An Aspirin a Day to Prevent Colon CA

Several studies have evaluated the correlation between low-dose aspirin and NSAID use and the development of colorectal cancer. In 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the use aspirin for the prevention of colorectal cancer in most adults.¹ However, there is mounting evidence that daily, long-term aspirin use may prevent colorectal cancer in patients aged 50-69.² Could something as simple as an aspirin a day prevent colon CA?

A recent population-based, case-control study published in the Annals of Internal Medicine by Søren Friis and colleagues examined the potential benefit of low-dose aspirin (75 – 150mg) and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colon cancer.³  The study used data from several Danish health registries (1994 to 2011) from four counties in Northern Denmark. Case patients had a first diagnosis of colorectal cancer, had prescription coverage for at least 5 years prior to diagnosis, were aged 30 to 85 years at the time of diagnosis, and had no previous history of cancer. Ten control patients, who did not use aspirin, were matched to each case patient. The study included 10,280 case patients and 102,800 control patients.  The use of aspirin and NSAIDs were defined according to type, dose, duration, and consistency of use (number of prescription fills). The majority of low-dose aspirin and NSAIDs use in Denmark is prescribed but patients can purchase these products over-the-counter. “Nonuse” was defined as fewer than 2 prescriptions and “ever use” of aspirin or NSAIDs was considered 2 or more prescriptions filled on separate dates. “Continuous use” was defined as overlapping treatment periods from the start of treatment until 1 year before the index date. The baseline characteristics were similar between the two groups but the case patients were less likely to have had a colonoscopy or have used high-dose aspirin, hormone replacement therapy, statins, or antidepressants. The median age of the cases and controls was 69.8 years (IQR 61.9-76.7) and 54.8% were men. Only 7% of patients had diabetes and 19.3% had a history of cardiovascular or cerebrovascular disease.

While ever use was not associated with a reduced risk of colon cancer, the continuous use of low-dose aspirin for more than 5 years was associated with 27% reduction (OR = 0.73) in the incidence of colorectal cancer (Table 1.). There was no information reported on adverse effects but it is well established that aspirin contributes to peptic ulcer disease and gastrointestinal bleeding.

Table 1. Aspirin Use in Study Population

The Friis study has several limitations. First, the rates of colorectal cancer were not reported for the the four Danish counties — so we are unsure whether the rate of colon cancer in these areas are similar to the national average. Without knowing the rate in these counties, we cannot accurately calculate a number needed to treat.  Assuming the annual incidence rate of colorectal cancer in these counties is similar to the national rate of colon cancer in Denmark, which is 40.5 cases per 100,000, the calculated number needed to treat would be approximately 9000.⁶ This is a very high number to prevent one case of colorectal cancer in patients who continuously use aspirin for more than 5 years.  Furthermore, Denmark has a relatively high rate of colorectal cancer; so the benefits of continuous aspirin use would likely be very lower in countries where colorectal cancer is less common. There may be underlying environmental or lifestyle factors in Denmark that contribute to the development of colon cancer that are not present in the United States. While the results of this study adds to the growing body of evidence that suggests that aspirin may prevent colorectal cancer, it is inappropriate to extrapolate the results to other populations.

Further limitations of this study include the lack of information regarding the over-the-counter use of aspirin and NSAIDs.  Case-control studies have inherent limitations due to the uncontrolled nature of the exposure.  The exposure period began at least 5 years before the index date but some patients may have been misclassified as using aspirin or NSAIDs for a shorter duration if they started either medication prior to the start of prescription registration.  Given there were multiple comparisons, a chance finding increases. Lastly, confounding based on colorectal cancer risk factors such as obesity, diet, alcohol use, and family history of colorectal cancer may have influenced the results and can not be ruled out.

A few prospective clinical trials have examined the relationship between aspirin use and the risk of colorectal cancer. A 2013 analysis of data from the Women’s Health Study evaluated the use of alternate-day, low-dose aspirin and its impact on colorectal cancer risk.⁴ Patients in the study took 100 mg of aspirin or placebo on alternating-days. Colorectal cancer was significantly reduced in the aspirin group (HR 0.80 [CI 0.67-0.97]).  In contrast, post-trial follow-up data from the Physician’s Health Study failed to show a benefit from aspirin use with regard to the incidence of colorectal cancer.⁵ Participants received 325 mg of aspirin every other day starting in 1982.  In 1988, the aspirin arm was stopped early and participants elected to receive either aspirin or placebo for the remainder of the study. The analysis found that aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% CI, 0.3 to 1.28) and the relative risk of colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (CI, 0.75 to 1.53).  Both of these studies did not find any benefit from aspirin for the prevention of colorectal cancer in the first ten years of follow up. However, the Women’s Health Study did find a benefit from long term use which suggests that low dose aspirin may reduce the incidence of colorectal cancer after many years of use. Most trials seem to suggest the benefits of aspirin for colon cancer prevention occur after 10 years of use.

A recent systematic review conducted the USPSTF identified fourteen randomized controlled trials and seven prospective cohort studies that assessed the effect of aspirin use on colorectal cancer outcomes in both primary and secondary prevention settings.²  In 4 studies that used aspirin for the primary and secondary prevention of cardiovascular disease (CVD) and followed patients for 20 or more years, the analysis found that aspirin reduced colorectal cancer mortality by slightly more than 30% (RR 0.67, 95% CI 0.52 to 0.86).  The benefits only emerged after 5 years of aspirin use. The analysis also found that aspirin reduced the incidence of colorectal cancer by 40% after ten to nineteen years of follow-up -(RR 0.6, 95% CI, 0.47 to 0.76). The authors conclude that there is now sufficient data to suggest that aspirin decreases colorectal cancer incidence after long-term use.  Proposed recommendations by the USPSTF would now give a grade B recommendation in favor of using aspirin for the primary prevention of both CVD and colorectal cancer is patients age 50-59 years old who have a 10% or greater 10-year risk of CVD,  have a life expectancy at least 10 years, and are at low risk for bleeding.  For those who are age 60-69, it’s a grade C recommendation.

Based on the evidence from the systematic review, it now seems likely that the USPSTF will support the use of aspirin for those at high risk of cardiovascular disease and for the prevention of colorectal cancer. ²  The Friis study, despite it limitations, further supports the long-term, continuous use of low-dose aspirin for the prevention of colorectal cancer.  In the absence of a prospective randomized controlled trial — which would likely require government funding, thousands of subjects, and a decade or more to complete — we can never truly know the benefits and risks of long-term aspirin use for colon cancer prevention.  None-the-less, we favor the use of low-dose aspirin in high risk patients, such as those with polyps or a strong family history of colon cancer, and to individualize therapy for the rest of our patients until more information is available.  Do the benefits outweigh the risks? Should we be recommending aspirin for colorectal cancer prevention?  If so, to whom?  Tell us what you think.