Hereditary forms of
colorectal cancer account for less than 5 % of
colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of
carcinogenesis.
Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and
Lynch syndrome or Hereditary Non-Polyposis
Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of
chemoprevention trials. There has been a longstanding interest in non-steroidal
anti inflammatories in FAP where trials have shown regression of
polyps with the "
pro drug"
sulindac and the selective
COX2 inhibitors though impact on long-term
cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design,
aspirin and
resistant starch or fermentable fibre.
Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to
short-chain fatty acids including
butyrate which have anti-
cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive
aspirin (600 mg
as 2 tablets/d) and/or 30 g
as 2 sachets/d in a 1:1 blend of potato
starch and high
amylose maize
starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased
polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (
aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest
polyp detected tended to be smaller in the
aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest
polyp in the
aspirin versus non-
aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009
Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600 mg enteric coated
aspirin and/or 30grams of the
resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic
neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and
polyp removal, 48 recruits developed CRC. Of these, 18 received
aspirin and 30 received AP; the HR for CRC for
aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary
colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect:
IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took
aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the
IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS
cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and
IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and
IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the
aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or
ulcers in the
aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend
aspirin to all
Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses.