Jakub Dobruch

Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes

CONTEXTnThe incidence of bladder cancer is three to four times greater in men than in women. However, women are diagnosed with more advanced disease at presentation and have less favorable outcomes after treatment.nnnOBJECTIVEnTo review the literature on potential biologic mechanisms underlying differential gender risk for bladder cancer, and evidence regarding gender disparities in bladder cancer presentation, management, and outcomes.nnnEVIDENCE ACQUISITIONnA literature search of English-language publications that included an analysis of the association of gender with bladder cancer was performed using Pubmed. Ninety-seven articles were selected for analysis with the consensus of all authors.nnnEVIDENCE SYNTHESISnIt has been shown that the gender difference in bladder cancer incidence is independent of differences in exposure risk, including smoking status. Potential molecular mechanisms include disparate metabolism of carcinogens by hepatic enzymes between men and women, resulting in differential exposure of the urothelium to carcinogens. In addition, the activity of the sex steroid hormone pathway may play a role in bladder cancer development, with demonstration that both androgens and estrogens have biologic effects in bladder cancer in vitro and in vivo. Importantly, gender differences exist in the timeliness and completeness of hematuria evaluation, with women experiencing a significantly greater delay in urologic referral and undergoing guideline-concordant imaging less frequently. Correspondingly, women have more advanced tumors at the time of bladder cancer diagnosis. Interestingly, higher cancer-specific mortality has been noted among women even after adjusting for tumor stage and treatment modality.nnnCONCLUSIONSnNumerous potential biologic and epidemiologic factors probably underlie the gender differences observed for bladder cancer incidence, stage at diagnosis, and outcomes. Continued evaluation to define clinical applications for manipulation of the sex steroid pathway and to improve the standardization of hematuria evaluation in women may improve future patient outcomes and reduce these disparities.nnnPATIENT SUMMARYnWe describe the scientific basis and clinical evidence to explain the greater incidence of bladder cancer in men and the adverse presentation and outcomes for this disease in women. We identify goals for improving patient survival and reducing gender disparities in bladder cancer.

Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection

Bladder cancer is the most common cancer of the urinary tract. It is estimated that in 2008, 68 810 new cases of bladder cancer will be diagnosed in the USA [1]. In Europe almost 120 000 cases of the disease are diagnosed each year [2]. Most present with non-muscleinvasive bladder cancer (NMIBC) and require conservative management in contrast to those who present with muscle-invasive disease (MIBC), which mandates early radical bladder removal. The definite establishment of bladder cancer character is usually done after pathological evaluation of the specimen obtained during transurethral resection of the bladder tumour (TURBT). Despite a thorough TURBT, 50–70% of bladder cancers recur and 15–30% progress to muscle invasion. Therefore, to predict future recurrence and/or progression of NMIBC, the European Organization for Research and Treatment of Cancer (EORTC) developed a scoring system. High-, intermediateand low-risk groups of patients in terms of recurrence and/or progression of bladder cancer can be recognized based on the number, size and the grade of the tumours, T category, previous recurrence rate and concomitant carcinoma in situ (Tis). The individual risk category influences follow-up of repeated cystoscopies. The first follow-up cystoscopy is recommended to be done 3 months after TURBT in each patient, but frequency of further endoscopies varies from one done every 3 months to once a year. For patients diagnosed with NMIBC there are various treatment methods. According to a recently published meta-analysis, patients who underwent TURBT followed by at least six intravesical instillations of BCG showed significantly lower rates of recurrence and progression compared with those in whom BCG was not used. BCG is reserved for highrisk tumours (T1 G3, Tis). In cases of highor intermediate-risk of recurrence (i.e. patients with multiple tumours), BCG is usually replaced by a series of instillations using various chemotherapeutic agents. Such therapy reduces the frequency of tumour recurrences but does not influence tumour progression. Traditionally, both BCG and chemotherapeutic agent instillations are performed every week for 6–8 consecutive weeks and many cases receive additional (maintenance) instillations at regular intervals.

