Alfuzosin 10 mg once daily for treating benign prostatic hyperplasia: a 3-year experience in real-life practice.

OBJECTIVES: To assess the 3-year efficacy and safety of the selective alpha(1)-blocker alfuzosin at 10 mg once daily in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in 'real-life practice'. The influence of treatment response on the risk of acute urinary retention (AUR) and BPH-related surgery was also analysed. PATIENTS AND METHODS: In all, 689 European men (mean age 67.6 years) were enrolled by general practitioners in a 3-year open-label study with alfuzosin at 10 mg once daily. They were asked to complete the International Prostate Symptom Score (IPSS), its eighth question (bother score), and the Danish Prostatic Symptom Score for sexual function (DAN-PSSsex). Efficacy was analysed at the endpoint in the intent-to-treat population. The impact of baseline variables (age, PSA level, IPSS and bother severity) and dynamic variables (IPSS worsening of >or=4 points and bother at the last available assessment under treatment) on the risk of AUR and BPH-related surgery was evaluated. RESULTS: With alfuzosin, IPSS improved by 6.4 points (-33.4%) from baseline (P < 0.001), reaching >or=3 points and >6 points in 71.3% and 47.2% of men, respectively. There were also significant (P < 0.001) improvements from baseline in nocturia (-0.8, -25.5%), bother score (-1.7, -40.7%) and DAN-PSSsex weighted scores with treatment. Symptom relief was rapid and maintained over 3 years. Overall, 78 men (12.4%) had an IPSS worsening of >or=4 points, 16 (2.6%) had AUR, and 36 (5.7%) required BPH-related surgery. Symptom deterioration during treatment and high baseline PSA values were the best predictors of AUR and BPH-related surgery. Alfuzosin was well tolerated, dizziness being the most frequent adverse event (4.5%) possibly related to vasodilatation. Ejaculatory disorders were uncommon (0.4%). Changes in blood pressure remained marginal, including in men aged >or=65 years and those receiving antihypertensive agents. CONCLUSION: Alfuzosin administered for 3 years at 10 mg once daily in real-life practice is effective and well tolerated. High PSA values and symptom worsening under treatment appear the best predictors of AUR and BPH-related surgery in the long term. Treatment with alfuzosin might thus help to identify patients at risk of LUTS/BPH progression in order to optimize their management.

Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups.

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.

Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study.

BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS: The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

Survival and PSA-markers for mortality and metastasis in nonmetastatic prostate cancer treated with androgen deprivation therapy.

BACKGROUND: Few studies have examined the risk of developing castration-resistant prostate cancer (CRPC), metastasis, and mortality among nonmetastatic prostate cancer (M0-PC) patients treated with androgen deprivation therapy (ADT). We estimated the incidence of these outcomes among M0-PC patients on ADT and identified prostate-specific antigen (PSA) based biomarkers for mortality and metastasis. METHODS: This population-based cohort study included all nonmetastatic prostate cancer patients in Northern and Central Denmark Regions during 1997-2010, identified through registry data. Primary outcomes were metastasis, overall survival, and bone metastasis-free survival (BMFS). We estimated relative risks (RR) associated with PSA and PSA doubling-time (PSA-DT), measured as time-varying variables beginning at ADT treatment start. RESULTS: We included 2494 M0-PC patients treated with ADT, of whom 1617 (80%) developed CRPC during follow-up. One-fourth of the patients developed metastases within 5 years; bone metastases (BM) accounted for 81% of all metastases. Median survival time was 4.4 years. Compared with PSA <8 ng/mL, PSA ≥8 ng/mL was associated with an adjusted RR of 14.0 (95% confidence interval [CI]: 10.2, 19.0) for BM, 4.4 (CI: 3.9, 5.0) for all-cause mortality, and RR of 4.8 (CI: 4.3, 5.4) for the inverse of BMFS. PSA-DT ≤6 months was associated with an adjusted RR of 7.6 (95% CI: 6.1, 9.5) for BM, RR of 5.9 (CI: 5.2, 6.6) for all-cause mortality, and RR 6.6 (CI: 5.9, 7.4) for the inverse of BMFS. CONCLUSIONS: PSA ≥8 ng/mL and PSA-DT ≤6 months are strong predictors of mortality and bone metastasis. The poor prognosis observed in this study may reflect inclusion of patients with severe prostate cancer by requiring repeated PSA measurements.

