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Upper tract urothelial carcinoma (UTUC) is a cancer that is often already in an advanced stage at the time of initial diagnosis. Although urothelial carcinoma of the upper and lower urinary tracts both originate from the urothelium and have similar genetic alterations, there are significant differences in their distribution. In localized high-risk UTUC, radical nephroureterectomy is the gold standard therapy. In metastatic UTUC, major changes are emerging in sequential therapy due to the investigation of new classes of drugs. In addition to platinum-based combination chemotherapy and immunotherapy, new substances such as antibody-drug conjugates (ADCs) and FGFR inhibitors are used., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Due to possible synergistic effects, the combination of radiation therapy (RT) and immune checkpoint inhibitors (ICI) represents an interesting therapeutic option. An increasing number of clinical trials are ongoing to investigate this combination in genitourinary malignancies and the first results are available., Objectives: To review and summarize available data on the combination of RT and ICI in genitourinary malignancies and update the evidence for this potential therapeutic approach., Evidence Acquisition: A study protocol was registered in the PROSPERO-Database. Terms of search were prostate cancer, bladder cancer, renal cell carcinoma, penile cancer, testicular cancer, radiotherapy, and immunotherapy in multiple literature databases and study registers. Clinical studies reporting on the combination treatment of RT and ICI were included. A systematic review of ongoing trials according to the PRISMA statement and a meta-analysis of available trials were performed., Evidence Synthesis: Overall, 43 studies met the inclusion criteria examining the therapeutic effect of combined RT and ICI. For bladder cancer, renal cell carcinoma, prostate cancer, and penile cancer 28, 9, 5, and 1 trial could be identified, respectively. No study was found for testicular cancer. Three phases III trials were identified, all other trials were phase I or II. Twelve studies have been completed so far. The meta-analysis of available data indicates comparable toxicity of RT plus ICI vs. ICI alone for grade 3/4 AEs. Mature efficacy data is limited with interesting early results., Conclusion: This article reviews the clinical trial landscape investigating RT and ICI in genitourinary malignancies. It provides an overview of ongoing trials and discusses available results. Actual data regarding efficacy is limited, while toxicities seem comparable to ICI alone. Especially in bladder and kidney cancer, further trial results might impact on the clinical use of the combination therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Polymerase I and transcript release factor (PTRF) has been implicated in cancer biology but its role in upper tract urothelial carcinoma (UTUC) is unknown. From a pilot transcriptome, we identified PTRF was significantly upregulated in high stage UTUC. Bladder cancer transcriptome from The Cancer Genome Atlas (TCGA) supported our finding and high PTRF level also predicted poor survival. We, therefore, investigated the correlation of PTRF with patients' clinicopathologic characteristics and outcomes in a multiracial UTUC cohort., Materials and Methods: By immunohistochemical staining, PTRF expression was determined using H-score. PTRF expression of 575 UTUCs from 8 institutions, including 118 Asians and 457 Caucasians, was compared with various clinicopathologic parameters. Human urothelial cancer cell lines were used to evaluate the level of PTRF protein and mRNA expression, and PTRF transcript level was assessed in fresh samples from 12 cases of the cohort. The impact of PTRF expression on disease progression, cancer-specific death and overall mortality was also examined., Results: High PTRF expression was significantly associated with multifocality (P = 0.023), high pathologic tumor stage (P < 0.00001), nonurothelial differentiation (P = 0.035), lymphovascular invasion (P = 0.003) and lymph node metastasis (P = 0.031). PTRF mRNA expression was also markedly increased in advanced stage UTUC (P = 0.0003). High PTRF expressing patients had consistently worse outcomes than patients with low PTRF expression regardless of demographic variation (all P < 0.005). In multivariate analysis, high PTRF expression was an independent predictor for progression-free survival (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.07-2.69, P = 0.025), cancer-specific survival (HR 2.09, 95% CI 1.28-3.42, P = 0.003), and overall survival (HR 2.04, 95% CI 1.33-3.14, P = 0.001)., Conclusions: Results indicate that PTRF is a predictive biomarker for progression and survival and an independent prognosticator of UTUC. Elevated PTRF could probably propel clinically aggressive disease and serve as a potential therapeutic target for UTUC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies., Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05., Results: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS., Conclusions: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.

