Aspirin associated with colorectal cancer prevention in Lynch syndrome

Administering two aspirin per day to patients with hereditary bowel cancer reduced their risk for colorectal cancer by more than half within 5 years, according to data from the Colorectal Adenoma/carcinoma Prevention Programme-2 trial.

"We set out to try and see if aspirin would prevent cancer, and today we are announcing that it does," Prof. Sir John Burn, professor of clinical genetics, Newcastle University and honorary consultant clinical geneticist at Newcastle Hospitals NHS Foundation Trust, United Kingdom, said during a press conference.

In 1999, Burn and Prof. Timothy Bishop, professor of genetic epidemiology and head of the section of epidemiology and biostatistics at the University of Leeds, United Kingdom, began the Colorectal Adenoma/carcinoma Prevention Programme-2 (CAPP2) study to determine whether aspirin has a chemopreventive effect against bowel cancer in those with Lynch syndrome. The study included 861 patients recruited until 2005.

Participants were randomly assigned in a 2-by-2 factorial fashion to 600 mg aspirin; aspirin placebo; or 30 g resistant starch or starch placebo for up to 4 years. According to Burn, in 2007, they reported there was no difference between the two groups.

"We didn't have many cancers at that stage, only polyps. The prevailing wisdom was that, if we didn't prevent polyps, we didn't prevent cancer," he said.

Giving it time

Anticipating the possibility that the protective effects of aspirin could be delayed, Burn and colleagues continued their study, determined to see whether there was a post-trial effect after 10 years. Per-protocol and intention-to-treat analyses were performed. The primary endpoint was colorectal cancer development.

The mean follow-up was 55.7 months, at which time 18 of 427 patients assigned to aspirin and 30 of 434 assigned to aspirin placebo developed primary colorectal cancers. The HR for time to first colorectal cancer was 0.63 (95% CI, 0.35-1.13), according to the intention-to-treat analysis. The incidence rate ratio, according to Poisson regression, was 0.56 (95% CI, 0.32-0.99), taking into account multiple primary events.

Among participants who completed 2 years of intervention, 10 of the 258 assigned to aspirin and 23 of the 250 assigned to aspirin placebo developed cancer, according to Burn. The HR for those who completed 2 years of intervention was 0.41 (95% CI, 0.19-0.86), and the incidence rate ratio was 0.37 (95% CI, 0.18-0.78).

A secondary planned analysis looked at the effect of aspirin on other Lynch syndrome cancers. Eighteen participants developed endometrial cancers, five of whom were randomly assigned to aspirin and 13 to aspirin placebo.

Thirty-eight participants developed Lynch syndrome cancers other than colorectal; 16 were assigned to placebo and 22 to aspirin placebo. For those assigned to aspirin, the HR was 0.63 (95% CI, 0.34-1.19) and the incidence rate ratio was 0.63 (95% CI, 0.34-1.16) compared with aspirin placebo. According to the per-protocol analysis, the HR for those assigned to aspirin for 2 years or more was 0.47 (95% CI, 0.21-1.06) and the incidence rate ratio was 0.49 (95% CI, 0.23-1.05).

"Despite regular colonoscopy, almost one in 14 participants not taking aspirin in CAPP2 developed colorectal cancer in less than 5 years, emphasizing the need for additional prevention strategies," Burn and colleagues wrote in their study. "Our results, taken in conjunction with recent research, provide a basis for recommendation of aspirin chemoprevention in Lynch syndrome as standard of care."

CAPP3 on the horizon

During the press conference, Burn said he and Bishop are launching a website for CAPP3 to recruit 3,000 people with Lynch syndrome worldwide. The plan is to randomly assign participants to a mini-dose of aspirin (75-100 mg), a standard dose of aspirin (300 mg) or two standard doses of aspirin. In addition, a parallel method will be tested by inviting gene carriers to purchase their own aspirin and contact a local study representative and keep them informed of their progress. According to Burn, they should be able to track thousands of people.

In an accompanying editorial, Andrew T. Chan, MD, MPH, division of gastroenterology at Massachusetts General Hospital and Channing Laboratory at Brigham and Women's Hospital at Harvard Medical School, and Scott M. Lippman, MD, department of thoracic/head and neck medical oncology and clinical cancer prevention at The University of Texas MD Anderson Cancer Center, said the results "provide a strong rationale for routine use of aspirin in individuals with Lynch syndrome."

However, they said this analysis does not allow a definitive conclusion for the standard regulatory approval of aspirin's ability to prevent colorectal cancer. "The data strongly support routine use of aspirin, however, for patients with Lynch syndrome as an adjunct to intensive cancer surveillance," they wrote.

For more information:

• Burn J. Lancet. 2011;doi:10.1016/S0140-6736(11)61049-0.
• Chan AT. Lancet. 2011;doi:10.1016/S0140-6736(11)61216-6.

Disclosure: The chief investigator received a fee as a speaker at a Bayer workshop in 2010. Dr. Chan reports consulting for Bayer HealthCare and Millennium Pharmaceuticals. Dr. Lippman reports no relevant financial disclosures.

Andrew H. Ko

The lifetime risk of colorectal cancer in patients with Lynch syndrome may be upward of 50%, depending on the gene that is mutated. Thus, intensive screening, surveillance and prevention for such individuals — who comprise approximately 3% to 5% of all colorectal cancer cases — is of paramount importance. This CAPP-2 study — a well-designed, double-blind, randomized trial — clearly demonstrates the effectiveness of higher-dose aspirin (600 mg daily) in reducing the risk of colorectal cancer in this at-risk patient population. Interestingly, it took a prolonged follow-up period, out to 10 years, before a significant risk reduction in the primary endpoint — invasive cancer — was observed, suggesting that aspirin, which was administered in this study for a mean of 2 years, may have a delayed protective effect against the development of cancer. In summary, these data are compelling, and physicians should discuss the potential benefits of aspirin with all carriers of Lynch syndrome — with, of course, equal time devoted to counseling them of the possible associated risks of long-term use.

– Andrew H. Ko, MD

HemOnc Today Editorial Board member

Disclosure: Dr. Ko did not report any relevant financial disclosures.

Follow HemOncToday.com on Twitter.