Trial Information

A Two-Arm Chemoprevention Trial in Familial Adenomatous Polyposis Coli Patients Using the Purified Free Fatty Acid, Eicosapentaenoic Acid

It has been found that people who consume a large amount of oily fish tend to have a lower
risk of developing colon cancer. This is thought to be due to the omega-3 fatty acids
present in oily fish, one of which is EPA. The effect of taking a 99% pure form of EPA (2g
per day) compared with placebo capsules on the number and size of polyps in the rectum over
a six month period will be investigated.

FAP is an inherited susceptibility to diffuse colorectal adenomas and colorectal carcinoma,
occurring in close to 100% of unresected colons. It is caused by a germline mutation in the
APC gene located in the long arm of chromosome 5. To prevent cancer development it is
recommended that patients with FAP undergo colectomy with ileo-anal or ileo-rectal
anastomosis (or colectomy and end-ileostomy) at a socially convenient time before polyp
progression to malignancy and before the age of 25. Patients with the attenuated FAP
phenotype, often associated with mutations at the 5' terminus (exon 4 and proximally), have
fewer polyps and may often delay colectomy. Patients with an ileo-rectal anastomosis are
still susceptible to polyp formation in the remaining rectal stump and require 6 monthly
check-ups with a flexible sigmoidoscope with removal of any polyps that develop. Therefore,
an effective chemopreventative agent with a favourable side-effect profile would be of
benefit to FAP patients with ileo-rectal anastomosis (IRA) and recurrent rectal polyps in
addition to young adults who prefer to delay colectomy. If such an agent were to be
effective in FAP patients in the prevention of colonic polyps, it may also be of benefit to
the larger population of patients with sporadic colorectal adenomatous polyps who are also
at risk of colorectal cancer.

Colorectal polyps are thought, at least in part, to arise from an imbalance in the levels of
cell proliferation and apoptosis (natural cell death) in the colonic mucosa. It has been
suggested that omega-3 polyunsaturated fatty acids (PUFAs) in fish oil can manipulate the
high levels of colonic-mucosal cell proliferation rates associated with colonic adenomas.

The rationale for this trial is based on the increasing evidence linking inflammatory
processes and the development of a number of cancers, including bowel cancer. This has
focused attention on the role of inflammatory mediators in the development of cancer. In
particular, the family of eicosanoids (including 2-series prostaglandins, 4-series
leukotrienes and thromboxanes) produced through conversion of the omega-6 PUFA, arachidonic
acid, via cyclo-oxygenase-2 (COX-2) is believed to contribute to the physiological processes
of inflammation and the development of tumours. Prostaglandin E2, a product of the
conversion of arachidonic acid via the COX-2 pathway, has been implicated in tumourigenesis
through:

1. promotion of angiogenesis

2. anti-apoptotic properties

3. increasing expression of matrix metalloproteinases and hence the ability of a tumour
cell to undergo metastasis

4. altering the cytokine expression profile of cells.

The class of eicosanoid synthesised will depend on the PUFA substrate. Whilst arachidonic
acid is converted to 2-series prostaglandins and 4-series leukotrienes, EPA is converted to
3-series prostaglandins and 5-series leukotrienes. Overall, the latter eicosanoids are less
potent as inflammatory mediators than those derived from arachidonic acid.

Increasing daily intake of EPA, the omega-3 PUFA analogue of arachidonic acid, alters the
balance between the cell content of these fatty acids. This results in reduced production
of the more active inflammatory/tumourigenic products of arachidonic acid metabolism. This
is supported by the results of recent work at St George's Hospital Medical School, London.
In patients with a history of colonic adenomas, daily dosing with a highly purified,
free-fatty acid form of the EPA produced a significant reduction in cell proliferation and
increase in apoptosis in the colonic mucosa. This preparation of EPA has the proprietary
name "Alfa" and is referred to here as EPA 99%.

This proposed study will be based upon the randomised, placebo-controlled National Cancer
Institute sponsored study in which three groups of FAP patients were assigned to one of two
doses of celecoxib (a COX-2 inhibitor) or placebo. The results showed a reduction in the
polyp burden of the group taking the higher (400mg twice daily (bd)) dose. However, there is
evidence to suggest that COX-2 inhibitors carry significant potential for side-effects.
Adopting a similar design, EPA 99% will be substituted for celecoxib in this randomised,
placebo-controlled trial, comparing 2g EPA 99% to placebo, with reduction in polyp burden as
the primary objective.