Beat Foerster

Repeat Transurethral Resection in Non–muscle-invasive Bladder Cancer: A Systematic Review

CONTEXT Initial treatment for most bladder cancers (BCs) involves transurethral resection (TUR) or tumours. Often more cancer is found after the initial treatment in around half of patients, requiring a second resection. Repeat transurethral resection (reTUR) is recommended for high-risk, non-muscle-invasive bladder cancer (NMIBC) to remove any residual disease and improve cancer outcomes. OBJECTIVE To systematically review the practice and therapeutic benefit of an early reTUR for high-risk NMIBC. EVIDENCE ACQUISITION A systematic review of original articles was performed using PubMed/Medline and Web of Science databases in December 2016 (initial) and October 2017 (final). We searched the references of included papers. EVIDENCE SYNTHESIS We screened 15 209 manuscripts and selected 31 detailing 8409 persons with high-grade Ta and T1BC for inclusion. Detrusor muscle was found at initial TUR histology in 30-100% of cases. Residual tumour at reTUR was found in 17-67% of patients following Ta and in 20-71% following T1 cancer. Most residual tumours (36-86%) were found at the original resection site. Upstaging occurred in 0-8% (Ta to ≥T1) and 0-32% (T1 to ≥T2) of cases. Conflicting data report the impact of reTUR on subsequent recurrence and cancer-specific mortality. Recurrence for Ta was 16% in the reTUR group versus 58% in the non-reTUR group. For T1, recurrence ranged from 18% to 56%, but no clear trend was identified between reTUR and control. No clear relationship between reTUR and progression was found for Ta, although for T1 rates were higher in the non-reTUR group in series with control populations (5/6 studies). Overall mortality was slightly reduced in the reTUR group in two studies with controls (22-30% vs 26-36% [no reTUR]). CONCLUSIONS Residual tumour is common after TUR for high-risk NMIBC. The reTUR helps in the diagnosis of this residual cancer and may improve outcomes for cancers initially staged as T1. PATIENT SUMMARY Some bladder cancers (BCs) are aggressive but confined to the bladder surface. Initial treatment includes endoscopic resection. More cancer is found after the initial treatment in approximately half of patients. In the aggressive but confined group of BC, a second resection, a few weeks after the first, may help find this residual cancer and improve outcomes, although the evidence quality for this is weak.

Management of muscle invasive, locally advanced and metastatic urothelial carcinoma of the bladder: a literature review with emphasis on the role of surgery

Locally advanced (T3b, T4 and N1−N3) and metastatic urothelial bladder cancer (BCa) is a lethal disease with poor survival outcomes. Combination chemotherapy remains the treatment of choice in patients with metastatic disease and an important part of treatment in addition to radical cystectomy (RC) in patients with locally advanced tumour. Approximately half of patients who underwent RC for muscle invasive BCa relapse after surgery with either local recurrence or distant metastasis. This review focuses on the management of muscle invasive, locally advanced and metastatic BCa with emphasis on the role of surgery; to summarize the current knowledge in order to enhance clinical decision-making and counselling process.

Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients

BackgroundPreoperative blood-based inflammatory biomarkers have been suggested to improve staging and prognostication in patients with upper-tract urothelial carcinoma (UTUC). Neutrophil-to-lymphocyte ratio (NLR) is the most studied blood-based biomarker. NLR is an indicator of systemic inflammation and has been shown to be associated with a poor prognosis in various malignancies. The aim of this study was to analyze the current evidence regarding the prognostic significance of preoperative NLR in patients undergoing radical nephroureterectomy (RNU) for UTUC to assess its prognostic potential.Materials and methodsA systematic search of Web of Science, Medline/PubMed and Cochrane library was performed on the 1st of October, 2017. Studies were deemed eligible if they compared patients with high NLR before surgical treatment for UTUC to patients with low NLR to determine its predictive value for survival using multivariable logistic regression analysis. We performed a formal meta-analysis for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS).ResultsNine studies including a total of 4385 patients assessing the importance of NLR were included in this meta-analysis. The cut-off NLR varied in the eligible studies ranging from 2 to 3. Increased pretreatment NLR predicted OS (pooled HR 1.64 95% CI; 1.23–2.17), RFS (pooled HR 1.60 95% CI; 1.16–2.20) and CSS (pooled HR 1.73 95% CI; 1.23–2.44) in multivariable analyses.ConclusionIn this meta-analysis, preoperative blood-based NLR is associated with worse prognosis in patients who underwent RNU for UTUC. NLR could be used to improve clinical decision making regarding RNU vs. kidney-sparing surgery, extent of lymphadenectomy, perioperative systemic therapy and follow-up schedule.

Preoperative anemia is associated with disease recurrence and progression in patients with non–muscle-invasive bladder cancer

PURPOSE To evaluate the effect of preoperative anemia (PA) on oncological outcomes in a multicenter cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) and adjuvant intravesical therapies. We hypothesize that PA represents a marker of disease aggressiveness and could be used to improve the discrimination of prognostic tools for the prediction of disease recurrence and progression. METHODS This multicenter retrospective study included 1,117 patients from 4 different centers. The presence of PA was assessed according to the World Health Organization classification as a preoperative hemoglobin level of≤13g/dl in men and≤12g/dl in women. PA evaluation was done at each institution, generally 1 to 3 days before surgery. Multivariable Cox regression models were performed to evaluate the prognostic effect of PA on survival outcomes. RESULTS Overall, 381 (34%) patients with NMIBC treated with TURB, had PA. Median follow-up for patients alive at last follow-up was 62.7 months (interquartile range: 25-110.7). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathologic prognosticators, PA was independently associated with recurrence-free survival (P = 0.045) and progression-free survival (P = 0.01). Adding PA to a model for the prediction of disease recurrence and progression improved the discrimination of the prognostic models marginally from 69.8% to 70.3% and from 71.6% to 73.1%, respectively. CONCLUSIONS PA was found in more than one-third of patients with NMIBC treated with TURB. PA was associated with poor oncological outcomes and was an independent predictor of intravesical disease recurrence and progression. However, the additional prognostic information provided by PA remains limited.

Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients

Purpose To evaluate the impact of pure and mixed histologic variant versus pure urothelial carcinoma in nonmetastatic bladder cancer (BCa) patients treated with radical cystectomy (RC). Patients and Methods We evaluated data from 1067 patients treated with RC and pelvic lymph node dissection between 1990 and 2013 at a single institution tertiary‐care referral center. All specimens were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the impact of the presence of pure and mixed histologic variants versus pure urothelial on recurrence, cancer‐specific mortality, and overall mortality after accounting for all available confounders. Results In total, 201 (19%) and 137 (13%) patients were found with mixed and pure variants at RC, respectively. Mixed preponderant variants were sarcomatoid, lymphoepitelial, squamous, and glandular; small‐cell and micropapillary variants were found mostly as pure variants. With a median follow‐up of 6.5 years, patients who harbored pure variant were found by multivariable analyses to have lower survival outcomes compared to pure urothelial carcinoma (all P < .01). Conversely, no differences were found between mixed variant versus pure urothelial by multivariable Cox regression analyses predicting recurrence, cancer‐specific mortality, and overall mortality (all P > .1). Conclusion The presence of histologic variants at RC is a common finding, accounting for approximately 30% of specimens. In this setting, the presence of a pure variant but not the presence of mixed variant with urothelial carcinoma is related to a detrimental effect on survival outcomes after RC. Micro‐Abstract The importance of a correct histologic variant classification in the decision making of bladder cancer patients have been recently highlighted by the new World Health Organization classification of the urothelial tract. Histologic variants at the time of radical cystectomy is a common finding, accounting for almost 30% of specimens, yet only pure histologic variants but not mixed histologic variants are associated with worse survival compared to pure urothelial cancer. Physicians should consider this parameter when counseling surgical patients.

