Aspirin and Colorectal Cancer

Aspirin, otherwise known as acetylsalicylic acid (ASA), is a medication that has been used for decades for its anti-inflammatory properties. Although ASA has many indications, recently its potential role in the prevention of colorectal cancer (CRC) has been of particular interest. ASA is a member of the nonsteroidal anti-inflammatory drug (NSAID) family and works by inhibiting cyclooxygenase-1 (COX-1). This COX-1 inhibition eventually leads to downstream inhibition of platelet aggregation by reducing the production of thromboxane A2. The COX-1 and COX-2 pathways are also implicated in the production of prostaglandins, which ASA has also been shown to reduce.

In addition to their traditional functions, prostaglandins have also been associated with cell proliferation, tumor angiogenesis, reduced immune surveillance of cancer cells, and less apoptosis.¹ This occurs through various pathways, though phosphatidylinositol 3-kinase (PI3K) signaling specifically has been studied in colorectal cancer.^1,2 Despite the fact that the exact mechanisms through which ASA could prevent CRC are still unknown, there are many clinical studies supporting ASA’s use for this indication. Results from studies attempting to link ASA to a reduction in the risk of developing CRC have been mixed so far.

There are randomized controlled trials (RCTs), systematic reviews, and meta-analyses that have evaluated ASA in CRC. When evaluating these studies, it is important to consider the ASA dosing parameters across groups, the duration of each study, each study’s patient population (eg, were high-risk patients included?), and whether detection of adenomas were included or omitted in study results.

In general, it appears that many of the positive studies have found between an approximately 15% to 40% reduction in the incidence of colonic adenomas and CRC.^3-5 This finding is not true of every study and is relatively variable on the ASA dosing and duration. It appears that longer use of ASA is needed in order to see a reduced risk of CRC, which also isn’t seen for many years after the ASA use. The dosing in most of the studies ranges from 81 mg to 1200 mg daily. There appears to be somewhat of a dose-response curve, with higher doses generally having a greater impact on risk reduction, but the elevated doses are also connected to more adverse events.

A systematic review conducted by Dube and associates found between a 13% to 28% reduction in colonic adenomas in patients taking ASA.³ The definition of “regular” use and dosages of ASA varied between studies. The studies on ASA usage in CRC demonstrated that some of the beneficial effects of administration with ASA (as it relates to CRC) do not appear until after at least a year of treatment. The doses of ASA seen across the studies ranged from 81 mg to 325 mg per day, however, the most significant reduction of CRC risk was seen in a cohort study where patients received at least six 325-mg tablets per week. This review also highlighted two RCTs in which ASA had no significant effect on CRC incidence, however, the 6 cohort studies evaluated in the review showed a 22% risk reduction in CRC incidence.

Flossmann and colleagues conducted a systematic review and found that within the RCTs evaluated, a 36% reduction in the incidence of CRC was seen in patients who were taking ASA (at least 300 mg daily) for at least 5 years.⁴ This benefit was only seen after 10 years of use. Algra and Rothwell found between a 38% and 42% reduction in CRC risk depending on whether the study in question was a case-controlled study or RCT, respectively.⁵

Interestingly, the authors also looked at whether or not ASA had an effect on the metastatic activity of CRC. They determined ASA was associated with a 31% reduced proportion of CRC with distant metastases, however, there was no significant difference in the rates of regional spread.

Before starting ASA, it is important to perform a detailed medication reconciliation as well as review any potential contraindications. Because research on the potential benefit of ASA in CRC prevention is ongoing, it is important to remind patients that the medication has not been approved by the US Food and Drug Administration for a cancer prevention indication.

References

1. Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol. 2005;23(2):254-266.
2. Xiaoyun L, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-1606.
3. Dubé C, Rostom A, Lewin G, et al. U.S. Preventive Services Task Force. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):365-375.
4. Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial.  Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies. Lancet. 2007;369(9573):1603-1613.
5. 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(5):518-527.