Search

Background Recent research has suggested that statins have an effect on prostate cancer prognosis. It is currently unclear how prostate cancer screening, tumor and patient characteristics, or treatment selection may affect this association. Objective To evaluate the risk of prostate cancer death among statin users. To determine how disease and treatment characteristics affect the association. Design, setting, and participants This is a population-based cohort study consisting of a general male population of Finland participating in the Finnish Randomized Study for Prostate Cancer Screening. The cohort of consisted of 6537 prostate cancer cases diagnosed in the Finnish Randomized Study of Screening for Prostate Cancer population during 1996–2012. The cohort was linked to the National Prescription Database for information on the use of statins and other drugs. Intervention Statin use before and after prostate cancer diagnosis compared with nonuse. Outcome measurements and statistical analysis Hazard ratios (HRs) for the risk of prostate cancer death by amount, duration, and intensity of statin use. Cox proportional hazards regression with postdiagnostic statin use as a time-dependent variable. Results During the median follow-up of 7.5 yr postdiagnosis 617 men died of prostate cancer. Statin use after diagnosis was associated with a decreased risk of prostate cancer death (HR 0.80; 95% confidence interval 0.65–0.98). A decreasing risk trend was observed by increasing intensity of usage (doses/year). The risk decrease was clearest in men managed with androgen deprivation therapy. Prediagnostic statin use was not associated with risk of prostate cancer death (HR 0.92; 95% confidence interval 0.75–1.12). Conclusions Decreased risk of prostate cancer death by statin use after diagnosis suggests that statins may delay or prevent prostate cancer progression. The risk decrease was significant only in men managed with androgen deprivation therapy, but statistical power was limited to estimate the association in men managed with surgery or radiotherapy. Patient summary Use of statins after prostate cancer diagnosis was associated with a decreased risk of prostate cancer death. The risk decrease was dose-dependent and observed especially among patients treated with hormone therapy.

Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study. Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996–2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable. No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94–1.18). Neither sotalol (HR 0.97 95% CI 0.76–1.24) nor digoxin (HR 1.01 95% CI 0.87–1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7–10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7–10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49–1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7–10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12–0.84 for men who had used digoxin for 5 years or longer). Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival.

Background Growing evidence suggests that aspirin is associated with decreased prostate cancer (PCa) mortality. The effect of other NSAID use on risk of PCa death remains controversial. We examined prostate cancer survival among aspirin and other NSAID users in the Finnish Prostate Cancer Screening Trial. Methods A total of 6,537 men were diagnosed with prostate cancer in 1996–2009 among the 80,144 men in the trial and 617 died from prostate cancer during the median follow-up of 7.5 years after the diagnosis. Prescription drug purchases information was obtained from the national reimbursement database. We calculated hazard ratios and 95% confidence intervals for PCa-specific survival using multivariable-adjusted Cox regression analysis separately for NSAID and aspirin usage before and after the diagnosis. Results We observed an increased risk of PCa death associated with both pre- and post-diagnostic NSAID usage (HR 1.30, 95%CI 1.07–1.58 and HR 2.09, 95%CI 1.75–2.50, respectively). An increasing risk trend was observed by cumulative dose and intensity of NSAID use. When the last three years were excluded from the analysis, the death risk diminished to a protective level (HR 0.42, 95%CI 0.34–0.51 and HR 0.30 95%CI 0.24–0.39). Aspirin use was not significantly associated with prostate cancer survival. Conclusions The survival decrease among NSAID users is likely explained by symptomatic treatment of metastatic pain in patients with advanced PCa. However, results of the lag time analysis support previous findings of a possible preventative action of NSAIDs. Prostate 75:1394–1402, 2015. © 2015 Wiley Periodicals, Inc.

Prostate cancer (PC) screening with prostate-specific antigen (PSA) has been shown to decrease PC mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). However, in the Finnish trial, which is the largest component of the ERSPC, no statistically significant mortality reduction was observed. We investigated which had the largest impact on PC deaths in the screening arm: non-participation, interval cancers or PSA threshold. The screening (SA) and control (CA) arms comprised altogether 80,144 men. Men in the SA were screened at four-year intervals and referred to biopsy if the PSA concentration was ≥ 4.0 ng/ml, or 3.0-3.99 ng/ml with a free/total PSA ratio ≤ 16%. The median follow-up was 15.0 years. A counterfactual exclusion method was applied to estimate the effect of three subgroups in the SA: the non-participants, the screen-negative men with PSA ≥ 3.0 ng/ml and a subsequent PC diagnosis, and the men with interval PCs. The absolute risk of PC death was 0.76% in the SA and 0.85% in the CA; the observed hazard ratio (HR) was 0.89 (95% confidence interval (CI) 0.76-1.04). After correcting for non-attendance, the HR was 0.78 (0.64-0.96); predicted effect for a hypothetical PSA threshold of 3.0 ng/ml the HR was 0.88 (0.74-1.04) and after eliminating the effect of interval cancers the HR was 0.88 (0.74-1.04). Non-participating men in the SA had a high risk of PC death and a large impact on PC mortality. A hypothetical lower PSA threshold and elimination of interval cancers would have had a less pronounced effect on the screening impact.

