Quality-of-life effects of prostate-specific antigen screening.

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.).

Screening for type 2 diabetes in a high-risk population: effects of a negative screening test after 4 years follow-up.

BACKGROUND: A negative diabetes screening test may unintentionally provide reassurance, resulting in reduced incentive to follow a healthy lifestyle. PURPOSE: The purpose of this study is to assess negative test result effects on lifestyle and risk perception at 4 years follow-up. METHODS: Risk perception and changes in smoking, physical activity, body mass index (BMI), and waist circumference were compared between 706 high-risk participants with a negative test result and 706 high-risk participants not offered screening (controls) in a randomized controlled trial of diabetes screening. RESULTS: Negative-screened individuals experienced a small but significant increase in BMI and waist circumference, but there was no significant difference with controls. The negative-screened group had significantly higher perception of risk of developing diabetes (p = 0.009) than controls, but no differences were observed in perceived personal control, worry, and optimistic bias. CONCLUSION: Screening negative for diabetes did not lead to overt long-term changes in lifestyle, despite a high perception of risk of developing diabetes. (ISRCTN75983009.).

Increased non-prostate cancer death risk in clinically diagnosed prostate cancer.

UNLABELLED: Study Type - Prognosis (case control). Level of Evidence 3a. What's known on the subject? and What does the study add? Treatment of advanced PC might put patients at an increased risk of cardiovascular events. Recent studies have suggested that the excess mortality is lower among men who were diagnosed with screen detected PC in comparison to men with clinically diagnosed PC, possibly due to the use of medications for cardiovascular disease and the change to a healthier lifestyle of men with a screen detected PC. Men with clinically diagnosed PC have an increased risk of death unrelated to PC itself, i.e., the excess mortality is based on an increased risk of dying from other neoplasm and diseases of the circulatory or respiratory system. OBJECTIVE: • To assess the cause-specific mortality unrelated to prostate cancer (PC) itself in patients with screen- and clinically diagnosed PC. PATIENTS AND METHODS: • The present study was conducted among participants of the European Randomized Study of Screening for Prostate Cancer. • Based on consensus of the causes of death committee (CODC), all patients who died from PC were excluded. • In the intervention arm, cases were patients with a screen-detected PC, aged 55-74 years, between 1993 and 2001. • These cases were matched to two controls in whom no cancer was found after biopsy, and two controls in whom no cancer was suspected after screening. In the control arm, cases were patients with clinically diagnosed PC, aged 55-74 years, between 1993 and 2001. These cases were matched to four controls without PC. Matching was done with respect to date of birth, screening and/or diagnosis. Men were followed up to 31 December 2007. RESULTS: • No statistically significant difference in overall mortality between cases and controls in the intervention arm was observed: relative risk (RR) 1.26 (95% confidence interval [CI] 0.96-1.65; P = 0.102) and RR 1.13 (95% CI 0.86-1.47; P = 0.381). • In the control arm, the overall mortality was statistically significantly higher in cases relative to controls: RR 1.43 (95% CI 1.03-2.00; P = 0.033). • This difference was because of an increased risk of dying from neoplasms and disease of the circulatory or respiratory system among cases: RR 1.61 (95% CI 1.12-2.29; P = 0.009). • The present study was limited by the relatively small sample size. CONCLUSIONS: • Increased mortality unrelated to PC itself was observed in men with clinically diagnosed PC, but not in screen-detected PC. • The excess mortality in men with clinically diagnosed PC seems to be as a result of a significantly increased risk of dying from neoplasm and disease of the circulatory or respiratory system. • Results have to be studied more thoroughly in further clinical trials.

Screening for type 2 diabetes in a high-risk population: study design and feasibility of a population-based randomized controlled trial.