Perioperative chemotherapy in upper tract urothelial carcinoma: a comprehensive review

PurposeTo evaluate the role of neoadjuvant (NAC) and adjuvant chemotherapy (AC) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).MethodsA comprehensive review of the current literature was performed searching for all studies investigating NAC and AC in UTUC in MEDLINE and https://clinicaltrials.gov, prior to April 2016. The following keywords were used: “ureteral neoplasms,” “urothelium,” “ureter,” “upper tract urothelial,” “chemotherapy,” “adjuvant,” “neoadjuvant” and relevant variants.ResultsNo randomized trials investigated the role of AC or NAC for UTUC. There was one prospective study with nxa0=xa036 patients investigating AC with carboplatin–paclitaxel. We included 14 retrospective studies (four in the NAC and ten in the AC setting), with a total of 694 patients receiving cisplatin-based or non-cisplatin-based AC after RNU and 1437 patients undergoing RNU alone. We found that the current literature, mainly based on retrospective studies, suggests significant overall and cancer-specific survival benefits for AC in UTUC. NAC appears promising, with favorable pathologic response rates up to 14%.ConclusionsEvidence is scarce for both NAC and AC use in UTUC. This comprehensive review suggests promising response rates for NAC and a survival benefit for patients treated with AC. Prospective randomized trials are needed to establish the role of AC and NAC in UTUC.

Discrepancy Between European Association of Urology Guidelines and Daily Practice in the Management of Non–muscle-invasive Bladder Cancer: Results of a European Survey

BACKGROUNDnThe European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be underuse of guideline-recommended care in this potentially curable cohort.nnnOBJECTIVEnTo assess European physicians current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines.nnnDESIGN, SETTING, AND PARTICIPANTSnInitial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnDescriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used.nnnRESULTS AND LIMITATIONSnGuidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71-100%). Cystoscopy (60-97%) and ultrasonography (42-95%) are the most used diagnostic techniques. Using EAU risk classification, 40-69% and 88-100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25-75% of low-risk and 55-98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24h after TURB. Adjuvant intravesical treatment is not given to 6-62%, 2-33%, and 1-20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians.nnnCONCLUSIONSnAlthough most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice.nnnPATIENT SUMMARYnOur survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non-muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied.

Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: A joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration

To analyse the outcomes of adjuvant chemotherapy vs observation in a multicentre cohort of patients with upper tract urothelial carcinoma (UTUC) in order to clarify whether such patients benefit from adjuvant chemotherapy after radical nephroureterectomy (RNU).

Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study of the EAU‐Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration

To analyse the outcomes of adjuvant chemotherapy vs observation in a multicentre cohort of patients with upper tract urothelial carcinoma (UTUC) in order to clarify whether such patients benefit from adjuvant chemotherapy after radical nephroureterectomy (RNU).

Molecular markers in bladder cancer

Purpose Use of molecular markers in urine, tissue or blood offers potential opportunities to improve understanding of bladder cancer biology which may help identify disease earlier, risk stratify patients, improve prediction of outcomes or help target therapy. Methods A review of the published literature was performed, without restriction of time. Results Despite the fast-growing literature about the topic and the approval of several urinary biomarkers for use in clinical practice, they have not reached the level of evidence for widespread utilization. Biomarkers could be used in different clinical scenarios, mainly to overcome the limitations of current diagnostic, predictive, and prognostic tools. They have been evaluated to detect bladder cancer in asymptomatic populations or those with hematuria and in surveillance of disease as adjuncts to cystoscopy. There is also a potential role as prognosticators of disease recurrence, progression and survival both in patients with non-invasive cancers and in those with advanced disease. Finally, they promise to be helpful in predicting the response to local and/or systemic chemotherapy and/or immunotherapy. Conclusions To date, due to the lack of high-quality prospective trials, the level of evidence provided by the current literature remains low and, therefore, the potential of biomarkers exceeds utilization in clinical practice.PurposeUse of molecular markers in urine, tissue or blood offers potential opportunities to improve understanding of bladder cancer biology which may help identify disease earlier, risk stratify patients, improve prediction of outcomes or help target therapy.MethodsA review of the published literature was performed, without restriction of time.ResultsDespite the fast-growing literature about the topic and the approval of several urinary biomarkers for use in clinical practice, they have not reached the level of evidence for widespread utilization. Biomarkers could be used in different clinical scenarios, mainly to overcome the limitations of current diagnostic, predictive, and prognostic tools. They have been evaluated to detect bladder cancer in asymptomatic populations or those with hematuria and in surveillance of disease as adjuncts to cystoscopy. There is also a potential role as prognosticators of disease recurrence, progression and survival both in patients with non-invasive cancers and in those with advanced disease. Finally, they promise to be helpful in predicting the response to local and/or systemic chemotherapy and/or immunotherapy.ConclusionsTo date, due to the lack of high-quality prospective trials, the level of evidence provided by the current literature remains low and, therefore, the potential of biomarkers exceeds utilization in clinical practice.

Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis.

BACKGROUNDnLimited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma.nnnOBJECTIVEnTo compare the outcomes of operated versus nonoperated patients after first-line chemotherapy.nnnDESIGN, SETTING, AND PARTICIPANTSnData from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given.nnnINTERVENTIONnLND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma.nnnOUTCOME MEASURES AND STATISTICAL ANALYSISnOverall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation.nnnRESULTS AND LIMITATIONSnOverall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations.nnnCONCLUSIONSnAlthough there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials.nnnPATIENT SUMMARYnWe found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.

Conditional analyses of recurrence and progression in patients with TaG1 non–muscle-invasive bladder cancer

OBJECTIVEnTo determine conditional recurrence-free survival (RFS) and progression-free survival (PFS) and improve decision-making toward surveillance protocols and scheduling. Furthermore, evaluating the evolution of predictors for disease recurrence over time, because TaG1 non-muscle-invasive bladder cancer harbors a risk of disease recurrence and progression.nnnMATERIAL AND METHODSnThe retrospective multicenter design study includes 1,245 TaG1 bladder cancer patients with median follow-up of 62.7 (interquartile range: 34.3-91.1) months. Conditional RFS and PFS estimates were calculated using the Kaplan-Meier method. Multivariable Cox regression model was calculated proportional for the prediction of recurrence and progression (covariables: age, tumor size, multiple tumors, prior recurrence, and immediate postoperative instillation of chemotherapy).nnnRESULTSnAfter 3 months without event, the conditional RFS and PFS (to ≥pT2) rates for 5 additional years without event were 57.5% and 93.4%, respectively. Given a 1-, 2-, 3-, and 5-year survival, the conditional RFS rates for 5 additional years without event improved by +9.8 (67.3%), +5.2 (72.5%), +6.5 (79.0%), +2.0 (81.0%), and +1.0% (82.0%), respectively. In contrast, the 5-year conditional PFS rates were more or less stable with 94.3% after 1 year to 94.1% after 5 years. Multivariable analyses showed decreasing impact of risk parameters on RFS estimates over time. Based on these findings, we suggest a risk stratification to individualize follow-up for intermediate risk TaG1. Main limitation was the retrospective design.nnnCONCLUSIONSnConditional-survival analyses demonstrates that the patient risk profile changes over time. RFS rates rise with increasing survival whereas PFS rates were stable. The impact of prognostic features decreases over time. Our findings can be used for patient counseling and planning of personalized follow-up.

3.0-T multiparametric MRI modifies the template of endoscopic, conventional radical prostatectomy in all cancer risk categories

Introduction We aimed to evaluate the diagnostic performance of 3.0-T multiparametric magnetic resonance imaging (mpMRI) in preoperative staging of prostate cancer (PCa) and its influence on the extent of resection during endoscopic radical prostatectomy (ERP) among cancer risk groups. Material and methods The data of 154 patients with PCa in whom mpMRI was performed prior to ERP between 2011 and 2015 were included. The initial decision whether to perform neurovascular bundle (NVB) sparing surgery was based on EAU guidelines. mpMRI images were reevaluated prior to prostatectomy to modify the surgical template. Imaging was compared with pathological reports to investigate the diagnostic performance of mpMRI. Results The surgical template was modified in 69 (44.8%) patients after reevaluation of mpMRI. More preserving NVB sparing was attempted in 17 (11.0%) men, in whom NVB would have been resected if mpMRI had not been available. More aggressive NVB resection was performed in 52 (33.8%) men, in whom innervation would have been spared if basing solely based on guidelines. Among all PCa risk groups mpMRI had an impact on the surgical template with more aggressive surgery in 63.0% and 33.3% of men in the low- and intermediate-risk group, respectively, and more preserving in 21.4% of the high-risk patients. The change in extent of resection was not correlated with a higher risk of positive surgical margins (p = 0.196). Conclusions Preoperative mpMRI exerts a significant impact on decision making concerning the extent of resection during ERP irrespective of the PCa risk group.