Michael Gierth

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.

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node-positive Urothelial Carcinoma

BACKGROUND Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined. OBJECTIVE To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival. DESIGN, SETTING, AND PARTICIPANTS A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%). INTERVENTION Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11-38). RESULTS AND LIMITATIONS Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p<0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p=0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p=0.856), and the incremental accuracy of prediction is of uncertain clinical value. CONCLUSIONS We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.

Clinical staging error in prostate cancer: localization and relevance of undetected tumour areas

To describe the localization and to assess the clinical implications of areas of undetected prostate cancer in radical prostatectomy (RP) specimens, focusing on patients with unilaterally negative preoperative biopsy cores.

Preoperative C-reactive protein in the serum: a prognostic biomarker for upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

Objective: To investigate the impact of preoperative serum C-reactive protein (CRP) on clinicopathological features and prognosis in patients with upper tract urothelial cancer (UTUC) after radical nephroureterectomy (RNU). Patients andMethods: Data of 265 patients from three German centers who underwent RNU for UTUC without neoadjuvant chemotherapy between 1990 and 2012 were evaluated. Mean follow-up was 37 months (interquartile range 9-48). CRP was analyzed as a categorical and continuous variable for the prediction of recurrence-free survival (RFS), disease-specific survival (DSS) and all-cause survival (ACS) using uni- and multivariate Cox regression analyses. Results: The optimal cutoff for CRP was calculated by the Youden index at 0.90 mg/dl. Elevated CRP was significantly associated with pT3/4 and pN+ in a preoperative model including age, gender, tumor multifocality, tumor localization and the Eastern Cooperative Oncology Group Performance Status. In a multivariable Cox regression model adjusted for features significant in univariable analysis, categorized and continuous CRP levels were both independent predictors for RFS [hazard ratio (HR) 1.18, p = 0.050; HR 1.03, p = 0.012] and DSS (HR 1.61, p = 0.026; HR 1.06, p = 0.001). Continuous CRP was an independent predictor for ACS (HR 1.05, p = 0.036). Conclusions: Elevated preoperative CRP is significantly associated with aggressive tumor biology and an independent predictor for poor survival after RNU. Preoperative serum CRP represents an easily obtainable and cost-effective marker in UTUC and may help in counseling patients with regard to operative management and/or adjuvant or neoadjuvant therapies.

The Charlson Comorbidity Index Predicts Survival after Disease Recurrence in Patients following Radical Cystectomy for Urothelial Carcinoma of the Bladder

Objective: To identify prognostic clinical and histopathological parameters, including comorbidity indices at the time of radical cystectomy (RC), for overall survival (OS) after recurrence following RC for urothelial carcinoma of the bladder (UCB). Materials and Methods: A retrospective multicenter study was carried out in 555 unselected consecutive patients who underwent RC with pelvic lymph node dissection for UCB from 2000 to 2010. A total of 227 patients with recurrence comprised our study group. Cox proportional hazards regression models were calculated with established variables to assess their independent influence on OS after recurrence. Results: The median time from RC to recurrence and the median OS after recurrence was 10.9 and 5.4 months, respectively. Neither the time to recurrence nor the type of recurrence (systematic vs. local) was predictive of the OS. In contrast, age (hazard ratio (HR) 1.53, p = 0.011), lymph node metastasis (HR 1.56, p = 0.007), and positive surgical margins (HR 1.53, p = 0.046) significantly affected the OS after disease recurrence. In addition, the dichotomized Charlson comorbidity index (CCI; dichotomized into >2 vs. 0-2) was the only comorbidity score with an independent prediction of OS (HR 1.41, p = 0.033). We observed a significant gain in the base models predictive accuracy, i.e. from 68.4 to 70.3% (p < 0.001), after inclusion of the dichotomized CCI. Conclusions: We present the first outcome study of comorbidity indices used as predictors of OS after disease recurrence in patients undergoing RC for UCB. The CCI at the time of RC had no significant influence on the time to recurrence but represented an independent predictor of OS after disease recurrence.

The Use of Neoadjuvant Chemotherapy in Patients With Urothelial Carcinoma of the Bladder: Current Practice Among Clinicians

Micro‐Abstract Neoadjuvant chemotherapy before radical cystectomy is recommended in patients with bladder cancer in clinical stages T2‐T4a, cN0M0. We analyzed the frequency and current practice of neoadjuvant chemotherapy in 679 patients using uni‐ and multivariable regression analyses and using a questionnaire. We found a great discrepancy between guideline recommendations and practice patterns, despite medical indication and interdisciplinary tumor board discussion. Introduction: Guidelines recommend neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in patients with urothelial carcinoma of the bladder in clinical stages T2‐T4a, cN0M0. We examined the frequency and current practice of NAC and sought to identify predictors for the use of NAC in a prospective contemporary cohort. Materials and Methods: We analyzed prospective data from 679 patients in the PROMETRICS (PROspective MulticEnTer RadIcal Cystectomy Series 2011) database. All patients underwent RC in 2011. Uni‐ and multivariable regression analyses identified predictors of NAC application. Furthermore, a questionnaire was used to evaluate the practice patterns of NAC at the PROMETRICS centers. Results: A total of 235 patients (35%) were included in the analysis. Only 15 patients (2.2%) received NAC before RC. Younger age (< 70 years; P = .035), lower case volume of the center (< 30 RC/year; P < .001), and advanced tumor stage (≥ cT3; P = .038) were identified as predictors for NAC. Of the 200 urologists who replied to the questionnaire, 69% (n = 125) declared tumor stage cT3‐4 a/o N1M0 to be the best indication for NAC application, although 45% of the urologists stated that they would not perform NAC despite recommendations. The decision for NAC was made by the individual urologist in 69% of cases, and only 29% reported that all cases were discussed in an interdisciplinary tumor board. Conclusion: NAC was rarely applied in the present cohort. We observed a discrepancy between guideline recommendations and practice patterns, despite medical indication and pre‐therapeutic interdisciplinary discussion. The potential benefit of NAC within a multimodal approach seems to be neglected by many urologists.

