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Background: Prostate cancer (PCa) (early) detection poses significant challenges, including unnecessary testing and the risk of potential overdiagnosis. The European Association of Urology therefore suggests an individual risk-adapted approach, incorporating risk calculators (RCs) into the PCa detection pathway. In the context of 'The PRostate Cancer Awareness and Initiative for Screening in the European Union' (PRAISE-U) project ( https://uroweb.org/praise-u ), we aim to provide an overview of the currently available clinical RCs applicable in an early PCa detection algorithm., Methods: We performed a systematic review to identify RCs predicting detection of clinically significant PCa at biopsy. A search was performed in the databases Medline ALL, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar for publications between January 2010 and July 2023. We retrieved relevant literature by using the terms "prostate cancer", "screening/diagnosis" and "predictive model". Inclusion criteria included systematic reviews, meta-analyses, and clinical trials. Exclusion criteria applied to studies involving pre-targeted high-risk populations, diagnosed PCa patients, or a sample sizes under 50 men., Results: We identified 6474 articles, of which 140 were included after screening abstracts and full texts. In total, we identified 96 unique RCs. Among these, 45 underwent external validation, with 28 validated in multiple cohorts. Of the externally validated RCs, 17 are based on clinical factors, 19 incorporate clinical factors along with MRI details, 4 were based on blood biomarkers alone or in combination with clinical factors, and 5 included urinary biomarkers. The median AUC of externally validated RCs ranged from 0.63 to 0.93., Conclusions: This systematic review offers an extensive analysis of currently available RCs, their variable utilization, and performance within validation cohorts. RCs have consistently demonstrated their capacity to mitigate the limitations associated with early detection and have been integrated into modern practice and screening trials. Nevertheless, the lack of external validation data raises concerns about numerous RCs, and it is crucial to factor in this omission when evaluating whether a specific RC is applicable to one's target population., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others., Materials and Methods: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease., Results: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden., Conclusion: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Previous research quantified the effect of prostate-specific antigen (PSA)-based prostate cancer (PCa) screening on quality-adjusted life years using 11-yr follow-up data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) extrapolated by the Microsimulation Screening Analysis (MISCAN). ERSPC data now matured to 21 yr of follow-up., Objective: To provide an overview of the effect of PSA-based screening on tumour characteristics and PCa treatment using long-term, detailed, empirical ERSPC data., Design, Setting, and Participants: Men were included from the ERSPC Rotterdam who were randomised to a PSA-based screening (S) or control (C) arm., Outcome Measurements and Statistical Analysis: We assessed the effects of PSA-based screening on the number of PCa diagnoses, tumour characteristics, treatments, and cumulative incidence of disease progression. We also evaluated the changes in tumour characteristics and treatments over time for both study arms., Results and Limitations: Among PCa patients in the S-arm, fewer patients were diagnosed with advanced tumour stages (T3/T4: 12% vs 23%; relative risk [RR] = 0.50; 95% confidence interval [CI] 0.44-0.57), less disease progression was observed, and less secondary treatment (30% vs 48%; RR = 0.61; 95% CI 0.57-0.66; p < 0.001) and less palliative treatment were needed (21% vs 55%; RR = 0.38; 95% CI 0.35-0.42) than among those in the C-arm. This was at the cost of overdiagnosis and increased local treatments (eg, radical prostatectomy: 32% vs 14%; RR = 2.18; 95% CI 1.92-2.48). Over time, the number of local treatments decreased, whereas expectant management strategies increased. The RRs of treatments were slightly different from those of the MISCAN., Conclusions: After 21 yr of follow-up, empirical data of the ERSPC showed that PSA-based screening reduces advanced PCa stages, disease progression, and extensive treatments at the cost of more overdiagnosis and probably more overtreatment. Our data showed reduced local treatments and increased expectant management strategies over time., Patient Summary: Prostate-specific antigen-based screening reduces the number of invasive prostate cancer treatments needed, however, at the cost of more overdiagnosis and probably more overtreatment. Limiting these costs remains crucial to benefit optimally from prostate cancer screening., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Population-based organised repeated screening for prostate cancer has been found to reduce disease-specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate-specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side-effects. The classic early detection protocols as were state-of-the-art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re-testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re-testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low-risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side-effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union-funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer-related death in European males, while minimising side-effects. Also, less efficacious opportunistic early detection may be indirectly reduced., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Trials of cancer screening present results in terms of deaths prevented, but metastasis is also a key endpoint that screening seeks to prevent. We developed a framework for projecting overall (de novo and progressive) metastases prevented in a screening trial using prostate cancer screening as a case study., Methods: Mechanistic simulation model in which screening shifts a fraction of cases that would be metastatic at diagnosis to being non-metastatic. This shift increases the incidence of non-overdiagnosed, organ-confined cases. We use estimates of the risk of metastatic progression for these cases to project how many progress to metastasis after diagnosis and tally the projected de novo and progressive metastatic cases with and without screening. We use data on stage shift from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and data on the risk of metastatic progression from the Scandinavian Prostate Cancer Group-4 trial. We estimate the relative risk and absolute risk reductions in metastatic disease at diagnosis and compare these with reductions in overall metastases., Results: Assuming no effect of screening beyond initial stage shift at diagnosis, the model projects a 43% reduction in metastasis at diagnosis but a 22% reduction in the cumulative probability of metastasis over 12 years in favor of screening. These results are consistent with the empirical findings from the ERSPC., Conclusion: Any reduction in metastatic disease at diagnosis under screening is likely to be an overly optimistic predictor of the impact of screening on overall metastasis and disease-specific mortality.

