http://repub.eur.nl/res/aut/13713/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37453/ 2012-11-01T00:00:00Z Background: Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective: To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. Design, setting, and participants: Data were available for 76 813 men aged 55-69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention: Regular screening based on serum PSA measurements was offered to 36 270 men randomized to the screening arm, while no screening was provided to the 40 543 men in the control arm. Outcome measurements and statistical analysis: The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations: After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p < 0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p = 0.001) in the intention-to-screen analysis and a 42% (p = 0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. Conclusions: PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736. http://repub.eur.nl/res/pub/37457/ 2012-11-01T00:00:00Z http://repub.eur.nl/res/pub/37466/ 2012-11-01T00:00:00Z http://repub.eur.nl/res/pub/38883/ 2012-09-01T00:00:00Z Objective: To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods: Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality. Results: In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%). Conclusions: Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced. http://repub.eur.nl/res/pub/39092/ 2012-08-16T00:00:00Z Background: After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. Methods: On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. Results: Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). Conclusions: The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.) Copyright http://repub.eur.nl/res/pub/37963/ 2012-03-01T00:00:00Z Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS). Objective: Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV. Design, setting, and participants: For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010-2011 as participants in ERSPC Rotterdam. Measurements: Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60 cm3) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage >T2b and/or Gleason score ≥7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study. Results and limitations: Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p = 0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p = 0.0075) in the relatively small validation cohort. Further validation is required. Conclusions: An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners. http://repub.eur.nl/res/pub/34948/ 2012-01-23T00:00:00Z A sophisticated reading of the randomized trial evidence suggests that, although screening for prostate cancer with prostate-specific antigen (PSA) can reduce cancer-specific mortality, it does so at considerable cost in terms of the number of men who need to be screened, biopsied, and treated to prevent one death. The challenge is to design screening programs that maximize benefits (reducing prostate cancer mortality) and minimize costs (overtreatment). Recent research has suggested that this can be achieved by risk-stratifying screening and biopsy; increasing reliance on active surveillance for low-risk cancer; restricting radical prostatectomy to high-volume surgeons; and using appropriately high-dose radiotherapy. In current U.S. practice, however, many men who are screened are unlikely to benefit, most men found to have low-risk cancers are referred for unnecessary curative treatment, and much treatment is given at low-volume centers. http://repub.eur.nl/res/pub/34955/ 2012-01-20T00:00:00Z Objective: To compare sexual function of men with localized prostate cancer (PCa) on active surveillance (AS) with similar patients who received radical therapy. Patients And Methods: Two groups of men with screening-detected localized PCa were compared. The first were men on AS within the prospective protocol-based Prostate Cancer Research International: Active Surveillance study. The second were men participating in the European Randomized Study of Screening for Prostate Cancer study who had received radical prostatectomy (RP) or radiation therapy (RT). Questionnaires were completed at two different timepoints after diagnosis or treatment (6 and 12-18 months). These contained 10 items on sexual function, the mental and physical component summary from the Short-Form 12-item health survey, the Center for Epidemiologic Studies Depression scale depression measure and the State Trait Anxiety Inventory general anxiety measure. Sexual function was compared between groups, and determinants were analysed in multivariable analysis, adjusting for baseline differences. Results: A total of 65-68% of men on AS, 35-36% of those who underwent RP, 36-37% of those who underwent RT and 36% of men in the RP and RT groups combined (combined Tx) were sexually active. A total of 20-30% of men in the AS group, 86-91% of men in the RP group, 56-60% of men in the RT group and 71-76% of men in the combined Tx group were sexually inactive as a result of erectile dysfunction. A total of 44-51% of men in the AS group, 96% of men in the RP group, 73-76% of men in the RT group and 84-85% of men in the combined Tx group who were sexually active had problems getting or keeping an erection. In multivariable analysis these differences were significant, except for AS vs RT. Conclusions: Men with localized PCa on AS were more often sexually active than similar men who received radical therapy, especially RP. If not sexually active, this was less often attributable to erectile dysfunction for those on AS. If sexually active, this was less often associated with problems getting or keeping an erection for those on AS. The study was non-randomized; the latest advances in RP and RT might impact results. © 2012 THE AUTHORS. BJU INTERNATIONAL http://repub.eur.nl/res/pub/32008/ 2012-01-01T00:00:00Z BACKGROUND The prostate may often harbor a prostate cancer (PC) which will not cause morbidity if left untreated. Screening for PC leads to increased detection of these insignificant cancers. Objective of this study is to compare PC detected by PSA screening at subsequent screening rounds and treated by radical prostatectomy (RP) with PC incidentally found in cystoprostatectomy specimens. METHODS Radical prostatectomy specimens of 617 screen-detected PC were compared with 123 PC identified in cystoprostatectomy specimens. Surgical specimens were systematically examined and stage, grade, tumor volume were recorded. Next, we classified PC as clinically significant or insignificant (i.e., tumor volume <0.5 cm3, absence of Gleason pattern 4/5, organ confined). Pathological features of incidentally detected PC were compared with PC detected in subsequent screening rounds and with screen-detected T1c PC. RESULTS Screen-detected PC overall were more often multifocal, larger in volume, more advanced in tumor stage and of higher grade, while the frequency of insignificant PC was lower as compared to those in cystoprostatectomy specimens. This effect became more pronounced during subsequent screening rounds. Screen-detected T1c PC were also more often multifocal (73% vs. 37%) in average fivefold larger (0.85 cm3vs. 0.16 cm3), less often organ confined (81% vs. 94%), and less frequently clinically insignificant (33% vs. 81%). CONCLUSIONS: Screen-detected (T1c) PC treated with RP shows more aggressive features than incidentally found PC. This PSA screening-related selection seems to be mainly driven by tumor volume and-in later screening rounds-by the preferential treatment by prostatectomy of more aggressive PC. Copyright http://repub.eur.nl/res/pub/34720/ 2012-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/33983/ 2011-12-01T00:00:00Z Background: Screening for prostate cancer (PC) with prostate-specific antigen (PSA) has been shown to decrease mortality, but has adverse effects, such as false-positive (FP) screening results. We describe the frequency of FP results and assess their relation to subsequent screening attendance, test results and prostate cancer risk in a large randomized trial. Materials and methods: We included data from five centres of the European Randomized Study of Screening for Prostate Cancer, altogether over 61,000 screened men. Men were screened with PSA test at a 2-7 year interval depending on the centre; PSA cut-off was 3.0-4.0 ng/ml. A positive screen with no histologically confirmed PC in biopsy within 1 year was defined as an FP result. Results: Of the 61,604 men who were screened at least once, 17.8% had one or more FP result(s). Almost 20% of men who participated at all screening rounds had one or more FP result(s). More than half of the men with an FP result had another FP if screened again. Men with FP results had a fourfold risk of PC at subsequent screen (depending on the round, 10.0% versus 2.6-2.7% of men with negative screen, risk ratio 3.8-3.9). The PCs following an FP result were in 92.8% of cases localised and low-grade versus 90.4% following a screen-negative result. Conclusions: Our results show that FP results are common adverse effects in PC screening, as they affect at least one in six screened men. False-positive men are more prone to be diagnosed with PC but are also likely to have consistently high PSA levels. http://repub.eur.nl/res/pub/34339/ 2011-11-24T00:00:00Z Study Type - Prognosis (cohort series) Level of Evidence2a 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 <20ng/mL, clinical stage T1 or T2a-c disease, <50% positive sextant biopsy cores, ≤20mm cancer tissue, ≥40mm 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 7ng/mL, P= 0.02), higher mean amount of cancer tissue (7 vs 3mm, 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. © 2011 THE AUTHORS. BJU INTERNATIONAL http://repub.eur.nl/res/pub/30770/ 2011-11-01T00:00:00Z http://repub.eur.nl/res/pub/33216/ 2011-11-01T00:00:00Z http://repub.eur.nl/res/pub/34152/ 2011-10-25T00:00:00Z The early detection of asymptomatic prostate cancer has led to the increased incidence of tumours that are unlikely to become symptomatic during life, so called indolent cancers. The prediction of low risk and indolent prostate cancer is needed to avoid overtreatment by unnecessary invasive therapies, and select men for active surveillance. Some of the currently available nomograms predicting these low risk tumours have been validated in independent populations. However, assessment to the compliance with their treatment advises based on the calculation of probability are scarce. The ultimate value of nomograms for the urologic practice can only be assessed by analysing their practical implementation. http://repub.eur.nl/res/pub/34356/ 2011-10-01T00:00:00Z What's known on the subject? and What does the study add? Cysteine-rich secretory protein 3 (CRISP-3) and β-microseminoprotein (β-MSP) both have independent prognostic value for biochemical recurrence of prostate cancer after radical prostatectomy. The study investigates whether CRISP-3 and β-MSP have prognostic value on diagnostic prostate needle-biopsies, which are more relevant for therapeutic decision-making. On needle-biopsies CRISP-3 and β-MSP do not have significant prognostic value. OBJECTIVES • To investigate whether cysteine-rich secretory protein 3 (CRISP-3) and/or β-microseminoprotein (β-MSP) expression in diagnostic prostate needle biopsies have predictive value for prostate cancer (PC) on radical prostatecomy (RP). • To evaluate their potential clinical implementation in a preoperative setting. PATIENTS AND METHODS • In total, 174 participants from the European Randomized Study of Screening for Prostate Cancer, Rotterdam section, treated by RP for PC were included in the present study. • CRISP-3 and β-MSP immunohistochemistry was performed on corresponding diagnostic needle biopsies. • Outcome was correlated with clinicopathological parameters (prostate-specific-antigen, PSA; number of positive biopsies; Gleason score, GS; pT-stage; surgical margins at RP) and significant PC at RP (pT3/4, or GS > 6, or tumour volume ≥0.5 mL) in the total cohort (n= 174) and in a subgroup with low-risk features at biopsy (PSA ≤ 10 ng/ml, cT a;circ 2, PSA density <0.20 ng/mL/g, GS < 7 and ≤2 positive biopsy cores; n= 87). RESULTS âcent β-MSP and CRISP-3 expression in PC tissue was heterogeneous, with variable staining intensities occurring in the same tissue specimen. âcent High expression of β-MSP significantly correlated with GS < 7 at RP; it was not a predictor for significant PC at RP neither in the total group (n= 174; odds ratio, OR, 0.319; 95% confidence interval, CI, 0.060-1.695; P= 0.180), nor in the low-risk group (n= 87; OR, 0.227; 95% CI, 0.040-1.274; P= 0.092). âcent CRISP-3 expression was not related to clinicopathological parameters, and did not predict significant PC at RP in the total group (n= 174; OR, 1.056; 95% CI, 0.438-2.545; P= 0.904) or the low-risk group (n= 87; OR, 1.856; 95% CI, 0.626-5.506; P= 0.265). CONCLUSIONS âcent High β-MSP expression correlated with low GS in subsequent RP specimens, supporting the view that β-MSP exerts a tumour-suppressive effect. âcent No significant prognostic value of β-MSP or CRISP-3 in prostate needle biopsies for significant PC at RP was found. âcent β-MSP or CRISP-3 do not have additional value in the therapeutic stratification of patients with PC. http://repub.eur.nl/res/pub/31331/ 2011-08-01T00:00:00Z Background: In a screening program, interval cancers are cancers diagnosed between two screening visits. Objective: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. Design, setting, and participants: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. Intervention: Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. Measurements: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. Results and limitations: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. Conclusions: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. Trial registration: ISRCTN49127736. http://repub.eur.nl/res/pub/31332/ 2011-08-01T00:00:00Z Background: In a screening program, interval cancers are cancers diagnosed between two screening visits. Objective: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. Design, setting, and participants: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. Intervention: Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. Measurements: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. Results and limitations: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. Conclusions: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. Trial registration: ISRCTN49127736. http://repub.eur.nl/res/pub/26645/ 2011-07-19T00:00:00Z Selectively identifying aggressive prostate cancer will reduce unnecessary testing and overdiagnosis. Multivariate models can be of assistance but require proper validation and users