Completeness of prostate cancer staging in the Danish Cancer Registry, 2004-2009.

OBJECTIVE: To investigate the completeness of TNM (Tumor-Node-Metastasis) staging for prostate cancer (PC) in the Danish Cancer Registry (DCR). METHODS: We identified 20,184 men registered with first-time PC in the DCR between 2004 and 2009. These patients were linked to the Danish National Patient Register to obtain data on comorbidity according to the Charlson Comorbidity Index (CCI). We calculated the completeness and corresponding 95% confidence intervals (CI) of TNM staging overall and by the individual components. We also defined a clinically-based algorithm classifying PC into four stage categories: localized, regional, distant, and unknown. RESULTS: The overall completeness of TNM staging was 34.2% (95% CI: 0.34-0.35). TNM completeness improved gradually over time reaching 41.2% in 2009. TNM completeness decreased substantially with age from 75.0% among patients 0-39 years to 11.3% among patients 80 years or older. Similarly, completeness decreased with increasing comorbidity level from 37.6% among patients with low CCI to 20.3% among those with high CCI. When classifying T1 cancer as a complete registration regardless of missing N or M stage, the overall TNM completeness increased to 48.7% (95% CI: 0.48-0.49). According to the clinically-based staging algorithm, 70.5% of PC cases could be categorized into a definite clinical stage. CONCLUSION: One-third of PC patients had a complete registration of all TNM components in the DCR. Although TNM completeness improved over time, older age and high comorbidity were consistently associated with missing TNM staging. Research and monitoring based on cancer registries such as the DCR should account for missing TNM staging. Failing to do so could otherwise lead to biased results of stage-specific analyses.

Completeness of bladder cancer staging in the Danish Cancer Registry, 2004-2009.

OBJECTIVE: To investigate the completeness of tumor, node, and metastasis (TNM) staging for invasive bladder cancer in the Danish Cancer Registry (DCR). METHODS: From the DCR, we retrieved data on TNM stage, year of diagnosis, sex, and age of all-incident invasive bladder cancer patients between 2004 and 2009. Data on comorbidity was obtained from the Danish National Patient Register. We estimated the completeness of TNM registration in the DCR overall and stratified the analysis by sex, age, year of cancer diagnosis, and Charlson comorbidity score. Through knowledge of pathophysiology and clinical coding practice, we designed a clinically based algorithm that allowed tumors with certain missing TNM-stage components to be placed in localized, regional, distant, and unknown categories. RESULTS: The overall completeness of TNM staging for bladder cancer was 44.1% (95% confidence interval [CI]: 42.7-45.5). Completeness decreased from 60.9% (95% CI: 40.6-78.6) in patients aged 0-39 years to 25.5% (95% CI: 23.2-27.9) in patients aged 80 years or older. Among patients with a low level of comorbidity, completeness was 48.4% (95% CI: 46.6-50.3), decreasing to 34.0% (95% CI: 30.4-37.8) among those with a high level of comorbidity. The highest proportion of missing TNM data was found for registration of lymph node metastases. Defining T1 cancer as completely registered, regardless of missing N and M stage, increased TNM-registration completeness to 61.8%. When we applied a clinically based algorithm, only 29.6% of tumors had an unknown stage. CONCLUSION: The overall completeness of TNM staging for bladder cancer in the DCR was low, especially with increasing age and high level of comorbidity. Thus, restricting analyses to bladder cancer patients with complete data on stage may produce substantially selected study populations. Careful considerations should thus be made on handling missing data.

