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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Prediction models need external validation to assess their value beyond the setting where the model was derived from. Objective: To assess the external validity of the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator (www.prostatecancer-riskcalculator.com) for the probability of having a positive prostate biopsy (P(posb)). Design, setting and participants: The ERSPC risk calculator was based on data of the initial screening round of the ERSPC section Rotterdam and validated in 1825 and 531 men biopsied at the initial screening round in the Finnish and Swedish sections of the ERSPC respectively. P(posb) was calculated using serum prostate specific antigen (PSA), outcome of digital rectal examination (DRE), transrectal ultrasound and ultrasound assessed prostate volume. Measurements: The external validity was assessed for the presence of cancer at biopsy by calibration (agreement between observed and predicted outcomes), discrimination (separation of those with and without cancer), and decision curves (for clinical usefulness). Results and limitations: Prostate cancer was detected in 469 men (26%) of the Finnish cohort and in 124 men (23%) of the Swedish cohort. Systematic miscalibration was present in both cohorts (mean predicted probability 34% versus 26% observed, and 29% versus 23% observed, both p <0.001). The areas under the curves were 0.76 and 0.78, and substantially lower for the model with PSA only (0.64 and 0.68 respectively). The model proved clinically useful for any decision threshold compared with a model with PSA only, PSA and DRE, or biopsying all men. A limitation is that the model is based on sextant biopsies results. Conclusions: The ERSPC risk calculator discriminated well between those with and without prostate cancer among initially screened men, but overestimated the risk of a positive biopsy. Further research is necessary to assess the performance and applicability of the ERSPC risk calculator when a clinical setting is considered rather than a screening setting. [Copyright &y& Elsevier]

The article offers information on a study which investigated the benefits of prostate cancer screening on an individual level. A total of 43,987 men, aged 55-74 years, were recruited between 1993 and 1999 for the intervention arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in the Netherlands, Sweden and Finland, while a total of 42,503 men, aged 55-74 years, were recruited for a clinical population in Northern Ireland. The findings of the study are presented and discussed in detail.

Background The incidence of prostate cancer has increased substantially since it became common practice to screen asymptomatic men for the disease. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in 1993 to determine how prostate-specific antigen (PSA) screening affects prostate cancer mortality. Variations in the screening algorithm, such as the interval between screening rounds, likely influence the morbidity, mortality, and quality of life of the screened population. Methods We compared the number and characteristics of interval cancers, defined as those diagnosed during the screening interval but not detected by screening, in men in the screening arm of the ERSPC who were aged 55-65 years at the time of the first screening and were participating through two centers of the ERSPC: Gothenburg (2-year screening interval, n = 4202) and Rotterdam (4-year screening interval, n = 13301). All participants who were diagnosed with prostate cancer through December 31, 2005, but at most 10 years after the initial screening were ascertained by linkage with the national cancer registries. A potentially life-threatening (aggressive) interval cancer was defined as one with at least one of the following characteristics at diagnosis: stage M1 or N1, plasma PSA concentration greater than 20.0 ng/mL, or Gleason score greater than 7. We used Mantel Cox regression to assess differences between rates of interval cancers and aggressive interval cancers at the two centers. All statistical tests were two-sided. Results The 10-year cumulative incidence of all prostate cancers in Rotterdam versus Gothenburg was 1118 (8.41%) versus 552 (13.14%) (P<.001), the cumulative incidence of interval cancer was 57 (0.43%) versus 31 (0.74%) (P = .51), and the cumulative incidence of aggressive interval cancer was 15 (0.11%) versus 5 (0.12%) (P= .72). Conclusion The rate of interval cancer, especially aggressive interval cancer, was low in this study. The 2-year screening interval had higher detection rates than the 4-year interval but did not lead to lower rates of interval and aggressive interval prostate cancers. [ABSTRACT FROM AUTHOR]

Objective: To compare the survival outcomes of patients treated with surgery or radiotherapy for prostate cancer., Design: Observational study., Setting: Sweden, 1996-2010., Participants: 34,515 men primarily treated for prostate cancer with surgery (n=21,533) or radiotherapy (n=12,982). Patients were categorised by risk group (low, intermediate, high, and metastatic), age, and Charlson comorbidity score., Main Outcome Measures: Cumulative incidence of mortality from prostate cancer and other causes. Competing risks regression hazard ratios for radiotherapy versus surgery were computed without adjustment and after propensity score and traditional (multivariable) adjustments, as well as after propensity score matching. Several sensitivity analyses were performed., Results: Prostate cancer mortality became a larger proportion of overall mortality as risk group increased for both the surgery and the radiotherapy cohorts. Among patients with non-metastatic prostate cancer the adjusted subdistribution hazard ratio for prostate cancer mortality favoured surgery (1.76, 95% confidence interval 1.49 to 2.08, for radiotherapy v prostatectomy), whereas there was no discernible difference in treatment effect among men with metastatic disease. Subgroup analyses indicated more clear benefits of surgery among younger and fitter men with intermediate and high risk disease. Sensitivity analyses confirmed the main findings., Conclusions: This large observational study with follow-up to 15 years suggests that for most men with non-metastatic prostate cancer, surgery leads to better survival than does radiotherapy. Younger men and those with less comorbidity who have intermediate or high risk localised prostate cancer might have a greater benefit from surgery.

