CORRESPONDENCE

Re: All-Cause Mortality in Randomized Trials of Cancer Screening

Noel S. Weiss, Thomas D. Koepsell

Affiliation of authors: N. S. Weiss, T. D. Koepsell, University of Washington, Seattle.

Correspondence to: Noel S. Weiss, M.D., Dr.P.H., University of Washington, Box 357236, Seattle, WA 98195 (e-mail: nweiss{at}u.washington. edu).

In their provocative article on the choice of outcomes in randomized trials of cancer screening, Black et al. (1) suggest that for a given trial (or series of trials), disease-specific mortality "should only be interpreted in conjunction with all-cause mortality." As a means of identifying possible problems in randomization or the completeness of ascertainment of outcome events, we agree with the authors that it is appropriate to look for differences in all-cause mortality that clearly exceed the plausible impact of screening.

However, we disagree with their conclusion that "a reduction in disease-specific mortality should not be cited as strong evidence of efficacy when the all-cause mortality is the same or higher in the screened group." Our concern stems from the fact that in most randomized screening trials, all-cause mortality will not differ to a statistically significant extent whether the screening modality does or does not lead to life-saving treatment in some persons. Moreover, the probability of "inconsistency" between the comparison based on all-cause mortality rates and that based on cause-specific mortality rates may be quite high because of chance alone. As an example, consider the Minnesota trial of screening for fecal occult blood, cited by Black et al. In that trial, the all-cause mortality rate was the same in both arms—183.6 deaths per 10 000 person-years—while the cancer mortality rates were 6.6 in the control group versus 5.4 in the screened group. Imagine that a hypothetical new trial is conducted to compare mortality from both all causes and colorectal cancer between two groups of equal size, each of which involves the same number of person-years of follow-up as in the control arm of the Minnesota trial. Moreover, suppose that the true effect of screening on colorectal cancer mortality is to reduce colon cancer mortality in the screened group by 50%, whereas screening has no effect on mortality from other causes. The expected all-cause mortality rates would be 183.6 in the control arm and 183.6 – (6.6 x 0.5) = 180.3 in the screened arm. According to the formula given by Rosner (2), such a trial would have only 11% power to detect such a difference in all-cause mortality by use of a two-sided test at the .05 level. Because of sampling variability, there would also be a 31% chance that all-cause mortality would actually be greater in the screened group.

Black et al. assert that "increasing the rigor of the death-review process might help to reduce the effects" of the biases in cause-of-death attribution that they have identified. We agree, and we suspect that, although errors may remain in assessment of cause of death after such a review, the magnitude of the bias produced by those errors will, in most instances, be relatively small. Accepting the possibility of a small bias in cause-specific mortality is, to us, preferable to relying on the presence of a difference in all-cause mortality before concluding that a screening intervention has prevented some deaths. Because it is not generally feasible to do studies that are large enough to reliably document the impact of screening on all-cause mortality, we fear that a number of truly effective cancer screening tests will incorrectly be deemed ineffective if we give undue emphasis to this parameter.

REFERENCES

1 Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst 2002;94:167–73.[Abstract/Free Full Text]

2 Rosner B. Fundamentals of biostatistics. 4th ed. Belmont (CA): Duxbury Press; 1995. p. 603.



             
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