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Background: Several groups have proposed features to identify low-risk patients who may benefit from endoscopic kidney-sparing surgery in upper tract urothelial carcinoma (UTUC)., Objective: To evaluate standard risk stratification features, develop an optimal model to identify ≥pT2/N+ stage at radical nephroureterectomy (RNU), and compare it with the existing unvalidated models., Design, Setting, and Participants: This was a collaborative retrospective study that included 1214 patients who underwent ureterorenoscopy with biopsy followed by RNU for nonmetastatic UTUC between 2000 and 2017., Outcome Measurements and Statistical Analysis: We performed multiple imputation of chained equations for missing data and multivariable logistic regression analysis with a stepwise selection algorithm to create the optimal predictive model. The area under the curve and a decision curve analysis were used to compare the models., Results and Limitations: Overall, 659 (54.3%) and 555 (45.7%) patients had ≤pT1N0/Nx and ≥pT2/N+ disease, respectively. In the multivariable logistic regression analysis of our model, age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.0-1.03, p = 0.013), high-grade biopsy (OR 1.81, 95% CI 1.37-2.40, p < 0.001), biopsy cT1+ staging (OR 3.23, 95% CI 1.93-5.41, p < 0.001), preoperative hydronephrosis (OR 1.37 95% CI 1.04-1.80, p = 0.024), tumor size (OR 1.09, 95% CI 1.01-1.17, p = 0.029), invasion on imaging (OR 5.10, 95% CI 3.32-7.81, p < 0.001), and sessile architecture (OR 2.31, 95% CI 1.58-3.36, p < 0.001) were significantly associated with ≥pT2/pN+ disease. Compared with the existing models, our model had the highest performance accuracy (75% vs 66-71%) and an additional clinical net reduction (four per 100 patients)., Conclusions: Our proposed risk-stratification model predicts the risk of harboring ≥pT2/N+ UTUC with reliable accuracy and a clinical net benefit outperforming the current risk-stratification models., Patient Summary: We developed a risk stratification model to better identify patients for endoscopic kidney-sparing surgery in upper tract urothelial carcinoma., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial., Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management., Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference., Setting: Online Delphi survey and consensus conference., Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management., Outcome Measurements and Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus)., Results and Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease., Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach., Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available., (Copyright © 2019 European Society of Medical Oncology and European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: This review focuses on risk assessment and prediction tools for bladder cancer (BCa)., Objective: To review the current knowledge on risk assessment and prediction tools to enhance clinical decision making and counseling of patients with BCa., Evidence Acquisition: A literature search in English was performed using PubMed in July 2013. Relevant risk assessment and prediction tools for BCa were selected. More than 1600 publications were retrieved. Special attention was given to studies that investigated the clinical benefit of a prediction tool., Evidence Synthesis: Most prediction tools for BCa focus on the prediction of disease recurrence and progression in non-muscle-invasive bladder cancer or disease recurrence and survival after radical cystectomy. Although these tools are helpful, recent prediction tools aim to address a specific clinical problem, such as the prediction of organ-confined disease and lymph node metastasis to help identify patients who might benefit from neoadjuvant chemotherapy. Although a large number of prediction tools have been reported in recent years, many of them lack external validation. Few studies have investigated the clinical utility of any given model as measured by its ability to improve clinical decision making. There is a need for novel biomarkers to improve the accuracy and utility of prediction tools for BCa., Conclusions: Decision tools hold the promise of facilitating the shared decision process, potentially improving clinical outcomes for BCa patients. Prediction models need external validation and assessment of clinical utility before they can be incorporated into routine clinical care., Patient Summary: We looked at models that aim to predict outcomes for patients with bladder cancer (BCa). We found a large number of prediction models that hold the promise of facilitating treatment decisions for patients with BCa. However, many models are missing confirmation in a different patient cohort, and only a few studies have tested the clinical utility of any given model as measured by its ability to improve clinical decision making., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Conditional survival (CS) provides better estimates of the survival probability at each follow-up time, and its usefulness has been proven in several solid malignancies., Objective: To assess the changes in 5-yr CS rates after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) and to determine how well-established prognostic factors evolve over time., Design, Setting, and Participants: We analysed data from 3544 patients treated with RNU at 15 international academic centres between 1989 and 2012., Intervention: RNU., Outcomes Measurements and Statistical Analysis: Conditional intravesical recurrence-free (IVRFS), cancer-specific survival (CSS), and overall survival (OS) estimates were calculated