Results at 1 Year from SATURN, A European, Prospective, Multicenter Registry for Male Stress Urinary Incontinence Surgery.

BACKGROUND AND OBJECTIVE: The European, prospective, multicenter SATURN registry was developed to analyze surgical devices for male stress urinary incontinence. The primary objective is the cure rate during follow-up. METHODS: Efficacy, complications, patient-reported outcomes, and prognostic factors are being analyzed at various intervals during 10-yr follow-up. The results at 1-yr follow-up are presented here. KEY FINDINGS AND LIMITATIONS: The cohort included 1046 patients (mean age 70 yr) from 28 centers in nine countries. The main cause of incontinence was radical prostatectomy (83.5%), followed by radiotherapy (4.5%), endourological procedures (9.7%), neurogenic conditions (1.0%), and trauma (0.2%). Some 19.5% of the patients underwent at least one incontinence procedure before registry inclusion. A baseline pad test was performed in 64% of the patients (mean 525 g, range 3.5-3600), urodynamics in 66%, and cystoscopy in 80%. The main implants used were AMS800 (n = 684) and Advance (n = 210) devices, followed by Atoms (n = 63) Victo/Plus (n = 33), ProACT (n = 30), and others (n = 24). A total of 896 patients had 1-yr follow-up data, of whom 164 completed a 1-yr pad test. Self-reported complete incontinence rates at baseline by device were as follows: Advance, 17%; other slings, 33%; ProACT, 0%; AMS800, 49%; other sphincter prosthesis, 100%; and overall group, 44%. The corresponding 1-yr self-reported continence rates were 73%, 37%, 50%, 76%, 11%, and 68%. Some 32% of the patients were still incontinent. Overall, 132 patients had at least one revision. Among the 110 patients with an artificial urinary sphincter (AUS), 122 revisions were performed, while there were 29 revisions for the 22 patients with a sling or ProACT device. International Consultation on Incontinence Questionnaire Short Form and EuroQol 5-dimensions 5-levels scores improved with all devices. CONCLUSIONS AND CLINICAL IMPLICATIONS: AUS implants are used in cases with more severe incontinence and are associated with better outcomes but more revisions than the alternatives. Patients report that every improvement is important. Choices for procedures should be made on the basis of these considerations. PATIENT SUMMARY: We collected data from 29 urology departments in Europe on surgical treatments for patients who suffer from incontinence during exercise, sneezing, and coughing. Results after 1 year show that an artificial urinary sphincter has the best outcomes overall and for patients with heavy urine loss. However, this surgery also requires more revisions. Patients report that every improvement in continence is important to them.

SATURN: A European, Prospective, Multicentre Registry for Male Stress Urinary Incontinence Surgery.

Surgery for male incontinence with artificial urinary sphincters and slings (SATURN) is a prospective, multicentre registry (observational cohort) for male stress urinary incontinence surgery to collect prospective data from multiple European centres and surgeons, to evaluate the short- and long-term success and the impact on quality of life.

Quality of Life in Patients with High-grade Non-muscle-invasive Bladder Cancer Undergoing Standard Versus Reduced Frequency of Bacillus Calmette-Guérin Instillations: The EAU-RF NIMBUS Trial.

Background: Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. Objective: To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. Design setting and participants: A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n = 182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n = 177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. Outcome measurements and statistical analysis: Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. Results and limitations: There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. Conclusions: Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. Patient summary: In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

Incidence of Nocturia in Men with Lower Urinary Tract Symptoms Associated with Benign Prostatic Enlargement and Outcomes After Medical Treatment: Results from the Evolution European Association of Urology Research Foundation Prospective Multinational Registry.

BACKGROUND: Nocturia is one of the most prevalent and bothersome lower urinary tract symptoms (LUTS) in men, leading to increased morbidity and mortality and a considerable economic burden on healthcare systems. Understanding its natural history, effect of pharmacotherapy, and predictors of failure of pharmacotherapy would allow optimised patient management. OBJECTIVE: To evaluate the prevalence and effect of clinically relevant nocturia (crN) on quality of life in a contemporary cohort of European men aged ≥50 yr in a "real-life" setting, to understand its natural history, to detect any effect of pharmacotherapy, and to identify predictors of pharmacotherapy failure. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the data from the Evolution Registry-a European, multicentre, prospective, observational registry, conducted in five European countries within a sample of general practitioners' and urologists' clinics. A consecutive sample of 2175 men aged ≥50 yr with LUTS in association with benign prostatic enlargement was enrolled between February 2010 and April 2011, and followed up for 2yr. Overall, data from 1838 men were suitable for analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was evaluation of the baseline incidence of nocturia in the study population. Secondary outcomes included the impact of nocturia on quality of life, efficacy of pharmacotherapy, and predictive factors associated with persistence of nocturia. Descriptive statistics were used to examine the data. Logistic regressions were used to analyse associations between comorbid conditions and risk factors in men with nocturia. RESULTS AND LIMITATIONS: Overall, 1198 men (65%) reported crN (two or more voids per night). This increased age dependently from 59% in the 50-59-yr age group (n=74) to 89% in the 80-99-yr age group (n=25). Overall, the incidence of crN improved in those who commenced pharmacological treatment at study entry, from 69% at baseline to 49% at 24 mo (p<0.00001). This was statistically significant only in those <80 yr old. A weak correlation was found between the severity of nocturia at baseline and quality-of-life scores on the International Prostate Symptom Score questionnaire (r=0.33, p<0.001). Of the patients treated with an alpha-blocker or a 5-alpha reductase inhibitor, 62% still had crN at 24 mo. CONCLUSIONS: Almost two-thirds of men in the Evolution Registry reported clinically significant nocturia with increased incidence with age. Despite prostate-targeted treatment, most patients, especially older men, still had persistent or worsening nocturia at 2-yr follow-up, and in this study, it was not possible to identify specific clinical factors that predicted those who could respond well to treatment in this regard. PATIENT SUMMARY: This large study of men from five different European countries has shown that waking up at night to pass urine (nocturia) is very common and becomes more common with older age, and treatments that target the prostate do not significantly improve symptoms over 2yr in most men.

Automated Bone Scan Index as an Imaging Biomarker to Predict Overall Survival in the Zometa European Study/SPCG11.

BACKGROUND: Owing to the large variation in treatment response among patients with high-risk prostate cancer, it would be of value to use objective tools to monitor the status of bone metastases during clinical trials. Automated Bone Scan Index (aBSI) based on artificial intelligence has been proposed as an imaging biomarker for the quantification of skeletal metastases from bone scintigraphy. OBJECTIVE: To investigate how an increase in aBSI during treatment may predict clinical outcome in a randomised controlled clinical trial including patients with high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively selected all patients from the Zometa European Study (ZEUS)/SPCG11 study with image data of sufficient quality to allow for aBSI assessment at baseline and at 48-mo follow-up. Data on aBSI were obtained using EXINIboneBSI software, blinded for clinical data and randomisation of zoledronic acid treatment. Data on age, overall survival (OS), and prostate-specific antigen (PSA) at baseline and upon follow-up were available from the study database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association between clinical parameters and aBSI increase during treatment was evaluated using Cox proportional-hazards regression models, Kaplan-Meier estimates, and log-rank test. Discrimination between prognostic variables was assessed using the concordance index (C-index). RESULTS AND LIMITATIONS: In this cohort, 176 patients with bone metastases and a change in aBSI from baseline to follow-up of ≤0.3 had a significantly longer median survival time than patients with an aBSI change of >0.3 (p<0.0001). The increase in aBSI was significantly associated with OS (p<0.01 and C-index=0.65), while age and PSA change were not. CONCLUSIONS: The aBSI used as an objective imaging biomarker predicted outcome in prostate cancer patients in the ZEUS/SPCG11 study. An analysis of the change in aBSI from baseline to 48-mo follow-up represents a valuable tool for prognostication and monitoring of prostate cancer patients with bone metastases. PATIENT SUMMARY: The increase in the burden of skeletal metastases, as measured by the automated Bone Scan Index (aBSI), during treatment was associated with overall survival in patients from the Zometa European Study/SPCG11 study. The aBSI may be a useful tool also in monitoring prostate cancer patients with newly developed bone metastases.

A European Registry Evaluating Symptomatic Effectiveness of Pharmacologically Treated Patients with Lower Urinary Tract Symptoms due to Benign Prostatic Enlargement: Lessons Learned.

