title: Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial.
abstract: BACKGROUND
  Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP.
  
  
  METHODS
  Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post-intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction.
  
  
  RESULTS
  In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1-3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1-2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo.
  
  
  CONCLUSIONS
  Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect. The benefit of long term use of celecoxib for duodenal cancer prevention needs to be weighed against the (risk of) adverse events.
  
  
  BACKGROUND
  http://ClinicalTrials.gov, identifier NCT00808743.
authors.affiliation: Departments of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands. b.vanheumen@mdl.umcn.nl
authors.forename: Bjorn W H
authors.initials: BW
authors.lastname: van Heumen
authors.forename: Hennie M J
authors.initials: HM
authors.lastname: Roelofs
authors.forename: M Elisa
authors.initials: ME
authors.lastname: Vink-Börger
authors.forename: Evelien
authors.initials: E
authors.lastname: Dekker
authors.forename: Elisabeth M H
authors.initials: EM
authors.lastname: Mathus-Vliegen
authors.forename: Jan
authors.initials: J
authors.lastname: Dees
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Koornstra
authors.forename: Alexandra M J
authors.initials: AM
authors.lastname: Langers
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: Ellen
authors.initials: E
authors.lastname: Kampman
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
authors.forename: Fokko M
authors.initials: FM
authors.lastname: Nagengast
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000068579:Celecoxib; D002756:Cholagogues and Choleretics / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004386:Duodenum / Q000473:pathology*; D005260:Female; D006801:Humans; D007417:Intestinal Polyps / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D002756:Cholagogues and Choleretics; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D014580:Ursodeoxycholic Acid; D000068579:Celecoxib
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