This study aimed to estimate the rates of biopsy undersampling and progression for four prostate cancer (PCa) active surveillance (AS) cohorts within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium. We used a hidden Markov model (HMM) to estimate factors that define PCa dynamics for men on AS including biopsy under-sampling and progression that are implied by longitudinal data in four large cohorts included in the GAP3 database. The HMM was subsequently used as the basis for a simulation model to evaluate the biopsy strategies previously proposed for each of these cohorts. For the four AS cohorts, the estimated annual progression rate was between 6%-13%. The estimated probability of a biopsy successfully sampling undiagnosed non-favorable risk cancer (biopsy sensitivity) was between 71% and 80%. In the simulation study of patients diagnosed with favorable risk cancer at age 50, the mean number of biopsies performed before age 75 was between 4.11 and 12.60, depending on the biopsy strategy. The mean delay time to detection of non-favorable risk cancer was between 0.38 and 2.17 years. Biopsy undersampling and progression varied considerably across study cohorts. There was no single best biopsy protocol that is optimal for all cohorts, because of the variation in biopsy under-sampling error and annual progression rates across cohorts. All strategies demonstrated diminishing benefits from additional biopsies., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The European Randomized study of Screening for Prostate Cancer (ERSPC) has shown a 20% relative reduction in prostate cancer mortality after 16yr [rate ratio (RR) 0.80], but centers varied by attendance, screen interval, biopsy compliance, contamination in the control arm, and treatments. We used a microsimulation model, calibrated to the ERSPC individual-level data, to predict influence of study features on the results. The relative reduction in prostate cancer mortality would have been somewhat larger with improved study features: increased attendance (90% attendance in all volunteer-based and 70% in all population-based centers, resulting in RR 0.77), a 2-yr screen interval (RR 0.75), and an 80% biopsy compliance (RR 0.79). The RR would have been substantially lower with a 30% attendance (RR 0.92), 40% biopsy compliance (RR 0.90), or 100% contamination (RR 0.85). The variations in results by trial center may reflect differences in study design and performance and results of our simulations highlight the effect of quality indicators in prostate-specific antigen screening in different settings. PATIENT SUMMARY: We evaluated the effect of various features of prostate-specific antigen (PSA) screening on its effectiveness. The compliance to PSA testing and those having a biopsy after an elevated PSA substantially influence the prostate cancer mortality., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55-69yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. PATIENT SUMMARY: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

For men interested in early detection of prostate cancer, the potential impact on decisional conflict of a decision aid with or without cost compensation for the prostate-specific antigen test will be investigated., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019. Published by Elsevier B.V.)

