to confusion, and clearer methodology will improve the overall readability of the manuscript.

As advised, we revised the methodology to improve the manuscript's readability.

We tried to bring more structure in methods by subdividing methods into:

Preoperative diagnostic and Surgical technique

Participants, exclusion criteria, and study design

Variables and Statistical Analysis

3. Interpretation of non-significant results: As noted by one reviewer, non-significant p-values alone are not valid or clinically meaningful when the sample size is very small. The revised manuscript should avoid overreliance on non-significance and consider alternative approaches to presenting and interpreting the data.

We thank you again for the tip. We tried to avoid excessive mention of all p-values in the abstract, results, and discussion. We tried focusing on the relevant outcomes and trends regardless of their p-values.

4. Inclusion of figures: Authors are encouraged to provide figures, especially Kaplan–Meier curves. These are essential for adequately presenting survival analyses.

We are grateful for the valuable recommendation. We added a flowchart for the inclusion criteria. We also included Kaplan-Meier curves for DFS, CCS, and OS. We hope we have improved our manuscripts by presenting the survival analysis.

Reviewers' comments:

Reviewer #1: Overall Assessment

Major Comments

Suggestion: Add a short CONSORT-style flow diagram or a clear descriptive paragraph stating the exact numbers excluded for each reason.

We apologize for the unclear inclusion/exclusion criteria in the methods. We tried to improve the description by adding a consort-style flow diagram to give a better overview of patient inclusion.

2. The manuscript uses the term muscle-invasive (e.g., “15% with muscle-invasive disease”). However, UTUC staging does not commonly use this term (unlike bladder cancer).

Suggestion: Replace with “≥pT2 disease” or specify explicitly that muscle-invasive corresponds to ≥pT2.

3. You state that 33% of patients had “locally advanced disease,” but the staging definition is not provided. Suggestion: Add a definition (e.g., locally advanced = pT3–T4 and/or cN+).

Answer to questions 2 and 3: We removed the term "muscle-invasive disease" and replaced it with ≥pT2 disease, which includes both muscle-invasive and locally advanced disease.

4. It is stated that LAD was performed “in high-risk cases,” but high-risk criteria are not clearly defined.

Suggestion: Specify the criteria (e.g., suspicious nodes on imaging, high-grade tumor, large tumor size).

We defined the high-risk criteria in methods as follows: “Patients with high-grade cytology or biopsy, evidence of local invasion on CT, variant histology, multifocal disease, tumor size ≥2 cm, or hydronephrosis were classified as high-risk UTUC.”

5. The Results section describes recurrence times, but adding a median time to bladder recurrence—even if the sample is small—would improve clarity.

We added the median time to bladder recurrence (9 months) to the abstract and the main text. We also added the median time for the distant metastasis (4 months).

6. There are several p-values written as “p = 0.9” or “p=0.1” without consistent spacing.

Suggestion: Standardize formatting (e.g., p = 0.90). Also specify whether all p-values are two-sided.

We apologize for the inconsistency. We repeated the entire statistical workup, standardized the formatting, and specified in the methods that p-values are two-sided.

7. CSS is reported as 98.1% and OS as 94.4%, but the follow-up period (median 29 months) is relatively short.

Suggestion: Explicitly highlight in the Results or Discussion that survival estimates may be inflated due to limited follow-up.

After we corrected the new CCS and OS rates in our study, we highlighted in the discussion that survival estimates may be inflated due to the limited follow-up period, as follows:

“The oncological outcomes within our cohort—comprising a bladder recurrence rate of 11%, a distant metastasis rate of 7.4%, and a cancer-specific survival rate of 94.4%—align with the findings documented in currently available literature. This finding may be inflated due to the limited follow-up.”

8. There are several minor grammatical inconsistencies and spacing issues throughout the manuscript (e.g., “64%%”, “5 lymph nodes”, “10 Adjuvant chemotherapy”).

A light language edit would improve readability.

We apologize for the inconsistencies. We thoroughly reviewed the manuscript to correct those mistakes.

We revised the description of the study throughout the manuscript to “retrospective single-center cohort study.”

2. The definitions of the survival outcomes and the methods used to assess them are not clearly described. Please explicitly define all primary and secondary endpoints (CSS, OS, RFS).

