Suzie J. Otto

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.

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.).

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.

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 cases 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 cases diagnosis. Cancer Epidemiol Biomarkers Prev; 21(1); 66–73. ©2011 AACR.

Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening

All screening participants in the first round of the screening trial were asked about their previous PSA tests (ever) using a selfadministered questionnaire mailed to the subjects with the invitation. A total of 20 699 men (97% of the participants) responded. The proportion of missing/don’t know answers was 3%. The overall prevalence of previous PSA tests was 10%. The proportion of participants in the screening arm reporting previous PSA test increased from 7% in 1996 to 14% in 1999.

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.

Low all-cause mortality in the volunteer-based Rotterdam section of the European randomised study of screening for prostate cancer: self-selection bias?

Objectives: The likelihood of self-selection bias in a cohort of men that entered the volunteer-based randomised prostate cancer screening trial was assessed. In addition, the accuracy of the randomisation was evaluated by comparison amongst the trial arms. Setting: The Rotterdam section of the European Randomised Study of Screening for Prostate Cancer (ERSPC). Participants were recruited from population registries and randomised after receipt of written informed consent (49% participation rate). Methods: Data from 37,614 men who entered the Rotterdam trial between June 1994 and July 1999 were linked to the Causes of Death Registry of Statistics Netherlands. For the assessment of self-selection bias, mortality in the trial cohort and the area of Rotterdam was compared by calculating standardised mortality ratios (SMRs, 95% confidence interval [CI]). Comparisons between the screening and the control arm were made by means of relative risk (RR). Results: There were a total of 1661 deaths (4.4%) in the trial cohort, during an average follow-up time of 2.8 years. The observed number of deaths in the two arms combined was lower than expected (SMR 86.7%, 95% CI 81.6-92.1), which was reflected in the major cause of death categories, especially in all malignant neoplasms. No difference was observed in the all-cause mortality rate among the screening and control arm, aged 55-69 years at entry (RR 1.00, 95% CI 0.89-1.12), nor when all causes, excluding prostate cancer mortality, were considered. Conclusions: The preliminary results show that the screening and the control arm were comparable, but men recruited for the trial seemed healthier than men in the target population.

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.

Effects of storage on venous and capillary blood samples: the influence of deferoxamine and butylated hydroxytoluene on the fatty acid alterations in red blood cell phospholipids.

Fatty acid concentrations in plasma and red blood cell phospholipids isolated from paired venous and capillary blood samples were compared and the effect of storage at -20 degrees C was evaluated as well. Plasma fatty acid profiles from venous and capillary blood were found to be comparable and not affected by up to four weeks of storage, while fatty acid profiles of venous and capillary red blood cells were no longer comparable after four weeks. Substantial losses of long-chain polyunsaturated fatty acids were observed in capillary red blood cells. To investigate whether the observed long-chain polyunsaturated fatty acids loss could be prevented, capillary red blood samples were stored for up to one year at -50 degrees C in the presence of the iron-binding agent deferoxamine or the free radical scavenger butylated hydroxytoluene. Both compounds protected the long-chain polyunsaturated fatty acids. Similarly, storage of red blood cell lipid extracts at -50 degrees C for up to one year was not associated with reduced levels of long-chain polyunsaturated fatty acids. In conclusion, the lipid loss from capillary red blood cells can be reduced for at least one year during storage at -50 degrees C with prior addition of either a metal chelating compound or a free radical scavenger, or by preparing lipid extracts of the samples within one week of blood collection.

PSA levels and cancer detection rate by centre in the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND To describe the variation in PSA level by age group and screening round in the ERSPC centres and the variation in cancer detection rates in relation to the underlying prostate cancer incidence. METHODS Individual data on men invited for the first and second screening rounds according to protocol (excluding early recalls and interval cancers) were obtained from the central database of the ERSPC (cut-off date 31st December 2006). Data were compared between and within centres for the core age group (55-69 at entry). The cancer detection rate (CDR) was compared with the expected background prostate cancer incidence rate in the absence of screening adjusted for the incidence rate in non-attenders and the control arm (IRS). RESULTS Mean PSA values in the age groups 55-59 years and 65-69 years showed little variation by centre, except for the Dutch centre, where an increase from 1.6 to 1.8 ng/ml and a decline from 2.9 to 2.5ng/ml was observed, respectively. Most tumours were detected at the PSA range 4.0-9.9 ng/ml, with a shift to more cancer detection at 3.0-3.9 ng/ml in the second screening round. There was high variability in the CDR between the centres in both the first (16-46 per 1000) and the second screening rounds (14-50 per 1000). Although the ratio CDR/IRS was less variable, it is somewhat lower in Italy and Switzerland (12 and 14,respectively) and higher in the Netherlands (28), than in most other centres and in Belgium the ratio increased markedly, from 20 to 44 between the first and second rounds. CONCLUSION There was no clear evidence of a relationship between the underlying incidence and mean PSA levels at screening or the cancer detection rate.