An Article We All Had Better Read

Oh dear – the CLAHRC WM Director would so like to think that disease-specific mortality is the appropriate outcome for cancer screening trials, rather than all-cause mortality. But Black and colleagues have published a very sobering article.[1] They found 12 trials of cancer screening (yes, only 12) where both cancer-specific mortality and all-cause mortality are reported. The effect size (in relative risk terms) is bigger for cancer-specific than for all-cause mortality in seven trials, about the same in four, and the other way in one. This suggests that the benefit is greater, even relatively, for cancer-specific than for all deaths. There are two explanations for this – one that the CLAHRC WM Director had thought of, and the other that was new to him.

  1. Investigation and treatment of false positives (including cancers that would never had presented) may increase risk of death as a result of iatrogenesis and heightened anxiety. There is some evidence for this.
  2. According to the ‘sticky diagnosis theory’, once a diagnostic label has been assigned, then a subsequent death is systematically more likely to be attributed to that diagnosis than if that diagnosis had not been made. There is some evidence for this hypothesis too.

And here is the thing – in screening trials a very small proportion of people in either arm of the study die from the index disease. The corollary is that a small mortality increase among the majority not destined to die has a relatively large effect.

So we have done many expensive trials, and implemented large, expensive screening programmes, yet our effects might have been nugatory. And there is a reason why so few trials have all-cause mortality outcomes – the trials have to be long and potential effects on this end-point are small and liable to be lost in the noise. Somewhere there is a ‘horizon of science’ where precision is hard to find, and where tiny biases can swamp treatment effects. At the risk of sounding nihilistic, the CLAHRC WM Director wonders whether cancer screening is such a topic.

— Richard Lilford, CLAHRC WM Director


  1. Black WC, Haggstrom DA, Welch HG. All-Cause Mortality in Randomized Trials of Cancer Screening. J Nat Cancer Instit. 2002; 94(3): 167-73.

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