Efficacy and Safety of Celecoxib on the Incidence of Recurrent Colorectal Adenomas: A Systematic Review and Meta-analysis
Cancer Management and Research
Effects on the primary efficacy outcomes
Based on the results from the meta-analyses, use of celecoxib at any dose (400–800 mg/day) for a duration of approximately 1–3 years showed a statistically significant reduction in the recurrence of advanced colorectal adenomas (RR, 0.42 [95% CI, 0.34–0.53]) and any adenomas (RR, 0.67 [95% CI, 0.62–0.72]) compared with placebo, with no heterogeneity (I2=0%; Figure 1). In the sensitivity analyses (Figures S2–S4; see original version of this article), findings were robust and consistent with the primary analysis. A subgroup analysis of celecoxib at 400 mg/day demonstrated similar effects on advanced adenomas (RR, 0.45 [95% CI, 0.35–0.58]) and any adenomas (RR, 0.69 [95% CI, 0.64–0.75]), with no heterogeneity (I2=0%; Figure 1). Both 400 mg once daily and 200 mg twice daily dosing regimens provided similar effect size (Figure S5; see original version of this article). For celecoxib at 800 mg/day, RR for advanced adenomas was 0.34 [95% CI, 0.24–0.50] and 0.55 [95% CI, 0.48–0.64] for any adenomas.
(To view a larger version of Figure 1, click here.)
Effects on the safety outcomes
Results from meta-analyses (Figure 2) showed that celecoxib at any dose for a duration of approximately 1–3 years significantly increases the risk of serious adverse events (RR, 1.15 [95% CI, 1.02–1.30]) and renal-hypertensive disorders (RR, 1.25 [95% CI, 1.09–1.42]) compared with placebo. Other safety outcomes including serious CV events (RR, 1.44 [95% CI, 0.73–2.84]), all-cause mortality (RR, 1.27 [95% CI, 0.66–2.44]), and CRCs (RR, 1.41 [95% CI, 0.24–8.27]) were not significantly increased compared to placebo. Subgroup analysis based on different dosing regimens showed that celecoxib 400 mg twice daily (800 mg/day) significantly increased the risk of serious adverse (RR, 1.2 [95% CI, 1.0–1.5]) and CV events (RR, 3.42 [95% CI, 1.56–7.46]). Interestingly, for celecoxib at 400 mg/day, a significant increase in CV risk was observed only with 200 mg twice daily regimen (RR, 2.48 [95% CI, 1.10–5.59]) but not with 400 mg once daily regimen (RR, 1.01 [95% CI, 0.70–1.46]), compared with placebo (Figures S6 and S7; see original version of this article).
(To view a larger version of Figure 2, click here.)
Grade summary of evidence
Our application of GRADE methodology led us to conclude that the accumulated evidence for celecoxib (at any dose and 400 mg/day) is of high quality for adenoma prevention. Detailed information on GRADE summary of evidence is presented in Table S3 (see original version of this article).
Risk–benefit integrated analysis
Based on integrated analysis, we estimated that the use of celecoxib at 800 mg/day compared with placebo may lead to 108 (95% CI, 82–124) and 49 (95% CI, 30–56) fewer advanced adenomas in 1,000 patients with high-risk and low-risk adenomas, respectively. On the other hand, this would lead to an excess of 38 (95% CI, 0–95) serious adverse events and 82 (95% CI, 19–186) CV events compared with placebo. As for celecoxib at 400 mg/day, there would be 90 (95% CI, 68–106) and 41 (95% CI, 32–48) fewer advanced adenomas in persons with high-risk and low-risk adenomas, respectively. As for harm, this intervention would lead to an excess of 25 (95% CI, 2 fewer to 53 more) serious adverse events and 11 (95% CI, 8 fewer to 44 more) CV events, per 1,000 patients treated compared with placebo. The risk–benefit balance may also be different when different dosing regimens of 400 mg/day are used. Interestingly, celecoxib at 400 mg once daily may be associated with less harm since this dosing regimen would only lead to 30 excess harmful events (29 serious adverse events and one CV event) compared with 65 events (15 serious adverse events and 50 CV events) with 200 mg twice daily regimen. Based on this analysis, the risk–benefit balance of celecoxib at 400 mg/day, especially with 400 mg once daily dosing may be acceptable especially among patients at high risk of CRC and at low CV risk (Table S4; see original version of this article).
Posttreatment effect on efficacy outcomes
Meta-analyses of post-trial studies demonstrated no effect on the recurrence of advanced colorectal adenomas (RR, 1.15 [95% CI, 0.67–1.99]) and any adenomas (RR, 1.15 [95% CI, 0.88–1.49]) after discontinuing celecoxib for more than 2 years (Figure S8; see original version of this article). There was moderate to substantial level of heterogeneity observed in both analyses.