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European society of mastology consensus conference on breast cancer screening, Paris, 4–5 February 1993: Report of the evaluation committee
Clinical Oncology (1994) 6:261-268 © 1994 The Royal College of Radiologists
Clinical Oncology
Consensus Statement European Society of Mastology Consensus Conference on Breast Cancer Screening, Paris, 4-5 February 1993: Report of the Evaluation Committee N. J. W a l d , J. C h a m b e r l a i n a n d A . H a c k s h a w , o n b e h a l f o f t h e E v a l u a t i o n C o m m i t t e e * D e p a r t m e n t of E n v i r o n m e n t a l and Preventive Medicine, Wolfson Institute of Preventive Medicine, St B a r t h o l o m e w ' s
Hospital Medical College, London, UK
INTRODUCTION 0.4
On 4 February 1993, the European Society of Mastology (EUSOMA) convened a meeting of experts in Paris to evaluate the current evidence on the value and hazards of breast cancer screening. The Committee consisted of individuals from different countries throughout Europe and from different disciplines. The following is a summary of the deliberations and conclusions of the Committee.
I
I
Relative
risk
1.0
1.5
I III
I
2.5
I
o
HIP s
;
Swedish 2 counties 3
THE EFFECT OF SCREENING ON BREAST CANCER MORTALITY There have been six randomized controlled trials of breast cancer screening [1-7] based on periodic mammographic examination in which mortality from breast cancer in a group of women offered screening was compared with a control group not offered screening. All indicated that such screening reduces breast cancer mortality. The studies [1-8] are summarized in Fig. 1. Table 1 presents further details relating to each of the trials together with information on other studies [9-16], namely the UK study using geographical controls, the two Canadian studies that compared different screening regimens and four studies of women who accepted screening. The Canadian trials were not included with the other randomized trials because there was no unscreened * Members o f the Evaluation Committee: Chairman: N. J. Wald (UK); Rapporteur: J. Chamberlain (UK); Members: T. Anderson (UK), P. Boyle (IT), P. Forrest (UK), H-J. Frischbier (GE), M. Hakama (FI), L. Rutqvist (SW), P. Schaffer (FR), B. Seradour (FR), L. Tabar (SW), M. RosseUi Del Turco (IT), E. Van Der Schueren (BE). This report was previously published in The Breast, 1993;2:209216 but is being reprinted here at the request of the European Society of Mastology. This version includes various corrections and is based on final (rather than provisional) data from the Edinburgh Trial. Correspondence and offprint requests to: Professor N. Wald, CRC Cancer Screening Group, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's Hospital Medical College, Charterhouse Square, London ECIM 6QB, UK.
Edinburgh
:,
Malmo Stockholm
-,7.
c
Gothenburg
All trials
Fig. 1. The relative risk of breast cancer mortality in women aged 40-74 years invited for screening compared with those not invited is shown for each trial together with the 95% CI. The combined estimate is also shown for all trials.
control group. One of these, a trial of women aged 40-49 years, was a study of annual mammography and physical examination compared with one initial physical examination only. The other, a trial of women aged 50-59, was a study of annual mammography and physical examination compared with an annual physical examination.
Women Aged 40-74 Years Among women offered screening in the randomized trials, the estimated reduction in breast cancer mortality based on the six trials was 22% (relative risk 0.78; 95% CI 0.70--0.87) after at least 5 years from the invitation for a mammographic examination. The estimated reduction with 100% compliance (in trials about 78% of women accepted the offer of screening) was 28%, assuming that the risk of
262
N. J. Wald et al.
Table 1. Studies of breast cancer screening
Trial [reference]
Screening interval (months)
Method
Age (years)
No. invited
Average follow-up (years)
Relative risk~(95% CI) women aged 40-74 years)
Health Insurance Plan [1,2]
12
M+P
40-64
31000 23 000
18 10f 10f
0.79 (0.62-0.99) e 0.71 (0.55-0.91) 0.83 (0.63-1.10)
Edinburgh [3a] Swedish trialsb Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg [8] Overview of the 4 Swedish trials [8]
24
M+P
45-64
24,33 18--21 28 18
M M M M
40-74 45-70 40-65 40-59
77000 21000 39 000 21000
11 9 7 5
0.78 0.81 0.76 0.81 0.77
40-74
212 000
Randomized controlled trials
All Trials g
(0.65-0.93) (0.62-1.07) (0.50-1.14) (0.50-1.29) (0.67-0.88)
0.78 (0.70-0.87)
Other randomized controlled trials Canada [9]
12 12
Mc Md
40-49 50-59
50 000 39 000
8 8
24
M+P
45-64
23 000
10
12 24 12-24 24-60
M+P M+P M+P M
35-74 35+ 50-64 40-70
30 000 21000 25 000
9f 7 7 8
1.36 (0.84-2.21) 0.97 (0.62-1.52)
Study with geographical controls" UK [10,11]
0.80 (0.69-0.94) ~
Studies of women accepting screening BCDDP [12] Nijmegen [13,14] Utrecht [15] Florence [16]
0.80 0.48 0.30 0.53
(0.72-0.87) (0.23-1.00) (0.13-0.70) (0.29-0.95)
M, mammography; P, physical examination. a Personal communication from Dr F. Alexander. b Relative risks and 95% CI calculated from data in reference [8]. c Women randomized to receive either annual mammography and physical examination or initial physical examination only. a Women randomized to receive either annual mammography and physical examination or an annual physical examination only. Not used in recta-analysis. fTotal follow-up (years). g Pooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance. hGuildford compared with comparison centres Dundee, Oxford, Southmead and Stoke; Edinburgh not included because reported separately as a randomized trial. t Individual relative risks (95% CI) taken from the relevant published papers or, where possible, calculated using the number of breast cancer deaths and number of person-years.
death from breast cancer was the same in women who accepted the offer of screening and in those who did not (Appendix). There is evidence that those who do not accept screening are at a higher risk, so the reduction in screened women would be greater than expected (Appendix).
Relative
risk
1 0
1.5
2.5
I
I
0.4
I
I
fill, ,c
:
HiP o
Edinburgh
Women Aged 50-74 Years Swedish 2 c o u n t i e s
Among women offered screening in this age group the reduction in breast cancer mortality in the randomized trials was 24% (relative risk 0.76; 95% CI 0.67-0.87). If the Canadian trial is included, the estimate is 22% (relative risk 0.78; 95% CI 0.690.88). Fig. 2 summarizes the results and Table 2 gives further details of these trials. In screened women the reduction in breast cancer mortality would be 31%, assuming, as before, comparability in risk of breast cancer death in women who accepted screening and in those who declined it.
Women Aged 40-49 Years In this group the reduction in breast cancer mortality based on published randomized trials is 16% (relative
Malmo
c
Stockholm
c
c
,,
,
Gothenburg
All trials
Fig. 2. The relative risk of breast cancer mortality in women aged 50-74 years invited for screening compared with those not invited is shown for each trial together with the 95% (2I. The combined estimate is also shown for all trials.
263
EUSOMA Consensus Conference on Breast Cancer Screening Table 2. Randomized controlled trials of breast cancer screening in women aged 50-74 years Trial [reference]
Screening interval (months)
Method
Age (years)
Health Insurance Plan [1,2]
12
M+P
50-64
15 000
Edinburgh [3a] Swedish Trials b Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg ]8] Overview of the 4 Swedish trials [8]
24
M+P
50-64
17000
33 18-21 28 18
M M M M
50-74 50-70 50-65 50-59
57000 13 000 25000 11000
50-74
127 000
All trials d
No. invited
Relative risk (95% CI) women aged 50-74 years) 0.80 (0.59-1.08) ° 0.69 (0.49-0.97) 0.84 (0.62-1,14) 0.72 0.86 0.65 0.91 0.75
(0.59-0.88) (0.64--1.16) (0.40-1.08) (0.53-1.55) (0.65-0.87)
0.76 (0.67-0.87)
M, mammography; P, physical examination. a Personal communication from Dr F. Alexander. bThe reference numbers cited for each of the four Swedish trials relate to the original publications. The relative risks shown in the table were derived from data presented at the International Workshop on Screening for Breast Cancer, Bethesda, USA, 1993 and the data presented in the overview analysis [8]. These estimates differ slightly for the trials as there were amendments to the source data. CEstimate at 18 years follow-up. Personal communication from Prof. S. Shapiro; not used in meta-analysis. Pooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance.