Family history (FH) is one of the few known risk factors for prostate cancer (PC). There is also new evidence about mortality reduction in screening of PC with prostate-specific antigen (PSA). Therefore, we conducted a prospective study in the Finnish Prostate Cancer Screening Trial to evaluate the impact of FH on outcomes of PC screening. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm and were invited for screening with PSA test (cut-off 4 ng/ml) every 4 years. At the time of each invitation, FH of PC (FH) was assessed through a questionnaire. The analysis covered a follow-up of 12 years from randomization for all men with data on FH. Of the 23,702 (74.3%) invited men attending screening, 22,756 (96.0%) provided information of their FH. Altogether 1,723 (7.3%) men reported at least one first-degree relative diagnosed with PC and of them 235 (13.6%) were diagnosed with PC. Men with a first-degree FH had increased risk for PC (risk ratio (RR) 1.31, p

Objective To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy. Materials and Methods Study subjects were men aged 54–67 years with an elevated PSA (≥4 ng/mL or 3–4 ng/mL and free to total PSA ratio ≤0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996. A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation. Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry. The median length of follow-up was 10.5 years. Cox regression analysis was used to assess PCa risk after the initial benign biopsy. Results Histological inflammation was found in 66% of the biopsies. Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35–1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46–1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42–1.07; P = 0.092). Conclusions Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance. Inflammation in prostate biopsy is not a useful risk indicator in PCa screening.

Prostate cancer (PC) screening with prostate-specific antigen (PSA) has been shown to decrease PC mortality by the European Randomized Study of Screening for Prostate Cancer (ERSPC). We evaluated mortality results in the Finnish Prostate Cancer Screening Trial, the largest component of ERSPC. The primary endpoint was PC-specific mortality.A total of 80 144 men were identified from the population registry and randomized to either a screening arm (SA) or a control arm (CA). Men in the SA were invited to serum PSA determination up to three times with a 4-year interval between each scan and referred to biopsy if the PSA concentration was greater than or equal to 4.0 ng/mL or 3.0 to 3.99 ng/mL with a free/total PSA ratio less than or equal to 16%. Men in the CA received usual care. The analysis covers follow-up to 12 years from randomization for all men. Hazard ratios (HRs) were estimated for incidence and mortality using Cox proportional hazard model. All statistical tests were two-sided.PC incidence was 8.8 per 1000 person-years in the SA and 6.6 in the CA (HR = 1.34, 95% confidence interval [CI] = 1.27 to 1.40). The incidence of advanced PC was lower in the SA vs CA arm (1.2 vs 1.6, respectively; HR = 0.73, 95% CI = 0.64 to 0.82; P.001). For PC mortality, no statistically significant difference was observed between the SA and CA (HR = 0.85, 95% CI = 0.69 to 1.04) (with intention-to-screen analysis). To avoid one PC death, we needed to invite 1199 men to screening and to detect 25 PCs. We observed no difference in all-cause mortality between trial arms.At 12 years, a relatively conservative screening protocol produced a small, non-statistically significant PC-specific mortality reduction in the Finnish trial, at the cost of moderate overdiagnosis.

Background Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. Design, setting, and participants Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. Outcome measurements and statistical analysis The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively ( p 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.

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. (C) 2011 Elsevier Ltd. All rights reserved.

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 (

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. (C) 2010 Elsevier Ltd. All rights reserved.

Screening for prostate cancer (PC) remains a controversial issue despite some new evidence on the mortality benefits of PC screening. We conducted a prospective, randomized screening trial in Finland to investigate whether screening decreases PC incidence. Here, we report the incidence results from three screening rounds during a 12-year period. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm (SA) and invited for screening with prostate-specific antigen test (cut-off 4.0 ng/ml) every 4 years, while the remaining men formed the control arm (CA) that received no interventions. The mean follow-up time for PC incidence in both arms was over 9 years. The incidence rate of PC (including screen-detected and interval cancers as well as cases among nonparticipants) was 9.1 per 1,000 person-years in the SA and 6.2 in the CA, yielding an incidence rate ratio (IRR) 1.5 (95% confidence interval 1.4-1.5). The incidence of advanced PC was 1.1 in the SA and 1.5 in the CA, IRR = 0.7 (0.6-0.8) and the difference emerges after 5-6 years of follow-up. The incidence of localized PC was 7.5 in the SA and 4.6 in the CA, IRR = 1.6 (1.5-1.7). The results from our large population-based trial indicate that screening for PC decreases the incidence of advanced PC. When compared with the CA, the PC detected in the SA there were substantially more often localized, low-grade PCs due to overdiagnosis.

Study Type – Decision analysis (patient preference) Level of Evidence 4 OBJECTIVE To evaluate attitudes to prostate cancer screening with prostate-specific antigen (PSA) of men who complied with offered screening and those who declined it within the Finnish randomized population-based screening trial, and to compare general health-related quality of life (HRQL) between participants and non-participants. SUBJECTS AND METHODS Self-administered questionnaires were sent to 500 men randomized into the screening arm in 1996–99 within the Finnish component of the European Randomized Study on Screening for Prostate Cancer. A similar survey was conducted among 500 non-participants. RESULTS Response proportions among the screening participants and non-participants were 59% and 28%, respectively. Current smoking was less frequent (P < 0.05) among the participants. In terms of attitude, the participants regarded the prostate cancer study as more important and the invitation letter as more informative than the non-participants (P < 0.001). There was no clear difference in worry about treatment consequences. The most commonly given reasons for not participating included previous PSA testing (41%), forgetting the invitation (51%), or not wanting to think of prostate cancer (39%) and regarding possible further diagnostic examinations as unpleasant (28%). The non-participants had a lower mental health score (P < 0.001) than the participants in the RAND-36 Survey. CONCLUSION Most men who chose not to attend screening had a positive attitude, but did not participate due to practical reasons. However, two-thirds of the non-participants indicated a willingness to participate in the next screening round.

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non-users of statins or other cholesterol-lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996-2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate-specific antigen (PSA) level was compared between current users and non-users of cholesterol-lowering drugs. Compared with medication non-users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63-0.89]. The inverse association was dose-dependent with cumulative amount of statin use, and strongest for low-grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol-lowering drugs (HR 0.62, 95% CI 0.28-1.38), but without dose-dependence. Age-adjusted median serum PSA tended to be lower among users of cholesterol-lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non-users was eliminated by systematical prostate cancer screening. Cholesterol-lowering with statins seems beneficial for prostate cancer prevention.