must be aware of the setting from which the models were derived. See also pages 000-000. http://repub.eur.nl/res/pub/26059/ 2011-07-01T00:00:00Z http://repub.eur.nl/res/pub/26247/ 2011-06-01T00:00:00Z 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 TMPRSS2â€"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. http://repub.eur.nl/res/pub/33772/ 2011-06-01T00:00:00Z The democratization of civil society and the development of modern medicine changed the sacrosanct doctor-patient relationship to a doctor-partner dialogue. Values and respect were lost in the process where common courtesy and empathy in trust were replaced by patient rights. Launch of Europa Uomo. Europa Uomo, the European prostate cancer coalition, represents 22 national, autonomous patient support groups. Its aim includes increasing the awareness of prostate diseases, support individualized treatment as a balance between optimal medical treatment and personalized care delivered by a multiprofessional team. We expect our information/education from dedicated professional societies while in return we share care for properly informed members as well as a fast, unbiased and cheap distribution of information/innovation across the European continent. The role of a patient group. Our advocacy role is focused on quality of life, tailored treatment, knowledge of risk factors, support for research and last but not least active partnerships. We believe that we can play a modest but basic role in common actions to overcome inequalities in treatment and care in Europe. Our responsibilities range from defining patient obligations to facilitating translational research and saving scarce health resources. The horizon of the patient. Our hope is to plead for a treatment policy on the man first and then on his cancer and to improve treatment outcomes by multiprofessional collaboration and the development of expert Prostate Units. Future expectations. A transparent, open communication line between the multiprofessional team and the patient is mandatory. The existing uncertainties should be discussed with common sense but always leave a factor of hope in survival or quality of life. http://repub.eur.nl/res/pub/34380/ 2011-06-01T00:00:00Z 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. http://repub.eur.nl/res/pub/26432/ 2011-05-01T00:00:00Z Purpose of Review: With increasing evidence that prostate-specific antigen (PSA)-based screening can reduce disease-specific mortality but coincides with unacceptable levels of unnecessary testing and the diagnosis of potentially nonlife-threatening disease, the need for new, more specific biomarkers is urgent. Within this context the role of the prostate cancer gene 3 (PCA3) test is evaluated. Recent Findings: Studies investigating the value of PCA3 as a diagnostic test virtually all show a beneficial effect as compared to PSA with respect to specificity. Beside the fact that most of these studies are subject to potential bias, the observed increased specificity was accompanied by relatively low sensitivities. Two studies, attempting to avoid selection bias as much as possible, show a marginal beneficial effect of the PCA3 test. Data on PCA3 as a staging tool for prostate cancer remain inconclusive. SUMMARY: The PCA3 test is not capable of replacing the PSA test in clinical practice and an appropriate cut-off level with acceptable performance characteristics is hard to define. Its value as a first-line diagnostic test is limited. The addition of PCA3 to risk assessment tools leads to an increase in predictive capability. Data relating to the accuracy of PCA3 on prostate cancer staging are contradictory and PCA3 as prognostic test should be subject of future studies. http://repub.eur.nl/res/pub/26475/ 2011-04-22T00:00:00Z Patients And Methods: At Princess Margaret Hospital, 982 consecutive patients with PCPT-RC and ERSPC-RC covariables were prospectively catalogued before prostate biopsy for suspicion of prostate cancer (PCa). Receiver-operating characteristic (ROC) curves were generated for each calculator and prostate-specific antigen (PSA). Comparisons by area under the curve (AUC) and calibration plots were performed. Predictors of PCa were identified by univariable and multivariable logistic regression. Results: PCa was detected in 46% and high-grade (HG) PCa (Gleason ≥4) in 23% of subjects with a median PSA level of 6.02 ng/mL. Multivariable analysis identified transrectal ultrasonography nodule, prostate volume and PSA as the most important predictors of PCa and HG PCa. ROC curve analysis showed that the ERSPC-RC (AUC = 0.71) outperformed the PCPT-RC (AUC = 0.63) and PSA (AUC = 0.55), for PCa prediction, P < 0.001. The PCPT-RC was better calibrated in the higher prediction range (40-100%) than the ERSPC-RC, whereas the ERSPC-RC had better calibration and avoided more biopsies in the lower risk range (0-30%). Discrimination of the ERSPC-RC continued to be superior to the PCPT-RC when the cohort was stratified by different clinical variables. Conclusions: The ERSPC-RC had better discrimination for predicting PCa compared to the PCPT-RC in this Canadian cohort. Calibration would need to be improved to allow routine use of the ERSPC-RC in Canadian practice. What's known on the subject? and What does the study add? The European Randomized Study of Screening for Prostate Cancer risk calculator (ERSPC-RC) has been validated in a European population and shown to outperform the Prostate Cancer Prevention Trial risk calculator (PCPT-RC) for predicting prostate cancer. However, the ERSPC-RC has not been validated in North America where the PCPT-RC has been extensively validated. This study is the first to compare these calculators in non-European patient cohort showing better performance of the ERSPC-RC, but poor calibration. © 2011 THE AUTHORS. BJU INTERNATIONAL http://repub.eur.nl/res/pub/26452/ 2011-04-21T00:00:00Z http://repub.eur.nl/res/pub/25532/ 2011-04-06T00:00:00Z We aim to identify and characterize "escapes," men who developed metastasis and/or died from prostate cancer (PCa) despite screening, in the framework of the novel international ESCAPE-project. With this knowledge, the ultimate goal is to improve screening strategy. In this article, we focus on the study cohort of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. In all, 21,210 men were randomized to the screening arm of whom 19,950 were actually screened. The screening interval was 4 years. Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The follow-up was complete until January 1, 2009. Of 19,950 screened men, 2,317 were diagnosed with PCa. Of these cancers 1,946 were detected in a screening round and 371 during an interval. The median follow-up was 11.1 years for the whole cohort and 7.3 years for men diagnosed with PCa. In total, we identified 168 escapes among 2,317 cancers (7.3%) within our screening cohort of 19,950 men (0.8%). More than half of these escapes were found in the initial screening round (94 of 168). Possible mechanisms behind escaping are nonattending, inadequate screening tests, the relative long screening interval, the age cut-off at 75 years, and undertreatment. International cooperation is crucial to compare the escapes of our cohort with other study groups participating in the ESCAPE-project which have different, more aggressive screening strategies. Subsequently, we can achieve improvements of the current screening algorithm, which hopefully will further decrease PCa-specific mortality without increasing overdiagnosis and overtreatment. Copyright http://repub.eur.nl/res/pub/22776/ 2011-04-01T00:00:00Z Background: The European Randomised Study of Screening for Prostate Cancer (ERSPC) applies a prostate-specific antigen (PSA) cut-off value ≥3.0 ng/ml as an indication for lateralised sextant biopsy. Objective: To analyse the incidence and disease-specific mortality for prostate cancer (PCa) in men with an initial PSA <3.0 ng/ml. Design, setting and participants: From November 1993 to December 1999, a total of 42 376 men identified from population registries in the Rotterdam region (55-74 yr of age) were randomised to an intervention or control arm. A total of 19 950 men were screened during the first screening round. Intervention: A PSA <3.0 ng/ml was below the biopsy threshold. PCa cases were identified at rescreens every 4 yr or as interval cancers. Measurements: Distribution of incidence, aggressiveness, and disease-specific mortality of PCa per PSA range was measured. Causes of death were evaluated by an independent committee, and follow-up was complete until 31 December 2008. Results and limitations: From 1993 to 2008, 915 PCa cases were diagnosed in 15 758 men (5.8%) with an initial PSA <3.0 ng/ml and a median age of 62.3 yr. Median overall follow-up was 11 yr. PCa incidence increased significantly with higher initial PSA levels. Aggressive PCa (clinical stage ≥T2c, Gleason score ≥8, PSA >20 ng/ml, positive lymph nodes, or metastases at diagnosis) was detected in 66 of 733 screen-detected PCa cases (9.0%) and 72 of 182 interval-detected PCa cases (39.6%). Twenty-three PCa deaths occurred in the total population (0.15%), with an increasing risk of PCa mortality in men with higher initial PSA values. Conclusions: The risk of PCa, aggressive PCa and PCa mortality in a screening population with initial PSA <3.0 ng/ml increases significantly with higher initial PSA levels. These results contribute to the risk stratification and individual management of men in PSA-based screening programmes. http://repub.eur.nl/res/pub/34085/ 2011-04-01T00:00:00Z 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. http://repub.eur.nl/res/pub/31584/ 2011-03-01T00:00:00Z http://repub.eur.nl/res/pub/31591/ 2011-03-01T00:00:00Z http://repub.eur.nl/res/pub/34234/ 2011-03-01T00:00:00Z Since the first publication describing the identification of prostate-specific antigen (PSA) in the 1960s, much progress has been made. The PSA test changed from being initially a monitoring tool to being also used as a diagnostic tool. Over time, the test has been heavily debated due to its lack of sensitivity and specificity. However, up to now the PSA test is still the only biomarker for the detection and monitoring of prostate cancer. PSA-based screening for prostate cancer is associated with a high proportion of unnecessary testing and overdiagnosis with subsequent overtreatment. In the early years of screening for prostate cancer, high rates of uptake were very important. However, over time the opinion on PSA-based screening has shifted towards the notion of informed choice. Nowadays, it is thought to be unethical to screen men without them being aware of the pros and cons of PSA testing, as well as the fact that an informed choice is related to better patient outcomes. Now, as the results of three major screening studies have been presented and the downsides of screening are becoming better understood, informed choice is becoming more relevant. http://repub.eur.nl/res/pub/31554/ 2011-02-01T00:00:00Z http://repub.eur.nl/res/pub/33563/ 2011-01-01T00:00:00Z Purpose The identification of clinically insignificant prostate cancer could help avoid overtreatment. Current criteria for insignificant prostate cancer use a tumor volume threshold of less than 0.5 ml for the index tumor. In this study we reassess this tumor volume threshold for clinically insignificant prostate cancer using an independent data set. Materials and Methods The rate of insignificant prostate cancer was calculated by modeling lifetime risk estimates of prostate cancer diagnosis in screened and nonscreened participants in a randomized prostate cancer screening trial. Using lifetime risk estimates 50.8% of screen detected prostate cancer was calculated to be clinically insignificant and the 49.2% largest tumor volume of 325 prostatectomy specimens was used to determine the threshold tumor volume for insignificant prostate cancer. Because stage and grade represent the strongest determinants of cancer aggressiveness, we also calculated the tumor volume threshold for insignificant cancer after the selection of patients with organ confined prostate cancer without Gleason pattern 4/5. The analyses were performed for total tumor volume and for index tumor volume. Results The minimum threshold tumor volume of the index tumor and total tumor was 0.55 and 0.70 ml, respectively. After accounting for tumor stage and grade we obtained a threshold volume for the index tumor and total tumor of 1.3 and 2.5 ml, respectively. Conclusions We confirmed the original value of the index tumor volume threshold of 0.5 ml for insignificant prostate cancer, and we demonstrated that clinically insignificant prostate cancer may include index Gleason score 6, pT2 tumors with volumes up to at least 1.3 ml. These results suggest a reconsideration of current methods and nomograms used for pretreatment risk assessment. http://repub.eur.nl/res/pub/21362/ 2010-12-01T00:00:00Z The European Randomized study of Screening for Prostate Cancer (ERSPC) has recently reported a 20% reduction in death from prostate cancer in a population-based prostate cancer screening (core age group: 55-69 years of age). The effect of screening may be diluted by noncompliance in the screening arm and contamination by PSA testing in the control arm. The purpose is to analyze the effect of prostate cancer screening on the incidence of metastatic prostate cancer, both with and without adjustment for noncompliance and contamination. We analyzed the occurrence of metastases in 42,376 men aged 55-75 years who were randomized in the Rotterdam section of the ERSPC between 1993 and 1999. Contamination adjustment was based on follow-up findings and questionnaire data from all men in the control group who developed prostate cancer and from a random sample of 291 men without cancer who had a PSA test. Prostate cancer screening significantly reduced the occurrence of metastatic prostate cancer in the intention-to-screen analysis [RR 0.75, 95% CI 0.59-0.95, p = 0.02] and more so in adjusted analyses; contamination adjusted RR 0.73, 95% CI 0.56-0.96; noncompliance adjusted RR 0.72, 95% CI 0.55-0.95 and fully adjusted analysis RR 0.68, 95% CI 0.49-0.94, p = 0.02. In the population of ERSPC Rotterdam (N = 42,376 men), screening reduces the risk to be diagnosed with metastatic prostate cancer considerably on population level, an effect which is even more pronounced in men who are in fact screened. http://repub.eur.nl/res/pub/21689/ 2010-12-01T00:00:00Z 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 ≥2.5 ng/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. http://repub.eur.nl/res/pub/22978/ 2010-12-01T00:00:00Z 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 personyears 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. http://repub.eur.nl/res/pub/21387/ 2010-11-01T00:00:00Z Objective: To