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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]

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. [ABSTRACT FROM AUTHOR]

With the new policy recommendation in 2022 to explore the possibilities of screening for prostate cancer by the European Commission, the landscape for prostate cancer early detection is evolving. In line with this recommendation, the PRAISE-U project aims to evaluate the early detection and diagnosis of prostate cancer through customised and risk-based screening programmes, with the goal to align protocols across European Union member states. This systematic review is part of the PRAISE-U project, with the goal to review the policy, medical guideline recommendations, and the current level of opportunistic screening presented in the scientific literature on prostate cancer early detection from 2016 to 2023 in European Union member states. An extensive literature search was performed on 1 June 2023 in a large number of databases, including Embase.com, Medline (Ovid), Web of Science Core Collection, Google Scholar, and Policy Commons. We identified 318 articles (qualitative, quantitative, and reviews), of which 41 were included in the full-text screening. Seventeen articles were ultimately identified as eligible for inclusion. The included articles revealed significant variations towards PSA-based early detection policies for prostate cancer in nine European countries. Despite official recommendations, opportunistic screening was prevalent across all nine countries regardless of recommendations for or against PSA-based early detection. This systematic review suggests that the current early detection policies are not fit for purpose. High levels of opportunistic screening and overdiagnosis persist, prompting policy recommendations for standardised guidelines, informed decision making, and increased awareness to improve efficiency and effectiveness in early detection. [ABSTRACT FROM AUTHOR]

The European Association of Urology, together with consortium partners, has launched PRAISE-U (Prostate Cancer Awareness and Initiative for Screening in the European Union), a project involving 25 institutions across 12 countries that is funded under the EU4Health program. The aim is to reduce the morbidity and mortality of prostate cancer in EU member states via customized and risk-based screening programs. [ABSTRACT FROM AUTHOR]

Over the last three decades, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening have steered the conversation around the early detection of prostate cancer. These two randomized trials assessed the effect of screening on prostate cancer disease-specific mortality. Elevated PSA levels were followed by a systematic sextant prostate biopsy. Standard repeat testing intervals were applied. After controversies from 2009 to 2016 due to contradicting results of the two trials, the results aligned in 2016 and showed that early PSA detection reduces prostate cancer-specific mortality. However, overdiagnosis rates of up to 50% were reported, and this sparked an intense debate on harms and benefits for almost 20 years. The balance between harms and benefits is highly debated and has initiated further research to investigate new ways of early detection. In the meantime, the knowledge and tools for the diagnostic algorithm improved. This is a continuously ongoing effort which focuses on individual risk-based screening algorithms that preserve the benefits of the purely PSA-based screening algorithms, while reducing the side effects. An important push towards investigating new techniques for early detection came from the European Commission on the 20th of September 2022. The European Commission published its updated recommendation to investigate prostate, lung, and gastric cancer early detection programs. This opened a new window of opportunity to move away from the trial setting to population-based early detection settings. With this review, we aim to review 30 years of historical evidence of prostate cancer screening, which led to the initiation of the 'The Prostate Cancer Awareness and Initiative for Screening in the European Union' (PRAISE-U) project, which aims to encourage the early detection and diagnosis of PCa through customized and risk-based screening programs. [ABSTRACT FROM AUTHOR]

In response to the rising incidence of indolent, low-risk prostate cancer (PCa) due to increased prostate-specific antigen (PSA) screening in the 1990s, active surveillance (AS) emerged as a treatment modality to combat overtreatment by delaying or avoiding unnecessary definitive treatment and its associated morbidity. AS consists of regular monitoring of PSA levels, digital rectal exams, medical imaging, and prostate biopsies, so that definitive treatment is only offered when deemed necessary. This paper provides a narrative review of the evolution of AS since its inception and an overview of its current landscape and challenges. Although AS was initially only performed in a study setting, numerous studies have provided evidence for the safety and efficacy of AS which has led guidelines to recommend it as a treatment option for patients with low-risk PCa. For intermediate-risk disease, AS appears to be a viable option for those with favourable clinical characteristics. Over the years, the inclusion criteria, follow-up schedule and triggers for definitive treatment have evolved based on the results of various large AS cohorts. Given the burdensome nature of repeat biopsies, risk-based dynamic monitoring may further reduce overtreatment by avoiding repeat biopsies in selected patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The survival rate for men with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa) without invasive cribriform (CR) and intraductal carcinoma (IDC) is similar to that for ISUP grade 1. If updated into the European Randomized Study of Screening for Prostate Cancer (ERSPC Rotterdam) risk calculator number 3 (RC3), this may further improve upfront selection of men who need a biopsy. Objective To improve the number of possible biopsies avoided, while limiting undiagnosed clinically important PCa by applying the updated RC3 for risk-based patient selection. Design, setting, and participants The RC3 is based on the first screening round of the ERSPC Rotterdam, which involved 3616 men. In 2015, histopathologic slides for PCa cases ( n = 885) were re-evaluated. Low-risk (LR) PCa was defined as ISUP grade 1 or 2 without CR/IDC. High-risk (HR) PCa was defined as ISUP grade 2 with CR/IDC and PCa with ISUP grade≥3. Outcome measurements and statistical analysis We updated the RC3 using multinomial logistic regression analysis, including data on age, PSA, digital rectal examination, and prostate volume, for predicting LR and HR PCa. Predictive accuracy was quantified using receiver operating characteristic analysis and decision curve analysis. Results and limitations Men without PCa could effectively be distinguished from men with LR PCa and HR PCa (area under the curve 0.70, 95% confidence interval [CI] 0.68–0.72 and 0.92, 95% CI 0.90–0.94). At a 1% risk threshold, the updated calculator would lead to a 34% reduction in unnecessary biopsies, while only 2% of HR PCa cases would be undiagnosed. Conclusions A relatively simple risk stratification tool augmented with a highly sensitive contemporary pathologic biopsy classification would result in a considerable decrease in unnecessary prostate biopsies and overdiagnosis of potentially indolent disease. Patient summary We improved a well-known prostate risk calculator with a new pathology classification system that better reflects disease burden. This new risk calculator allows individualized prediction of the chance of having (potentially aggressive) biopsy-detectable prostate cancer and can guide shared decision-making when considering prostate biopsy. [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]

