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The CAPP Studies
Colorectal cancer is second only to lung cancer as a cause of cancer death. Up to 20% of cases are attributed to genetic predisposition, with 5% due to mutations in the APC gene or the mismatch repair genes causing familial adenomatous polyposis (FAP) and Lynch Syndrome (HNPCC) respectively.
Colon cancer is one of the most common inherited cancer syndromes known. The genes known to be involved in colorectal cancer are MSH2 and MSH6 both on chromosome 2 and MLH1 on chromosome 3. Normally the protein products of these genes help to repair mistakes made in DNA replication. If the MSH2, MSH6 and MLH1 proteins are mutated and therefore don't work properly, the replication mistakes are not repaired, leading to damaged DNA, and in this case colon cancer.
Dietary factors have been observed to be a major reason why so many people develop this disease in developed countries. It has been observed that regular users of non-steroidal anti-inflammatory drugs (such as aspirin) are at a significantly reduced risk.
The CAPP studies aim to try and prove if these observations are true.
CAPP1 - FAP
CAPP1 commenced in 1993 in 34 European countries and closed recruitment in 2002. Carriers of familial adenomatous polyposis (FAP) were recruited to a randomised controlled trial of 600mg aspirin and/or 30g resistant starch. In total 206 FAP carriers received treatment. Completed data on 133 subjects, followed for 1 year, have now been analysed. Neither intervention resulted in a significant reduction in polyp number as assessed either by the endoscopist or blinded review of rectal videos. The mean size of largest polyps was, however, significantly reduced in the aspirin only group (p=0.01). A secondary analysis using data from those who had stayed more than one year, suggesting higher compliance. Here, both aspirin alone and the combined aspirin/resistant starch group achieved significance (p=0.04 and p=0.03).
Those treated with starch had significantly shorter crypts (p<0.0001,95% CI 0.87,0.96); those treated with aspirin had longer crypts and a 37% increase in crypt cell proliferation. These data suggest that aspirin and resistant starch are protective against cancer but with different modes of action. Aspirin may act later, preventing progression of small adenomata.
FAP carriers are an ideal study group since their molecular defect is shared with a majority of sporadic colorectal cancers and any FAP chemoprevention strategy is likely to have general relevance. Such studies need sustained infrastructure investment as planned by the new International Society for Gastrointestinal Hereditary Tumours - InSiGHT.
CAPP2 - HNPCC
There is good evidence that people who take aspirin are less likely to develop colon cancer than those who don't take aspirin. This information is about people in the general population who probably don't have HNPCC (Hereditary non polyposis colon cancer). We do not know if aspirin will protect people who carry an HNPCC gene. CAPP2 will answer this question.
In some countries, eating a lot of starchy food appears to reduce the risk of developing polyps and bowel cancer. We believe that starch that reaches the bowel without being digested is the most important. This is called resistant starch. As this starch is broken down in the bowel it seems to make the bowel wall less prone to cancer.
These two facts are the basis for the CAPP2 project. We are testing aspirin and starch to discover if they do make a difference to polyp growth.
We hope to recruit at least 1000 people with the HNPCC gene across the world who are having regular bowel checks. They will be asked to take 2 aspirin tablets and add 2 packets of starch to their food each day.
To be eligible for CAPP2 participants must be either a proven gene carrier or belong to a recognised HNPCC family based on the modified Amsterdam criteria and have been treated for an HNPCC related cancer.
CAPP2 began recruiting in March 1999 and to date we have almost 700 people who have taken our interventions. We hope to complete enrolment by the autumn of 2005 and to have a final analysis of the data by the end of 2007.
Relevant publications:
- Burn J, Chapman PD, Bishop DT, Mathers J; Diet and cancer prevention: the concerted action polyp prevention (CAPP), Proc Nutr Soc. 1998 May; 57(2):183-6.
- Mathers JC, Mickleburgh I, Chapman PC, Bishop DT, Burn J.; Can resistant starch and/or aspirin prevent the development of colonic neoplasia? The Concerted Action Polyp Prevention (CAPP) 1 Study. Proc Nutr Soc. 2003 Feb; 62(1):51-7
- Mathers JC, Burn J.; Nutrition in cancer prevention; Curr Opin Oncol. 1999 Sep; 11(5):402-7
- CAPP1 abstract