In early duodenal disease, the risks of surgery far outweigh the risk of malignant progression. There are also those patients who are unsuitable for surgery even if they have advanced disease, due to other co-morbid conditions, and those lesions which cannot be removed endoscopically for technical reasons. Consequently, pharmacological treatment options have become a focus of ongoing research.
In 1983, sulindac (a non-selective cyclo-oxygenase inhibitor) was shown to be effective in FAP (Waddell et al. 1983), reducing the number of colorectal adenomas by greater than 50%, as well as in the retained rectal segment after colectomy. However, it did not prevent initial adenoma development in FAP (Giardiello et al. 2002). Further studies have since confirmed that non-steroidal anti-inflammatory drugs (NSAIDs) are beneficial in both sporadic and FAP-associated colorectal adenomas due to their anti-proliferative effects. Table 1.6 provides a brief summary of their mechanisms of action.
COX DEPENDENT MECHANISMS
COX INDEPENDENT MECHANISMS Inhibition of COX-1 & COX-2
enzymes
Block conversion of arachidonic acid to prostaglandins
Inhibition of prostaglandin synthesis
Disruption of cellular functions involving prostaglandins such as angiogenesis and cell
proliferation.
COX-2 inhibition may induce apoptosis, via inhibition of PGE2
NB: COX-1 expressed in most tissues, COX-2 expressed in response to growth factors, lipopolysaccharide, cytokines, mitogens and tumour promoters.
High doses of NSAIDs induce apoptosis in COX-1 or COX-2 deficient cells
Prostaglandins do not rescue cells from apoptosis
Apoptosis induced via membrane bound and mitochondrial pathway Other targets for NSAIDS:
Beta-catenin
Proteins of the Bcl-2 family
TGF-beta signalling
Peroxisome proliferator activated receptor (PPAR) family
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However, these results have not been reproduced in the duodenum. Nugent et al (1993b) found no statistically significant difference in patients on 400mg sulindac daily after 6 months, although they did reveal a statistically significant effect on duodenal polyps less than 2mm. The authors reported that sulindac treatment actively reduced mucosal proliferation in both the duodenum and rectum. Cell proliferation is a well validated marker of tumour formation in the gastrointestinal tract, and an increase in the cell proliferation rate has been shown to equate with a rise in the rate of tumour formation in the colon in both animal and human studies. However the fall in mucosal proliferation was associated with significant polyp regression in the rectum, but not the duodenum. Another study of 8 patients with residual small periampullary polyps treated with 300mg sulindac daily for at least 10 months, found that no patient showed regression of adenomas (Richards et al. 1997). In addition, side effects meant that sulindac was discontinued in 3 patients.
Celecoxib, a selective cyclo-oxygenase-2 inhibitor (COX-2) has been shown to reduce the number of colorectal adenomas by 25% (Steinbach et al. 2000) and is the only agent to have been shown to be of benefit in duodenal adenomas in FAP. At a dose of 400mg twice daily, celecoxib was found to have a statistically significant effect on duodenal polyp number, but not total polyp area, with a 14% reduction in the number of polyps after 16 months compared to placebo (Phillips et al. 2002). Although COX-2 inhibitors are reported to have fewer gastrointestinal related side effects than non-selective NSAIDs, there are significant concerns about the reported cardiovascular side effects. Meta-analysis has shown rofecoxib to have an increased risk of stroke or myocardial infarction (Wallace et al. 2001) but showed that celecoxib at a dose of 200mg per day was not associated with a higher risk of cardiovascular disease. At present, data is being collected to determine the long term side effects of higher dose celecoxib use in FAP. The Mallorca group guidelines conclude that the use of celecoxib might be justifiable for patients with
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severe duodenal polyposis (Spigelman stage III-IV), because the endoscopic and surgical treatment in such cases are associated with significant complications, and that COX-2 inhibitors should only be considered in those patients with no cardiovascular risk factors until more data is available.
Other agents that have been used in small trials include H2 receptor anatagonists (rantidine) (Wallace et al. 2001) and calcium with calciferol (Seow-Choen et al. 1996). None of these trials found a significant reduction in the duodenal polyp number over the study period. A recently published randomised, placebo controlled trial described the use of an enteric coated formulation of eicosapentaenoic acid (EPA), as the free fatty acid EPA-FFA in patients with a retained rectum after ileorectal anastomosis in FAP (West et al. 2010). EPA is an omega-3 polyunsaturated fatty acid which has been shown to have anticolorectal cancer activity in vitro and in pre-clinical models, although the precise mechanism of its antineoplastic action remains unclear. Polyp number, size and overall polyp burden all decreased significantly after treatment with EPA-FFA 2g daily compared with placebo over a 6 month period. This exciting development should now prompt future studies of this agent in duodenal adenomatosis. Oestrogen receptors (ERs) have been suggested as having a pivotal role in preventing malignant transformation of colon epithelial cells in humans (Weyant et al. 2001). Thus vegetable rich diets may prevent CRC due to their high content of phytoestrogens (Bjork et al. 2001). Phytoestrogens include a variety of vegetable derived compounds with oestrogen- like chemical structure, and a recent study evaluating the effect of a patented blend of phytoestrogens and indigestible and insoluble fibres (Eviendep, CM&D Pharma Limtied, UK) has been shown to reduce the number of duodenal polyps in FAP patients with IPAA (Calabrese et al. 2013). The polyp number in the duodenum reduced by 33% and size was reduced by 51%, however this was a small study totalling 11 patients.
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1.8 AimsThe current study had threefold aims:
a) To investigate the impact of chromoendoscopy on the characterisation of duodenal adenomatosis in patients with MAP and compare this to patients with FAP to establish effects on Spigelman staging and clinical management.
b) To initiate a long term prospective study of duodenal disease in MAP and describe disease characteristics via a cross sectional study using initial data
c) To characterise the somatic mutational landscape in duodenal adenomatosis in MAP and FAP using genomic approaches