Finnish Prostate Cancer Screening Trial Research Articles

Sojourn-time-corrected receiver operating characteristic curve (ROC) for prostate specific antigen (PSA) test in population-based prostate cancer screening

Evaluating the performance of serum prostate-specific antigen (PSA) test in population-based screening with receiver operating characteristics (ROC) curve often neglects the time dimension. Asymptomatic cases with negative PSA test would have been missed if sojourn time is not taken into account to allow for cases surfacing into the clinical phase. Data included 20,796 men with PSA test at the first screening round was used from population-based Finnish prostate cancer screening trial during 1996–1999. Cancers detected at the first screen, together with interval cancers ascertained during 4-year follow-up were expediently used to estimate sensitivity and specificity. A sojourn-time-corrected model was applied to estimating the possible false negative cases for those with PSA < 4 ng/ml for correcting the ROC curve. The estimated sensitivity estimate was reduced from 94.4% without correction to 68.8% with correction but the estimated specificity was identical (89.4% vs. 89.2%) at cutoff of 3 ng/ml. The corrected area under curve (AUC) [77.0% (74.9–79.1%)] of the PSA test was significantly lower than the uncorrected AUC [95.9% (95.3–96.6%)]. The failure of considering the time since last negative screen due to incomplete ascertainment for asymptomatic cancer led to the overestimation of PSA test performance that further affects the cut-off value of PSA tests for population-based prostate cancer screening.

776 Prostate cancer incidence and cardiovascular mortality among users of testosterone replacement therapy in the Finnish Prostate Cancer Screening Trial

776 Prostate cancer incidence and cardiovascular mortality among users of testosterone replacement therapy in the Finnish Prostate Cancer Screening Trial

Postscreening follow-up of the Finnish Prostate Cancer Screening Trial on putative prostate cancer risk factors: vitamin and mineral use, male pattern baldness, pubertal development and non-steroidal anti-inflammatory drug use

Objective The etiology of prostate cancer (PCa) is still unclear. This study aimed to investigate the association between PCa risk and the indicators of endogenous androgen production at puberty, male pattern baldness, over-the-counter use of non-steroidal anti-inflammatory drugs and vitamin supplement use. Materials and methods Participants in the third round of the Finnish Prostate Cancer Screening Trial were sent a survey on possible PCa risk factors and 11,795 out of 12,740 (93%) men returned the questionnaire. PCa cases were identified from the Finnish Cancer Registry. Results During the median follow-up of 6.6 years, 757 PCa cases were diagnosed and 21 men died from PCa. Compared to earlier onset, puberty onset after 15 years of age was associated with a borderline significant decrease in PCa risk [hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.75–1.00] but not with PCa mortality. Weekly use of ibuprofen was associated with an increased risk of PCa overall (HR 1.43, 95% CI 1.08–1.91) and with metastatic PCa (HR 1.49, 95% CI 1.12–1.99) compared to less frequent use. No statistically significant association was found between vitamin use and PCa. Conclusions This study suggests that the timing of initiation of endogenous androgen production at puberty may have importance for later PCa development. Current use of over-the-counter ibuprofen is associated with an increased risk of PCa. There was no evidence of any protective effects of vitamin use on PCa risk.

5-Alpha reductase inhibitor use and prostate cancer survival in the Finnish Prostate Cancer Screening Trial.

Randomized clinical trials have shown that use of 5α-reductase inhibitors (5-ARIs) lowers overall prostate cancer (PCa) risk compared to placebo, while the proportion of Gleason 8-10 tumors is elevated. It is unknown whether this affects PCa-specific survival. We studied disease-specific survival by 5-ARI usage in a cohort of 6,537 prostate cancer cases diagnosed in the Finnish Prostate Cancer Screening Trial and linked to the national prescription database for information on medication use. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for prostate cancer-specific deaths. For comparison, survival among alpha-blocker users was also evaluated. During the median follow-up of 7.5 years after diagnosis a total of 2,478 men died; 617 due to prostate cancer and 1,861 due to other causes. The risk of prostate cancer death did not differ between 5-ARI users and nonusers (multivariable adjusted HR 0.94, 95% CI 0.72-1.24 and HR 0.98, 95% CI 0.69-1.41 for usage before and after the diagnosis, respectively). Alpha-blocker usage both before and after diagnosis was associated with increased risk of prostate cancer death (HR 1.29, 95% CI 1.08-1.54 and HR 1.56, 95% CI 1.30-1.86, respectively). The risk increase vanished in long-term alpha-blocker usage. Use of 5-ARIs does not appear to affect prostate cancer mortality when used in management of benign prostatic hyperplasia. Increased risk associated with alpha-blocker usage should prompt further exploration on the prognostic role of lower urinary tract symptoms.

