1 Queen Mary University of London, London, UK; 2 Falun Central Hospital, Falun, Sweden; 3 University of Linköping, Linköping, Sweden; 4 American Cancer Society, Atlanta, GA, USA; 5 Institute of Preventive Medicine, National Taiwan University, Taipei, Taiwan
Received 19 July 2002; accepted 3 April 2003
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Abstract |
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The Swedish Two-County Trial has been criticised on the grounds of the cluster randomisation and alleged bias in classification of cause of death.
Patients and methods:
In the Two-County Trial, 77 080 women were randomised to regular invitation to screening (active study population, ASP) and 55 985 to no invitation (passive study population, PSP), in 45 geographical clusters. After 7 years, the PSP was invited to screening and the trial closed. We analysed data using hierarchical statistical models to take account of cluster randomisation, and performed a conservative analysis assuming a systematic difference between ASP and PSP in baseline breast cancer mortality in one of the counties. We also analysed deaths from causes other than breast cancer and from all causes among breast cancer cases diagnosed in the ASP and PSP.
Results:
Taking account of the cluster randomisation there was a significant 30% reduction in breast cancer mortality in the ASP. Conservatively, assuming a systematic difference between ASP and PSP clusters in baseline breast cancer mortality, there was a significant 27% reduction in mortality in the ASP. Ignoring classification of cause of death, there was a significant 13% reduction in all-cause mortality in breast cancer cases in the ASP.
Conclusions:
Breast cancer mortality is a valid end point and mammographic screening does indeed reduce mortality from breast cancer. The criticisms of the Swedish Two-County Trial are unfounded.
Key words: breast screening, mammography, randomised trial
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Introduction |
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Although these and other alleged shortcomings in the Two-County Trial have been shown to be ill-founded [5, 6], it is worthwhile to revisit the issues of randomisation and end point classification, as these are most crucial to interpretation and because the issue of classification of cause of death has been taken up by others [7]. We therefore address the issues of potential biases resulting from the cluster randomisation and the effect of invitation to screening on other causes of death among the breast cancer cases. In approaching the latter problem, we take account of the additional time for study group cases to die of other causes due to lead time. Previous analyses have omitted to do so and have consequently come to erroneous conclusions [4, 6].
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Patients and methods |
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The ASP were invited to single-view mammography every 33 months for women aged 5074 years at randomisation, and every 24 months for women aged 4049 years. At the end of 1984, a significant 31% mortality reduction was observed in the ASP [8]. The PSP was invited to screening and the trial closed after the first screen of the PSP. All cancers diagnosed in both groups up to and including the end of the first screen of the PSP were then followed-up for mortality from breast cancer. The most recent follow-up is to the end of 1998 [1].
To take account of variation between strata or clusters, we quote results from our analysis of the 1996 follow-up data by a series of hierarchical models [9]. Model 1: Poisson regression, ignoring cluster randomisation; model 2: allowing baseline breast cancer mortality to vary from stratum to stratum; model 3: allowing variation in the effect of invitation to screening from stratum to stratum; model 4: allowing variation between clusters within strata in baseline breast cancer mortality. We also estimated the effect of invitation to screening adjusting for observed differences between clusters in breast cancer mortality in the 10 years before the trial took place.
To investigate possible biases in cause of death, we estimated the relative risk of death from other causes and from all causes within the breast cancer cases, taking into account the additional time for ASP cases to die from causes other than breast cancer (due to early detection, the ASP cases were diagnosed almost 2 years earlier than the PSP cases). We only considered deaths within the breast cancer cases, since only those with breast cancer can die of breast cancer, and because mammographic screening cannot affect risk of death in women who do not have breast cancer. For further details, see Tabar et al. [10].
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Results |
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Discussion |
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These results are not surprising. We have dealt with the issues of cluster randomisation and cause of death in our previous publications [8, 9, 1113]. In addition, the Swedish overview has published an excess mortality analysis that did not rely on classification of cause of death and which came to the same conclusions as the breast cancer mortality analysis [14].
Concerns about the screening of the PSP or its timing should be allayed by two factors. First, the published result in 1985 (of breast cancer mortality to the end of 1984) is essentially the pre-PSP screening result. Although the planned first screen of the PSP had started by the end of 1984, it was only 5% complete and had no bearing on mortality at the time. Also, while 13% of the control group had experienced mammography by this time, <2% had received screening mammography (i.e. true contamination). Secondly, the Swedish overview [15] analysed the results by the follow-up model including all breast cancers diagnosed up to the end of 1989, and obtained a similar result to ours for the Two-County Trial.
We therefore conclude that the major criticisms of the Two-county Trial are unfounded. The trial is not perfect, nor is any other study. Breast cancer mortality is a valid end point and mammography screening does reduce deaths from breast cancer.
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Acknowledgements |
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Footnotes |
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References |
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