Background: There is evidence that prostate cancer (PC) screening with prostate-specific antigen (PSA) serum test decreases PC mortality, but screening has adverse effects, such as a high false-positive (FP) rate. We investigated the proportion of FPs in a population-based randomised screening trial in Finland. Methods: Finland is the largest centre in the European Randomized Study of Screening for Prostate Cancer. We have completed three screening rounds with a 4-year screening interval (mean follow-up time 9.2 years) using a PSA cutoff level of 4.0 ng ml−1; in addition, men with PSA 3.0–3.9 and a positive auxiliary test were referred. An FP result was defined as a positive screening result without cancer in biopsy within 1 year from the screening test. Results: The proportion of FP screening results varied from 3.3 to 12.1% per round. Of the screened men, 12.5% had at least one FP during three rounds. The risk of next-round PC following an FP result was 12.3–19.7 vs 1.4–3.7% following a screen-negative result (depending on the screening round), risk ratio 3.6–9.9. More than half of the men with one FP result had another one at a subsequent screen. Men with an FP result were 1.5 to 2.0 times more likely to not participate in subsequent rounds compared with men with a normal screening result (21.6–29.6 vs 14.0–16.7%). Conclusion: An FP result is a common adverse effect of PC screening and affects at least every eighth man screened repeatedly, even when using a relatively high cutoff level. False-positive men constitute a special group that receives unnecessary interventions but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men.

Background: The Prostate Cancer Prevention Trial has shown a protective effect of finasteride on prostate cancer in low-risk men. It is uncertain whether similar results can be expected when finasteride is used to treat benign prostatic hyperplasia. Methods: We performed an observational cohort study within the Finnish Prostate Cancer Screening Trial. Using a comprehensive prescription database on medication reimbursements during 1995–2004 of men using finasteride or alpha-blockers for benign prostatic hyperplasia, we evaluated prostate cancer incidence among 23 320 men screened during 1996–2004. Results: Compared to medication non-users, overall prostate cancer incidence was not significantly affected in finasteride users (hazard ratio 0.87; 95% CI 0.63–1.19). Incidence of Gleason 2–6 tumours, however, was decreased among finasteride users (HR 0.59; 95% CI 0.38–0.91), whereas incidence of Gleason 7–10 tumours was unchanged (HR 1.33; 95% CI 0.77–2.30). The protective effect concerned mainly screen-detected tumours. Overall prostate cancer risk was not significantly reduced among alpha-blocker users relative to non-users, but decreased incidence of high-grade tumours was observed (0.55; 95% CI 0.31–0.96). Conclusions: The detection of low-grade, early-stage tumours is decreased among men who use finasteride for symptomatic BPH. The protective effect of finasteride can also be expected in men with benign prostatic hyperplasia.

Prostate cancer aggressiveness was evaluated based on pathologic characterization of cases detected in the Finnish prostate cancer screening trial. The trial population consists of 80,458 men aged 55-67 years. A total of 32,000 men were randomized to the screening arm. The remaining 48,000 men formed the control arm. The interval cases and cancers among nonparticipants and in the control arm were identified from the Finnish Cancer Registry. Random samples were selected from screen-detected cases (126 of 543 in the first and 133 of 508 in the second round) and control arm cancers (133 out of 863), in addition to all 92 interval cancers and 106 cases among nonparticipants. All the biopsies were regraded according to the Gleason system. The expression of the proliferation antigen Ki-67 was determined in 479 cases (72%). More than half of the tumors diagnosed in the first round of screening were high-grade cancers (Gleason 7 or higher). In the second round, the proportion of low-grade cancers increased from 47% to 70%. Cancers in the screening arm were more commonly focal and fewer bilateral cancers were detected. The cancers among nonparticipants were the most aggressive group. The aggressiveness of the interval cancers was between the cancers detected in the first and the second round. Our results indicate that prostate cancers detected through screening are less biologically aggressive. This was most notable after the first screening round. Nonparticipants had more aggressive cancers.

Accurate assessment of the causes of death is crucial for a conclusive evaluation of the ongoing prostate cancer screening trials. Here, we report the validity of the official causes of death as compared with an independent expert review in the Finnish prostate cancer screening trial. Because nearly 80,000 men were involved, death-cause evaluation was restricted to men diagnosed for prostate cancer. Medical charts were retrieved and the cause of death was assigned by an expert review panel for all deaths among men with prostate cancer during the study period, 1996-2003. The panel decision was compared with both death certificates and the official causes of death as assigned by Statistics Finland. Of a total of 315 deaths, the review panel attributed 127 (41%) to prostate cancer and 184 (59%) to other causes, the corresponding figures in death certificates being 124 (40%) and 187 (60%). Four cases were excluded because of insufficient information. The death-certificate data were in agreement with the panel's assessment in 305 out of 311 cases (overall agreement 97.7%, kappa = 0.95). The overall agreement between the official causes of death and the panel's decision was 97.4% (304/311, kappa = 0.95). The sensitivity of the certificates in identifying prostate cancer deaths was 96.1% (panel as golden standard). Correspondingly, specificity was 98.9%. The official causes of death thus provide an accurate means for evaluating disease-specific mortality in a large population-based prostate-cancer screening trial in Finland.

