REDUCTION OF BREAST CANCER MORTALITY THROUGH MASS SCREENING WITH MODERN MAMMOGRAPHY

1222

Screening for Disease REDUCTION OF BREAST CANCER MORTALITY THROUGH MASS SCREENING WITH MODERN MAMMOGRAPHY First Results of the Nijmegen Project, 1975 - 1981 A. L. M. VERBEEK R. HOLLAND F. STURMANS

J. H. C. L. HENDRIKS M. MRAVUNAC N. E. DAY

Departments of Social Medicine, Radiology, and Pathology, University of Nijmegen, The Netherlands; Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen; Department of Epidemiology, University of Limburg, The Netherlands; and International Agency for Research on Cancer, Lyon, France Since 1975 four rounds of screening with modern mammography for breast cancer have been carried out among 30 000 Nijmegen women born before 1940. The results up to the end of 1981 show that the odds ratio of screened vs unscreened subjects among women who died from breast cancer compared with women who did not, was 0·48 (95% confidence interval 0·23-1·00) in all age

Summary

groups. INTRODUCTION

A RANDOMISED, controlled trial of about 62 000 women who were insured with the Health Insurance Plan of Greater New York, (HIP study) was started 21 years ago to find out whether screening could reduce breast cancer mortality. The study group was offered four annual screenings, including physical examination and mammography, and the control group had their usual medical care. Over 5 years periodic screening led to a 30% reduction in mortality from breast cancer.’ Even after longer follow-up2 the reduction in mortality was still evident. The discussion about the effect of screening on women under 50 years old has not yet been closed, although a recent analysis of the HIP data suggests that screening does have a statistically significant effect in this age group.3 Since the HIP study the technique of mammography has improved greatly and mass screening for breast cancer has been started in several places. Unfortunately, in many of these screening programmes, like ours in Nijmegen, a nonexperimental design has been used, which makes it difficult to evaluate the effect of screening on mortality.

aged 40-64,

SUBJECTS

AND METHODS

Subjects Nijmegen (150 000 inhabitants) a population-based breast screening programme started on Jan 1, 1975. Single-view mammography (before August, 1981, lateromedial projection: since then, mediolatero-oblique projection) was carried out as the only In

cancer

screening examination every 2 years. For the first screening round all women living in Nijmegen, born between 1910 and 1939, were invited to take part (aged 35-65, n=23 000). For the next three rounds all women living in Nijmegen, born before 1940, were invited (n=30 000).4 Methods In the period 1976-81 in Nijmegen the crude mortality rate for breast cancer in women of 35 and over remained stable at 0’9per 1000 woman-years. A case-control design has been used to assess the efficacy of screening on morbidity and, in accord with recent

recommendations, 5-7 on mortality. series consists of female residents of Nijmegen, their death certificates, died from breast cancer in who, according 1975-81 and who were diagnosed as having primary breast cancer after their first screening invitation; there were 46 such deaths. Controls.-All women invited who had not died from breast cancer at the time when the case died were eligible for the control group. To control the confounding influence of age, the controls were matched for age. For each case, 5 controls of the same year of birth were selected at random from the statistical tape. Then we checked whether the case and the 5 controls had had a screening examination before the date of diagnosis of the case. Non-experimental studies are liable to self-selection bias. The existence and influence of such bias can be studied by estimating the underlying incidence of breast-cancer in the screened and unscreened groups. In a randomised, controlled trial the incidence rate in the control group can be used to estimate the rate in the screened group if there had been no screening. In this study women of the city of Arnhem, where mass screening has never taken place, were used as the control group. Arnhem (150 000 inhabitants) is about 15 miles from Nijmegen. Since 1975, data on Arnhem patients diagnosed as having primary breast cancer have been carefully recorded by the Carcinoma Werkgroep. The data about patients diagnosed before 1975 were gathered with the help of the pathology department of the Arnhem hospitals. In 1970-74, Arnhem and Nijmegen had the same age-adjusted breast cancer incidence and mortality rates.4We have assumed that since the start of the screening programme in Nijmegen the age-year specific rates if there had been no screening would have been similar to those in Arnhem. The Arnhem age-year rates were applied to the Nijmegen unscreened group to determine whether the underlying breast cancer incidence rates in the screened and unscreened groups differed. Data analysis. -The odds ratio of screened vs unscreened subjects among women who died from breast cancer compared with women 8 who did not was estimated by means of a matched data according to the formula of Mantel and Haenszel. Cases. -The

