Aspirin Reduces Colorectal Cancer Occurrence in Patients with Lynch Syndrome: Implications for Cancer Prevention

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Long-term follow-up of Lynch syndrome patients who completed 2 years of treatment (aspirin or placebo) on the CAPP2 colorectal cancer prevention trial revealed a significant reduction in colorectal cancer development. This was the first large-scale colon cancer prevention trial using aspirin as an intervention. Implications for the prevention of sporadic colon cancer remain conjectural, however tempting it is to extrapolate these findings to the general adult population.

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

Long-term observational studies have shown that risk of colorectal cancer is significantly reduced among regular users of aspirin.1 Although randomized controlled trials have shown reduced risk of adenomas,2,3 before the current study none had employed prevention of colorectal cancer as a primary endpoint. Nevertheless, in a meta-analysis of long-term data from five randomized trials of cardiovascular prevention, aspirin reduced the 20-year risk of colorectal cancer by 24% and of associated mortality by 35%.4 The Colorectal Adenoma/Carcinoma Prevention Program trial 2 (CAPP2) was designed to determine the antineoplastic effects of aspirin and/or a resistant starch in carriers of Lynch syndrome (hereditary nonpolyposis colon cancer [HNPCC]) with the primary outcome being the occurrence of colorectal cancer. The current report describes the long-term follow-up of participants randomly assigned to aspirin or placebo.

In the CAPP2 trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. The primary endpoint was development of colorectal cancer, and secondary outcomes included the development of other Lynch syndrome cancers including endometrial cancer. Analysis was by intention to treat and per protocol.

The trial included 861 participants who were randomly assigned to aspirin or placebo. At a mean follow-up of 55.7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to placebo). The time to first colorectal cancer including all enrolled subjects (by intent-to-treat analysis) showed a hazard ratio (HR) of 0.3 (95% confidence interval [CI] 0.35-1.13, P = 0.12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32-0.99, P = 0.05). For participants completing 2 years of intervention (258 aspirin, 250 placebo), per-protocol analysis yielded an HR of 0.41 (0.19-0.86, P = 0.02) and an IRR of 0.37 (0.18-0.78, P = 0.008). During the treatment phase, adverse events did not differ between aspirin and placebo groups. During the post-intervention phase, no data had been collected on adverse events.

Commentary

HNPCC (Lynch syndrome) is the most common inherited form of colorectal cancer. It results from germline mutations in mismatch repair genes that confer a high lifetime risk of colorectal (70%) and other cancers, including those of the uterus, small intestine, and ovaries.5

Thus, 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer. This is a remarkable finding and corroborates the potential role of aspirin in cancer prevention. Certainly, for those with Lynch syndrome, the findings present a strong rationale for aspirin treatment. Such patients are currently managed by frequent colonoscopies (every 1 or 2 years) and the risk of colorectal cancer approaches 6% per decade.6 The CAPP2 study also revealed a reduction of other Lynch syndrome tumors, including those arising in the small intestine and endometrium, tumors for which routine screening is more problematic.

Are the findings of CAPP2 applicable to the more common sporadic colorectal cancer? There remain concerns regarding potential toxicity of long-term aspirin use. However, adverse events in this trial were not different between those on aspirin or placebo. Furthermore, with the well-appreciated vascular benefits in addition to the reduction in colon cancer deaths derived from the studies primarily investigating cardiovascular endpoints, a case could be argued for routine use of aspirin. It would seem unlikely that a long-term randomized trial of aspirin or placebo with colon cancer as the primary outcome will be forthcoming. Thus, the data available, including that from CAPP2 and from the prior studies, argue that such should be considered on an individualized basis, based upon other medical conditions, risks, etc. Certainly there remain a number of major unanswered questions, none the least of which are what dose of aspirin and for how long?

References

1. Cuzick J, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international consensus statement. Lancet Oncol 2009;10:501-507.

2. Burn J, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 2008;359:2567-2578.

3. Cole BF, et al. Aspirin for the chemoprevention of colorectal adenomas: Meta-analysis of the randomized trials. J Natl Cancer Inst 2009;101: 256-266.

4. Rothwell PM, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010;376:1741-1750.

5. Lindor NM, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: A systematic review. JAMA 2006;296:1507-1517.

6. Vasen HF, et al. One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 2010;138: 2300-2306.