Auvinen, A.

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

2012-11-01T00:00:00Z

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 36 270 men randomized to the screening arm, while no screening was provided to the 40 543 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.

Quality-of-life effects of prostate-specific antigen screening (Article)

2012-08-16T00:00:00Z

Background: After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. Methods: On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. Results: Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). Conclusions: The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.) Copyright

False-positive screening results in the European randomized study of screening for prostate cancer (Article)

2011-12-01T00:00:00Z

Background: Screening for prostate cancer (PC) with prostate-specific antigen (PSA) has been shown to decrease mortality, but has adverse effects, such as false-positive (FP) screening results. We describe the frequency of FP results and assess their relation to subsequent screening attendance, test results and prostate cancer risk in a large randomized trial. Materials and methods: We included data from five centres of the European Randomized Study of Screening for Prostate Cancer, altogether over 61,000 screened men. Men were screened with PSA test at a 2-7 year interval depending on the centre; PSA cut-off was 3.0-4.0 ng/ml. A positive screen with no histologically confirmed PC in biopsy within 1 year was defined as an FP result. Results: Of the 61,604 men who were screened at least once, 17.8% had one or more FP result(s). Almost 20% of men who participated at all screening rounds had one or more FP result(s). More than half of the men with an FP result had another FP if screened again. Men with FP results had a fourfold risk of PC at subsequent screen (depending on the round, 10.0% versus 2.6-2.7% of men with negative screen, risk ratio 3.8-3.9). The PCs following an FP result were in 92.8% of cases localised and low-grade versus 90.4% following a screen-negative result. Conclusions: Our results show that FP results are common adverse effects in PC screening, as they affect at least one in six screened men. False-positive men are more prone to be diagnosed with PC but are also likely to have consistently high PSA levels.

No excess mortality after prostate biopsy: Results from the European Randomized Study of Screening for Prostate Cancer (Article)

2011-06-01T00:00:00Z

OBJECTIVE To assess possible excess mortality associated with prostate biopsy among screening participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC). patientS AND METHODS From three centres in the ERSPC (Finland, The Netherlands and Sweden) 50 194 screened men aged 50.2-78.4 years were prospectively followed. A cohort of 12 959 first-time screening-positive men (i.e. with biopsy indication) was compared with another cohort of 37 235 first-time screening-negative men. Overall mortality rates (i.e. other cause than prostate cancer mortality) were calculated and the 120-day and 1-year cumulative mortality were calculated by the Kaplan-Meier method, with a log-rank test for statistical significance. Incidence rate ratios (RR) and statistical significance were evaluated using Poisson regression analyses, adjusting for age, total PSA level, screening centre and whether a biopsy indication was present, or whether a biopsy was actually performed or not. RESULTS There was no statistically significant difference in cumulative 120-day other cause mortality between the two groups of men: 0.24% (95% CI, 0.17-0.34) for screening-positive men vs 0.24% (95% CI, 0.20-0.30) for screening-negative men (P= 0.96). This implied no excess mortality for screening-positive men. Screening-positive men who were not biopsied (n= 1238) had a more than fourfold risk of other cause mortality during the first 120 days compared to screening-negative men: RR, 4.52 (95% CI, 2.63-7.74) (P < 0.001), adjusted for age, whereas men who were actually biopsied (n= 11 721) had half the risk: RR, 0.41 (95% CI, 0.23-0.73) (P= 0.002), adjusted for age. Only 14/31 (45%) of the screening-positive men who died within 120 days were biopsied and none died as an obvious complication to the biopsy. CONCLUSION Prostate biopsy is not associated with excess mortality and fatal complications appear to be very rare.

Foreword: Meeting the challenge of prostate cancer (Article)

2010-11-01T00:00:00Z

Prostate cancer is a key medical and public health challenge. Though it is currently the most common cancer among men in Europe, its natural history, prognosis and treatment are poorly understood in comparison to breast cancer. Prostate cancers diagnosed are very small and prediction of their progression at the individual level is difficult and hence need for aggressive management is unclear. The number of randomised treatment trials remains shamefully small and hence the relative effectiveness of the new treatment modalities introduced is unclear.

