Petra M. M. Beemsterboer

Quantitative Interpretation of Age-Specific Mortality Reductions From the Swedish Breast Cancer-Screening Trials

BACKGROUND Results from five Swedish randomized trials may provide the most conclusive evidence on the effect of mammographic screening and have been used to forecast the expected reduction in breast cancer mortality in other programs. However, those trials demonstrated different degrees of reduction. The interpretation of observed mortality reduction after long follow-up for women aged 40-49 years at trial entry is both important and controversial. PURPOSE We estimated what percentage of the observed mortality reduction for women aged 40-49 years at entry into the five Swedish screening trials might be attributable to screening these women at 50 years of age or older. Moreover, we calculated the most likely percentage mortality reduction for specific screening programs if the Swedish results were generalized and analyzed whether characteristics of each trial might at least partly explain the observed differences in reductions among the trials. METHODS Each Swedish trial was simulated with one underlying computer simulation model (MISCAN--MIcrosimulation SCreening ANalysis) of the natural history of the disease and the performance of screening, taking into account nine important trial characteristics. Improvement in prognosis for screen-detected case patients was estimated with age-specific reduction for all trials and each trial design as a reference. RESULTS An expected 7% reduction in breast cancer mortality for women aged 40-49 years at trial entry (relative risk [RR] = 0.93) was determined by computer modeling, assuming no improvement in prognosis for cancers that are screen detected before 50 years of age. This result indicates that, of the overall 10% observed reduction (RR = 0.90) in the five Swedish trials analyzed, most (70%) of this reduction might be attributable to screening these women in later rounds after their 50th birthday. Using additional trial information, predictions of breast cancer mortality reduction in women 50 years or older might be 11% larger than previously expected, assuming that high-quality mammographic screening can be achieved in nationwide programs. For women aged 50-69 years at trial entry, the differences in expected versus observed mortality reduction among the trials are estimated to be relatively small. (Expected mortality reductions range from 24% to 32%). CONCLUSIONS Results from the Swedish randomized breast cancer-screening trials should be seen as more favorable regarding the effect of mammographic screening in reducing breast cancer mortality for women aged 50-69 years than was estimated earlier. Our analyses also suggest that the improvement in prognosis due to screening for women aged 40-49 years is much smaller than that for women aged 50 years or older. Approximately, 70% of the 10% observed reduction in breast cancer mortality (i.e., 7%) for women aged 40-49 years at trial entry might be attributable to a reduction due to screening these women after they reach age 50. IMPLICATIONS Detailed screening data for the 40- to 49-year age group of all Swedish trials should be analyzed to specifically estimate the natural history and performance of screening in this age group.

Nation wide breast cancer screening in the Netherlands: Results of initial and subsequent screening 1990-1995

Based on an extensive cost‐effectiveness analysis, the Dutch nation‐wide breast cancer screening programme started in 1990, providing a biennial screen examination to women aged 50 to 69 years. The programme is monitored by the National Evaluation Team, which annually collects tabulated regional evaluation data to determine performance indicators. This study presents (trends in) the outcomes of initial and subsequent screening rounds, 1990–1995, and compares them to the predictions of the cost‐effectiveness‐analysis. Up to 1996, 88% of the target population was covered by the programme and more than 2.4 × 106 women were invited. The overall attendance rate was 77.5% with little differences between screening rounds and age groups; the highest rate was found in non‐urbanised areas (82.4%). Of 1,000 initially (and 2 years thereafter) screened women, 13.4 (6.6) were referred for further investigation, 9.7 (4.4) were biopsied and 6.4 (3.4) had breast cancer. The positive predictive values of screen test and biopsy were 47% (51%) and 66% (78%), respectively. DCIS was diagnosed in 0.9 (0.5) and invasive cancers ≤10 mm in 1.5 (1.0) per 1,000 screens. Lymph node metastases were found in 28% (24%) of the invasive cancers. Except the increasing attendance, which was much higher than expected, the results were fairly constant over the years. Contrary to initial screens, the results of subsequent screens did not fulfil expectations with regard to breast cancer detection and tumour size distribution. We conclude that the nation‐wide screening programme is being implemented successfully. Given the results, the programme should contribute to a substantial breast cancer mortality reduction in the future. The discrepancy between observed and expected results in subsequent screens has to be watched carefully. Int. J. Cancer 75:694–698, 1998.© 1998 Wiley‐Liss, Inc.

Predictors for biopsy outcome in the European Randomized Study of Screening for Prostate Cancer (Rotterdam region)

In the European Randomized Study of Screening for Prostate Cancer (ERSPC, Rotterdam region), men aged 55–74 years are screened for prostate cancer by prostate‐specific antigen (PSA) sampling, digital rectal examination (DRE), and transrectal ultrasound investigation (TRUS). All men with a PSA ≥4 ng/ml and/or a suspicious DRE and/or a suspicious TRUS are biopsied.

Changing role of 3 screening modalities in the European randomized study of screening for prostate cancer (Rotterdam)

A randomized screening trial was started in Europe to show the effect of early detection and treatment of prostate cancer on mortality (European Study on Screening of Prostate Cancer). In one centre (Rotterdam), the screening protocol initially consisted of 3 screening tests for all men: prostate‐specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasonography (TRUS). A PSA value of ≥4 ng/ml and/or an abnormality on DRE and/or TRUS were taken to indicate that biopsy was required. In this study, we examined the possibilities for a more efficient screening protocol. A logistic‐regression model was used to predict the number of cancers for PSA < 4 ng/ml if all men were biopsied (predictive index, PI). Effects of a change in PSA cut‐off on the screening results were explored. Weights were applied to procedures and cancers to explore the possibility of expressing differences between protocols in one overall figure. Biopsies in men with PSA < 1 ng/ml and a positive DRE or TRUS were very inefficient. Applying DRE and TRUS only in the PSA ranges 1.5 to 3.9 and 2 to 3.9 ng/ml to determine whether a biopsy was required would result in a decrease of 29 to 36% in biopsies and a decrease of 5 to 8% in cancers. However, the results of DRE and TRUS could not be duplicated entirely. A protocol with only PSA ≥ 3 ng/ml as a direct biopsy indicator resulted in a decrease of detected cancers by 7.6% and of biopsies by 12%, also a much simpler screening procedure. Use of the PI would give more efficient protocols, but this should be viewed as a preliminary finding, with the disadvantage of necessitating many additional screening visits. Since the results of DRE and TRUS could not be duplicated, a change in protocol towards PSA ≥ 3 ng/ml appears acceptable. If this proves effective, a final judgement about the optimal combination of screening tests may be made. Int. J. Cancer (Pred. Oncol.) 84:437–441, 1999.

Interval cancers in the Dutch breast cancer screening programme.

The nationwide breast cancer screening programme in The Netherlands for women aged 50–69 started in 1989. In our study we assessed the occurrence and stage distribution of interval cancers in women screened during 1990–1993. Records of 0.84 million screened women were linked to the regional cancer registries yielding a follow-up of at least 2.5 years. Age-adjusted incidence rates and relative (proportionate) incidences per tumour size including ductal carcinoma in-situ were calculated for screen-detected and interval cancers, and cancers in not (yet) screened women, comparing them with published data from the UK regions North West and East Anglia. In total 1527 interval cancers were identified: 0.95 and 0.99 per 1000 woman-years of follow-up in the 2-year interval after initial and subsequent screens respectively. In the first year after initial screening interval cancers amounted to 27% (26% after subsequent screens) of underlying incidence, and in the second year to 52% (55%). Generally, interval cancers had a more favourable tumour size distribution than breast cancer in not (yet) screened women. The Dutch programme detected relatively less (favourable) invasive cancers in initial screens than the UK programme, whereas the number of interval cancers confirms UK findings. Measures should be considered to improve the detection of small invasive cancers and to reduce false-negative rates, even if this will lead to increasing referral rates.

Radiation risk of mammography related to benefit in screening programmes: a favourable balance?