case

to

specific

analysis,8

RESULTS

Four screening rounds for breast cancer were carried out in Nijmegen between 1975 and 1982. The attendance rates according to age at time of invitation are shown in table I.

Attendance the fourth.

rates

fell in all age groups from the first round to

46 women diagnosed as having breast cancer after their first invitation died from the disease. Of these women, 13 were younger than 50 at the time of their first invitation, 20 aged

TABLE I-AGE-SPECIFIC ATTENDANCE RATES IN FOUR SCREENING ROUNDS

*Age

at time

of invitation.

1223 TABLE 11-DISTRIBUTION OF

46 CASE-CONTROL COMBINATIONS,

SCREENED VS UNSCREENED

* ARNHEM*

TABLE III-INCIDENCE OF BREAST CANCER IN -

I

*For age groups 35-64,

in

1975-82; for age group >65,

breast cancer mortality rate in Nijmegen up to the end of 1981 that the attendance rate for screening in the older age groups was low and that many women are still dying from breast cancer diagnosed before their first invitation-in 1981 almost 65% of those who died were diagnosed before the study. A time trend in breast cancer mortality could also be an explanation. Since the upper 95% confidence limit of the odds ratio is 1’ 0, more data are required to ensure that the odds ratio really does differ from unity. The confounding influence of age on the odds ratio is controlled by the matched design and analysis. The selfselection bias is probably small, because the underlying breast cancer incidence rate in the unscreened group is the same as that in the screened group on the basis of the Arnhem data. Because there is no national cancer registry in the Netherlands, a special study will be done to determine the time trend of the breast cancer incidence in Arnhem. It is possible that publicity about the Nijmegen screening programme has led to an increased rate of physical and mammographic examinations in Arnhem. Consequently, an excess number of breast cancer cases may have been diagnosed in Arnhem. An increase in the incidence in Arnhem compared with other unscreened areas, would lead to too large a number of expected cases in the nonparticipating group in Nijmegen and would invalidate comparison of the underlying incidence rates. Variables like age at diagnosis, stage at diagnosis, and treatment are not necessarily independent of screening and should therefore not be taken into account in the analysis.9 are

r

in

1977-82.

TABLE IV-OBSERVED AND EXPECTED NUMBERS OF BREAST CANCER

CASES IN UNSCREENED NIJMEGEN WOMEN*

It is

possible that the screening history ofNijmegen breast patient might increase the likelihood of her death

cancer

being attributed to breast cancer. However, it is assumed that

*Adjusted for breast cancers, deaths, removals, and participation after the next invitation. For birth cohort 1910-39, in 1975-82, and for birth cohort 1885-1909, in 1977-82. Birth cohorts correspond to age groups in table III.

50-64, and 13aged 65 and over. 26 of the 46 women who died from breast cancer had been screened; 12 were diagnosed at their first screening, 3 before their next screening, and 11 at or after the time of their second screening. The results of the matched data analysis are summarised in table II. The odds ratio estimate of screened vs unscreened among women who died from breast cancer compared with those who did not, was 0-48 (95% confidence interval,

0-23-1 -00). The 5-year age-specific incidence rates ofArnhem (table III) were applied to the Nijmegen unscreened women. 84 - 6 cases would have been. expected in this group, whereas 84 occurred (table IV). Thus, the underlying incidence rate for the screened group is similar

to

that in the unscreened group.

