Harun Fajkovic

Impact of gender on bladder cancer incidence, staging, and prognosis

IntroductionWhile patient gender is an important factor in the clinical decision-making for the management of bladder cancer, there are minimal evidence-based recommendations to guide health care professionals. Recent epidemiologic and translational research has shed some light on the complex relationship between gender and bladder cancer. Our aim was to review the literature on the effect of gender on bladder cancer incidence, biology, mortality, and treatment.MethodsUsing MEDLINE, we performed a search of the literature between January 1975 and April 2011.ResultsAlthough men are nearly 3–4 times more likely to develop bladder cancer than women, women present with more advanced disease and have worse survival. Recently, a number of population-based and multicenter collaborative studies have shown that female gender is associated with a significantly higher rate of cancer-specific recurrence and mortality after radical cystectomy. The disparity between genders is proposed to be the result of a differences exposure to carcinogens (i.e., tobacco and chemicals) as well as reflective of genetic, anatomic, hormonal, societal, and environmental factors. Explanations for the differential behavior of bladder cancer between genders include sex steroids and their receptors as well as inferior quality of care for women (inpatient length of stay, referral patterns, and surgical outcomes).ConclusionsIt is imperative that health care practitioners and researchers from disparate disciplines collectively focus efforts to appropriately develop gender-specific evidence-based guidelines for bladder cancer patients. We must strive to develop multidisciplinary collaborative efforts to provide tailored gender-specific care for bladder cancer patients.

Death certificates are valid for the determination of cause of death in patients with upper and lower tract urothelial carcinoma.

Accurate appraisal of cause of death (COD) is critically important for determining correct cause-specific survival in cancer patients. Death certificates are used for assessment of COD in case control [1], cohort outcomes [2], and occupational mortality studies [3]. Likewise, large data sets, such as the Surveillance Epidemiology and End Results program, and tumor registries rely on death certificates to assign COD [4,5]. However, this method may become inaccurate (1) when patients get older, (2) when patients have serious comorbidities associated with a risk of dying of other causes [6,7], or (3) when cancer patients are long-term survivors. Urothelial cancer (UC) is the second most common genitourinary cancer in the United States and represents an important cause of morbidity and mortality [8]. UC is generally a disease of the elderly, who have considerable comorbidities [9,10]. Although meticulous review of medical records has been shown to reliably ascertain COD in other urologic diseases such as prostate cancer (PCa) [5,11], the validity of death certificates for UC patients remains mainly uninvestigated. Therefore, we assessed whether the underlying COD on death certificates for men with UC agreed with an independent review of medical records for UC patients. This was an institutional review board–approved study. In our institutional database, we identified a sample of 137 patients with UC of the urinary bladder (UCB) treated with radical cystectomy and 62 patients with upper tract UC (UTUC) treated with radical nephroureterectomy who died at one tertiary care center during follow-up. Two trained urologists who were blinded to the COD assigned by the death certificate used a standardized data extraction form to independently review medical records and evaluate clinical course before death and effect of comorbidities. COD was assigned to one of three prospectively defined categories: (1) related to UCB or UTUC, (2) unrelated to UCB or UTUC, or (3) uncertain. Cohen’s k test was used to evaluate the agreement between both raters. Statistical analyses were performed with SPSS 17 (IBM Corp., Armonk, NY, USA). Death certificates were available for 119 UCB patients (86.9%) and 54 UTUC patients (87.1%). Median age was 67 yr (interquartile range [IQR]: 13) for UCB patients and 69 yr (IQR: 15) for UTUC patients. Both urologists agreed on the underlying COD in 166 of 173 UC patients (96%); consensus was reached on the COD of the remaining 7 patients. The comparison of underlying COD when assigned by death certificate and clinician assessment of medical records is shown in Table 1. Overall agreement was 96.1% for UCB patients who died of their disease and 92.5% for those patients who died of causes other than UCB (k = 0.89; p < 0.001). In UTUC patients, agreement was 93.9% and 85.0% in patients dying of disease and those patients dying of other causes, respectively (k = 0.80; p < 0.001). The agreement between the death certificate COD and the medical record review consensus assessment of COD was higher for UCB (92.4%) than for UTUC (88.9%). The UCB patients who died of their disease but were misclassified as dead from other cause by death certificate died of metastatic complications of UCB: One patient was misclassified as having a brain tumor, whereas he had brain metastasis of UCB; one patient had a pulmonary embolism due to tumor-induced coagulopathy; and one patient had

Predicting Clinical Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

BACKGROUND Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. OBJECTIVE We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. DESIGN, SETTING, AND PARTICIPANTS Our study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971). INTERVENTIONS All patients underwent RNU. MEASUREMENTS Univariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping. RESULTS AND LIMITATIONS At a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. CONCLUSIONS Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

The Impact of Tumor Multifocality on Outcomes in Patients Treated With Radical Nephroureterectomy

BACKGROUND The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood. OBJECTIVE To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter. INTERVENTION All patients were treated with either open or laparoscopic RNU. MEASUREMENTS Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality. RESULTS AND LIMITATIONS Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p=0.032), lymph node involvement (p=0.036), tumor location in the ureter (p=0.003), higher tumor stage (p<0.001), higher tumor grade (p<0.001), sessile tumor architecture (p=0.003), and LVI (p=0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p=0.019) and cancer-specific mortality (HR: 1.46; p=0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable (p=0.005 and p=0.006, respectively) but not in multivariable analyses (p=0.468 and p=0.798, respectively). The main limitation is the retrospective design of the study. CONCLUSIONS Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy.

