Kirsi Talala

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.

Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish section of the ERSPC

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.

Estimate of Opportunistic Prostate Specific Antigen Testing in the Finnish Randomized Study of Screening for Prostate Cancer

Purpose: Screening for prostate cancer remains controversial, although ERSPC (European Randomized Study of Screening for Prostate Cancer) showed a 21% relative reduction in prostate cancer mortality. The Finnish Randomized Study of Screening for Prostate Cancer, which is the largest component of ERSPC, demonstrated a statistically nonsignificant 16% mortality benefit in a separate analysis. The purpose of this study was to estimate the degree of contamination in the control arm of the Finnish trial. Materials and Methods: Altogether 48,295 and 31,872 men were randomized to the control and screening arms, respectively. The screening period was 1996 to 2007. The extent of prostate specific antigen testing was analyzed retrospectively using laboratory databases. The incidence of T1c prostate cancer (impalpable prostate cancer detected by elevated prostate specific antigen) was determined from the national Finnish Cancer Registry. Results: Approximately 1.4% of men had undergone prostate specific antigen testing 1 to 3 years before randomization. By the first 4, 8 and 12 years of followup 18.1%, 47.7% and 62.7% of men in the control arm had undergone prostate specific antigen testing at least once and in the screening arm the proportions were 69.8%, 81.1% and 85.2%, respectively. The cumulative incidence of T1c prostate cancer was 6.1% in the screening arm and 4.5% in the control arm (RR 1.21, 95% CI 1.13–1.30). Conclusions: A large proportion of men in the control arm had undergone a prostate specific antigen test during the 15‐year followup. Contamination is likely to dilute differences in prostate cancer mortality between the arms in the Finnish screening trial.

Statin Use and Prostate Cancer Survival in the Finnish Randomized Study of Screening for Prostate Cancer

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.

Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Abstract Objective: Diabetic men have lowered overall prostate cancer (PCa) risk, while their risk of high-grade disease may be elevated. The antidiabetic drug metformin may reduce the risk. This study evaluated PCa incidence among users of metformin and other antidiabetic drugs in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Methods: The study population (78,615 men) was linked to the national prescription database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PCa were estimated using Cox regression, with medication use as a time-dependent variable. The effect of diabetes was estimated by comparing antidiabetic drug users to non-users, while drug-specific effects were evaluated within antidiabetic drug users. Analyses were performed in both study arms of FinRSPC. Results: Compared to non-users, men using antidiabetic drugs had lowered overall PCa risk (HR 0.85, 95% CI 0.79–0.92), and this association was not affected by PCa screening. However, the risk of metastatic PCa was increased (HR 1.44, 95% CI 1.09–1.91). Among antidiabetic drug users, metformin decreased overall PCa risk (HR 0.81, 95% CI 0.69–0.95) in a dose-dependent manner. When stratified by FinRSPC study arm, the risk reduction was observed only in the screening arm. Sulphonylureas increased the risk of metastatic PCa (HR 2.04, 95% CI 1.11–3.77). Use of thiazoledenediones or insulin was not associated with PCa risk. Conclusion: Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa.

Non-Steroidal Anti-Inflammatory Drugs and Cancer Death in the Finnish Prostate Cancer Screening Trial

Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have been associated with lowered cancer incidence and mortality. We examined overall cancer mortality and mortality from specific cancer sites among the 80,144 men in the Finnish Prostate Cancer Screening Trial. Information on prescription drug use was acquired from the national drug reimbursement database. Over-the-counter use information was gathered by a questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) by prescription and over-the-counter NSAID use for overall and specific cancer deaths were calculated using Cox regression. During the median follow-up time of 15 years, 7,008 men died from cancer. Men with prescription NSAID use had elevated cancer mortality (HR 2.02 95% CI 1.91–2.15) compared to non-users. The mortality risk was increased for lung, colorectal and pancreas cancer mortality (HR 2.68, 95%CI 2.40–2.99, HR 1.91, 95% CI 1.57–2.32 and HR 1.93, 95% CI 1.58–2.37, respectively). The increased risk remained in competing risks regression (HR 1.11, 95% CI 1.05–1.18). When the usage during the last three years of follow-up was excluded, the effect was reversed (HR 0.69, 95% CI 0.65–0.73). Cancer mortality was not decreased for prescription or over-the-counter aspirin use. However, in the competing risk regression analysis combined prescription and over-the-counter aspirin use was associated with decreased overall cancer mortality (HR 0.76, 95% CI 0.70–0.82). Cancer mortality was increased for NSAID users. However, the risk disappeared when the last 3 years were excluded.

Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Abstract Objective: Anticoagulants, especially vitamin K antagonists (VKAs) such as warfarin, have been hypothesized to have antitumor properties, and use of VKAs has been associated with a lower prostate cancer (PCa) risk. This study estimated PCa risk among users of warfarin and other anticoagulants. Materials and methods: All anticoagulant use among 78,615 men during 1995–2009 was analyzed. Cox regression, adjusted for age, screening trial arm and use of other medications, with medication use as a time-dependent variable, was used to estimate PCa risk overall, and by tumor grade and stage. Results: In total, 6537 men were diagnosed with PCa during 1995–2009 (1210 among warfarin users). Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01–1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7–10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00–1.43). The increase in risk disappeared in long-term, high-dose use. Conclusions: This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants.

The effect of non‐steroidal anti‐inflammatory drugs on risk of benign prostatic hyperplasia

Inflammation may play a role in pathogenesis of benign prostatic hyperplasia (BPH). However, the role of non‐steroidal anti‐inflammatory drugs (NSAIDs) as BPH risk factor is unclear. The objective of this study was to examine risk of BPH by NSAID use in a population‐based cohort.

Outcomes of Prostate-specific Antigen-based Prostate Cancer Screening Among Men Using Nonsteroidal Anti-inflammatory Drugs

BACKGROUND The Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC), the largest component of the European Randomized Study of Screening for Prostate Cancer (ERSPC), showed a smaller, nonsignificant reduction in prostate cancer-specific mortality by systematic prostate-specific antigen (PSA)-based screening compared with the overall ERSPC results. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammation and also PSA elevations due to intraprostatic inflammation. OBJECTIVE To explore whether NSAID usage modifies the effects of PSA-based screening on prostate cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS A cohort of 78 165 men from the FinRSPC were linked to a comprehensive national prescription database to obtain information on NSAID reimbursements prior to screening. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Prostate cancer risk and mortality were compared between the FinRSPC screening arm and the control arm among NSAID users and nonusers using an age-adjusted Cox regression model. RESULTS AND LIMITATIONS Screening increased the detection of Gleason 6 (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.47-1.72 and HR 1.39, 95% CI 1.26-1.54) and localized prostate tumors (HR 1.25, 95% CI 1.18-1.32 and HR 1.11, 95% CI 1.03-1.20) more among baseline NSAID nonusers than among users, respectively (p for interaction <0.04 for both). This difference was observed in all three screening rounds. Detection of metastatic prostate cancer was similar in both NSAID users and nonusers. Screening decreased prostate cancer mortality among men using NSAIDs at FinRSPC randomization (HR 0.66, 95% CI 0.49-0.90) but not among nonusers (HR 0.95, 95% CI 0.81-1.12); p for interaction=0.04. CONCLUSIONS Screening detected fewer well-differentiated localized tumors among NSAID users than among nonusers. This suggests that PSA screening may cause less overdiagnosis within this subgroup, whereas mortality benefit may be greater among NSAID users. PATIENT SUMMARY Prostate cancer screening causes less overdiagnosis of well-differentiated localized prostate tumors among men who use nonsteroidal anti-inflammatory drugs.

Impact of cause of death adjudication on the results of the European prostate cancer screening trial.

Background:The European Randomised Study of Prostate Cancer Screening has shown a 21% relative reduction in prostate cancer mortality at 13 years. The causes of death can be misattributed, particularly in elderly men with multiple comorbidities, and therefore accurate assessment of the underlying cause of death is crucial for valid results. To address potential unreliability of end-point assessment, and its possible impact on mortality results, we analysed the study outcome adjudication data in six countries.Methods:Latent class statistical models were formulated to compare the accuracy of individual adjudicators, and to assess whether accuracy differed between the trial arms. We used the model to assess whether correcting for adjudication inaccuracies might modify the study results.Results:There was some heterogeneity in adjudication accuracy of causes of death, but no consistent differential accuracy by trial arm. Correcting the estimated screening effect for misclassification did not alter the estimated mortality effect of screening.Conclusions:Our findings were consistent with earlier reports on the European screening trial. Observer variation, while demonstrably present, is unlikely to have materially biased the main study results. A bias in assigning causes of death that might have explained the mortality reduction by screening can be effectively ruled out.