Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

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

Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study.

PURPOSE: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). METHODS: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. RESULTS: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). CONCLUSIONS: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.

Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI: The ProScreen Randomized Trial.

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.

Screening history and risk of death from prostate cancer: a nested case-control study within the screening arm of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

PURPOSE: We assessed the risk of death from prostate cancer (PCa) in relation to men's screening histories, i.e., screening attendance among men who were offered screening. METHODS: Men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996-2007. Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa. Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis. The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Having ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45-0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51-0.87). The effect by time since last screen for the risk of PCa death was significantly lower 2-7 years since last screen. CONCLUSION: Among men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men.

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Antidiabetic drugs, glycemic control and risk of benign prostatic hyperplasia.

BACKGROUND: Diabetes has been associated with an increased risk of benign prostatic hyperplasia (BPH). However, the role of antidiabetic drugs as a BPH risk factor is unclear. The objective of our study was to examine the risk of BPH by antidiabetic drug use and glycemic control in a large population-based cohort of Finnish men. METHODS: A total of 74,754 men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) free of BPH at baseline in 1996-1999 were linked to the national medication reimbursement database for information on physician-prescribed antidiabetic drug purchases. Information on recorded BPH procedures and diagnoses was obtained from the National Care Register for Health Care, and for a subgroup of 17,739 men, information on blood glucose levels (BGLs) from the Fimlab Laboratories database. Cox regression with antidiabetic drug use and BGL as time-dependent variables was used to analyze the risks for starting BPH medication, recorded BPH diagnosis, and undergoing BPH surgery. The analysis was adjusted for age, use of statins, antihypertensive medication, and nonsteroidal anti-inflammatory drugs. RESULTS: Of the subjects, 14,012 men (18.7%) used antidiabetic medication. Of the subgroup with fasting blood glucose data available, 7487 (42.2%) had diabetic level. The risks for BPH diagnosis (HR: 1.08, 95% CI: 1.03-1.13) and surgery (HR: 1.16, 95% CI: 1.09-1.24) were slightly elevated among antidiabetic drug users compared to nonusers. The association was strongest for insulin use. Similarly, risk of BPH surgery was increased in men with diabetic blood glucose compared to normoglycemic men. The risk association was attenuated by use of antidiabetic drugs. CONCLUSIONS: Diabetic BGL and antidiabetic medication use, especially insulin, are associated with an elevated risk of BPH surgery compared to nondiabetic men. These findings support the roles of insulin use and untreated hyperglycemia as possible BPH risk factors.

Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer.

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.

Allopurinol and prostate cancer survival in a Finnish population-based cohort.

BACKGROUND: Allopurinol is gout medication that inhibits uric acid formation. Its possible anti-carcinogenic properties have been under research in past years. Studies based on Taiwanese registries showed that long term allopurinol use might reduce prostate cancer (PCa) incidence. However, our studies based on Finnish registries did not support those findings. In this study, we evaluate whether allopurinol use is associated with prostate cancer-specific survival (CSS) or overall survival (OS) in a Finnish population-based cohort. METHODS: The study cohort was originally enrolled for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). We included all newly diagnosed PCa cases during 1996-2015, 9252 men in total. Information on allopurinol purchases was from the national prescription registry of the Social Insurance Institution of Finland. Information about deaths, treatments, and use of other medications was obtained from registries, and tumor stage and PSA at diagnosis from medical records. Follow-up started at diagnosis, and we analysed separately two endpoints: PCa-specific death and overall death. We used an extended Cox regression with adjustment for age at diagnosis, Charlson comorbidity index, FinRSPC trial arm, use of other drugs and EAU PCa risk group. RESULTS: During a median follow-up of 9.86 years, 2942 deaths occurred, including 883 from PCa. There was no difference in CSS between allopurinol user and non-users, but allopurinol users had lower OS (multivariable-adjusted hazard ratio 1.77; 95% CI: 1.57-2.00). However, this decrease in OS was mitigated along with increasing intensity of allopurinol use. CONCLUSIONS: We found no marked difference in CSS by allopurinol use. Allopurinol users had lower OS but there were no significant differences by duration or intensity of allopurinol use. Allopurinol use may not have anticancer effects against prostate cancer; instead, it may be a surrogate for metabolic problems causing shorter OS among men with PCa.

Inverse Association between Statin Use and Cancer Mortality Relates to Cholesterol Level.

