Cancer Prevention by Aspirin: A New Evaluation of Existing Data

Abstract & Commentary

By William B. Ershler, MD

Synopsis: By a systematic review of observational (case-control and cohort) studies, data regarding aspirin use and cancer risk were compared to data obtained from randomized clinical trials. In general, there was very good correlation regarding reduced risk for several types of cancer and the development of metastatic disease. The analysis provides confidence that observational studies can be of value in addressing the many outstanding questions regarding aspirin and cancer prevention.

Source: Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomized trials. Lancet Oncol 2012;13:518-527.

It has been proposed that aspirin is effective in the prevention of cancer. Data derived from randomized trials of aspirin in prevention of vascular events showed that daily aspirin reduced the incidence of colorectal cancer and several other cancers1 and reduced metastasis.2 However, statistical power was inadequate to establish effects on less common cancers and on cancers in women. Newly designed randomized trials projected to gather data for 20 or more years would be an optimal but impractical methodological approach. However, careful evaluation of existing observational studies might also provide insight. To determine the reliability of data derived from such studies compared to that from randomized controlled trials, Algra and Rothwell performed a systematic evaluation of the effects of aspirin on cancer outcomes from both types of investigation.

For this, the authors searched for case-control and cohort studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. For the observational studies, papers were considered eligible for this analysis if they reported results of case-control or cohort studies of use of aspirin or nonsteroidal anti-inflammatory drugs (NSAID) in the context of cancer development. For the randomized trials, the current analysis required a randomization to aspirin vs no aspirin and a mean scheduled duration of treatment for 4 years or more. Of the large existing literature, 150 case-control studies and 45 cohort studies were considered appropriate for the final analysis.

Associations were pooled across studies by meta-analysis and stratified by duration, dose, and frequency of aspirin use and by stage of cancer. They went on to compare associations from observational studies with the effect of aspirin on 20-year risk of cancer death and on metastasis in the recent reports of randomized trials.

In case-control studies, regular use of aspirin was associated with reduced risk of colorectal cancer (pooled odds ratio [OR] 0.62, 95% confidence interval [CI] 0.58–0.67), and there was good agreement with the effect of daily aspirin use on 20-year risk of death due to colorectal cancer from the randomized trials (OR 0.58, 95% CI 0.44–0.78). Similarly consistent reductions were seen in risks of esophageal, gastric, biliary, and breast cancer. Overall, estimates of effect of aspirin on individual cancers in case-control studies were highly correlated with those in randomized trials (r = 0.71, P = 0.0006), particularly with regard to gastrointestinal cancers. Estimates of effects in cohort studies were similar when analyses were stratified by frequency and duration of aspirin use, were based on updated assessments of use during follow-up, and were appropriately adjusted for baseline characteristics. Although fewer observational studies stratified analyses by the stage of cancer at diagnosis, regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR 0.69, 95% CI 0.57–0.83), but not with any reduction in regional spread (OR 0.98, 95% CI 0.88–1.09), consistent again with the findings in randomized trials.

Commentary

Although cancer prevention is high priority, cancer prevention studies are methodologically difficult and very expensive. With regard to aspirin, we have known for decades that this drug has potential for reducing cancer development and/or spread on the basis of its effects on platelet function,3 inhibition of COX-2,4 or by other pro-apoptotic effects.5-7 Yet, until recently there have been few randomized cancer prevention trials. Recently, aspirin was shown to reduce colorectal cancer in patients with the precancerous Lynch syndrome,8 but cancer prevention within the general population has not been adequately demonstrated by such methodology. That stated, recent analysis of data from trials in which aspirin was used for stroke or other vascular disease prevention have now clearly been shown to reduce the risk of certain cancers, particularly in men.1

The data reported in the current report are welcome because they indicate the value of case-control and careful cohort study analyses as they demonstrate very good correlation with observations from the randomized trials. Accordingly, such methodology will be useful in addressing the large number of outstanding questions, such as dose, schedule, and duration; which tumors are likely to be prevented; and whether aspirin could reduce the development of metastases when applied in an adjuvant setting.

References

1. Rothwell PM, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602-1612.

2. Rothwell PM, et al. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet 2012;379:1591-1601.

3. Gasic GJ, et al. Anti-metastatic effect of aspirin. Lancet 1972;2:932-933.

4. Doherty GA, Murray FE. Cyclooxygenase as a target for chemoprevention in colorectal cancer: Lost cause or a concept coming of age? Expert Opin Ther Targets 2009;13:209-218.

5. Elwood PC, et al. Aspirin, salicylates, and cancer. Lancet 2009;373:1301-1309.

6. McIlhatton MA, et al. Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells. Cancer Res 2007;67:10966-10975.

7. Ruschoff J, et al. Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci U S A 1998;95:11301-11306.

8. Burn J, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial. Lancet 2011;378:2081-2087.