BACKGROUND: We describe the design and present the results of the first year of a population-based study of screening for type 2 diabetes in individuals at high risk of developing the disease. High risk is defined as having abdominal obesity. METHODS: Between 2006 and 2007, 79,142 inhabitants of two Dutch municipalities aged 40-74 years were approached to participate in screening. Eligible participants had a self-reported waist circumference of ≥ 80 cm for women and ≥ 94 cm for men, and no known pre-existing diabetes. Of the respondents (n = 20,578; response rate 26%), 16,135 were abdominally obese. In total, 10,609 individuals gave written informed consent for participation and were randomized into either the screening (n = 5305) or the control arm (n = 5304). Participants in the screening arm were invited to have their fasting plasma glucose (FPG) measured and were referred to their general practitioner (GP) if it was ≥ 6.1 mmol/L. In addition, blood lipids were determined in the screening arm, because abdominal obesity is often associated with cardiovascular risk factors. Participants in both arms received written healthy lifestyle information. Between-group differences were analyzed with Chi-square tests and logistic regression (categorical variables) and unpaired t-tests (continuous variables). RESULTS: The screening attendance rate was 84.1%. Attending screening was associated with age at randomization (OR = 1.03, 95% CI 1.02-1.04), being married (OR = 1.57, 95% CI 1.33-1.83) and not-smoking currently (OR = 0.52, 95% CI 0.44-0.62). Of the individuals screened, 5.6% had hyperglycemia, and a further 11.6% had an estimated absolute cardiovascular disease risk of 5% or higher, according to the Systematic Coronary Risk Evaluation risk model. These participants were referred to their GP. CONCLUSIONS: Self-reported home-assessed waist circumference could feasibly detect persons at high risk of hyperglycemia or cardiovascular disease. Continuation of the large-scale RCT is warranted to test the hypothesis that targeted population-based screening for type 2 diabetes leads to a significant reduction in cardiovascular morbidity and mortality. TRIAL REGISTRATION: ISRCTN75983009.

Impressive time-related influence of the Dutch screening programme on breast cancer incidence and mortality, 1975-2006.

The aim of this study was to assess changes in the trends in breast cancer mortality and incidence from 1975 to 2006 among Dutch women, in relation to the implementation of the national breast cancer screening programme. Screening started in 1989 for women aged 50-69 and was extended to women aged 70-75 years in 1998 (attendance rate approximately >80%). A joinpoint Poisson regression analysis was used to identify significant changes in rates over time. Breast cancer mortality rates increased until 1994 (age group 35-84), but thereafter showed a marked decline of 2.3-2.8% per annum for the age groups 55-64 and 65-74 years, respectively. For the age group of 75-84 years, a decrease started in the year 2001. In women aged 45-54, an early decline in breast cancer mortality rates was noted (1971-1980), which is ongoing from 1992. For all ages, breast cancer incidence rates showed an increase between 1989 and 1993, mainly caused by the age group 50-69, and thereafter, a moderate increase caused by age group 70-74 years. This increase can partly be explained by the introduction of screening. The results indicate an impressive decrease in breast cancer mortality in the age group invited for breast cancer screening, starting to show quite soon after implementation.

Breast cancer screening halves the risk of breast cancer death: a case-referent study.

Large-scale epidemiologic studies have consistently demonstrated the effectiveness of mammographic screening programs, however the benefits are still subject to debate. We estimated the effect of the Dutch screening program on breast cancer mortality. In a large multi-region case-referent study, we identified all breast cancer deaths in 2004 and 2005 in women aged 50-75 who had been invited for screening (cases). Cases were individually matched to referents from the population invited to screening. Conditional logistic regression was used to estimate the odds ratio (OR) of breast cancer death according to individual screening history. The OR was adjusted for self-selection bias using regional correction factors for the difference in baseline risk for breast cancer death between screened and unscreened women. A total of 1233 cases and 2090 referents were included in this study. We found a 58% reduction in breast cancer mortality in screened versus unscreened women (adjusted OR = 0.42, 95% CI 0.33-0.53). Screening, i.e. early detection and treatment, has resulted in a substantial reduction in breast cancer mortality, indicating that the Dutch breast cancer screening program is highly effective.

[Effects of the population screening into breast cancer]. / Effecten van het bevolkingsonderzoek naar borstkanker.

Annually, in the Netherlands around 900,000 women between the ages of 50-75 years undergo mammography as part of a population screening into breast cancer. In this way more than 5000 cases of breast cancer are detected (0.6% of women screened); 70% of these malignancies are < stage II, which is prognostically favourable. Due to the early detection and treatment of breast cancer, the breast cancer death risk in those women who participate in the population screening is half that of women who choose not to be screened. The downside of the population screening is that participants are relatively often referred to a hospital for a diagnostic work-up (around 2%), and 70% of them are ultimately found not to have cancer. The positive predictive value of the population screening is 30%. Early discovery also leads to over-diagnosis in patients with breast cancer that without screening would never have manifested itself. Based on computer simulations it has been estimated that in the Netherlands over-diagnosis occurs in 9% of patients in whom breast cancer is detected during a population screening.