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., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa)., Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation., Design, Setting, and Participants: We compared data from 10296 men on AS from 21 centres across 12 countries., Outcome Measurements and Statistical Analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation., Results and Limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5yr, 4561 had follow-up for <5yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4-28.6%) at 5yr and 38.2% (95% CI: 36.7-39.9%) at 10yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up., Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression., Patient Summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To systematically review and meta-analyse evidence regarding the additional value of magnetic resonance imaging (MRI) and MRI-targeted biopsies to confirmatory systematic biopsies in identifying high-grade prostate cancer in men with low-risk disease on transrectal ultrasonography (TRUS) biopsy, as active surveillance (AS) of prostate cancer is recommended for men with Gleason 3 + 3 on standard TRUS-guided biopsy. Confirmatory assessment can include repeat standard TRUS-guided biopsy, and/or MRI with targeted biopsy when indicated., Methods: A systematic review of the Embase, Medline, Web-of-science, Google scholar, and Cochrane library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 criteria. Studies reporting men with Gleason 3 + 3 prostate cancer who had chosen AS based on transrectal systematic biopsy findings and had undergone MRI with systematic ± targeted biopsy at confirmatory assessment were included. The primary outcome was detection of any Gleason pattern ≥4., Results: Included reports (six) of men on AS (n = 1 159) showed cancer upgrading (Gleason ≥3 + 4) in 27% (95% confidence interval [CI] 22-34%) using a combined approach of MRI-targeted biopsies and confirmatory systematic biopsies. MRI-targeted biopsies alone would have missed cancer upgrading in 10% (95% CI 8-14%) and standard biopsies alone would have missed cancer upgrading in 7% (95% CI 5-10%). No pathway was more favourable than the other (relative risk [RR] 0.92, 95% CI 0.79-1.06). In all, 35% (95% CI 27-43%) of men with a positive MRI were upgraded, compared to 12% (95% CI 8-18%) of men with a negative MRI being upgraded (RR 2.77, 95% CI 1.76-4.38)., Conclusions: A pre-biopsy MRI should be performed before confirmatory systematic TRUS-guided biopsies in men on AS, together with MRI-targeted biopsies when indicated. A combined approach maximises cancer detection, although other factors within multivariate risk prediction can be used to aid the decision to biopsy in these men., (© 2018 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates., Methods: The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials., Results: Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0., Conclusions: The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Objectives: To assess the level of agreement between digital rectal examination findings of two urologists and its effect on risk prediction using the digital rectal examination-based Rotterdam Prostate Cancer Risk Calculator., Methods: The study sample consisted of a prospective cohort of asymptomatic unscreened men with prostate-specific antigen ≤50.0 ng/mL and transrectal ultrasound volume ≤110 mL who underwent transrectal ultrasound-guided prostate biopsy. Both urologists' digital rectal examination findings were graded normal or abnormal (nodularity and/or induration), and volume classified as 25, 40 or 60 mL, according to the risk calculator algorithm. Interrater agreement analysis using Cohen's kappa (κ) statistic was carried out to determine consistency of digital rectal examination outcome and volume assessment. Receiver operating characteristic curve analysis and calibration plots were constructed to determine the effect of interrater differences. Decision curve analysis was applied to evaluate the clinical usefulness of the model., Results: Of the 241 men included in the study, 41% (n = 98) had prostate cancer (81 were clinically significant, i.e. Gleason ≥3 + 4). There was substantial agreement in the digital rectal examination (abnormal/normal; κ = 0.78; P < 0.001) and volume estimation (κ = 0.79; P < 0.001). Receiver operating characteristic analyses showed good discrimination (0.75-0.78) and were comparable for both urologists. In the high-risk cohort, at a probability threshold of 25%, the risk calculator reduced the prostate biopsy rate by 9%, without missing cancers., Conclusions: Slight differences in digital rectal examination findings seem to have very limited impact on the performance of the Rotterdam Prostate Cancer Risk Calculator. Therefore, this can be considered a useful prostate biopsy outcome prediction tool., (© 2017 The Japanese Urological Association.)

Background: The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction., Objective: To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO., Design: Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models., Setting: Randomized controlled trials in Europe and the United States., Participants: Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization., Intervention: Prostate cancer screening., Measurements: Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began., Results: Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening., Limitation: The MLT is a simple metric of screening and diagnostic work-up., Conclusion: After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality., Primary Funding Source: National Cancer Institute.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

Objectives: A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score., Methods: Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death., Results: A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011)., Conclusions: Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score., (© 2017 The Japanese Urological Association.)