Specificity constitutes a component of validity for a screening test. The number of false-positive (FP) results has been regarded as one of major shortcomings in prostate cancer screening. We estimated the specificity of serum prostate-specific antigen (PSA) determination in prostate cancer screening using data from a randomised, controlled screening trial conducted in Finland with 32 000 men in the screening arm. We calculated the specificity as the proportion of men with negative findings (screen negatives, SN) relative to those with negative and FP results (SN/(SN+FP)). A SN finding was defined as either PSA

Background: We derived estimates of overdiagnosis by polygenic risk groups and examined whether polygenic risk-stratified screening for prostate cancer reduces overdiagnosis. Methods: We calculated the polygenic risk score based on genotypes of 66 known prostate cancer loci for 4967 men from the Finnish section of the European Randomised Study of Screening for Prostate Cancer. We stratified the 72 072 men in the trial into those with polygenic risk below and above the median. Using a maximum likelihood method based on interval cancers, we estimated the mean sojourn time (MST) and episode sensitivity. For each polygenic risk group, we estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers. Results: Of the prostate cancers, 74% occurred among men with polygenic risk above population median. The sensitivity was 0.55 (95% confidence interval (CI) 0.45–0.65) and MST 6.3 (95% CI 4.2–8.3) years. The overall overdiagnosis was 42% (95% CI 37–52) of the screen-detected cancers, with 58% (95% CI 54–65) in men with the lower and 37% (95% CI 31–47) in those with higher polygenic risk. Conclusion: Targeting screening to men at higher polygenic risk could reduce the proportion of cancers overdiagnosed.

We estimated the sensitivity of serum prostate-specific antigen (PSA) as a screening test for prostate cancer in the Finnish randomised, population-based prostate cancer screening trial. The study population consisted of 80,458 men aged 55-67 years identified from the national population registry and randomised to the screening or control arm of the trial. The screening algorithm was based on determination of serum PSA concentration. Test sensitivity was estimated based on interval cancer incidence during the first 4 years of follow-up among screening participants with a negative screening test. Interval cancers were defined as those occurring among men with a negative screening test. Altogether, 19 interval cancers were detected among 17,897 men with serum PSA or = 0.16. Test sensitivity based on serum PSA of 3 ng/ml was estimated to be 0.89 (95% confidence interval 0.84-0.93) and that based on PSA of 4 ng/ml combined with an ancillary test (digital rectal examination or free total PSA ratio in the PSA range 3.0-3.9) was 0.87 (0.82-0.92). Test sensitivity achieved with serum PSA in prostate cancer screening appears excellent in the context of a population-based effectiveness trial.

Growing evidence suggests that aspirin is associated with decreased prostate cancer (PCa) mortality. The effect of other NSAID use on risk of PCa death remains controversial. We examined prostate cancer survival among aspirin and other NSAID users in the Finnish Prostate Cancer Screening Trial.A total of 6,537 men were diagnosed with prostate cancer in 1996-2009 among the 80,144 men in the trial and 617 died from prostate cancer during the median follow-up of 7.5 years after the diagnosis. Prescription drug purchases information was obtained from the national reimbursement database. We calculated hazard ratios and 95% confidence intervals for PCa-specific survival using multivariable-adjusted Cox regression analysis separately for NSAID and aspirin usage before and after the diagnosis.We observed an increased risk of PCa death associated with both pre- and post-diagnostic NSAID usage (HR 1.30, 95%CI 1.07-1.58 and HR 2.09, 95%CI 1.75-2.50, respectively). An increasing risk trend was observed by cumulative dose and intensity of NSAID use. When the last three years were excluded from the analysis, the death risk diminished to a protective level (HR 0.42, 95%CI 0.34-0.51 and HR 0.30 95%CI 0.24-0.39). Aspirin use was not significantly associated with prostate cancer survival.The survival decrease among NSAID users is likely explained by symptomatic treatment of metastatic pain in patients with advanced PCa. However, results of the lag time analysis support previous findings of a possible preventative action of NSAIDs.

Background and Objective: Approximately 70% of the men with an elevated serum prostate-specific antigen (PSA) identified in prostate cancer screening do not have prostate cancer. Other available diagnostic variables may be utilized to reduce the number of false positive PSA results, but few algorithms for calculation of the combined impact of multiple variables are available. The objective of this study was to establish nomograms showing the probability of detecting prostate cancer at biopsy on the basis of total PSA, and the percentage of free PSA in serum, prostate volume and digital rectal examination (DRE) findings. Methods: In a randomized, population-based prostate cancer screening trial 10284 men aged 55–67 years were screened during 1996 and 1997 in two metropolitan areas in Finland. Results for men ( n =758) with a serum PSA of 4–20μg/l were used to establish the risk nomograms. Of these 200 (26%) had prostate cancer at biopsy. Results: Prostate cancer probability depended most strongly on the percentage of free PSA. Total PSA, prostate volume, and DRE also contributed to prostate cancer probability, whereas age and family history of prostate cancer did not. More false positive PSA results could be eliminated by using the multivariate risk model rather than the percentage of free PSA ( p p =0.003) alone. Conclusions: Wide variation in probability of detecting prostate cancer among screened men with a serum PSA of 4–20μg/l was observed. The nomograms established can be used to avoid or defer biopsy in men with a low prostate cancer probability in spite of a serum PSA level exceeding 4μg/l.

Objective: Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial. Methods: Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model. Results: Based on findings among 10,000 men screened in 1996–1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5–7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10–14 years, given that the cancers were detected on average at the midpoint of the DPCP. Conclusions: The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.

