Background: Celecoxib has previously been shown to be effective in reducing recurrent colorectal adenomas, but its long-term effects are unknown. In addition, safety issues are of major concern. Therefore, we examined the efficacy and safety of celecoxib as a chemopreventive agent along with its posttreatment effect.
Methods: We performed a meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing celecoxib at various doses (400 mg once daily, 200 mg twice daily, and 400 mg twice daily) vs placebo in persons with history of colorectal adenomas. Several databases were searched from inception up to April 2018. Long-term follow-ups of RCTs were also included to evaluate posttreatment effect. Primary outcome was the incidence of recurrent colorectal adenomas. Various safety outcomes were evaluated, especially cardiovascular (CV) events. Risk–benefit integrated analyses were also performed.
Results: A total of three RCTs (4,420 patients) and three post-trial studies (2,159 patients) were included in the analysis. Use of celecoxib at any dose for 1–3 years significantly reduced the incidence of recurrent advanced adenomas (risk ratio, 0.42 [95% CI, 0.34–0.53]) and any adenomas (0.67 [95% CI, 0.62–0.72]) compared with placebo. Subgroup analysis on different dosing suggested a greater effect with 400 mg twice daily. However, celecoxib 400 mg twice daily significantly increased the risk of serious adverse (1.2 [95% CI, 1.0–1.5]) and CV events (3.42 [95% CI, 1.56–7.46]), while celecoxib at 400 mg/day, especially with once daily dosing, did not increase CV risk (1.01 [95% CI, 0.70–1.46]). Analysis of post-trial studies indicated that the treatment effect disappeared (1.15 [95% CI, 0.88–1.49]) after discontinuing celecoxib for >2 years.
Conclusion: Celecoxib 400 mg once daily dosing could potentially be considered as a viable chemopreventive option in patients with high risk of adenomas but with low CV risk. Long-term trials on celecoxib at a dose of ≤400 mg either once or twice daily are warranted.


Keywords: colorectal cancer, colorectal adenomas, chemoprevention, celecoxib, meta-analysis, randomized controlled trials, risk–benefit integrated analyses 


BACKGROUND

Colorectal cancer (CRC) is the third most common cancer worldwide, with over 1.4 million new cases estimated to have occurred in 2012.1 It is widely accepted that adenomas/polyps are well-known precursors of sporadic CRCs.2 Early detection and removal of adenomatous polyps by colonoscopic screening has been showed to reduce mortality from CRC.3 Unfortunately, surveillance colonoscopic screening is underutilized.4–6 A variety of reasons, including suboptimal adherence to screening, availability, and cost, may play a part in this problem. For those who undergo polypectomy, the recurrence rate is still relatively high.2,3,7 Therefore, the use of chemoprevention strategies to complement surveillance screening may have a potential to further reduce CRC morbidity and mortality among those with adenomatous polyps.

Protective effect of non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) on colorectal adenomas have been documented in previous systematic reviews.8–12 However, concerns about cardiovascular (CV) safety and risk of serious bleeding events hamper the acceptance of these strategies for secondary prevention of CRC.11,13 Cyclooxygenase-2 (COX-2) inhibitors14 selectively interfere with COX-2 enzyme and have been shown to cause less major bleeding compared with traditional NSAIDs.15–18 For CV safety, most non-aspirin NSAIDs and COX-2 inhibitors have been shown to increase the risk of thrombotic CV events.15,19–21 However, the risk of these events may be a result of complex interplay among a specific drug molecule, dose, and baseline CV risk.16,22 Rofecoxib, which was withdrawn from the market, was shown to have a much higher risk compared with celecoxib.21 For celecoxib, the risk appeared to be dose dependent and was evident among patients with high CV risk at baseline.19 In addition, available evidence suggested that twice daily dosing, not once daily dosing, was associated with increased CV risk.19,23,24 Recently, celecoxib at approved doses (200–400 mg/day), was found to be noninferior to ibuprofen or naproxen with regard to CV safety in a large, randomized, controlled trial with over 24,000 patients.25 As a result, celecoxib at approved doses could be a viable option for patients with history of adenomas where the risk of CRC may outweigh the risk of CV events.8,26 We, therefore, conducted a systematic review and meta-analysis to evaluate efficacy and safety of celecoxib in patients with a history of adenomas. We performed risk–benefit integrated analysis to comprehensively evaluate celecoxib’s multidimensional effects in this setting. Moreover, we also investigated whether the adenoma-preventive effect of celecoxib waned after withdrawal.