using the Kaplan-Meier method. A multivariable Cox regression model was used to calculate proportional hazard ratios for the prediction of mortality., Results and Limitations: The 5-yr bladder cancer recurrence-free survival, CSS, and OS rates were 54.9%, 72.2%, and 62.6%, respectively. Given a 1-, 2-, 3-, and 4-yr survivorship, the 5-yr conditional OS rates improved to 65.2%, 69.3%, 71.5%, and 73.0%, respectively. The 5-yr CS improvement was primarily noted among surviving patients with advanced-stage disease. The impact of pathologic parameters on CS estimates decreased over time for both CSS and OS, whereas the impact of age and gender increased with survivorship. No survival benefit was noted regarding the adjuvant chemotherapy status. Findings were confirmed upon multivariable analyses. Tumour location, the presence of carcinoma in situ, and the type of bladder cuff excision were continuously predictive for IVRFS whatever the survivorship. A limitation is the retrospective design., Conclusions: CS analysis demonstrates that the patient risk profile evolves during the post-RNU follow-up. The probability of survival markedly increases over time in patients having high-stage disease. The impact of prognostic pathologic features decreases over time and can disappear for long-term CS., Patient Summary: In this study, we found that the risk of intravesical recurrence, cancer-specific survival, and overall mortality evolves over the follow-up after surgery. Taking into account the survivorship provides better estimates of the survival probability at each follow-up time., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting., Objective: We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort., Design, Setting, and Participants: Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013., Intervention: NAC and RC., Outcome Measurements and Statistical Analysis: The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages., Results and Limitations: Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6)., Conclusions: Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined., Patient Summary: There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making., Objective: To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment., Design, Setting, and Participants: Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011., Outcome Measurements and Statistical Analysis: Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS)., Results and Limitations: With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise., Conclusions: T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression., Patient Summary: Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood., Objective: To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC)., Design, Setting, and Participants: Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed., Outcome Measurements and Statistical Analysis: Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI)., Results and Limitations: Female patients were older at the time of RC (p=0.033) and had higher rates of pathologic stage T3/T4 disease (p<0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p=0.022 and p=0.11, respectively). Female gender was an independent predictor for CSM (p=0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05)., Conclusions: We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Disease recurrence occurs frequently after surgical treatment for squamous cell carcinoma of the penis (SCCp). We sought to determine prognostic factors that influence cancer-specific mortality (CSM) after disease recurrence in patients with SCCp. We performed a retrospective analysis of 314 patients who experienced disease recurrence after surgical treatment for SCCp between 1949 and 2012. Competing risk regression analysis addressed factors associated with CSM after SCCp recurrence. Median time from surgery to disease recurrence was 10.5 mo (interquartile range [IQR]: 5.9-21.3). Of the recurrences, 165 (53%), 118 (38%), and 31 (9.9%) were local, regional, or distant, respectively. Within a median follow-up of 4.5 yr (IQR: 2.0-6.5), 108 patients died of SCCp and 41 patients died of causes other than SCCp. Shorter time to disease recurrence was found to be significantly associated with a higher risk of CSM (p=0.0006). Lymph node metastasis at the time of initial treatment (subdistribution hazard ratio [SHR]: 1.96; 95% confidence interval [CI] 1.23- 3.11; p=0.005) and regional recurrence (SHR: 4.14; 95% CI, 2.16-7.93; p<0.0001) or distant recurrence (SHR: 5.75; 95% CI, 2.59-12.73; p<0.0001) were associated with increased risk of CSM after disease recurrence. Inclusion of time to recurrence into risk stratification may help patient counseling and treatment planning., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume., Objective: To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates., Design, Setting, and Participants: Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011., Outcome Measurements and Statistical Analyses: The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort., Results and Limitations: Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload., Conclusions: This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases., Patient Summary: In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Although different prognostic factors for patients with renal cell carcinoma (RCC) and vena cava tumor thrombus (TT) have been studied, the prognostic value of histologic subtype in these patients remains unclear., Objective: We analyzed the impact of histologic subtype on cancer-specific survival (CSS)., Design, Settings, and Participants: We retrospectively analyzed the records of 1774 patients with RCC and TT who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 US and European centers., Outcome Measurements and Statistical Analysis: Multivariable ordered logistic and Cox regression models were used to quantify the impact of tumor histology on CSS., Results and Limitations: Overall 5-yr CSS was 53.4% (confidence interval [CI], 50.5-56.2) in the entire group. TT level (according to the Mayo classification of macroscopic venous invasion in RCC) was I in 38.5% of patients, II in 30.6%, III in 17.3%, and IV in 13.5%. Histologic subtypes were clear cell renal cell carcinoma (cRCC) in 89.9% of patients, papillary renal cell carcinoma (pRCC) in 8.5%, and chromophobe RCC in 1.6%. In univariable analysis, pRCC was associated with a significantly worse CSS (p<0.001) compared with cRCC. In multivariable analysis, the presence of pRCC was independently associated with CSS (hazard ratio: 1.62; CI, 1.01-2.61; p<0.05). Higher TT level, positive lymph node status, distant metastasis, and fat invasion were also independently associated with CSS., Conclusions: In our multi-institutional series, we found that patients with pRCC and vena cava TT who underwent radical nephrectomy and tumor thrombectomy had significantly worse cancer-specific outcomes when compared with patients with other histologic subtypes of RCC. We confirmed that higher TT level and fat invasion were independently associated with reduced CSS., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Nodal metastasis is the strongest risk factor of disease recurrence in patients with localized prostate cancer (PCa) treated with radical prostatectomy (RP)., Objective: To develop a model that allows quantification of the likelihood that a pathologically node-negative patient is indeed free of nodal metastasis., Design, Setting, and Participants: Data from patients treated with RP and pelvic lymph node dissection (PLND; n=7135) for PCa between 2000 and 2011 were analyzed. For external validation, we used data from patients (n=4209) who underwent an anatomically defined extended PLND., Intervention: RP and PLND., Outcome Measurements and Statistical Analysis: We developed a novel pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative based on the number of examined nodes and the patient's characteristics., Results and Limitations: In the development and validation cohorts, the probability of missing a positive node decreases with an increasing number of nodes examined. Whereas in pT2 patients, a 90% pNSS was achieved with one single examined node in both the development and validation cohort, a similar level of nodal staging accuracy was achieved in pT3a patients by examining five and nine nodes, respectively. The pT3b/T4 patients achieved a pNSS of 80% and 70% when 17 and 20 nodes in the development and validation cohort were examined, respectively. This study is limited by its retrospective design and multicenter nature. The number of nodes removed was not directly correlated with the extent/template of PLND., Conclusions: Every patient needs PLND for accurate nodal staging. However, a one-size-fits-all approach is too inaccurate. We developed a tool that indicates a node-negative patient is indeed free of lymph node metastasis by evaluating the number of examined nodes, pT stage, RP Gleason score, surgical margins, and prostate-specific antigen. This tool may help in postoperative decision making., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. 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.)

Background: Standard survival statistics do not take into consideration the changes in the weight of individual variables at subsequent times after the diagnosis and initial treatment of bladder cancer., Objective: To assess the changes in 5-yr conditional survival (CS) rates after radical cystectomy for bladder cancer and to determine how well-established prognostic factors evolve over time., Design, Setting, and Participants: We analyzed data from 8141 patients treated with radical cystectomy at 15 international academic centers between 1979 and 2012., Interventions: Radical cystectomy and pelvic lymph node dissection., Outcome Measurements and Statistical Analysis: Conditional cancer-specific survival (CSS) and overall survival (OS) estimates were calculated using the Kaplan-Meier method. The multivariable Cox regression model was used to calculate proportional hazard ratios for the prediction of mortality after stratification by clinical characteristics (age, perioperative chemotherapy status) and pathologic characteristics (pT stage, grade, lymphovascular invasion, pN stage, number of nodes removed, margin status). The median follow-up was 32 mo., Results and Limitations: The 5-yr CSS and OS rates were 67.7% and 57.5%, respectively. Given a 1-, 2-, 3-, 5- and 10-yr survivorship, the 5-yr conditional OS rates improved by +5.6 (60.7%), +8.4 (65.8%), +7.6 (70.8%), +3.0 (72.9%), and +1.9% (74.3%), respectively. The 5-yr conditional CSS rates improved by +5.6 (71.5%), +9.8 (78.5%), +7.9 (84.7%), +7.2 (90.8%), and 5.6% (95.9%), respectively. The 5- and 10-yr CS improvement was primarily noted among surviving patients with advanced stage disease. The impact of pathologic parameters on CS estimates decreased over time for both CSS and OS. Findings were confirmed on multivariable analyses. The main limitation was the retrospective design., Conclusions: CS analysis demonstrates that the patient risk profile changes over time. The risk of mortality decreases with increasing survivorship. The CS rates improve mainly in the case of advanced stage disease. The impact of prognostic pathologic features decreases over time and can disappear for long-term CS., (Copyright © 2013. Published by Elsevier B.V.)