Purpose: This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients., Methods: This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety., Results: A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension., Conclusions: Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence., Trial Registration: NCT01613846, www.clinicaltrials.gov., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma., Materials and Methods: Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell Marque™ NAT105 diluted 1:250 and prediluted E1L3N® via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes., Results: Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003)., Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To determine the prognostic significance of Forkhead Box A1 (FOXA1) expression in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU)., Materials and Methods: A retrospective analysis of 566 patients undergoing RNU at seven academic medical centers was performed. Tissue microarrays were subjected to immunohistochemistry using a commercially available polyclonal FOXA1 antibody. Logistic regression determined the association of FOXA1 expression with pathologic features and survival outcomes., Results: Three hundred twenty-two men and 244 women were included. The pathologic distribution of specimens included 53% muscle-invasive or greater (≥pT2), 74% high-grade, 16% with flat architecture, 13% with necrosis, 21% with lymphovascular invasion, 18% with concomitant carcinoma in situ, and 8% with positive lymph nodes. The median FOXA1 score was 5.0 (range: 0-8). Lower FOXA1 expression was significantly correlated with advanced pathologic stage (≥pT3) (P = .02), concomitant carcinoma in situ (P = .006), and renal pelvis (vs ureter) location (P < .0001). At a median follow-up of 27.0 months (range: 3-196), 139 patients (25%) experienced disease recurrence and 121 (21%) died from the disease. In a multivariate model, lower FOXA1 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.05-1.62, P = .04), cancer-specific mortality (HR: 1.17, 95% CI: 1.03-1.92, P = .04), and all-cause mortality (HR: 1.08, 95% CI: 1.02-1.18, P = .05)., Conclusion: Lower FOXA1 expression is associated with adverse pathologic features and inferior survival outcomes for UTUC patients undergoing RNU. These data indicate lower FOXA1 expression may be a marker of aggressive disease in UTUC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Excision repair cross-complementing 1 (ERCC1) has been associated with outcomes of urothelial carcinoma of the bladder, but was not yet studied in upper tract urothelial carcinoma (UTUC). The aim of this study was to assess the prognostic role of ERCC1 expression in a large international cohort of UTUC patients., Methods: Immunohistochemical ERCC1 expression was evaluated in 716 UTUC patients who underwent radical nephroureterectomy with curative intent. ERCC1 was considered positive when the H-score was >1.0. Associations with overall survival and cancer-specific survival were assessed using univariable and multivariable Cox models., Results: ERCC1 was expressed in 303 tumors (42.3 %) and linked with the presence of tumor necrosis (16.2 vs. 10.4 %, p = 0.023), but not with any other clinical or pathological variable. ERCC1 status did not predict cancer-specific survival and overall survival on both univariable (p = 0.70 and 0.32, respectively) and multivariable analyses (p = 0.48 and 0.33, respectively)., Conclusions: ERCC1 is expressed in a significant proportion of UTUC and is linked with tumor necrosis, but its expression appears not to be associated with prognosis following radical nephroureterectomy.

Purpose: The aim of the study was to externally validate the Zonal NePhRO Score (ZNS) published in 2014 as latest and superior nephrometry score in terms of prediction of perioperative complications and outcome of open partial nephrectomies (OPNs)., Methods: We identified 200 consecutive patients who underwent OPN. Analysis of preoperative CT or MRI scans and retrospective analysis of the patients' clinical records were performed. Tumour complexity was stratified according to the ZNS into three categories: low (4-6), moderate (7-9) and high (10-12) complexity. Predictors for perioperative complications and surgical parameters were identified using univariate and multivariate logistic regression., Results: Tumour complexity was graded in 19.8 % of the cases as low, in 50.3 % as moderate and in 29.9 % as high. In the multivariate analysis, ZNS was significantly associated with a higher complication rate (OR 1.25, 95 % CI 1.04-1.49, p = 0.014), longer ischaemia time (IT) (β = 1.19, 95 % CI 0.33-2.05, p = 0.007), postoperative drop of estimated glomerular filtration rate (eGFR) (β = -1.86, 95 % CI -3.71 to -0.01, p = 0.049) and opening of the collecting system (CS) (OR 1.72, 95 % CI 1.40-2.10, p < 0.001). In addition, age and body mass index were identified as independent predictors for complications (OR 1.03, 95 % CI 1.00-1.06, p = 0.043 and OR 1.08, 95 % CI 1.00-1.15, p = 0.031)., Conclusion: The present study is the first external validation of the ZNS as a predictor of perioperative complications in patients undergoing OPN. A higher ZNS score was associated with a longer IT, a higher rate of opening the CS and drop of eGFR.