Background: The European Randomised Study of Prostate Cancer Screening has shown a 21% relative reduction in prostate cancer mortality at 13 years. The causes of death can be misattributed, particularly in elderly men with multiple comorbidities, and therefore accurate assessment of the underlying cause of death is crucial for valid results. To address potential unreliability of end-point assessment, and its possible impact on mortality results, we analysed the study outcome adjudication data in six countries., Methods: Latent class statistical models were formulated to compare the accuracy of individual adjudicators, and to assess whether accuracy differed between the trial arms. We used the model to assess whether correcting for adjudication inaccuracies might modify the study results., Results: There was some heterogeneity in adjudication accuracy of causes of death, but no consistent differential accuracy by trial arm. Correcting the estimated screening effect for misclassification did not alter the estimated mortality effect of screening., Conclusions: Our findings were consistent with earlier reports on the European screening trial. Observer variation, while demonstrably present, is unlikely to have materially biased the main study results. A bias in assigning causes of death that might have explained the mortality reduction by screening can be effectively ruled out., Competing Interests: Dr Sigrid Carlsson's work on this paper was supported in part by a Cancer Center Support Grant from the National Cancer Institute made to Memorial Sloane Kettering Cancer Center (P30 CA008748). Dr Carlsson is also supported by a post-doctoral grant from AFA Insurance. Dr Carlsson has received travel reimbursement from Sanofi-aventis. No other authors have any conflicts of interest.

Guidelines regarding recommendations for PSA screening for early detection of prostate cancer are conflicting. In 2012, the United States Preventive Services Task Force (USPSTF) assigned a grade of D (recommending against screening) for men aged ≥75 years in 2008 and for men of all ages in 2012. Understanding temporal trends in rates of screening before and after the 2012 recommendation in terms of usage patterns in PSA screening, changes in prostate cancer incidence and biopsy patterns, and how the recommendation has influenced physician's and men's attitudes about PSA screening and subsequent ordering of other screening tests is essential within the scope of prostate cancer screening policy. Since the 2012 recommendation, rates of PSA screening decreased by 3-10% in all age groups and across most geographical regions of the USA. Rates of prostate biopsy and prostate cancer incidence have declined in unison, with a shift towards tumours being of higher grade and stage upon detection. Despite the recommendation, some physicians report ongoing willingness to screen appropriately selected men, and many men report intending to continue to ask for the PSA test from their physician. In the coming years, we expect to have an improved understanding of whether these decreased rates of screening will affect prostate cancer metastasis and mortality.

Background: Prostate-specific antigen (PSA) screening and concomitant treatment can be implemented in several ways. The authors investigated how the net benefit of PSA screening varies between common practice versus "good practice.", Methods: Microsimulation screening analysis (MISCAN) was used to evaluate the effect on quality-adjusted life-years (QALYs) if 4 recommendations were followed: limited screening in older men, selective biopsy in men with elevated PSA, active surveillance for low-risk tumors, and treatment preferentially delivered at high-volume centers. Outcomes were compared with a base model in which annual screening started at ages 55 to 69 years and were simulated using data from the European Randomized Study of Screening for Prostate Cancer., Results: In terms of QALYs gained compared with no screening, for 1000 screened men who were followed over their lifetime, recommended good practice led to 73 life-years (LYs) and 74 QALYs gained compared with 73 LYs and 56 QALYs for the base model. In contrast, common practice led to 78 LYs gained but only 19 QALYs gained, for a greater than 75% relative reduction in QALYs gained from unadjusted LYs gained. The poor outcomes for common practice were influenced predominantly by the use of aggressive treatment for men with low-risk disease, and PSA testing in older men also strongly reduced potential QALY gains., Conclusions: Commonly used PSA screening and treatment practices are associated with little net benefit. Following a few straightforward clinical recommendations, particularly greater use of active surveillance for low-risk disease and reducing screening in older men, would lead to an almost 4-fold increase in the net benefit of prostate cancer screening. Cancer 2016;122:3386-3393. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose of Review: The aim of this review was to highlight important articles in the field of prostate cancer screening published during 2015 and early 2016. Four major areas were identified for the purpose: screening strategies, post-United States Preventive Services Task Force (USPSTF) 2011-2012, screening trends/patterns, and shared decision making., Recent Findings: Several studies furthered the evidence that screening reduces the risk of metastasis and death from prostate cancer. Multiplex screening strategies are of proven benefit; genetics and MRI need further evaluation. Prostate-specific antigen (PSA) screening rates declined in men above age of 50 years, as did the overall prostate cancer incidence following the USPSTF 2011-2012 recommendation against PSA. The consequences of declining screening rates will become apparent in the next few years. More research is needed to identify the most optimal approach to engage in, and implement, an effective shared decision-making in clinical practice., Summary: Data emerging in 2015 provided evidence on the question of how best to screen and brought more steps in the right direction of 'next-generation prostate cancer screening'. Screening is an ongoing process in all men regardless of whether or not they might benefit from early detection and treatment. After the USPSTF 2011-2012 recommendation, the rates of PSA testing are declining; however, this decline is observed in all men and not solely in those who will not benefit from the screening. The long-term effect of this recommendation might not be as anticipated. More studies are needed on how to implement the best available evidence on who, and when, to screen in clinical practice.