Background: Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA., Methods: Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162)., Results: If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality., Conclusions: Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.

Background: The rate of decrease in advanced cancers is an estimate for determining prostate cancer (PCa) screening program effectiveness., Objective: Assess the effectiveness of PCa screening programs using a 2- or 4-yr screening interval., Design, Setting, and Participants: Men aged 55-64 yr were participants at two centers of the European Randomized Study of Screening for Prostate Cancer: Gothenburg, Sweden (2-yr screening interval, n=4202), and Rotterdam, the Netherlands (4-yr screening interval, n=13 301). We followed participants until the date of PCa, the date of death, or the last follow-up at December 31, 2008, or up to a maximum of 12 yr after initial screening. Potentially life-threatening (advanced) cancer was defined as cancer with at least one of following characteristics: clinical stage ≥T3a, M1, or N1; serum prostate-specific antigen (PSA) >20.0 ng/ml; or Gleason score ≥8 at biopsy., Intervention: We compared the proportional total (advanced) cancer incidence (screen-detected and interval cases), defined as the ratio of the observed number of (advanced) cancers to the expected numbers of (advanced) cancers based on the control arm of the study., Measurements: The proportional cancer incidence from the second screening round until the end of observation was compared using a 2- or 4-yr screening interval., Results and Limitations: From screening round 2 until the end of observation, the proportional cancer incidence was 3.64 in Gothenburg and 3.08 in Rotterdam (relative risk [RR]: 1.18; 95% confidence interval [CI], 1.04-1.33; p=0.009). The proportional advanced cancer incidence was 0.40 in Gothenburg and 0.69 in Rotterdam (RR: 0.57; 95% CI, 0.33-0.99; p=0.048); the RR for detection of low-risk PCa was 1.46 (95% CI, 1.25-1.71; p<0.001). This study was limited by the assumption that PSA testing in the control arm was similar in both centers., Conclusions: A 2-yr screening interval significantly reduced the incidence of advanced PCa; however, the 2-yr interval increased the overall risk of being diagnosed with (low-risk) PCa compared with a 4-yr interval in men aged 55-64 yr. Individualized screening algorithms must be improved to provide the strategy for this issue., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: • To assess possible excess mortality associated with prostate biopsy among screening participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC)., Patients and Methods: • From three centres in the ERSPC (Finland, The Netherlands and Sweden) 50,194 screened men aged 50.2-78.4 years were prospectively followed. A cohort of 12,959 first-time screening-positive men (i.e. with biopsy indication) was compared with another cohort of 37,235 first-time screening-negative men. • Overall mortality rates (i.e. other cause than prostate cancer mortality) were calculated and the 120-day and 1-year cumulative mortality were calculated by the Kaplan-Meier method, with a log-rank test for statistical significance. • Incidence rate ratios (RR) and statistical significance were evaluated using Poisson regression analyses, adjusting for age, total PSA level, screening centre and whether a biopsy indication was present, or whether a biopsy was actually performed or not., Results: • There was no statistically significant difference in cumulative 120-day other cause mortality between the two groups of men: 0.24% (95% CI, 0.17-0.34) for screening-positive men vs 0.24% (95% CI, 0.20-0.30) for screening-negative men (P= 0.96). This implied no excess mortality for screening-positive men. • Screening-positive men who were not biopsied (n= 1238) had a more than fourfold risk of other cause mortality during the first 120 days compared to screening-negative men: RR, 4.52 (95% CI, 2.63-7.74) (P < 0.001), adjusted for age, whereas men who were actually biopsied (n= 11,721) had half the risk: RR, 0.41 (95% CI, 0.23-0.73) (P= 0.002), adjusted for age. • Only 14/31 (45%) of the screening-positive men who died within 120 days were biopsied and none died as an obvious complication to the biopsy., Conclusion: • Prostate biopsy is not associated with excess mortality and fatal complications appear to be very rare., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Background: It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy., Objective: To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort., Design, Setting, and Participants: There were 2742 screening-arm participants with PSA <3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Göteborg, Sweden, and who were subsequently biopsied during rounds 2-6 due to elevated PSA., Measurements: Total, free, and intact PSA and human kallikrein 2 were measured for 1-6 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC)., Results and Limitations: PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study., Conclusions: In men with PSA of about ≥3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy.