Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

Indication for Active Surveillance in the Era of MRI-Targeted Prostate Biopsies.

INTRODUCTION: Active surveillance (AS) strategies were established to avoid overtreatment of low-risk prostate cancer (PCa) patients. Low tumor volume represents one indication criteria; however, applying this criterion after MRI-targeted prostate biopsies may lead to overestimation of tumor volume; wherefore, patients suitable for AS would be exposed to the risk of overtreatment. METHODS: This retrospective analysis included 318 patients in which PCa was detected by MRI-TRUS fusion prostate biopsy. Classic and extended indication for AS included Gleason 6 and Gleason 3 + 4 cancer, respectively. We assessed the effect of targeted biopsies and temporary rating strategies on eligibility for AS and developed new "composite" algorithms to more accurately assess eligibility for AS. RESULTS: Forty-four (13.8%) and 60 (18.9%) of the 318 patients qualified for AS according to "classic" and "extended" criteria, respectively. Application of the "composite 1" definition led to AS eligibility of 52 of 248 patients (20.97%) in the classic and of 77 of 248 patients (31.05%) in the "extended" group. CONCLUSIONS: We could demonstrate that classic algorithms led to ineligibility of patients for AS. We propose a new rating algorithm to improve tumor assessment for a more accurate indication for AS.

Influence of regular aspirin intake on PSA values, prostate cancer incidence and overall survival in a prospective screening trial (ERSPC Aarau).

OBJECTIVES: To analyze the influence of aspirin (ASA) intake on PSA values and prostate cancer (PCa) development in a prospective screening study cohort. METHODS: 4314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were included. A transrectal prostate biopsy was performed in men with a PSA level ≥ 3 ng/ml. Mortality data were obtained through registry linkages. PCa incidence and grade, total PSA, free-to-total PSA and overall survival were compared between ASA users and non-users. RESULTS: Median follow-up time was 9.6 years. In 789 men (18.3%) using aspirin [ASA +], the overall PCa incidence was significantly lower (6.8% vs. 9.6%, p = 0.015), but the multivariate Cox regression analysis showed no significant decrease in risk of PCa diagnosis (HR 0.84, p = 0.297). Total PSA values were significantly lower in ASA users for both baseline (1.6 vs. 1.8 ng/ml, p = 0.007) and follow-up visits (1.75 vs. 2.1 ng/ml, p < 0.001). Multivariate Cox regression analysis predicted significantly higher overall mortality risk among ASA users (HR 1.46, p = 0.009). CONCLUSIONS: In our study population, PCa incidence was significantly reduced among patients on aspirin. While we did not observe a statistically significant PCa risk reduction during the follow-up period, we found lower PSA values among ASA users compared to non-users, with a more distinct difference after 4 years of ASA intake, suggesting a cumulative effect and a potential protective association between regular ASA intake and PCa development. As for clinical practice, lowering PSA cutoff values by 0.4 ng/ml could be considered in long-term ASA users to avoid a potential bias towards delayed PCa detection.

Could Differences in Treatment Between Trial Arms Explain the Reduction in Prostate Cancer Mortality in the European Randomized Study of Screening for Prostate Cancer?

BACKGROUND: Differential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). OBJECTIVE: To quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA). DESIGN, SETTING, AND PARTICIPANTS: A total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55-69yr) at 16yr of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths. RESULTS AND LIMITATIONS: The difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from -3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] -0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar-0.01% (95% CI -0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available. CONCLUSIONS: Use of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms. PATIENT SUMMARY: This study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. OBJECTIVE: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. DESIGN, SETTING, AND PARTICIPANTS: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. RESULTS AND LIMITATIONS: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently. CONCLUSIONS: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level. PATIENT SUMMARY: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.

Summary statement on screening for prostate cancer in Europe.

The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55-59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer.

Background: There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa). Methods: We surveyed the Kallikrein ( KLK ) region ( KLK 1-15) for single-nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason Score ≥ 8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n = 379; Toronto, Canada, n = 540) and a validation cohort (Prostate, Lung, Colorectal and Ovarian [PLCO] screening trial, n = 939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort, whereas PLCO data were provided through database of Genotypes and Phenotypes ( dbGaP ). The influence of SNPs of interest on biochemical-free survival was evaluated in a cohort of localized PCa from the International Cancer Genome Consortium (ICGC; n = 130) analyzed with next-generation sequencing. Single- and multi-SNP association studies, as well as haplotype analyses, were performed. All statistical tests were two-sided. Results: Several SNPs in very strong linkage disequilibrium in the KLK 6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (odds ratio [OR] = 3.51-3.64, 95% confidence interval [CI] = 2.01 to 6.36, P = 1.0x10 -5 -8.4x10 -6 ) and validation (OR = 1.89-1.96, 95% CI = 0.99 to 3.71, P = .04-.05) cohorts. The overall test of haplotype association was highly statistically significant in each cohort ( P = 3.5x10 -4 and .006, respectively) and in the three data sets combined ( P = 2.3x10 -5 ). These germline SNPs independently predicted relapse in the ICGC cohort (hazard ratio = 3.15, 95% CI = 1.57 to 6.34, P = .001). Conclusions: Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa.