evaluate a change in tumour characteristics and applied treatments over time in the control arm of all centres of the European Randomized study of Screening for Prostate Cancer (ERSPC) and to compare this with similar data of the screening arm. Methods: Between 1993 and 2003, 182,160 men, aged 50-74 years, were randomised to the screening arm (N = 82,816) and the control arm (N = 99,184). Men in the screening arm were offered Prostate Specific Antigen (PSA) testing every 4 years whilst men in the control arm received usual care. Tumour characteristics and treatment were evaluated in all men diagnosed with prostate cancer up to December 2006 or the third screening round. Data on the control arm were divided into 3 periods: 1994-1998, 1999-2002 and 2003-2006. Results: Tumour characteristics were more favourable over time in both the control and the screening arm, with especially increasing proportions of T1C tumours with 29% in 1994-1998 versus 50% in 2003-2006 and 48% at the initial screening round versus 75% at the third screening round, respectively. Tumour characteristics observed in the last period of the control arm were comparable to tumour characteristics in the initial screening round. In the control arm, treatment changed over time with surgery as the most common treatment in the entire observed period, but almost doubling of expectant management and the combination of hormone therapy and radiotherapy over time. In the initial screening round, surgery was the most common treatment (42%), changing over time to expectant management as the most frequently applied treatment in the third screening round (33%). Conclusion: Tumour characteristics in the control arm became more favourable over time and show similarity with prostate cancer cases detected at the initial screening round. The most prominent change in treatment over time was an increase of application of expectant management in both arms of the ERSPC. These observations reflect an increasing rate of opportunistic testing over time in men randomised to the control arm. http://repub.eur.nl/res/pub/21388/ 2010-11-01T00:00:00Z The aim of the study: This article presents the incidence of prostate cancer, isolated high grade prostatic intraepithelial neoplasia (PIN) and atypical lesions suspicious for prostate cancer (LSPC) during subsequent screening rounds in the centres of five of the countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC). The incidence and predictive value of high grade PIN and LSPC for prostate cancer in subsequent biopsy following these diagnoses were evaluated. Patients and methods: Study group consisted of 56,653 screened men in the ERSPC centres of Finland, Italy, Netherlands, Sweden and Switzerland, who underwent 3-7 screening rounds at 2-4 year interval. Data for prostate cancer were obtained from the ERSPC central database. Data for high grade PIN and LSPC were gathered from each ERSPC centre. Detection rates of subsequent prostate cancer in the first re-biopsy after these diagnoses were determined. Results: The average cancer detection rate was 3.5%, 3.2% and 3.5% for the completed rounds 1, 2 and 3, respectively, in all five centres. Incidence of high grade PIN increased from 1.5% in the first round to 5.0% in the third round, varying among centres in the first round between 0.8% and 7.6%. The cancer detection rate in the first re-biopsy after the diagnosis of high grade PIN was 12.9%. Incidence of LSPC was 2.4%, 2.7%, 2.2% and 2.6% in the first, second, third and fourth round, respectively. The cancer detection rate at the first re-biopsy after the diagnosis of LSPC was in average 33.8%. Conclusions: Cancer detection rate was stable during the three screening rounds. The wide variation in frequency in particular of high grade PIN among the ERSPC centres suggests a considerable inter-observer variation. The average comparatively low detection rate of isolated high grade PIN in the first screening round may be screening-related, while its consistent increase during three screening rounds could be the consequence of a.o. previous screening and ageing of the population. The observed low risk of prostate cancer after isolated high grade PIN in this screening setting is in line with the current recommendation to abstain from early repeat biopsies after this diagnosis. The association of LSPC with high incidence of prostate cancer in re-biopsies confirms the need for early repeat biopsies and follow-up of these men. The low percentage of LSPC (<3% of biopsies) throughout all rounds is reassuring as it limits the biopsy burden in a screening setting. http://repub.eur.nl/res/pub/21389/ 2010-11-01T00:00:00Z 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 ≥4.0 ng/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. http://repub.eur.nl/res/pub/21390/ 2010-11-01T00:00:00Z Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC. http://repub.eur.nl/res/pub/21391/ 2010-11-01T00:00:00Z Background: To describe the variation in PSA level by age group and screening round in the ERSPC centres and the variation in cancer detection rates in relation to the underlying prostate cancer incidence. Methods: Individual data on men invited for the first and second screening rounds according to protocol (excluding early recalls and interval cancers) were obtained from the central database of the ERSPC (cut-off date 31st December 2006). Data were compared between and within centres for the core age group (55-69 at entry). The cancer detection rate (CDR) was compared with the expected background prostate cancer incidence rate in the absence of screening adjusted for the incidence rate in non-attenders and the control arm (IRS). Results: Mean PSA values in the age groups 55-59 years and 65-69 years showed little variation by centre, except for the Dutch centre, where an increase from 1.6 to 1.8 ng/ml and a decline from 2.9 to 2.5 ng/ml was observed, respectively. Most tumours were detected at the PSA range 4.0-9.9 ng/ml, with a shift to more cancer detection at 3.0-3.9 ng/ml in the second screening round. There was high variability in the CDR between the centres in both the first (16-46 per 1000) and the second screening rounds (14-50 per 1000). Although the ratio CDR/IRS was less variable, it is somewhat lower in Italy and Switzerland (12 and 14,respectively) and higher in the Netherlands (28), than in most other centres and in Belgium the ratio increased markedly, from 20 to 44 between the first and second rounds. Conclusion: There was no clear evidence of a relationship between the underlying incidence and mean PSA levels at screening or the cancer detection rate. http://repub.eur.nl/res/pub/21393/ 2010-11-01T00:00:00Z Background: To assess the agreement between the causes of death assigned by a blinded and uniform review panel of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer and the official vital statistics and to explore the possible effect of the use of either of these two sources on the outcome of the screening trial. Methods: A total of 670 deaths amongst men with prostate cancer, reviewed by the causes of death committee (CODC) up to 31st December 2006 were included in this study. The kappa statistics with confidence intervals (CI), sensitivity and specificity of the official statistics were determined, with the CODC considered the gold standard. The rate ratio (RR) and 95% confidence intervals (95% CI) for prostate cancer mortality, official statistics relative to CODC, were calculated following the Mantel-Haenszel procedure. Results: The overall concordance and the kappa between official statistics and the CODC were 90.6% and 0.76 (0.71-0.82), remaining comparable when only the CODC category definitely prostate cancer was applied, with the sensitivity of official statistics increasing from 88.3% to 91.3% and specificity hardly changing (91.3% and 90.5%). High specificity and lower sensitivity is observed in the screening arm, whilst the opposite was seen in the control arm in men aged 55-69 and 70-74 years at entry. Considerable lower false positive rate was seen for both age groups in the screening arm (3.9% and 4.7%) compared to the control arm (8.4% and 14.3%). A statistically significant excess of prostate cancer death was observed for the official statistics in the age group 70-74 years, 1.53 (1.07-2.19), whilst it was not significant for men aged 55-69 at entry, 1.06 (0.83-1.36). Conclusion: In the Rotterdam ERSPC section, official statistics tended to overreport prostate cancer as an underlying cause of death, particularly in the age group 70-plus in the control arm, which would overestimate the true effect in favour of screening. http://repub.eur.nl/res/pub/21421/ 2010-11-01T00:00:00Z Background: The European randomised study of screening for prostate cancer (ERSPC) was initiated to evaluate the effect of Prostate Specific Antigen (PSA) screening on prostate cancer mortality. Variations in screening modalities between participating centres, such as the interval between screening rounds are likely to affect the outcome of screening. Methods: The study describes the number and characteristics of interval cancers in men in the screening arm of the Antwerp ERSPC aged 55-65 years at the time of randomisation and participating in the screening rounds they were invited for. The interval between the first screening rounds was 6 years on average. Interval cancers were defined as cancers diagnosed during the screening interval but not detected by screening. Cases with a positive screening test were considered as interval cancers if diagnosis through biopsy occurred more than 1 year after screening. Interval cancer cases were identified through linkage with cancer registries. Aggressive interval cancer was defined as cancer with at least one of the following characteristics: stage M1 or N1, Gleason score higher than 7 or World Health Organisation (WHO) score of 3. Results: The 10 year cumulative incidence of interval cancers was 3.0% (n = 50) and the cumulative incidence of aggressive interval cancers was 0.5% (n = 8). During the first screening interval 36 interval cancers were detected. Of these 20 (55.6%) were detected more than 4 years after the initial screening and 5 (13.9%) were considered aggressive. All aggressive interval cancers emerged more than 4 years after initial screening. Conclusion: The occurrence of interval cancers in this study was higher than in the ERSPC centres that used a shorter screening interval. Aggressive interval cancers only started to emerge 4 years after initial screening. http://repub.eur.nl/res/pub/28274/ 2010-11-01T00:00:00Z Introduction: The prognosis of bladder cancer (BC) depends mainly on its histology, grade, and stage. Patients with superficial BC (70% of the urothelial carcinomas) have a relatively good prognosis, but patients diagnosed with invasive, high grade BC, and those who progress to invasive BC, have a poor prognosis and will not survive their disease in many cases due to their metastases, despite the currently available treatment options. Early detection can only be beneficial regarding mortality if the high risk cancers are recognized and treated at a localized stage. Materials and methods: Previous pilot studies on early detection consisted of home-based repeated hematuria testing and, in case of hematuria, a urologic evaluation with cytology and cystoscopy was carried out. This design resulted in too many cystoscopies. The recently initiated [Bladder Cancer Urine Marker Project (BLU-P) study www.blu-project.org] assesses the feasibility of a population-based screening for BC and at the same time evaluates a screening algorithm using next to hematuria testing, sensitive specific urine markers for BC (NMP22, FGFR3, MA analyses and MLPa) in an attempt to circumvent the high number of cystoscopies. Results: So far 1,611 men are included and 23.5% tested positive for hematuria (11.6% had one or more true positive test results). The additional molecular-based screening tests before referring to cystoscopy resulted in a decrease of the number of cystoscopies from 378 to 66 (82.5%). In those men referred for cystoscopy, so far only 1 BC case was detected. Conclusions: Further research is needed to evaluate whether this extremely low detection rate is caused by, e.g., a healthy screenee bias or that the additional selection step using the molecular urine tests is too strict and diagnoses are missed. http://repub.eur.nl/res/pub/27465/ 2010-10-15T00:00:00Z BACKGROUND: The benefits of prostate cancer screening on an individual level remain unevaluated. METHODS: Between 1993 and 1999, a total of 43,987 men, aged 55-74 years, were included in the intervention arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in the Netherlands, Sweden, and Finland. A total of 42,503 men, aged 55-74 years, were included in a clinical population in Northern Ireland. Serum prostate-specific antigen (PSA) <20.0 ng/mL was measured in all men at study entry. All men were followed for prostate cancer incidence and causes of death until December 31, 2006. RESULTS: The adjusted absolute difference in prostate cancer specific mortality between the intervention population and the clinical population increased with increasing PSA level at study entry, ie, 0.05 per 10,000 person-years for men who had a serum PSA level of 0.0-1.9 ng/mL and 8.8 per 10,000 person-years for men who had a serum PSA level of 10-19.9 ng/mL. To evaluate the risks of early detection, the number needed to investigate (NNI) and number needed to treat (NNT) to save 1 death from prostate cancer were calculated. Both NNI and NNT were higher for those who had lower PSA levels at study entry. The NNI was 24,642 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 133 men for patients who had a serum PSA level of 10-19.9 ng/mL; the NNT was 724 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 60 men for patients with a serum PSA level of 10-19.9 ng/mL. CONCLUSIONS: For men with a low serum PSA level, the benefits of aggressive investigation and treatment may be limited because they are associated with a large increase in cumulative incidence and potential overtreatment. http://repub.eur.nl/res/pub/20605/ 2010-10-01T00:00:00Z 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 ≥3.0 ng/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 <3.0 ng/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 ≥3.0 ng/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. http://repub.eur.nl/res/pub/27455/ 2010-09-01T00:00:00Z 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 Gteborg 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. http://repub.eur.nl/res/pub/28269/ 2010-09-01T00:00:00Z Purpose: The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study. Experimental Design: We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing. Results: The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for >6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005). Conclusions: Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated. http://repub.eur.nl/res/pub/28671/ 2010-09-01T00:00:00Z Purpose of review Prostate cancer (PCa) screening has long been a source of controversy. In this review, we discuss the interim results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Implications of these studies will also be underlined. Recent findings With systematic prostate-specific antigen-based screening, the ERSPC reported a statistically significant PCa-specific mortality reduction of 20% favouring screening in the intention-to-treat analysis and 31% in the secondary analysis. In contrast, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial showed no mortality reduction. On the basis of critical appraisal of the study design and methods, it is justified to rely on the results of the ERSPC, as the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial is rather a comparison between a screening group and a less screened group. Summary Despite the effects demonstrated by the ERSPC, there is currently insufficient evidence to introduce a population-based screening programme. The studies evaluating quality of life and cost-efficiency need to be completed with the highest urgency and their results should be considered together with more mature data from the ERSPC to reach an effective implementation of screening on PCa. Meanwhile, we have to improve the screening test, screening protocol and further develop an accurate individualized risk assessment to decrease the rates of overdiagnosis and overtreatment, while the mortality reduction and the detection of clinically relevant PCa should be maintained. Copyright http://repub.eur.nl/res/pub/20966/ 2010-08-19T00:00:00Z http://repub.eur.nl/res/pub/27909/ 2010-08-03T00:00:00Z http://repub.eur.nl/res/pub/19685/ 2010-08-01T00:00:00Z http://repub.eur.nl/res/pub/21090/ 2010-08-01T00:00:00Z Background: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA. Methods: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (≥3 ng ml-1), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy. Results: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason 7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P<0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less. Conclusions: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies. http://repub.eur.nl/res/pub/27991/ 2010-07-01T00:00:00Z http://repub.eur.nl/res/pub/32863/ 2010-07-01T00:00:00Z The benefits of population-based prostate cancer screening are the detection of clinically important prostate cancers at an early, still curable, stage and the subsequent reduction of prostate cancer-specific mortality. However, a prostate-specific antigen (PSA)-based prostate cancer screening program is currently insufficient to warrant its introduction as a public health policy. The main reasons are insufficient knowledge regarding the optimal screening strategy and overdiagnosis and overtreatment of indolent prostate cancers that are unlikely to lead to complaints or death. In some countries, guidelines have been developed on screening for prostate cancer, but the diversity of recommendations illustrates the limited knowledge on the optimal strategy. Therefore, men should be well informed about the benefits and potential harms of PSA screening in order to enable them to make an informed decision. Although a mortality reduction can be achieved by early detection of prostate cancer, patients and physicians must be aware of the current side effects of screening. Algorithms that advise screening at a young age (<55 years), with screening intervals of less than 4 years and low PSA thresholds (<3 ng/ml) for prostate biopsy seem premature and are not supported by evidence. http://repub.eur.nl/res/pub/20314/ 2010-06-15T00:00:00Z Purpose: We have developed a statistical prediction model for prostate cancer based on four kallikrein markers in blood: total, free, and intact prostate-specific antigen (PSA), and kallikrein-related peptidase 2 (hK2). Although this model accurately predicts the result of biopsy in unscreened men, its properties for men with a history of PSA screening have not been fully characterized. Experimental Design: A total of 1,501 previously screened men with elevated PSA underwent initial biopsy during rounds 2 and 3 of the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 388 cancers diagnosed. Biomarker levels were measured in serum samples taken before biopsy. The prediction model developed on the unscreened cohort was then applied and predictions compared with biopsy outcome. Results: The previously developed four-kallikrein prediction model had much higher predictive accuracy than PSA and age alone (area under the curve of 0.711 versus 0.585, and 0.713 versus 0.557 with and without digital rectal exam, respectively; both P < 0.001). Similar statistically significant enhancements were seen for high-grade cancer. Applying the model with a cutoff of 20% cancer risk as the criterion for biopsy would reduce the biopsy rate by 362 for every 1,000 men with elevated PSA. Although diagnosis would be delayed for 47 cancers, these would be predominately low-stage and low-grade (83% Gleason 6 T1c). Conclusions: A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA. Use of a statistical model based on the panel would substantially decrease rates of unnecessary biopsy. http://repub.eur.nl/res/pub/18594/ 2010-06-01T00:00:00Z Background: Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity. Objective: To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia-associated PSA (BPHA). Design, setting, and participants: Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University. Measurements: BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA). Results and limitations: The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity. Conclusions: This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7). http://repub.eur.nl/res/pub/27565/ 2010-05-15T00:00:00Z Prostate cancer (PC) mortality is the most valid end-point in screening trials, but could be influenced by the choice of initial treatment if treatment has an effect on mortality. In this study, PC treatment was compared between the screening and control arms in a screening trial. Data were collected from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The characteristics and initial treatment of PC cases detected in the screening and the control arm were compared. Polytomous logistic regression analysis was used to assess the influence of study arm on treatment, adjusting for potential confounders and with statistical imputation of missing values. A total of 8,389 PC cases were detected, 5,422 in the screening arm and 3,145 in the control arm. Polytomous regression showed that trial arm was associated with treatment choice after correction for missing values, especially in men with high-risk PC. A control subject with high-risk PC was more likely than a screen subject to receive radiotherapy (OR: 1.43, 95% CI: 1.01-2.05, p = 0.047), expectant management (OR: 2.92, 95% CI: 1.33-6.42, p = 0.007) or hormonal treatment (OR: 1.77, 95% CI: 1.07-2.94, p = 0.026) instead of radical prostatectomy. However, trial arm had only a minor role in treatment choice compared to other variables. In conclusion, a small effect of trial arm on treatment choice was seen, particularly in men with high-risk PC. Therefore, differences in treatment between arms are unlikely to play a major role in the interpretation of the results of the ERSPC. http://repub.eur.nl/res/pub/27456/ 2010-05-01T00:00:00Z Purpose: Anxiety and distress may be present in patients with low risk prostate cancer who are on active surveillance. This may be a reason to discontinue active surveillance. Materials and Methods: A total of 150 Dutch patients with prostate cancer on active surveillance in a prospective active surveillance study received questionnaires at study inclusion and 9 months after diagnosis. We assessed changes in scores on decisional conflict with the decisional conflict scale, depression with the Center for Epidemiologic Studies Depression Scale, generic anxiety with the State Trait Anxiety Inventory, prostate cancer specific anxiety with the Memorial Anxiety Scale for Prostate Cancer and the self-estimated risk of progression. We explored scores 9 months after diagnosis vs those at study inclusion for physical health (SF-12® physical component summary), personality (Eysenck Personality Questionnaire), shared decision making, prostate cancer knowledge, demographics, medical parameters and prostate specific antigen doubling time during followup. Results: Questionnaires at study inclusion and 9 months after diagnosis were completed by 129 of 150 (86%) and 108 of 120 participants (90%) a median of 2.4 and 9.2 months after diagnosis, respectively. Anxiety and distress at study inclusion were previously found to be generally favorable. Significant but clinically irrelevant decreases were seen in mean scores of the State Trait Anxiety Inventory (p = 0.016), Memorial Anxiety Scale for Prostate Cancer fear of progression subscale (p = 0.005) and the self-estimated risk of progression (p = 0.049). Anxiety and distress 9 months after diagnosis were mainly predicted by scores at study inclusion. Higher Eysenck Personality Questionnaire neuroticism score and an important role of the physician in the treatment decision had additionally unfavorable effects. Good physical health, palpable disease and older age had favorable effects. No association was seen for prostate specific antigen doubling time. Nine men discontinued active surveillance, including 2 due to nonmedical reasons. Conclusions: Anxiety and distress generally remain favorably low during the first 9 months of surveillance. http://repub.eur.nl/res/pub/27946/ 2010-05-01T00:00:00Z Background: The independent prognostic value of tumour volume in radical prostatectomy (RP) specimens is controversial, and it remains a matter of debate whether pathologists should report a measure of tumour volume. In addition, tumour volume might be of value in substaging of pathologic tumour stage (pT2) prostate cancer (PCa). Objective: To assess the prognostic value of PCa tumour volume. Design, setting, and participants: The cohort consisted of 344 participants in the European Randomised Study of Screening for Prostate Cancer (ERSPC), Rotterdam section, whose PCa was treated with RP. Mean time of follow-up was 96.2 mo. Measurements: Tumour volume was measured in totally embedded RP specimens with a morphometric, computer-assisted method and assessed as a continuous variable, as relative tumour volume (tumour volume divided by prostate volume), and in a binary fashion (≥0.5 ml or <0.5 ml). These variables were related to prostate-specific antigen (PSA) progression, local recurrence, or distant metastasis and PCa-related mortality using univariate and multivariable Cox proportional hazards analyses. The analyses were repeated in the subgroup with pT2 tumours. Results and limitations: Tumour volume was related to tumour stage, Gleason score, seminal vesicle invasion (SVI), and surgical margin status. In univariate analyses, tumour volume and relative tumour volume were predictive for all outcome variables. In multivariable analyses, including age, tumour stage, Gleason score, SVI, and surgical margin status, neither tumour volume nor relative volume were independent predictors of progression or mortality. Tumour volume ≥0.5 ml was predictive for PSA recurrence and local and/or distant progression in univariate analyses but not in multivariable analyses. Tumour volume was not predictive for recurrence or mortality in univariate or multivariable analyses in the pT2 subgroup. Conclusions: Tumour volume did not add prognostic value to routinely assessed pathologic parameters. Therefore, there seems to be little reason to routinely measure tumour volume in RP specimens. http://repub.eur.nl/res/pub/28480/ 2010-04-01T00:00:00Z Study Type - Therapy (prospective cohort) Level of Evidence 2b Objective To evaluate the short-term outcomes of the prospective international Prostate Cancer Research International: Active Surveillance ('PRIAS') study (Dutch Trial Register NTR1718), as active surveillance (AS) for early prostate cancer might provide a partial solution to the current overtreatment dilemma in this disease. Patients and methods The first 500 (of >950) participants with asymptomatic T1c/T2 prostate cancer, with a prostate-specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, a Gleason score of ≤3 + 3 = 6, and one or two positive biopsy cores, were analysed. The follow-up protocol consisted of frequent PSA measurements, digital rectal examinations, and standard repeat biopsies (the first after 1 year). The primary outcome is survival free of active therapy; the secondary endpoints are reasons for stopping AS, findings in 1-year repeat biopsies, and outcomes after radical prostatectomy (RP). Results Patients were included between December 2006 and July 2008. The median (25-75th percentile) follow-up after diagnosis was 1.02 (0.6-1.5) years. The 2-year survival rate free from active therapy was 73%. Of the 82 men who changed to active therapy during the follow-up, 68 (83%) did so based on the protocol. Of the 261 repeat biopsies available for analysis, 90 (34%) showed no cancer, while 57 (22%) showed a Gleason score of >6 or more than two positive biopsy cores. There was a relatively unfavourable PSA doubling time of 0-10 years in 53% (102/194) and 62% (33/53) of men with favourable and unfavourable re-biopsy results, respectively. After RP, four of 24 (17%) men had T3 disease and 12 (50%) had a Gleason score of >6. Conclusion AS seems feasible, but mortality outcomes are unknown. A strict follow-up protocol including standard 1-year repeat biopsies resulted in a quarter of men stopping AS after 2 years. http://repub.eur.nl/res/pub/19949/ 2010-03-01T00:00:00Z BACKGROUND: Strategies of active surveillance (AS) of low-risk screen-detected prostate cancer have emerged, because the balance between survival outcomes and quality of life issues when radically treating these malignancies is disputable. Delay before radical treatment caused by active surveillance may be associated with an impaired chance of curability. METHODS: Men diagnosed with low-risk (T1c/T2; prostate-specific antigen [PSA] = <10.0; PSA density, <0.2 ng/mL; Gleason score, 3 + 3=6; 1-2 positive biopsies) prostate cancer in the Swedish section of the European Randomized Study of Screening for Prostate Cancer who received radical prostatectomy (RP) were studied. One group received immediate RP, whereas another group received delayed RP after an initial period of expectant management. These groups were compared regarding histopathological