Department of Public Health, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
Received 23 September 2002; accepted 3 April 2003
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Abstract |
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All randomised breast cancer screening trials have shown a reduction in breast cancer mortality in the invited for mammography screening arm compared with the control arm for women aged 50 years and older at randomisation (overall 25%). However, individually published point estimates differ and concern has been raised about methodological quality and outcome measures.
Materials and Methods
Review of the evidence on breast cancer mortality reduction and discussion of the causes of difference in point estimates in the five Swedish and Canadian trials. A summary of the prerequisites for methodological quality and its available evidence from the trials is given. Data to support breast cancer mortality as a correct outcome measure are presented.
Results:
There is no reason not to use breast cancer mortality as an outcome measure for trials intended to reduce breast cancer mortality, both from a clinical and a methodological point of view. Everything possible was performed in these trials in order to determine this outcome measure as accurately as possible. The fact that a few of the trials showed a relatively large breast cancer mortality reduction and others far lower reduction rates is irrelevant, if one does not consider the background situation in the region before the trial started, the design of the trial or quality of screening.
Conclusions:
There seems no reason to change or halt the current nation-wide population-based screening programmes. Nor is there any justifiable reason for negative reports towards women or professionals.
Key words: breast cancer, randomised trials, screening
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Introduction |
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Still, such long-term large-scale randomised screening trials are crucial, and there is no second-best option. Individual randomisation leads to comparable groups that can be traced for follow-up and evaluation and the final outcome can be linked directly to screening and intermediate outcome measures. If there is variation in screening intensity, this sometimes can be evaluated. There are enough examples where the lack of randomised trials hamper present-day evaluations of service screening practice [57].
In breast cancer, both clinical and laboratory work support the theory of breast cancer screening. In the past, women treated by surgery for smaller tumours had a lower chance of distant metastases after long follow-up [8], and empirical work showed that treatment before a critical number of blood vessels had formed might prevent occurrence of metastases [9].
At the request of the Danish Institute for Health Technology Assessment, Danish researchers analysed and summarised all available literature on the nine randomised breast cancer screening trials performed in the past, which was then (partly) approved by the Cochrane group for publication in their library [10]. The breast cancer screening trials in question were all initiated during the period 19631982, and were concluded at least 10 years ago. In a more narrow sense, the review did not include any of the many breast screening programmes currently ongoing in Europe. All trials differed in age categories and number of women enrolled, starting year and place, and the way women were enrolled or selected. If we confine ourselves to the group of women aged 50 years and older at randomisation, as this is the group that is invited for screening in every centrally organised European screening programme, rather than women under the age of 50 years, all trials had published a reduction in breast cancer mortality in the invited for mammography screening arm compared with the control arm, ranging from 3% to 36% [11, 12].
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Causes of difference in point estimates on breast cancer mortality in the Swedish and Canadian trials |
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The entire discussion as to whether or not a reduction in breast cancer mortality could be established as a result of screening in women aged 50 years is therefore limited to the five Swedish studies and the Canadian study, comprising a total of 356 000 women. Figure 1 and Table 1 show the relative risk (RR) of women aged
50 years at the start of the trials (Malmö; age
55 years) dying of breast cancer in the intervention arm (mammography screening) compared with the control arm of these trials, summarised in the official Cochrane review [19]. An overall 25% (1138%) statistically significant reduction in breast cancer mortality was seen in the intervention arms compared with the control arms. The overview shows a 12% reduction in breast cancer mortality in the Malmö and Canada trials (RR = 0.88) and a 31% reduction in breast cancer mortality (RR = 0.69) in the four other Swedish trials. All the trials show a breast cancer mortality reduction for this age group, but only a few were on a large enough scale individually to reveal a significant reduction.
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The Canadian trial was the only trial that was uniquely different in design. The women assigned to the control groups in the Swedish trials were offered no examination, while in the Canadian trial, the women allotted to the control group annually received an extensive clinical breast examination, performed by a specially instructed and trained nurse or physician [22]. This yielded detection rates in the control arm rivalling those found in some decentral mammography screening programmes in Europe [23]. In short, one part of the explanation for the relatively small difference between the two arms in the Canadian trial (a mere 3%) is explained by the effective screening carried out in the control arm. This reported point estimate could therefore not be pooled in the same way with the Malmö trial to compare the effect of mammography screening to a no-screen situation, as the effect has been diluted.
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Prerequisites for methodological quality of the trials |
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All the Swedish trials were population-based, which means that in principle, a population list of women was compiled in advance and randomised. Obviously, it is possible and even likely that this included women in whom breast cancer had been diagnosed prior to the randomisation date. These women will have to be excluded later, for example on the basis of information derived from the cancer registry. This was the case for a few hundred women in each Swedish trial. Equal exclusions were reported for Östergötland, Malmö and Göteborg, and no age differences were seen between arms in Stockholm. The Canadian trial was the sole trial conducted on a volunteer basis, i.e. on women who approached the centres on their own initiative. Hence, this trial had almost no exclusions, as women already diagnosed with breast cancer are unlikely to join, or will not be randomised if they do volunteer. The Canadian trial is therefore more likely to fulfil this exclusion criterion, while at the same time saying nothing about a methodological error or quality criterion. The discussion concerning age differences between arms constituting the criterion for correct randomisation [26] has proven to be obsolete and wrong.
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Breast cancer mortality as outcome measure |
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Evaluation service screening |
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Conclusions |
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There is no reason not to use breast cancer mortality as an outcome measure for trials intended to reduce breast cancer mortality. Everything possible was performed in these trials in order to determine this outcome measure as correctly as possible.
It is more than likely that the reduction in breast cancer mortality in the various countries may indeed be attributed to the screening programmes, although it is still too early for a well-founded, scientific opinion in this respect. It goes without saying that evaluation of breast cancer mortality during the next 5 years will be crucial.
There seems no reason to change or to halt the current screening programmes, for example in The Netherlands. Nor is there any justifiable reason for negative reports towards women or professionals.
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Footnotes |
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References |
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