Long-term efficacy and safety of alfuzosin 10 mg once daily: a 2-year experience in 'real-life' practice.

OBJECTIVE: To assess the 2-year efficacy and safety of alfuzosin 10 mg once daily, a selective alpha(1)-adrenoceptor antagonist, in men complaining of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH), in 'real life' practice. PATIENTS AND METHODS: In all, 839 European men with LUTS (mean age 67.3 years) were enrolled by general practitioners in a 2-year open-label study with alfuzosin 10 mg once daily. They were asked to complete the International Prostate Symptom Score (IPSS), its appended eighth question (bother score), and the five domains (sexual drive, erection, ejaculation, problem assessment, and overall satisfaction) of the Brief Male Sexual Function Inventory (BSFI). The results were analysed at the endpoint in the intent-to-treat population. RESULTS: At the endpoint the total IPSS improved by 7 points (-38.5%) from baseline (P < 0.001) with 76.9% and 49.7% of men having an improvement of > or = 3 points and >6 points, respectively. There were also significant improvements in nocturia (-0.9, -30%; P < 0.001) and bother score (-1.8, -43%; P < 0.001) from baseline. Most patients (56%) perceived symptom relief within the first 2 weeks of treatment. All BSFI domains significantly improved from baseline (P < 0.05; <0.001 for overall satisfaction) and these improvements were more marked in men with severe LUTS at baseline. Alfuzosin 10 mg was well tolerated; the most common adverse event related to vasodilatation was dizziness/postural dizziness (3.1%). Ejaculatory disorders were uncommon (0.3%). Changes in blood pressure remained marginal, including in elderly men and those receiving antihypertensive agents. CONCLUSIONS: Alfuzosin 10 mg administered for 2 years in real practice is effective in improving LUTS and quality of life, and is well tolerated from a cardiovascular perspective, including in elderly men and those receiving antihypertensive co-medication. Ejaculatory disorders are uncommon. Alfuzosin may even slightly improve various domains of sexual function, such as sexual drive, erection, ejaculation and satisfaction with sexual life.

Alfuzosin 10 mg once daily improves sexual function in men with lower urinary tract symptoms and concomitant sexual dysfunction.

OBJECTIVE: To assess the effect on sexual function of alfuzosin 10 mg once daily, a uroselective alpha(1)-blocker, in men with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction. PATIENTS AND METHODS: In all, 3076 men (mean age 65.9 years) were treated for 1 year with alfuzosin 10 mg in 'real life' practice. They were asked to complete the International Prostatic Symptom Score (IPSS), its appended eighth question (bother score) and the Danish Prostatic Symptom Score questionnaire for sexual dysfunction (DAN-PSSsex). The results were analysed at the endpoint in the intent-to-treat population. RESULTS: At baseline, 2434 (79.1%) men were sexually active and answered correctly at least one item of the DAN-PSSsex. Sexual dysfunction was highly prevalent (reduced stiffness of erection, 65.3%; reduced volume of ejaculate, 63.2%; pain/discomfort on ejaculation, 20.2%), and was strongly related to the severity of LUTS and impairment of quality of life. At the endpoint, alfuzosin significantly improved the total IPSS (-6.1, - 32%) and bother score (-1.4, - 33.2%, both P < 0.001) over baseline. In those men with sexual dysfunction there were significant improvements in weighted scores related to reduced rigidity of erection (-0.5), reduced amount of ejaculate (-0.4) and pain/discomfort on ejaculation (-1.2, all P < 0.001) over baseline. The perceived improvements were more marked in men with severe LUTS or a severe bother score at baseline. CONCLUSIONS: Sexual dysfunction is highly prevalent in men with LUTS and related to the baseline IPSS and bother score. Alfuzosin 10 mg once daily for 1 year is effective in improving LUTS and quality of life, and is well tolerated. It may even improve sexual function in those men with concomitant erectile and/or ejaculatory dysfunction.

Symptom deterioration during treatment and history of AUR are the strongest predictors for AUR and BPH-related surgery in men with LUTS treated with alfuzosin 10 mg once daily.