and biochemical outcomes, correcting for baseline differences. RESULTS: Mean follow-up after diagnosis was 5.7 years (standard deviation [SD], 3.2). The immediate RP group (n = 158) received RP a mean of 0.5 (SD, 0.2) years after diagnosis; the delayed RP group (n =69) received RP after 2.6 (SD, 2.0) years (P < .001). After adjustment for small baseline dissimilarities, no differences in RP frequencies of Gleason score >6 (odds ratio [OR], 1.54; P = .221), capsular penetration (OR, 2.45; P = .091), positive margins (OR, 1.34; P = .445), RP tumor volume (difference, 0.099; P = .155), or biochemical progression rates (P = .185, P = .689) were found between groups, although all data were in favor of immediate RP. CONCLUSIONS: With limited patient numbers available for analysis, differences in intermediate outcomes between immediate RP and delayed RP were nonsignificant. The delayed RP group may be subject to a selection bias. Prospective evaluation of active surveillance protocols is essential. http://repub.eur.nl/res/pub/27479/ 2010-03-01T00:00:00Z Dissemination of prostate-specific antigen (PSA) testing in the United States coincided with an increasing incidence of prostate cancer, a shift to earlier stage disease at diagnosis, and decreasing prostate cancer mortality. We compared PSA screening performance with respect to prostate cancer detection in the US population vs in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC-Rotterdam). We developed a simulation model for prostate cancer and PSA screening for ERSPC-Rotterdam. This model was then adapted to the US population by replacing demography parameters with US-specific ones and the screening protocol with the frequency of PSA tests in the US population. We assumed that the natural progression of prostate cancer and the sensitivity of a PSA test followed by a biopsy were the same in the United States as in ERSPC-Rotterdam. The predicted prostate cancer incidence peak in the United States was then substantially higher than the observed prostate cancer incidence peak (13.3 vs 8.1 cases per 1000 man-years). However, the actual observed incidence was reproduced by assuming a substantially lower PSA test sensitivity in the United States than in ERSPC-Rotterdam. For example, for nonpalpable local-or regional-stage cancers (ie, stage T1M0), the estimates of PSA test sensitivity were 0.26 in the United States vs 0.94 in ERSPC-Rotterdam. We conclude that the efficacy of PSA screening in detecting prostate cancer was lower in the United States than in ERSPC-Rotterdam. http://repub.eur.nl/res/pub/27508/ 2010-03-01T00:00:00Z http://repub.eur.nl/res/pub/27947/ 2010-02-01T00:00:00Z Background: The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening? Objective: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies. Design, setting, and participants: This retrospective study included 19 970 men ages 55-74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men. Intervention: Sextant biopsies initially, later lateralized, in screen-positive men. Measurements: The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups. Results and limitations: In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis. Conclusions: The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied. http://repub.eur.nl/res/pub/28168/ 2010-02-01T00:00:00Z 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 55-65 years, 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 2 weeks 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. http://repub.eur.nl/res/pub/28501/ 2010-02-01T00:00:00Z Objective: To investigate the levels of knowledge of prostate cancer and the perception of active surveillance (AS) in men on AS, as AS for early prostate cancer instead of radical treatment might partly solve the over-treatment dilemma in this disease, but might be experienced as a complex and contradictory strategy by patients. PATIENTS AND METHODS In all, 150 Dutch men recently diagnosed with early prostate cancer participating in a prospective protocol-based AS programme (PRIAS study) received questionnaires, including a 15-item measure on their general knowledge of prostate cancer, and open-ended questions on the most important disadvantages and advantages of AS, and on the specific perception of AS. We assessed knowledge scores and explored potentially associated factors, the stated (dis)advantages and specific perceptions. Results: The questionnaire response rate was 86% (129/150). Participants provided correct answers to a median (interquartile range) of 13 (12-14) of 15 (87%) knowledge items. Younger and higher educated men had higher knowledge scores. In line with a priori hypotheses, the most frequently reported advantage and disadvantage of AS were the delay of side-effects and the risk of disease progression, respectively. Specific negative experiences included the feeling of losing control over treatment decisions, distress at follow-up visits, and the desire for a more active participation in disease management. No conceptually wrong understandings or expectations of AS were identified. Conclusions: We found adequate knowledge of prostate cancer levels and realistic perceptions of the AS strategy in patients with early prostate cancer and on AS. These findings suggest adequate counselling by the physician or patient self-education. http://repub.eur.nl/res/pub/20155/ 2010-01-01T00:00:00Z Tumor volume was measured in 344 totally embedded radical prostatectomy specimens of screen detected prostate cancer cases. In univariate analyses, tumor volume was predictive for biochemical and local progression, metastasis and mortality. In multivariable analyses, tumor volume did not add prognostic value to routinely assessed pathological parameters, like tumor stage, Gleason score, seminal vesicle invasion and surgical margin status. Therefore, there seems to be little reason to routinely measure tumor volume in RP specimens. http://repub.eur.nl/res/pub/27765/ 2010-01-01T00:00:00Z Little is known about the frequency, histopathologic characteristics, and clinical consequences of false-negative prostate biopsies, that is, biopsies classified as benign but containing adenocarcinoma or atypical suspicious glands [atypical small acinar proliferations (ASAP)]. Objective of this study was to evaluate false-negative prostate biopsy in a prostate cancer screening setting. Prostate biopsy sets of 196 participants of a screening trial, which had been reported as "benign" at initial diagnosis, followed by a diagnosis of adenocarcinoma in a subsequent screening round were reviewed by 2 urologic pathologists. Adenocarcinoma was identified in 19 biopsy cores corresponding to 16 (8.2%) patients and ASAP in 24 cores, corresponding to 19 patients (9.7%). All missed prostate cancers were Gleason score 6 (3+3). After correction for patient selection, the overall false-negative biopsy rate was estimated to be 2.4%; 1.1% for prostate cancer; and 1.3% for ASAP. Clinicopathologic features at the time of initial biopsy and of subsequent prostate cancer diagnosis did not differ between patients with a false-negative or true benign biopsy. Relatively low number of atypical glands (<10 glands), intense intermingling with preexistent glands or lack of architectural disorganization were the most prominent risk factors for a false-negative diagnosis. Another potential pitfall was the presence of prostate cancer variants, as 1 adenocarcinoma was of foamy gland type and 3 of pseudohyperplastic type. Routine examination of at least 1 level of prostate biopsy sets at high magnification and awareness of histologic prostate cancer variants might reduce the risk of missing or misinterpreting a relevant lesion at prostate biopsy evaluation. http://repub.eur.nl/res/pub/27963/ 2010-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/28101/ 2010-01-01T00:00:00Z Background: To estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening. Methods: Between 1997 and 1999, a total of 11,970 men, aged 55-74 years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55-74 years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006. Results: Median age in both groups was 63 years at study entry (p = 0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1 ng/ml. In NI, 3962 men (3.0%, p < 0.001) were diagnosed with Pca with median baseline PSA of 18.0 ng/ml (p < 0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35-0.63; p < 0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5 years: 0.63 (95% CI, 0.45-0.88; p = 0.008); absolute mortality reduction was 1.8 deaths per 1000 men. Conclusions: A relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5 years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended. http://repub.eur.nl/res/pub/24593/ 2009-12-01T00:00:00Z Background:Prostate cancer screening with prostate-specific antigen (PSA) has shown to reduce prostate cancer mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC) trial. Overdetection and overtreatment are substantial unfavourable side effects with consequent healthcare costs. In this study the effects of introducing widespread PSA screening is evaluated.Methods:The MISCAN model was used to simulate prostate cancer growth and detection in a simulated cohort of 100 000 men (European standard population) over 25 years. PSA screening from age 55 to 70 or 75, with 1, 2 and 4-year-intervals is simulated. Number of diagnoses, PSA tests, biopsies, treatments, deaths and corresponding costs for 100 000 men and for United Kingdom and United States are compared.Results:Without screening 2378 men per 100 000 were predicted to be diagnosed with prostate cancer compared with 4956 men after screening at 4-year intervals. By introducing screening, the costs would increase with 100% to \[euro]60 695 000. Overdetection is related to 39% of total costs (\[euro]23 669 000). Screening until age 75 is relatively most expensive because of the costs of overtreatment.Conclusion:Introduction of PSA screening will increase total healthcare costs for prostate cancer substantially, of which the actual screening costs will be a small part. http://repub.eur.nl/res/pub/17502/ 2009-11-01T00:00:00Z Purpose: We assessed the risk of prostate cancer over time, and the implications for screening strategies and potential risk reduction approaches to provide a framework for clinical use of this approach concordant with the use of prostate specific antigen as a marker of current prostate cancer risk. Materials and Methods: A comprehensive review of the relevant literature was performed. In this article the phrase risk of/for prostate cancer refers to the risk of developing prostate cancer. Results: Prostate specific antigen is the single most significant predictive factor for identifying men at increased risk for prostate cancer. A suspicious digital rectal examination, a family history of prostate cancer, the presence of high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation and black ethnicity are also important predictive factors, while larger prostate volume and a previous negative biopsy are negative predictors. For men of screening age (50 to 70 years) a prostate specific antigen of greater than 1.5 ng/ml is a marker for greater than average risk up to 8 years (7.5-times greater risk vs 1.5 ng/ml or less). This prostate specific antigen threshold for a man at above average risk can be modified by the presence of other predictive factors. It should be lower for men with a prostate volume less than 40 cc, black ethnicity or a family history of prostate cancer. For younger men with longer followup a lower prostate specific antigen may be considered. Conclusions: The risk of prostate cancer can be estimated in individual men primarily using prostate specific antigen, but also using prostate volume, previous biopsy status, family history and ethnicity. Men at increased risk warrant enhanced surveillance and in the future may also be candidates for active risk reduction strategies. http://repub.eur.nl/res/pub/24366/ 2009-11-01T00:00:00Z 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. http://repub.eur.nl/res/pub/17266/ 2009-10-01T00:00:00Z Objective: To assess the number of missed prostate cancers and the frequency of aggressive disease when taking lateralized sextant prostate biopsies, irrespective of the total prostate volume (Pvol), during screening for prostate cancer. Subjects and Methods: Men participating in the European Randomized Study of Screening for Prostate Cancer, Rotterdam section, aged 55-74 years, with a prostate-specific antigen (PSA) level of ≥3.0 ng/mL, and a negative sextant biopsy result at the initial screening round, were followed for 8 years. Cases of prostate cancer detected during the follow-up by screening, or detected clinically as interval cancers, were assessed. Pvol at the initial screening round was related to the number of cancers found during the follow-up. Furthermore, the frequency of aggressive cancer (N1 or M1, PSA >20 ng/mL, Gleason >7) was evaluated using multivariate logistic regression analysis, including age, PSA level and Pvol. Results: In the total of 1305 men, 152 prostate cancers were detected during 8 years of follow-up (11.6%); 23 were classified as aggressive (15.1%), and 50 (32.9%) were detected as interval cancers. There was a significant relation between a larger Pvol at the initial screening round and fewer cancers (odds ratio 0.1, P < 0.001). In multivariate logistic regression, the initial PSA level (odds ratio 3.21, 95% confidence interval, CI 1.2-8.3) and smaller Pvol (0.08, 95% CI 0.03-0.26) were statistically significant predictors for all cancers and aggressive cancers (PSA odds ratio 70.37, 95% CI 13.5-366.2; Pvol odds ratio 0.03, 95% CI 0.01-0.35). Conclusions: Men with a smaller Pvol and an initially high PSA level were at greater risk of cancer detection and of an aggressive cancer during the follow-up. The use in clinical practice of volume-adjusted biopsy schemes should not be implemented automatically in screening programmes with repeated screening. http://repub.eur.nl/res/pub/24365/ 2009-10-01T00:00:00Z 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. http://repub.eur.nl/res/pub/17027/ 2009-09-01T00:00:00Z BACKGROUND: Patients on active surveillance (AS) for early prostate cancer (PC) may experience feelings of anxiety and distress while living with "untreated" cancer. In this study, these feelings were quantified, and their associations with various psychologic, medical, demographic, and decision-related factors were assessed. METHODS: Men with recently diagnosed PC who participated in a prospective protocol-based AS program (the Prostate Cancer Research International: Active Surveillance study [PRAIS]) received a questionnaire (N = 150). Scores concerning decisional conflict (the Decisional Conflict Scale), depression (the Center for Epidemiologic Studies Depression