We thank the respected reviewer for his comment. We tried to define our study endpoints in the methods as follows: “The primary endpoint of the study was to assess how UTUC tumor location affects surgical outcomes. The secondary endpoint was to evaluate its influence on disease-free survival and overall survival.”

We thank the respected reviewer for this very important point. As mentioned, due to the small number of events, the Cox regression analysis is not robust and won’t help draw reliable conclusions regarding the impact of UTUC location on survival. We removed the Cox regression from the methods and focused on describing Kaplan-Meier curves with univariable log-rank tests. To improve the interpretation of our results, we included Kaplan-Meier curves for DFS, CCS, and OS in the manuscript. We also stated the following sentence in the limitation (Because of the limited number of events, the study has reduced ability to identify meaningful differences between locations.)

We apologize for the missed details about the chemotherapy doses and regimes. The intravesical instillation was with mitomycin 40 mg (single dose). We added this information in the methods. The chemotherapy/immunotherapy regimes and doses were described in detail in the methods as follows: “Out of 26 patients with muscle-invasive and locally advanced cancer, 13 received adjuvant therapy. Of them, 10 patients received three cycles of polychemotherapy gemcitabine/cisplatin. When renal function didn’t allow a full dose, patients received a 60% or 80% reduction in cisplatin dose to improve tolerability, and in such cases, the dose was split over two days. Two patients received Nivolumab for 1 year (4 weeks schema), and one patient was planned for adjuvant therapy with nivolumab, yet in the subsequent staging, new metastases were found, and he received Enfortumab Vedotin in combination with Pembrolizumab.”

We thank the respected reviewer for his point. We softened the conclusion as follows: “In our single-center retrospective study of patients undergoing robot-assisted nephroureterectomy for upper tract urothelial carcinoma, considering the small sample size and short follow-up period, no statistically significant difference in survival was observed between ureteral and renal pelvis tumors.”

To address the points raised by the editor and reviewers, we repeated the entire statistical workup of our study and conducted a new round of follow-up. The median hospital stay across the study groups was 5 days. We corrected those results in both the results and the discussion. And we apologize for the inconsistency.

We apologize for this inconsistency. We corrected and harmonized the values.

8. In Table 1, the p-value for gender is 0.5; however, in the first sentence of the Results section, it is described as if the p-value for BMI were 0.5 instead of gender, which seems an error.

After repeating the statistical workup of our study, we corrected all the relevant results in the section. Based on the recommendation of the editor, we abstained from mentioning all the non-significant p-values as well. The baseline results now read as follows: “The median age of the patients was 73 years. Patients in the ureteral tumors group were more obese, with a median BMI of 30.5 kg/m², versus a BMI of 27 kg/m² for the renal pelvis group (p = 0.04). 65% of patients were males. Patients presented with multiple comorbidities; however, ASA scores were comparable across groups.”

We integrated the point of higher BMI in discussion as follows: “Despite being

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PLoS One. doi: 10.1371/journal.pone.0341638.r003

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Yudai Ishiyama

11 Jan 2026

Impact of Tumor Location on Oncological and Perioperative Outcomes after Robot-Assisted Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

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Data Availability Statement

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PERMALINK

Impact of tumor location on oncological and perioperative outcomes after robot-assisted radical nephroureterectomy for upper tract urothelial carcinoma

Mahmoud Farzat

Ibrahim Altaie

Sami-Ramzi Leyh-Bannurah

Mykyta Kachanov

Florian M Wagenlehner

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Methods

Participants, exclusion criteria and study design

Fig 1. Consort flow chart of the patients included in the study.

Preoperative diagnostic and surgical technique

Variables and statistical analysis

Results

Baseline parameters

Table 1. Baseline characteristics and preoperative clinical and oncological parameters.

Intra- and postoperative data

Table 2. Intra- and postoperative results and pathological outcomes.

Complications, oncological and survival outcomes

Fig 2. Kaplan-Meier curve estimating disease-free survival.

Fig 3. Kaplan-Meier curve estimating cancer-specific survival.

Fig 4. Kaplan-Meier curve estimating overall survival.

Table 3. Complications, readmission, oncological, and survival outcomes.

Discussion

Conclusion

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Yudai Ishiyama

Roles

Author response to Decision Letter 1

Decision Letter 1

Yudai Ishiyama

Roles

Acceptance letter

Yudai Ishiyama

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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