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. [ABSTRACT FROM AUTHOR]

The authors discuss the study which examines the correlation between stage shift and differences in mortality in a randomised setting like the European Randomised Study of Screening for Prostate Cancer (ERSPC). Results of the study which indicated that changes in prostate cancer mortality could be explained by changes in incidence are offered. The authors believe that misuse of PSA testing is the only way to prevent the loss of screening test and a balance harm-benefit ratio needs to be found.

What's known on the subject? and What does the study add? Previous studies have shown that a statistical model based on a panel of kallikrein markers in blood (total, free and intact PSA and kallikrein-related peptidase 2) can predict prostate cancer on biopsy., The current study explores the relationship between the above-mentioned panel and prostate volume, and whether this panel could be an alternative for clinical measures such as DRE and TRUS in predicting prostate cancer on biopsy., 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. [ABSTRACT FROM AUTHOR]

The article presents a study that assesses the impact of screening of excess mortality in men with prostate cancer (PC). It outlines the method of the study which observes a total of 141,578 men aged 55-69 who have undergone randomized to systematic screening or usual care in European Randomized Study of Screening for Prostate Cancer (ERSPC). It notes the result of the study which indicates that the reduction in PC mortality in ERSPC trial was not due to a bias in cause of death adjudication.

The article presents a study that examines the effectiveness of mortality evaluation on patients with prostate cancer. It describes the method of the study that uses estimation procedure in the expected number of deaths related to prostate cancer diagnoses. It outlines the findings of the study which indicates that attendees have lower all-cause mortality rate and higher probability of prostate cancer compared to non-attendees.

Study Type - Diagnosis (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA-based screening at a median follow-up of 11 years. In the ERSPC, men are screened at 4-year intervals. A prostate biopsy is recommended for men with a PSA level ≥3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA-based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics. OBJECTIVE To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate-specific antigen (PSA) threshold of ≥3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC)., PATIENTS AND METHODS In the Rotterdam section of the ERSPC, a total of 42 376 participants, aged 55-74 years, identified from population registries were randomly assigned to a screening or control arm., For the ERSPC men undergo PSA screening at 4-year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55-69 years at the first screening were eligible for the present study., RESULTS PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively)., Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively)., Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥7) decreased after the first round of screening from 44.4 to 23.8% in the second ( P < 0.001) and 18.6% in the third round ( P < 0.001)., Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers., CONCLUSIONS In consecutive screening rounds the PPV of PSA-based screening remains equal in previously unbiopsied men., In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics., Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Radical prostatectomy was previously shown to improve long-term outcomes among men with clinically-detected prostate cancer. Our data suggests that radical prostatectomy is also associated with improved outcomes in men with screen-detected prostate cancer. OBJECTIVE To examine the long-term outcomes of radical prostatectomy (RP) among men diagnosed with prostate cancer from the screening and control arms of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC)., PATIENTS AND METHODS Among 42 376 men randomised during the period of the first round of the trial (1993-1999), 1151 and 210 in the screening and control arms were diagnosed with prostate cancer, respectively., Of these men, 420 (36.5%) screen-detected and 54 (25.7%) controls underwent RP with long-term follow-up data (median follow-up 9.9 years)., Progression-free (PFS), metastasis-free (MFS) and cancer-specific survival (CSS) rates were examined, and multivariable Cox proportional hazards models were used to determine whether screen-detected (vs control) was associated with RP outcomes after adjusting for standard predictors., RESULTS RP cases from the screening and control arms had statistically similar clinical stage and biopsy Gleason score, although screen-detected cases had significantly lower prostate-specific antigen (PSA) levels at diagnosis., Men from the screening arm had a significantly higher PFS ( P= 0.003), MFS ( P < 0.001) and CSS ( P= 0.048)., In multivariable models adjusting for age, PSA level, clinical stage, and biopsy Gleason score, the screening group had a significantly lower risk of biochemical recurrence (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.83, P= 0.011) and metastasis (HR 0.18, 95% CI 0.06-0.59, P= 0.005)., Additionally adjusting for tumour volume and other RP pathology features, there was no longer a significant difference in biochemical recurrence between the screening and control arms., Limitations of the present study include lead-time bias and non-randomised treatment selection., CONCLUSIONS After RP, screen-detected cases had significantly improved PFS, MFS and CSS compared with controls within the available follow-up time., The screening arm remained significantly associated with lower rates of biochemical recurrence and metastasis after adjusting for other preoperative variables., However, considering also RP pathology, the improved outcomes in the screening group appeared to be mediated by a significantly lower tumour volume. [ABSTRACT FROM AUTHOR]

Study Type - Prognosis (cohort series) Level of Evidence 2a What's known on the subject? and What does the study add? The present study is one of the first to investigate urologists' and patients' compliance with recommendations based on a risk calculator that calculates the probability of indolent prostate cancer. A threshold was set for a recommendation of active surveillance vs active treatment. Active surveillance recommendations based on a prostate cancer risk calculator were followed by most patients, but 30% with active treatment recommendations chose active surveillance instead. This indicates that the threshold may be too high for urologists and patients. OBJECTIVES To assess urologists' and patients' compliance with treatment recommendations based on a prostate cancer risk calculator (RC) and the reasons for non-compliance., To assess the difference between patients who were compliant and non-compliant with recommendations based on this RC., PATIENTS AND METHODS Eight urologists from five Dutch hospitals included 240 patients with prostate cancer (PCa), aged 55-75 years, from December 2008 to February 2011., The urologists used the European Randomized Study of Screening for Prostate Cancer RC which predicts the probability of potentially indolent PCa (P[indolent]), using serum prostate-specific antigen (PSA), prostate volume and pathological findings on biopsy., Inclusion criteria were PSA <20 ng/mL, clinical stage T1 or T2a-c disease, <50% positive sextant biopsy cores, ≤20 mm cancer tissue, ≥40 mm benign tissue and Gleason ≤3 + 3. If the P(indolent) was >70%, active surveillance (AS) was recommended, and active treatment (AT) otherwise., After the treatment decision, patients completed a questionnaire about their treatment choice, related (dis)advantages, and validated measurements of other factors, e.g. anxiety., RESULTS Most patients (45/55, 82%) were compliant with an AS recommendation. Another 54 chose AS despite an AT recommendation (54/185, 29%)., The most common reason for non-compliance with AT recommendations by urologists was the patient's preference for AS ( n= 30). These patients most often reported the delay of physical side effects of AT as the main advantage ( n= 19)., Those who complied with AT recommendations had higher mean PSA levels (8 vs 7 ng/mL, P= 0.02), higher mean amount of cancer tissue (7 vs 3 mm, P < 0.001), lower mean P(indolent) (36% vs 55%, P < 0.001), and higher mean generic anxiety scores (42 vs 38, P= 0.03) than those who did not comply., CONCLUSIONS AS recommendations were followed by most patients, while 29% with AT recommendations chose AS instead., Although further research is needed to validate the RC threshold, the current version is already useful in treatment decision-making in men with localized PCa. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

The serum PSA test still is the most important biomarker for the detection and follow-up of prostate cancer. PSA-based screening can reduce disease specific mortality but coinciding unnecessary testing and overdiagnosis warrant further research for more specific biomarkers. Numerous studies of both serum and urine-based prostate cancer biomarker candidates have been presented the last ten years. However, biomarkers for identifying the most aggressive subsets of this malignancy are still missing. Being non-invasive, urine-based tests might be suitable for both clinical and (mass) screening purposes, but also for prediction and to gain prognostic information. Protein-based, DNA-based and RNA-based urine biomarkers have been developed and tested. Protein markers in urine. Data on protein-based urine biomarkers (i.e. Annexin A3, matrix metalloproteinases and the urinary: serum PSA ratio) show up to now contradictory results and further studies are warranted to be able to assess their clinical value in which the cost aspect should not be overlooked. DNA markers in urine. Studies on DNA-based urine biomarkers focus on hypermethylation of gene panels with GSTP1 hypermethylation being the most promising individual marker. Larger prospective clinical studies of single markers and gene panels are however needed to validate their clinical utility. RNA markers in urine. RNA-based urine biomarkers are by far the most developed. The PCA3 test, the TMPRSS2 -- ERG fusion gene, transcript expression levels of GOLPH2, SPINK1 and their combination have been subject of many studies showing encouraging results. Conclusion. Up to now urine-based biomarkers represent a promising alternative or addition to serum-based biomarkers. Prospective studies in a multivariate setting, including larger sample sizes and avoiding attribution bias caused by preselection on the basis of serum PSA are however required. [ABSTRACT FROM AUTHOR]

Abstract: Background: Prostate cancer antigen 3 (PCA3) is considered to be prostate cancer (PCa) specific and highly overexpressed in cancer. Therefore a high PCA3 score should result in a high positive predictive value (PPV) and specificity for a positive biopsy. Objective: Our aim was to reevaluate, retest PCA3, and rebiopsy men with an initial PCA3 ≥100 and no PCa detected and compare the results with a random cohort of men with an initial PCA3<100. Design, setting, and participants: We invited men 63–75 yr of age with a PCA3 ≥100 for retesting and a control group with an initial PCA3<100 to participate in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. Interventions: Blood and urine sampling were used to determine prostate-specific antigen (PSA) and PCA3. Prostate biopsies were performed if the PSA was ≥2.5ng/ml and/or the PCA3 score was ≥35. Measurements: We correlated the initial and reevaluated PCA3 scores. Our assessment of the PPV after rebiopsy was based on the newly determined PCA3 score. Results and limitations: After a mean study period of 19 mo, more cases of PCa were detected in rebiopsied men with initial PCA3 scores ≥100 than in the controls with PCA3 scores <100 (30.0% vs 18.8%). Combining initial and rebiopsy data resulted in a PPV of 52.2% in men with PCA3 ≥100. Over time, changes in PSA and PCA3 levels were quite different. Conclusions: In spite of our rescreened population, PPV and specificity were comparable with all reported studies of men with PCA3 scores ≥100. These findings do not explain why these PCA3 scores were excessively high in spite of the absence of biopsy-detectable PCa. [ABSTRACT FROM AUTHOR]