Relative risk
0.4
I
I
I III !
3
1.0
1.5
I
2.5 .I HIP Edinburgh
Swedish 2 counties Malrno Stockholm Gothenburg
age when women are screened. At present there is a suggestion that screening women under age 50 may be less effective than screening older women, and may have no effect at all. Data on screening women under 50 years of age are, however, sparse and the results therefore still inconclusive. It has been suggested that breast cancer screening in women under 50 years of age may have a reduced effect on mortality because the ability of mammography to detect early breast cancer lesions is less in younger women [17]. There is evidence that the prevalence to incidence ratio in women under 50 years is lower than that in older women. From the Swedish two-counties study [4,5], this ratio is 1.95 in women aged 40-49 years, 3.09 in those aged 50-59 years and 4.59 in women 60-69 years. This could arise because it is harder to see small lesions in the breast of a premenopausal woman or because the rate of growth of cancers in younger women is faster than in older women, or indeed both may apply.
All trials
Fig. 3. The relative risk of breast cancer mortality in women aged 40-49 years invited for screening compared with those not invited is shown for each trial together with the 95% CI. The combined estimate is also shown for all trials.
risk 0.84; 95% CI 0.67-1.06) although this is not significant (Fig. 3; Table 3). If the Canadian trial is included the estimate is 7% (relative risk 0.93; 95% CI 0.76--1.15). The results of the randomized trials show, without doubt, that breast cancer screening by periodic mammographic examination reduces mortality from breast cancer. The split between women aged 50 years or more and those who are younger is arbitrary. Primary analysis of the trials should relate to all the women randomized, not subsets classified subsequently. Nevertheless, secondary analyses can provide a tentative indication about whether there are differences in screening effects according to the
TRANSLATION OF RESEARCH RESULTS INTO PRACTICE Nationally or regionally organized population based screening programmes are underway in a number of European countries, namely the United Kingdom, Sweden, Finland, The Netherlands and Iceland. In addition, there are a number of local programmes being conducted in most other European countries. Table 4 provides details of the early results of the national screening programmes. The performance indicators specified were accepted as being of proven value for use in monitoring screening programmes; the results shown indicate the extent to which the screening programmes are on target. None of the screening programmes has been under way for long enough to assess any effect on breast
264
N. J. Wald et al.
Table 3. Randomized controlled trials of breast cancer screening in women aged 40-49 years Trial [reference]
Screening interval (months)
Method
Age (years)
Health Insurance Plan [1,2] Edinburgh [3a] Swedish Trialsu Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg [8] Overview of the 4 Swedish trials [8]
12 24
M+P M+P
40-49 45-49
16000 6 000
0.78 (0.52-1.18) 0.78 (0.41-1.48)
24 18-21 28 18
M M M M
40-49 45-49 40-49 40-49
20000 8 000 14000 10000
1.04 (0.68-1.59) 0.51 (0.22-1.19) 1.00 (0.49-2.04) 0.72 (0.26-1.99) 0.90 (0.65-1.24)
40-49
64 000
0.84 (0.67-1.06)
All trials~
No. invited
Relative risk (95% CI) women aged 40-49 years
M, mammography; P, physical examination. aPersonal communication from Dr F. Alexander. bThe reference numbers cited for each of the four Swedish trials relate to the original publications. The relative risks shown in the table were derived from data presented at the InternationalWorkshop on Screening for Breast Cancer, Bethesda, USA, 1993. These estimates differ slightly for three of the trials and to a greater extent for the Malta6 trial. The differences arise because the age group in the Malta6 trial was originally 45-54 years (not 45-49) and in the overview analysis upon which the InternationalWorkshop results were based, there were amendments made to the source data. cPooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance.
Table 4. Monitoring of national screening programmes in Europe
Population coverage (%) Screening uptake (%) Referral rate (%) Benign biopsies (per 1000 women screened) Detected cancer prevalence (per 1000 women screened) Malignant:benignratio Proportion of cancers with tumours <10 mm diameter (%)
UK
Sweden
Finland
Iceland
n/a 73 6.2 2.67 6.23 2.3:1 22
53 75 5.0 n/a 6--7 4:1 n/a
>80 89 2.9 2.30 3.75 1.6:1 40a
67 67 4.2 2.73 5.45 2:1 31
Population coverage: Proportion of the eligible population that has been screened; Uptake: Proportion of those invited who have been screened; Referral rate: Proportion of the screened women who have been referred for consideration of a diagnostic test; Benign biopsies: Proportion of the screened women without cancer who had a biopsy; Detected cancer prevalence: Proportion of the screened women diagnosed to have breast cancer; Malignant:benignratio: Benign biopsies:Detected cancer prevalence (not all malignant tumours are identified by biopsy; some use fine needle aspiration; n/a: Not available. a In the Tampere area only; national figures not available. Results kindly given by Professor J, Chamberlain (UK), Dr E. Lithander (Sweden), Dr M. Hakama (Finland) and Dr B. Sigfusson (Iceland). c a n c e r m o r t a l i t y . It will t a k e a n o t h e r d e c a d e for such a n effect to b e discernible. It is, h o w e v e r , a p p a r e n t f r o m the m o n i t o r i n g i n f o r m a t i o n a l r e a d y collected t h a t a r e d u c t i o n in m o r t a l i t y is expected. T h e indicators of p e r f o r m a n c e m i r r o r those that were f o u n d i n the r a n d o m i z e d trials.
w o m e n a n d with details, if available, of the p r e v a l e n c e / i n c i d e n c e ratio a n d the ratio of interval cancers to screen d e t e c t e d plus i n t e r v a l cancers a m o n g s c r e e n e d w o m e n . 2. Pathological size of t u m o u r t o g e t h e r with p a t h o logical n o d a l status, histological grade a n d p r e s e n c e or a b s e n c e of m e t a s t a s e s in all the a b o v e categories of cancer.
PERFORMANCE INDICATORS UNDER DEVELOPMENT O t h e r a d d i t i o n a l p e r f o r m a n c e i n d i c a t o r s were r e g a r d e d as v a l u a b l e b u t systems for r o u t i n e l y collecting such data in n a t i o n a l p r o g r a m m e s w e r e still u n d e r d e v e l o p m e n t in several c o u n t r i e s . T h e s e indicators were: 1. N a t i o n a l or r e g i o n a l i n c i d e n c e of all b r e a s t c a n c e r ( s c r e e n d e t e c t e d cancers, i n t e r v a l cancers, a n d cancers in n o n - a t t e n d e r s ) a m o n g all eligible
THE ADVERSE EFFECTS OF SCREENING T h e aim of a n y s c r e e n i n g p r o g r a m m e is to m a x i m i z e benefit to a s c r e e n e e that is affected or w o u l d b e c o m e affected i n the a b s e n c e of s c r e e n i n g while, at the s a m e t i m e , m i n i m i z i n g w o r r y a n d h a z a r d i n the target p o p u l a t i o n . T h e adverse effects of s c r e e n i n g m a y b e s u b d i v i d e d i n t o those arising from:
EUSOMA ConsensusConferenceon Breast Cancer Screening 1. The screening process itself 2. The false positive results 3. The detection of slow growing, non-lethal breast cancers Although these side effects are a source of concern, there have been relatively few attempts to quantify them.
265 but the women with breast symptoms still had significantly greater psychological morbidity. While the questionnaires used in the studies may not be sensitive enough to measure acute episodes of anxiety generated by a positive screening result, it is nonetheless reassuring that anxiety is not sustained after completion of investigations [21].
Benign Biopsies Screening Process Risks The risks here involve various psychological and physical factors:
Anxiety It has been postulated that recruitment of people into a screening programme, whether by personal invitation or general publicity, may cause anxiety by raising awareness of vulnerability [18]. However, the few studies [19-21] which compared women attending for screening in response to invitation with those not invited have found no evidence of a difference in various anxiety and stress levels.
The favourable malignant to benign biopsy ratio now achievable in screening is partly due to utilization of ultrasound and fine needle aspiration cytology after a positive mammogram. Where the cancer prevalence is high, the ratio may conceal a high rate of benign biopsies. The absolute rate of benign biopsies per 1000 screened women should therefore be monitored and, if possible, compared with that in an unscreened group of women of the same age. Anxiety in women who require a biopsy is likely to be particularly great; one study [211 found that 10% of such women needed professional preoperative counselling, but, as with referrals, there was no evidence of sustained anxiety.