Purpose: We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma., Materials and Methods: A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki-67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models., Results: The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p <0.001) and cancer specific survival (HR 15.8, p <0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p <0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model., Conclusions: Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC., Objective: To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU)., Design, Setting, and Participants: We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008., Intervention: All patients were diagnosed with UTUC and underwent RNU., Outcome Measurement and Statistical Analysis: Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality., Results and Limitations: IMP3 was expressed in 12.2% of patients with UTUC (n=76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12-53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p<0.01), cancer-specific survival (34.5% vs 78.9%; p<0.01), and overall survival (15.6% vs 64.8%; p<0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p<0.01), cancer-specific mortality (HR: 2.15; p<0.01), and all-cause mortality (HR: 2.07; p<0.01). Major limitations include the retrospective design and relatively short follow-up time., Conclusions: IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Upper tract urothelial carcinoma is rare and less well studied than bladder cancer. It remains questionable if findings in bladder cancer can safely be extrapolated to upper tract urothelial carcinoma. We prospectively evaluate molecular profiles of upper tract urothelial carcinoma and bladder cancer using a cell cycle biomarker panel., Materials and Methods: Immunohistochemical staining for p21, p27, p53, cyclin E and Ki-67 was prospectively performed for 96 patients with upper tract urothelial carcinoma and 159 patients with bladder cancer with nonmetastatic high grade urothelial carcinoma treated with extirpative surgery. Data were compared between the groups according to pathological stage. Primary outcome was assessment of differences in marker expression. Secondary outcome was difference in survival according to marker status., Results: During a median followup of 22.0 months 31.2% of patients with upper tract urothelial carcinoma and 28.3% of patients with bladder cancer had disease recurrence, and 20.8% and 27.7% died of upper tract urothelial carcinoma and bladder cancer, respectively. The number of altered markers was not significantly different between the study groups. Overall 34 patients (35.4%) with upper tract urothelial carcinoma and 62 (39.0%) with bladder cancer had an unfavorable marker score (more than 2 markers altered). There were no significant differences between upper tract urothelial carcinoma and bladder cancer in the alteration status of markers, the number of altered markers and biomarker score when substratified by pathological stage. There were no significant differences in survival outcomes between patients with upper tract urothelial carcinoma and those with bladder cancer according to the number of altered markers and biomarker score., Conclusions: Our results demonstrate the molecular similarity of upper tract urothelial carcinoma and bladder cancer in terms of cell cycle and proliferative tissue markers. These findings have important implications and support the further extrapolation of treatment paradigms established in bladder cancer to upper tract urothelial carcinoma., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We conceived and proposed a unique and optimized nomogram to predict cancer specific survival after radical nephroureterectomy in patients with upper tract urothelial carcinoma by merging the 2 largest multicenter data sets reported in this population., Materials and Methods: The international and the French national collaborative groups on upper tract urothelial carcinoma pooled data on 3,387 patients treated with radical nephroureterectomy for whom full data for nomogram development were available. The merged study population was randomly split into the development cohort (2,371) and the external validation cohort (1,016). Cox regressions were used for univariable and multivariable analyses, and to build different models. The ultimate reduced nomogram was assessed using Harrell's concordance index (c-index) and decision curve analysis., Results: Of the 