Impact of Distal Ureter Management on Oncologic Outcomes Following Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

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.

Prediction of Cancer Specific Survival After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: Development of an Optimized Postoperative Nomogram Using Decision Curve Analysis

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 Harrells 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.

Clinical nodal staging scores for bladder cancer: A proposal for preoperative risk assessment

BACKGROUND Radical cystectomy (RC) with pelvic lymph node dissection (LND) is the standard of care for refractory non-muscle-invasive and muscle-invasive bladder cancer. Although consensus exists on the need for LND, its extent is still debated. OBJECTIVE To develop a model that allows preoperative determination of the minimum number of lymph nodes (LNs) needed to be removed at RC to ensure true nodal status. DESIGN, SETTING, AND PARTICIPANTS We analyzed data from 4335 patients treated with RC and pelvic LND without neoadjuvant chemotherapy at 12 academic centers located in the United States, Canada, and Europe. MEASUREMENTS We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed clinical (preoperative) nodal staging scores (cNSS), which represent the probability that a patient has LN metastasis as a function of the number of examined nodes. RESULTS AND LIMITATIONS The probability of missing a positive LN decreased with an increasing number of nodes examined (52% if 3 nodes were examined, 40% if 5 were examined, and 26% if 10 were examined). A cNSS of 90% was achieved by examining 6 nodes for clinical Ta-Tis tumors, 9 nodes for cT1 tumors, and 25 nodes for cT2 tumors. In contrast, examination of 25 nodes provided only 77% cNSS for cT3-T4 tumors. The study is limited due to its retrospective design, its multicenter nature, and a lack of preoperative staging parameters. CONCLUSIONS Every patient treated with RC for bladder cancer needs an LND to ensure accurate nodal staging. The minimum number of examined LNs for adequate staging depends preoperatively on the clinical T stage. Predictive tools can give a preoperative estimation of the likelihood of nodal metastasis and thereby allow tailored decision-making regarding the extent of LND at RC.

Immunohistochemical biomarkers for bladder cancer prognosis.

Urothelial carcinoma of the bladder (UCB) is an especially complex and heterogeneous disease with a broad spectrum of histologic findings and potentially lethal behavior. Despite advances in surgical techniques, as well as intravesical and systemic therapies, up to 30% of patients with non‐muscle‐invasive UCB and 50% of patients with muscle‐invasive UCB experience disease progression, recurrence, and eventual death. Standard prognostic features, such as pathologic stage and grade, have limited ability to predict the outcomes of this heterogeneous population. Current risk‐stratification algorithms using clinical and pathologic parameters are limited in their prognostic ability. Molecular medicine holds the promise that clinical outcomes will be improved by more accurate prognostication and directing therapy towards the mechanisms and targets associated with the growth of an individual patients tumor. Immunohistochemical analysis of biomarker expression has provided insight into the molecular pathogenesis of UCB and offers the potential for improving clinical decision making. Numerous candidate immunohistochemical biomarkers for patients with UCB have been identified, with those relating to the cell cycle and apoptosis/cell proliferation being the most extensively studied. The present review discusses the most promising immunohistochemical biomarkers. Special attention is paid to recent data from a multi‐institutional collaboration that has implemented a regulated, phased biomarker discovery and validation pathway. Because UCB tumorigenesis and progression is a process involving multiple genetic and epigenetic alterations, multiple biomarkers need to be integrated into a prognostic signature to accurately predict outcomes. There is no doubt that biomarkers will eventually guide our clinical decision making regarding follow‐up scheduling and treatment choice.

Prediction of Intravesical Recurrence After Radical Nephroureterectomy: Development of a Clinical Decision-making Tool

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.

Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy.

Little is known on the association between obesity and urothelial carcinoma of the bladder (UCB). Most studies have shown that higher body mass index (BMI) is associated with higher rates of perioperative complications. Only one study specifically investigated obesity and bladder cancer‐specific outcomes and reported no significant association between higher BMI and disease‐specific survival in patients with UCB treated with radical cystectomy. However, that study was limited by its small sample size and a high rate of preoperative therapies. In contrast to the only previous study evaluating the association of BMI with oncological outcomes in UCB, we found that obesity (BMI ≥30 kg/m2) was associated with features of biologically aggressive UCB and clinical outcomes after radical cystectomy and, even when adjusting for the effects of standard clinicopathological features, obesity remained an independent predictor of cancer recurrence, cancer‐specific mortality and overall mortality.