Discomfort and Pain
Detection of Slow Growing Breast Cancer
Compression of the breast against the X-ray plate is necessary to obtain a clear view of all the breast tissue, but this is uncomfortable. Rutter et al. [22] found that 35% of 597 screened women experienced some form of discomfort and 6% experienced pain, although in the majority this lasted less than 10 minutes. More than two-thirds ranked a dental filling, cervical smear and venepuncture as more uncomfortable than mammography. A survey in the USA [23] of 1847 women reported similar levels of discomfort and pain.
Recent screening trials [4,6,10] have found a cumulative incidence of breast cancer in the screening population which is 10%-20% higher than that in the control population, which suggests an 'overdiagnosis' pr0blem. This has been investigated in three studies. In the Health Insurance Plan (HIP) trial [1] the cumulative incidence in the control group was similar to that in the study group after 7 years (3 years after the screening stopped), showing there was no overdiagnosis. In Nijmegen [26], although there was an overall excess of 11% in the screening population compared with geographical controls, the incidence of breast cancer in the first cohort to be screened was higher than in the control group during the first 4 years, but 8-12 years after the onset of screening it was lower than in the controls. This is interpreted as showing that the excess cancers diagnosed in the early years would have presented several years later and were therefore not 'overdiagnosed'. In the Swedish two-counties trial [5], it was concluded that overdiagnosis was limited to the first mammographic examination because thereafter, the annual incidence of breast cancer in screened women (i.e. interval cancers plus those detected at the following screen) was similar to the annual incidence in the control group. A related problem results from advancing the date of diagnosis of a breast cancer whose prognosis is unaltered by screening, either because it is already metastatic or because it would anyway by curable if left until symptomatic. These women live with the knowledge of their diagnosis for longer than would otherwise be the case, and hence many suffer practical problems such as failure to obtain life insurance, as well as a possible greater period of anxiety. It is not possible to. separate patients with screen detected cancers into those who will benefit from early detection and those with slow growing cancer who will not: all must be considered together, recognizing that
Radiation Hazard There is a small risk of inducing breast cancer by radiation exposure from mammography which will depend on the radiation dose and age at screening [24].
False Positive Results of Screening A proportion of women referred for further investigation of a suspicious mammogram will be found not to have cancer. Low specificity of mammographic screening in some programmes, notably in the USA and the UK, means that at least 5% without cancer will be referred for diagnostic investigation. Again, there will be psychological and physical considerations.
Anxiety Induced by Referral One study [25] compared psychiatric morbidity in the 'false positive' referrals with that in women attending for routine screening, and in those attending for investigation because of breast symptoms. After 3 months, there was no difference in psychological morbidity between the referrals and normal women,
266 lives will only be saved for some women. Although it has been suggested that excess years as a breast cancer patient diminish quality of life [27,28], a study of long term survivors with screen detected cancer found that psychological morbidity was less than in age matched women without breast cancer [291.
Conclusions on the Adverse Effects There are several concerns regarding the risks of screening, but, when these were specifically studied, they were found to be either infrequent or relatively minor. They are a reason for maintaining quality assurance measures in all screening programmes, ranging from physical measurement of radiation dose, maintaining high sensitivity and specificity of mammography, providing professional psychological support for referred women, and to ensuring consistency of histological diagnosis.
SCREENING BY ROUTINE BREAST SELF EXAMINATION Routine breast self examination (BSE) has not been shown to be an effective method of screening, though studies are still in progress that may alter this conclusion [30]. The survival of women who practised BSE appears to be higher than those who did not [31,32]. However, such comparisons are unable to correct for lead-time bias, length-biased sampling and selection bias. The first two of these can be eliminated in a population based retrospective study, in which the BSE history of Cases of breast cancer which was advanced at diagnosis are compared with that in age matched controls. A retrospective study [33] of women with breast cancer and controls found that the frequency of BSE did not differ between advanced stage breast cancer patients and controls, and the odds ratio of developing advanced cancer in a BSE practitioner relative to a non-practitioner was 1.15 (95% CI 0.73-1.81), suggesting that it has no effect. Two non-randomized trials have been conducted and two randomized controlled trials are in progress. The first non-randomized study was the UK trial of Early Detection of Breast Cancer [34] in which 63 000 45-64-year-old women in two populations were all personally invited to BSE classes and provided with self referral clinics. Their breast cancer mortality over the ensuing 10 years was compared with that of 126 000 women of the same age in other populations without any intervention. The odds ratio of breast cancer death in the BSE populations relative to the comparison populations was 1.01 (95% CI 0.86-1.17), indicating no effect. The uptake of BSE classes was low (30% in one centre, 54% in the other) and no information was available regarding the proportion of women who regularly practised BSE throughout the study period. This method of public education was not shown to be effective but it does not confidently exclude a small benefit. The second
N.J. Waldet al. prospective study was from Finland [35]; breast cancer mortality among several thousand women who attended a programme of BSE education with annual reminders was lower than the national rates for age matched women from the same localities, but this may have been due at least in part to selection bias. The two prospective randomized controlled trials of BSE are in Russia [36] and China [37] but are still in relatively early stages. It will still be many years before the mortality outcome of these trials is available. At present therefore, there is no satisfactory evidence that screening by routine breast self examination is of value and there is no case for setting up public health programmes for education in BSE. This is not to say that women should refrain from being aware of any changes in their breasts. Women should continue to be encouraged to seek medical advice if changes do occur and they are concerned.
RESEARCH NEEDS A number of research needs arose in the discussion. The most important is to determine whether breast cancer screening in women aged under 50 years reduces breast cancer mortality and, if so, by how much. There is also a need to determine the extent to which older women (say 70 years of age or more) are likely to benefit from screening programmes. At present, there are limited data on this. The only randomized trial that included data on women aged 70 or more was from the Swedish two-counties trial [5,8] and this showed a 2% reduction in mortality with wide confidence intervals (relative risk 0.98; 95% CI 0.63-1.53) [14]. A third question is to determine the appropriate screening interval, recognizing that a shorter interval would lead to fewer interval cancers but with substantially increased costs. There is a need to obtain quantitative estimates of the net gain in terms of deaths avoided in relation to the extra costs arising from the more frequent mammographic examinations. It was agreed that the European Society of Mastology should set up a screening research committee to formulate and promote research into breast cancer screening and into aspects of breast cancer that can readily be researched within a screening programme.
CONCLUSIONS AND RECOMMENDATIONS 1. Screening for breast cancer by inviting women for periodic mammographic examination, followed by diagnosis and treatment as necessary, leads to a significant reduction in breast cancer mortality. The overall reduction observed in six randomized trials among women aged 4074 years was 22%. 2. Screening women aged 50 years and over has been
EUSOMA Consensus Conference on Breast Cancer Screening
shown to be effective and worthwhile. The randomized trials have shown a significant reduction in mortality of 24%. Screening women aged 50 years and over should be part of public health programmes organized on an invitation basis with full quality control and monitoring. 3. While it is clear that screening women aged 50 years and over is effective, there is uncertainty over its effect in younger women. It is important that any screening in women aged under 50 years should only be performed as part of a properly controlled research programme. 4. Younger women who request mammography should have it performed only after informing them of the uncertainty and advising them of the possible consequences. 5. The benefits of screening demonstrated in the research trials can be translated into practice, but with appropriate conditions, quality assurance and monitoring. Performance indicators of recognized value that have been used successfully on a national basis: • Population coverage (%) • Screening uptake (%) • Referral rate (%) • Benign biopsy rate (per 1000 women screened) • Detected cancer prevalence (per 1000 women screened) • Malignant : benign ratio • Proportion of screen detected invasive cancers <10 mm diameter (%) Performance indicators of recognized value that are still under development in monitoring national programmes: • Incidence of all breast cancers in eligible women Screen detected Interval Non-attenders • Incidence (per 1000) of stage II or greater, using pathological size of tumour histological nodal involvement presence of metastases. 6. The side-effects of screening need to be recognized, specifically: • Anxiety in women attending screening • Discomfort and pain • Radiation • Anxiety in screen positive women • High absolute rate of benign biopsies (not necessarily revealed by malignant : benign ratio) • Screen detected cancer that would not otherwise have adversely affected the woman 7. Breast self-examination. On the basis of current evidence, breast self examination programmes are not an effective method of population screening and therefore should not be recommended as public health policy. 8. Research. Screening women under 50 years of age is currently widespread in Europe and there is a perception of benefit in spite of the scientific uncertainty. In view of this, it is important that the issue is resolved to the extent that new research evidence will influence medical practice one way or the other; otherwise there is the potential for much waste and
267
even harm if such screening turns out to have little effect. 9. EUSOMA should set up a screening research committee to formulate and promote research into breast cancer screening and into aspects of breast cancer that can readily be researched within a screening programme. Research and service should be undertaken hand-in-hand.
References 1. Shapiro S, Venet W, Strax P, et al. Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-86. London: Johns Hopkins University Press, 1988. 2. Aron JL, Prorok PC. An analysis of the mortality effect in a breast cancer screening study. Int J Epidemiol 1986;15:36-43. 3. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: Mortality at seven years. Lancet 1990;335:241-6. 4. Tabar L, Fagerberg G, Duffy SW, et al. The Swedish twocounty trial of mammographic screening for breast cancer: Recent results and calculation of benefit. J Epidemiol Community Health 1989;43:107-12. 5. Tabar L, Fagerberg G, Duffy SW, et al. Update of the Swedish 2-county program of mammography screening for breast cancer. Radiol Clin North Am 1992;30:187-210. 6. Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malta6 mammographic screening trial. Br Med J 1988;297:943-8. 7. Frisell J, Eklund G, Hellstrom L, et al. Randomized study of mammography screening - preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 1991;18:49-56. 8. Nystrom L, Rutqvist LE, Stig W, et al. Breast cancer screening with mammography: An overview of Swedish randomised trials. Lancet 1993;341:973-8. 9. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening Study. Can Med Assoc J 1992;147:1459--88. 10. UK Trial of Early Detection of Breast Cancer Group. First results on mortality reduction in the UK trial of early detection of breast cancer. Lancet 1988;ii:411-6. 11. UK Trial of Early Detection of Breast Cancer Group. Breast cancer mortality after 10 years in the UK trial of early detection of breast cancer. Breast 1993 ;2:13-20. 12. Morrison AS, Brisson J, Khalid N. Breast cancer incidence and mortality in the breast cancer detection demonstration project. J Natl Cancer Inst 1988;80:1540--7. 13. Verbeek ALM, Hendriks JHCL, Holland R, et al. Reduction of breast cancer mortality through mass screening with modern mammography: First results of the Nijmegen project, 1975-1981. Lancet 1984;i:1222-4. 14. Verbeek ALM, Hendriks JHCL, Holland R, et al. Mammographic screening and breast cancer mortality: Age-specific effects in Nijmegen project, 1975-82. Lancet 1985;i:865-6. 15. Collette HJA, Rombach JJ, Day NE, et al. Evaluation of screening for breast cancer in a non-randomised study (the DOM project) by means of a case-control study. Lancet 1984;i: 1224-6. 16. Palli D, del Turco MR, Buiatti E, et al. A case-control study of the efficacy of a non-randomized breast cancer screening program in Florence (Italy). Int J Cancer 1986;38:501-4. 17. Tabar L, Fagerberg G, Day NE. What is the optimum interval between mammographic screening examination? An analysis based on the latest results of the Swedish two-county breast cancer screening trial. Br J Cancer 1987;55:547-551. 18. Marteau TM. Psychological costs of screening. Br Med J 1989;299:527. 19. Dean C, Roberts MM, French K, Robinson S et al. Psychiatric morbidity after screening for breast cancer. J Epidemiol Community Health 1986;40:71-5. 20. Hunt SM, Alexander F, Roberts M. Attenders and nonattenders at a breast screening clinic: A comparative study. PuN Health 1988;102:3-10. 21. Bull AR, Campbell MJ. Assessment of the psychological impact of a breast screening programme. Br J Radiol 1991 ;64:510-5. 22. Rutter DR, Calnan M, Vaile MS et al. Discomfort and pain
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23. 24. 25. 26.
27. 28.
N . J . Wald et al. during mammography: Description, prediction and prevention. Br Med J 1992;289:415-8. Stomper PC, Kopans DB, Sadowsky NL, et al. Is mammography painful? A multicentre survey. Arch Intern Med 1988;148:521-4. Gohagan JK, Darby WP, Spitznagal EL, et al. Radiogenic breast cancer effects of mammographic screening. J Natl Cancer Inst 1986;77:71-6. Ellman R, Angeli N, Christians A, et al. Psychiatric morbidity associated with screening for breast cancer. Br J Cancer 1989;60:781-4. Peeters PHM, Verbeek AL, Straatman H et al. Evaluation of over diagnosis of breast cancer in screening with mammography: Results of the Nijmegen Programme. Int J Epidemiol 1989;18:295-9. De Koning H. Cost-effectiveness of Screening. E U S O M A Conference, 1993. Maguire P. Questions of morbidity and compliance. E U S O M A Conference, 1993.
29. Ellman RE, Thomas BE. Personal communication. 30. Morrison AS. Is self-examination effective in screening for breast cancer? J Natl Cancer Inst 1991;83:226-7. 31. Foster RS, Constanza MC. Breast self-examination practices and breast cancer survival. Cancer 1984;53:999-1005. 32. Huguley CM, Brown RL, Greenberg RS, et al. Breast self examination and survival from breast cancer. Cancer 1988;62:1389-96. 33. Newcomb PA, Weiss NS, Storer BE, et al. Breast selfexamination in relation to occurrence of advanced breast cancer. J Natl Cancer Inst 1991 ;83:260--5. 34. Ellman R, Moss SM, Coleman D, et al. Breast selfexamination programmes in the trial of early detection of breast cancer: 10-year findings. Br J Cancer 1993;68:208-12. 35. Gastrin G, Hakama M, Miller AB. Personal communication. 36. Semiglazov VF, Moiseenko VM. Breast self-examination for the early detection of breast cancer: a USSR/WHO controlled trial in Leningrad. WHO Bull 1987;65:391-6. 37. Thomas DB. Personal communication.
APPENDIX Estimating the reduction in breast cancer mortality if all women accepted the invitation to be screened For illustration, assume a 'background' death rate from breast cancer of 6 per 1000 (the actual rate is unimportant). So in a group of, say, 10 000 unscreened women, 60 deaths are expected. Suppose that in the intention-to-screen group the observed mortality is 30%, but only 75% of the women in this group were actually screened (i.e. relative risk with 75% compliance RRv5 = 0.70). We thus need to estimate the possible reduction in mortality if 100% of those women were screened. Group invited for screening e.g. n=10000 (say)
If women who decline screening have the same mortality as controls: Expected deaths without screening Observed deaths after screening If women who decline screening have 20% higher mortality than controls: Expected deaths without screening Observed deaths after screening
Control group e,g. n=10000 (say)
RR75*
RRlo0
75% Accepted n=7500
Declined n=2500
45 27
15 15
6O 60
0.70 ((27+15)/60)
0.60 (27/45)
42a 24
i8 a 18
60 60
0.70 ((24+18)/60)
0.57 (25/42)
tRR75 is the observed relative risk of dying from breast cancer among a group of women invited for screening with 75% accepting screening. RRloo is the estimated relative risk in women who accept screening. It is derived from a relative risk determined on an intention-to-screen basis. (i.e. RR75). General formula for estimating the relative risk of breast cancer mortality assuming 100% compliance: RRloo = RRc - a ( l - a ) 1-a (1-c) where C = proportion of women who accepted the invitation to be screened (i.e. compliance); RRc = relative risk in the intention-toscreen group; a = extra mortality in women who decline screening (if controls have mortality M then women who decline have mortality a×M). In the randomized trials, compliance ranged from 60-90%. An estimate of overall compliance is approximately 78%. From the table, the pooled estimate of reduction in mortality is 22% (RRT8 = 0.78). Hence, estimates of this reduction if all the invited women were screened are as follows. If women who declined screening have: Same mortality as controls:a 20% greater mortality: a 50% greater mortality: a Twice the mortality: a
= = = =
1.0 1.2 1.5 2.0
RRlo0 = RR~oo = RRa00 = RRlo0 =
0.72 0.70 0.67 0.61
i.e. i.e. i.e. i.e.
