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Aspirin to prevent colorectal cancer: time to act? Editorial
  The Lancet, Early Online Publication, 22 October 2010
Robert Benamouzig aEmail Address, Bernard Uzzan b a Department of Gastroenterology, Avicenne Hospital, Bobigny 93009, France b Department of Pharmacology, Avicenne Hospital, Bobigny 93009, France
In The Lancet today, Peter Rothwell and colleagues1 present the 20-year follow-up of five pooled randomised trials,2-6 which assessed the effect of aspirin on colorectal cancer incidence and mortality, and focused on dose, scheduled duration of treatment, and site of tumour. The study of 14 033 patients used data from death certificates in the UK and Sweden, and from cancer registries in the UK. During the 20-year follow-up, aspirin reduced long-term risk of colon cancer (incidence hazard ratio [HR] 0·76, 95% CI 0·60-0·96, p=0·02; mortality HR 0·65, 0·48-0·88, p=0·005) with a latent period of 7-8 years between aspirin intake and its preventive effect. Aspirin doses that were higher than 75 mg per day showed no additional benefit, but doses of 30 mg per day seemed to be less effective. The investigators previously showed a similar effect of aspirin in randomised trials and in case-control or cohort studies, but after only 10 years of use.7 In today's study, aspirin reduced cancer risk in the proximal colon by 55%, but not in the distal colon. 5-year therapy with aspirin reduced subsequent risk of proximal colon cancer by about 70%.
Rothwell and colleagues' study provides original information. First, it provides an extremely long follow-up (20 years) of patients treated with aspirin for about 5 years in randomised, double-blind, placebo-controlled trials, except for the British Doctors Aspirin Trial5 (open-control group) or the Dutch TIA Aspirin Trial6 (283 mg vs 30 mg of aspirin, both daily, with no untreated group). Aspirin reduced colorectal cancer incidence and mortality. Data from randomised trials for this issue are scarce. The US Physicians' Health Study8 randomised 22 071 men to aspirin 325 mg or placebo every other day for 5 years; the risk of colorectal cancer was similar in both groups. In a larger trial, aspirin 100 mg on alternate days did not prevent colorectal cancer in women.9 Second, the 27% overall decrease in long-term incidence of colorectal cancer by lower-dose aspirin was greater than the 17% reduction in adenomas noted in short-term trials, but consistent with the 28% decrease in advanced adenomas in these trials.10 Third, by contrast with several case-control and cohort studies, Rothwell and colleagues' study found a similar reduction in colorectal cancer incidence with lower (75 mg per day) and higher (300-1200 mg per day) doses of aspirin. Fourth, the preventive effect of aspirin predominated on proximal cancers, but this subgroup analysis relied on small numbers. Only one randomised preventive study, which was restricted to serrated polyps, showed similarly that the effect of aspirin predominated on proximal lesions (40-50% reduction) with no effect on distal lesions.11 If confirmed, this original finding might present a strong argument for the addition of aspirin chemoprevention to screening sigmoidoscopy.
Today's study has several limitations. First, colorectal cancer was not the primary outcome in any of the trials included. Additionally, the choice of studies seemingly relied more on practical than scientific reasons. Second, the investigators reported specific mortality and not overall mortality, and did not assess mortality related to aspirin side-effects. In a systematic review, aspirin reduced colorectal cancer incidence, especially when used for more than 10 years, but with a dose-related increase in gastrointestinal complications.12 Whether the digestive-tract complications of aspirin are dose-related, especially from 75 mg to 300-500 mg per day, is still controversial. Third, these side-effects, especially digestive-tract bleeding, might have allowed earlier diagnosis of cancer in aspirin users via additional colonoscopies (the distribution of which was unknown between aspirin and control groups), although such an effect was not observed in Rothwell and colleagues' study. Fourth, there were important proportions of withdrawals in the original studies. Such withdrawals seem unavoidable in long-term clinical trials. Fifth, patients in the trials were mostly men with cardiovascular risk (men only in two trials), thus, no conclusions can be made about women and patients with no cardiovascular risk. The mechanisms of colon carcinogenesis might differ between cardiovascular and other patients-eg, because of increased tobacco consumption. Finally, after completion of the randomised periods of the trials, all patients were exposed to aspirin, which would have underestimated its benefits.
No randomised trial is currently exploring the effect of aspirin on colorectal cancer. In a prospective cohort study of 1279 men and women, regular aspirin use after colorectal cancer diagnosis was associated with a reduced risk of cancer-specific and overall mortality, specifically in patients whose initial tumour overexpressed COX-2.13
This interesting study could incite clinicians to turn to primary prevention of colorectal cancer by aspirin, at least in high risk-populations. Specific guidelines for aspirin chemoprevention would be the next logical step.
We declare that we have no conflicts of interest.
1 Rothwell PM, Wilson M, Elwin C-E, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 201010.1016/S0140-6736(10)61543-7. published online Oct 22.
2 Meade TW, Wilkes HC, Stirling Y, Brennan PJ, Kelleher C, Browne W. Randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study. Eur Heart J 1988; 9: 836-843.
3 The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345-1349.
4 Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044-1054.
5 Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313-316.
6 The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-1266.
7 Flossmann E, Rothwell PMfor the British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369: 1603-1613.
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9 Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005; 294: 47-55.
10 Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst 2009; 101: 256-266.
11 Wallace K, Grau MV, Ahnen D, et al. The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum. Cancer Epidemiol Biomarkers Prev 2009; 18: 2310-2317.
12 Dube C, Rostom A, Lewin G, et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the US Preventive Services Task Force. Ann Intern Med 2007; 146: 365-375.
13 Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009; 302: 649-658.
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