Familial Bowel Cancer and the Use of aspirin

Of the young adults with thousands of polyps in the colon, all will die, said Professor Burn, if the colon is not removed. These young people with familial adenomatous polyposis are of special interest because they have inherited a faulty version of the APC gene. It is loss of that same gene in a single cell which triggers 30,000 cases of colon cancer in the UK population each year. Anything which slows the disease in the young people with FAP is good for them as it delays the need for surgery and it provides vital information on how to slow or prevent colon cancer in the general population.

A typical patient is Jonathan, a young man whose mother had had a pan-proctocolectomy and had three children, two being cancer gene carriers. One side effect of this is osteomas. Jonathan had two bony bumps on his forehead, making it obvious without needing to test him that he was one of the carriers. People who carry the genes are motivated to help themselves. They know why the cancers happen and are under surveillance, so it should be possible for them to take part in good trials.

In 1993 Professor Burn's unit was given an EU grant for a study called concerted action polyp prevention (CAPP). It is now called Colorectal Adenoma/carcinoma Prevention Programme (CAPP). The first trial, CAPP1, based on carriers of FAP is now complete. A second trial ,CAPP2, based on carriers of a second high risk group known as Hereditary Non Polyposis Colon Cancer has been running for five years and should finish in 2006 Both trials are testing the same interventions, resistant starch and aspirin; resistant starch reaches the colon undigested and there is fermented to short chain fatty acids which are thought to protect against cancer. The second treatment is aspirin; epidemiological studies on bowel adenoma or cancer, and on cancer-associated mortality, show a 50% reduction in the incidence of colorectal cancer with aspirin. There is powerful supportive evidence from laboratory research in human cells and in plants. Salicylate triggers apoptosis in green plants in response to infection, so could salicylates be an essential diet ingredient that triggers cancer cell apoptosis in bowel polyposis?

Professor Burn's trial had a factorial design using starch, aspirin and placebo. Endpoints were estimated on polyp number by endoscopists and using a video recording of rectum. A blinded expert reviewer scored them better, worse, or the same. Also used as an endpoint was the size of the largest polyp seen at endoscopy. Mucosal biopsy-markers of cell proliferation and crypt growth were also noted. There was a secondary analysis of patients who had been on the trial more than a year, on the assumption that they were more compliant.

The biopsy allowed assessment of cytokinetics - the numbers of cells per crypt. Professor Burn also looked at the proliferative zone at the bottom of the crypts in a series of observations on the wall of the gut. Of the 227 randomised, 133 subjects could be analysed. One area examined was bifid crypts: they declined significantly throughout adolescence, after reproducing in large numbers during adolescence. aspirin modestly increased crypt length and increased crypt proliferation. Starch did the opposite: the indigestible supplement significantly reduced the length of the crypts, damping down activity in the colon.

There was no significant reduction in the number of polyps assessed either by endoscopists or on video. However, the difference in the largest polyp measurement was impressive. The placebo groups had bigger polyps than the aspirin groups. After more than a year the biggest impact was in the aspirin-starch group. The polyps were half the size in the aspirin group, a result very encouraging for an effect on cancer.

Other NSAIDs have been used in colon cancer prevention trials. On high doses of celecoxib there was a reduction in polyps. Sulindac will suppress polyps but may not suppress cancer: there has been a case of cancer developing in a bowel with fewer polyps on Sulindac. Giardiello and Winde concluded that Sulindac was of uncertain long term benefit. Gunther Winde has been using rectal suppositories of sulindac and has reported on one patient with very rapidly developing rectal cancer while using them.

In summary, there is very strong epidemiological evidence that aspirin prevents colorectal cancer.Two recently published randomised trials indicate that aspirin suppressed sporadic adenoma formation. CAPP1 has shown aspirin prevents small adenomas from becoming big adenomas in carriers of familial adenomatous polyposis.

The British Familial Cancer records provide a mechanism for setting up long term low cost prevention trials. They can only be done if they are inexpensive. Celecoxib, being much more expensive than aspirin, will never be the answer for numbers needing treatment for the whole of Britain. Professor Burn concluded 'We aren't finished, but we are getting there'.

Professor Peter Elwood, of the University of Wales College of Medicine, has had an interest in aspirin since the 1960s. His team conducted the first randomised controlled trial (RCT) of Aspirin in Cardiovascular Disease, published in 1974. Recently he and Gareth Morgan set up the Welsh aspirin Group to stimulate and coordinate aspirin research in Wales, and to promote the appropriate use of the drug. WAG includes experts from a wide range of disciplines and a major aim of the group focuses on the use of aspirin in cancer prevention. His brief at this meeting was to ask who will do the RCTs of Aspirin and Cancer?