Elsevier

The Lancet

Volume 376, Issue 9754, 20–26 November 2010, Pages 1741-1750
The Lancet

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Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials

https://doi.org/10.1016/S0140-6736(10)61543-7Get rights and content

Summary

Background

High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75–300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour.

Methods

We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data.

Results

In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60–0·96, p=0·02; mortality HR 0·65, 0·48–0·88, p=0·005), but not rectal cancer (0·90, 0·63–1·30, p=0·58; 0·80, 0·50–1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28–0·74, p=0·001; 0·34, 0·18–0·66, p=0·001), but not the distal colon (1·10, 0·73–1·64, p=0·66; 1·21, 0·66–2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20–0·63; 0·24, 0·11–0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36–0·92, p=0·02; 0·47, 0·26–0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61–2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75–300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70–6·05, p=0·15).

Interpretation

Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

Funding

None.

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

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