Prostate cancer risk among users of digoxin and other antiarrhythmic drugs in the Finnish Prostate Cancer Screening Trial.

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.

Use of non-steroidal anti-inflammatory drugs and prostate cancer survival in the Finnish prostate cancer screening 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.

Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin

BackgroundEnergy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear. ObjectiveWe explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association. Design, setting, and participantsThe PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database. Outcome measurements and statistical analysisGenetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5×10−3. Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses. Results and limitationsA total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p<0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population. ConclusionsSNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death. Patient summaryGenetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes.

114 5-alpha reductase inhibitor use and prostate cancer survival in the Finnish Prostate Cancer Screening Trial

114 5-alpha reductase inhibitor use and prostate cancer survival in the Finnish Prostate Cancer Screening Trial

The Finnish prostate cancer screening trial: analyses on the screening failures.

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 in the Finnish Prostate Cancer Screening Trial.

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.

Prostate cancer risk and nonsteroidal antiinflammatory drug use in the Finnish prostate cancer screening trial.

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.

856 Anti-diabetic drugs and prostate cancer incidence in the Finnish Prostate Cancer Screening Trial

856 Anti-diabetic drugs and prostate cancer incidence in the Finnish Prostate Cancer Screening Trial

Abstract C64: SNPs in genes of the glucose-metabolism pathway and prostate cancer: Interplay with metformin

Abstract Background: Energy metabolism is important for cancer progression. Energy-producing mitochondria also regulate cell growth and survival. Type II diabetes affects systemic energy metabolism, while both diabetes and antidiabetic treatment likely affect prostate cancer. We studied whether SNPs in genes of the energy-metabolism pathways associate with prostate cancer risk and prognosis, and whether the associations are modified by antidiabetic treatment. Materials and methods: As part of an international PRACTICAL Consortium, 397 SNPs were genotyped on Illumina's custom array (iCOGS) among 3,719 participants of the Finnish Prostate Cancer Screening Trial and 1,528 hospital-based cases. The study population was linked to Finnish national prescription database for information on medication use. After correction for multiple testing using adaptive permutation, SNPs showing an association with prostate cancer incidence or mortality at p &amp;lt; 5 x 10-3 significance level were further explored in multivariable-adjusted Cox regression analyses. Analyses on prostate cancer risk and mortality were adjusted for age and screening trial arm. Analyses on prostate cancer case-fatality were additionally adjusted for tumor stage and grade at diagnosis. Results: After permutation, a total of 30 and 10 SNPs were associated with prostate cancer risk or mortality, respectively. Of these, SNPs in genes PDK1, PGM1 and ENO1 showed consistent associations with prostate cancer risk, disease grade/stage and prostate cancer mortality/case fatality in both study cohorts. The associations with prostate cancer were stronger among antidiabetic drug users in general, although the interaction terms were not significant. Higher cumulative amount of metformin use attenuated the risk increase among antidiabetic drug users. Conclusions: Polymorphisms in genes of the energy-metabolism pathways associate with prostate cancer risk, disease severity and prognosis. This association may be modified by diabetes and antidiabetic drug usage. If validated in further studies, these polymorphisms could be used in risk stratification of prostate cancer patients. Citation Format: Teemu J. Murtola, Tiina Wahlfors, Teuvo LJ Tammela, Liisa Mååttånen, Johanna Schleutker. SNPs in genes of the glucose-metabolism pathway and prostate cancer: Interplay with metformin. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C64.

Prostate Cancer Mortality in the Finnish Randomized Screening Trial

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.

Prostate Cancer Screening: A Survey of Attitudes and Practices among Finnish Physicians in 1999 and 2007

To evaluate the attitudes and practices related to prostate-specific antigen (PSA) screening for prostate cancer (PC) among Finnish physicians in 1999 and 2007. 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. 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). 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.

Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trial

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.

False-positive screening results in the Finnish prostate cancer screening trial

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.

Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial

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.

Biological aggressiveness of prostate cancer in the Finnish screening trial

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.

Assessment of causes of death in a prostate cancer screening trial

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.