OBJECTIVES: To assess the predictors of acute urinary retention (AUR) and/or surgery related to benign prostatic hyperplasia (BPH) in 3514 men complaining of lower urinary tract symptoms and treated for 6 months with the selective alpha1-blocker alfuzosin at 10 mg once daily. METHODS: The impact of baseline (age, prior AUR, prostate-specific antigen tertiles, lower urinary tract symptoms severity, and bother score) and dynamic (International Prostate Symptom Score [IPSS] worsening of 4 points or greater and bother greater than 3 during treatment) variables on the risk of AUR/BPH-related surgery was assessed using Kaplan-Meier curves and log-rank tests. Associated hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. RESULTS: Of the 3514 men analyzed, 140 (4%) experienced a first episode of conservatively managed AUR before inclusion. Of those 140 men, 5 (3.6%) had AUR relapse during alfuzosin treatment and 6 (4.3%) underwent BPH-related surgery. Of those 3374 men without prior AUR, 19 (0.6%) experienced AUR during treatment and 41 (1.2%) underwent BPH-related surgery. During treatment, the most important predictors of AUR were prior AUR (HR 6.35, 95% CI 2.31 to 17.40; P < 0.01), IPSS worsening of 4 or greater (HR 3.34, 95% CI 1.11 to 9.99; P = 0.03), and bother score greater than 3 (HR 3.32, 95% CI 1.29 to 8.53; P < 0.01) at endpoint. Other variables (age, PSA, baseline IPSS, and bother) had much less predictive value. Similar results were observed regarding the risk of AUR and/or BPH-related surgery. CONCLUSIONS: The results of this 6-month real life practice study suggest that prior AUR and symptom deterioration during treatment with alfuzosin 10 mg once-daily (IPSS worsening of 4 or more points, bother score greater than 3) were the strongest predictors of AUR and AUR/BPH-related surgery in men with lower urinary tract symptoms.

Sexual dysfunction in 1,274 European men suffering from lower urinary tract symptoms.

PURPOSE: We determine the prevalence and bothersomeness of erectile and ejaculatory dysfunction in men with lower urinary tract symptoms suggestive of bladder outlet obstruction in real life practice, and analyze predictors of sexual dysfunction in this population. MATERIALS AND METHODS: Sexual function of 1,274 European men with lower urinary tract symptoms was assessed by the DAN-PSSsex questionnaire. The relationship between sexual dysfunction and selected clinical characteristics was analyzed. RESULTS: The proportion of sexually active men decreased from 91% in those 60 years old or younger to 60% in those 70 years old or older. Erectile dysfunction, reduced ejaculation and pain/discomfort on ejaculation were reported by 62%, 63% and 23% of patients, respectively. Erectile dysfunction strongly related with age (40% younger than 60 years, 80% 70 years old or older), lower urinary tract symptom severity (55% mild, 70% severe) and body mass index, hypertension and concomitant treatment with calcium channel antagonists. Reduced ejaculation was significantly related to age (42% younger than 60 years, 82% 70 years old or older), lower urinary tract symptom severity (55% mild, 68% severe) and previous benign prostatic hyperplasia surgery. Pain/discomfort on ejaculation was only related to lower urinary tract symptom severity (7% mild, 31% severe). Erectile dysfunction, reduced ejaculation and pain/discomfort on ejaculation were considered a problem by 96%, 82% and 91% of patients younger than 60 years, respectively. These 3 sexual symptoms were still highly bothersome in patients 70 years old or older. CONCLUSIONS: Erectile dysfunction and reduced ejaculation are highly prevalent in men with lower urinary tract symptoms, and are strongly related to increasing age and lower urinary tract symptom severity. Both these aspects of sexual dysfunction are also highly bothersome, even in advanced age. Sexual function should be carefully assessed in the initial evaluation of patients with lower urinary tract symptoms and in deciding on treatment options, as it may have a negative impact on sex life.