2,371 patients in the nomogram development cohort 510 (21.5%) died of upper tract urothelial carcinoma during followup. The actuarial cancer specific survival probability at 5 years was 73.7% (95% CI 71.9-75.6). Decision curve analysis revealed that the use of the best model was associated with benefit gains relative to the prediction of cancer specific survival. The optimized nomogram included only 5 variables associated with cancer specific survival on multivariable analysis, those of age (p = 0.001), T stage (p <0.001), N stage (p = 0.001), architecture (p = 0.02) and lymphovascular invasion (p = 0.001). The discriminative accuracy of the nomogram was 0.8 (95% CI 0.77-0.86)., Conclusions: Using standard pathological features obtained from the largest data set of upper tract urothelial carcinomas worldwide, we devised and validated an accurate and ultimate nomogram, superior to any single clinical variable, for predicting cancer specific survival after radical nephroureterectomy., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: The primary endpoint in trials of perioperative systemic therapy for urothelial carcinoma is 5-year overall survival (OS). A shorter-term endpoint could significantly speed the translation of advances into practice. We hypothesized that disease-free survival (DFS) could be a surrogate endpoint for OS in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU)., Patients and Methods: The study included 2,492 patients treated with RNU with curative intent for UTUC., Results: 2/3-year DFS estimates were 78/73 %, and the 5-year OS estimate was 64 %. The overall agreements between 2- and 3-year DFS with 5-year OS were 85 and 87 %, respectively. Agreements were similar when analyzed in subgroups stratified by pathological stages, lymph node status, and adjuvant chemotherapy. The kappa statistic was 0.59 (95 % CI 0.55-0.63) for 2-year DFS/5-year OS and 0.64 (95 % CI 0.61-0.68) for 3-year DFS/5-year OS, indicating moderate reliability. The hazard ratio for DFS as a time-dependent variable for predicting OS was 11.5 (95 % CI 9.1-14.4), indicating a strong relationship between DFS and OS., Conclusions: In patients treated with RNU for UTUC, DFS and OS are highly correlated, regardless of tumor stage and adjuvant chemotherapy. While significant differences in DFS, assessed at 2 and 3 years, are highly likely to persist in OS at 5 years, marginal DFS advantages may not translate into OS benefit. External validation is necessary before accepting DFS as an appropriate surrogate endpoint for clinical trials investigating advanced UTUC patients.

Objective: To evaluate temporal trends in clinicopathological features and oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma., Methods: Utilizing a multi-institutional database of patients treated with radical nephroureterectomy between 1983 and 2007, we compared clinicopathological features and survival outcomes over the past three decades using the following cohorts: group 1 comprised of patients treated before the 1990s (n = 106), group 2 from 1990 to1999 (n = 655), and group 3 from 2000 to 2007 (n = 701). Survival rates were compared using Kaplan-Meier survival analysis., Results: The study included 1462 patients, 992 men and 470 women, with 36 months median follow up (range 1-250 months) after radical nephroureterectomy. Tumors were organ confined (≤T2/N0) in 88% and high-grade in 64%. Neoadjuvant and adjuvant systemic chemotherapy was administered in 47 (3.2%) and 171 (11.7%) patients, respectively. There was a significant increase in the use of laparoscopic radical nephroureterectomy, endoscopic management of urothelial carcinoma and utilization of perioperative chemotherapy between decades 1 to 3. There were no significant differences in pathological stage distribution. The overall 5-year disease-free survival rates were 66 ± 5%, 68.5 ± 2% and 71 ± 2%, and the 5-year cancer-specific survival rates were 75 ± 5%, 72 ± 2%, and 75 ± 2% for groups 1, 2 and 3, respectively, with no significant statistical differences between the three decades (P > 0.05)., Conclusion: Outcomes after radical nephroureterectomy have not changed significantly over the past three decades, despite staging and surgical refinements. Utilization of perioperative systemic chemotherapy in urothelial carcinoma management remains low. Further improvements in outcomes of urothelial carcinoma patients necessitate rigorous investigation of multimodal treatment approaches., (© 2012 The Japanese Urological Association.)