Scale), generic anxiety (the abridged State-Trait Anxiety Inventory), and PC-specific anxiety (the Memorial Anxiety Scale for Prostate Cancer) were compared with reference values and the literature. Associations with scores on physical health (the Medical Outcomes Study 12-item short-form Physical Component Summary), personality (the Eysenck Personality Questionnaire), shared decision-making, knowledge of PC, and demographic and medical parameters were determined with univariate and multivariate linear regression analyses. RESULTS: The questionnaire response rate was 86% (129 of 150 men). Of all respondents, 81%, 92%, 83%, and 93% scored better than reference values for clinically significant uncertainty regarding the treatment decision, depression, generic anxiety, and PC-specific anxiety, respectively. Scores were comparable to or more favorable than those of men (reported in literature) who underwent other treatments for localized PC. In multivariate analysis, the following associations emerged: a perceived important role of the physician in shared decision-making was associated with higher decisional conflict, better physical health was associated with lower depression, neurotic personality was associated with higher depression and with generic and PC-specific anxiety, and higher prostate-specific antigen level was associated with higher PC-specific anxiety. CONCLUSIONS: Men on protocol-based AS mainly reported favorable levels of anxiety and distress. A neurotic personality score was associated with unfavorable effects. These findings may help to optimize patient selection for AS or to select men for supportive measures. http://repub.eur.nl/res/pub/16475/ 2009-08-15T00:00:00Z 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. # 2006 European Association of Urology http://repub.eur.nl/res/pub/25267/ 2009-07-01T00:00:00Z Test sensitivity pertains to the ability of a test to identify subjects with the target disorder. In cancer screening, test sensitivity can be estimated using interval cancer incidence as an indicator of false-negative result. A randomized trial provides the optimal approach for estimating test sensitivity, as the control arm provides the expected rates. We estimated the sensitivity of the prostate-specific antigen test using incidence method, i.e., based on incidence of interval cancer among subjects with negative screening results, compared with that in the control arm. Data from three centers in the European randomized screening trial were used to estimate interval cancer incidence (II) among 39,389 men with negative screening tests. This was compared with incidence among the 79,525 men in the control arm of the trial (Ic) to estimate test sensitivity (S = 1 - II/ IC). Confidence intervals were calculated using simulations, assuming that the number of cases follows a Poisson distribution. The estimated test sensitivity following the first screen was 0.87 (0.83-0.92) in Finland, 0.87 (0.62-1.00) in Sweden, and 0.93 (95% confidence interval, 0.90-0.96) in the Netherlands. There was some indication of a higher test sensitivity for aggressive cancers (0.85-0.98 for non-organ-confined cases or Gleason 8-10) and for the second screening round (approximately 0.85-0.95). Test sensitivity varied to some extent between the three centers in the European trial, probably reflecting variation in screening protocols, but was acceptable in the first screening round, and may be better for aggressive cancers and in the second screening round. Copyright http://repub.eur.nl/res/pub/26913/ 2009-07-01T00:00:00Z The early detection of prostate cancer has led to the increased incidence of tumors that are unlikely to become symptomatic during life: so-called indolent cancers. The ability to predict indolent prostate cancer is needed to avoid over treatment by unnecessary invasive therapies and to select men for active surveillance. For this report, the currently available nomograms that predict these low-risk tumors were reviewed. Many of these nomograms were based on clinical patient series, thus, their general application is restricted. Those nomograms based on screening series of the general population need further validation before generalized application is feasible. http://repub.eur.nl/res/pub/16359/ 2009-06-01T00:00:00Z Objective To assess whether men newly diagnosed with Gleason 7 prostate cancer are eligible for active surveillance (AS) instead of radical treatment. AS is an appropriate initial strategy in selected men who are presently diagnosed with prostate cancer, as many tumours will not progress during a patient's lifetime. Patients and Methods Cancer-specific-, overall and treatment-free survival were analysed retrospectively in men with Gleason score 7 cancer who were initially managed expectantly. All were screen-detected in four centres of the European Randomized Study of Screening for Prostate Cancer. Results In 50 men active therapy was initially withheld if they had Gleason 7 disease; 29 of 50 (58%) would otherwise have been suitable for AS, as they had a prostate-specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, stage T1c/T2, and two or fewer positive biopsy-cores; 44 of 50 (88%) had a Gleason score 3 + 4 = 7. The mean (range) age of the men was 69.5 (59.6-76.2) years and the median (interquartile range) follow-up was 2.6 (0.8-5.0) years; the mean American Society of Anesthesiologists score was 1.8. The 6-year cancer-specific survival (nine patients at risk) was 100%, which sharply contrasted with the 68% overall survival. Men alive at the time of analysis had a favourable PSA level and PSA-doubling time. The 6-year treatment-free survival was only 59%, with most patients switching to active therapy, justified on the basis of their PSA level. However, men with otherwise favourable tumour characteristics and a Gleason score of 3 + 4 = 7 remained treatment-free significantly longer than their counterparts with unfavourable other tumour features and a Gleason score of 4 + 3 = 7. Conclusion In selected patients with screen-detected Gleason 3 + 4 = 7 prostate cancer, AS might be an option, especially in those with comorbidity and/or a short life-expectancy. http://repub.eur.nl/res/pub/27145/ 2009-05-01T00:00:00Z PURPOSE OF REVIEW: Prostate-specific antigen (PSA)-driven testing for prostate cancer is common around the world. There is uncertainty about its proper use in diagnosing prostate cancer. This review describes the background of the addressed problem and summarizes relevant, recent findings reported during 2008. RECENT FINDINGS: Available data suggest that the performance characteristics of PSA do not permit the identification of a valid cutoff value that balances sensitivity and specificity in indicating a biopsy of the prostate. However, biopsy in all men by age would only lead to unacceptably high biopsy and detection rates. Data reported in this study show that within the population of men aged 55-75 years, 80% have PSA values of less than 3.0 ng/ml and 87% below 4.0 ng/ml. Data from European Randomized Study of Screening for Prostate Cancer, Rotterdam suggest that, on the basis of a 12-year follow-up period, biopsy in men with PSA values of less than 3.0 ng/ml can safely be delayed. Several of the studies suggest that in following such men, other risk factors such as prostatic volume, previous screens and biopsies, rectal examination, age and family history may be helpful in decision making. Molecular markers, which may replace PSA or identify selectively indolent, aggressive prostate cancer, are under investigation. SUMMARY: At this time, PSA cutoff values (>2.5, 3.0 or 4.0 ng/ml) provide a reasonable balance between excessive detection rates and the risk of missing relevant prostate cancer. Men presenting with PSA values of 2.0-3.0 ng/ml should be reexamined more frequently. Available nomograms applying risk modifiers should be used specifically in this category of men. http://repub.eur.nl/res/pub/32574/ 2009-03-26T00:00:00Z 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.) Copyright http://repub.eur.nl/res/pub/27005/ 2009-03-01T00:00:00Z Context: Over the past decades, prostate-specific antigen (PSA), its isoforms, and other members of the tissue kallikrein family have been of continuous interest with regard to early detection and screening for prostate cancer (PCa). Objective: This review strives to give an overview of the possible clinical utilities of these markers, focused on early diagnostics and PCa screening. Evidence acquisition: Using the Medline database, a literature search was performed on the role of molecular subforms of PSA and other members of the tissue kallikrein family in PCa detection. Evidence synthesis: With respect to PSA isoforms, only the combination of the various truncated forms (pPSA) shows additional value over total PSA (tPSA) and free PSA (fPSA) in PCa detection within the range of 2-10 ng/ml tPSA. At a high sensitivity for PCa, the specificity of the ratio of pPSA to fPSA (%pPSA) is, in general, better than that of the ratio of fPSA to tPSA (%fPSA), with a gain of 5-11%. The (-2)pPSA, (-4)pPSA, (-5)pPSA, (-7)pPSA, and benign PSA (BPSA) isoforms generally show no additional value over either pPSA or the existing parameters of tPSA and fPSA. Of the other members of the tissue kallikrein family, most studies on human kallikrein 2 (hK2) show an additional value of the ratio of hK2 to fPSA (%hK2) over %fPSA alone in PCa prediction. Other tissue kallikreins cannot be recommended for diagnosing PCa, due to the lack of additional value over tPSA or fPSA or to insufficient research. Regarding a prognostic role, the value of PSA subforms as well as of other members of the tissue kallikrein family is limited with regard to existing parameters. Conclusions: pPSA and hK2 are able to improve PCa diagnosis in the range of 4-10 ng/ml tPSA over the existing variables tPSA and fPSA. http://repub.eur.nl/res/pub/15838/ 2009-02-09T00:00:00Z Introduction. Erectile dysfunction (ED) is more prevalent with increasing age. Previous studies showed that ED was negatively associated with mental health (MH) in specific patient groups. Aim. To examine the association, and potential mediating factors, between ED and MH in healthy elderly men. Main Outcome Measures. ED was defined as (almost) always having problems in achieving or maintaining an erection if desired, or not being sexually active because of erectile problems. MH was assessed with 36-item Short-Form Health Survey scale MH5 with five items on, e.g., being happy or depressed (range 0-100). Potential mediators between ED and MH were satisfaction with and importance attached to sex life. Methods. The study population consisted of a consecutive sample of 3,810 participants from the European Randomized Study of Screening for Prostate Cancer, aged 57-78 years, who had screened negatively for prostate cancer. Associations between ED, potential mediating factors, and MH were tested by analysis of variance and analysis of covariance. Results. Covariance analysis, adjusted for age, comorbidity, and use of erectile aids, showed that men with ED had significantly lower MH scores (80.8 ± 1.2) than men without ED (83.7 ± 1.2; P < 0.001). ED was also associated with the potential mediator "satisfaction with sex life" but not with "importance attached to sex life." Men with ED were significantly more often dissatisfied with their sex lives (P < 0.001). Adjustment for satisfaction with sex life, but not for importance attached to sex life, reduced the strength of the association (β value) between ED and poor MH from 2.88 to -0.84. Conclusions. ED was associated with poorer MH. Satisfaction with sex life, but not importance attached to sex life, may play a mediating role in this association. These results suggest that if men with ED can be helped to be satisfied with their sex lives despite ED, MH can be preserved. http://repub.eur.nl/res/pub/24362/ 2009-02-01T00:00:00Z 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. http://repub.eur.nl/res/pub/25052/ 2009-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/27178/ 2009-01-01T00:00:00Z http://repub.eur.nl/res/pub/32386/ 2008-12-01T00:00:00Z BACKGROUND: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. METHODS: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 μg/L. RESULTS: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 μg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 μg/L, respectively). CONCLUSIONS: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary. http://repub.eur.nl/res/pub/14412/ 2008-11-01T00:00:00Z BACKGROUND. Ongoing research on the best way to diagnose prostate cancer has yielded and will continue to yield vast amounts of information. Based on, for example, information from prostate cancer screening trials models have been made that enable urologists to predict which man has prostate cancer on the basis of pre-biopsy data. In patients with screen detected prostate cancer, the presence of indolent disease can now be identified with reasonable certainty by a different model. For these men active surveillance may be a better option than aggressive treatment with its possible side effects as impotence, incontinence and bowel damage. Both models mentioned above are logistic regression models. Nomograms enable their use in daily clinical practice. METHODS. Nomograms require the memorization and addition of intermediate results. We aimed to design a device that has the same function as a nomogram without this draw back. RESULTS. A new device that resembles a circular slide rule was developed and is currently being tested in prostate cancer diagnosis and in prostate cancer patient counseling. CONCLUSIONS. The new device has identical functionality to the nomogram without the drawback of the latter. The application of the device is not limited to the field of prostate cancer research. http://repub.eur.nl/res/pub/14593/ 2008-11-01T00:00:00Z OBJECTIVE: To assess the potential problem that different tools for predicting a positive outcome of prostate biopsy can produce divergent outcomes in the same man, by comparing the risk calculators based on the Prostate Cancer Prevention Trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). MATERIALS AND METHODS: In the prostate-specific antigen (PSA) range of 0.2-30.0 ng/mL, the prediction curves of 'virtual' standard study participants were evaluated using both prediction tools. The effects of prostate volume, digital rectal examination, transrectal ultrasonography (TRUS), previous negative biopsy, family history, race, and age were also assessed. RESULTS: Important differences in underlying study design and populations between the PCPT and ERSPC cause an essential discrepancy between the risk calculators. In the PCPT there were few biopsies in the higher PSA ranges, and in the ERSPC in the lower PSA ranges. Both risk indicators