PURPOSE: We evaluated unmet needs of lower urinary tract symptoms-benign prostatic enlargement pharmacological treatment by measuring symptom improvement, persistence and deterioration in real life. A prospective registry was conducted for 24 months in 5 European countries and analyzed by the European Association of Urology Research Foundation. MATERIALS AND METHODS: Previously untreated and treated patients were enrolled to the registry in both primary care and urology referral centers in France, Germany, Italy, Spain and the UK. RESULTS: Overall, 2,175 patients were enrolled with 1,838 analyzed, consisting of 575 previously untreated lower urinary tract symptoms-benign prostatic enlargement patients (no alpha blockers for at least 1 month or no 5-alpha reductase inhibitors for at least 6 months) and 1,263 previously treated patients. During the registry 90% of patients adhered to the prescribed regimen. After 24 months, 70% of previously untreated and 42% of previously treated patients experienced symptom improvement (International Prostate Symptom Score [IPSS] reduction of ≥3 points). Symptomatic patients (IPSS ≥8) remained in both groups (59% in previously untreated and 61% in previously treated), with greater symptom deterioration (IPSS increase ≥3 points) in 18.9% in previously treated vs 7.8% in previously untreated patients. Both clinical lower urinary tract symptoms-benign prostatic enlargement progression and surgery rates were similar in untreated vs treated groups at 16% vs 17% and 5% vs 7%, respectively, at 24 months. CONCLUSIONS: This prospective registry confirmed lower urinary tract symptoms-benign prostatic enlargement pharmacological treatment effectiveness in a real-world setting, with low clinical progression observed in about 1 in 6 patients and lower surgery rates below 1 in 20, by 24 months.

Treatment of High-grade Non-muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS".

BACKGROUND: Intravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to prevent recurrence of non-muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. OBJECTIVE: NIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. DESIGN, SETTING, AND PARTICIPANTS: A total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. INTERVENTION: The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. RESULTS AND LIMITATIONS: In total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. CONCLUSIONS: The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. PATIENT SUMMARY: After surgical removal of the tumour, patients with high-grade non-muscle-invasive bladder cancer are treated with bacillus Calmette-Guérin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today's perspective, complete tumour resection and a standard number of instillations remain the standard of care.

Adjuvant recMAGE-A3 Immunotherapy After Cystectomy for Muscle-invasive Bladder Cancer: Lessons Learned from the Phase 2 MAGNOLIA Clinical Trial.

The MAGNOLIA study, investigating the concept of perioperative immunotherapy in muscle- invasive bladder cancer, was prematurely terminated. The lessons learned that should be considered before initiating and conducting future clinical trials in this field are highlighted.

Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS).

BACKGROUND: Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo. OBJECTIVE: To investigate ZA for the prevention of BMs in high-risk localised PCa. DESIGN, SETTING, AND PARTICIPANTS: Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10. INTERVENTION: Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups. RESULTS AND LIMITATIONS: A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients. CONCLUSIONS: ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr. PATIENT SUMMARY: Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr. TRIAL REGISTRATION: The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762.

Comparison of expected treatment outcomes, obtained using risk models and international guidelines, with observed treatment outcomes in a Dutch cohort of patients with non-muscle-invasive bladder cancer treated with intravesical chemotherapy.

OBJECTIVE: To compare the risks according to the American Urological Association (AUA), EAU, European Organization for Research and Treatment of Cancer (EORTC) and Club Urológico Español de Tratamiento Oncologico (CUETO) classifications with real outcomes in a cohort of patients in the Netherlands, and to confirm that patients who were undertreated according to these risk models have worse outcomes than adequately treated patients. PATIENTS AND METHODS: Patients treated with complete transurethral resection of bladder tumour and intravesical chemotherapy were included. Not all patients would have received intravesical chemotherapy had they been treated to current standards, and thus comparison of the observed outcomes in our Dutch cohort vs expected outcomes based on the EORTC risk tables and CUETO scoring model was possible. The cohort was reclassified according to the definitions of five index patients (IPs), as defined by the AUA guidelines, and three risk groups, defined according to the EAU guidelines, to compare the outcomes of undertreated patients with those of adequately treated patients. RESULTS: A total of 1001 patients were available for comparison with the AUA definitions and 728 patients were available for comparison with the EORTC and CUETO models. There was a large overlap between the observed outcomes and expected recurrence and progression probabilities when comparison was made using the EORTC risk tables. The observed recurrence outcomes were in general higher than the expected probabilities according to the CUETO risk classification, especially in the long term. No differences in progression were found when comparing these two models to the Dutch cohort. Patients who were undertreated according to the guidelines showed, in general, a higher risk of developing recurrence and progression. Limitations are i.a. its retrospective nature and the differences in grading system. CONCLUSION: Comparisons between the observed outcomes in our Dutch cohort and the expected outcomes based on EAU and CUETO risk models and the EORTC and AUA guidelines showed that lack of adherence to existing guidelines translates into worse outcomes.

Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial.

