Departments of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.
Orphanet J Rare Dis. 2013 Aug 6;8:118. doi: 10.1186/1750-1172-8-118.
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.
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.
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.
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.
http://ClinicalTrials.gov, identifier NCT00808743.
由于预防性结肠切除术，家族性腺瘤性息肉病（FAP）患者的死亡率发生了变化，目前十二指肠癌是主要死亡原因。虽然塞来昔布可降低 FAP 患者十二指肠息肉密度，但长期使用可能会增加心血管事件的风险，因此需要探索替代药物。临床前研究表明，塞来昔布与熊去氧胆酸（UDCA）联合使用可能是一种有效的策略。我们进行了一项随机、双盲、安慰剂对照试验，以研究塞来昔布和 UDCA 联合治疗对 FAP 患者十二指肠腺瘤的影响。
FAP 患者接受塞来昔布（每日两次，每次 400mg）和 UDCA（每日 1000-2000mg，约 20-30mg/kg/天，n=19）或塞来昔布和安慰剂（n=18）口服治疗 6 个月。主要终点是药物疗效，通过盲法内镜记录评估治疗前后十二指肠息肉密度来比较。次要终点是通过免疫组化或实时定量聚合酶链反应评估正常十二指肠黏膜中的细胞增殖、凋亡和 COX-2 水平。
意向治疗分析显示，塞来昔布/安慰剂治疗后可见息肉密度降低（p=0.029），而塞来昔布/UDCA 治疗后可见息肉密度增加（p=0.014）。两组间十二指肠息肉密度变化的差异具有统计学意义（p=0.011）。未观察到次要终点的变化。30 名患者（81%）报告了 1 种或多种不良事件，16 名（84%，不良事件通用毒性标准 3.0 版（CTCAE）分级 1-3）接受塞来昔布/UDCA 治疗，14 名（78%，CTCAE 分级 1-2）接受塞来昔布/安慰剂治疗。9 名患者（24%）提前退出干预，5 名（26%）接受塞来昔布/UDCA 治疗，4 名（22%）接受塞来昔布/安慰剂治疗。
塞来昔布可降低 FAP 患者的十二指肠息肉密度，但令人意外的是，高剂量 UDCA 联合治疗会抵消这种作用。长期使用塞来昔布预防十二指肠癌的获益需要与（发生）不良事件的风险相权衡。
http://ClinicalTrials.gov，标识符 NCT00808743。
