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Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial.

van Heumen BW, Roelofs HM, Vink-Börger ME, Dekker E, Mathus-Vliegen EM, Dees J, Koornstra JJ, Langers AM, Nagtegaal ID, Kampman E, Peters WH, Nagengast FM - Orphanet J Rare Dis (2013)

Bottom Line: Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy.No changes in secondary outcomes were observed.Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands. b.vanheumen@mdl.umcn.nl

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.

Trial registration: http://ClinicalTrials.gov, identifier NCT00808743.

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Box-Whisker plots of intention-to-treat and per-protocol analysis. Intention-to-treat analysis of mean score of change in duodenal polyp density comparing duodenoscopic recordings pre- and post-intervention with either celecoxib & UDCA (group A) or celecoxib & placebo (group B): clinical deterioration in group A (n=17, Wilcoxon Signed Rank, p=0.014), clinical improvement in group B (n=15, Wilcoxon Signed Rank, p=0.029); difference in mean score between groups statistically significant (Mann–Whitney U, p=0.011). Per-protocol analysis: clinical deterioration in group A (n=12, Wilcoxon Signed Rank, p=0.271), clinical improvement in group B (n=11, Wilcoxon Signed Rank, p=0.004); difference in mean score between groups statistically significant (Mann–Whitney U, p<0.001). UDCA = ursodeoxycholic acid.
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Figure 2: Box-Whisker plots of intention-to-treat and per-protocol analysis. Intention-to-treat analysis of mean score of change in duodenal polyp density comparing duodenoscopic recordings pre- and post-intervention with either celecoxib & UDCA (group A) or celecoxib & placebo (group B): clinical deterioration in group A (n=17, Wilcoxon Signed Rank, p=0.014), clinical improvement in group B (n=15, Wilcoxon Signed Rank, p=0.029); difference in mean score between groups statistically significant (Mann–Whitney U, p=0.011). Per-protocol analysis: clinical deterioration in group A (n=12, Wilcoxon Signed Rank, p=0.271), clinical improvement in group B (n=11, Wilcoxon Signed Rank, p=0.004); difference in mean score between groups statistically significant (Mann–Whitney U, p<0.001). UDCA = ursodeoxycholic acid.

Mentions: In the intention-to-treat analysis, clinical deterioration (n=17, median= −0.2, range: -0.6-+0.4) in duodenal polyp density was observed in group A (Wilcoxon Signed Rank, p=0.014), receiving celecoxib & UDCA, while clinical improvement (n=15, median=0.6, range: -0.5-+1.0) was observed in group B (Wilcoxon Signed Rank, p=0.029), receiving celecoxib & placebo (Figure 2). The difference in mean score of change in duodenal polyp density was statistically significant between groups (Mann–Whitney U, p=0.011).


Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial.

van Heumen BW, Roelofs HM, Vink-Börger ME, Dekker E, Mathus-Vliegen EM, Dees J, Koornstra JJ, Langers AM, Nagtegaal ID, Kampman E, Peters WH, Nagengast FM - Orphanet J Rare Dis (2013)

Box-Whisker plots of intention-to-treat and per-protocol analysis. Intention-to-treat analysis of mean score of change in duodenal polyp density comparing duodenoscopic recordings pre- and post-intervention with either celecoxib & UDCA (group A) or celecoxib & placebo (group B): clinical deterioration in group A (n=17, Wilcoxon Signed Rank, p=0.014), clinical improvement in group B (n=15, Wilcoxon Signed Rank, p=0.029); difference in mean score between groups statistically significant (Mann–Whitney U, p=0.011). Per-protocol analysis: clinical deterioration in group A (n=12, Wilcoxon Signed Rank, p=0.271), clinical improvement in group B (n=11, Wilcoxon Signed Rank, p=0.004); difference in mean score between groups statistically significant (Mann–Whitney U, p<0.001). UDCA = ursodeoxycholic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750541&req=5

Figure 2: Box-Whisker plots of intention-to-treat and per-protocol analysis. Intention-to-treat analysis of mean score of change in duodenal polyp density comparing duodenoscopic recordings pre- and post-intervention with either celecoxib & UDCA (group A) or celecoxib & placebo (group B): clinical deterioration in group A (n=17, Wilcoxon Signed Rank, p=0.014), clinical improvement in group B (n=15, Wilcoxon Signed Rank, p=0.029); difference in mean score between groups statistically significant (Mann–Whitney U, p=0.011). Per-protocol analysis: clinical deterioration in group A (n=12, Wilcoxon Signed Rank, p=0.271), clinical improvement in group B (n=11, Wilcoxon Signed Rank, p=0.004); difference in mean score between groups statistically significant (Mann–Whitney U, p<0.001). UDCA = ursodeoxycholic acid.
Mentions: In the intention-to-treat analysis, clinical deterioration (n=17, median= −0.2, range: -0.6-+0.4) in duodenal polyp density was observed in group A (Wilcoxon Signed Rank, p=0.014), receiving celecoxib & UDCA, while clinical improvement (n=15, median=0.6, range: -0.5-+1.0) was observed in group B (Wilcoxon Signed Rank, p=0.029), receiving celecoxib & placebo (Figure 2). The difference in mean score of change in duodenal polyp density was statistically significant between groups (Mann–Whitney U, p=0.011).

Bottom Line: Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy.No changes in secondary outcomes were observed.Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands. b.vanheumen@mdl.umcn.nl

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.

Trial registration: http://ClinicalTrials.gov, identifier NCT00808743.

Show MeSH
Related in: MedlinePlus