The results are from a 10-year follow-up and were published in The Lancet magazine
Lynch syndrome is associated with an increased risk of colorectal cancer. Randomized controlled trials demonstrated a reduced risk of adenomas in regular aspirin users, but none were primarily aimed at preventing colorectal cancer. The CAPP2 study – conducted by international researchers and published in The Lancet – evaluated the use of aspirin in primary prophylaxis for colorectal cancer related to Lynch syndrome after a planned 10-year follow-up.
This is a randomized double-blind study in which 861 patients from 43 international centers worldwide (707 [82%] in Europe, 112 [13%] in Australasia, 38 [4%] in Africa and four [<1%] of the Americas) with Lynch Syndrome were randomly assigned to receive 600 mg daily of aspirin or placebo. Cancer incidence results have been monitored for at least 10 years after recruitment, with English, Finnish and Wales participants being monitored for up to 20 years.
The primary objective was the number, size and histological stage of the development of colorectal cancer. The analysis was by intention to treat and by protocol.
Between January 1999 and March 2005, 937 eligible patients with Lynch Syndrome, with a mean age of 45 years, started treatment, of which 861 agreed to be randomly assigned to the aspirin (50%; 427) or placebo group (50 %; 434). They were followed for an average of 10 years, approaching 8500 person-years.
Of the 427 participants who received aspirin, 40 (9%) developed colorectal cancer, compared with 58 (13%) of the 434 who received placebo.
Cox proportional hazards analysis with intention to treat revealed a significantly reduced risk rate (HR) of 0.65 (95% CI 0.43-0.97; p = 0.035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate of 0.58 (0.39–0.87; p = 0.0085). The analyzes per protocol restricted to the 509 that reached the 2-year intervention had an HR of 0.66 (0.34-0.91; p = 0.019) and an incidence rate of 0.50 (0.31-0, 82; p = 0.0057).
For non-colorectal cancers related to Lynch Syndrome, no analysis by intention to treat (HR = 0.94, 95% CI 0.59-1.50; p = 0.81) or per protocol (HR = 0.75, 0,42-1,34; p = 0,33) showed any significant effect of aspirin chemoprevention. Separate analyzes of 10 and 20 years are less consistent in the estimates between analyzes, with no evidence of a cancer prevention effect in general.
For endometrial cancer, the most common cancer of Lynch syndrome after colorectal cancer, the observation of only 7 cases among women using aspirin compared to 17 using placebo is suggestive, but not conclusive, of a protective effect of aspirin (HR = 0.50; 95% CI 0.22–1.11; p = 0.09).
For all cancers of Lynch Syndrome, the intention-to-treat analysis showed no significant effect (HR = 0.75; 95% CI 0.66-1.03; p = 0.881) with similar results for the analysis of the incidence rate. However, the analysis by protocol showed a reduced risk among those taking aspirin (HR = 0.63, 0.43–0.92; p = 0.018).
There was no significant evidence of any effect of aspirin on cancer risk in Lynch syndrome. In the data available for the second decade, there were 5 types of cancer in the aspirin group and 12 in the placebo group (HR = 0.66, 95% CI 0.27–1.19; p = 0.13).
The incidence of colorectal cancer started to diverge about 5 years after starting aspirin treatment and this lower incidence of cancer was maintained throughout the observation period. This pattern is similar to that observed in the long-term follow-up of participants randomly assigned to aspirin in cardiovascular disease prevention trials.
Adverse events during the intervention phase between the aspirin and placebo groups were similar and no significant difference in adherence between the groups was found.
The CAPP2 study tested the effect of a dose of aspirin (600 mg / day), providing evidence that this dose was effective in the long-term prevention of colorectal cancer. However, it has not yet been determined whether this is the best dose of aspirin taking into account the balance between the benefit in reducing the risk of cancer and the risk of gastrointestinal bleeding.
Brun, BD et al. Double Blind Randomised Placebo Controlled Trial of Cancer Prevention With Aspirin In Hereditary Colorectal Cancer (Lynch Syndrome): Planned 10 Year Follow-Up And Registry Based 20 Year Data In The CAPP2 Study. The Lancet, 2020, 13;395(10240):1855-1863.