Prostate cancer (PC) screening with prostate-specific antigen (PSA) has been shown to decrease PC mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). However, in the Finnish trial, which is the largest component of the ERSPC, no statistically significant mortality reduction was observed. We investigated which had the largest impact on PC deaths in the screening arm: non-participation, interval cancers or PSA threshold. The screening (SA) and control (CA) arms comprised altogether 80,144 men. Men in the SA were screened at four-year intervals and referred to biopsy if the PSA concentration was ≥ 4.0 ng/ml, or 3.0-3.99 ng/ml with a free/total PSA ratio ≤ 16%. The median follow-up was 15.0 years. A counterfactual exclusion method was applied to estimate the effect of three subgroups in the SA: the non-participants, the screen-negative men with PSA ≥ 3.0 ng/ml and a subsequent PC diagnosis, and the men with interval PCs. The absolute risk of PC death was 0.76% in the SA and 0.85% in the CA; the observed hazard ratio (HR) was 0.89 (95% confidence interval (CI) 0.76-1.04). After correcting for non-attendance, the HR was 0.78 (0.64-0.96); predicted effect for a hypothetical PSA threshold of 3.0 ng/ml the HR was 0.88 (0.74-1.04) and after eliminating the effect of interval cancers the HR was 0.88 (0.74-1.04). Non-participating men in the SA had a high risk of PC death and a large impact on PC mortality. A hypothetical lower PSA threshold and elimination of interval cancers would have had a less pronounced effect on the screening impact.

Family history (FH) is one of the few known risk factors for prostate cancer (PC). There is also new evidence about mortality reduction in screening of PC with prostate-specific antigen (PSA). Therefore, we conducted a prospective study in the Finnish Prostate Cancer Screening Trial to evaluate the impact of FH on outcomes of PC screening. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm and were invited for screening with PSA test (cut-off 4 ng/ml) every 4 years. At the time of each invitation, FH of PC (FH) was assessed through a questionnaire. The analysis covered a follow-up of 12 years from randomization for all men with data on FH. Of the 23,702 (74.3%) invited men attending screening, 22,756 (96.0%) provided information of their FH. Altogether 1,723 (7.3%) men reported at least one first-degree relative diagnosed with PC and of them 235 (13.6%) were diagnosed with PC. Men with a first-degree FH had increased risk for PC (risk ratio (RR) 1.31, p 0.001) and the risk was especially elevated for interval cancer (RR 1.65, 95% CI 1.27-2.15). Risk for low-grade (Gleason 2-6) tumors was increased (RR 1.46, 95% CI 1.15-1.69), but it was decreased for Gleason 8-10 tumors (RR 0.48, 95% CI 0.25-0.95). PSA test performance (sensitivity and specificity) was slightly inferior for FH positives. No difference in PC mortality was observed in terms of FH. Our findings provide no support for selective PSA screening targeting men with FH of PC.

Background: The association between nonsteroidal antiinflammatory drugs (NSAIDs) and prostate cancer risk remains controversial. We examined the risk among NSAID users in 78 615 men in the Finnish Prostate Cancer Screening Trial. Methods: We obtained information on NSAID prescription usage from Finnish nationwide prescription database and on over-the-counter use by a questionnaire. Prostate cancer cases were identified from the Finnish Cancer Registry. Results: Prostate cancer risk was elevated among current NSAID prescription users irrespective of screening (hazard ratio (HR)=1.45, confidence interval (95% CI)=1.33–1.59 and HR=1.71, 95% CI=1.58–1.86 in the screening and control arm, respectively), but not for previous use of NSAIDs. The risk increase was similar among coxib and acetaminophen current users, and stronger for metastatic prostate cancer (HR=2.41, 95% CI=1.59–3.67 and HR=3.44, 95% CI=2.60–4.55 in the screening and control arm, respectively). Previous use of NSAIDs, aspirin use and over-the-counter NSAID usage were not associated with prostate cancer. Conclusions: Differing association for current and previous use suggests that the risk increase is unlikely to be directly caused by the medication, but may be due to the conditions indicating NSAID prescription usage, such as symptoms of undiagnosed prostate cancer. To reduce inconsistency between the study outcomes, future epidemiological studies on NSAID use and prostate cancer risk should assess the indications for NSAID usage.

Decisions on policies for screening for prostate cancer require that information upon health-related quality of life (HRQL) and cost-effectiveness (CE) be available, as the lead time for some of the cases detected by screening will be very long and detriments in quality of life could have a major impact on the subjects remaining life-span. A framework within which both HRQL and cost-effectiveness of prostate cancer screening can be assessed is presented. Studies of both are ongoing in the European Randomised Study of screening for prostate cancer and the US Prostate, Lung, Colon and Ovary trial. Preliminary information confirms that it is important to study screened subjects and controls, and not to assume that inferences derived from study of prostate cancer outside screening trials can be extrapolated to the trials. However, it will require prolonged study to enable the overall effects on quality of life, and on cost-effectiveness to be determined. Such studies are ongoing for the two trials.

High serum levels of insulin-like growth factor I (IGF-I) and low levels of IGF-binding protein-3 (IGFBP-3) have been shown to correlate with increased prostate cancer risk. To evaluate this, IGF-I, IGFBP-3, and prostate-specific antigen (PSA) were measured in serum from 665 consecutive men (179 with prostate cancer), aged 55–67 yr, with elevated serum prostate-specific antigen (PSA; ≥4 μg/L) in a screening trial. Men in the highest quartile of IGF-I levels had an odds ratio (OR) for prostate cancer of 0.50 [95% confidence interval (CI) 0.26–0.97] when adjusting for serum IGFBP-3. IGFBP-3 itself was not significantly associated with prostate cancer risk (OR, 1.24; 95% CI, 0.68–2.24). Prostate volume was larger in men without than in those with prostate cancer (P < 0.001), and after adjustment for prostate volume, the negative association between serum IGF-I and prostate cancer risk was no longer significant (OR, 0.57; 95% CI, 0.28–1.16). In screen-positive men with elevated serum PSA, serum IGF-I is not a useful diagnostic test for prostate cancer, but it may be associated with benign prostatic hyperplasia and enlargement.