Statins have been associated with a decreased cancer mortality. However, cholesterol level as such may modify the risk of cancer death. To clarify the complex interplay between statins, cholesterol level, and cancer mortality, we conducted a comprehensive analysis to separate the effects of cholesterol level and statin medication on cancer mortality. Our study population consisted of 16,924 men participating in the Finnish Randomized Study of Screening for Prostate Cancer with at least one cholesterol measurement during follow-up (1996-2017). Cox proportional regression was used to estimate hazard ratios. In total, 1699 cancer deaths were observed during the median follow-up of 19 years. When statins' association with the risk of cancer death was estimated without adjustment for cholesterol level, statin use was associated with a lowered cancer mortality (HR 0.87; 95% CI 0.79-0.97) compared to non-users. However, with further adjustment for total cholesterol level, statin use was no longer associated with a lower cancer mortality (HR 1.08; 95% CI 0.97-1.20). Upon stratified analysis, statin use was associated with a decreased cancer mortality only if the total cholesterol level decreased after the initiation of statin use (HR 0.66; 95% CI 0.58-0.76). The inverse association between statin use and cancer mortality is limited to men with a reduction in total cholesterol level after the commencement of statins, i.e., statin use is associated with a lowered cancer mortality only if the total cholesterol level decreases. This suggests that the effect of statin use on cancer mortality relates to the decreased total cholesterol level.

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. METHODS: A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. RESULTS: The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). CONCLUSIONS: AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.

Population-based randomized trial of screening for clinically significant prostate cancer ProScreen: a pilot study.

OBJECTIVES: To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit. PATIENTS AND METHODS: Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk >7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3-5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies. RESULTS: Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%. CONCLUSION: The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal.

Outcomes of Screening for Prostate Cancer Among Men Who Use Statins.

IMPORTANCE: Prostate-specific antigen (PSA) screening for prostate cancer has resulted in a slight reduction in prostate cancer mortality but also a concomitant overdiagnosis of low-risk tumors. Prostate-specific antigen levels are affected by use of cholesterol-lowering statin drugs, but the association of statin use with PSA screening performance is unknown. OBJECTIVE: To investigate whether statin use was associated with outcomes of a randomized PSA-based prostate cancer screening intervention. DESIGN, SETTING, AND PARTICIPANTS: This post hoc subgroup analysis of a cohort from a population-based randomized clinical trial used data from the population-based Finnish Randomized Study of Prostate Cancer Screening, which randomized men to PSA screening or routine care from March 1, 1996, to December 31, 1999, with follow-up continuing until December 31, 2015. The population included all men aged 55 to 67 years at baseline and residing in the Tampere or Helsinki districts of Finland. Information on statin purchases from 1996 to 2009 was obtained from a national prescription registry. Eligible men were identified from the population registry of Finland. Prevalent prostate cancer cases at baseline were excluded. Data were analyzed from January 1, 2019 to March 31, 2021. INTERVENTIONS: Three invitations for PSA screening at 4-year intervals from 1996 to 2007 vs routine care. MAIN OUTCOMES AND MEASURES: Risk for prostate cancer overall, high-risk disease, and prostate cancer mortality in the screening group vs the control group as an intention-to-treat analysis. The analysis was stratified by statin use. RESULTS: The study comprised 78 606 men (median age, 59 years [range, 55-67 years]) with statin purchase data available. Although PSA screening was associated with increased prostate cancer incidence among statin nonusers (screening vs control, 11.2 vs 8.6 per 1000 person-years); rate ratio [RR], 1.31; 95% CI, 1.24-1.38), no similar increase in incidence was observed among statin users (6.9 vs 5.9 per 1000 person-years; RR, 1.02; 95% CI, 0.95-1.10; P < .001 for interaction). Incidence of low-risk (Gleason score 6) and localized tumors was lower among statin users, whereas detection of tumors with a Gleason score of 8 to 10 was similar. Screening was associated with a lower incidence of metastatic tumors regardless of statin use. CONCLUSION AND RELEVANCE: In this post hoc subgroup analysis of a cohort from a population-based randomized clinical trial, PSA screening among statin users was associated with a decreased incidence of advanced prostate cancer that was similar among statin nonusers, but with less increase in detection of low-grade localized tumors in statin users than in nonusers. These findings suggest that statin use does not materially compromise benefits of PSA-based screening.

Digital rectal examination in prostate cancer screening at PSA level 3.0-3.9 ng/ml: long-term results from a randomized trial.

