Michael Rink

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

Urothelial carcinoma of the bladder and the upper tract: disparate twins.

PURPOSE Urothelial carcinoma of the bladder is the 4th most common malignancy in men and the 8th most common cause of male cancer death in the United States. Conversely, upper tract urothelial carcinoma accounts for only 5% to 10% of all urothelial carcinoma. Due to the relative preponderance of urothelial carcinoma of the bladder, much of the clinical decision making regarding upper tract urothelial carcinoma is extrapolated from evidence that is based on urothelial carcinoma of the bladder cohorts. In fact, only 1 major urological organization has treatment guidelines specific for upper tract urothelial carcinoma. While significant similarities exist between these 2 diseases, ignoring the important differences may be preventing us from optimizing therapy in patients with upper tract urothelial carcinoma. Therefore, we explored these dissimilarities, including the differential importance of gender, anatomy, staging, intracavitary therapy, surgical lymphadenectomy and perioperative systemic chemotherapy on the behavior of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. MATERIALS AND METHODS A nonsystematic literature search using the MEDLINE/PubMed® database was conducted to identify original articles, review articles and editorials. Searches were limited to the English language and studies in humans and in adults, and used the key words urothelial carcinoma, upper tract urothelial carcinoma or transitional cell carcinoma combined with several different sets of key words to identify appropriate publications for each section of the manuscript. The key words, broken down by section, were 1) epidemiology, sex, gender; 2) location, tumor location; 3) staging, stage; 4) intracavitary, intravesical, topical therapy; 5) lymphadenectomy, lymph node, lymph node dissection and 6) adjuvant, neoadjuvant, chemotherapy. RESULTS Women who present with urothelial carcinoma of the bladder do so with less favorable tumor characteristics and have worse survival than men. However, gender does not appear to be associated with survival outcomes in upper tract urothelial carcinoma. The prognostic effect that urothelial carcinoma tumor location has on outcomes prediction is a matter of debate, and the influence of tumor location may reflect our technical ability to accurately stage and treat the disease more than the actual tumor biology. Moreover, technical limitations of upper tract urothelial carcinoma sampling compared to transurethral resection for urothelial carcinoma of the bladder are the most important source of staging differences between the 2 diseases. Intravesical chemotherapy and immunotherapy are essential components of standard of care for most nonmuscle invasive bladder cancer, while adjuvant intracavitary therapy for patients with upper tract urothelial carcinoma treated endoscopically or percutaneously has been sparsely used and without any clear guidelines. The widespread adoption of the use of intracavitary therapy in the upper tract will likely not only require additional data to support its efficacy, but will also require a less cumbersome means of administration. Lymphadenectomy at the time of radical cystectomy is widely accepted while lymphadenectomy at the time of radical nephroureterectomy is performed largely at the discretion of the surgeon. Among other reasons, this may be due in part to the variable lymphatic drainage along the course of the ureter compared to the relatively confined lymphatic landing sites for the bladder. Level I evidence has demonstrated a clear survival benefit for systemic chemotherapy before radical surgery or radiation in patients with clinical T2-4N0M0 urothelial carcinoma of the bladder. Such data are not available in the population with upper tract urothelial carcinoma. However, the use of neoadjuvant chemotherapy may be even more important in upper tract urothelial carcinoma than in urothelial carcinoma of the bladder because of the obligatory kidney function loss that occurs at radical nephroureterectomy. CONCLUSIONS While urothelial carcinoma of the bladder and upper tract urothelial carcinoma share many characteristics, they represent 2 distinct diseases. There are practical, anatomical, biological and molecular differences that warrant consideration when risk stratifying and treating patients with these disparate twin diseases. To overcome the challenges that impede progress toward evidence-based medicine in upper tract urothelial carcinoma, we believe that focused collaborative efforts will best augment our understanding of this rare disease and ultimately improve the care we deliver to our patients.

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.

Hexyl Aminolevulinate–Guided Fluorescence Cystoscopy in the Diagnosis and Follow-up of Patients with Non–Muscle-invasive Bladder Cancer: A Critical Review of the Current Literature

CONTEXT Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. EVIDENCE ACQUISITION We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. CONCLUSIONS Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required.

Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective Study

BACKGROUND Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB). OBJECTIVE Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB. DESIGN, SETTING, AND PARTICIPANTS Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. INTERVENTION Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. MEASUREMENTS Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis. RESULTS AND LIMITATIONS CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤ 0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤ 0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size. CONCLUSIONS Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.

Effect of Smoking on Outcomes of Urothelial Carcinoma: A Systematic Review of the Literature

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.

Impact of Smoking and Smoking Cessation on Oncologic Outcomes in Primary Non–muscle-invasive Bladder Cancer

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.

Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladder cancer

What’s known on the subject? and What does the study add?

Prediction of 90-day Mortality After Radical Cystectomy for Bladder Cancer in a Prospective European Multicenter Cohort

BACKGROUND Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. OBJECTIVE To validate the performance of the Isbarn nomogram incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. DESIGN, SETTING, AND PARTICIPANTS Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. INTERVENTION RC for BCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics-derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. RESULTS AND LIMITATIONS The 30-, 60-, and 90-d mortality rates in the development cohort (n=597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio [OR]:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p<0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. CONCLUSIONS The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. PATIENT SUMMARY The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.

Impact of Smoking and Smoking Cessation on Outcomes in Bladder Cancer Patients Treated with Radical Cystectomy

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.