Approximately 20 000 men 55–67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml−1 or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1–T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means. © 1999 Cancer Research Campaign

As prostate cancer (PC) mortality reduction results are not unequivocal, a special emphasis has to be put on other aspects of the prostate-specific antigen (PSA) screening, including effects on quality of life. In the present study we describe the short-term effects of various phases of PC screening on health-related quality of life (HRQL).The study participants were randomized into the screening arm within the Finnish component of the European Randomized Study on Screening for Prostate Cancer (ERSPC). The RAND 36-Item Health Survey on HRQL and questionnaires on sociodemographic and behavioral factors were delivered to participants at various phases of the first screening round: 1) 500 participants at invitation; 2) 500 after screening; 3) 500 after obtaining the PSA result; 4) to 300 participants after undergoing digital rectal examination (DRE) (but prior to being informed of its result); and 5) approximately 300 after prostate biopsy. At each stage, a new sample of participants was recruited.Response rates were 59% at invitation, 77% after PSA blood test, 54% after PSA result and 69% after DRE. The men recruited at each stage were comparable in respect to socioeconomic variables. The HRQL scores in RAND-36 subscales showed little variation in the different phases of the screening process. Compared with the previous phase, the social function score was slightly lower after obtaining the PSA result than after blood test, the emotional role score lower after DRE than after PSA result and the pain-related score lower after DRE than after TRUS and biopsy. The screening participants were comparable to the general population as their HRQL scores were similar to an age-stratified general Finnish male population.Short-term HRQL effects of prostate cancer screening appear minor and transient.

To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy.Study subjects were men aged 54-67 years with an elevated PSA (≥4 ng/mL or 3-4 ng/mL and free to total PSA ratio ≤0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996. A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation. Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry. The median length of follow-up was 10.5 years. Cox regression analysis was used to assess PCa risk after the initial benign biopsy.Histological inflammation was found in 66% of the biopsies. Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35-1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46-1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42-1.07; P = 0.092).Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance. Inflammation in prostate biopsy is not a useful risk indicator in PCa screening.

Background Evidence of the potential impact of systematic screening for prostate cancer (PCa) on health-related quality of life (HRQoL) at a population-based level is currently scarce. Objective This study aims to quantify the long-term HRQoL impact associated with screening for PCa. Design, setting, and participants Postal questionnaire surveys were conducted in 1998, 2000, 2004, and 2011 among men in the Finnish PCa screening trial diagnosed with PCa (total n =7011) and among a random subsample of the trial population ( n =2200). In 2011, for example, 1587 responses were received from men with PCa in the screening arm and 1706 from men in the control arm. In addition, from the trial subsample, 549 men in the screening arm and 539 in the control arm provided responses. Outcome measurements and statistical analysis Health-state-value scores were compared between the intervention and control arms using three distinct HRQoL measures (15D, EQ-5D, and SF-6D), and statistical significance was assessed using t tests . In addition, differences over repeated assessments of HRQoL between groups were evaluated using generalised estimating equations. Results and limitations In the 2011 survey, a small but statistically significant difference emerged between the trial arms among men diagnosed with PCa (mean scores, screening vs control arm: 15D: 0.872 vs 0.866, p =0.14; EQ-5D: 0.852 vs 0.831, p =0.03; and SF-6D: 0.763 vs 0.756, p =0.06). Such differences in favour of the screening arm were not found among the sample of men from the trial (15D: 0.889 vs 0.892, p =0.62; EQ-5D: 0.831 vs 0.852, p =0.08; and SF-6D: 0.775 vs 0.777, p =0.88). The slight advantage with screening among men with PCa was reasonably consistent across time in the longitudinal analysis and was strongest among men with early-stage disease. Conclusions These results show some long-term HRQoL benefit from screening for men with PCa but suggest little impact overall in the trial population.

Objective To evaluate the attitudes and practices related to prostate-specific antigen (PSA) screening for prostate cancer (PC) among Finnish physicians in 1999 and 2007. Materials and Methods The first questionnaire survey was conducted in 1999 with a mailing to 102 urologists, 679 community physicians and 684 occupational health physicians identified from the membership files of three medical associations. The area of residence was divided into the study area of the Finnish PC screening trial and the rest of Finland. The second survey was carried out in 2007 targeting 168 urologists, 1039 community physicians and 938 occupational health physicians. Results The response proportion was 48% in 1999 and 50% in 2007. In both rounds, urologists regarded PC as a more important public health issue than other physicians. On the other hand, the non-urologists considered early diagnosis and screening more important than the urologists PC was rated by all physicians as a less important public health problem in 2007 than in 1999. A smaller proportion of urologists found routine PSA testing indicated for asymptomatic men, compared with other physicians (40% versus 74-60% in 1999, P < 0.001 and 35% versus 44-37% in 2007, P = 0.005). The proportion of physicians reporting regular PSA screening in asymptomatic men was reduced from 1999 to 2007 (from 18% to 9%, P < 0.0001). Conclusion Based on reported practices of Finnish urologists, community physicians and occupational health physicians, popularity of PSA testing declined between 1999 and 2007. Urologists found PSA testing among asymptomatic men justified less frequently than the other physicians.

