The Canadian Task Force on Preventive Health Care recently released recommendations about screening for breast cancer.
These recommendations have been criticized by some because they emphasize the results of randomized trials.
This article explores the advantages and limitations of randomized trial evidence regarding screening mammography.
The recent recommendations by the Canadian Task Force on Preventive Health Care have been criticized on a number of grounds.
What is a randomized controlled trial?
A randomized controlled trial is a research design in which patients or communities are randomly allocated (like the flip of a coin) to receive one of two treatments or tests. The patients are then followed over time to see if there are differences in outcomes between the two groups. In the case of the randomized trials of mammography, patients or regions were randomly allocated to a mammography screening program or no screening program. The women were then followed for an average of 11 years, and the number of breast cancers diagnosed, deaths from breast cancer and breast biopsies (among other outcomes) were compared between the two groups.
In health care, randomized trials are considered the “gold standard” if one wants to understand the benefits of a treatment or screening program. This is because randomization makes it likely that any benefit detected at the end of follow-up has occurred because of the treatment and not because the participants in one group are healthier than those in the other group.
The importance of randomization is illustrated by the history of hormone replacement therapy, such as Premarin, as a treatment to prevent heart disease in post menopausal women. Many non-randomized studies found that post-menopausal women who took hormone replacement therapy were less likely to develop heart disease than those who didn’t take hormone replacement therapy. The results were considered so convincing that hormone replacement therapy was strongly recommended by many influential medical associations as a way to prevent heart disease in women.
However, two large randomized trials subsequently showed that not only did hormone replacement therapy not decrease the risk of developing heart disease; the treatment actually increased the risk. It is likely that the apparent benefit from hormone replacement treatment seen in the non-randomized studies was because women who take preventive medicines are generally healthier than those who do not. The non randomized studies made it seem that the drug was responsible for decreasing the risk of heart disease, when in fact life style and other unmeasured factors were likely responsible.
Results of randomized trails of mammographic screening
Women who volunteer for mammographic screening are likely healthier than those who do not, thus creating similar problems with interpreting the results of non-randomized studies as with hormone replacement therapy. For this reason, most groups who develop screening guidelines use the results of randomized trials as the main basis for their guidelines.
The Task Force reviewed 8 published randomized trials of mammographic screening in women younger than 49 years of age. They found that, on average, regular screening with mammography led to a 15% relative risk reduction in death from breast cancer. Because these results come from large randomized trials, it is highly likely that the 15% relative risk reduction really is due to mammography and not due to differences in the risk of developing breast cancer between the women who were screened and the women who were not.
Criticisms of randomized trials of mammographic screening
One criticism is that some women randomized to mammography screening decided not to be screened. Conversely, some women randomized to no screening had a mammogram. In the epidemiology literature, this phenomenon is called “contamination”, and it means that these studies likely under-estimated the maximum potential benefit of screening. Because no screening program will ever convince all eligible women to undergo mammography, and because some women will be screened even in the absence of a formal screening program, the results of these randomized trials likely reflect what will happen in the “real world” when screening programs are introduced.
These results are perhaps most useful for policy makers who are deciding whether or not to pay for a mammographic screening program. However, for a woman contemplating screening mammography who will be complaint with screening recommendations, the results of these trials likely underestimate the benefits of screening for her by a small amount. A second criticism is that the randomized trials studied old mammographic technologies. Since newer technologies are better at detecting cancers in younger women and women with dense breasts than older mammograms, it is argued by some that the randomized trials under-estimate the benefits of mammography as practiced in 2011.
The oldest randomized trial of mammography enrolled women in 1963 and the most recent study enrolled women between 1991 and 1997. Women were followed for an average of 11 years from the time of enrolment. The most recent trial found that mammography led to a 17% relative reduction in the risk of dying from breast cancer in women between 40 and 49 years of age. This is almost the same as the 15% average found when combining all of the studies, and suggests that the newest technology available in the mid 1990s didn’t have a much greater impact on deaths from breast cancer than the older mammographic technologies.
Could 21st century mammographic screening technologies prevent more deaths than the older technologies? The Task Force’s answer to this is that we “require further randomized trials” to sort this out. Is this realistic? Any future randomized trial would need to compare the new technology with an older one. Most women are unlikely to agree to be randomized to such a study. Also, the study would need to include a very large number of women, and even if the study was feasible, the results would not be available for 15-20 years.
Another approach would be to model the impact of current mammographic technology on deaths from breast cancer, using information about how much better the current technology is, and data from the older randomized trials. Although such a modelling exercise would invariably involve making several assumptions, it would lay out how much of an impact on deaths from breast cancer the newer technologies might realistically be expected to have. Given that the most recent study comparing newer mammography with older techniques found very little difference between the two, except in young women with dense breasts, it seems unlikely that the newer techniques would markedly increase the number of breast cancer deaths prevented compared to the published randomized trials.
What about information from non-randomized trials?
One potential approach to the limitations of published randomized trials is to use information from non randomized studies that have looking at breast cancer deaths in regions with no screening, those using older screening technologies and those using newer screening technologies. However, because the populations being studied were not randomized to the type of screening they received, it is possible (some would say likely) that some of the differences in deaths from breast cancer found in such studies are due to differences in the characteristics of the women and/or differences in the management of breast cancer.
It turns out that advocates on both sides of the mammography debate have turned to non-randomized studies to make their arguments, but it appears as if they selectively mention the studies that support their point of view and ignore those that do not.
For example, Peter Goetzsche, a researcher from Denmark has published extensively on this issue, arguing that mammography does more harm than good. In a recent Canadian Medical Association Journal editorial, he referred to non-randomized studies from Sweden that found that death rates from breast cancer had decreased at the same rate in regions with, and without, screening programs.
On the other hand, Martin Yaffe, a researcher from Toronto who argues that the randomized trials under-estimate the benefits of mammography, refers to a non-randomized study of mammography from British Columbia which suggests dramatic benefits from mammographic screening.
Many advocates for one position or the other refer only to non-randomized studies that support their position. If the results of non randomized studies are to be considered alongside the results of randomized trials, it is important that individuals not selectively choose the studies that agree with their position and ignore the ones that do not.
A systematic review on non-randomized studies, which includes the results of all relevant studies, could provide useful input to the debate. However, while there has been a call from some in the scientific community for such a study to be conducted, it has not yet occurred.