Purpose: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC)., Experimental Design: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers., Results: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200-7,000 and NNO, 16-69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, β = 33; 95% confidence interval (CI), 5-62; R(2) = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers., Conclusions: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear., (©2015 American Association for Cancer Research.)

Purpose: To evaluate the utility of percentage of free serum PSA (%fPSA) as a predictor of adverse rebiopsy findings, treatment change and radical prostatectomy (RP) findings in a prospective active surveillance (AS) trial., Methods: Patients enrolled in the global PRIAS study with baseline %fPSA available were included. Putative baseline predictors (e.g. PSA, %fPSA) of adverse rebiopsy findings were explored using logistic regression analysis. Association of variables with treatment change and RP findings over time were evaluated with Cox regression analysis. Active treatment-free survival was assessed with a Kaplan-Meier method., Results: Of 3701 patients recruited to PRIAS, 939 had %fPSA measured at study entry. Four hundred and thirty-eight of them had %fPSA available after 1 year. Median follow-up was 17.2 months. First rebiopsy results were available for 595 patients and of those, 144 (24.2 %) had adverse findings. A total of 283 (30.1 %) patients discontinued surveillance, of those 181 (64.0 %) due to protocol-based reasons. Although median %fPSA values were significantly lower in patients who changed treatment, according to the multivariate regression analysis, initial %fPSA value was not predictive for treatment change or adverse rebiopsy findings. However, the probability of discontinuing AS was significantly lower in patients with "favourable" initial %fPSA characteristics and %fPSA during follow-up (initial %fPSA ≥15 and positive %fPSA velocity) compared to those with "adverse" %fPSA characteristics (initial %fPSA <15 and negative %fPSA velocity)., Conclusions: Diagnostic %fPSA provides no additional prognostic value when compared to other predictors already in use in AS protocols. However, %fPSA velocity during surveillance may aid in predicting the probability for future treatment change.

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality., Design, Setting, and Participants: Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis., Outcome Measurements and Statistical Analysis: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis., Results and Limitations: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller., Conclusions: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr., Patient Summary: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if screening did not result in a clinically apparent lower stage or grade, it might still lead to less disease recurrence after treatment with curative intent (radical prostatectomy [RP] and radiation therapy [RT]) because the tumor had less time to develop outside the prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, we compared differences in the treatment quality of the screening and control arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often ≥69Gy. This most likely resulted from changes over time in treatment that coincided with the later detection in the control arm. DFS was higher in the screening arm in all risk groups. After correction for lead time, these differences were minimal, however. We concluded that treatment quality differed between the screening and control arms of the ERSPC Rotterdam. RT quality was especially superior in the control arm with higher dosages and more often RT in combination with hormonal therapy. Despite these differences favoring the control arm, DFS differences were minimal., Patient Summary: We looked at differences in prostate cancer (PCa) treatment and outcome after PCa treatment in men diagnosed after screening and men diagnosed after normal clinical practice. Treatment differed with superior treatment given to men diagnosed in normal clinical practice. We propose a likely explanation for this apparently counterintuitive finding (progressive insight combined with, on average, a later detection of tumors in unscreened men). Although unscreened men received better treatment, this advantage seemed to be outweighed by the advantage associated with the earlier detection, on average, of the tumor in screened men., Trial Registration: ISRCTN49127736., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prostate-specific antigen-based prostate cancer screening remains a controversial topic. Up to now, there is worldwide consensus on the statement that the harms of population-based screening, mainly as a result of overdiagnosis (the detection of clinically insignificant tumors that would have never caused any symptoms), outweigh the benefits. However, worldwide opportunistic screening takes place on a wide scale. The European Randomized Study of Screening for Prostate Cancer showed a reduction in prostate cancer mortality through prostate-specific antigen based-screening. These population-based data need to be individualized in order to avoid screening in those who cannot benefit and start screening in those who will. For now, lacking a more optimal screening approach, screening should only be started after the process of shared decision-making. The focus of future research is the reduction of unnecessary testing and overdiagnosis by further research to better biomarkers and the value of the multiparametric magnetic resonance imaging, potentially combined in already existing prostate-specific antigen-based multivariate risk prediction models., (© 2015 The Japanese Urological Association.)

