Unmarried Status Effect on Stage at Presentation and Treatment Patterns in Non-Metastatic Upper Tract Urothelial Carcinoma Patients.

BACKGROUND: Unmarried status has been associated with higher proportions of locally advanced stage and lower treatment dose intensification rates in several urological and non-urological malignancies. However, no previous investigators focused on the association between unmarried status and advanced stage (T3-4N0-2) at presentation and lower nephroureterectomy (RNU) and systemic therapy (ST) rates in non-metastatic upper tract urothelial carcinoma (UTUC) patients. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020, all non-metastatic UTUC patients were identified. Multivariable logistic regression models (LRMs) tested for differences in stage at presentation and treatment (RNU and ST) according to marital status (married vs unmarried), in a sex-specific fashion. RESULTS: Of all 8544 non-metastatic UTUC patients, 4748 (56%) were male vs 3190 (44%) were female. Of all 4748 male UTUC patients, 1191 (25%) were unmarried. Of all 3190 female UTUC patients, 1608 (50%) were unmarried. In multivariable LRMs predicting RNU, unmarried status was an independent predictor of lower RNU rates in male (Odds Ratio [OR]: 0.56; P < .001), but not in female (OR: 0.81; P = .1) non-metastatic UTUC patients. In multivariable LRMs predicting ST exposure, unmarried status was an independent predictor of lower ST rates in both male (OR:0.73; P = .03) and female (OR:0.64; P < .001) UTUC patients. In multivariable LRMs predicting locally advanced stage (T3-4N0-2), unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male (OR: 0.95; P = .5) or female (OR: 0.99; P = .9) UTUC patients. CONCLUSIONS: Unmarried male UTUC patients appear at risk of less being able to access RNU, relative to their married counterparts. Moreover, unmarried UTUC patients appear to less benefit from ST, regardless of sex. Conversely, unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male or female UTUC patients.

Totally retroperitoneal approach for robot-assisted nephroureterectomy with bladder cuff without repositioning.

INTRODUCTION: Robot-assisted nephroureterectomy (RANU) for upper urinary tract urothelial carcinoma is typically performed via the transperitoneal approach because of limited surgical space. However, a retroperitoneal approach may be preferable in patients with a history of abdominal surgery or in those in whom pelvic lymph node dissection is unnecessary. MATERIALS AND SURGICAL TECHNIQUES: RANU via the retroperitoneal approach was selected for two patients diagnosed with high-grade upper urothelial carcinoma with a history of abdominal surgery. Nephrectomy was performed in the 90° flank position, and the bed was tilted at 20°. The retroperitoneal space was extended, and the robot trocar was subsequently repositioned in the left lower quadrant. After redocking the robot, the distal ureter was dissected, and the bladder cuff was resected en bloc along with the kidney and the ureter. Neither patient had any complications within 3 months postoperatively. DISCUSSION: By devising a new technique for trocar placement, total retroperitoneal RANU without repositioning was possible, even in a small patient.

Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

Endoscopic intervention versus radical nephroureterectomy for the management of localized upper urinary tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies.

OBJECTIVE: Localized Upper Urinary Tract Urothelial Carcinoma (UTUC) is an uncommon cancer typically detected at an advanced stage. Currently, radical nephroureterectomy (RNU) with bladder cuff excision is the standard treatment for high-risk UTUC. This meta-analysis aims to evaluate the 5-year overall and cancer-specific survival and bladder recurrence rates in studies comparing endoscopic kidney-sparing surgeries (E-KSS) with RNU in localized UTUC. EVIDENCE ACQUISITION: We performed a literature search on 20th April 2023 through PubMed, Web of Science, and Scopus. The PICOS model was used for study inclusion: P: adult patients with localized UTUC; I: E-KSS. C: RNU; O: primary: overall survival (OS); secondary: cancer-specific survival (CSS), bladder recurrence rate, and metastasis-free survival (MFS). S: retrospective, prospective, and randomized studies. EVIDENCE SYNTHESIS: Overall, 11 studies involving 2284 patients were eligible for this meta-analysis, 737 in the E-KSS group and 1547 in the RNU group. E-KSS showed a similar overall 5-year OS between E-KSS and RNU, and for low-grade tumors, while 5-year OS favored RNU for high-grade tumors (RR 1.84, 95% CI 1.26-2.69, p = 0.002). No difference emerged for 5-year CSS between the two groups, even when the results were stratified for low- and high grade tumors. Bladder recurrence rate and 5-year MFS were also similar between the two groups. CONCLUSIONS: Our review showed that E-KSS is a viable option for patients with localized UTUC with non-inferior oncological outcomes as compared with RNU, except for 5-year OS in high-grade tumors which favoured RNU.

Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience.

PURPOSE: The study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU. TTR and OS were evaluated using Kaplan-Meier and Cox proportional hazard regression, covariates adjusted for age, postoperative GFR, history of neoadjuvant chemotherapy, T and N stage with stabilized inverse probability of treatment weighting (sIPTW). RESULTS: The application of adjuvant chemotherapy showed a significant extension in TTR (P = .01), but no substantial impact on OS (P = .19) after sIPTW adjustment for covariates. Multivariate analysis revealed adjuvant chemotherapy, tumor size, and lymphovascular invasion as significant prognostic factors for TTR. In contrast, only tumor size and perineural invasion were significant for OS. Adjuvant chemotherapy reduced the progression risk in certain VUTUC subtypes (squamous or glandular/micropapillary), but not in sarcomatoid variants. CONCLUSIONS: Adjuvant chemotherapy appears to improve TTR, albeit without a significant effect on OS, in nonmetastatic localized and locally advanced VUTUC patients post-RNU. While beneficial to some VUTUC subtypes, it did not yield significant advantages for sarcomatoid variants. Despite adjustments for known confounders, the study's findings may be subject to potential selection bias and unmeasured confounding factors.

Open versus minimally invasive nephroureterectomy in octogenarians: An analysis of surgical approach trends, outcomes, and survival analysis with propensity matching.

INTRODUCTION: Upper tract urothelial carcinoma (UTUC) is a rare disease accounting only for 5%-10% of urothelial carcinoma (UC). For localized high-risk disease, radical nephroureterectomy (RNU) is the standard of care. While minimally invasive (MIS) RNU has not been shown to decisively improve overall survival (OS) compared to open surgery, MIS RNU has been associated with reduced hospital length of stay (LOS), blood transfusion requirements and improved recovery, which are important considerations when treating older patients. The purpose of this study is to examine trends in surgical approach selection and outcomes of open vs. MIS RNU in patients aged ≥80 years. METHODS: Using the National Cancer Database (NCDB), patients aged ≥80 years who underwent open or MIS (either robotic or laparoscopic) RNU were identified from 2010 to 2019. Demographic, patient-related, and disease-specific factors associated with either open or MIS RNU were assessed using multivariate logistic regression models. Survival analysis was conducted using Kaplan-Meier plots and Cox-proportional hazard regression. Inverse probability of treatment weighting (IPTW) was utilized to adjust for confounding variables. Survival analysis was also conducted on the IPTW adjusted cohort using Kaplan-Meier plots and Cox-proportional hazard regression. RESULTS: 5,687 patients were identified, with 1,431 (25.2%) and 4,256 (74.8%) patients undergoing open and MIS RNU respectively. The proportion of RNU performed robotically has increased from 12.5% in 2010 to 50.4% in 2019. MIS was associated with a shorter hospital LOS (4.7 days versus 5.9 days, SMD 23.7%). Multivariate analysis revealed that MIS was associated with a significant reduction in 90-day mortality (OR: 0.571; 95%CI: 0.34-0.96, P = 0.033) and improved median OS (53.8 months [95%CI: 50.9-56.9] vs 42.35 months [95%CI: 38.6-46.8], P < 0.001) compared to open surgery. IPTW-adjusted survival analysis revealed improved median OS with MIS when compared to open surgery, with a survival benefit of 46.1 months (95%CI: 40.2-52.4 months) versus 37.7 months (95%CI: 32.6-46.5 months, P = 0.0034) respectively. IPTW-adjusted cox proportional hazard analysis demonstrated that MIS was significantly associated with reduced mortality (HR 0.76, 95%CI: 0.66-0.87, P < 0.001). CONCLUSION: In octogenarians undergoing RNU, MIS is associated with improved median OS and 90-day mortality.