As with wide-spread use of prostate cancer (Pca) screening with prostate-specific antigen testing, overdetection has increasingly gained attention. The authors aimed to estimate absolute risk of overdetection (RO) in Pca screening with various interscreening intervals and ages at start of screening. We estimated age-specific preclinical incidence rates (per 100,000 person-years) for progressive cancer (from 128 for age group 55–58 years to 774 for age group 67–71 years) and nonprogressive cancer (from 40 for age group 55–58 years to 66 for age group 67–71 years), the mean sojourn time (7.72 years) and the sensitivity (42.8% at first screen and 59.8% at the second screen) by using a multistep epidemiological model with data from the Finnish randomized controlled trial. The overall number of screens for overdetection (NSO) was 29 (95% confidence interval (CI): 18, 48) for screenees aged 55–67 years, equivalent to 3.4 (95% CI: 2.1, 5.7) overdetected Pcas per 100 screenees. The NSO decreased from 63 (95% CI: 37, 109) at the first screen to 29 (95% CI: 18, 48) at the third screen and from 43 (95% CI: 36, 52) for age 55 years to 25 (95% CI: 8, 75) at age 67 years at the first screen. In conclusion, around 3.4 cases for every 100 screened men would be overdetected during three screen rounds (~ 13 years of follow-up) in the Finnish randomized controlled trial. Elucidating the absolute RO under various scenarios makes contribution for evaluating the benefit and harm of Pca screening.

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. (C) 2010 Elsevier Ltd. All rights reserved.

To evaluate attitudes to prostate cancer screening with prostate-specific antigen (PSA) of men who complied with offered screening and those who declined it within the Finnish randomized population-based screening trial, and to compare general health-related quality of life (HRQL) between participants and non-participants.Self-administered questionnaires were sent to 500 men randomized into the screening arm in 1996-99 within the Finnish component of the European Randomized Study on Screening for Prostate Cancer. A similar survey was conducted among 500 non-participants.Response proportions among the screening participants and non-participants were 59% and 28%, respectively. Current smoking was less frequent (P0.05) among the participants. In terms of attitude, the participants regarded the prostate cancer study as more important and the invitation letter as more informative than the non-participants (P0.001). There was no clear difference in worry about treatment consequences. The most commonly given reasons for not participating included previous PSA testing (41%), forgetting the invitation (51%), or not wanting to think of prostate cancer (39%) and regarding possible further diagnostic examinations as unpleasant (28%). The non-participants had a lower mental health score (P0.001) than the participants in the RAND-36 Survey.Most men who chose not to attend screening had a positive attitude, but did not participate due to practical reasons. However, two-thirds of the non-participants indicated a willingness to participate in the next screening round.

Accurate assessment of the causes of death is crucial for a conclusive evaluation of the ongoing prostate cancer screening trials. Here, we report the validity of the official causes of death as compared with an independent expert review in the Finnish prostate cancer screening trial. Because nearly 80,000 men were involved, death-cause evaluation was restricted to men diagnosed for prostate cancer. Medical charts were retrieved and the cause of death was assigned by an expert review panel for all deaths among men with prostate cancer during the study period, 1996-2003. The panel decision was compared with both death certificates and the official causes of death as assigned by Statistics Finland. Of a total of 315 deaths, the review panel attributed 127 (41%) to prostate cancer and 184 (59%) to other causes, the corresponding figures in death certificates being 124 (40%) and 187 (60%). Four cases were excluded because of insufficient information. The death-certificate data were in agreement with the panel's assessment in 305 out of 311 cases (overall agreement 97.7%, kappa = 0.95). The overall agreement between the official causes of death and the panel's decision was 97.4% (304/311, kappa = 0.95). The sensitivity of the certificates in identifying prostate cancer deaths was 96.1% (panel as golden standard). Correspondingly, specificity was 98.9%. The official causes of death thus provide an accurate means for evaluating disease-specific mortality in a large population-based prostate-cancer screening trial in Finland.

Background The US Preventive Services Task Force (USPSTF) recommends against serum prostate specific antigen (PSA) based screening for prostate cancer, on the grounds that the expected harms of screening (mainly overdiagnosis and subsequent overtreatment) outweigh the potential benefits (mainly reduction in cancer-specific mortality). This study aims to estimate the mean sojourn time (MST) and sensitivity and then use these estimates to derive the probability of overdiagnosis by polygenic risk group. Methods We calculated the polygenic risk score based on genotypes of 66 known prostate cancer susceptibility variants for 4,967 men from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). We stratified the 80,179 Finnish trial participants into two risk groups below and above 50th percentile risk. Using a maximum likelihood method based on interval cancers, we estimated the MST and episode sensitivity. We calculated the expected number of non-overdiagnosed screen-detected cancers over three rounds of screening. We estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers. We derived overall and separate estimates of overdiagnosis by polygenic risk group. Result Men in the above average genetic risk group accounted for 74 percent of the prostate cancers cases. The episode sensitivity was 0.55 (95% CI 0.45 to 0.65) and MST 6.3 (95% CI 4.2 to 8.3) years. The overall overdiagnosis was 42% (95% CI 37 to 52) with 58% (95% CI 54 to 65) in the lower risk group and 37% (95% CI 31 to 47) in the higher risk group. Targeting screening to men in the higher polygenic risk group would reduce screening episodes by half while detecting 80% of the non-overdiagnosed cancers and preventing 38% of the overdiagnosed cancers at a cost of missing 20% of the non-overdiagnosed cancers. Conclusion Polygenic risk-stratified screening for prostate cancer is a promising approach to decrease overdiagnosis. Further research is needed to study the effect of targeted screening on cancer-specific mortality. Citation Format: Nora Pashayan, Paul D.P. Pharoah, Johanna Schleutker, Kirsi Talala, Teuvo LJ Tammela, Liisa Määttänen, Patricia Harrington, Jonathan Tyrer, Rosalind Eeles, Stephen W. Duffy, Anssi Auvinen. Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2015-4681

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. Prostate 67: 439–446, 2007. © 2006 Wiley-Liss, Inc.

