Chemoprevention of colorectal adenomas with celecoxib in an international, randomized, placebo-controlled, double-blind trial
Abramson Cancer Center of the University of Pennsylvania
Last Modified: April 27, 2006
Presenter: Nadir Arber
Presenter's Affiliation: Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
Presenter's Financial Interest Disclosure: Pfizer and GI View
Type of Session: Clinical Plenary
- Cyclooxygenase-2 (COX-2) converts arachidonic acids to prostaglandin endoperoxides, which in turn are converted to biologically active mediators that mediate inflammation and other biologic effects
- COX-2 upregulation 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
- Like the Adenoma Prevention with Celecoxib (APC) trial, the Prevention of colorectal Sporadic Adenomatous Polyps (PreSAP) 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: Industry-sponsored, international, randomized, double-blind, placebo-controlled chemoprevention trial
- 1,561 patients from 107 centers in 32 countries were randomized
- Eligibility: Patients > 30 yrs old, who were found to have either: one large ( > 6 mm) polyp or > 2 adenomas
- Of note, patients with a history of cardiovascular (CV) disease were NOT excluded
- Randomized 3:2 to:
- Celecoxib 400 mg once per day (n=933)
- Placebo (n=628)
- Stratification: Low dose aspirin use
- Evaluation: Colonoscopy at 1 and 3 yrs after randomization
- Primary Endpoint: Cumulative rate of adenoma detection
- Follow-up colonoscopies were performed in the majority of patients (89% at 1 yr, 79% at 3 yr). Compliance was excellent, with >80% of patients taking >80% doses
- The incidence of any polyp was 33.6% in the placebo group, and 33.6% in the celecoxib group (RR 0.64, 95% CI 0.56-0.75, p<0.0001)
- The incidence of advanced adenomas was 5.3% in the placebo group, and 10.4% in the celecoxib group (RR 0.49, 95% CI 0.33-0.73, p=0.0003)
- Interestingly, there were 6 cases of invasive colorectal cancer on the celecoxib arm, compared with 1 case on the placebo arm. These cases were investigated further, and it was felt that these tumors arose from incompletely resected malignant polyps.
- Adverse Events:
- Deaths from any cause: 7 placebo vs. 11 in celecoxib group, which was proportional to the randomization distribution
- There was an increase in renal/hypertensive events in the celecoxib group (15.3 vs. 20.7, p<0.01)
- There was an increase in all CV adverse events in the celecoxib group (4.8% placebo vs. 7.5% celecoxib, p<0.05) and in serious CV events (1.9% placebo vs. 2.5% celecoxib, HR=1.3, 95% CI 0.6-2.6)
- Once-daily use of celecoxib 400 mg significantly reduced colorectal adenoma occurrence within 3 years after polypectomy.
- Once-daily use offers not only a simpler chemopreventive regimen but may possibly provide an alternative to the benefit-risk profile of twice-daily dosing.
- A similar randomized trial, the Adenoma Prevention with Celecoxib (APC) trial, was presented in the same session. This study also found that celecoxib given 200 mg twice per day, or 400 mg twice per day, decreased the rate of polyp formation in a dose-dependent fashion. Unfortunately, there was a significantly increased rate of serious CV adverse events in the APC trial.
- Given the role of COX-2 in colon cancer and the numerous retrospective studies showing 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 adverse CV events, which was reflected by the fact that reporting of CV events in this trial, as well as another similar trial, were adjudicated.
- Despite the intense interest in the toxicity outcomes of these trials, especially adverse CV events, the studies were not originally powered to look at this as an endpoint.
- The increased risk of CV events preclude recommendation of a 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, and 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 colorectal polyps, continued endoscopic monitoring and removal of recurrent polyps is currently the standard strategy for risk reduction.