Objectives To study the difference between the disease-specific and excess mortality rate in the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Methods A total of 42,376 men were randomized to systematic screening or usual care. 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 possible diagnosis with PC. The disease-specific mortality rate was based on the number of men who died from PC. The excess mortality rate based on the arm-specific excess number of deaths and the disease-specific mortality rate were compared between the two study arms. Results The overall mortality rate was not significantly different between the intervention and the control arms of the study: RR 1.02 (95% CI 0.98-1.07). The disease-specific mortality rate was 0.42 men per 1000 person-years in the intervention and 0.48 men per 1000 person-years in the control arm: RR 0.86 (95% CI 0.64-1.17). The excess mortality rate was 0.40 per 1000 person-years in the intervention arm and 0.61 men per 1000 person-years in the control arm, and the RR for excess mortality was 0.66 (95% CI 0.39-1.13). Conclusions In contrast to the disease-specific mortality rates an increased difference in the excess mortality rates was observed between the two arms. This observation may be due to a systematic underestimation of the disease-specific deaths, and/or an additional disease-related mortality that is measured by an excess mortality analysis but not by a disease-specific mortality. [ABSTRACT FROM AUTHOR]

Abstract: Background: The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown. Objective: Assess the value of PCA3 as a first-line diagnostic test. Design, setting and participants: Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section. Interventions: Lateral sextant biopsies were performed if the serum PSA value was ≥3.0ng/ml and/or the PCA3 score was ≥10. Measurements: Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0ng/ml. Results and limitations: In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ=0.14; p <0.0001). A PSA ≥3.0ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n =19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers. Conclusions: PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population. [Copyright &y& Elsevier]

The article focuses on the dispute over prostate cancer (PCa) screening and the European Randomized Study of Screening for Prostate Cancer (ERSPC) and Prostate, Lung, Colorectal and Ovarian (PLCO) trials. Several elements have been enumerated that are said to contribute to this controversy including oppositeness between the impacts of the studies and the absence of international consensus on regular screening. It is said that the extensive use of PSA trial contributed to the decrease in the US PCa mortality rate in 1990s.

Purpose: Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy. Materials and Methods: We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer and who underwent 1 or more subsequent prostate biopsies after an initial negative finding. We evaluated whether prostate specific antigen velocity improved predictive accuracy beyond that of prostate specific antigen alone. Results: Of the 2,579 repeat biopsies 363 (14%) were positive for prostate cancer, of which 44 (1.7%) were high grade (Gleason score 7 or greater). Prostate specific antigen velocity was statistically associated with cancer risk but had low predictive accuracy (AUC 0.55, p <0.001). There was some evidence that prostate specific antigen velocity improved AUC compared to prostate specific antigen for high grade cancer. However, the small increase in risk associated with high prostate specific antigen velocity (from 1.7% to 2.8% as velocity increased from 0 to 1 ng/ml per year) had questionable clinical relevance. Conclusions: Men with prior negative biopsy are at lower risk for prostate cancer at subsequent biopsies with high grade disease particularly rare. We found little evidence to support prostate specific antigen velocity to aid in decisions about repeat biopsy for prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Background: Population-based screening for prostate cancer (PCa) remains controversial. To help men making informed decisions about prostate specific antigen (PSA) screening a risk indicator (www.uroweb.org) was developed. This risk indicator is embedded in a leaflet that informs men about the pros and cons of PCa screening and enables calculation of the individual risk of having a biopsy detectable PCa. Aim: To assess the effect of providing a leaflet including individualized risk estimation on informed decision making of men, i.e. knowledge about PCa and PSA screening, attitude towards undergoing a PSA test and intention to have a PSA test. Methods: An intervention study among 2000 men, aged 55–65years, randomly selected from the population registry of the city of Dordrecht, the Netherlands, in 2008. Men were sent a questionnaire on knowledge of PCa, attitude and intention to have a PSA test. Men without a history of (screening for) PCa were sent the leaflet and Questionnaire 2 within 2weeks after returning Questionnaire 1. Validated health and anxiety measures were used. Results: One thousand and twenty seven of 2000 men completed Questionnaire 1 (51%), of whom 298 were excluded due to a history of (screening for) PCa. Of the 729 remaining men, 601 completed Questionnaire 2 as well. At the second assessment significantly more men met the requirements of informed decision making (15% versus 33%, p <0.001), more men had relevant knowledge (284/601, 50% versus 420/601, 77%, p <0.001) and the intention to have a PSA test had increased (p <0.001). Conclusions: Providing information on PCa screening combined with individualized risk estimation enhanced informed decision making and may be used for shared decision making on PSA screening of physicians and patients. [Copyright &y& Elsevier]

Abstract: Background: Screening for prostate cancer (PC) is controversial due to uncertainties about its efficiency. Objective: We aimed to develop strategies to reduce the number of unnecessary biopsies while still detecting most clinically important PC cases. Design, setting, and participants: In 1850 men initially screened and biopsied (prostate-specific antigen [PSA] value ≥3.0 ng/ml) in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we calculated both the probability of having a positive lateralized sextant biopsy [P(biop+)] and the probability of having an indolent cancer [P(ind)] if PC was detected at biopsy (n =541). Analyses of repeat screening included 225 cancers in 1201 men. Interventions: The P(biop+) was based on applying a logistic regression model that included ultrasound volume, digital rectal exam, and transrectal ultrasound in addition to the PSA value. The P(ind) was based on a recently validated nomogram. Measurements and limitations: At initial screening the fraction of positive biopsies was 29% (541 of 1850). Applying an additional P(biop+) cut-off of 12.5% implied that 613 of the 1850 men (33%) would not have been biopsied. This would result in an increase in the positive predictive value (PPV) to 38% (468 of 1237). At repeat screening a similar P(biop+) cut-off would result in an increase in the PPV from 19% (225 of 1201) to 25% (188 of 760). Thirteen percent of PC cases would not have been diagnosed, of which 70% (initial screening) and 81% (repeat screening) could be considered as potentially indolent. None of the deadly PC cases would have been missed. A PSA cut-off of ≥4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses. Conclusions: An individualized screening algorithm using other available prebiopsy information in addition to PSA level can result in a considerable reduction of unnecessary biopsies. Very few important PC cases, for which diagnosis at a subsequent screening visit might be too late for treatment with curative intent, would be missed. [Copyright &y& Elsevier]

Abstract: Background: Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. Objective: To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. Design, setting, and participants: We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162 243 men 55–69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). Intervention: Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. Measurements: Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. Results and limitations: In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68–0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58–0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51–0.92) to 0.71 (95% CI, 0.55–0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. Conclusions: PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening. [Copyright &y& Elsevier]

Abstract: Background: The value of prostate-specific antigen velocity (PSAV) in screening for prostate cancer (PCa) and especially for clinically significant PCa is unclear. Objective: To assess the value of PSAV in screening for PCa. Specifically, the role of PSAV in lowering the number of unnecessary biopsies and reducing the detection rate of indolent PCa was evaluated. Design, Setting, and Participants: All men included in the study cohort were participants in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section. Intervention: During the first and second screening round, a PSA test was performed on 2217 men, and all underwent a biopsy during the second screening round 4 yr later. Measurements: PSAV was calculated and biopsy outcome was classified as benign, possibly indolent PCa, or clinically significant PCa. Results and Limitations: A total of 441 cases of PCa were detected, 333 were classified as clinically significant and 108 as possibly indolent. The use of PSAV cut-offs reduced the number of biopsies but led to important numbers of missed (indolent and significant) PCa. PSAV was predictive for PCa (OR: 1.28, p <0.001) and specifically for significant PCa (OR: 1.46, p <0.001) in univariate analyses. However, multivariate analyses using age, PSA, prostate volume, digital rectal examination and transrectal ultrasonography outcome, and previous biopsy (yes/no) showed that PSAV was not an independent predictor of PCa (OR: 1.01, p =0.91) or significant PCa (OR: 0.87, p =0.30). Conclusions: The use of PSAV as a biopsy indicator would miss a large number of clinically significant PCa cases with increasing PSAV cut-offs. In this study, PSAV was not an independent predictor of a positive biopsy in general or significant PCa on biopsy. Therefore, PSAV does not improve the ERSPC screening algorithm. [Copyright &y& Elsevier]

Abstract: Background: Evidence indicates that an abnormal digital rectal examination (DRE) is a risk factor for high-grade prostate cancer (PC). Objective: To determine whether men with an initially suspicious DRE, a prostate-specific antigen (PSA) level ≥3.0ng/ml, and a benign prostate biopsy are at higher risk for significant PC at rescreening than men with an initially normal DRE, and whether an adaptation of the rescreening interval is warranted for this group. Design, Setting, and Participants: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam, 2218 men underwent biopsy of the prostate (from 1993 to 2000) with a benign result at initial screening. The serum PSA was determined every 4 yr. A PSA level of ≥3.0ng/ml prompted a DRE and a lateralised sextant biopsy. Measurements: Number and characteristics of PCs found at repeat screenings and as interval cancers (ICs) were compared between men with or without a suspicious DRE result at initial screening. Multivariate logistic regression analyses were performed to evaluate if an initially suspicious DRE was a significant predictor for detecting cancer at consecutive screenings. Results and Limitations: After 4 yr, the total number of PCs detected in men with and without an initially suspicious DRE was, respectively, 27 (6%) versus 103 (6%) (p =0.99). After 8 yr these numbers increased, respectively, to,45 (10%) versus 167 (10%) (p =0.88). The proportion of clinically significant PCs was 2% and 3%, respectively, for the group with initially normal and abnormal DRE after 8 yr. Having a suspicious DRE result at initial screening was not a significant predictor for detecting PC after 4 yr [odds ratio (OR)=1.15, p =0.59) or 8 yr (OR=1.41, p =0.43)]. A limitation of this study is the relatively short follow-up of 8 yr. Conclusions: During a follow-up of 8 yr after initial cancer-negative biopsy, an initially suspicious DRE did not influence the chance for detection of cancer or significant cancer at later screens. An adaptation of the rescreening interval on the basis of the initial DRE-outcome is not warranted in future population-based screening for prostate cancer. [Copyright &y& Elsevier]