Comparative Analysis of Gender-Related Differences in Symptoms and Referral Patterns prior to Initial Diagnosis of Urothelial Carcinoma of the Bladder: A Prospective Cohort Study

Objective: To analyze gender-specific differences regarding clinical symptoms, referral patterns and tumor biology prior to initial diagnosis of urothelial carcinoma of the bladder (UCB). Methods: A consecutive series of patients with an initial diagnosis of UCB was included. All patients completed a questionnaire on demographics, clinical symptoms and referral patterns. Results: In total, 68 patients (50 men, 18 women) with newly diagnosed UCB at admission for transurethral resection of bladder tumors were recruited. Dysuria was more often observed in women (55.6 vs. 38.0%, p = 0.001). Direct consultation of the urologist was conducted by 84.0% of males and 66.7% of females (p = 0.120). One third of the women saw their general practitioner and/or gynecologist once or twice (p = 0.120) before referral to the urologist. Furthermore, women were significantly more often treated for urinary tract infections than men (61.1 vs. 20.0%, p = 0.005). Cystoscopy at first presentation to the urologist was more often performed in men than women (88.0 vs. 66.7%, p = 0.068), with a more favorable tumor detection rate at first cystoscopy in men (96.0 vs. 50.0%, p < 0.001). Conclusions: Delayed referral patterns might lead to deferred diagnosis of UCB and consequently to adverse outcome. Thus, primary care physicians might consider referring patients with bladder complaints to specialized care earlier.

Oncological Outcome of Primary versus Secondary Muscle-Invasive Bladder Cancer Is Comparable after Radical Cystectomy

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. Objective: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. Materials and Methods: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. Results: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. Conclusion: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC.

Comparative analysis of comorbidity and performance indices for prediction of oncological outcomes in patients with upper tract urothelial carcinoma who were treated with radical nephroureterectomy

OBJECTIVE Comorbidity and performance indices (CPIs) are useful tools to evaluate patients risk of comorbidities and thus may guide clinical decision making regarding surgery or multimodal therapy approaches. Hence, the aim of the current study was to assess the predictive capacity of CPIs comprising the American Society of Anaesthesiologists (ASA)-score, the Charlson comorbidity index (CCI), the age-adjusted CCI (ACCI), and the Eastern Cooperative Oncology Group performance status (ECOG-PS) in patients with upper tract urothelial carcinoma (UTUC) who were treated with radical nephroureterectomy (RNU). METHODS AND MATERIALS A total of 242 patients with UTUC underwent RNU without neoadjuvant chemotherapy between 1992 and 2012 at 3 German academic centers. Patients were stratified according to the pre-RNU CPIs dichotomized as ASA 1/2 vs .≥ 3, CCI 0 to 2 vs. > 2, ACCI 0 to 5 vs. > 5, and ECOG-PS 0 to 1 vs. > 1. We assessed the associations of CPIs with clinicopathologic features, as well as the prognostic effect on recurrence-free survival, cancer-specific survival (CSS), overall survival, and cancer-independent mortality (CIM), using univariable and multivariable Cox regression analyses. RESULTS Sixty-two patients (25.6%) had an ASA-score ≥ 3, 71 patients (29.3%) a CCI>2, 50 patients (20.7%) an ACCI > 5, and 122 (50.4%) patients an ECOG-PS > 1. The ASA-score (P = 0.001), CCI (P = 0.029), and the ECOG-PS (P < 0.001) were significantly associated with age. In addition, the ECOG-PS was associated with pelvicalyceal tumors (P = 0.012), and the CCI with preoperative hydronephrosis (P = 0.026). The median follow-up was 30 months. In Kaplan-Meier analyses, ACCI > 5 (P ≤ 0.025) and ECOG-PS > 1 (P ≤ 0.042) were associated with recurrence-free survival, CSS, and overall survival, and ASA-score ≥ 3 (P = 0.011) and ACCI > 5 (P = 0.006) with CIM. In multivariable analysis that adjusted for standard clinicopathologic parameters, an ECOG-PS > 1 was an independent predictor for CSS (hazard ratio = 1.89, P = 0.019), and an ASA-score ≥ 3 (hazard ratio = 1.86, P = 0.026) was a predictor for CIM. CONCLUSION CPIs are easy assessable predictors for outcome in patients with UTUC who were treated with RNU. CPIs have carefully to be taken into account in patient counseling regarding operative decision making and multimodal treatment.