28% 30% 33% 39%
reduction reduction reduction reduction
Received for publication December 1993 Accepted following revision January 1994
Clinical Oncology
Consensus Statement European Society of Mastology Consensus Conference on Breast Cancer Screening, Paris, 4-5 February 1993: Report of the Evaluation Committee N. J. W a l d , J. C h a m b e r l a i n a n d A . H a c k s h a w , o n b e h a l f o f t h e E v a l u a t i o n C o m m i t t e e * D e p a r t m e n t of E n v i r o n m e n t a l and Preventive Medicine, Wolfson Institute of Preventive Medicine, St B a r t h o l o m e w ' s
Hospital Medical College, London, UK
INTRODUCTION 0.4
On 4 February 1993, the European Society of Mastology (EUSOMA) convened a meeting of experts in Paris to evaluate the current evidence on the value and hazards of breast cancer screening. The Committee consisted of individuals from different countries throughout Europe and from different disciplines. The following is a summary of the deliberations and conclusions of the Committee.
I
I
Relative
risk
1.0
1.5
I III
I
2.5
I
o
HIP s
;
Swedish 2 counties 3
THE EFFECT OF SCREENING ON BREAST CANCER MORTALITY There have been six randomized controlled trials of breast cancer screening [1-7] based on periodic mammographic examination in which mortality from breast cancer in a group of women offered screening was compared with a control group not offered screening. All indicated that such screening reduces breast cancer mortality. The studies [1-8] are summarized in Fig. 1. Table 1 presents further details relating to each of the trials together with information on other studies [9-16], namely the UK study using geographical controls, the two Canadian studies that compared different screening regimens and four studies of women who accepted screening. The Canadian trials were not included with the other randomized trials because there was no unscreened * Members o f the Evaluation Committee: Chairman: N. J. Wald (UK); Rapporteur: J. Chamberlain (UK); Members: T. Anderson (UK), P. Boyle (IT), P. Forrest (UK), H-J. Frischbier (GE), M. Hakama (FI), L. Rutqvist (SW), P. Schaffer (FR), B. Seradour (FR), L. Tabar (SW), M. RosseUi Del Turco (IT), E. Van Der Schueren (BE). This report was previously published in The Breast, 1993;2:209216 but is being reprinted here at the request of the European Society of Mastology. This version includes various corrections and is based on final (rather than provisional) data from the Edinburgh Trial. Correspondence and offprint requests to: Professor N. Wald, CRC Cancer Screening Group, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's Hospital Medical College, Charterhouse Square, London ECIM 6QB, UK.
Edinburgh
:,
Malmo Stockholm
-,7.
c
Gothenburg
All trials
Fig. 1. The relative risk of breast cancer mortality in women aged 40-74 years invited for screening compared with those not invited is shown for each trial together with the 95% CI. The combined estimate is also shown for all trials.
control group. One of these, a trial of women aged 40-49 years, was a study of annual mammography and physical examination compared with one initial physical examination only. The other, a trial of women aged 50-59, was a study of annual mammography and physical examination compared with an annual physical examination.
Women Aged 40-74 Years Among women offered screening in the randomized trials, the estimated reduction in breast cancer mortality based on the six trials was 22% (relative risk 0.78; 95% CI 0.70--0.87) after at least 5 years from the invitation for a mammographic examination. The estimated reduction with 100% compliance (in trials about 78% of women accepted the offer of screening) was 28%, assuming that the risk of
262
N. J. Wald et al.
Table 1. Studies of breast cancer screening
Trial [reference]
Screening interval (months)
Method
Age (years)
No. invited
Average follow-up (years)
Relative risk~(95% CI) women aged 40-74 years)
Health Insurance Plan [1,2]
12
M+P
40-64
31000 23 000
18 10f 10f
0.79 (0.62-0.99) e 0.71 (0.55-0.91) 0.83 (0.63-1.10)
Edinburgh [3a] Swedish trialsb Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg [8] Overview of the 4 Swedish trials [8]
24
M+P
45-64
24,33 18--21 28 18
M M M M
40-74 45-70 40-65 40-59
77000 21000 39 000 21000
11 9 7 5
0.78 0.81 0.76 0.81 0.77
40-74
212 000
Randomized controlled trials
All Trials g
(0.65-0.93) (0.62-1.07) (0.50-1.14) (0.50-1.29) (0.67-0.88)
0.78 (0.70-0.87)
Other randomized controlled trials Canada [9]
12 12
Mc Md
40-49 50-59
50 000 39 000
8 8
24
M+P
45-64
23 000
10
12 24 12-24 24-60
M+P M+P M+P M
35-74 35+ 50-64 40-70
30 000 21000 25 000
9f 7 7 8
1.36 (0.84-2.21) 0.97 (0.62-1.52)
Study with geographical controls" UK [10,11]
0.80 (0.69-0.94) ~
Studies of women accepting screening BCDDP [12] Nijmegen [13,14] Utrecht [15] Florence [16]
0.80 0.48 0.30 0.53
(0.72-0.87) (0.23-1.00) (0.13-0.70) (0.29-0.95)
M, mammography; P, physical examination. a Personal communication from Dr F. Alexander. b Relative risks and 95% CI calculated from data in reference [8]. c Women randomized to receive either annual mammography and physical examination or initial physical examination only. a Women randomized to receive either annual mammography and physical examination or an annual physical examination only. Not used in recta-analysis. fTotal follow-up (years). g Pooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance. hGuildford compared with comparison centres Dundee, Oxford, Southmead and Stoke; Edinburgh not included because reported separately as a randomized trial. t Individual relative risks (95% CI) taken from the relevant published papers or, where possible, calculated using the number of breast cancer deaths and number of person-years.
death from breast cancer was the same in women who accepted the offer of screening and in those who did not (Appendix). There is evidence that those who do not accept screening are at a higher risk, so the reduction in screened women would be greater than expected (Appendix).
Relative
risk
1 0
1.5
2.5
I
I
0.4
I
I
fill, ,c
:
HiP o
Edinburgh
Women Aged 50-74 Years Swedish 2 c o u n t i e s
Among women offered screening in this age group the reduction in breast cancer mortality in the randomized trials was 24% (relative risk 0.76; 95% CI 0.67-0.87). If the Canadian trial is included, the estimate is 22% (relative risk 0.78; 95% CI 0.690.88). Fig. 2 summarizes the results and Table 2 gives further details of these trials. In screened women the reduction in breast cancer mortality would be 31%, assuming, as before, comparability in risk of breast cancer death in women who accepted screening and in those who declined it.
Women Aged 40-49 Years In this group the reduction in breast cancer mortality based on published randomized trials is 16% (relative
Malmo
c
Stockholm
c
c
,,
,
Gothenburg
All trials
Fig. 2. The relative risk of breast cancer mortality in women aged 50-74 years invited for screening compared with those not invited is shown for each trial together with the 95% (2I. The combined estimate is also shown for all trials.
263
EUSOMA Consensus Conference on Breast Cancer Screening Table 2. Randomized controlled trials of breast cancer screening in women aged 50-74 years Trial [reference]
Screening interval (months)
Method
Age (years)
Health Insurance Plan [1,2]
12
M+P
50-64
15 000
Edinburgh [3a] Swedish Trials b Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg ]8] Overview of the 4 Swedish trials [8]
24
M+P
50-64
17000
33 18-21 28 18
M M M M
50-74 50-70 50-65 50-59
57000 13 000 25000 11000
50-74
127 000
All trials d
No. invited
Relative risk (95% CI) women aged 50-74 years) 0.80 (0.59-1.08) ° 0.69 (0.49-0.97) 0.84 (0.62-1,14) 0.72 0.86 0.65 0.91 0.75
(0.59-0.88) (0.64--1.16) (0.40-1.08) (0.53-1.55) (0.65-0.87)
0.76 (0.67-0.87)
M, mammography; P, physical examination. a Personal communication from Dr F. Alexander. bThe reference numbers cited for each of the four Swedish trials relate to the original publications. The relative risks shown in the table were derived from data presented at the International Workshop on Screening for Breast Cancer, Bethesda, USA, 1993 and the data presented in the overview analysis [8]. These estimates differ slightly for the trials as there were amendments to the source data. CEstimate at 18 years follow-up. Personal communication from Prof. S. Shapiro; not used in meta-analysis. Pooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance.
Relative risk
0.4
I
I
I III !