Context: Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC). However, the effect of smoking on outcomes of UC patients remains debated., Objective: To integrate the available evidence regarding the impact of smoking status and smoking exposure on recurrence, progression, cancer-specific mortality, and any-cause mortality in patients with UC of the bladder (UCB) and upper tract UC (UTUC) treated with transurethral resection of the bladder (TURB), radical cystectomy (RC), or radical nephroureterectomy (RNU)., Evidence Acquisition: A systematic search of the literature was conducted using the Medline, Embase, and Scopus databases, which was limited to articles published in English between January 1974 and March 2013. Articles were also extracted from the reference lists of identified studies and reviews. We selected 29 articles (15 TURB, 7 RC, and 7 RNU) according to predefined inclusion criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analyses., Evidence Synthesis: The majority of studies demonstrated an association with disease recurrence in patients treated with TURB, while evidence for associations with disease progression, cancer-specific mortality, and any-cause mortality was less abundant. While two studies showed no association of smoking with outcomes of T1 UCB, there was mixed evidence for an association of smoking with response to intravesical therapy. For patients treated with RC, there was minimal support for an association of smoking with all outcomes. In a majority of studies of patients receiving RNU for UTUC, smoking was associated with intravesical recurrence, disease recurrence, cancer-specific mortality, and any-cause mortality. There was also evidence for a beneficial effect of smoking cessation on UC prognosis. Finally, findings regarding gender-specific effects of smoking on prognosis were contradictory. We note that there was marked heterogeneity in patient populations and smoking categorizations across studies, precluding a meta-analysis., Conclusions: Smoking may lead to less favorable outcomes for UCB and UTUC patients, and smoking cessation may mitigate this effect. The current evidence base lacks studies on the effects of smoking on prognosis in numerous clinical demographic subgroups of UC patients, as well as prospective investigation of smoking cessation., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU., Objective: The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration., Design, Setting, and Participants: We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe., Interventions: RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%)., Outcome Measurements and Statistical Analyses: Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms., Results and Limitations: With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% ± 1%, 78% ± 1%, 68% ± 1%, and 47% ± 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤ 0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study., Conclusions: Intravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU., (Copyright © 2013. Published by Elsevier B.V.)

Background: Few studies have investigated the natural history of TaG1 urothelial carcinoma of the bladder (UCB)., Objective: To assess the long-term outcomes of patients with TaG1 UCB and the impact of immediate postoperative instillation of chemotherapy (IPIC)., Design, Setting, and Participants: A retrospective analysis of 1447 patients with TaG1 UCB treated between 1996 and 2007 at eight centers. Median follow-up was 67.2 mo (interquartile range: 67.9). Patients were stratified into three European Association of Urology (EAU) guidelines risk categories; high-risk patients (n=11) were excluded., Intervention: Transurethral resection of the bladder with or without IPIC., Outcome Measurements and Statistical Analysis: Univariable and multivariable Cox regression models addressed factors associated with disease recurrence, disease progression, death of disease, and any-cause death., Results and Limitations: Of the 1436 patients, 601 (41.9%) and 835 (58.1%) were assigned to low- and intermediate-risk categories, respectively. The actuarial estimate of 5-yr recurrence-free survival was 56% (standard error: ± 1). Advancing age (p=0.04), tumor >3 cm (p=0.001), multiple tumors (p<0.001), and recurrent tumors (p<0.001) were independently associated with increased risk of disease recurrence, whereas IPIC was associated with decreased risk (p=0.001). The actuarial estimate of 5-yr progression-free survival was 95% ± 1. Advancing age (p<0.001) and multiple tumors (p=0.01) were independent risk factors for disease progression. Five-year cancer-specific survival was 98% ± 1. Advancing age (p=0.001) and previous recurrence (p=0.04) were associated with increased risk, whereas female gender (p=0.02) was associated with decreased risk of cancer-specific mortality. Compared with low-risk patients, intermediate-risk patients were at significantly higher risk of disease recurrence, disease progression, and cancer-specific mortality (all p<0.01). Limitations include the