Accuracy and prognostic value of variant histology and lymphovascular invasion at transurethral resection of bladder

ObjectivesTo evaluate the concordance rate of lymphovascular invasion (LVI) and variant histology (VH) of transurethral resection (TUR) with radical cystectomy (RC) specimens. Furthermore, to evaluate the value of LVI and VH at TUR for predicting non-organ confined (NOC) disease, lymph node metastasis, and survival outcomes.Patients and methodsTwo hundred and sixty-eight patients who underwent TUR and subsequent RC were reviewed. Logistic regression analyses were performed to evaluate the association of LVI and VH with NOC and lymph node metastasis at RC. Cox regression analyses were used to estimate recurrence-free survival (RFS) and cancer-specific survival (CSS).ResultsLVI and VH were detected in 13.8 and 11.2% of TUR specimens, and in 30.2 and 25.4% of RC specimens, respectively. The concordance rate between LVI and VH at TUR and subsequent RC was 69.8 and 83.6%, respectively. They were both associated with adverse pathological features such as lymph node metastasis and advanced stage. TUR LVI and VH were both independently associated with lymph node metastasis and TUR VH was independently associated with NOC. On univariable Cox regression analyses, TUR LVI was associated with RFS and CSS while TUR VH was only associated with RFS. Only TUR LVI was independently associated with RFS.ConclusionDetection of LVI is missed in a third of TUR specimens while VH seems more accurately identified. TUR LVI and VH are associated with more advanced disease and LVI predicts disease recurrence. Assessment and reporting of LVI and VH on TUR specimen are important for risk stratification and decision-making.

Prognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non–muscle-invasive bladder cancer (NMIBC): A systematic review and meta-analysis

OBJECTIVE The aim of this study was to summarize and analyze the current evidence regarding the prognostic and predictive value of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients undergoing transurethral resection of bladder tumors (TURBT) for non-muscle-invasive bladder cancer (NMIBC). MATERIAL AND METHODS A systematic search of Web of Science, Medline/PubMed, Google Scholar, and Cochrane library was performed on the 1st of March, 2018. Studies were deemed eligible if they compared NMIBC patients with high vs. low NLR before TURBT to determine its value for prognosticating disease recurrence and progression using multivariable analysis. We performed a formal meta-analysis for both recurrence-free (RFS) and progression-free survival (PFS). RESULTS Six studies encompassing 2,298 patients (477 [20.7%] females) assessed the prognostic value of NLR in NMIBC patients treated with TURBT. NLR predicted worse RFS (pooled HR = 1.78; 95% CI: 1.32-2.4, P<0.001) and PFS (pooled HR = 2.14; 95% CI: 1.59-2.87, P<0.001). In 4 studies encompassing 599 patients, high pretreatment NLR was associated with decreased RFS (pooled HR = 2.31; 95% CI: 1.27-4.22, P = 0.006) and in 3 of them high pretreatment NLR was associated with decreased PFS (pooled HR = 2.54; 95% CI: 1.36-4.71, P = 0.003) in high-risk NMIBC patients treated with BCG. CONCLUSION In this meta-analysis, peripheral blood levels of NLR were associated with an increased risk of disease recurrence and progression in patients who underwent TURBT for NMIBC. Furthermore, NLR was an independent predictor of disease recurrence and progression in NMIBC treated with BCG patients. NLR could be used to improve clinical decision-making regarding treatment and follow-up scheduling.

Association of Smoking Status With Recurrence, Metastasis, and Mortality Among Patients With Localized Prostate Cancer Undergoing Prostatectomy or Radiotherapy: A Systematic Review and Meta-analysis

Importance Studies investigating the association of cigarette smoking with prostate cancer incidence and outcomes have revealed controversial results. Objective To systematically review and analyze the association of smoking status with biochemical recurrence, metastasis, and cancer-specific mortality among patients with localized prostate cancer undergoing primary radical prostatectomy or radiotherapy. Data Sources A systematic search of original articles published between January 2000 and March 2017 was performed using PubMed, MEDLINE, Embase, and Cochrane Library databases in March 2017. Study Selection Observational studies reporting Cox proportional hazards regression or logistic regression analyses were independently screened. Data Extraction and Synthesis This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. Available multivariable hazard ratios (HRs) and corresponding 95% CIs were included in quantitative analysis. A risk-of-bias assessment was completed for nonrandomized studies. Main Outcomes and Measures Prespecified outcomes of interest were biochemical recurrence, metastasis, and cancer-specific mortality. Results A total of 5157 reports were identified, of which 16 articles were selected for qualitative analysis and 11 articles were selected for quantitative analysis. All included studies were observational and nonrandomized and comprised a total of 22 549 patients. Overall, 4202 patients (18.6%) were current smokers. The overall median follow-up was 72 months. Current smokers had a statistically significantly higher risk of biochemical recurrence (HR, 1.40; 95% CI, 1.18-1.66; P < .001 [10 studies]), as did former smokers (HR, 1.19; 95% CI, 1.09-1.30; P < .001 [7 studies]). Current smokers were also at a higher risk of metastasis (HR, 2.51; 95% CI, 1.80-3.51; P < .001 [3 studies]) and cancer-specific mortality (HR, 1.89; 95% CI, 1.37-2.60; P < .001 [5 studies]), whereas former smokers were not (metastasis: HR, 1.61; 95% CI, 0.65-3.97; P = .31 [2 studies]; cancer-specific mortality: HR, 1.05; 95% CI, 0.81-1.37; P = .70 [4 studies]). Conclusions and Relevance Current smokers at the time of primary curative treatment for localized prostate cancer are at higher risk of experiencing biochemical recurrence, metastasis, and cancer-specific mortality.

Prognostic role of N-cadherin expression in patients with non–muscle-invasive bladder cancer

PURPOSE To assess the role of N-cadherin as a prognostic biomarker in patients with non-muscle-invasive bladder cancer (NMIBC) treated with transurethral resection with or without adjuvant intravesical therapy. PATIENTS AND METHODS Immunohistochemistry using monoclonal mouse antibody was used to evaluate the expression status of N-cadherin in 827 patients with NMIBC. N-cadherin was considered positive if any immunoreactivity with membranous staining was detected. Multivariable Cox regression models were performed to evaluate the prognostic effect of N-cadherin on survival outcomes. RESULTS N-cadherin expression was observed in 333 patients (40.3%); it was associated with pT1 stage and high tumor grade (both were P<0.001). Median follow-up was 55 months (interquartile range: 18-106). On multivariable Cox regression analyses that adjusted for the effect of the standard clinicopathologic features, N-cadherin expression remained associated with recurrence-free survival (P = 0.007) but not progression-free survival (P = 0.3), cancer-specific survival (P = 0.2), or overall survival (P = 0.9). Adding N-cadherin to a model for prediction of disease recurrence modestly improved its discrimination from 72.8% to 73.4%. CONCLUSION N-cadherin is expressed in approximately 2/5 patients with NMIBC. Its expression is associated with adverse pathological features and higher risk of disease recurrence but not progression. N-cadherin could be incorporated in predictive tools to assist in recurrence prediction helping thereby in patient selection regarding adjuvant therapies and follow-up planning.

Is transurethral resection alone enough for the diagnosis of histological variants? A single-center study

INTRODUCTION To evaluate incidence of histological variants and grade agreement between transurethral resection (TUR) and radical cystectomy (RC) in patients with bladder cancer. METHODS A total of 779 patients treated with TUR and subsequently with RC between 1990 and 2013 at a single center were analyzed retrospectively. Variant histology classifications used in our analyses were sarcomatoid, small cell, squamous, or micropapillary. Grade agreement was calculated using the Cohen kappa coefficient. Logistic regression analyses were built to predict adverse pathologic features from histological variants at TUR. RESULTS Considering TUR, 213 (27.3%) patients were diagnosed with histological variants. Of these, 2.1% (n = 16) were found with sarcomatoid variant, 1.7% (n = 13) with small cell, 7.1% (n = 55) with squamous, 12.5% (n = 97) with micropapillary. Considering RC, 212 (27.2%) patients were diagnosed with histological variants. Poor agreement was found considering micropapillary variant and the presence of a histological variant in general (0.11 and 0.27, respectively). Intermediate agreement was found analyzing the presence of sarcomatoid, small cell, and squamous variants (0.43, 0.61, and 0.61, respectively). Small cell carcinoma at TUR was found associated with an increased risk of harboring positive soft tissue surgical margin (odds ratio = 2.08; CI: 1.27-3.41; P = 0.03). CONCLUSIONS One out of our patients with bladder cancer was diagnosed with a histological variant either at TUR and RC. We found poor agreement between TUR and RC. Our findings highlight that TUR alone is not sufficient to accurately evaluate the presence of histological variants that may have an effect on treatment and survival outcomes.