3
1.0
1.5
I
2.5 .I HIP Edinburgh
Swedish 2 counties Malrno Stockholm Gothenburg
age when women are screened. At present there is a suggestion that screening women under age 50 may be less effective than screening older women, and may have no effect at all. Data on screening women under 50 years of age are, however, sparse and the results therefore still inconclusive. It has been suggested that breast cancer screening in women under 50 years of age may have a reduced effect on mortality because the ability of mammography to detect early breast cancer lesions is less in younger women [17]. There is evidence that the prevalence to incidence ratio in women under 50 years is lower than that in older women. From the Swedish two-counties study [4,5], this ratio is 1.95 in women aged 40-49 years, 3.09 in those aged 50-59 years and 4.59 in women 60-69 years. This could arise because it is harder to see small lesions in the breast of a premenopausal woman or because the rate of growth of cancers in younger women is faster than in older women, or indeed both may apply.
All trials
Fig. 3. The relative risk of breast cancer mortality in women aged 40-49 years invited for screening compared with those not invited is shown for each trial together with the 95% CI. The combined estimate is also shown for all trials.
risk 0.84; 95% CI 0.67-1.06) although this is not significant (Fig. 3; Table 3). If the Canadian trial is included the estimate is 7% (relative risk 0.93; 95% CI 0.76--1.15). The results of the randomized trials show, without doubt, that breast cancer screening by periodic mammographic examination reduces mortality from breast cancer. The split between women aged 50 years or more and those who are younger is arbitrary. Primary analysis of the trials should relate to all the women randomized, not subsets classified subsequently. Nevertheless, secondary analyses can provide a tentative indication about whether there are differences in screening effects according to the
TRANSLATION OF RESEARCH RESULTS INTO PRACTICE Nationally or regionally organized population based screening programmes are underway in a number of European countries, namely the United Kingdom, Sweden, Finland, The Netherlands and Iceland. In addition, there are a number of local programmes being conducted in most other European countries. Table 4 provides details of the early results of the national screening programmes. The performance indicators specified were accepted as being of proven value for use in monitoring screening programmes; the results shown indicate the extent to which the screening programmes are on target. None of the screening programmes has been under way for long enough to assess any effect on breast
264
N. J. Wald et al.
Table 3. Randomized controlled trials of breast cancer screening in women aged 40-49 years Trial [reference]
Screening interval (months)
Method
Age (years)
Health Insurance Plan [1,2] Edinburgh [3a] Swedish Trialsu Two-counties [4,5] Maim6 [6] Stockholm [7] Gothenburg [8] Overview of the 4 Swedish trials [8]
12 24
M+P M+P
40-49 45-49
16000 6 000
0.78 (0.52-1.18) 0.78 (0.41-1.48)
24 18-21 28 18
M M M M
40-49 45-49 40-49 40-49
20000 8 000 14000 10000
1.04 (0.68-1.59) 0.51 (0.22-1.19) 1.00 (0.49-2.04) 0.72 (0.26-1.99) 0.90 (0.65-1.24)
40-49
64 000
0.84 (0.67-1.06)
All trials~
No. invited
Relative risk (95% CI) women aged 40-49 years
M, mammography; P, physical examination. aPersonal communication from Dr F. Alexander. bThe reference numbers cited for each of the four Swedish trials relate to the original publications. The relative risks shown in the table were derived from data presented at the InternationalWorkshop on Screening for Breast Cancer, Bethesda, USA, 1993. These estimates differ slightly for three of the trials and to a greater extent for the Malta6 trial. The differences arise because the age group in the Malta6 trial was originally 45-54 years (not 45-49) and in the overview analysis upon which the InternationalWorkshop results were based, there were amendments made to the source data. cPooled estimate based on the individual trial results whereby each log (relative risk) is weighted by the inverse of its variance.
Table 4. Monitoring of national screening programmes in Europe
Population coverage (%) Screening uptake (%) Referral rate (%) Benign biopsies (per 1000 women screened) Detected cancer prevalence (per 1000 women screened) Malignant:benignratio Proportion of cancers with tumours <10 mm diameter (%)
UK
Sweden
Finland
Iceland
n/a 73 6.2 2.67 6.23 2.3:1 22
53 75 5.0 n/a 6--7 4:1 n/a
>80 89 2.9 2.30 3.75 1.6:1 40a
67 67 4.2 2.73 5.45 2:1 31
Population coverage: Proportion of the eligible population that has been screened; Uptake: Proportion of those invited who have been screened; Referral rate: Proportion of the screened women who have been referred for consideration of a diagnostic test; Benign biopsies: Proportion of the screened women without cancer who had a biopsy; Detected cancer prevalence: Proportion of the screened women diagnosed to have breast cancer; Malignant:benignratio: Benign biopsies:Detected cancer prevalence (not all malignant tumours are identified by biopsy; some use fine needle aspiration; n/a: Not available. a In the Tampere area only; national figures not available. Results kindly given by Professor J, Chamberlain (UK), Dr E. Lithander (Sweden), Dr M. Hakama (Finland) and Dr B. Sigfusson (Iceland). c a n c e r m o r t a l i t y . It will t a k e a n o t h e r d e c a d e for such a n effect to b e discernible. It is, h o w e v e r , a p p a r e n t f r o m the m o n i t o r i n g i n f o r m a t i o n a l r e a d y collected t h a t a r e d u c t i o n in m o r t a l i t y is expected. T h e indicators of p e r f o r m a n c e m i r r o r those that were f o u n d i n the r a n d o m i z e d trials.
w o m e n a n d with details, if available, of the p r e v a l e n c e / i n c i d e n c e ratio a n d the ratio of interval cancers to screen d e t e c t e d plus i n t e r v a l cancers a m o n g s c r e e n e d w o m e n . 2. Pathological size of t u m o u r t o g e t h e r with p a t h o logical n o d a l status, histological grade a n d p r e s e n c e or a b s e n c e of m e t a s t a s e s in all the a b o v e categories of cancer.
PERFORMANCE INDICATORS UNDER DEVELOPMENT O t h e r a d d i t i o n a l p e r f o r m a n c e i n d i c a t o r s were r e g a r d e d as v a l u a b l e b u t systems for r o u t i n e l y collecting such data in n a t i o n a l p r o g r a m m e s w e r e still u n d e r d e v e l o p m e n t in several c o u n t r i e s . T h e s e indicators were: 1. N a t i o n a l or r e g i o n a l i n c i d e n c e of all b r e a s t c a n c e r ( s c r e e n d e t e c t e d cancers, i n t e r v a l cancers, a n d cancers in n o n - a t t e n d e r s ) a m o n g all eligible
THE ADVERSE EFFECTS OF SCREENING T h e aim of a n y s c r e e n i n g p r o g r a m m e is to m a x i m i z e benefit to a s c r e e n e e that is affected or w o u l d b e c o m e affected i n the a b s e n c e of s c r e e n i n g while, at the s a m e t i m e , m i n i m i z i n g w o r r y a n d h a z a r d i n the target p o p u l a t i o n . T h e adverse effects of s c r e e n i n g m a y b e s u b d i v i d e d i n t o those arising from:
EUSOMA ConsensusConferenceon Breast Cancer Screening 1. The screening process itself 2. The false positive results 3. The detection of slow growing, non-lethal breast cancers Although these side effects are a source of concern, there have been relatively few attempts to quantify them.
265 but the women with breast symptoms still had significantly greater psychological morbidity. While the questionnaires used in the studies may not be sensitive enough to measure acute episodes of anxiety generated by a positive screening result, it is nonetheless reassuring that anxiety is not sustained after completion of investigations [21].
Benign Biopsies Screening Process Risks The risks here involve various psychological and physical factors:
Anxiety It has been postulated that recruitment of people into a screening programme, whether by personal invitation or general publicity, may cause anxiety by raising awareness of vulnerability [18]. However, the few studies [19-21] which compared women attending for screening in response to invitation with those not invited have found no evidence of a difference in various anxiety and stress levels.
The favourable malignant to benign biopsy ratio now achievable in screening is partly due to utilization of ultrasound and fine needle aspiration cytology after a positive mammogram. Where the cancer prevalence is high, the ratio may conceal a high rate of benign biopsies. The absolute rate of benign biopsies per 1000 screened women should therefore be monitored and, if possible, compared with that in an unscreened group of women of the same age. Anxiety in women who require a biopsy is likely to be particularly great; one study [211 found that 10% of such women needed professional preoperative counselling, but, as with referrals, there was no evidence of sustained anxiety.
