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Familial adenomatous polyposis: efficacy of Celexoxib in duodenal adenomatosis


In the past decades, prophylactic colectomy to prevent development of colorectal cancer substantially has improved prognosis in patients with familial adenomatous polyposis ( FAP ). The mortality pattern has changed and duodenal cancer now is the main cancer-related cause of death. Lifetime risk of duodenal adenomas approaches 100%, and approximately 3-7% of patients develop duodenal cancer.
As duodenal cancer in patients with familial adenomatous polyposis has a poor prognosis, the clinical challenge is to identify patients with high-risk duodenal adenomas and intervene before progression to cancer occurs.
Prophylactic duodenectomy may offer a prolonged disease-free interval, but is associated with substantial morbidity and mortality.
Therefore, chemoprevention would be highly desirable to postpone or even avoid the necessity for radical surgery.

Cyclooxygenase ( COX ) inhibiting non-steroidal anti-inflammatory drugs ( NSAIDs ) have been investigated extensively as potential chemopreventive drugs.
COX-2 is induced in inflammatory and tumorigenic settings. Overexpression of COX-2, as found in colorectal adenomas and carcinomas, was linked to reduced apoptosis, enhanced cell growth, tumour angiogenesis, tissue invasion, and metastasis.
Treatment with the COX-2 inhibitor Celecoxib ( Celebrex ) resulted in regression of colorectal adenomas in patients with familial adenomatous polyposis, as well as in significant decrease in sporadic colorectal adenomas.

For duodenal polyposis, the value of COX inhibiting agents is not yet established. Sulindac showed regression of small duodenal polyps in patients with FAP, but had no benefit in controlling periampullary polyposis.
The significant reduction in duodenal polyp density after 6 months of treatment with high dose Celecoxib in patients with familial adenomatous polyposis with clinically significant disease was promising.

Unfortunately, suitability of COX-2 inhibitors for long-term use is subject of discussion, due to increased risks of adverse cardiovascular events. Combining Celecoxib with other potentially effective drugs could be a more effective strategy.

A candidate drug is Ursodeoxycholic acid ( UDCA ), for a number of reasons. First, the clustering of adenomas around the ampulla of Vater suggests that bile plays a role in duodenal adenomatosis. In in vitro models of human colorectal cancer cells, UDCA significantly reduced cytotoxicity of secondary bile acids, and Celecoxib and UDCA co-treatment inhibited cell growth in colorectal adenoma cells from a patient with familial adenomatous polyposis.
Second, clinical studies showed chemopreventive effects of UDCA on development of colorectal neoplasms, in patients with sporadic colorectal adenomas, and in patients with ulcerative colitis ( UC ) and primary sclerosing cholangitis ( PSC ).
Third, UDCA was found to suppress COX-2 levels in a rat model of colonic carcinogenesis, suggesting an alternative pathway for COX-2 inhibition.
Finally, in a mouse model of familial adenomatous polyposis, Sulindac and UDCA co-treatment showed synergistic effects in the prevention of intestinal adenomas.

Based on these findings, a randomized controlled trial has examined the effect of Celecoxib plus UDCA co-treatment, in comparison to Celecoxib plus placebo, on duodenal adenomatosis in patients with familial adenomatous polyposis.
Researchers hypothesized that adding UDCA to the treatment with Celecoxib results in a further reduction of duodenal polyp density.

High dose UDCA co-treatment completely counteracts the positive effect of Celecoxib, namely the reduction of duodenal polyp density in patients with familial adenomatous polyposis. It still needs investigation whether low dose UDCA co-treatment does have a beneficial effects in this respect.
The benefit of long term use of Celecoxib for duodenal cancer prevention in patients with familial adenomatous polyposis needs to be weighed against the potential risk of cardiovascular adverse events. ( Xagena )

van Heumen BWH et al, Orphanet Journal of Rare Diseases 2013, 8:118

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