Affiliations of authors: W. C. Black, Department of Radiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, and Center for the Evaluative Clinical Sciences, Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH; D. A. Haggstrom, Department of Medicine, Medical College of Wisconsin, Milwaukee; H. G. Welch, Department of Medicine, Dartmouth-Hitchcock Medical Center, Center for the Evaluative Clinical Sciences, Department of Community and Family Medicine, Dartmouth Medical School, and VA Outcomes Group, Veterans Affairs Hospital, White River Junction, VT.
Correspondence to: William C. Black, M.D., Department of Radiology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr., Lebanon, NH 03756 (e-mail: william.black{at}Hitchcock. org).
Begg and Bach, Church et al., Gail and Katki, Kopans and Halpern, and Weiss and Koepsell point out that the inconsistencies between the disease-specific and all-cause mortality rates in Table 1 of our article could be due to chance alone. We agree (as we acknowledged in our discussion) and appreciate the estimates for the probabilities of discordance provided by Begg and Bach, Gail and Katki, and Weiss and Koepsell. Nevertheless, we provided Table 1 to show that these inconsistencies existregardless of causeand to show that the deaths from the target cancers are only small proportions of all deaths (3%16%). We suspect that many individuals contemplating screening and their referring clinicians would be surprised that these proportions are so low and that there is not even a trend toward a decrease in all-cause mortality in the screening arms (higher in six trials, lower in five, and the same in one). These facts are certainly not conveyed in the promotional materials for cancer screening that stress saving lives.
Incidentally, Church et al. state that the death rate from colon cancer was 4.5 per 10 000 person-years in the screening arm of the Minnesota trial. However, there were actually two screening arms (and one control arm) in that trial. While the colon cancer death rate was 4.5 per 10 000 person-years in the arm screened annually, it was 6.4 per 10 000 person-years in the arm screened biennially. We did not think that inclusion of only one of the screening armsthe one with the much better outcomeswould fairly represent screening in that trial. Therefore, we combined the number of colon cancer deaths (82 and 117), all deaths (3361 and 3396), and person-years of follow-up (184, 160, and 183 934) in the two screening arms to calculate the mortality rates for screening that are shown in Table 1.
Returning to the issue of the inconsistencies between the disease-specific and all-cause mortality rates in Table 1, that they can be explained by chance alone does not mean that chance is the only, or even the most important, explanation. Clinicians and the public health community must also consider alternative explanations. We devoted much of our article to discussing the plausibility of bias in the classification of death as well as design flaws that could cause inconsistencies between the mortality rates. Although we cited some empirical evidence concerning misclassification of death, we failed to cite one particularly relevant article by Brown et al. (1). These investigators examined deaths in patients diagnosed with cancer and found that the overall noncancer death rate was 1.37 times that expected from U.S. age- and sex-specific mortality data (P<<.001). Brown et al. also found that most of the excess noncancer deaths occurred shortly after diagnosis, and they concluded that a large proportion of these deaths were probably due to cancer treatment. Parker and Dearnaley provide further evidence that cancer treatments can be associated with excess noncancer mortality and that the potential for net harm is greatest for those with early, low-grade diseasethe very individuals most likely to be identified by screening.
Weiss and Koepsell think that a statistically significant reduction in all-cause mortality is too stringent a requirement for the determination of screening efficacy. We agree, and we think that a trend in the right direction along with a statistically significant reduction in disease-specific mortality may be sufficient. However, we do not think that a randomized trial showing an increase in all-cause mortality should ever be cited as "strong evidence" of efficacy, regardless of the reduction in disease-specific mortality. We recognize that the probability of an increase in all-cause mortality from chance alone can be high when the disease-specific mortality is proportionally very low. In the example described by Weiss and Koepsell, in which colon cancer causes only 3.6% of all deaths, the probability of an increase in all-cause mortality is 31% if screening reduces colon cancer mortality by 50% and causes no other deaths. However, when the disease-specific mortality is proportionally very low, it is also true that only a very slight increase in noncancer mortality is required to offset a reduction in cancer mortality. In this colon cancer example, if screening and the subsequent diagnostic evaluation and treatment increase the noncancer mortality by as little as 2%, then screening would cause more deaths than it prevents, even if it does reduce colon cancer mortality by 50%. Thus, even when there is a statistically significant reduction in disease-specific mortality, we do not think the case for screening should be closed when the all-cause mortality is higher in the screened group.
With regard to the appropriate burden of proof, a conservative statistical significance level of 5% is conventionally used in medicine to avoid the acceptance of a new treatment that is not effective. It would be ironic if this 5% significance level were reversed to avoid the rejection of a new screening test that may cause more deaths than it prevents. Furthermore, it is generally agreed that the level of evidence for effectiveness should be especially high for screening because it "converts some ostensibly healthy individuals into patients" (2). (We don't think most individuals considering screening would be reassured by the argument that the observed increase in all-cause mortality could be dismissed as chance [P>.05]).
In conclusion, we stand by our recommendation that all-cause mortality should always be reported and considered in conjunction with disease-specific mortality. Disregarding the vast majority of deaths that occur in a randomized trial of screening for the sake of statistical power simply hides an important uncertainty. Establishing the net effect of screening healthy peopleonly a few of whom can be helped, some of whom will be harmed, and most of whom will experience little effectwill often exceed the limits of medical science. Thus, there is all the more reason for full disclosure of both what is known and what is unknown about screening for informed decision making.
REFERENCES
1 Brown BW, Brauner C, Minnotte MC. Noncancer deaths in white adult cancer patients. J Natl Cancer Inst 1993;85:97987.[Abstract]
2 Prorok PC, Kramer BS, Gohagan JK. Screening theory and study design: the basics. In: Kramer BS, Gohagan JK, Prorok PC, editors. Cancer screening: theory and practice. New York (NY): Marcel Dekker; 1999. p. 2953.
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