Screening for prostate cancer: results of the Rotterdam section of the European randomized study of screening for prostate cancer.

BACKGROUND: Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. OBJECTIVE: To assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993-1999, a total of 42 376 men aged 54-74 yr were randomized to a screening arm (S-arm) (n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen [PSA] level cut-off ≥ 3.0 ng/ml as biopsy indication) or a control arm (C-arm) (n = 21 166; no intervention). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55-74 yr at randomization and separately in the predefined age group of 55-69 yr. RESULTS AND LIMITATIONS: After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 [21.0%] were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55-69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55-74 yr; p = 0.042) and 31.6% (age: 55-69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70-74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55-69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55-74 yr, and 392 and 24, respectively, for age group 65-69 yr. Given the slow natural history of the disease, follow-up might be too short. CONCLUSIONS: Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55-69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening.

Mammography screening and risk of breast cancer death: a population-based case-control study.

BACKGROUND: Because the efficacy of mammography screening had been shown in randomized controlled trials, the focus has turned on its effectiveness within the daily practice. Using individual data of women invited to screening, we conducted a case-control study to assess the effectiveness of the Dutch population-based program of mammography screening. METHODS: Cases were women who died from breast cancer between 1995 and 2003 and were closely matched to five controls on year of birth, year of first invitation, and number of invitations before case's diagnosis. ORs and 95% confidence intervals (CI) for the association between attending either of three screening examinations prior to diagnosis and the risk of breast cancer death were calculated using conditional logistic regression and corrected for self-selection bias. RESULTS: We included 755 cases and 3,739 matched controls. Among the cases, 29.8% was screen-detected, 34.3% interval-detected, and 35.9% never-screened. About 29.5% of the never-screened cases had stage IV tumor compared with 5.3% of the screen-detected and 15.1% of the interval-detected cases. The OR (95% CIs), all ages (49-75 years), was 0.51 (0.40-0.66) and for the age groups 50-69, 50-75, and 70-75 years were 0.61 (0.47-0.79), 0.52 (CI 0.41-0.67), and 0.16 (0.09-0.29), respectively. CONCLUSION: The study provides evidence for a beneficial effect of early detection by mammography screening in reducing the risk of breast cancer death among women invited to and who attended the screening. IMPACT: This is the first case-control study that accurately accounts for equal screening opportunity for both cases and matched controls by number of invitations before case's diagnosis.

Disease-specific survival of men with prostate cancer detected during the screening interval: results of the European randomized study of screening for prostate cancer-Rotterdam after 11 years of follow-up.

BACKGROUND: In a screening program, interval cancers are cancers diagnosed between two screening visits. OBJECTIVE: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. DESIGN, SETTING, AND PARTICIPANTS: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. INTERVENTION: Men with prostate-specific antigen ≥ 3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. MEASUREMENTS: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. RESULTS AND LIMITATIONS: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. CONCLUSIONS: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. TRIAL REGISTRATION: ISRCTN49127736.

Limited contamination in the Dutch-Belgian randomized lung cancer screening trial (NELSON).

Purpose of this study was to determine the rate of contamination, defined as lung cancer screening in the control arm, of the Dutch-Belgian randomized lung cancer screening trial (NELSON) as contamination adversely affects the power of a trial. The NELSON cohort includes 15,822 high-risk current and former smokers, aged 50-75 years, equally randomized to the screen and control arm. Questionnaires were sent to a sample of 1460 male subjects of the control arm, stratified on smoking determinants. The response rate was 73.0%. The participants were asked whether they received a chest X-ray or CT scan in the last 4 years and, if so, when and for what reason it had been performed. Examinations performed after randomization because of "Precaution" or "No examination was offered by NELSON" were regarded as contamination. In the first 24 months after randomization 3.1% (2.3-3.8%) of the respondents received a lung cancer screening examination. Contamination reached a non-significant peak within the first 3 months after randomization, with a lower limit of 2.5 and an upper limit of 3.1 per 1000 person-months. This screening rate did not differ from the background rates in the last 18 months before randomization. No significant differences were observed between current and former smokers. In conclusion, the rate of contamination among male subjects of the control arm of the NELSON trial is low and is not likely to jeopardize the power of the trial.

Prostate-specific antigen screening in the United States vs in the European Randomized Study of Screening for Prostate Cancer-Rotterdam.

Dissemination of prostate-specific antigen (PSA) testing in the United States coincided with an increasing incidence of prostate cancer, a shift to earlier stage disease at diagnosis, and decreasing prostate cancer mortality. We compared PSA screening performance with respect to prostate cancer detection in the US population vs in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC-Rotterdam). We developed a simulation model for prostate cancer and PSA screening for ERSPC-Rotterdam. This model was then adapted to the US population by replacing demography parameters with US-specific ones and the screening protocol with the frequency of PSA tests in the US population. We assumed that the natural progression of prostate cancer and the sensitivity of a PSA test followed by a biopsy were the same in the United States as in ERSPC-Rotterdam. The predicted prostate cancer incidence peak in the United States was then substantially higher than the observed prostate cancer incidence peak (13.3 vs 8.1 cases per 1000 man-years). However, the actual observed incidence was reproduced by assuming a substantially lower PSA test sensitivity in the United States than in ERSPC-Rotterdam. For example, for nonpalpable local- or regional-stage cancers (ie, stage T1M0), the estimates of PSA test sensitivity were 0.26 in the United States vs 0.94 in ERSPC-Rotterdam. We conclude that the efficacy of PSA screening in detecting prostate cancer was lower in the United States than in ERSPC-Rotterdam.

Overall survival in the intervention arm of a randomized controlled screening trial for prostate cancer compared with a clinically diagnosed cohort.

OBJECTIVES: This population-based study provides comparisons of prostate cancer characteristics at diagnosis of two cohorts of men from two well-defined geographical areas exposed to different intensities of prostate cancer screening. Overall survival in both cohorts was compared with that in the general population. METHODS: A cohort of 822 men randomized to the intervention arm of a prostate cancer screening trial and subsequently diagnosed with prostate cancer was compared with a nonrandomized cohort of 947 men who were clinically diagnosed with prostate cancer in a geographically neighboring region. In both cohorts, cases were diagnosed with prostate cancer between January 1989 and December 1997. A partitioning of overall survival by variables associated with cancer onset such as age at diagnosis, stage at diagnosis, and grade at diagnosis was performed. RESULTS: Age at diagnosis, tumor extent at diagnosis, and grade at diagnosis were significantly different between the screened and clinically diagnosed cohort. The 5- and 10-yr survival rates were higher in the screened cohort than in the clinically diagnosed cohort (88.8% vs. 52.4%, and 68.4% vs. 29.6%, respectively). Significant differences in survival were evident for all age, stage, and grade subgroups, except for metastatic disease at diagnosis. CONCLUSIONS: Differences in overall survival favoring the screened population were observed for all baseline characteristics (age, stage, and grade of disease), and these variables may all explain differences in overall survival because screening achieves early diagnosis as well as a stage and grade shift. As observed survival rates in the screened population mirrored those within the general population, the contribution of lead time and overdiagnosis to final patient outcome is considered to be large as well.

Feasibility study of adjustment for contamination and non-compliance in a prostate cancer screening trial.

BACKGROUND: The use of PSA as a screening test has become increasingly prevalent in the general population and therefore also in the control arm of the European Randomized study of Screening for Prostate Cancer (ERSPC). We present a feasibility study and impact simulation of a secondary analysis, which imitates a situation where all participants in the study are managed according to their random assignment. METHODS: The results of the Rotterdam section of the ERSPC were adjusted for contamination and non-compliance according to Cuzick et al. [Stat Med 1997; 16:1017-1029]. Endpoints of this analysis were simulated reductions in prostate cancer mortality. RESULTS: Of the men allocated to the screen arm, 27.1% were non-compliant. In the control arm 30.7% had their PSA-level measured by a general practitioner (GP) (i.e., contamination). For a scenario in which the intention-to-screen analysis was assumed to give a decrease in the mortality in the men randomized to screening of 6.7%, the secondary analysis resulted in a decrease of 16.1% for those actually screened. CONCLUSION: Although the definition of contamination as "PSA ever tested" gives an indication of the proportion of contamination, it will be important to differentiate the screening use of PSA from its diagnostic use. For the rest, adjustment for non-compliance and contamination was shown to be feasible in this prostate cancer screening trial. It can therefore be used to carry out a secondary analysis on the definitive outcome of the ERSPC and will provide accurate information for those men who are in fact screened.

Risk of cardiovascular mortality in prostate cancer patients in the Rotterdam randomized screening trial.

PURPOSE: To estimate the risk of cardiovascular disease (CVD) mortality in prostate cancer patients in the Rotterdam section of European Randomized Study of Screening for Prostate Cancer, in both arms, and to compare this with the risk in the general population. METHODS: Standardized mortality ratios (SMRs) of cardiovascular mortality for 2,211 prostate cancer patients were calculated including analyses for treatment subgroups (surgery, radiotherapy, watchful waiting, and hormone therapy). Cardiovascular mortality was defined as death as a result of all CVD and as a result of coronary heart disease, acute myocardial infarction, other diseases of the heart, and cerebrovascular accidents. The prevalence of self-reported comorbidities at entry of the trial was evaluated as well. RESULTS: After a mean follow-up of 5.5 years, 258 prostate cancer patients (12%) had died. The SMR of all-cause mortality was 0.90 (95% CI, 0.79 to 1.01). The risk for cardiovascular mortality was low compared with that in the general population; the SMRs varied between 0.37 and 0.49. Low cardiovascular mortality risks were also seen within each treatment subgroup. CVD was the most frequently self-reported comorbidity at entry and prostate cancer patients undergoing radical prostatectomy reported the lowest rates (24%) compared with those receiving other therapies (40% to 42%). CONCLUSION: Although some self-selection has occurred, prostate cancer treatment did not increase the risk of dying as a result of cardiovascular causes in our cohort. The risk was significantly lower for all primary treatment modalities, suggesting that less emphasis should be put on CVD as a contraindication for aggressive (surgical) treatment for prostate cancer patients.

Update on screening and early detection of prostate cancer.

PURPOSE OF REVIEW: The aim of this review is to discuss advances in the field of screening and early detection of prostate cancer from papers published in 2003. RECENT FINDINGS: The fall in distant prostate cancer mortality accounted for the overall decline in cause-specific mortality rates in the USA. In the European prostate cancer screening trial (European Randomized Study of Screening for Prostate Cancer), there is considerable stage migration towards organ-confined disease, which becomes more pronounced in the second screening round. The high sensitivity of the screening protocol (approximately 90%), low interval cancer rate (13-19%) and lead time estimates of 10 years and longer support a 4-year screening interval, current procedure in the European Randomized Study of Screening for Prostate Cancer trial. Advances achieved in research on the discriminative power of the free prostate-specific antigen forms, particularly pro-prostate-specific antigen, have progressed and may be introduced in cancer detection at low prostate-specific antigen levels rather than a further reduction of the current prostate-specific antigen threshold. SUMMARY: Definitive evidence on the effectiveness of prostate cancer screening with prostate-specific antigen should come from the ongoing European Randomized Study of Screening for Prostate Cancer and Prostate, Lung, Colorectal and Ovary cancer trials, and should further elucidate the debate about the appropriate prostate-specific antigen threshold. Free prostate-specific antigen sub-forms offer prospects for prostate cancer detection at low prostate-specific antigen levels.

Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Screening for prostate cancer advances the time of diagnosis (lead time) and detects cancers that would not have been diagnosed in the absence of screening (overdetection). Both consequences have considerable impact on the net benefits of screening. METHODS: We developed simulation models based on results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled 42,376 men and in which 1498 cases of prostate cancer were identified, and on baseline prostate cancer incidence and stage distribution data. The models were used to predict mean lead times, overdetection rates, and ranges (corresponding to approximate 95% confidence intervals) associated with different screening programs. RESULTS: Mean lead times and rates of overdetection depended on a man's age at screening. For a single screening test at age 55, the estimated mean lead time was 12.3 years (range = 11.6-14.1 years) and the overdetection rate was 27% (range = 24%-37%); at age 75, the estimates were 6.0 years (range = 5.8-6.3 years) and 56% (range = 53%-61%), respectively. For a screening program with a 4-year screening interval from age 55 to 67, the estimated mean lead time was 11.2 years (range = 10.8-12.1 years), and the overdetection rate was 48% (range = 44%-55%). This screening program raised the lifetime risk of a prostate cancer diagnosis from 6.4% to 10.6%, a relative increase of 65% (range = 56%-87%). In annual screening from age 55 to 67, the estimated overdetection rate was 50% (range = 46%-57%) and the lifetime prostate cancer risk was increased by 80% (range = 69%-116%). Extending annual or quadrennial screening to the age of 75 would result in at least two cases of overdetection for every clinically relevant cancer detected. CONCLUSIONS: These model-based lead-time estimates support a prostate cancer screening interval of more than 1 year.