Purpose: Previous studies have examined the relationship among prostate specific antigen, other predictive factors and current prostate cancer risk. We examined the population risk during 4 years, defined a prostate specific antigen associated with this risk and clarified the contribution of other predictive factors. Materials and Methods: The population consisted of men 55 to 70 years old screened at the first and second screening rounds 4 years apart in the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. The proportion of men with a positive prostate biopsy (initiated for a prostate specific antigen of 3.0 ng/ml or greater) and the mean population prostate specific antigen were calculated. Multivariate modeling was conducted using a proportional odds regression model to establish significant predictors of a positive biopsy from round 1 to round 2 of screening. Results: Among men with no previous prostate biopsy the 4-year risk of prostate cancer was 5.1%, which was associated with a mean prostate specific antigen of 1.5 ng/ml at the first screening. An increased prostate specific antigen was a highly significant predictive factor for biopsy detectable prostate cancer 4 years later. Increasing log total prostate volume and a previous negative biopsy were associated with a significant reduction in risk of a positive prostate biopsy 4 years later. Conclusions: A prostate specific antigen of 1.5 ng/ml or greater in men older than 50 years represents an indicator for greater than average future risk of prostate cancer. Prostate specific antigen and other factors can be used to define future prostate cancer risk in addition to current use as a diagnostic marker for prostate cancer. [Copyright &y& Elsevier]

OBJECTIVES To identify pathological features in non-malignant sextant prostate needle biopsies and assess their predictive value for detecting prostate cancer on biopsy 4 years later. PATIENTS AND METHODS We selected and reviewed the biopsy specimens of 121 men that were diagnosed as non-malignant during the first screening round of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section. Of these 61 (50.4%) were positive for cancer during the second round (the result of a matched random sample). The biopsies were indicated by prostate-specific antigen levels of ≥ 3.0 ng/mL. Specimens were scored for high-grade prostatic intraepithelial neoplasia (HGPIN), active and chronic inflammation, biopsy core length and glandular core length. The predictive value of the pathological features for detecting prostate cancer after 4 years was assessed. RESULTS In the first-round biopsies the incidence of HGPIN was 7.1%; there was active inflammation in 22.4% and chronic inflammation in 51.0%. The mean core length was 9.3 mm and mean glandular core length 7.4 mm; the mean total biopsy length (sum of core lengths) was 56.3 mm and mean total glandular length (sum of glandular core lengths) was 44.6 mm. None of the pathological features in the initial round was significantly related to the detection of cancer in the second round. CONCLUSIONS In this study of non-malignant prostate biopsy specimens from a screened population, no pathological features could be identified that were predictive for detecting prostate cancer on biopsy 4 years later. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. Patients and methods: We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. Results: Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 yr (25–75p; 66.1–72.8); median PSA 3.6ng/ml (25–75p; 3.1–4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 yr, 103 men (44.2%) had a PSA doubling time that was negative (ie, half-life) or longer than 10 yr. Men detected at rescreening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 yr; the cause-specific survival was 100%. Conclusions: This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men. [Copyright &y& Elsevier]

Abstract: Objectives: Ongoing randomized controlled screening trials for prostate cancer have not shown a beneficial effect on prostate cancer mortality reduction yet. A large number of observational (non-randomized) studies on prostate cancer screening have been published with contradictory outcome. This paper reviews the current case-control studies. Methods: Seven case-control studies of screening for prostate cancer were identified in a PubMed search, published from 1991 onwards, all conducted in North America. The screening test was either digital rectal examination (DRE) alone or in combination with PSA. Results: One DRE case-control study, found a significant preventive effect, whereas two others showed no effect of DRE screening on prostate cancer mortality nor on the occurrence of metastatic disease. Conflicting results were also observed in the studies assessing the effect of PSA/DRE. Only one study showed a significant 27% mortality reduction in the White male cohort, but found no effects in Blacks. The most recent study showed that screening with PSA/DRE was not protective in reducing prostate cancer mortality. Conclusions: Our review of the case-control studies does not indicate a benefit of prostate cancer screening. An answer has to come from the ERSPC trial, in Europe, and the PLCO trial, in the US, of which the outcomes are expected in 2007–2010. [Copyright &y& Elsevier]

Abstract: Objective: Screening practices for prostate cancer have resulted in an increasing incidence of prostate cancers. Our knowledge about which prostate cancers are life threatening and which are not is limited. Thus, for ethical, medical, and economic reasons we need to define which patients can be managed by active surveillance. Methods: From 1993 through 1999, men from the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC) were screened by two strict protocols, which were based on prostate-specific antigen (PSA), digital rectal examination, and transrectal ultrasound. For this study, men with criteria that reflect current active surveillance studies were selected: those with a biopsy Gleason score ≤3+3 in two or fewer cores, with a PSA density <0.2 and a maximum PSA-level of 15ng/ml. Clinical stage had to be T1C or T2. Results: Of the 1,014 prostate cancers detected in the prevalence screen, 293 men (28.9%) met the criteria for active surveillance. Their mean age was 65.7 and the mean PSA level was 4.8ng/ml. Radical prostatectomy was elected by 136 men (46.4%), radiotherapy by 91 (31.1%), and watchful waiting by 64 (21.8%). The mean follow-up was 80.8 months. The eight-year prostate cancer-specific survival was 99.2%; the overall survival was 85.4%. Nineteen men who chose watchful waiting changed to definitive treatment during follow-up. Conclusion: Only three men died of prostate cancer, none of whom were on watchful waiting. Our observations provide preliminary validation of the arbitrary selection criteria for active surveillance. [Copyright &y& Elsevier]

Abstract: Objectives: Currently, several prostate cancer rescreening intervals are in use in different countries worldwide, varying from 1 to 4 years. Recently, it has been proposed to determine the rescreening interval relative to the initial prostate-specific antigen (PSA) level and possibly to extend the rescreening interval up to 5 years. Methods: We evaluated the screening results of two subsequent screening visits (4-year interval) of 1703 men aged 55 to 65 years with an initial PSA level of 1.0 ng/mL or less within a randomized screening trial. We assessed the PSA values, numbers of men biopsied (biopsy indication: PSA level of 3.0 ng/mL or greater), and numbers of cancers detected at the second and third screening visits. Results: A total of 1327 men (79.3%) attended the second screening visit. Of these men, 13 (0.98%) had a PSA level of 3.0 ng/mL or greater, and three cancers were detected (cancer detection rate 0.23%). At the third screening visit, 1017 men (76.8%) attended, 34 men (3.3%) had a PSA level of 3.0 ng/mL or greater, and five cancers were detected (cancer detection rate 0.49%). The 2344 subsequent PSA determinations in an 8-year period after the initial screening resulted in eight cancers detected, for an overall cancer detection rate of 0.47%. Through linkage of all men with the cancer registry, no additional cancers were found. Conclusions: A strategy of PSA screening every 8 years for men with a PSA level of 1.0 ng/mL or less will lead to a considerable decrease in the number of screening visits (with the associated costs and stress), with a minimal risk of missing aggressive cancer at a curable stage. [Copyright &y& Elsevier]

Men aged 70–74 yr who had have undergone protocolled prostate-specific antigen (PSA) screening without being diagnosed with prostate cancer face a minimal risk of prostate cancer death. Continued screening is appropriate only for those with high PSA and extended life expectancy (>10 yr). The optimal timing for discontinuing screening of prostate cancer (PCa) in elderly men is currently not known and remains debated. To assess prostate cancer–specific mortality (PCSM) in elderly men who previously underwent prostate-specific antigen (PSA)-based screening and to identify those who may benefit from continued screening. A total of 7052 men, who participated in the screening arm of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer and were aged 70–74 yr at their last screening visit after undergoing a maximum of three screening rounds without being diagnosed with PCa, were included. The cumulative incidence of PCSM by the age of 85 yr was assessed. Additionally, a competing risk regression was performed to assess the potential predictors of PCSM. The median follow-up was 16 yr. The cumulative incidence of PCSM by the age of 85 yr was 0.54% (95% confidence interval [CI]: 0.40–0.70) in all men, 0.11% (95% CI: 0.05–0.27) in men with PSA <2 ng/ml, 0.85% (95% CI: 0.47–1.5) in men with PSA 2–3 ng/ml, and 6.8% (95% CI: 3.1–15) in men with PSA ≥6.5 ng/ml and no previous benign biopsy. PSA (subdistribution hazard ratio [sHR]: 2.0; 95% CI: 1.7–2.3), previous benign prostate biopsy (sHR: 0.41; 95% CI: 0.23–0.72), and hypertension (sHR: 0.48; 95% CI: 0.25–0.91) were significantly associated with PCSM. Men aged 70–74 yr who have previously undergone PSA-based screening without receiving a PCa diagnosis have a very low risk of dying from PCa by the age of 85 yr. These data suggest that screening may be discontinued in men with PSA <3.0 ng/ml or previous benign prostate biopsies. Those with higher PSA levels and no prior biopsies may consider continued screening if life expectancy exceeds 10 yr. This study shows that men who participated in a prostate cancer screening trial have a very low risk of dying from prostate cancer if they have not been diagnosed with prostate cancer by the age of 74 yr. [ABSTRACT FROM AUTHOR]

The article discusses screening for prostate cancer (PC) and prostate specific antigen (PSA). It references a 2009 report from the European Randomized Study of Screening for Prostate Cancer (ERSPC) to apply the results for health care providers and men considering screening. Also included are data on the relative reduction in PC mortality due to PC screening, the number of patients needed to treat (NNT) to avoid one PC death and PSA testing as an offshoot of PC screening.

Repeated, prostate-specific antigen–based screening with a 4-yr interval in men aged 55–69 yr reduces prostate cancer–specific mortality and metastatic prostate cancer after a median follow-up of 21 yr. Additionally, coinciding overdiagnosis is lower than previously suggested. Considering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial. To provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC. Between 1993 and 2000, a total of 42 376 men, aged 55–74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55–69 yr (n = 34 831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr. Intention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa. After a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61–0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58–0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87–1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr. The current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70–74 yr and show that repeated screening is essential. Prostate-specific antigen–based prostate cancer screening reduces metastasis and mortality. Longer follow-up shows fewer invitations and diagnoses needed to prevent one death, a positive note towards the issue of overdiagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article offers information on prostate screening (PS) conducted by the European Randomized Study of Screening for Prostate Cancer. The results reveal the detection of prostate cancer (PC) in 9.6% of the intervention group and 3% of the control population. It was also found that men undergoing prostate-specific antigen screening has 3.2 times more chances of diagnosis compared to men with no screening, and PC metastasis is 53% lower when proper intervention is taken.