The early diagnosis of prostate cancer presents certain dilemmas, and various prostate cancer guidelines have been developed to support clinicians in decision making. However, these guidelines often give contradictory advice and should be appraised critically. We will discuss how the general practitioner (GP) should deal with the frequently used, often contradictory guidelines on this topic. A number of dilemmas concerning the early diagnosis of prostate cancer are discussed in this clinical lesson, based on a single case in the GP's practice; this concerns a 49-year-old male who approached his GP for prostate cancer screening. After the process of shared decision making, the patient was screened and diagnosed with a low-grade prostate carcinoma for which active surveillance was initiated.

Background: Prostate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa)., Objective: To assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men., Design, Setting, and Participants: Participants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples., Outcome Measurements and Statistical Analysis: Outcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models., Results and Limitations: PCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs. 0.62; p=0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs. 0.56; p=0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p=0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs. 0.70; p=0.02). Decision curves confirmed these patterns, although numbers were small., Conclusions: Both PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men., Patient Summary: We studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability., (Copyright © 2014. Published by Elsevier B.V.)

Objective: To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting., Subjects and Methods: The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (≥3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n = 2914) and Göteborg (n = 740). A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome., Results: The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Göteborg. Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer. There was a strong correlation between the blood measurements and TRUS-estimated prostate volume (Spearman's correlation 0.60 in Rotterdam and 0.57 in Göteborg)., Conclusions: In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice. Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches., (© 2013 BJU International.)

Background: Inconclusive test results often occur after prostate-specific antigen (PSA)-based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing., Objective: To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen., Design, Setting, and Participants: We analyzed data from 15 791 screen-negative men aged 55-70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer., Outcome Measurements and Statistical Analysis: Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥ 7 and/or PSA ≥ 10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening., Results and Limitations: Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0-4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤ 1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥ 5%) might benefit from immediate retesting. These findings need to be validated externally., Conclusions: This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial., Methods: The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial., Setting: The European prostate cancer screening trial (ERSPC)., Results: In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9-3.6 deaths per 1000 person-years., Conclusions: Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.

Objectives To assess the effect of screening in terms of excess mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods A total of 141,578 men aged 55-69 were randomized to systematic screening or usual care in ERSPC sections in Finland, Italy, the Netherlands and Sweden. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a diagnosis with PC adjusted for study centre, study arm and study attendance. The excess mortality rates were compared between the two study arms. Results The PC incidence was 9.25 per 1000 person-years in the intervention arm and 5.49 per 1000 person-years in the control arm, relative risk (RR) 1.69 (95% confidence interval [CI] 1.62-1.76). The excess mortality among men with PC was 0.29 per 1000 person-years in the intervention arm and 0.37 per 1000 person-years in the control arm; the RR for excess mortality was 0.77 (95% CI 0.55-1.08). The absolute risk reduction in the excess mortality was 0.08 per 1000 person-years. The overall mortality was not significantly different between the intervention and the control arms of the study: RR 0.99 (95% CI 0.96-1.01). Conclusions Although the reduction in excess mortality was not statistically significant, the between-arm reduction in excess mortality rate was in line with the previously reported 20% reduction in the disease-specific mortality. This finding indicates that the reduction in PC mortality in the ERSPC trial cannot be due to a bias in cause of death adjudication.

Screening for prostate cancer is a controversial topic within the field of urology. The US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial did not demonstrate any difference in prostate-cancer-related mortality rates between men screened annually rather than on an 'opportunistic' basis. However, in the world's largest trial to date--the European Randomised Study of Screening for Prostate Cancer--screening every 2-4 years was associated with a 21% reduction in prostate-cancer-related mortality rate after 11 years. Citing the uncertain ratio between potential harm and potential benefit, the US Preventive Services Task Force recently recommended against serum PSA screening. Although this ratio has yet to be elucidated, PSA testing--and early tumour detection--is undoubtedly beneficial for some individuals. Instead of adopting a 'one size fits all' approach, physicians are likely to perform personalized risk assessment to minimize the risk of negative consequences, such as anxiety, unnecessary testing and biopsies, overdiagnosis, and overtreatment. The PSA test needs to be combined with other predictive factors or be used in a more thoughtful way to identify men at risk of symptomatic or life-threatening cancer, without overdiagnosing indolent disease. A risk-adapted approach is needed, whereby PSA testing is tailored to individual risk.

Objective: To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC)., Methods: Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality., Results: In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%)., Conclusions: Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced.

Background: After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain., Methods: On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled., Results: Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56)., Conclusions: The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.).

Objectives: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume., Methods: We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves)., Results: The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts., Conclusions: Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.