DISCUSSION

The odds ratio of 0 - 48 shows that the breast cancer mortality rate in women of 35 and over can be reduced by roughly 50% by regular mammographic screening of all eligible women. Possible reasons why there has been no fall in

any such misclassification on death certificates is small. Further analysis, which will focus on the clinical history of the breast cancer patients in Nijmegen, is necessary to determine the sensitivity and specificity of the death certificates. Early treatment of breast cancer may not influence the chance of recovery, but may merely postpone death due to breast cancer. Longer follow-up of the Nijmegen breast cancer patients is necessary to see whether the odds ratio remains constant or returns to unity. Longer follow-up is also necessary to determine the effect of screening on the slowgrowing type of breast cancer. In this study the odds ratio for women of 55 and older is 0-49. Because of the small number of cases and the higher attendance rate in the younger age-groups, we cannot yet study the effect of screening on women under age 55. The negative effects of the introduction of the screening programme should be mentioned. The positive predictive value of mammography is 35%;4 thus, for each screendetected case 2 women had a referral and 1 of them had a biopsy that they would not have had if there had been no screening. Strong efforts should be made to reduce the number of false-positive results by further improving the specificity of mammography. Another important side-effect of screening may be the diagnosis and treatment of clinically irrelevant non-invasive cancers. The annual diagnostic rate of primary breast cancer in Nijmegen is still somewhat higher than the rate before the screening programme. We are investigating whether this rate corresponds to the current rate in unscreened areas. Ahother difficulty associated with screening is the false-negative rate; the sensitivity of mammography in Nijmegen was estimated to be 80%. About a third of the false-negative cancers on’screening

1224 caused by technical faults, a third are radiologically occult, and a third are fast-growing tumours not yet detectable at screening,.10 By following a number of strict rules, we are attempting to reduce the number of falsenegative cases to the theoretical minimum.1’I mammograms

are

We thank S. Veling, H. Straatman, H. Coopmans, Ms I. vd Steen (Department of Social Medicine), and K. Jannmk (Department of Radiology) for data analysis, processing, and gathering; F. de Groot for his comments; and the Carcinoma Werkgroep Arnhem who made available to us data on breast cancer incidence in Arnhem, the Central Bureau for Statistics, and the local authorities. This work was supported by the Praeventiefonds and the Ministry of Health.

Correspondence should be addressed to A. L. M. V., Department of Social Medicine, Katholieke Universiteit Nijmegen, Verlengde Groenestraat 75, 6525 EJ Nijmegen, The Netherlands.

were 50 - 64 years of age at the start of the project. A comparison of mortality in Utrecht with that of other cities in the Netherlands with similar population characteristics and degrees of health care was postponed owing to the extended period of study required, since in such a comparison deaths of

who

whose breast cancer was diagnosed before the start of the project would also be included. A matched case-control study was used to investigate whether there is any association between the risk of mortality from breast cancer and participation in a population-based screening programme. This approach has been recommended as an epidemiological method to evaluate nonwomen

randomised

designs.3-6 SUBJECTS AND METHODS

REFERENCES

Strax P, Venet L. Periodic breast cancer screening in reducing mortality from breast cancer. JAMA 1971, 215: 1777-85. 2. Shapiro S, Venet W, Strax PH, Venet L, Roeser R. Ten-to-fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982, 69: 349-55 3 Habbema JDF, Putten DJ van, Lubbe JThN, Maas PJ van der, Oortmarssen GJ van. Geen verschillen in resultaten tussen vrouwen onder en boven de 50 jaar bij bevolkingsonderzoek op borstkanker. T Soc Gezondheidsz 1983, 61: 694-97 4. Hendriks JHCL. Population screening for breast cancer by means of mammography in Nijmegen 1975-1980. Ph D Thesis. University of Nijmegen, the Netherlands, 1

Shapiro S,

1982.