The Evolution of Upper Tract Urothelial Carcinoma Management in Kidney Recipients.

INTRODUCTION: Urothelial cancers were one of the most common malignancies in patients with kidney transplants. Although radical nephroureterectomy is still the standard of care in current guidelines, studies have shown that significantly improved perioperative outcomes can be achieved for patients who underwent bilateral nephroureterectomy. Our study provides evidence on the outcome of bilateral nephroureterectomy and unilateral nephroureterectomy in kidney recipients with upper tract urothelial carcinoma. MATERIAL AND METHODS: In the study, the data of patients from a single center, Chang Gung Memorial Hospital Linkou branch, were collected retrospectively from 1981 to 2023. The patient's detailed information was collected through the medical records in the hospital. RESULTS: A total of 44 cases of kidney recipients with upper urinary tract urothelial carcinoma were collected in this study. Of the patients, 19 nephroureterectomies were performed before 2008 and 24 afterward. Incidental findings of contralateral tumors were noted in 3 out of 6 patients who underwent bilateral nephroureterectomy before 2008 and 3 out of 12 after 2008. Contralateral upper urinary tract urothelial carcinoma after unilateral nephroureterectomy was noted in 3 patients within a median of 8.1 years. The progression-free survival of bilateral nephroureterectomy was significantly better compared with a unilateral group (not reached, 15.8 years, respectively). DISCUSSION: Our study, along with previous studies, provides evidence that bilateral nephroureterectomy may be a better treatment option in kidney recipients with upper tract urothelial carcinoma. Our study has several limitations based on its retrospective nature.

Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

Prediction of pathological up-staging after radical nephroureterectomy in patients with upper tract urothelial carcinoma.

PURPOSE: The diagnostic accuracy of computed tomography urography for upper tract urothelial carcinoma is high; however, difficulties are associated with precisely assessing the T stage. Preoperative tumor staging has an impact on treatment options for upper tract urothelial carcinoma. We herein attempted to identify preoperative factors that predict pathological tumor up-staging, which will facilitate the selection of treatment strategies. MATERIALS AND METHODS: We retrospectively identified 148 patients with upper tract urothelial carcinoma who underwent computed tomography urography preoperatively followed by radical nephroureterectomy without preoperative chemotherapy at our institution between 2000 and 2021. Preoperative factors associated with cT2 or lower to pT3 up-staging were examined using a multivariate logistic regression analysis. RESULTS: Ninety out of 148 patients were diagnosed with cT2 or lower, and 22 (24%) were up-staged to pT3. A multivariate analysis identified a positive voided urine cytology (HR 4.69, p = 0.023) and tumor length ≥ 3 cm (HR 6.33, p = 0.003) as independent predictors of pathological tumor up-staging. CONCLUSIONS: Patients diagnosed with cT2 or lower, but with preoperative positive voided urine cytology and/or tumor diameter ≥ 3 cm need to be considered for treatment as cT3.

Testing the external validity of the POUT III trial (adjuvant platnium-based chemotherapy in upper tract urothelial carcinoma) in a North American cohort.