Discomfort and Pain
Detection of Slow Growing Breast Cancer
Compression of the breast against the X-ray plate is necessary to obtain a clear view of all the breast tissue, but this is uncomfortable. Rutter et al. [22] found that 35% of 597 screened women experienced some form of discomfort and 6% experienced pain, although in the majority this lasted less than 10 minutes. More than two-thirds ranked a dental filling, cervical smear and venepuncture as more uncomfortable than mammography. A survey in the USA [23] of 1847 women reported similar levels of discomfort and pain.
Recent screening trials [4,6,10] have found a cumulative incidence of breast cancer in the screening population which is 10%-20% higher than that in the control population, which suggests an 'overdiagnosis' pr0blem. This has been investigated in three studies. In the Health Insurance Plan (HIP) trial [1] the cumulative incidence in the control group was similar to that in the study group after 7 years (3 years after the screening stopped), showing there was no overdiagnosis. In Nijmegen [26], although there was an overall excess of 11% in the screening population compared with geographical controls, the incidence of breast cancer in the first cohort to be screened was higher than in the control group during the first 4 years, but 8-12 years after the onset of screening it was lower than in the controls. This is interpreted as showing that the excess cancers diagnosed in the early years would have presented several years later and were therefore not 'overdiagnosed'. In the Swedish two-counties trial [5], it was concluded that overdiagnosis was limited to the first mammographic examination because thereafter, the annual incidence of breast cancer in screened women (i.e. interval cancers plus those detected at the following screen) was similar to the annual incidence in the control group. A related problem results from advancing the date of diagnosis of a breast cancer whose prognosis is unaltered by screening, either because it is already metastatic or because it would anyway by curable if left until symptomatic. These women live with the knowledge of their diagnosis for longer than would otherwise be the case, and hence many suffer practical problems such as failure to obtain life insurance, as well as a possible greater period of anxiety. It is not possible to. separate patients with screen detected cancers into those who will benefit from early detection and those with slow growing cancer who will not: all must be considered together, recognizing that
Radiation Hazard There is a small risk of inducing breast cancer by radiation exposure from mammography which will depend on the radiation dose and age at screening [24].
False Positive Results of Screening A proportion of women referred for further investigation of a suspicious mammogram will be found not to have cancer. Low specificity of mammographic screening in some programmes, notably in the USA and the UK, means that at least 5% without cancer will be referred for diagnostic investigation. Again, there will be psychological and physical considerations.
Anxiety Induced by Referral One study [25] compared psychiatric morbidity in the 'false positive' referrals with that in women attending for routine screening, and in those attending for investigation because of breast symptoms. After 3 months, there was no difference in psychological morbidity between the referrals and normal women,
266 lives will only be saved for some women. Although it has been suggested that excess years as a breast cancer patient diminish quality of life [27,28], a study of long term survivors with screen detected cancer found that psychological morbidity was less than in age matched women without breast cancer [291.
Conclusions on the Adverse Effects There are several concerns regarding the risks of screening, but, when these were specifically studied, they were found to be either infrequent or relatively minor. They are a reason for maintaining quality assurance measures in all screening programmes, ranging from physical measurement of radiation dose, maintaining high sensitivity and specificity of mammography, providing professional psychological support for referred women, and to ensuring consistency of histological diagnosis.
SCREENING BY ROUTINE BREAST SELF EXAMINATION Routine breast self examination (BSE) has not been shown to be an effective method of screening, though studies are still in progress that may alter this conclusion [30]. The survival of women who practised BSE appears to be higher than those who did not [31,32]. However, such comparisons are unable to correct for lead-time bias, length-biased sampling and selection bias. The first two of these can be eliminated in a population based retrospective study, in which the BSE history of Cases of breast cancer which was advanced at diagnosis are compared with that in age matched controls. A retrospective study [33] of women with breast cancer and controls found that the frequency of BSE did not differ between advanced stage breast cancer patients and controls, and the odds ratio of developing advanced cancer in a BSE practitioner relative to a non-practitioner was 1.15 (95% CI 0.73-1.81), suggesting that it has no effect. Two non-randomized trials have been conducted and two randomized controlled trials are in progress. The first non-randomized study was the UK trial of Early Detection of Breast Cancer [34] in which 63 000 45-64-year-old women in two populations were all personally invited to BSE classes and provided with self referral clinics. Their breast cancer mortality over the ensuing 10 years was compared with that of 126 000 women of the same age in other populations without any intervention. The odds ratio of breast cancer death in the BSE populations relative to the comparison populations was 1.01 (95% CI 0.86-1.17), indicating no effect. The uptake of BSE classes was low (30% in one centre, 54% in the other) and no information was available regarding the proportion of women who regularly practised BSE throughout the study period. This method of public education was not shown to be effective but it does not confidently exclude a small benefit. The second
N.J. Waldet al. prospective study was from Finland [35]; breast cancer mortality among several thousand women who attended a programme of BSE education with annual reminders was lower than the national rates for age matched women from the same localities, but this may have been due at least in part to selection bias. The two prospective randomized controlled trials of BSE are in Russia [36] and China [37] but are still in relatively early stages. It will still be many years before the mortality outcome of these trials is available. At present therefore, there is no satisfactory evidence that screening by routine breast self examination is of value and there is no case for setting up public health programmes for education in BSE. This is not to say that women should refrain from being aware of any changes in their breasts. Women should continue to be encouraged to seek medical advice if changes do occur and they are concerned.
RESEARCH NEEDS A number of research needs arose in the discussion. The most important is to determine whether breast cancer screening in women aged under 50 years reduces breast cancer mortality and, if so, by how much. There is also a need to determine the extent to which older women (say 70 years of age or more) are likely to benefit from screening programmes. At present, there are limited data on this. The only randomized trial that included data on women aged 70 or more was from the Swedish two-counties trial [5,8] and this showed a 2% reduction in mortality with wide confidence intervals (relative risk 0.98; 95% CI 0.63-1.53) [14]. A third question is to determine the appropriate screening interval, recognizing that a shorter interval would lead to fewer interval cancers but with substantially increased costs. There is a need to obtain quantitative estimates of the net gain in terms of deaths avoided in relation to the extra costs arising from the more frequent mammographic examinations. It was agreed that the European Society of Mastology should set up a screening research committee to formulate and promote research into breast cancer screening and into aspects of breast cancer that can readily be researched within a screening programme.
CONCLUSIONS AND RECOMMENDATIONS 1. Screening for breast cancer by inviting women for periodic mammographic examination, followed by diagnosis and treatment as necessary, leads to a significant reduction in breast cancer mortality. The overall reduction observed in six randomized trials among women aged 4074 years was 22%. 2. Screening women aged 50 years and over has been
EUSOMA Consensus Conference on Breast Cancer Screening
shown to be effective and worthwhile. The randomized trials have shown a significant reduction in mortality of 24%. Screening women aged 50 years and over should be part of public health programmes organized on an invitation basis with full quality control and monitoring. 3. While it is clear that screening women aged 50 years and over is effective, there is uncertainty over its effect in younger women. It is important that any screening in women aged under 50 years should only be performed as part of a properly controlled research programme. 4. Younger women who request mammography should have it performed only after informing them of the uncertainty and advising them of the possible consequences. 5. The benefits of screening demonstrated in the research trials can be translated into practice, but with appropriate conditions, quality assurance and monitoring. Performance indicators of recognized value that have been used successfully on a national basis: • Population coverage (%) • Screening uptake (%) • Referral rate (%) • Benign biopsy rate (per 1000 women screened) • Detected cancer prevalence (per 1000 women screened) • Malignant : benign ratio • Proportion of screen detected invasive cancers <10 mm diameter (%) Performance indicators of recognized value that are still under development in monitoring national programmes: • Incidence of all breast cancers in eligible women Screen detected Interval Non-attenders • Incidence (per 1000) of stage II or greater, using pathological size of tumour histological nodal involvement presence of metastases. 6. The side-effects of screening need to be recognized, specifically: • Anxiety in women attending screening • Discomfort and pain • Radiation • Anxiety in screen positive women • High absolute rate of benign biopsies (not necessarily revealed by malignant : benign ratio) • Screen detected cancer that would not otherwise have adversely affected the woman 7. Breast self-examination. On the basis of current evidence, breast self examination programmes are not an effective method of population screening and therefore should not be recommended as public health policy. 8. Research. Screening women under 50 years of age is currently widespread in Europe and there is a perception of benefit in spite of the scientific uncertainty. In view of this, it is important that the issue is resolved to the extent that new research evidence will influence medical practice one way or the other; otherwise there is the potential for much waste and
267
even harm if such screening turns out to have little effect. 9. EUSOMA should set up a screening research committee to formulate and promote research into breast cancer screening and into aspects of breast cancer that can readily be researched within a screening programme. Research and service should be undertaken hand-in-hand.
