Aspirin and Cancer Prevention
Abstract & Commentary
By Howell Sasser, PhD, Research Review Coordinator, Manila Consulting, McLean, VA. Dr. Sasser reports no financial relationships relevant to this field of study.
Synopsis: Aspirin is a common preventive agent for cardiovascular disease. Its use for cancer prevention has been studied for many years, but meta-analytic results were lacking until now. An international group reports findings from analyses of short- and long-term outcomes of aspirin use for cancer prevention. Key findings are a reduced risk of short-term incidence of and death from cancer, and a reduced risk of long-term incidence of some kinds of cancer and distant metastasis. With a few caveats, these results strengthen the case for aspirin as a tool in cancer prevention.
Sources: 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 Published online March 21, 2012.
Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials. Lancet Published on-line March 21, 2012.
The role of aspirin in the prevention of cardiovascular disease events is well known.1,2 The recommendation of daily low-dose aspirin (< 100 mg/day) is common, though not without clinical concern because of the potential side effect of bleeding events.3 This and other issues have motivated an ongoing body of observational and interventional research representing a large number of people. This resource has now been recruited for secondary analyses of aspirin and cancer risk.
Aspirin has been hypothesized to influence cancer incidence, metastasis, and mortality by altering platelet function, by inhibiting the cyclooxygenase-II (COX-II) enzyme's role in inflammation, or by promoting programmed cell death (apoptosis).4,5,6 These relationships have been explored in laboratory settings since at least the late 1960s. The difficulty in showing such a mechanism in vivo relates to the relative rarity of cancer especially any specific type of cancer and to the modest size of the expected protective effect of aspirin. These were among the challenges addressed and largely overcome in recent articles published in the Lancet by an international group of researchers.7,8
Briefly, the group published the results of analyses of the short-term (up to 10 years) and long-term (up to 20 years or more) effects of regular aspirin treatment, in which they combined and summarized the findings of many individual studies. The analysis of short-term effects used data from clinical trials designed to assess the effect of aspirin in preventing vascular events, with cancer cases reported as incidental findings. The analysis of long-term effects was based on original studies, both clinical trials and observational designs, focusing directly on aspirin and cancer risk.
The short-term analysis included trials testing aspirin regimens of any dose, in the absence of any other antiplatelet therapy, although a "background of anticoagulation" was permitted. It excluded those with treatment durations of less than 90 days. Those receiving aspirin and not receiving it were pooled into groups and analyzed using appropriate meta-analytic methods. The outcomes of interest were cancer incidence, death from cancer, and non-vascular death (included because some trials specified the cause of death only as vascular or non-vascular in origin).
There was a reduced risk of death both when the analysis was limited to known cancer deaths (odds ratio [OR] = 0.85, P = 0.008), and when non-vascular deaths were included as well (OR = 0.85, P = 0.005). When deaths were grouped by duration of follow-up (0-2.9 years, 3-4.9 years, > 5 years), there was a reduced risk with aspirin in all intervals, but it became statistically significant only after 5 years of follow-up. There was also a reduced incidence of cancer among those treated with aspirin (hazard ratio = 0.88, P = 0.017), and a similar pattern of stronger protection with longer duration of treatment was noted.
The long-term analysis cast a wider net, including both observational and experimental studies published between 1950 and 2011, but only those in which aspirin's effect on cancer was the primary focus. The definition of aspirin use was necessarily different across study types. In the clinical trials, an aspirin/no aspirin comparison was possible. In the observational studies, categories of "Any aspirin" and "Maximum reported aspirin" were used when it was not possible to determine the dose or frequency of aspirin use. A study might qualify under more than one method of categorization. A number of individual cancer types were analyzed separately, of which colorectal cancer was numerically the largest. The outcomes of interest were cancer incidence and metastasis. Studies were pooled by type (clinical trial, case-control, cohort, or nested case control) and analyzed with meta-analytic methods.
There was a statistically significant reduction in the risk of colorectal cancer across all study types and almost all definitions of aspirin use (risk reductions between 13% and 49%, P-values between 0.012 and 0.0001). There were also significant reductions in biliary, esophageal, gastric, and breast cancers with any aspirin use seen in the observational studies. The numbers of cases in the clinical trials, and for other kinds of cancer, were often too small to permit stable estimation of risk. Aspirin use was associated with a reduced risk of distant metastasis (OR = 0.69, P < 0.0001), but not more local spread of cancer.
Taken as a whole, these results are important for a number of reasons. First, they include information from numerous studies done over many years. This limits the impact of study-specific conditions or secular changes that might be difficult to recognize, let alone control for, in an individual study. Second, they show generally good agreement between the findings of observational and experimental research in this area. This serves to validate the results of the much more numerous observational studies, enabling us to rely on them more than would otherwise be the case. Third, they show that at least over the long term, use of aspirin of any dose (and perhaps even with less than daily frequency) confers some protection, even if it is not as great as that seen with daily use.
There are, however, a few limitations in these studies worth noting. The short-term studies were not originally designed to focus on cancer. This may have had an impact on the quality of their collection of cancer data and certainly limits their precision whenever specific causes of death were not recorded. The heterogeneity of dosing in the clinical trials, and the uncertainty about both the amount and frequency of aspirin use in the observational studies makes it difficult to draw conclusions about what to recommend to patients. The potential benefit of aspirin in prevention of adverse health events must be balanced against the risk of bleeding. In all of the studies, the possibility exists that participants used "unprescribed" over-the-counter aspirin, although if anything this should weaken the apparent associations.
These findings strengthen the case for regular use of aspirin in the prevention of cancer. It appears to confer at least a modest degree of protection without a large increase in the risk of side effects. As with any other preventive strategy, patients should be cautioned that aspirin is only one part of a complete medical and lifestyle program. It should not be used to offset other modifiable risk factors. Used realistically, however, it does appear to be a valuable tool in the promotion of health and prevention of disease.
References
1. Hennekens CH, et al. Aspirin as a therapeutic agent in cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circ 1997;96:2751-2753.
2. U.S. Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Int Med 2009;150:396-404.
3. Berger JS, et al. Aspirin for the primary prevention of cardiovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295:306-313.
4. Gasic GJ, et al. Anti-metastatic effect of aspirin. Lancet 1972;300:932-933.
5. Wang D, Dubois RN. Prostaglandins and cancer. Gut 2006;55:115-122.
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. 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 Published online March 21, 2012.
8. Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials. Lancet Published online March 21, 2012.
Aspirin is a common preventive agent for cardiovascular disease. Its use for cancer prevention has been studied for many years, but meta-analytic results were lacking until now.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content