Affiliation of authors: D. B. Kopans, E. Halpern, Massachusetts General Hospital/Harvard Medical School, Department of Radiology, Boston, MA.
Correspondence to: Daniel Kopans, M.D., Massachusetts General Hospital, Department of Radiology, Ambulatory Care Center, 15 Parkman St., 2nd Floor, Rm. 219, Boston, MA 02114 (e-mail: kopans.daniel{at}mgh.harvard.edu).
Black et al. (1), in their article entitled "All-Cause Mortality in Randomized Trials of Cancer Screening," argue that the only measure of benefit from a screening intervention is a reduction in "all-cause mortality." All cause mortality may be the best way to avoid bias in the determination of the causes of death, as they explain. It may be appropriate in therapy trials in which the disease being studied is a major cause of death, but the goal is impossible to achieve, for all practical purposes, for screening trials.
There are two essential differences between trials of therapies and trials of screening that make all-cause mortality appropriate in the former but impractical in the latter. Both are consequences of the fact that, in trials of therapies for a terminal disease, patients are eligible only if diseased, whereas in screening trials, both diseased and nondiseased individuals are included. As a result, the number of expected deaths per studied patient is much larger in trials of therapies. Furthermore, a much larger fraction of the deaths from all causes are caused by the specific disease in trials of therapies. Thus, required sample sizes for both disease-specific and all-cause mortality may be similar in therapy trials but very different in screening studies.
Their graphic nicely demonstrates the difference between dying from a single disease, such as breast cancer, and dying from all other causes of death. Rather than supporting the concept that screening efficacy should be judged by its effect on all causes of death, their summary provides clear evidence that basing efficacy on "all cause mortality" in a screening trial is neither feasible nor necessary. Breast cancer accounts for only a small percentage of deaths each year. Consequently, if screening reduces the number of deaths from breast cancer by approximately 25%, there will be little change in the overall per capita death rate from all causes as shown in their Fig. 1. For instance, if there are four incident cancers per 1000 women, and if screening reduces the death rate from breast cancer by 25%, and if breast cancer accounts for 10% of all deaths, then a trial would need a minimum of 1.5 million women in each arm for that reduction to show a significant reduction in all-cause mortality. Because breast cancer accounts for far fewer than 10% of all deaths each year, a trial would have to involve many more than 3 million women.
What the authors have shown is nothing more than that the larger statistical fluctuation in all-cause mortality can mask a real benefit that would be apparent if the benefit is evaluated for breast cancer mortality alone. It is not appropriate to dismiss the fact that screening reduces the rate of death from breast cancer simply because deaths from all causes do not appear to be influenced.
Most women would prefer to not die from breast cancer. The screening trials show that the likelihood of dying from breast cancer can be reduced by earlier detection. There is no good evidence that the blinded assignment of the causes of death in the trials was biased. Even if there were cardiovascular deaths from irradiation that were not counted in the trials, these deaths would have occurred in fewer than 5% of women irradiated with the old "hockey-stick" fields (2,3) and would be virtually the same for screen-detected as well as control women with breast cancer. Decreasing breast cancer deaths will clearly translate into fewer total deaths in a given year, but proving this decrease in deaths is impossible because the trials would have to be so large that they could not be performed.
REFERENCES
1
Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst 2002;94:16773.
2 Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12:44753.[Abstract]
3 Favorable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 2000;355:175770.[Medline]
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