A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau).

OBJECTIVE: To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate-specific antigen (PSA) screening in a population-based study. SUBJECTS AND METHODS: The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first-degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan-Meier and Cox regression analyses were used. RESULTS: Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6-65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow-up duration was 11.6 (10.3-13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) [odds ratio 1.6, 95% confidence interval (CI) 1.2-2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio [HR] 1.04, 95% CI 1.02-1.06), baseline PSA level (HR 1.13, 95% CI 1.12-1.14), and FH (HR 1.6, 95% CI 1.24-2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12-1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in-between the screening rounds was not significantly different. CONCLUSION: Irrespective of the FH status, the current PSA-based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4-year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low-grade but not aggressive prostate cancer.

Is further screening of men with baseline PSA < 1 ng ml(-1) worthwhile? The discussion continues-Results of the Swiss ERSPC (Aarau).

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA <1.0 ng ml(-1) in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA <1.0 ng ml(-1) were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow-up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml(-1) (upper baseline PSA quartile). The 10-year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA < 0.40 ng ml(-1) ) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml(-1) ), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml(-1) ) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml(-1) ) (all p values <0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8-year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA < 0.40 ng ml(-1) ), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml(-1) ), 100 (baseline PSA 0.56 ≤ 0.75 ng ml(-1) ) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml(-1) ), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA < 0.4 ng ml(-1) . Between 0.4 and 1.0 ng ml(-1) , an 8-year interval can be discussed.

Differences among men on active surveillance for very low-risk prostate cancer detected through population-based versus opportunistic prostate-specific antigen-screening.

INTRODUCTION: Very low-risk prostate cancer (PCa) is being increasingly managed by active surveillance (AS). Our aim was to assess the influence of the origin of diagnosis on PCa characteristics and treatment rates among men with very low-risk PCa in our prospective AS cohort. METHODS: Overall, 191 men with very low-risk PCa fulfilling Epstein-criteria underwent protocol-based AS. These men originated either from the prospective population-based screening program (P-AS) or were diagnosed by opportunistic screening (O-AS). RESULTS: Overall, n = 86 (45.0%) originated from the P-AS group, whereas n = 105 (55.0%) from the O-AS group. On univariate Cox regression analysis, age (HR 0.96, 95% CI 0.92-1.00; p = 0.05), origin of diagnosis (HR 0.72, 95% CI 0.41-1.28; p = 0.001), number of positive cores (HR 2.15, 95% CI 1.18-3.90; p = 0.01) and maximum core involvement (HR 1.03, 95% CI 0.99-1.05; p = 0.05) were predictors for treatment necessity. On multivariate analysis, age (HR 0.95, 95% CI 0.89-0.99; p = 0.05), number of positive cores (HR 2.07, 95% CI 1.10-3.88; p = 0.02), maximum core involvement (HR 1.03, 95% CI 1.00-1.06; p = 0.04) but not origin of diagnosis were independent predictors for treatment necessity. Four men developed biochemical recurrence (all from O-AS group [p = 0.05]). CONCLUSION: The origin of PCa diagnosis in men undergoing AS had no influence on disease progression and treatment necessity.

Influence of metformin use on PSA values, free-to-total PSA, prostate cancer incidence and grade and overall survival in a prospective screening trial (ERSPC Aarau).