Objective: •To assess the impact of differences in ethnicity on clinico-pathological characteristics and outcomes of patients with upper urinary tract urothelial carcinoma (UTUC) in a large multi-center series of patients treated with radical nephroureterectomy (RNU)., Materials and Methods: •We retrospectively collected the data of 2163 patients treated with RNU at 20 academic centres in America, Asia, and Europe. •Univariable and multivariable Cox regression models addressed recurrence-free survival (RFS) and cancer-specific survival (CSS)., Results: •In all, 1794 (83%) patients were Caucasian and 369 (17%) were Japanese. All the main clinical and pathological features were significantly different between the two ethnicities. •The median follow-up of the whole cohort was 36 months. At last follow-up, 554 patients (26%) developed disease recurrence and 461 (21%) were dead from UTUC. •The 5-year RFS and CSS estimates were 71.5% and 74.2%, respectively, for Caucasian patients compared with 68.8% and 75.4%, respectively, for Japanese patients. •On univariable Cox regression analyses, ethnicity was not significantly associated with either RFS (P= 0.231) or CSS (P= 0.752). •On multivariable Cox regression analyses that adjusted for the effects of age, gender, surgical type, T stage, grade, tumour architecture, presence of concomitant carcinoma in situ, lymphovascular invasion, tumour necrosis, and lymph node status, ethnicity was not associated with either RFS (hazard ratio [HR] 1.1; P= 0.447) or CSS (HR 1.0; P= 0.908)., Conclusions: •There were major differences in the clinico-pathological characteristics of Caucasian and Japanese patients. •However, RFS and CSS probabilities were not affected by ethnicity and race was not an independent predictor of either recurrence or cancer-related death., (© 2011 THE AUTHORS; BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Purpose: We created a prognostic tool for the accurate preoperative prediction of nonorgan confined upper tract urothelial carcinoma., Materials and Methods: A computerized data bank containing comprehensive information on 1,453 patients who underwent radical nephroureterectomy at 13 academic institutions was generated and continuously updated. This study comprised a subset of 659 patients in whom all appropriate preoperative prognostic variables (age, gender, race, symptoms, Eastern Cooperative Oncology Group performance status, primary tumor location, tumor architecture, tumor grade and history of previous bladder cancer) were available for statistical analysis. A multivariable logistic regression model containing relevant clinicopathological variables addressed the prediction of nonorgan confined stage disease (T3-4 and/or N+) at radical nephroureterectomy. A backward step-down selection process was applied to achieve the most informative and parsimonious model. Internal validation was performed using 200 bootstrap resamples., Results: Pathological nonorgan confined urothelial carcinoma was found in 40% of patients. Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer., Conclusions: We developed a simple and accurate prognostic tool for the prediction of locally advanced upper tract urothelial cancer. This preoperative prediction model can be used for designing clinical trials, selecting patients for preoperative systemic therapy and guiding the extent of concomitant lymph node dissection at nephroureterectomy., (Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC)., Objective: To investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU)., Design, Setting, and Participants: A retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC., Intervention: The 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007., Measurements: Data accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor., Results and Limitations: The 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p<0.001), grade (p<0.02), and lymph node status (p<0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p=0.133) or cancer death (HR: 1.23; p=0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design., Conclusions: There is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prognostic factors after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) are inconclusive, because most data in the literature have been obtained from small series., Objective: To assess the association of tumour necrosis with cancer recurrence and survival in a large international series of patients treated with RNU., Design, Setting, and Participants: Data were collected from 1425 patients treated with RNU at 13 centres and combined into a relational database. Pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria. Extensive tumour necrosis was scored as >10% of the tumour area., Intervention: Patients underwent either open or laparoscopic RNU. Lymph node dissection was performed in the presence