A letter to the editor is presented in response to the editorial "Is a Screening Interval of Every 4 Years for Prostate Cancer Acceptable?" by E. David Crawford published in a previous issue in 2007.

Focuses on the main purpose of the initiation of the European Randomized Study of Screening for Prostate Cancer in the Netherlands. Total number of men suffering from the disease; Analysis on the blood samples of the patients; Assessment on the response of the immune system from the treatment.

Individual approaches to prostate cancer screening in European countries could occur as a result of individual decision taking, public health policies or the relevance of the prostate cancer problem determined by incidence and mortality in individual countries. Methods: An attempt is made to analyse current literature with respect to factors that could influence the individual or country-wide preference for or against the use of PSA driven screening. To obtain background information the incidence and mortality of prostate cancer in the EU countries participating in the ERSPC study, as well as the results of a recent join-point analysis of prostate cancer mortality for the same countries are reviewed. In addition, the question whether geographic differences in incidence and mortality could influence the value of screening tests in the different countries is evaluated. Results: Our literature review shows large regional differences in incidence and mortality of prostate. Proportions of men testing positive with PSA values ⩾4.0ng/ml and PPVs do not reflect these regional differences. Also, regional differences are not in line with negative outcomes for any ERSPC center in an exploratory analysis of prostate cancer mortality. In all centers a decrease of prostate cancer mortality at various degrees was seen. Differences in attitude may be visible in the join-point regression analysis which shows differences in mortality trends for some countries. Detection of T1c cancers in the control group is a measure of opportunistic screening (limitations addressed in the text). The differences reported may best reflect regional decision patterns. As far as the validity of PSA driven testing in countries with a different incidence and mortality is concerned, it seems that neither the levels nor the predictive value of PSA is influenced by such differences. Conclusions: A number of factors are identified which may explain the different individual decisions and different levels of use of opportunistic screening in the different EU countries. [Copyright &y& Elsevier]

Background: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific–antigen (PSA) testing on death rates from prostate cancer. Methods: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. Results: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). Conclusions: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.) N Engl J Med 2009;360:1320-8. [ABSTRACT FROM AUTHOR]

Abstract: Background: The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative. Objective: To retrospectively validate the currently used criteria for eligibility for AS. Design, setting, and participants: For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] ≤10.0ng/ml, PSA-density <0.2ng/ml per ml, stage T1C/T2, Gleason score ≤3+3=6, and ≤2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr. Measurements: Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated. Results and limitations: The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available. Conclusions: AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered. [Copyright &y& Elsevier]

Abstract: Objective: To compare tumour characteristics at the time of diagnosis of cancers detected in the screening and control arm at the Rotterdam section of the European Randomized study of Screening for Prostate Cancer. Methods: Data were retrieved from the Rotterdam section of the ERSPC. Men were randomized to the screening arm (n =21,210) or the control arm (n =21,166). Men randomized to screening were offered PSA testing every 4 years. Through linkage with the cancer registry, men randomized to the control arm were detected. The biopsy Gleason score was determined in 1,591 and 373 patients in the screening and control arm, respectively. TURP, radical prostatectomy (RP) and cystoprostatectomy were evaluated for Gleason score, pathological (p)T stage and tumour volume. Results: More prostate cancers were detected in the screening arm (15.9 vs. 4.2 per 1000 man years, p <0.0001). Clinical stage distribution as well as biopsy and RP Gleason score distribution were significantly less favourable in the control arm. The incidence in man years of advanced disease (i.e. T4/N1/M1) was higher in the screening arm (6.0 per 100,000) as compared to the control arm (4.6 per 100,000). The 5-year PSA progression free survival after RP was 68% in the control arm and 89% in the screening arm (p <0.0001). The proportion of Incidental prostate cancers was 9.3% of all cancers detected in the control arm. Conclusions: Although the number of men with advanced prostate cancer is slightly higher in the screening arm, the proportion of prostate cancers with favourable features is increased in the screening arm as compared to that in the control arm. [Copyright &y& Elsevier]

Objective: We aimed to assess to what extent men make informed choices in the context of prostate cancer screening and how written material contributes to that process.Methods: We developed a leaflet describing prostate cancer screening, and a questionnaire consisting of knowledge, attitude, and intended screening uptake components to assess informed decision-making. The leaflet and questionnaire were pilot-tested among men of the target population, adapted accordingly, and sent to 761 members of an online research panel. We operationalized whether the leaflet was read as spending one minute on the leaflet page and by a self-reported answer of respondents.Results: The response rate was 66% (501/761). The group who read the leaflet (n = 342) correctly answered a knowledge item significantly more often (10.9 versus 8.8; p < 0.001) than those who did not read the leaflet (n = 159), and made more informed choices (73% versus 56%; p = 0.001). There were no significant differences in attitude and intended screening uptake between both groups.Conclusion: Having read the leaflet could be one of the factors associated with increased levels of knowledge and informed decision-making.Practical Implications: The results of this study showed that increasing knowledge and supporting informed decision-making with written material are feasible in prostate cancer screening. [ABSTRACT FROM AUTHOR]

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 ≥69 Gy. 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 [ABSTRACT FROM AUTHOR]