PURPOSE: To analyze the effect of the oral antidiabetic drug metformin on PSA level, free-to-total PSA ratio (f/t-ratio), PCa incidence and grade as well as mortality in men participating in a population-based screening trial. METHODS: Data from 4,314 men aged 55-70 years from a population-based PSA-screening trial (ERSPC Aarau) were analyzed. Information on metformin exposure was obtained by a self-administered questionnaire. Serum PSA threshold at ≥3 ng/ml triggered prostate biopsy. Data on PCa incidence and mortality were obtained through registry linkages. RESULTS: Median follow-up time was 7.6 years. Mean age at baseline was 65.5 years (±SD 4.4). In all, n = 150 (3.5 %) men used metformin [metf+]. Mean baseline PSA levels were comparable between both groups ([metf+] 1.6 ng/ml ± 2.4 vs. [metf-] 1.8ug/l ± 2.2, p = 0.4) while f/t-ratio was slightly higher in metformin users ([metf+] 30.7 % ± 10.9 vs. [metf-] 27.3 % ± 10.9, p = 0.01). Overall, n = 372 (8.6 %) PCa cases were detected. Neither cumulative PCa incidence (n = 11; 7.3 % [metf+] vs. n = 361 8.7 % [metf-]; p = 0.5) nor d`Amico risk groups were significantly different between both groups. One man in each group (metf+ 0.7 % and metf- 0.02 %) died from PCa (p < 0.0001), respectively. All-cause mortality was significantly higher among met + compared to met- (adjusted OR 2.50, 95 %CI 1.59-3.82; p = 0.0001). CONCLUSION: No significant differences in PSA levels or PCa incidence and grade were observed. The slightly higher f/t-ratio did not result in lower PCa detection rate. Metformin users were at significantly higher risk of all-cause mortality. The relatively small number of men on metformin is a main limitation of the study.

A "PSA pyramid" for men with initial prostate-specific antigen ≤3 ng/ml: a plea for individualized prostate cancer screening.

BACKGROUND: In daily routine business, various prostate-specific antigen (PSA) retest strategies are being promoted. OBJECTIVE: To investigate rescreening intervals according to baseline PSA <3 ng/ml stratified by any and aggressive prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: From 1998 to 2012, data from 4350 men aged 55-70 yr were analyzed from a population-based prospective screening study (median follow-up: 11.6 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was detection of aggressive PCa (Gleason score 7-10). Cox regression analysis was used to examine the relationship between covariates. RESULTS AND LIMITATIONS: Baseline PSA of <1.0 ng/ml, 1-1.9 ng/ml, and 2-2.9 ng/ml was present in 2416 men (55.5%: group 1), 1371 men (31.6%: group 2), and 563 men (12.9%: group 3), respectively. Stratified according to these PSA groups, aggressive PCa was detected in 25 patients (1.0%), 80 patients (5.8%), and 34 patients (6.0%), respectively. During 4 yr, these numbers were 0.0%, 0.29%, and 1.8%, whereas during 8 yr, the numbers were 0.2%, 1.4%, and 2.5%, respectively. In multivariable Cox regression analysis, the only independent risk factor for aggressive PCa was baseline PSA (hazard ratio [HR]: 6.06; 95% confidence interval [CI], 3.82-9.61; p<0.0001, group 2 vs group 1; and HR: 7.33; 95% CI, 4.29-12.52; p<0.0001, group 3 vs group 1). CONCLUSIONS: Baseline PSA was the only predictor regarding aggressive PCa. According to the low rate of potentially missed PCa in these groups, rescreening intervals can be safely adapted to baseline PSA values corresponding to a "PSA pyramid": 6-8 yr if baseline PSA is <1.0 ng/ml, 3-4 yr if baseline PSA is 1-1.99 ng/ml, and yearly if baseline PSA is 2-2.99 ng/ml. PATIENT SUMMARY: We observed men with a prostate-specific antigen (PSA) value ≤3 ng/ml during 12 yr and found that men can be retested according to their initial PSA value ("PSA pyramid"): PSA <1 (base), retest interval every 8 yr; PSA 1-2 (center), retest interval every 4 yr; and PSA 2-3 (top), retest yearly after risk stratification.

Prostate cancer screening: and yet it moves!

The debate of prostate cancer (PCa) screening has been shaped over decades. There is a plethora of articles in the literature supporting as well as declining prostate-specific antigen (PSA) screening. Does screening decrease PCa mortality? With the long-term results of the European Randomized Study of Screening for Prostate (ERSPC) the answer is clearly YES. It moves! However, in medicine there are no benefits without any harm and thus, screening has to be performed in targeted and smart way-or in other words-in a risk-adapted fashion when compared with the way it was done in the past. Here, we discuss the main findings of the ERSPC trials and provide insights on how the future screening strategies should be implemented.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

A comparative assessment of active surveillance for localized prostate cancer in the community versus tertiary care referral center.

OBJECTIVES: To date, evidence on active surveillance (AS) is restricted to protocol-based studies. Conversely, practice patterns outside of such protocols are unknown. The aim of this study was to capture the current AS treatment patterns for localized prostate cancer in patients managed by office-based urologists compared to patients treated at a tertiary care center. METHODS AND MATERIALS: Two prospective cohorts were investigated: 361 AS arm patients of the German Hormonal treatment, Active surveillance, Radiation therapy, OP, Watchful waiting (HAROW) study, an observational health service study and 387 protocol-based AS patients treated at the Department of Urology of the Kantonsspital Aarau, Switzerland were included. Observational non-protocol HAROW versus on-protocol Kantonsspital Aarau (KSA) was compared, and active-treatment-free survival represented the primary outcome. RESULTS: Study population of the observational HAROW versus tertiary care protocol-based KSA cohorts differed statistically significantly regarding age (p < 0.001) and proportion of patients meeting the Chism criteria (p < 0.001). In stratified analyses, AFTS at 1 and 2 years was, respectively, 87.7 % (95 % CI 84.0-91.7) and 75.0 % (95 % CI 69.7-80.8) in HAROW patients compared to 90.8 % (95 % CI 87.8-93.9) and 75.3 % (95 % CI 70.7-80.1) for patients in the KSA cohort (p = 0.97). CONCLUSION: We demonstrate significant differences in terms of AS inclusion, surveillance and discontinuation criteria between patients managed by office-based urologists compared to their tertiary care counterparts. Interestingly, the risk of deferred active therapy was equally moderate for both groups in the short-term follow-up.

Bacillus Calmette-Guérin failure in patients with non-muscle-invasive urothelial carcinoma of the bladder may be due to the urologist's failure to detect urothelial carcinoma of the upper urinary tract and urethra.

BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.

Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer.

DNA methylation plays an important role in carcinogenesis and is being recognized as a promising diagnostic and prognostic biomarker for a variety of malignancies including Prostate cancer (PCa). The human kallikrein-related peptidases (KLKs) have emerged as an important family of cancer biomarkers, with KLK3, encoding for Prostate Specific Antigen, being most recognized. However, few studies have examined the epigenetic regulation of KLKs and its implications to PCa. To assess the biological effect of DNA methylation on KLK6 and KLK10 expression, we treated PC3 and 22RV1 PCa cells with a demethylating drug, 5-aza-2'deoxycytidine, and observed increased expression of both KLKs, establishing that DNA methylation plays a role in regulating gene expression. Subsequently, we have quantified KLK6 and KLK10 DNA methylation levels in two independent cohorts of PCa patients operated by radical prostatectomy between 2007-2011 (Cohort I, n = 150) and 1998-2001 (Cohort II, n = 124). In Cohort I, DNA methylation levels of both KLKs were significantly higher in cancerous tissue vs. normal. Further, we evaluated the relationship between DNA methylation and clinicopathological parameters. KLK6 DNA methylation was significantly associated with pathological stage only in Cohort I while KLK10 DNA methylation was significantly associated with pathological stage in both cohorts. In Cohort II, low KLK10 DNA methylation was associated with biochemical recurrence in univariate and multivariate analyses. A similar trend for KLK6 DNA methylation was observed. The results suggest that KLK6 and KLK10 DNA methylation distinguishes organ confined from locally invasive PCa and may have prognostic value.

Protocol-based active surveillance for low-risk prostate cancer: anxiety levels in both men and their partners.

OBJECTIVE: To assess anxiety levels and health-related quality of life in partners of patients with prostate cancer (PCa) on active surveillance. METHODS: For low-risk PCa, active surveillance is frequently chosen as a monitoring strategy. Active surveillance has been shown to be associated with low anxiety levels and a fair health-related quality of life in patients. However, little is known about the impact on their partners. We hypothesized that the latter suffer more from PCa diagnosis than the men themselves. Therefore, between February and August 2010, 133 couples-a response rate of 46.9%-completed a written questionnaire at their individual time lags from PCa diagnosis. A Wilcoxon test was performed to assess how distress levels affected the couples' quality of life. Binary logistic regression was used to determine factors affecting distress levels. RESULTS: The mean age was 66.2 years in partners and 69.3 in men. At the time quartiles, partners had anxiety scores of 5.5, 4.6, 5.4, and 5.6. Scores in men were statistically significantly lower: 3.9 (P = .05), 2.0 (P < .001), 3.3 (P = .002), and 3.3 (P = .02), respectively. However, the partners' scores were still well below 7 (ie, normal). Prostate-specific anxiety scores were below the clinical threshold as well: 15.5, 9.5, 6.5, and 9.0, respectively. CONCLUSION: Active surveillance preserves an encouragingly high health-related quality of life in both men on active surveillance and their partners. Fortunately, the more adverse values of the partners are well within the normal range and thus clinically not relevant.

Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC).

BACKGROUND: Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. OBJECTIVE: To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. DESIGN, SETTING, AND PARTICIPANTS: Data were available for 76,813 men aged 55-69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. INTERVENTION: Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. RESULTS AND LIMITATIONS: After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p<0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p=0.001) in the intention-to-screen analysis and a 42% (p=0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. CONCLUSIONS: PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

Prostate-cancer mortality at 11 years of follow-up.

BACKGROUND: Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS: The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS: After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS: Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).