retrospective design of the study and the lack of a central pathology review., Conclusions: TaG1 UCB patients experience heterogeneous risks of disease recurrence. We validated the EAU guidelines risk stratification in TaG1 UCB patients. IPIC was associated with a reduced risk of disease recurrence in patients with low- and intermediate-risk TaG1 UCB., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There is a lack of consensus regarding the optimal approach to the bladder cuff during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Objectives: To compare the oncologic outcomes following RNU using three different methods of bladder cuff management., Design, Setting, and Participants: Retrospective analysis of 2681 patients treated with RNU for UTUC at 24 international institutions from 1987 to 2007., Intervention: Three methods of bladder cuff excision were performed: transvesical, extravesical, and endoscopic., Outcome Measurements and Statistical Analysis: Univariable and multivariable models tested the effect of distal ureter management on intravesical recurrence, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS)., Results and Limitations: Of the 2681 patients, 1811 (67.5%) underwent the transvesical approach; 785 (29.3%), the extravesical approach; and 85 (3.2%), the endoscopic approach. There was no difference in terms of RFS, CSS, and OS among the three distal ureteral management approaches. Patients who underwent the endoscopic approach were at significantly higher risk of intravesical recurrence compared with those who underwent the transvesical (p=0.02) or extravesical approaches (p=0.02); the latter two groups did not differ from each other (p=0.40). Actuarial intravesical RFS estimates at 2 and 5 yr after RNU were 69% and 58%, 69% and 51%, and 61% and 42% for the transvesical, extravesical, and endoscopic approaches, respectively. In multivariate analyses, distal ureteral management (p=0.01), surgical technique (open vs laparoscopic; p=0.02), previous bladder cancer (p<0.001), higher tumor stage (trend; p=0.01), concomitant carcinoma in situ (CIS) (p<0.001), and lymph node involvement (trend; p<0.001) were all associated with intravesical recurrence. Excluding patients with history of previous bladder cancer, all variables remained independent predictors of intravesical recurrence., Conclusions: The endoscopic approach was associated with higher intravesical recurrence rates. Interestingly, concomitant CIS in the upper tract is a strong predictor of intravesical recurrence after RNU. The association of laparoscopic RNU with intravesical recurrence needs to be further investigated., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Lymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable., Objective: To assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters., Design, Setting, and Participants: A retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo)., Intervention: All subjects underwent RC and bilateral pelvic lymphadenectomy., Outcome Measurements and Statistical Analysis: Each LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC., Results and Limitations: A total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p<0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55-2.31; p<0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52-2.37; p<0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p<0.001) and from 71.8% to 77.8% (p=0.007), respectively. The main limitation of the study is its retrospective nature., Conclusions: ENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cigarette smoking is the best-established risk factor for urothelial carcinoma development., Objective: To elucidate the association of pretreatment smoking status, cumulative exposure, and time since smoking cessation on outcomes of patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC)., Design, Setting, and Participants: We retrospectively collected clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation, for 1506 patients treated with RC for UCB. Lifetime cumulative smoking exposure was categorized as light short-term (≤20 CPD for ≤20 yr), light long-term (≤20 CPD for >20 yr), heavy short-term (>20 CPD for ≤20 yr), and heavy long-term (>20 CPD for >20 yr)., Intervention: RC and bilateral lymph node (LN) dissection without neoadjuvant chemotherapy., Outcome Measurements and Statistical Analysis: Logistic regression and competing risk analyses assessed the association of smoking with disease recurrence, cancer-specific mortality, and overall mortality., Results and Limitations: There was no difference in clinicopathologic factors between patients who had never smoked (20%), former smokers (46%), and current smokers (34%). Smoking status was associated with the cumulative incidence of disease recurrence (p=0.004) and cancer-specific mortality (p=0.016) in univariable analyses and with disease recurrence in multivariable analysis (p=0.02); current smokers had the highest cumulative incidences. Among ever smokers, cumulative smoking exposure was associated with advanced tumor stages (p<0.001), LN metastasis (p=0.002), disease recurrence (p<0.001), cancer-specific mortality (p=0.001), and overall mortality (p=0.037) in multivariable analyses that adjusted for standard characteristics; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation ≥10 yr mitigated the risk of disease recurrence (hazard ratio [HR]: 0.44; p<0.001), cancer-specific mortality (HR: 0.42; p<0.001), and overall mortality (HR: 0.69; p=0.012) in multivariable analyses. The study is limited by its retrospective nature., Conclusions: Smoking is associated with worse prognosis after RC for UCB. This association seems to be dose-dependent, and its effects are mitigated by >10 yr smoking cessation. Health care practitioners should counsel smokers regarding the detrimental effects of smoking and the benefits of smoking cessation on UCB etiology and prognosis., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Approximately 10-20% of recurrences in patients treated with nephrectomy for renal cell carcinoma (RCC) develop beyond 5 yr after surgery (late recurrence)., Objective: To determine features associated with late recurrence., Design, Setting, and Participants: A total of 5009 patients from a multicenter database comprising 13 107 RCC patients treated surgically had a minimum recurrence-free survival of 60 mo (median follow-up [FU]: 105 mo [range: 78-135]); at last FU, 4699 were disease free (median FU: 103 mo [range: 78-134]), and 310 patients (6.2%) experienced disease recurrence (median FU: 120 mo [range: 93-149])., Interventions: Patients underwent radical nephrectomy or nephron-sparing surgery., Outcome Measurements and Statistical Analysis: Multivariable regression analyses identified features associated with late recurrence. Cox regression analyses evaluated the association of features with cancer-specific mortality (CSM)., Results and Limitations: Lymphovascular invasion (LVI) (odds ratio [OR]: 3.07; p<0.001), Fuhrman grade 3-4 (OR: 1.60; p=0.001), and pT stage >pT1 (OR: 2.28; p<0.001) were significantly associated with late recurrence. Based on accordant regression coefficients, these parameters were weighted with point values (LVI: 2 points; Fuhrman grade 3-4: 1 point, pT stage >1: 2 points), and a risk score was developed for the prediction of late recurrences. The calculated values (0 points: late recurrence risk 3.1%; 1-3 points: 8.4%; 4-5 points: 22.1%) resulted in a good-, intermediate- and poor-prognosis group (area under the curve value for the model: 70%; 95% confidence interval, 67-73). Multivariable Cox regression analysis showed LVI (HR: 2.75; p<0.001), pT stage (HR: 1.24; p<0.001), Fuhrman grade (HR: 2.40; p<0.001), age (HR: 1.01; p<0.001), and gender (HR: 0.71; p=0.027) to influence CSM significantly. Limitations are based on the multicenter and retrospective study design., Conclusions: LVI, Fuhrman grade 3/4, and a tumor stage >pT1 are independent predictors of late recurrence after at least 5 yr from surgery in patients with RCC. We developed a risk score that allows for prognostic stratification and individualized aftercare of patients with regard to counseling, follow-up scheduling, and clinical trial design., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cigarette smoking is a common risk factor for developing upper tract urothelial carcinoma (UTUC)., Objective: To assess the impact of cigarette smoking status, cumulative smoking exposure, and time from cessation on oncologic UTUC outcomes in patients treated with radical nephroureterectomy (RNU)., Design, Setting, and Participants: A total of 864 patients underwent RNU at five institutions. The median follow-up in this retrospective study was 50 mo. Smoking history included smoking status, quantity of cigarettes per day (CPD), duration in years, and years from smoking cessation. The cumulative smoking exposure was categorized as light-short-term (≤ 19 CPD and ≤ 19.9 yr), moderate (all combinations except light-short-term and heavy-long-term), and heavy-long-term (≥ 20 CPD and ≥ 20 yr)., Interventions: RNU with or without lymph node dissection. No patient received neoadjuvant chemotherapy., Outcome Measurements and Statistical Analysis: Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on oncologic outcomes., Results and Limitations: A total of 244 patients (28.2%) never smoked; 297 (34.4%) and 323 (37.4%) were former and current smokers, respectively. Among smokers, 87 (10.1%), 331 (38.3%), and 202 (23.4%) were light-short-term, moderate, and heavy-long-term smokers, respectively. Current smoking status, smoking ≥ 20 CPD, ≥ 20 yr, and heavy-long-term smoking were associated with advanced disease (p values ≤ 0.004), greater likelihood of disease recurrence (p values ≤ 0.01), and cancer-specific mortality (p values ≤ 0.05) on multivariable analyses that adjusted for standard features. Patients who quit smoking ≥ 10 yr prior to RNU did not differ from never smokers regarding advanced tumor stages, disease recurrence, and cancer-specific mortality, but they had better oncologic outcomes then current smokers and those patients who quit smoking <10 yr prior to RNU. The study is limited by its retrospective nature., Conclusions: Cigarette smoking is significantly associated with advanced disease stages, disease recurrence, and cancer-specific mortality in patients treated with RNU for UTUC. Current smokers and those with a heavy and long-term smoking exposure have the highest risk for poor oncologic outcomes. Smoking cessation >10 yr prior to RNU seems to mitigate some detrimental effects. These results underscore the need for smoking cessation and prevention programs., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC) development, but the impact on oncologic outcomes remains poorly understood., Objective: To analyse the effects of smoking status, cumulative exposure, and time from smoking cessation on the prognosis of patients with primary non-muscle-invasive bladder cancer (NMIBC)., Design, Setting, and Participants: We collected smoking data from 2043 patients with primary NMIBC. Smoking variables included smoking status, average number of cigarettes smoked per day (CPD), duration in years, and time since smoking cessation. Lifetime cumulative smoking exposure was categorised as light short term (≤ 19 CPD, ≤ 19.9 yr), light long term (≤ 19 CPD, ≥ 20 yr), heavy short term (≥ 20 CPD, ≤ 19.9 yr) and heavy long term (≥ 20 CPD, ≥ 20 yr). The median follow-up in this retrospective study was 49 mo., Interventions: Transurethral resection of the bladder with or without intravesical instillation therapy., Outcome Measurements and Statistical Analysis: Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on outcomes., Results and Limitations: There was no difference in clinicopathologic factors among never (24%), former (47%), and current smokers (29%). Smoking status was associated with the cumulative incidence of disease progression in multivariable analysis (p=0.003); current smokers had the highest cumulative incidences. Among current and former smokers, cumulative smoking exposure was associated with disease recurrence (p<0.001), progression (p<0.001), and overall survival (p<0.001) in multivariable analyses that adjusted for the effects of standard clinicopathologic factors and smoking status; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation >10 yr reduced the risk of disease recurrence (hazard ratio [HR]: 0.66; 95% confidence interval [CI], 0.52-0.84; p<0.001) and progression (HR: 0.42; 95% CI, 0.22-0.83; p=0.036) in multivariable analyses. The study is limited by its retrospective nature., Conclusions: Smoking status and a higher cumulative smoking exposure are associated with worse prognosis in patients with NMIBC. Smoking cessation >10 yr abrogates this detrimental effect. These findings underscore the need for integrated smoking cessation and prevention programmes in the management of NMIBC patients., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard of care for high-risk non-muscle-invasive and muscle-invasive bladder cancer (BCa)., Objective: To develop a model that allows quantification of the likelihood that a pathologically node-negative patient has, indeed, no positive nodes., Design, Setting, and Participants: We analyzed data from 4335 patients treated with RC and PLND without neoadjuvant chemotherapy at 12 international academic centers., Interventions: Patients underwent RC and PLND., Outcome Measurements and Statistical Analysis: We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative as a function of the number of examined nodes., Results and Limitations: Overall, the probability of missing a positive node decreases with the increasing number of nodes examined (52% if 3 nodes are examined, 40% if 5 are examined, and 26% if 10 are examined). The proportion of having a positive node increased proportionally with advancing pathologic T stage and lymphovascular invasion (LVI). Patients with LVI who had 25 examined nodes would have a pNSS of 80% (pT1), 88% (pT2), and 66% (pT3-T4), whereas 10 examined nodes were sufficient for pNSS exceeding 90% in patients without LVI and pT0-T2 tumors. This study is limited because of its retrospective design and multicenter nature., Conclusions: We developed a tool that estimates the likelihood of lymph node (LN) metastasis in BCa patients treated with RC by evaluating the number of examined nodes, the pathologic T stage, and LVI. The pNSS indicates the adequacy of nodal staging in LN-negative patients. This tool could help to refine clinical decision making regarding adjuvant chemotherapy, follow-up scheduling, and inclusion in clinical trials., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context and Objective: To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an evidence-based strategy., Evidence Acquisition: A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched., Evidence Synthesis: The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed., Conclusions: Cystoscopy alone is the most cost-effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer., (Copyright © 2012 European Association of Urology. All rights reserved.)