Effective PSA contamination in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

The extent of effective prostate-specific antigen (PSA) contamination in the Rotterdam section of the ongoing European Randomized Study of Screening for Prostate Cancer (ERSPC) trial was evaluated and defined as when opportunistic PSA testing of >/= 3.0 ng/ml was followed by biopsy, similar to the regular procedure within the trial. Records of participants aged 55-74 years at entry were linked to the regional database of the general practitioner (GP) laboratory to obtain PSA tests requested by GPs in the period 1 July 1997 to 31 May 2000 (2.9 years), and to the national pathology database to quantify the number of biopsies. All men randomized were included, only those with prostate cancer screen-detected or clinically diagnosed before July 1997 were omitted from the analyses. 2,895 out of the 14,349 men (20.2%) in the control arm and 1,981 out of the 14,052 men (14.1%) in the screening arm were PSA-tested, at an average annual rate of 73 and 52 per 1,000 person-years, respectively. These rates were higher than those recorded at the national and regional levels, 33 and 38 per 1,000 person-years, respectively. Opportunistic PSA testing in the control arm reached a peak within the first months of randomization, after which it decreased to around 70 per 1,000 person-years. An opposite pattern was observed in the screening arm, where participants already had received the scheduled screening within the trial. The proportion of men in the control arm with PSA >/= 3.0 ng/ml followed by biopsy and prostate cancer was 7-8% and 3%, respectively (3% and 0.4-0.6% in the screening arm), over the whole study period. Over a 4-year rescreening interval, the average PSA and effective contamination amount were approximately 28% and 10%, respectively. PSA testing in the control arm in the Rotterdam ERSPC section is high, but was not followed by a substantial increase in prostate biopsies. Although the reasons for ordering PSA test or indicating biopsy are unknown, effective PSA contamination in the Rotterdam ERSPC section is low and not likely to jeopardize the power of the trial.

Initiation of population-based mammography screening in Dutch municipalities and effect on breast-cancer mortality: a systematic review.

BACKGROUND: More than a decade ago, a mammography screening programme for women aged 50-69 years was initiated in the Netherlands. Our aim was to assess the effect of this programme on breast-cancer mortality rates. METHODS: We examined data for 27948 women who died of breast-cancer aged 55-74 years between 1980 and 1999 (30560 cases until 2001). We grouped individuals into 93 clusters, depending on where they lived, and analysed data by use of national population statistics. We analysed time trends in breast-cancer mortality, adjusting for gradual implementations at municipality level, taking as year 0 the month and year in which screening began in a particular municipality. We used a Poisson regression model to estimate the time at which the trend started to turn. We assessed indirectly whether this turning point was related to initiation of screening or adjuvant systemic therapy in four clusters defined according to when screening was implemented. FINDINGS: Compared with rates in 1986-88, breast-cancer mortality rates in women aged 55-74 years fell significantly in 1997 and subsequent years as predicted, reaching -19.9% in 2001. Mortality rates had been increasing by an annual 0.3% until screening was introduced; thereafter we noted a decline of 1.7% per year (95% CI 2.39-0.96) in women aged 55-74 years and of 1.2% in those aged 45-54 (2.40 to 0.07). The turning point in mortality trends arose at around year 0. Adjuvant systemic therapy is unlikely to be the cause of this turning point, since the mortality rates continued to rise up to 1 year after implementation in municipalities where screening began after 1995. INTERPRETATION: Routine mammography screening can reduce breast-cancer mortality rates in women aged 55-74 years.