Celecoxib reduces sporadic colorectal adenomas: Results from the Adenoma Prevention with Celecoxib (APC) trial
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado:: 27 de abril de 2006
Presenter: Monica M. Bertagnolli
Presenter's Affiliation: Brigham and Women's Hospital, Boston, MA
Type of Session: Clinical Plenary
- Cyclooxygenase-2 (COX-2) converts arachidonic acid to prostaglandin endoperoxides, which in turn are converted to biologically active mediators that mediate inflammation and other biologic effects
- COX-2 up-regulation has been associated with colorectal carcinogenesis as benign adenomas progress to invasive carcinomas
- Non-selective inhibitors of the cyclooxygenases (non-steroidal anti-inflammatory drugs) have been associated with decreased rates of colorectal adenomas, carcinomas, and death from colorectal cancer
- The Adenoma Prevention with Celecoxib trial was designed to test whether celecoxib, a selective inhibitor of COX-2, could prevent the development of sporadic colorectal adenomas
Material and Methods
- Design: Large randomized, double-blind, placebo-controlled chemoprevention trial
- 2035 patients, over 30 yrs old, who were found on colonoscopy to have either: one large ( > 6 mm) polyp or multiple adenomas
- Pts were randomized to:
- Placebo (n=679)
- Celecoxib 200 mg bid (n=685)
- Celecoxib 400 mg bid (n=671)
- Stratification: geography and low-dose aspirin use
- Evaluation: Colonoscopy at 1 and 3 yrs after randomization. Safety was monitored by telephone interviews at 2-month intervals
- Primary Endpoint: any adenoma, found on follow-up colonoscopy at either 1 yr or 3 yrs
- The patient groups were well balanced, except for a slight discrepancy in smoking history (18% in placebo and low-dose group, 13% in high-dose group)
- Follow-up colonoscopies were performed in the majority of patients (89% at 1 yr, 76% at 3 yr)
- The incidence of any polyp was 61% in the placebo group, and celecoxib use decreased this in a dose-dependent manner (RR 0.67 in 200 mg bid group, 0.55 in 400 mg bid group, p<0.0001)
- The magnitude of the reduction was even greater in patients with higher risk tumors, such as those with a villous component, > 1 cm in size, high-grade dysplasia, or invasion (RR 0.43 in 200 mg bid group, RR 0.34 in 400 mg bid group, p<0.0001)
- Adverse Events:
- There was no dose-dependent increase in renal/hypertensive events
- There was a dose-dependent increase in GI ulceration, but only in those who were also taking low-dose aspirin (11% in placebo vs. 15% in high dose group)
- There was a dose-dependent increase in serious cardiovascular (CV) adverse events (MI, stroke, CHF, CV death)
- Placebo: 1%
- 200 mg bid group: 2.5%
- 400 mg bid group 3.4%
- Those who had a defined prior history of CV events had the greatest absolute risk increase, although the proportional increase was similar
- Prior CV history: Placebo: 3%, Celecoxib 8.8%
- No prior CV history: Placebo: 0.7%, Celecoxib 2.0%
- Celecoxib decreased the 3-year adenoma recurrence rate by 33-45% overall and by 57-66% in patients with high-risk adenomas.
- Celecoxib use was associated with an increased risk of CV events.
- These data provide valuable information regarding the risk:benefit ratio of celecoxib chemoprevention.
- A similar randomized trial, the Prevention of colorectal Sporadic Adenomatous Polyps (PreSAP) trial presented in the same session also found that celecoxib (400 mg once per day) decreased the rate of polyp formation by 36% over 3 yrs. Celecoxib treatment was also associated with an increased risk of CV events in this trial.
- Given the role of COX-2 in colon cancer and the numerous retrospective studies that show that non-selective COX inhibitors decrease colorectal tumors, it is not surprising that celecoxib decreased rates of adenoma recurrence, but the magnitude of the efficacy was surprising.
- There has been a lot of legal and media attention surrounding selective COX-2 inhibitors due to the association with adverse CV events, reflected by the fact that reporting of CV events were adjudicated in this and a similar trial (PreSAP). In fact, the increased rate of CV events in the APC trial led to early closure.
- Despite the intense interest in the toxicity outcomes of these trials, and specifically adverse CV events, they were not originally powered to study this as an endpoint.
- The increased risk of CV events precludes recommendation of this chemoprevention strategy with celecoxib. By adjusting for relative risks, i.e. high risk for colorectal cancer death compared to CV death, carefully selected patients could potentially benefit from selective COX-2 chemoprevention, but further studies are required.
- It appears that PGE 2 may be the critical downstream regulator of colorectal carcinogenesis.
- Targeted agents that either inhibit PGE 2 synthesis or accelerate PGE 2 metabolism may prevent polyps without excess CV risk.
- For patients with a history of colorectal polyps, continued endoscopic monitoring and removal of recurrent polyps is currently the standard strategy for risk reduction.