Liisa Määttänen

Screening and Prostate-Cancer Mortality in a Randomized European Study

BACKGROUND The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

Prostate-cancer mortality at 11 years of follow-up

BACKGROUND Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Screening for prostate cancer decreases the risk of developing metastatic disease: Findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC)

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<0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p=0.001) in the intention-to-screen analysis and a 42% (p=0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. CONCLUSIONS PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

European randomized study of prostate cancer screening: first-year results of the Finnish trial.

SummaryApproximately 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.

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.

Prostate Cancer Mortality in the Finnish Randomized Screening Trial

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Lead-time in prostate cancer screening (Finland).

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.

Second Round Results of the Finnish Population-Based Prostate Cancer Screening Trial

Purpose: Large randomized trials provide the only valid means of quantifying the benefits and drawbacks of prostate-specific antigen (PSA) screening, but the follow-up of ongoing studies is still too short to allow evaluation of mortality. We report here the intermediate indicators of screening efficacy from the second round of the Finnish trial. Experimental Design: The Finnish trial, with ∼80,000 men in the target population, is the largest component in the European Randomized Study of Screening for Prostate Cancer. The first round was completed in 1996–1999. Each year 8,000 men 55–67 years of age were randomly assigned to the screening arm, and the rest formed the control arm. Men randomized to the screening arm in 1996 were reinvited 4 years later, in 2000, and PSA was determined. Results: Of the eligible 6415 men, 4407 (69%) eventually participated in the second round of screening. Of the first-round participants, up to 84% (3833 of 4556) attended rescreening. A total of 461 screenees (10.5%) had PSA levels of ≥4 μg/liter. Altogether, 97 cancers were found, yielding an overall detection rate of 2.2% (97 of 4407). Seventy-nine cases were found among the 3833 second-time screenees (detection rate 2.1%) and 18 in those 574 men (3.1%) who had not participated previously. A PSA of ≥4 μg/liter, but negative biopsy in the first screening round was associated with an up to 9-fold risk of cancer in rescreening relative to those with lower PSA levels at baseline. Ninety-one (94%) of all of the detected cancers were clinically localized. Conclusions: As surrogate measures of an effective screening program, both compliance as well as the overall and advanced prostate cancer detection rates remained acceptable. Men defined as screen-positive but with a negative confirmation of cancer at prevalence screen formed a high-risk group at rescreening.

Estimation of Prostate Cancer Risk on the Basis of Total and Free Prostate-Specific Antigen, Prostate Volume and Digital Rectal Examination

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 4-20 microg/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<0.001) or PSA density (p=0.003) alone. CONCLUSIONS Wide variation in probability of detecting prostate cancer among screened men with a serum PSA of 4-20 microg/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 4 microg/l.

Prediction of prostate cancer in unscreened men: External validation of a risk calculator

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.