Fast track — ArticlesLong-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials
Introduction
Colorectal cancer is the second most common cancer in developed countries, with a lifetime risk of 5% and about 1 million new cases and 600 000 deaths worldwide each year.1 Most colorectal cancers develop from adenomas,1, 2 and trials have shown that aspirin3, 4, 5, 6, 7 and cyclo-oxygenase-2 enzyme (COX-2) inhibitors8, 9, 10 reduce the recurrence by about 20%. However, with a mean follow-up of only 2–3 years these trials were unable to establish any effect on colorectal cancer. Prevention with COX-2 inhibitors is not feasible because of an increased risk of vascular events, but long-term use of aspirin is feasible.11 On long-term follow-up of two large trials of high-dose aspirin (≥500 mg daily) versus control for prevention of vascular events, daily aspirin for about 5 years reduced risk of colorectal cancer after a latent period of about 10 years.12 However, the greater risk of bleeding complications in patients on high-dose aspirin11 might limit its potential for primary prevention of colorectal cancer.
The risk of major bleeding on aspirin is dose-dependent,11 but the effect of dose on risk of colorectal cancer is uncertain. First, although 81–325 mg daily is effective in secondary prevention of adenomas,3, 4, 5, 6, 7 the likelihood of malignant transformation of adenomas that develop despite these doses is uncertain. Second, there is evidence that aspirin reduces the development of tumours by inhibition of COX-2,13, 14, 15, 16 which needs higher doses than inhibition of COX-1.17 Third, most observational studies have only shown strong associations with high-dose aspirin.12, 18 Finally, two large trials of low-dose alternate day aspirin (100 mg and 325 mg)19, 20 in primary prevention of vascular disease showed no effect on risk of colorectal cancer during 10-year follow-up. Given the delay from early development of an adenoma to presentation with colorectal cancer,21, 22 follow-up might have been insufficient. However, aspirin also failed to prevent colorectal adenomas in the Women's Health Study,19 suggesting that the dose might have been insufficient or that giving it on alternate days is ineffective.
We therefore did long-term follow-up of three large trials of daily low-dose aspirin (75–300 mg) in prevention of vascular events,23, 24, 25 and pooled these data with our previously reported long-term follow-up of two trials of high-dose aspirin,12, 26, 27 to establish the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose and duration of trial treatment. Given evidence that aspirin might have a greater effect on cancer of the proximal colon than on cancer of the distal colon or rectum,28, 29, 30, 31 which would have implications for combination with sigmoidoscopic screening,32 we also stratified our analyses by site of cancer.
Section snippets
Trials
We studied trials of aspirin versus control in the UK or Sweden in the 1980s and early 1990s, because these two countries had centralised death certification established by the 1980s (and cancer registration in the UK) making these data available for research. Eligible trials had to have recruited at least 1000 participants and to have a median scheduled treatment period of at least 2·5 years (since the effect of aspirin on risk of colorectal cancer increased with treatment duration at the high
Results
Table 1 shows the baseline clinical characteristics of patients at randomisation in the five trials studied, and gives details of scheduled treatment and of post-trial follow-up. A total of 14 033 patients were randomly assigned to aspirin or control in TPT, SALT, UK-TIA, and BDAT.
Duration of follow-up was extended to 17–20 years in TPT, 21–27 years in UK-TIA, 18–23 years in SALT, and 22–23 years in BDAT. Follow-up to 17 years had been done in the Dutch TIA trial. 391 patients (172 in BDAT, 141
Discussion
In a previous report of data from UK-TIA and BDAT,12 we showed that the 20-year incidence of colorectal cancer was reduced by about 30% by treatment with high-dose aspirin for about 5 years. Our new report adds several important observations. First, we have shown the same effect for 75–300 mg doses of aspirin, with 75 mg daily being as effective as higher doses. Second, we had statistical power to show this effect of aspirin more reliably than previously and particularly to show a statistically
References (52)
- et al.
Colorectal cancer
Lancet
(2005) - et al.
Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial
Gastroenterology
(2003) - et al.
Aspirin and folic acid for the prevention of recurrent colorectal adenomas
Gastroenterology
(2008) - et al.
A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas
Gastroenterology
(2006) - et al.
Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies
Lancet
(2007) - et al.
Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas
Gastroenterology
(1994) - et al.
Once-only flexible sigmoidoscopy in prevention of colorectal cancer: a multicentre randomised controlled trial
Lancet
(2010) - et al.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris
Lancet
(1992) - et al.
Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study
Lancet
(2005) - et al.
Reliability of cancer registration data in Scotland, 1997
Eur J Cancer
(2002)
Registration of colorectal cancer in Scotland: an assessment of data accuracy based on review of medical records
Public Health
Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer
Lancet
Localisation of cyclooxygenase-2 in human sporadic colorectal adenomas
Am J Pathol
Cyclooxygenase-2 expression in right- and left-sided colon cancer: a rationale for optimisation of cyclooxygenase-2 inhibitor therapy
Clin Colorectal Cancer
Colorectal cancer deaths as determined by expert committee and from death certificate: a comparison—The Minnesota Study
J Clin Epidemiol
Adenomatous polyps of the colon
N Engl J Med
A randomized trial of aspirin to prevent colorectal adenomas
N Engl J Med
A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer
N Engl J Med
Aspirin for chemoprevention of colorectal adenomas: meta-analysis of the randomised trials
J Natl Cancer Inst
Celecoxib for the prevention of sporadic colorectal adenomas
N Engl J Med
Celecoxib for the prevention of colorectal adenomatous polyps
N Engl J Med
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients
BMJ
Aspirin and risk of colorectal cancer in relation to expression of COX-2
N Engl J Med
Aspirin use and survival after diagnosis of colorectal cancer
JAMA
Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence—data from a randomized clinical trial
Cancer Epidemiol Biomarkers Prev
Aspirin
Circulation
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