ArticlesEffect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies
Introduction
Colorectal cancer is the second most common cancer in developed countries, with a lifetime risk of 5%, and about 1 million new cases worldwide every year.1 Most colorectal cancers develop from adenomas (the so-called adenoma-carcinoma sequence1, 2), and several randomised trials have shown that aspirin3, 4, 5 and cyclo-oxygenase-2 enzyme (COX-2) inhibitors6, 7, 8 reduce the recurrence of adenomas by about 40% in patients with previous adenomas or colorectal cancer. However, these trials had only 2–3 years follow-up and were therefore unable to establish any effect of aspirin or COX-2 inhibitors on colorectal cancer. The likelihood of malignant transformation of adenomas that develop despite aspirin or COX-2 inhibitors versus those that are prevented is uncertain. However, such information is important because, although up to 40% of people in developed countries have one or more colorectal adenomas by age 60 years, less than 10% of these adenomas progress to cancer.9 Moreover, the secondary prevention of adenomas by short-term treatment with aspirin or COX-2 inhibitors cannot be assumed to be maintained on long-term treatment, nor can we assume that the same effect would be seen in primary prevention. Indeed, no effect of aspirin on diagnosis of colonic adenomas (2510 vs 2578, relative risk 0·97, 95% CI 0·92–1·02) was reported during an average of 10 years follow-up in the Women's Health Study randomised trial of low dose aspirin versus placebo.10
Long-term use of COX-2 inhibitors is not recommended because of adverse effects on vascular risk,11, 12 but long-term treatment with aspirin is feasible in patients with or without vascular disease.13, 14 Aspirin has been shown to reduce experimentally-induced colonic malignancies in animals,2 and some observational studies have reported a reduced incidence of colorectal cancers in regular users of aspirin (or non-steroidal anti-inflammatory drugs [NSAID]),15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 although there is substantial heterogeneity in apparent effect between studies,61, 62 and the two most recent large cohort studies reported no effect.46, 59 Experience with other observational risk associations has highlighted the need for randomised trials in proving causation,63, 64 and two large trials of aspirin in primary prevention showed no effect on colorectal cancer during 10 years of follow-up.10, 65 However, a latency of more than 10 years would be expected, considering that the delay between the initiation of development of an adenoma, the point at which aspirin is believed to act,9 and presentation of colorectal cancer is estimated to be 10–15 years.66, 67
We therefore studied the effects of aspirin on the subsequent incidence of colorectal cancers in two large randomised trials of aspirin versus no aspirin in which reliable post-trial follow-up data of more than 20 years were available. We also did a systematic review of relevant observational studies to assess whether, with appropriate stratification by duration and extent of exposure, findings for colorectal cancer were consistent with the randomised studies and, if so, what additional conclusions could be drawn about the likely effects of dose and regularity of aspirin, other NSAID, long-term continuous treatment, and the effect of age, sex, race, and family history, and site or aggressiveness of cancer.
Section snippets
Randomised trials
Two randomised trials of aspirin versus no aspirin began in the UK around 1980: the British Doctors Aspirin Trial68 and the UK Transient Ischaemic Attack Aspirin Trial (UK-TIA trial).69 The methods and results of these trials have been published previously.68, 69 Sustained long-term post-trial follow-up was available for all cancers via the UK National Cancer Registry. Our follow-up study was approved by our institutional research ethics committee.
In the British Doctors Aspirin Trial, 5139 male
Randomised trials
5139 individuals (mean [SD] age 61·6 [7·0] years; 31% smokers) were randomised in the British Doctors Aspirin Trial and 2449 (mean [SD] age 60·3 [9·0] years; 73% male, 53% smokers) in the UK-TIA trial. All recruits to the British Doctors Aspirin Trial were treated for 5–6 years (mean 5·7, SD 0·89) and 99% of survivors completed a final questionnaire at the end of scheduled follow up in 1984.68 Patients in the UK-TIA trial were treated for 1–7 years and all were accounted for at the end of the
Discussion
The randomised studies provide good evidence that at least 300 mg aspirin a day for about 5 years is effective in the primary prevention of colorectal cancer, with a 10-year latency of effect that is consistent with the apparent effects in the observational studies and with our understanding of the adenoma-carcinoma sequence.1, 9, 66, 67 The greater effect of aspirin allocation on incidence of colorectal cancer in the double-blind placebo controlled UK-TIA trial than in the open-label British
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