Prevention of progression of duodenal adenomas to cancer in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant disease,
associated with mutations in the APC gene and characterised by the development
of numerous adenomas in the gastrointestinal tract, especially in the large
bowel. When untreated, this will lead to colorectal cancer early in life. A
prophylactic colectomy is the treatment of choice. As a result, patients grow
older and subsequently up to 90% of patients develop adenomas in the duodenum,
with increasing duodenal cancer risk, which at present is the main cause of
death in these patients. Duodenectomy is the only curative treatment for
duodenal cancer, but due to its complexity, mortality and morbidity are high. A
promising future treatment may be chemoprevention of carcinomas by
cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, which has been shown to
slow down or inhibit duodenal or colorectal adenomatosis in patients with FAP.
Normal tissue homeostasis requires a proper balance between cell proliferation
and apoptosis and COX-2 is a key enzyme in these processes. In the
adenoma-carcinoma sequence of FAP, up-regulation of cell proliferation and
down-regulation of apoptosis plays an important role. Since in many sporadic
colon cancer cases, APC mutations are also present, this suggests that the
mechanism of carcinogenesis may have common pathways in sporadic colorectal
cancer and FAP. Strikingly, within the duodenum, adenomas cluster around the
ampulla of Vater, suggesting that luminal factors, such as cytotoxic bile
acids, pancreatic juice or other toxins in bile may trigger duodenal cell
proliferation in patients with FAP. Adjunct to COX-2 inhibitors, treatment with
ursodeoxycholic acid, which has been shown to reduce cytotoxicity of bile, and
may lead to recurrence of colorectal adenomas with high-grade dysplasia, may be
an option in patients with FAP. When toxins (in bile) are involved in
stimulation of adenoma growth, up-regulation of the mucosal detoxification
potential could also be beneficial. Thus, modulation of mucosal (cell
proliferation and apoptosis, COX-2, detoxification enzymes such as glutathione
S-transferases and UDP-glucuronosyltransferases) and luminal (bile) factors may
be of pivotal importance in the search for (new) chemoprevention strategies of
duodenal adenomas and carcinomas in patients with FAP.

In the Netherlands, approximately 500 patients with FAP have been recognized,
who are at high risk for developing duodenal carcinoma. Better insights in the
pathogenesis of duodenal cancer and development of chemoprevention strategies
are of pivotal importance for these patients. In addition, studies on the
interaction of the intestinal content and mucosal cell homeostasis may yield
new insights with respect to FAP related duodenal cancers

1. Chemoprevention trial. A randomized placebo-controlled multicenter clinical
trial will be performed on eighty patients with FAP and duodenal adenomas
(Spigelman stage II and III), by administration of either celecoxib (400 mgbid
) + placebo, or celecoxib (400 mgbid ) + ursodeoxycholic acid (25mg/kg/day) for
6 months. Pre- and post intervention biopsies (two sites: near ampulla and more
distal duodenum) and duodenal bile will be sampled. Also biopsies from adenomas
will be taken. Primary endpoint will be the effect of the intervention on the
number, size and degree of dysplasia of duodenal adenomas. Secondary endpoints
will be the effects of the intervention on mucosal cell proliferation and
apoptosis rates at both sites of the duodenum and in the adenomas, as well as
on expression levels of COX-2 and detoxification enzymes. In addition, pre- and
post intervention bile will be studied with respect to composition,
genotoxicity and cytotoxicity.

2. Observational study. Forty patients with FAP in whom endoscopic inspection
of their duodenum takes place in Nijmegen at least once a year will be included
in this study. Six biopsies of duodenal mucosa near the ampulla, and 6 biopsies
from the more distal duodenum will be taken. In addition, duodenal bile will be
collected. Duodenal biopsies and bile will also be collected from 40 non-FAP
controls, matched for age and gender. Analyses: A) The duodenal mucosa of the
patients will be
compared at two sites with that of non-FAP controls for: rates of cell
proliferation and apoptosis; levels of COX-2 and detoxification enzymes B) Bile
of patients with FAP as well as bile from non-FAP controls will be analysed for
composition and concentration of bile acids and fatty acids. In addition,
genotoxicity and cytotoxicity will be quantified in the bile samples of
patients and controls

The chemoprevention study will be a randomised double-blind placebo
controlled trial with two arms; each arm including at least 40 patients with
FAP. The study design is depicted in Figure 1. Patients with a history of
gastric or duodenal ulcers, a prior allergic reaction on NSAIDs or UDCA or
disturbed renal- or liver functions will be excluded. Moreover patients with
cardiovascular risk factors will also be excluded. No NSAIDs or UDCA may have
been used during enrolment.

An upper gastrointestinal endoscopy will be performed with an oblique
viewing instrument (Olympus TJF-160), at which number and size of duodenal
adenomas will be counted. The procedure will be videotaped and photograph
images will be taken of the ampulla, areas of dense polyposis, and areas of
mild or no disease, for later assessment. The endoscopist will be unaware of
the therapy the patient is receiving. At this endoscopy, 6 biopsies from the
normal appearing mucosa in the papillary region as well as 6 biopsies from the
distal duodenum will be taken. By staining with indigo-carmine normal mucosa
can be differentiated from adenomatous tissue. Moreover, bile will be collected
after a CCK bolus.
The patients will be randomised in two groups. Group I will receive celecoxib,
400 mg twice daily and placebo according to the scheme in Figure 1. Group II
will receive celecoxib 400 mg twice daily and UDCA (25mg/kg body weight) in a
double blind fashion. After six months, a second endoscopy, with collection of
biopsies and bile will be performed (Figure 1). At endoscopy, the size and
number of adenomas will be counted (primary endpoint) as outlined below.

Figure 1. Scheme outlining the chemoprevention study.


Month 1 2 3 4 5 6


Duodenal biopsies x x
Collection of bile x x


Group I
Celecoxib + placebo x x x x x x

Group II
Celecoxib +
ursodeoxycholic acid x x x x x x

All patients will be informed by a Gastroenterologist about the burden and
possibel complicatiions of the duodenoscopy, Moreover all patients wille be
informed about possibel side-effects of the CCk injection to contract the
gallbaldder . Endoscopies will be carreid out by experienced
Gastroenterologists.

* FAP patients in the intervention study are under regular surveillance by
endoscopy already.
* All participants will sign an informed consent.

Risks:

- Minimal risk of perforation and bleeding by taking biopsies (< 0.1%).
- Minimal risk of pancreatitis by administration of CCK-8 (<1%).