have incorporated some variables that are not used in the other, because they were insignificant in multivariate analysis. TRUS and especially prostate volume (not available in the PCPT) have a considerably larger effect on predictions in comparable PSA ranges than race, age, family history of prostate cancer, and previous negative biopsy (indicators that were excluded in ERSPC). CONCLUSIONS: Before using risk calculators users must consider the properties of the underlying populations and what are the included or unavailable risk factors, and compare these to the patient. When these prerequisites are disregarded, dissimilarities will result in grossly inaccurate predictions for individual patients. http://repub.eur.nl/res/pub/13624/ 2008-10-25T00:00:00Z We assessed if urinary, bowel, and sexual dysfunction and associated bother were part of the “normal” aging process in the general male Dutch population. Methods Randomly selected participants of a screening trial were mailed a questionnaire on dysfunction and bother in the urinary, bowel, and sexual domains. A Dutch version of the Expanded Prostate Cancer Index Composite (EPIC) was used. Results Three thousand eight hundred ten (3810) men responded (81%), mean age 67 years, range 58 to 78. The prevalence of urinary dysfunction was low, and although the difference between younger versus older men was significant (P <0.001), it did not exceed the minimal important difference. Bowel dysfunction and bother were not related to age. Erectile dysfunction was reported by 19%, ranging from 12% in the youngest to 26% in the oldest group (P <0.001). The overall use of erectile aids was negatively associated with the satisfaction with sex life and positively with the importance attached to it (P <0.001), but not with age or sexual activity. Conclusions Urinary and bowel dysfunction were not part of the “normal” aging process. Erectile dysfunction was significantly more prevalent in older men. In men treated for localized prostate cancer, decreasing urinary or bowel function is thus not attributable to age, but may well be related to prior treatment. Decreasing erectile function, however, may be attributable to other causes as wellt. These data provide a benchmark for urologic functioning in men after treatment relative to age-related patterns, and will enable better interpretation of treatment outcomes. http://repub.eur.nl/res/pub/29584/ 2008-09-01T00:00:00Z Background: The value of digital rectal examination (DRE) as a screening test for prostate cancer (PC) is controversial in the current prostate-specific antigen (PSA) era. Objectives: To determine (1) the additional value of a suspicious DRE for the detection of PC in men with an elevated PSA level in subsequent screenings and (2) the tumour characteristics of PCs detected in men with a suspicious DRE. Design, setting, participants: Within the screening study, from 1997-2006 men aged 55-75 years were invited for an every 4-yr PSA determination. A PSA level ≥3.0 ng/ml prompted a DRE and a transrectal ultrasound (TRUS)-guided, lateralized sextant biopsy. Throughout the three screenings of the ERSPC, Rotterdam, 5040 biopsy sessions were evaluated. Measurements: We determined the positive predictive values (PPVs) of a suspicious DRE and normal DRE, which entailed, respectively, the proportion of PCs detected in men with a suspicious DRE or normal DRE divided by, respectively, all biopsied men with a suspicious DRE or normal DRE. Results and limitations: At initial screening, the PPV of a suspicious DRE, in conjunction with an elevated PSA level, to detect PC was 48.6% compared to 22.4% for men with a normal DRE. Both PPVs decreased in consecutive screens: respectively, 29.9% versus 17.1% (screen 2) and 21.2% versus 18.2% (screen 3). Respectively, 71.0% (p < 0.001), 68.8% (p < 0.001), and 85.7% (p = 0.002) of all PCs with a Gleason score >7 were detected in men with a suspicious DRE at screens 1, 2, and 3. A limitation is that only biopsied men were evaluated. Conclusions: At initial and subsequent screenings, the chance of having cancer at biopsy was higher in men with a suspicious DRE compared to men with a normal DRE (to a lesser extent in subsequent screenings), and the combination of a PSA level ≥3.0 ng/ml with a suspicious DRE resulted in detecting significantly more PCs with Gleason score >7. DRE may be useful in more selective screening procedures to decrease unnecessary biopsies and overdiagnosis. http://repub.eur.nl/res/pub/29634/ 2008-09-01T00:00:00Z Context: The kinetics of prostate specific antigen (PSA) are generally assumed to be indicative of tumour progression and are therefore used in clinical decision-making in men on active surveillance for early prostate cancer. Objective: This review aims to provide support for exploiting PSA kinetics in an active surveillance setting. Evidence acquisition: We searched the Medline database and reviewed the evidence on both the relation between PSA kinetics before radical treatment for prostate cancer and outcome, as well as the role of PSA kinetics during active surveillance. Furthermore, the benefits and setbacks of different derivatives of PSA kinetics, minimum required time interval and number of measurements, practical recommendations, and pitfalls of their use in clinical practice are discussed. Evidence synthesis: The evidence concerning the prognostic value of the PSA velocity (PSA-V) and PSA doubling time (PSA-DT) is sparse, especially in active surveillance. PSA kinetics should therefore be combined with other diagnostic measures as the trigger for deferred radical treatment or repeat prostate biopsies. There seems to be consensus among several reports on the unfavourable outcome relating to a PSA-DT <3-4 yr and on the favourable prognostic value of a PSA-DT >10 yr or a decreasing PSA level. Online tools provide help with calculations and insight on disease development. The best method of calculation, number of measurements, and time interval between measurements is unknown for now. Conclusions: Despite the current deficits in our understanding of the natural behaviour of early prostate cancer and its relation to serum PSA levels, and despite several secondary factors playing a role in PSA kinetics, PSA kinetics are a practical parameter we can offer men on active surveillance to assess the status of their disease. http://repub.eur.nl/res/pub/30460/ 2008-08-01T00:00:00Z As a consequence of the detection of prostate cancer at an earlier stage, urologists increasingly must deal with the finding of a single small focus of prostatic cancer identified in prostate needle biopsies. Detection of these small cancer foci raises both diagnostic and clinical problems. For pathologists, it may be challenging to make a definite diagnosis of prostate cancer, avoiding confusion with look-alike benign lesions. A small cancer focus may be overlooked or misdiagnosed and consequences may be serious if the missed lesion, in fact, represents a high-grade cancer. Urologists should be aware of a potential variation in the pathologist's threshold to call a cancer despite the introduction of helpful ancillary techniques. For urologists, the finding of a single small focus of prostatic cancer may present a dilemma whether to treat or defer treatment given the limited correlation between biopsy and prostatectomy findings. From a clinical perspective it is important to find means to differentiate between indolent and more aggressive cancers, which may include extensive prostate mapping by numerous biopsies and application of nomograms. Future developments may be that improved imaging techniques would enable an accurate assessment of the actual size of the prostate cancer. http://repub.eur.nl/res/pub/29505/ 2008-06-15T00:00:00Z BACKGROUND. To analyze to what extent the percentage of suspicious digital rectal examination (DRE) findings vary between examiners and to what extent the percentage of prostate cancers (PCs) detected in men with these suspicious findings varies between examiners. METHODS. In the first screening round of the European Randomized study of Screening for PC (ERSPC) Rotterdam, 7,280 men underwent a PSA-determination and DRE of whom 2,102 underwent prostate biopsy (biopsy indication PSA ≥ 4.0 ng/ml and/or suspicious DRE and/or TRUS). Descriptive statistics of DRE-outcome per PSA-range were used to determine the observer variability of six examiners. Because this analysis did not correct properly for other predictors of a suspicious DRE (PSA-level, biopsy indication, TRUS-outcome, prostate volume and age), a logistic regression analysis controlling for these explanatory variables was performed as well. RESULTS. In 2,102 men biopsied, 443 PCs were detected (PPV = 21%). For all PSA levels the percentage suspicious DRE varied between examiners from 4% to 28% and percentage PC detected in men with a suspicious DRE varied from 18% to 36%. Logistic regression analysis showed that three of six examiners considered DRE significantly more often abnormal than others (ORs 3.48, 2.80, 2.47, P < 0.001). For all examiners the odds to have PC was statistically significantly higher in case of a suspicious DRE (ORs 2.21 -5.96, P < 0.05). This increased chance to find PC was not significantly observer-dependent. CONCLUSIONS. Three of six examiners considered DRE significantly more often suspicious than the others. However, under equal circumstances a suspicious DRE executed by each examiner increased the chance of the presence of PC similarly. http://repub.eur.nl/res/pub/29812/ 2008-06-09T00:00:00Z Purpose: Prostate cancer is the most commonly diagnosed cancer in men. However, only about 12% of the men diagnosed with prostate cancer will die of their disease. Result: The serum PSA test can detect prostate cancers early, but using a PSA based cut-off indication for prostate biopsy results in unnecessary testing in app. 75-80% of the men and perhaps even more important the serum PSA test cannot tell how aggressive the cancer is. To decrease unnecessary testing different test results are often combined, converted into a probability and displayed graphically. There are more than 40 of these so called nomograms in the case of prostate cancer. These nomograms can be divided into two categories, namely those that predict biopsy outcome using results from serum determination(s) or non-invasive tests such as the DRE and TRUS. The second category represents those nomograms that predict tumor characteristics and prognosis using information coming from pathology review. Conclusion: The ultimate nomogram able to predict tumor characteristics and progression purely based on non-invasive testing will for a large part put an end to the negative side effects and uncertainties that coincide with the early detection of prostate cancer, if it will ever be made. http://repub.eur.nl/res/pub/29719/ 2008-05-01T00:00:00Z Context: The European Randomized Study of Screening for Prostate Cancer (ERSPC) section Rotterdam was initiated in 1993. Men who initially presented with prostate-specific antigen (PSA) values <3.0 ng/ml were not biopsied (with few exceptions). In the Prostate Cancer Prevention Trial (PCPT) eligible men who initially presented with PSA values <3.0 ng/ml were all biopsied during or at the end of a 7-yr study period. Objective: To compare biopsy rates in PCPT and cancer detection rates, interval cancers, and prostate cancer deaths in ERSPC. Report the number of additional biopsies needed to detect these cases using PCPT policy. Evidence acquisition: 21,210 men, aged 55-74 yr, were randomised to screening; 19,970 were actually screened between November 1993 and December 1999. A total of 15,852 initially presented with PSA values of <3.0 ng/ml; after excluding 79 detected at first screens, 15,773 remained as the study population. A second and third screening round followed after 4- and 8-yr intervals. All cancers found in three rounds of screening or as interval cancers during the 12-yr interval were identified and characterised. Evidence synthesis: Screening for prostate cancer and routine clinical management, comparison of detection rates and outcome data. During the 12-yr observation period, which may be too short, 700 cancers were found, 620 through screening and 80 as interval cancers. None of the screen-detected cases but 6 of the 80 men with interval cancers died of prostate cancer. Applying the positive predictive value of 21.7% of the PCPT trial 3472 cancers would have been detected in ERSPC Rotterdam had all men with PSA values <3.0 ng/ml been biopsied. Assuming 80 interval cancers and 6 deaths from prostate cancer might have been prevented if all 15,773 eligible men had undergone biopsy. Conclusions: The present data suggest a very much unfavourable "number needed to be biopsied" to find one missed cancer or to detect the deadly interval cancers. http://repub.eur.nl/res/pub/29708/ 2008-03-01T00:00:00Z Objective: This is the first of two review papers attempting to clarify the best way to detect prostate cancer (PCa) in 2007. Screening for PCa has not yet been shown to lower PCa mortality. Still, opportunistic screening is wide spread in Europe and in most other parts of the world. Methods: Current literature and data from screening studies are reviewed and discussed. Prostate-specific antigen (PSA) has been and remains one of the corner stones of early detection of PCa. Traditionally used cut-off values cannot be applied in an uncritical fashion after it was shown that a significant amount of overdiagnosis and that large proportions of cancers and poorly differentiated cancers are present in the low PSA ranges. The paper addresses the continued relevance of PSA cut-off values. The diagnostic value of PSA velocity is reviewed in conjunction with PSA cut-off values and as a possible replacement of total PSA. A need for more selective screening in the low PSA ranges is pointed out. Results and conclusions: The data show that men presenting initially with PSA values below 1 do not have to be rescreened for a period of 8 yr. In the PSA range 1-2.9 ng/ml, new parameters are needed that improve specificity and are selective for screening for aggressive lesions. PSA velocity so far has not been shown to be useful in the early detection of PCa but may be useful in detecting aggressive PCa selectively. For the time being, it seems sensible to continue using PSA cut-off values such as 3.0 or 4.0 ng/ml provided overtreatment is decreased by using available nomograms. http://repub.eur.nl/res/pub/30341/ 2008-03-01T00:00:00Z OBJECTIVE: To determine the value of a hypoechoic lesion (HL)-directed biopsy in addition to a systematic sextant biopsy for detecting prostate cancer. SUBJECTS AND METHODS: Within the European Randomized study of Screening for Prostate Cancer, 37 627 assays for prostate-specific antigen (PSA) were done in men aged 55-75 years (screening round 1-3, interval 4 years). A PSA level of ≥3.0 ng/mL prompted a systematic transrectal ultrasonography (TRUS)-guided lateralized sextant biopsy (4986 biopsy sessions were evaluated). If there was a HL, an additional lesion-directed biopsy was taken. RESULTS: At the initial screening, 1840 men were biopsied and 532 cancers were detected (28.9%). Of the men biopsied, 436 had a HL and an additional biopsy (23.7%). In these men, 230 cancers were detected (52.8%). In 3.5% (eight of 230) only the HL-directed core showed malignancy. At the repeat and third screening, respectively, 19.3% and 18.9% of the men biopsied had prostate cancer, 16.8% and 9.3% had an HL and the additional core detected two (2.2%) and one (5.9%) cancers. At the first screen most cancers found by the additional core were clinically relevant. In later screens these cancers seemed to be minimal. CONCLUSION: The performance of TRUS as a screening tool is poor. The value of the additional core was limited as only 3.5% of the visible cancers were detected solely by the additional biopsy (round 1). However, a substantial part of these cancers were clinically relevant and would have been missed without the additional biopsy. This finding was less clear in screening round 2 and 3, even in men who were not previously biopsied. http://repub.eur.nl/res/pub/28943/ 2008-02-01T00:00:00Z http://repub.eur.nl/res/pub/30318/ 2008-02-01T00:00:00Z 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. http://repub.eur.nl/res/pub/35993/ 2007-12-01T00:00:00Z http://repub.eur.nl/res/pub/35104/ 2007-11-15T00:00:00Z BACKGROUND. Screening for prostate cancer has resulted in an increased incidence-to-mortality ratio. Not all cancers deserve immediate treatment. It has therefore become more important to be able to identify those cases of screen-detected prostate cancer most likely to show indolent behavior. METHODS. The Kattan-nomogram for the prediction of indolent prostate cancer was validated and recalibrated for use in a screening setting. The recalibrated nomogram was used to calculate the number of men who were predicted to have indolent cancer in a screen-detected cohort from the European Randomized study of Screening for Prostate Cancer (ERSPC), section Rotterdam. RESULTS. Of 1629 cancers detected in 2 subsequent screening rounds 825 were suitable for nomogram use. The remainder were very unlikely to have indolent cancer. A total of 485 men (485 of 825 = 59%) were predicted to have indolent cancer, which is 30% (485 of 1629) of all screen-detected cases. Cancers found at repeated screening after 4 years had a higher probability of indolent cancer than cases from the prevalence screening (44% vs 23%; P < .001). CONCLUSIONS. The current nomogram can identify substantial groups of screen-detected cancers that are likely indolent and can therefore be considered for active surveillance. http://repub.eur.nl/res/pub/37105/ 2007-10-01T00:00:00Z http://repub.eur.nl/res/pub/35204/ 2007-09-05T00:00:00Z 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. http://repub.eur.nl/res/pub/35939/ 2007-07-01T00:00:00Z BACKGROUND. The use of PSA as a screening test has become increasingly prevalent in the general population and therefore also in the control arm of the European Randomized study of Screening for Prostate Cancer (ERSPC). We present a feasibility study and impact simulation of a secondary analysis, which imitates a situation where all participants in the study are managed according to their random assignment. METHODS. The results of the Rotterdam section of the ERSPC were adjusted for contamination and non-compliance according to Cuzick et al. [Stat Med 1997; 16:1017-1029]. Endpoints of this analysis were simulated reductions in prostate cancer mortality. RESULTS. Of the men allocated to the screen arm, 27.1% were non-compliant. In the control arm 30.7% had their PSA-level measured by a general practitioner (GP) (i.e., contamination). For a scenario in which the intention-to-screen analysis was assumed to give a decrease in the mortality in the men randomized to screening of 6.7%, the secondary analysis resulted in a decrease of 16.1% for those actually screened. CONCLUSION. Although the definition of contamination as "PSA ever tested" gives an indication of the proportion of contamination, it will be important to differentiate the screening use of PSA from its diagnostic use. For the rest, adjustment for non-compliance and contamination was shown to be feasible in this prostate cancer screening trial. It can therefore be used to carry out a secondary analysis on the definitive outcome of the ERSPC and will provide accurate information for those men who are in fact screened. http://repub.eur.nl/res/pub/36066/ 2007-07-01T00:00:00Z Objectives: To evaluate the features, rates, and characteristics of prostate cancer detected during two subsequent screening rounds. Methods: Data were retrieved from the database of European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. Men, ages 55-74 yr were screened with a 4-yr interval. Different biopsy indications were used in the first and second screens in the PSA range <4.0 ng/ml. Clinical features and a total of 1548 sextant biopsies were recorded for Gleason score and tumour extent, and 550 radical prostatectomy specimens were evaluated for Gleason score, pathologic T category, and tumour volume. Results: Clinical stage, Gleason score, involvement of biopsy by tumour, and PSA levels were more favourable in patients of the second round compared with those of the first round. The number of men chosen for watchful waiting increased from 98 (10%) to 123 (22%) in the second round (p < 0.0001). In patients undergoing radical prostatectomy, median tumour volume in the first and second screening round was 0.65 and 0.45 ml (p = 0.001). Minimal cancer (cancer <0.5 ml, organ-confined, no Gleason pattern 4 or 5) was found in 122 (31.6%) in the first and 60 (42.6%) in the second screening round (p = 0.03). The 5-yr PSA progression-free survival after radical prostatectomy was 87%. Conclusions: Despite the 4-yr interval an important shift of all prognostic factors occurred in favour of round 2. In those men who underwent radical prostatectomy, 42.6% fulfilled the criteria of minimal cancer. These data suggest that overdiagnosis increases with repeat screening. http://repub.eur.nl/res/pub/36101/ 2007-05-01T00:00:00Z 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 3.6 ng/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. http://repub.eur.nl/res/pub/36124/ 2007-03-01T00:00:00Z A Swedish randomized screening study, which is a part of European Randomized Study of Screening for Prostate Cancer (ERSPC), reported the risks involved in diagnosing prostate cancer among men. The study included the effectiveness of intention-to-screen analysis program in terms of reducing metastatic disease at the time of diagnosis. The study found a total of 48% and 70% of different control group prostate cancers. The ERSPC study also found that the metastatic disease and the avoidance of metastatic disease are important end points of the study, and the proportion of men with metastatic disease are predicted to die of prostate cancer depending on the the diagnosis of the disease. The death rates in different cancer control arms change with mortality follow-up during the years after the 8-10 yr period. The results of ERSPC study show that over 10-yr period, the incidence of metastatic disease in men can be reduced by almost 50%. http://repub.eur.nl/res/pub/35968/ 2007-03-01T00:00:00Z BACKGROUND. Although serum PSA testing is widely used as a screening test for prostate cancer (PC), it is known that it is not specific for PC. The study described here focuses on the value of screening tests next to PSA in identifying men with an elevated risk of having PC and the differences between three centers of the European Randomised study of Screening for Prostate Cancer (ERSPC). METHODS. The study population consists of 2,483 men with a PSA ≥4.0 ng/ml, all biopsied. We assessed data on age, serum PSA level at initial and repeat screening, prostate volume, number of positive DRE and TRUS findings, number of previous negative biopsies, and PPV of the three centers and overall. Using logistic regression analysis, predictors for biopsy outcome at repeat screening in men with a PSA value ≥4.0 ng/ml were determined on the complete dataset and per center. RESULTS. In 2,483 men biopsied, 665 cancers were detected (PPV = 26.8%). Data show that all predictors except prostate volume loose their predictive value in men previously biopsied. In men not previously biopsied, the predictive value of DRE and TRUS vary considerably among the three centers. CONCLUSIONS. Looking at the differences in the predictive value of screening tests in three "comparable" centers, generasibility is not as straightforward as it seems. Using a nomogram for predictive purposes developed elsewhere will require a thorough knowledge of the patient population of which it is derived, and one should interpret its results with a critical mind. http://repub.eur.nl/res/pub/35974/ 2007-02-01T00:00:00Z OBJECTIVES. To compare tumor characteristics of screen-detected prostate cancers (PCs) either by digital rectal examination (DRE) or by prostate-specific antigen (PSA) as biopsy indication at low PSA. METHODS. Two populations with PSA between 2.0 and 3.9 ng/ml were studied. Group-1 was biopsied if DRE was suspicious (1st screening round, N = 1877). In group-2 all men were offered biopsy, regardless of DRE result (side-study in 2nd screening-round, N = 801). We compared cancer detection rates (CDRs) and tumor characteristics. RESULTS. In group-1 abnormal DRE prompted biopsy in 253 (13.5%) men (236 (93.3%) actually biopsied). Forty-nine PCs were detected, CDR 49/1877 = 2.6%. In group-2 we found 120 cancers in 666 (83.1%) men actually biopsied, CDR = 120/801 = 15.0%. Of all cancers detected, organ confinement (clinical T2) was found in 77.5% (group-1) and 96.6% (group-2; of which 99 T1c). Of all PCs 46.9% in group-1 and 15.0% in group-2 had biopsy Gleason score (GS) ≥ 7. In the latter, 15.2% of T1cs were classified GS ≥ 7. Considering only PCs with organ confinement or GS ≥ 7 for each group, CDRs amounted to 2.0% versus 14.5% and 1.2% versus 2.3% for group-1 and group-2, respectively. CONCLUSIONS. PSA-based screening detected a considerable amount (15.2%) of potentially aggressive tumors as T1cs, but in addition large numbers of possibly insignificant cancers (T1c, GS = 6) were diagnosed. DRE seemed to detect more selectively high-grade cancers, but also missed many of these. Considering both populations and the need to detect aggressive but confined cancers, PSA as biopsy indication outperformed DRE at the price of more biopsies (13.5% vs. 100% if all would comply). http://repub.eur.nl/res/pub/35674/ 2007-01-01T00:00:00Z Purpose: Screening with serum prostate specific antigen testing leads to the detection of many prostate cancers early in their natural history. Statistical models have been proposed to predict indolent cancer. We validated and updated model predictions for a screening setting. Materials and Methods: We selected 247 patients with clinical stage T1C or T2A from the European Randomized Study on Screening for Prostate Cancer who were treated with radical prostatectomy. We validated a nomogram that had previously been developed in a clinical setting. Predictive characteristics were serum prostate specific antigen, ultrasound prostate volume, clinical stage, prostate biopsy Gleason grade, and total length of cancer and noncancer tissue in biopsy cores. Indolent cancer was defined as pathologically organ confined cancer 0.5 cc or less in volume without poorly differentiated elements. Logistic regression was used to update the previous model and examine the contribution of other potential predictors. Results: Overall 121 of 247 patients (49%) had indolent cancer, while the average predicted probability was around 20% (p <0.001). Effects of individual variables were similar to those found before and discriminative ability was adequate (AUC 0.76). An updated model was constructed, which merely recalibrated the nomogram and did not apply additional predictors. Conclusions: Prostate cancers identified in a screening setting have a substantially higher likelihood of being indolent than those predicted by a previously proposed nomogram. However, an updated model can support patients and clinicians when the various treatment options for prostate cancer are considered. http://repub.eur.nl/res/pub/13495/ 2004-09-01T00:00:00Z Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels.To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area.At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer.Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores.Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer. http://repub.eur.nl/res/pub/9698/ 2001-01-01T00:00:00Z BACKGROUND: The currently recommended frequency for prostate-specific antigen (PSA) screening tests for prostate cancer is 1 year, but the optimal screening interval is not known. Our goal was to determine if a longer interval would compromise the detection of curable prostate cancer. METHODS: A cohort of 4491 men aged 55-75 years, all participants in the Rotterdam section of the European Randomized Study of (population-based) Screening for Prostate Cancer, were invited to participate in an initial PSA screening. Men who received that screening were invited for a second screen 4 years later. Pathology findings from needle biopsy cores were compared for men in both rounds. Statistical tests were two-sided. RESULTS: A total of 4133 men were screened in the first round (the prevalence screen), and 2385 were screened in the second round. The median amount of cancer in needle biopsy sets was 7.0 mm (95% confidence interval [CI] = 5.4 mm to 8.6 mm) in the first round and 4.1 mm (95% CI = 2.6 mm to 5.6 mm) in the second round (P =.001). Thirty-six percent of the adenocarcinomas detected in the first round but only 16% of those detected in the second round had a Gleason score of 7 or higher (mean difference = 20% [95% CI = 10% to 30%]; P<.001). Whereas 25% of the adenocarcinomas detected in the first round had adverse prognostic features, only 6% of those detected in the second round did (mean difference = 19% [95% CI = 11% to 26%]; P<.001). Baseline PSA values were predictive for the amount of tumor in biopsies in men with cancer in the first round but not for that in the second round. CONCLUSION: Most large prostate cancers with high serum PSA levels were effectively detected in a prevalence screen. In this population, a screening interval of 4 years appears to be short enough to constrain the development of large tumors, although it is inconclusive whether this will result in a survival benefit.