OBJECTIVE: To evaluate digital rectal examination (DRE) as a predictor of prostate cancer (PC) at serum PSA level 3.0-3.9 ng/ml. We compared the PC incidence rates of men with different screening test results in this PSA range and analyzed DRE in comparison with free/total PSA ratio as an additional screening test. MATERIALS AND METHODS: Using data from the FinRSPC trial, PC incidence rate ratios (IRR) for groups defined by the secondary screening test results (DRE vs. free/total PSA) were calculated for 17-year follow-up, using adjustment for age, family history of PC and place of residence. Screening test performance was evaluated by calculating sensitivity, specificity, positive and negative predictive value, and likelihood ratio. RESULTS: The IRR for men with a positive DRE compared to those with a negative result was 1.40 (95% confidence interval (CI) 1.00-1.96), while the IRR for men with a positive free/total PSA result compared to those with a negative one was 1.62 (95% CI 1.08-2.43). The estimated sensitivity was 0.15 (95% CI 0.11-0.20, 40/270) for DRE and 0.32 (95% CI 0.23-0.41, 36/113) for free/total PSA, and the specificity 0.91 (95% CI 0.88-0.93, 419/461) for DRE and 0.85 (95% CI 0.78-0.90, 134/158) for free/total PSA. CONCLUSIONS: Our results do not support utility of DRE as a screening test for PC at serum PSA level 3.0-3.9 ng/ml, while the results regarding free/total PSA determination were more encouraging and reconfirm the decision to switch from DRE to free/total PSA.

Estimating the rate of overdiagnosis with prostate cancer screening: evidence from the Finnish component of the European Randomized Study of Screening for Prostate Cancer.

PURPOSE: Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are identified that would not have become evident during the man's lifetime if screening had not taken place. The present study aims to estimate the rate of overdiagnosis using Finnish data from the European randomized trial of prostate cancer screening. METHODS: We used data from 80,149 men randomized to a screening or a control group, distinguishing four birth cohorts. We used the "catch-up method" to identify when the difference in the cumulative incidence of prostate cancer between the screening and control groups had stabilized, implying that the screening has no further effect. We define the overdiagnosis rate to be the relative excess cumulative incidence in the screened group at that point. As an independent method, we also examined the diagnosis rates of T1c tumors as an indicator of early tumors detected by PSA. RESULTS: The estimates of overdiagnosis rates from the catch-up method using the full period of available follow-up ranged between cohorts from 2.3% to 15.4%, and the T1c analysis gave very similar results. CONCLUSION: Some overdiagnosis has occurred, but there is uncertainty about its extent. A long follow-up is required to demonstrate the full impact of screening. We evaluated the overdiagnosis rates at a population level, associated with being offered screening, taking account of contamination (screening among the controls). The overall evaluation of screening should incorporate mortality benefit, cost-effectiveness, and quality of life.

Antidiabetic Drugs and Prostate Cancer Prognosis in a Finnish Population-Based Cohort.

BACKGROUND: Hyperinsulemia and glycemic control may play a role as prostate cancer prognostic factors, whereas use of certain antidiabetic drugs, that is metformin, could improve the prognosis. We examined the link between antidiabetic medication use and prostate cancer survival taking into account simultaneous use of multiple drugs. METHODS: The study cohort composed of 6,537 men in The Finnish Randomized Study of Screening for Prostate Cancer with prostate cancer diagnosed 1996 to 2009. Use of medication was attained from the nationwide prescription database of the Social Insurance Institution of Finland. Median follow-up was 9.2 years postdiagnosis. A total of 1,603 (24,5%) men had used antidiabetic medication. A total of 771 men died of prostate cancer during the follow-up. We used multivariable-adjusted Cox regression to evaluate the risk of prostate cancer death and onset of androgen deprivation therapy (ADT) with adjustment for prostate cancer clinical characteristics, comorbidities and use of other drugs. Separate analyses were further adjusted for blood glucose. RESULTS: Risk of prostate cancer death was higher among antidiabetic drug users overall (HR = 1.42; 95% CI, 1.18-1.70) compared with nonusers, separately among insulin and metformin users. Adjustment for blood glucose level abolished the risk increase. Risk of ADT initiation was increased among the medication users (HR = 1.26; 95% CI, 1.05-1.49). CONCLUSIONS: Men with prostate cancer using antidiabetic medication are generally at increased risk of dying from prostate cancer compared with nonusers. The risk association is driven by underlying diabetes, as adjustment for blood glucose level ameliorates the risk increase. IMPACT: Type 2 diabetes should be considered as a risk factor when considering prostate cancer prognosis.