Objectives To estimate the number of breast cancer deaths induced by low dose radiation in breast cancer screening programmes compared with numbers prevented. Methods A computer simulation model on the natural history of breast cancer was combined with a model from BEIR-V on induced breast cancer mortality from low levels of radiation. The improvement in prognosis resulting from screening was based on the results of the Swedish overview of the randomised screening trials for breast cancer and the performance of screening in the Netherlands. Different scenarios (ages and intervals) were used to explore the objectives. Sensitivity analyses were carried out for latency period, dose of mammography, sensitivity of the screening test, early detection by screening of induced breast tumours, and new 1996 risk estimates by Howe and McLaughlin. Results For a screening programme, age group 50–69, two year interval, 2 mGy per view, the balance between the number of deaths induced versus those prevented was favourable: 1:242. When screening is expanded to the age group 40–49 with a one or two year interval the results may be less favourable, that is, 1:66 and 1:97. According to these scenarios and with the Dutch scenario as reference, one breast cancer death from radiation may be expected to occur to save eight extra deaths from breast cancer. If screening was equally effective in young women as in women aged 50–69, the marginal value was 1:±30. Assuming detection of induced cancers by screening could influence the ratios by about 30%, but did not substantially change the conclusions. The new risk estimates by Howe and McLaughlin resulted in five times to eight times favourable ratios breast cancer deaths induced to prevented. Besides age group of screening, dose of mammography is the other determinant of risk. Conclusions For screening under the age of 50, the balance between the number of breast cancer deaths prevented by screening compared with the number induced by radiation seem less favourable. Credibility intervals were however wide, because of many uncertainties of radiation risk at very low doses.

PROSTATE SPECIFIC ANTIGEN TESTING AND DIGITAL RECTAL EXAMINATION BEFORE AND DURING A RANDOMIZED TRIAL OF SCREENING FOR PROSTATE CANCER: EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER, ROTTERDAM

PURPOSE Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population. MATERIALS AND METHODS Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population. RESULTS Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years. CONCLUSIONS PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.

Advanced prostate cancer: Course, care, and cost implications

If prostate cancer screening proves to be effective, some cases will be prevented from reaching the advanced stage. In order to evaluate screening programs thoroughly, it is important to quantify course, care, and accompanying costs of advanced disease.

Mammography requests in general practice during the introduction of nationwide breast cancer screening, 1988-1995.

Introducing an organised breast cancer screening programme for certain age groups in a population might induce opportunistic screening in adjacent (non-invited) age groups and influence health behaviour in the target population. We analysed the effect of the start of the Dutch national screening programme on the number of mammographies requested by 43-45 general practices for the age groups 30-39, 40-49, 50-69 and 70+ years, using logistic regression analysis. In all age groups an immediate increase was observed in the number of mammography requests after the start of the screening, which was largest and statistically significant in the target population of the screening programme (age 50-69 years). More than 2 years after the start of screening, the number of mammography requests in all age groups had decreased to the level before the start and in the age group 50-69 years the number of mammographies was significantly lower than before the screening started. The unexpected increase in mammographies after the start of the breast cancer screening programme might be related to registry problems or to the process of building up the screening programme. Eventually there was a decrease in the number of mammographies in the target population, probably an effect of the introduction of the national screening programme. Opportunistic screening was not clearly demonstrated in adjacent age groups.

Anticipating the consequences for the primary therapy of breast cancer after introducing screening : A more global picture for health care policy making

A breast cancer screening program mainly aims at reducing mortality. However, it also has an effect, often not assessed, on the utilization of health care resources that is relevant to health care policy making. Using a simulation model, this paper forecasts the impact of introducing a breast cancer screening program on the utilization of resources for the primary therapy of breast cancer. The most important consequences from a health care point of view will be an increased use of breast-conserving therapy and an increased need for postoperative radiotherapy; there will also be a higher number of women diagnosed with noninvasive breast cancer. The results of this study could provide support for health care decision making by showing the consequences of policy decisions on the introduction of screening programs for health care utilization.