Finasteride has been reported to reduce prostate cancer risk in asymptomatic men. However, in clinical practice finasteride and alpha-blockers are used to treat benign prostatic hyperplasia (BPH). We evaluated prostate cancer risk among users of BPH pharmacotherapy at the population level. Comprehensive Finnish national registries provided information on 24723 prostate cancer cases and controls. Overall, prostate cancer risk was elevated among users of both drug categories compared to non-users (odds ratio, OR=1.41; 95% confidence interval, CI 1.31-1.51 for finasteride and OR=1.79; 95% CI 1.67-1.91 for alpha-blockers). However, the risk was lower among finasteride users when compared with alpha-blocker users (OR=0.80; 95% CI 0.64-1.00). Regular finasteride users had the lowest risk. The increased risk is probably due to enhanced diagnostics of prostate cancer in men with BPH. Finasteride use does not decrease prostate cancer incidence compared with non-users. Nevertheless, the risk is lower when compared with alpha-blocker users.

Neill Booth *, Pekka Rissanen , Teuvo L.J. Tammela , Liisa Maattanen , Kimmo Taari , Anssi Auvinen a a School of Health Sciences, University of Tampere, Tampere, Finland; Department of Surgery, Tampere University Hospital, and School of Medicine, University of Tampere, Tampere, Finland; Mass Screening Registry, Finnish Cancer Registry, Helsinki, Finland; Helsinki University Hospital and University of Helsinki, Helsinki, Finland

We estimated the sensitivity of serum prostate-specific antigen (PSA) as a screening test for prostate cancer in the Finnish randomised, population-based prostate cancer screening trial. The study population consisted of 80,458 men aged 55-67 years identified from the national population registry and randomised to the screening or control arm of the trial. The screening algorithm was based on determination of serum PSA concentration. Test sensitivity was estimated based on interval cancer incidence during the first 4 years of follow-up among screening participants with a negative screening test. Interval cancers were defined as those occurring among men with a negative screening test. Altogether, 19 interval cancers were detected among 17,897 men with serum PSA3 ng/ml during the first screening interval. A further 5 cases were diagnosed among 811 men with PSA 3.0-3.9 ng/ml with a benign digital rectal examination or free total PSA ratioor = 0.16. Test sensitivity based on serum PSA of 3 ng/ml was estimated to be 0.89 (95% confidence interval 0.84-0.93) and that based on PSA of 4 ng/ml combined with an ancillary test (digital rectal examination or free total PSA ratio in the PSA range 3.0-3.9) was 0.87 (0.82-0.92). Test sensitivity achieved with serum PSA in prostate cancer screening appears excellent in the context of a population-based effectiveness trial.

Early diagnosis of prostate cancer is a necessary, but not sufficient, prerequisite for an effective screening program aiming at mortality reduction. We compared tumor characteristics between the screening and control arms in the Finnish population-based screening trial.The Finnish trial is the largest component in the European Randomized Study of Screening for Prostate Cancer. A total of 24,000 men aged 55-67 years were randomized to the screening arm, whereas 35,973 men formed the control arm during the first three screening years. At the time of invitation, 22,732 men were eligible for screening, and 15,685 (69%) participated. A prostate-specific antigen (PSA) concentration ofor ==" BORDER="0"4 micro g/liter was defined as a screening-positive finding.The detection rate among screenees was 2.4% (377 of 15,685), whereas 0.6% (40 of 7,047) of nonparticipants in the screening arm and 0.3% (112 of 35,973) of the controls were diagnosed with prostate cancer during the first postrandomization year in the absence of screening. In the screening arm, 82% of the cancers were clinically organ confined compared with 65% in the control arm. Yet, both the absolute number and cumulative incidence of advanced cancer were higher in the screening arm. No differences were seen in the WHO grade distribution between the study groups. The median PSA was substantially lower among screen-detected cases (7.1 micro g/liter) than among nonattenders (15.7 micro g/liter) and controls (13.2 micro g/liter).Our findings on intermediate indicators of PSA screening provide encouraging, yet inconclusive evidence for eventual mortality reduction.

Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial.Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model.Based on findings among 10,000 men screened in 1996-1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5-7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10-14 years, given that the cancers were detected on average at the midpoint of the DPCP.The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.

Performing biopsy in all men with a serum prostate specific antigen (PSA) of 3 to 3.9 ng./ml. increases the sensitivity of prostate cancer screening compared with a PSA cutoff of 4 ng./ml. but decreases specificity and may contribute to over diagnosis. Therefore, we evaluated the detection rate and specificity attributable to digital rectal examination and percent free PSA within the PSA range of 3 to 3.9 ng./ml.Serum PSA was determined in 20,716 participants in the Finnish population based screening trial. Supplementary digital rectal examination was offered to men with a PSA of 3 to 3.9 ng./ml. during 1996 to 1998 (protocol 1). Those with a suspicious digital rectal examination finding were referred for biopsy. The screening algorithm was modified by substituting percent free PSA for digital rectal examination with a cutoff of 16% as a biopsy criterion in 1999 (protocol 2). In addition, biopsies were performed in all men with PSA 4 ng./ml. or greater.A total of 23 cancers (2.9%) were detected by digital rectal examination among 801 men, while percent-free PSA resulted in the diagnosis of 13 cases (4.8%) among 270 men with a PSA of 3 to 3.9 ng./ml. The detection rate of tumors with a Gleason score of 5 or greater increased from 1.6% (13 of 801 cases) to 4.4% (12 of 270) in the modified screening program. The PSA cutoff of 3 ng./ml. alone showed 88.6% and 87.5% specificity in protocols 1 and 2 but specificity increased to 93.3% and 91.7% using digital rectal examination and percent free PSA, respectively.Using percent free PSA increased the detection rate of aggressive disease compared with digital rectal examination and provided higher specificity than PSA alone.