Lead-time in the european randomised study of screening for prostate cancer (Article)

2010-11-01T00:00:00Z

Background: Lead-time is defined as the time by which screening advances the diagnosis compared with absence of screening. A sufficiently long lead-time needs to be achieved so that cancer can be detected while still curable. A very short lead-time may indicate poor sensitivity of the screening test, while a very long lead-time suggests overdiagnosis. Material and methods: In the first screening round, a total of 56,294 men aged 55-74 years were screened with serum prostate specific antigen (PSA) in five countries of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with an overall detection rate (prevalence) of 2.8% (1972 prostate cancers). Prostate cancer incidence among 92,142 men randomly allocated to the control arm of the trial was also assessed. Lead-time was estimated as the time required to accumulate a similar cumulative risk of prostate cancer in the control arm to the detection rate in the intervention arm, i.e. from the ratio of detection rate (prevalence of screen-detected cases) and expected incidence (cumulative risk). Results: Using a serum PSA cut-off of 4 ng/ml, the mean lead-time in the whole study population was estimated as 6.8 years (95% confidence interval (95% CI) 7.9-8.4). It was 8 years in The Netherlands, 6 in Sweden and Finland, 5 in Italy and 4 in Belgium. The mean lead-time was similar, 6-7 years, at ages 50-64 years, but close to 8 years among men aged 65-74 years. A lower PSA cut-off level of 3 ng/ml used in Sweden and The Netherlands prolonged the mean lead-time by approximately 1 year. Lead-time based on advanced prostate cancer only was slightly shorter, mean 5.3 years (95% CI 4.6-6.0). The lead-time for the second screening round was slightly shorter than that for the first (5.9, 95% CI 5.4-6.4), reflecting a similar relation between detection rate and control group incidence. Conclusion: The lead-time for prostate cancer found in ERSPC substantially exceeded that found for breast, cervical and colorectal cancer screening. One round of prostate cancer screening can advance clinical diagnosis by 4-8 years. Overdiagnosis or detection of non-progressive tumours may contribute substantially to the lead-time.

Balancing the harms and benefits of early detection of prostate cancer. (Article)

2010-10-15T00:00:00Z

BACKGROUND: The benefits of prostate cancer screening on an individual level remain unevaluated. METHODS: Between 1993 and 1999, a total of 43,987 men, aged 55-74 years, were included in the intervention arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in the Netherlands, Sweden, and Finland. A total of 42,503 men, aged 55-74 years, were included in a clinical population in Northern Ireland. Serum prostate-specific antigen (PSA) <20.0 ng/mL was measured in all men at study entry. All men were followed for prostate cancer incidence and causes of death until December 31, 2006. RESULTS: The adjusted absolute difference in prostate cancer specific mortality between the intervention population and the clinical population increased with increasing PSA level at study entry, ie, 0.05 per 10,000 person-years for men who had a serum PSA level of 0.0-1.9 ng/mL and 8.8 per 10,000 person-years for men who had a serum PSA level of 10-19.9 ng/mL. To evaluate the risks of early detection, the number needed to investigate (NNI) and number needed to treat (NNT) to save 1 death from prostate cancer were calculated. Both NNI and NNT were higher for those who had lower PSA levels at study entry. The NNI was 24,642 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 133 men for patients who had a serum PSA level of 10-19.9 ng/mL; the NNT was 724 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 60 men for patients with a serum PSA level of 10-19.9 ng/mL. CONCLUSIONS: For men with a low serum PSA level, the benefits of aggressive investigation and treatment may be limited because they are associated with a large increase in cumulative incidence and potential overtreatment.

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC) (Article)

2009-10-01T00:00:00Z

Background: Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. Objective: To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. Design, setting, and participants: We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162 243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). Intervention: Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. Measurements: Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. Results and limitations: In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. Conclusions: PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

Test sensitivity in the European prostate cancer screening trial: Results from Finland, Sweden, and the Netherlands (Article)

2009-07-01T00:00:00Z

Test sensitivity pertains to the ability of a test to identify subjects with the target disorder. In cancer screening, test sensitivity can be estimated using interval cancer incidence as an indicator of false-negative result. A randomized trial provides the optimal approach for estimating test sensitivity, as the control arm provides the expected rates. We estimated the sensitivity of the prostate-specific antigen test using incidence method, i.e., based on incidence of interval cancer among subjects with negative screening results, compared with that in the control arm. Data from three centers in the European randomized screening trial were used to estimate interval cancer incidence (II) among 39,389 men with negative screening tests. This was compared with incidence among the 79,525 men in the control arm of the trial (Ic) to estimate test sensitivity (S = 1 - II/ IC). Confidence intervals were calculated using simulations, assuming that the number of cases follows a Poisson distribution. The estimated test sensitivity following the first screen was 0.87 (0.83-0.92) in Finland, 0.87 (0.62-1.00) in Sweden, and 0.93 (95% confidence interval, 0.90-0.96) in the Netherlands. There was some indication of a higher test sensitivity for aggressive cancers (0.85-0.98 for non-organ-confined cases or Gleason 8-10) and for the second screening round (approximately 0.85-0.95). Test sensitivity varied to some extent between the three centers in the European trial, probably reflecting variation in screening protocols, but was acceptable in the first screening round, and may be better for aggressive cancers and in the second screening round. Copyright

Screening and prostate-cancer mortality in a randomized european study (Article)

2009-03-26T00:00:00Z

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.) Copyright