Antiepileptic drugs and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

Antiepileptic drugs (AEDs) with histone deacetylase (HDAC) inhibitor properties decrease prostate cancer (PCa) cell proliferation in vitro. A population-based cohort of 78 615 men was used to evaluate the risk of PCa among users of AEDs. Study population was linked to the Finnish national prescription database to obtain information on individual medication reimbursements in 1996 to 2015. Cox regression with antiepileptic medication use as a time-dependent variable was used to analyze PCa risk overall, and low, medium and high-risk PCa separately. The analysis was adjusted for age, screening trial arm, and other drugs in use, including statins, antidiabetic drugs, antihypertensive drugs, aspirin, and nonsteroidal anti-inflammatory drugs. Compared to the nonusers of AEDs, overall PCa risk was decreased among AED users (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.76-0.96). A similar PCa risk decrease was observed among users of HDACi AEDs (HR = 0.87, 95% CI = 0.76-1.01), but no risk difference was found when comparing HDACi AED users to users of other AEDs (HR = 0.98, 95% CI = 0.76-1.27). Our study showed a decrease in overall PCa risk among men using AEDs compared to nonusers. The risk associations were similar for HDAC inhibitors as for AEDs in general.

Prognostic Index for Predicting Prostate Cancer Survival in a Randomized Screening Trial: Development and Validation.

We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa (N = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0-3, 3-9 and 9-20 years) for development and two corresponding validation periods (3-6 and 9-15 years). A multivariable complementary log-log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3-6 year and 9-15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.

Number of screening rounds attended and incidence of high-risk prostate cancer in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer has shown a 20% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening. In addition, screening has been shown to reduce the risk of advanced PC. The objective of the current study was to analyze the impact of screening participation on the incidence of PC by risk group. METHODS: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance; they then remained in the once-screened group until the second screen and similarly for the possible third round. The control arm formed the reference group. Follow-up started at randomization and ended at the time of diagnosis of PC, emigration, or the end of 2015. PC cases were divided into risk groups according to European Association of Urology definitions. RESULTS: The incidence of low-risk PC increased with the number of screens, whereas no clear relation with participation was noted in the intermediate-risk and high-risk cases. For patients with advanced PC, attending screening at least twice was associated with a lower risk. CONCLUSIONS: Screening reduces the risk of advanced PC after only 2 screening cycles. A single screen demonstrated no benefit in terms of PC incidence. Repeated screening is necessary to achieve screening advantages.

Prostate cancer risk prediction using a polygenic risk score.

Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90-2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60-0.63). Men in the highest polygenic risk score quartile were 2.8-fold (95% CI 2.4-3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.

Expected impact of MRI-related interreader variability on ProScreen prostate cancer screening trial: a pre-trial validation study.

BACKGROUND: The aim of this study is to investigate the potential impact of prostate magnetic resonance imaging (MRI) -related interreader variability on a population-based randomized prostate cancer screening trial (ProScreen). METHODS: From January 2014 to January 2018, 100 men aged 50-63 years with clinical suspicion of prostate cancer (PCa) in Helsinki University Hospital underwent MRI. Nine radiologists individually reviewed the pseudonymized MRI scans of all 100 men in two ProScreen trial centers. All 100 men were biopsied according to a histological composite variable comprising radical prostatectomy histology (N = 38) or biopsy result within 1 year from the imaging (N = 62). Fleiss' kappa (κ) was used to estimate the combined agreement between all individual radiologists. Sample data were subsequently extrapolated to 1000-men subgroups of the ProScreen cohort. RESULTS: Altogether 89% men of the 100-men sample were diagnosed with PCa within a median of 2.4 years of follow-up. Clinically significant PCa (csPCa) was identified in 76% men. For all PCa, mean sensitivity was 79% (SD ±10%, range 62-96%), and mean specificity 60% (SD ±22%, range 27-82%). For csPCa (Gleason Grade 2-5) MRI was equally sensitive (mean 82%, SD ±9%, range 67-97%) but less specific (mean 47%, SD ±20%, range 21-75%). Interreader agreement for any lesion was fair (κ 0.40) and for PI-RADS 4-5 lesions it was moderate (κ 0.60). Upon extrapolating these data, the average sensitivity and specificity to a screening positive subgroup of 1000 men from ProScreen with a 30% prevalence of csPCa, 639 would be biopsied. Of these, 244 men would be true positive, and 395 false positive. Moreover, 361 men would not be referred to biopsy and among these, 56 csPCas would be missed. The variation among the radiologists was broad as the least sensitive radiologist would have twice as many men biopsied and almost three times more men would undergo unnecessary biopsies. Although the most sensitive radiologist would miss only 2.6% of csPCa (false negatives), the least sensitive radiologist would miss every third. CONCLUSIONS: Interreader agreement was fair to moderate. The role of MRI in the ongoing ProScreen trial is crucial and has a substantial impact on the screening process.