OBJECTIVE: The European POUT III randomized controlled trial provided level-one evidence that adjuvant platinum-based chemotherapy is the standard of care following nephroureterectomy (RNU) for locally invasive or node-positive upper tract urothelial carcinoma. We aim to assess this European randomized controlled trial's generalizability (external validity) to a North American cohort, using a nationwide database. MATERIALS AND METHODS: To compare trial patients with those seen in real-world practice, we simulated the trial inclusion criteria using data from the National Cancer Database (NCDB). We identified patients with histologically confirmed transitional cell carcinoma who underwent RNU. The available demographic characteristics of the NCDB cohort were compared with the POUT III trial cohort using Chi-squared test. RESULTS: The NCDB cohort (n = 3,380) had a significantly higher proportion of older patients (age ≥ 80: 23.5% vs. 5%), and more males (68% vs. 56.2%) than the POUT cohort (Table 1, both p < 0.001). Additionally, the rate of advanced nodal disease was higher in the NCDB (N1 9.6%, N2 9.3%) than in the POUT (N1 6%, N2 3%) cohort (p < 0.001). A more extensive lymph node dissection was performed in NCDB vs. POUT patients (node≥10 10.9% vs. 3%, p < 0.001). Sensitivity analysis removing all subjects with a Charlson Comorbidity Index > 0 did not change the significance of any results. CONCLUSIONS: While the primary disease stage was similar, the rate of advanced nodal disease was significantly higher in NCDB, which might be explained partially by the more extensive lymph node dissection performed in the latter. These differences warrant caution when applying the POUT III findings to North American patients.

Focused UTUC pathways with a risk-stratified approach to diagnostic ureteroscopy: is it the need of the hour? A retrospective cohort analysis.

INTRODUCTION: Upper urinary tract urothelial cancer is a rare, aggressive variant of urinary tract cancer. There is often delay to diagnosis and management for this entity in view of diagnostic and staging challenges needing additional investigations and risk stratifications for improved outcomes. In this article, we share our experience in developing a dedicated diagnostic and treatment pathway for UTUC and assess its impact on time lines to radical nephroureterectomy (RNU). We also evaluate the impact of diagnostic ureteroscopy (DUR) on UTUC care pathways timelines. MATERIALS AND METHODS: A prospective database was maintained for all patients who underwent a RNU from January 2015 to August 2022 in a high-volume single tertiary care centre in the UK. In 2019, a Focused UTUC pathway (FUP) was implemented at the centre to streamline diagnostic and RNU pathways. A retrospective analysis of the database was conducted to compare time lines and diagnostic trends between the pre-FUP and FUP cohorts. Primary outcome measures were time to RNU from MDT. Secondary outcome measures were: impact of DUR on time to RNU from MDT and negative UTUC rates between DUR and non-DUR cohorts. Differences in continuous variables across categories were assessed using the independent sample t test. Categorical variables between cohorts were analysed using the chi-square (χ2). Statistical significance in this study was set as p < 0.05. RESULTS: A total of 500 patients with complete data were included in the analysis. The pre-FUP and FUP cohorts consisted of 313 patients and 187 patients, respectively. The overall cohort had a mean age (SD) of 70 years (9.3). 66% of the overall cohort were males. The median time to RNU from MDT in the FUP was significantly lower compared to the pre-FUP cohort; 62 days (IQR 59) vs. 48 days (IQR 41.5), p < 0.0001. The median time to RNU from MDT in patients who underwent a diagnostic URS in the FUP cohort was significantly lower compared to the pre-FUP cohort; 78.5 days (IQR 54.8) vs. 68 days (IQR 48), p-NS. The non-UTUC rates in the DUR and non-DUR cohorts were 6/248 (2.4%) and 14/251 (5.6%), respectively (NS). CONCLUSION: In this series, we illustrate the effectiveness of integrating a multidisciplinary approach with specialised personnel, ring-fenced clinics, efficient diagnostic assessment and optimised theatre capacity. By adopting a risk-stratified approach to diagnostic ureteroscopy, we have achieved a significant reduction in time to RNU.

Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.