PURPOSE: Despite current treatment after transurethral resection of a bladder tumor, recurrences and progression remain a problem. Keyhole limpet hemocyanin (KLH) was beneficial in earlier studies. In this study, safety and efficacy of KLH were compared with that of mitomycin (MM). PATIENTS AND METHODS: Patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ were enrolled in a randomized phase III trial. In all, 283 patients were randomly assigned for 16 adjuvant intravesical instillations with KLH after preimmunization, and 270 patients were randomly assigned for 11 adjuvant intravesical instillations with MM. Primary outcome measurement was recurrence-free survival (RFS). Secondary outcome measurements were progression-free survival, adverse events (AEs), and the effect of delayed-type hypersensitivity (DTH) response on clinical outcome. RESULTS: There were significantly more pT1 tumors in the MM group (P = .01). In a log-rank test, univariate and multivariate Cox regression analysis, KLH was less effective than MM regarding RFS (all P < .001). Progression was uncommon (n = 20). In univariate Cox regression analyses, KLH tended to prevent progression more effectively than MM, but in multivariate Cox regression analyses, this could not be shown. AEs were common but mild. Fever, flu-like symptoms, and fatigue occurred significantly more after KLH treatment. Allergic reactions and other skin disorders occurred significantly more after MM treatment. Significantly more DTH-positive patients developed a recurrence than DTH-negative patients. CONCLUSION: KLH had a different safety profile and was inferior to MM in preventing NMIBC recurrences. KLH tended to be more effective than MM in preventing progression. More research is needed to clarify the immunologic effects of KLH and the effects of KLH on progression.

Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer.

BACKGROUND: Cigarette smoking is the most well-established risk factor for developing bladder cancer. OBJECTIVE: To investigate the role of smoking status on the clinical outcome of patients with non-muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Data obtained during a prospective phase 3 study with three schedules of epirubicin were used for statistical analysis. Smoking status (obtained when entering the study), other prognostic variables, and clinical outcome measures of 718 patients were analyzed. Mean follow-up was 2.5 yr. MEASUREMENTS: The primary outcome measure was recurrence-free survival (RFS). RESULTS AND LIMITATIONS: Demographics were similar for nonsmokers versus ex-smokers and current smokers, except for gender (p<0.001) and grade (p=0.022). In univariate analyses, RFS was significantly shorter in male patients (p=0.020), in patients with a history of recurrences (p<0.003), in patients with multiple tumors (p<0.004), in patients with a history of intravesical therapy (p=0.037), and in ex-smokers and current smokers (p=0.005). In multivariate analyses, a history of recurrences, multiplicity, and smoking status remained significant factors for predicting RFS. Gender and initial therapy were no longer a significant influence on RFS. Because progression was uncommon (n=25) and follow-up was short and focused only on recurrences, no conclusion can be drawn on progression-free survival. A limitation of the study were the questionnaires. They were only used when entering the study, and there were no questions about passive smoking and other causal factors. CONCLUSIONS: In this prospective study, the significance of known factors (history of recurrences and number of tumors) in predicting RFS was confirmed. Another significant factor that appears to predict RFS is smoking status: ex-smokers and current smokers had a significantly shorter RFS compared with nonsmokers.

Comparison of three schedules of intravesical epirubicin in patients with non-muscle-invasive bladder cancer.

OBJECTIVES: To study the additive effect of either an early instillation or maintenance instillations of adjuvant intravesical epirubicin, as compared to the epirubicin "standard" treatment schedule only, in patients with non-muscle-invasive bladder cancer. METHODS: Patients with intermediate- and high-risk urothelial cell carcinoma of the bladder, except carcinoma in situ, were randomised for adjuvant intravesical instillations with 50mg epirubicin/50 ml NaCl for 1h. Group 1 received 4 weekly and 5 monthly instillations (standard schedule), group 2 received the same schedule as group 1, but with an additional instillation <48 h after transurethral resection of bladder tumour (TURBT), and group 3 received the same scheme as group 1, but with additional instillations at 9 and 12 mo (maintenance schedule). Standard follow-up was 5 yr and consisted of cystoscopy, cytology, and registration of adverse events. RESULTS: A total of 731 patients were eligible for quasi intention-to-treat analysis. Side-effects were minimal for all treatment groups. After 5-yr follow-up, respectively, 44.4%, 42.7%, and 45.0% (log-rank test, p=0.712) of the patients in groups 1, 2, and 3 were recurrence free, and 90.0%, 87.7%, and 88.2% (log-rank test, p=0.593) of the patients, respectively, were progression free. CONCLUSIONS: In the quasi intention-to-treat analysis there is no difference in the 5-yr recurrence-free period between the treatment groups, despite one instillation within 48 h of TURBT or two maintenance instillations up to 1 yr, in addition to the "standard" schedule.