of enlarged nodes., Measurements: Recurrence was defined as tumour relapse in the operative field, lymph node (LN) metastasis, and/or distant metastases. Bladder recurrences were not considered. Associations of extensive tumour necrosis with recurrence-free survival and cancer-specific survival were evaluated by univariate and multivariate analyses., Results and Limitations: Extensive tumour necrosis was observed in 364 patients (25.5%) and was associated with advanced tumour stage, high tumour grade, sessile architecture, lymphovascular invasion (LVI), concomitant carcinoma in situ, and LN metastasis (p<0.0001 each). Extensive tumour necrosis was independently associated with disease recurrence and survival (p=0.037 and p=0.046, respectively) after adjusting for the effects of pathologic stage, grade, LVI, and LN status. The addition of extensive tumour necrosis to a base model comprising standard pathologic predictors marginally improved its predictive accuracy for both cancer-specific recurrence (1.5%) and survival (1.4%)., Conclusions: Extensive tumour necrosis is an independent predictor of clinical outcomes in patients who undergo RNU for UTUC. Assessment of tumour necrosis may help to identify patients who could benefit from multimodal therapy after RNU in the future. Evaluation of extensive tumour necrosis should be part of standard pathologic reporting., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: We examined papillary renal cell carcinoma prognostic variables and validated the 2002 UICC TNM staging system in a multicenter analysis., Materials and Methods: From 10 urological institutions in Germany followup data were collected on a total of 675 patients with papillary renal cell carcinoma. Central pathological review was done to validate external histopathological diagnoses. The Kaplan-Meier method was used to derive cumulative cancer specific and overall survival, and the log rank test was used to compare the curves of 2 or more groups. For multivariate analysis of prognostic factors Cox regression analysis was done. All proportional hazard assumptions were systemically verified using the Grambsch-Therneau test., Results: Cancer specific survival was significantly related to TNM stage and histological grading on univariate and multivariate analyses. Five-year cancer specific survival in pT1b cases was significantly shorter than in pT1a cases (90.0% vs 98.3%, p = 0.017). No significant difference was found between pT1b and pT2 tumors. Patients with pT3 or greater disease were at high risk for metastasis (50.6%) while metastatic disease associated with pT2 or less tumors occurred in 7.8% (p <0.0001). After metastatic disease was present the prognosis was poor with 7.2% 5-year cancer specific survival. Age was associated with poor prognosis in the subgroup with pT3 or greater tumors on univariate analysis (p = 0.026) but not on multivariate analysis., Conclusions: In its current form the 2002 UICC TNM staging system is not applicable to papillary renal cell carcinoma. Clinical and radiological followup should be offered at frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear but should not be underestimated in risk stratification after surgery., (Copyright 2010 American Urological Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether a minimum number of lymph nodes (LNs) exist to detect lymph node invasion (LNI) in patients undergoing radical nephroureterectomy (RNU) for upper tract urothelial carcinoma., Methods: The study included 551 consecutive patients, from 13 centers worldwide, who underwent RNU and lymphadenectomy (LND) between 1992 and 2006. LND was performed at the discretion of the surgeon. All pathological slides were re-reviewed by uropathologists according to strict criteria. Receiver-operating characteristic curve coordinates were used to determine the probability of diagnosing LNI according to the total number of nodes removed. Additionally, the relationship between the number of nodes removed and the rate of positive LNs was tested in univariate and multivariate logistic regression models., Results: Median patient age was 68 years (range: 27-97). Of 551 patients, 140 (25.4%) had positive lymph nodes. Median number of lymph nodes removed was 5 (mean 6.7, range 1-41). The Receiver-operating characteristic coordinates plot indicated that the removal of 13 nodes yielded a 90% probability to detect >or=1 positive LNs. The removal of 8 nodes resulted in a 75% probability of finding >or=1 positive nodes. Removal of >8 LNs (P = .03; odds ratio 1.49) was independently associated with LNI after adjusting for pathological stage and grade., Conclusions: Our data indicate that 8 LNs need to be removed at radical nephroureterectomy to achieve a 75% probability of finding >or=1 positive nodes. Further improvement of the specificity of LND will require the removal of more lymph nodes.