References 1. Shapiro S, Venet W, Strax P, et al. Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-86. London: Johns Hopkins University Press, 1988. 2. Aron JL, Prorok PC. An analysis of the mortality effect in a breast cancer screening study. Int J Epidemiol 1986;15:36-43. 3. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: Mortality at seven years. Lancet 1990;335:241-6. 4. Tabar L, Fagerberg G, Duffy SW, et al. The Swedish twocounty trial of mammographic screening for breast cancer: Recent results and calculation of benefit. J Epidemiol Community Health 1989;43:107-12. 5. Tabar L, Fagerberg G, Duffy SW, et al. Update of the Swedish 2-county program of mammography screening for breast cancer. Radiol Clin North Am 1992;30:187-210. 6. Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malta6 mammographic screening trial. Br Med J 1988;297:943-8. 7. Frisell J, Eklund G, Hellstrom L, et al. Randomized study of mammography screening - preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 1991;18:49-56. 8. Nystrom L, Rutqvist LE, Stig W, et al. Breast cancer screening with mammography: An overview of Swedish randomised trials. Lancet 1993;341:973-8. 9. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening Study. Can Med Assoc J 1992;147:1459--88. 10. UK Trial of Early Detection of Breast Cancer Group. First results on mortality reduction in the UK trial of early detection of breast cancer. Lancet 1988;ii:411-6. 11. UK Trial of Early Detection of Breast Cancer Group. Breast cancer mortality after 10 years in the UK trial of early detection of breast cancer. Breast 1993 ;2:13-20. 12. Morrison AS, Brisson J, Khalid N. Breast cancer incidence and mortality in the breast cancer detection demonstration project. J Natl Cancer Inst 1988;80:1540--7. 13. Verbeek ALM, Hendriks JHCL, Holland R, et al. Reduction of breast cancer mortality through mass screening with modern mammography: First results of the Nijmegen project, 1975-1981. Lancet 1984;i:1222-4. 14. Verbeek ALM, Hendriks JHCL, Holland R, et al. Mammographic screening and breast cancer mortality: Age-specific effects in Nijmegen project, 1975-82. Lancet 1985;i:865-6. 15. Collette HJA, Rombach JJ, Day NE, et al. Evaluation of screening for breast cancer in a non-randomised study (the DOM project) by means of a case-control study. Lancet 1984;i: 1224-6. 16. Palli D, del Turco MR, Buiatti E, et al. A case-control study of the efficacy of a non-randomized breast cancer screening program in Florence (Italy). Int J Cancer 1986;38:501-4. 17. Tabar L, Fagerberg G, Day NE. What is the optimum interval between mammographic screening examination? An analysis based on the latest results of the Swedish two-county breast cancer screening trial. Br J Cancer 1987;55:547-551. 18. Marteau TM. Psychological costs of screening. Br Med J 1989;299:527. 19. Dean C, Roberts MM, French K, Robinson S et al. Psychiatric morbidity after screening for breast cancer. J Epidemiol Community Health 1986;40:71-5. 20. Hunt SM, Alexander F, Roberts M. Attenders and nonattenders at a breast screening clinic: A comparative study. PuN Health 1988;102:3-10. 21. Bull AR, Campbell MJ. Assessment of the psychological impact of a breast screening programme. Br J Radiol 1991 ;64:510-5. 22. Rutter DR, Calnan M, Vaile MS et al. Discomfort and pain
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23. 24. 25. 26.
27. 28.
N . J . Wald et al. during mammography: Description, prediction and prevention. Br Med J 1992;289:415-8. Stomper PC, Kopans DB, Sadowsky NL, et al. Is mammography painful? A multicentre survey. Arch Intern Med 1988;148:521-4. Gohagan JK, Darby WP, Spitznagal EL, et al. Radiogenic breast cancer effects of mammographic screening. J Natl Cancer Inst 1986;77:71-6. Ellman R, Angeli N, Christians A, et al. Psychiatric morbidity associated with screening for breast cancer. Br J Cancer 1989;60:781-4. Peeters PHM, Verbeek AL, Straatman H et al. Evaluation of over diagnosis of breast cancer in screening with mammography: Results of the Nijmegen Programme. Int J Epidemiol 1989;18:295-9. De Koning H. Cost-effectiveness of Screening. E U S O M A Conference, 1993. Maguire P. Questions of morbidity and compliance. E U S O M A Conference, 1993.
29. Ellman RE, Thomas BE. Personal communication. 30. Morrison AS. Is self-examination effective in screening for breast cancer? J Natl Cancer Inst 1991;83:226-7. 31. Foster RS, Constanza MC. Breast self-examination practices and breast cancer survival. Cancer 1984;53:999-1005. 32. Huguley CM, Brown RL, Greenberg RS, et al. Breast self examination and survival from breast cancer. Cancer 1988;62:1389-96. 33. Newcomb PA, Weiss NS, Storer BE, et al. Breast selfexamination in relation to occurrence of advanced breast cancer. J Natl Cancer Inst 1991 ;83:260--5. 34. Ellman R, Moss SM, Coleman D, et al. Breast selfexamination programmes in the trial of early detection of breast cancer: 10-year findings. Br J Cancer 1993;68:208-12. 35. Gastrin G, Hakama M, Miller AB. Personal communication. 36. Semiglazov VF, Moiseenko VM. Breast self-examination for the early detection of breast cancer: a USSR/WHO controlled trial in Leningrad. WHO Bull 1987;65:391-6. 37. Thomas DB. Personal communication.
APPENDIX Estimating the reduction in breast cancer mortality if all women accepted the invitation to be screened For illustration, assume a 'background' death rate from breast cancer of 6 per 1000 (the actual rate is unimportant). So in a group of, say, 10 000 unscreened women, 60 deaths are expected. Suppose that in the intention-to-screen group the observed mortality is 30%, but only 75% of the women in this group were actually screened (i.e. relative risk with 75% compliance RRv5 = 0.70). We thus need to estimate the possible reduction in mortality if 100% of those women were screened. Group invited for screening e.g. n=10000 (say)
If women who decline screening have the same mortality as controls: Expected deaths without screening Observed deaths after screening If women who decline screening have 20% higher mortality than controls: Expected deaths without screening Observed deaths after screening
Control group e,g. n=10000 (say)
RR75*
RRlo0
75% Accepted n=7500
Declined n=2500
45 27
15 15
6O 60
0.70 ((27+15)/60)
0.60 (27/45)
42a 24
i8 a 18
60 60
0.70 ((24+18)/60)
0.57 (25/42)
tRR75 is the observed relative risk of dying from breast cancer among a group of women invited for screening with 75% accepting screening. RRloo is the estimated relative risk in women who accept screening. It is derived from a relative risk determined on an intention-to-screen basis. (i.e. RR75). General formula for estimating the relative risk of breast cancer mortality assuming 100% compliance: RRloo = RRc - a ( l - a ) 1-a (1-c) where C = proportion of women who accepted the invitation to be screened (i.e. compliance); RRc = relative risk in the intention-toscreen group; a = extra mortality in women who decline screening (if controls have mortality M then women who decline have mortality a×M). In the randomized trials, compliance ranged from 60-90%. An estimate of overall compliance is approximately 78%. From the table, the pooled estimate of reduction in mortality is 22% (RRT8 = 0.78). Hence, estimates of this reduction if all the invited women were screened are as follows. If women who declined screening have: Same mortality as controls:a 20% greater mortality: a 50% greater mortality: a Twice the mortality: a
= = = =
1.0 1.2 1.5 2.0
RRlo0 = RR~oo = RRa00 = RRlo0 =
0.72 0.70 0.67 0.61
i.e. i.e. i.e. i.e.
28% 30% 33% 39%
reduction reduction reduction reduction
Received for publication December 1993 Accepted following revision January 1994