EA, Anderson TW. Does screening by "Pap" smears help prevent cervical cancer? Lancet 1979; ii: 1-4 Morrison AS. Case definition in case-control studies of the efficacy of screening. Am J Epidemiol 1982, 115: 6-8 Weiss NS Control definition in case-control studies of the efficacy of screening and diagnostic testing. Am J Epidemiol 1983; 118: 457-60 Breslow NE, Day NE. Classical methods of analysis of matched data. In Davis W, ed Statistical methods in cancer research. IARC Scientific publication no 32. Lyon: IARC, 1980. 170-72. Prorok PC, Hankey BF, Bundy BN. Concepts and problems in the evaluation of screening programs J Chron Dis 1981, 34: 159-71. Holland R, Mravunac M, Hendriks JHCL, Bekker BV. So-called interval cancers of the breast; pathologic and radiologic analysis of 64 cases Cancer 1982; 49: 2527-33. Holland R, Hendriks JHCL, Mravunac M. Mammographically occult breast cancer, a pathologic and radiologic study Cancer 1983, 52: 1810-19.

5. Clarke 6 7

8.

9 10 11.

EVALUATION OF SCREENING FOR BREAST CANCER IN A NON-RANDOMISED STUDY (THE DOM PROJECT) BY MEANS OF A CASE-CONTROL STUDY H.

J. A. COLLETTE J. J. ROMBACH

N. E. DAY F. DE WAARD

Preventicon, Utrecht, The Netherlands; and International Agency for Research on Cancer, Lyon, France In 1974 a non-randomised study of the effect of mass screening by physical examination and xeromammography on mortality from breast cancer was started. Of the 20 555 eligible women in the city of Utrecht born between 1911 and 1925 (aged 50-64 at the start of the study), 14 796 attended for screening. Four rounds of screening were carried out. The relative risk of dying from breast cancer among women ever screened compared with women never screened was 0·30 (95% confidence interval 0&mid ot; 13 - 0 ·70).

Summary

Of 20 555 eligible women in Utrecht, 14 796 (72%) women attended for screening. Screening, which consisted of a clinical examination and xeromammography, was carried out at the first visit and subsequently after 12, 18, and 24 months. All breast cancer patients, irrespective of age or method of diagnosis, diagnosed from 1973 onwards were included in a breast cancer registry attached to the DOM project. Follow-up data on all women with breast cancer, born between 1911 and 1925, were regularly updated. The names and dates of birth of all Utrecht residents who died from breast cancer were supplied, under strict confidentiality, by the Chief Medical Office of Health. Dates of diagnosis in these women were checked, first against the cancer registry, and with other sources, such as the general practitioners, if the name was not present in the registry. In this study a case is defined as a breast cancer death in a woman born between 1911 and 1925, diagnosis and death occurring after the screening project started. With the help of the local authorities three controls for each case were selected at random. Criteria for eligibility as a control were that the woman should have lived in Utrecht when the case died and have the same year of birth as the case. Age matching was done because of the positive relation between death from breast cancer and age and the negative relation between the percentage attending for screening and age. For both the case and the corresponding controls the screening history was taken for the time up to and including the date of diagnosis of the case (a "restricted period", to be distinguished from the period of the total screening programme). Table I gives the total number of deaths from breast cancer and from the birth cohort under study (1911-1925) in the city of Utrecht for the period 1973-1981. The last group is divided into cases diagnosed before and after the start of the DOM project. The 10 misclassified deaths were removed from the study. Accordingly, 46 cases were included. There is no reason to assume that misclassifications were made in one direction only and checks are being made of this question. TABLE I-DEATHS FROM BREAST CANCER IN UTRECHT

INTRODUCTION

AFTER the publication of the results of the Health Insurance Plan (HIP) study on mortality from breast cancer in postmenopausal women,’ we decided to obtain more insight into the natural history of breast cancer in such women and to confirm whether a screening programme in older women would affect mortality from this disorder. In 1974 a population-based, non-randomised study of women in the city of Utrecht (the DOM project) was initiated.2 The population consisted of women born between 1911 and 1925

*For example, stomach cancer unclassified as breast cancer. The Dutch words for breast and stomach are very similar and when handwritten may be

misleading. ’{’Division not applicable. diagnosis not confirmed.