CORRESPONDENCE

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

Colin B. Begg, Peter B. Bach

Affiliation of authors: C. B. Begg, P. B. Bach, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Correspondence to: Colin B. Begg, Ph.D., Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: beggc{at}mskcc.org).

In their interesting and provocative review of 12 large randomized cancer screening trials, Black et al. (1) draw attention to the fact that the direction of the effect of screening on cancer-specific mortality is not consistent with the direction of the effect of screening on all-cause mortality in many of the trials. The authors point out that in "five of the 12 trials, differences in the two mortality rates went in opposite directions," and they use this seemingly disturbing observation to suggest that bias in assessing cause of death is responsible for this lack of concordance.

We do not dispute that there are ambiguities inherent in the ascertainment of cause of death, nor do we disagree that exposure to screening may potentially bias the ascertainment process. Yet the evidence presented by the authors (lack of concordance) is entirely predictable on the basis of random variation in the absence of any bias. Because these screening trials were all conducted on healthy populations, occurrences of death from causes other than the cancer under investigation vastly outnumber the cancer-specific deaths. Therefore, relatively small random fluctuations in the overall death rates easily swamp the differences in cancer-specific mortality.

We have re-analyzed the data by using the death frequencies derived from the same source publications cited by Black et al., with the exception of the Health Insurance Plan (HIP) trial, for which the numbers were extracted from the Cochrane Library (Table 1Go). Consider, for example, the Funen study (2) of colorectal cancer screening. In this study, there were 454 deaths attributed to colorectal cancer, and the screened group experienced 44 fewer deaths than the control group. There were 12 077 deaths attributed to other causes, and these deaths should be randomly distributed between the two groups in the absence of bias. In the paradigm described by Black et al., discordance will occur if the number of deaths from causes other than colorectal cancer in the screened group exceeds by more than 44 the number observed in the control group. At the outset, this event is not unlikely. In fact, given the disparity of 44 deaths attributed to colorectal cancer, the approximate probability that discordance would occur in this trial by chance alone is 34%, as determined by the tail area of the normal score corresponding to z = d/t1/2 (where d = the difference in the number of cancer-specific deaths and t = the total number of deaths attributed to other causes). The corresponding probabilities of discordance for the other studies range from 21% to 48%. Viewed together, the average probability of discordance in these studies was 33%, so in a sample of 12 studies, such as those in Black et al., we would expect to observe about four discordant studies by chance alone.


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Table 1. Concordance probabilities for cancer screening trials
 
These results confirm the dilemma that has always faced investigators when designing cancer-screening trials. Although many methodologists would argue that all-cause mortality is ultimately the end point of interest, cancer-specific mortality has been used because of its much greater statistical power. An important measure of the utility of a surrogate end point of this nature is the probability of concordance with the real end point (3). The study by Black et al. shows the unfortunate fact that this probability is not especially high for cancer screening trials.

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 Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348:1467–71.[Medline]

3 Begg CB, Leung DH. On the use of surrogate endpoints in randomized trials (with discussion). J R Stat Soc [Ser A] 2000;163:15–28.



             
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