Background: The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated., Objective: To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC., Design, Setting, and Participants: The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006., Intervention: Patients were treated with RNU and lymphadenectomy., Measurements: Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified., Results and Limitations: In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001)., Conclusions: The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Purpose: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival., Materials and Methods: Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts., Results: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival., Conclusions: Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

Purpose: We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy., Materials and Methods: Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival., Results: Overall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only., Conclusions: Nodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

Purpose: Our goal was to prospectively evaluate self-reported quality-of-life (QoL) during second-line therapy in 51 consecutive patients with cytokine-refractory kidney cancer treated with sorafenib or sunitinib., Methods: QoL was assessed by the EORTC QoL questionnaire QLQ-C30 at baseline and at weeks 4, 6, 10, 12 and 16., Results: Global QoL deteriorated significantly during the first 4 weeks of treatment (P < 0.0001). Patients experienced a reduction of their role, cognitive, and social function (all P < 0.0001). In addition, fatigue (P < 0.0001), nausea/vomiting (P = 0.003), and pain (P < 0.0001) as well as dyspnoea (P < 0.0001), insomnia (P = 0.026), appetite loss (P = 0.013), and diarrhoea (P < 0.0001) increased significantly. After 16 weeks, fatigue (P < 0.0001), pain (P = 0.015), appetite loss (P = 0.002) and diarrhoea (P = 0.038) were still influenced by the therapy, while all functional scales recovered. Global QoL at baseline was predictive of overall response (P = 0.006) and progression free survival (PFS) (P < 0.0001). A better physical function at baseline, a better ECOG performance status, and a low risk profile according to MSKCC risk groups correlated with a longer PFS (all P < 0.0001). No significant differences regarding QoL were found between sorafenib and sunitinib during the study period., Conclusions: Second-line therapy with sorafenib or sunitinib does not adversely affect patients global QoL after 16 weeks of treatment. Evaluation of baseline QoL can help to further stratify patients into risk groups predicting overall response and PFS.

Purpose: To describe the current use and administration of multitargeted tyrosine kinase inhibitors (sunitinib and sorafenib) in the management of metastatic renal cell carcinoma (RCC) and to characterise frequent adverse events., Materials and Methods: A questionnaire was sent to 104 urologists and medical oncologists having their own practice. The common use of medical treatment with sunitinib and sorafenib in patients with metastatic RCC was recorded. Data on the most frequent drug-associated adverse events were registered and described in a preliminary patient cohort., Results: Medical oncologists in private practice treat over twice as many patients with metastatic RCC (8/year) as established urologists. Most medical oncologists but not urologists already use multitargeted tyrosine kinase inhibitors. For the initiation of treatment, most urologists admit patients to a hospital, whereas medical oncologists start and carry out medical treatment themselves. In all patients adverse events occurred due to medical treatment, leading to therapy stop or pause in 53% of patients. The most frequent adverse events were abnormal fatigue, arterial hypertension, diarrhoea and the hand-foot skin syndrome., Conclusions: Multitargeted tyrosine kinase inhibitor therapy in Germany is currently done predominantly by medical oncologists rather than urologists. Adverse events caused by sunitinib and sorafenib frequently required medical care, and in our initial series of patients prompted physicians to pause treatment.

Objectives: To assess the sex differences in the clinical and pathologic characteristics of upper tract urothelial carcinoma (UTUC) and to determine the effect on prognosis after radical nephroureterectomy (RNU) in a large multicenter series., Methods: The records of 1363 patients who had undergone RNU were reviewed from the UTUC Collaboration database. The median follow-up was 47 months (range 0-250). The pathologic slides were re-evaluated by genitourinary pathologists unaware of the original findings from the slides and the clinical outcomes. The endpoints were freedom from tumor recurrence and disease-specific survival., Results: The male-to-female ratio was 2.1:1. The women were older than the men at diagnosis (70 +/- 11 vs 68 +/- 11 years; P < .001). No significant sex-related differences were found in the presence of symptoms at presentation (P = .70), pathologic stage (P = .98), tumor grade (P = .28), tumor architecture (P = .27), presence of lymphovascular invasion (P = .42), presence of concomitant carcinoma in situ (P = .08), or the presence of lymph node metastases (P = .24). Recurrence developed in 379 patients (28%), and 313 patients (23%) died of their disease. Sex was not associated with disease recurrence (P = .07) or disease-specific survival (P = .13). An adjustment for the effects of the pathologic features did not change the lack of association of sex with the clinical outcomes., Conclusions: To our knowledge, this is the largest series analyzing the effect of sex on the outcomes after RNU. No difference was found in the clinicopathologic features or prognosis between women and men treated with RNU for UTUC. The results of this large, international series show that RNU provides durable local control and disease-specific survival for both men and women with UTUC.