Celecoxib Prevents Colon Polyp Recurrence

WASHINGTON—Two large randomized trials have shown that the COX-2 inhibitor celecoxib (Celebrex) significantly reduces the recurrence of colorectal adenomas, according to data presented at the 97th Annual Meeting of the American Association of Cancer Research. However, the trials also found a significantly increased risk of serious cardiovascular (CV) events—strokes and heart attacks—among trial participants taking the drug. Celecoxib researchers and other experts at the meeting emphasized that more needs to be known about how and why celecoxib raises CV risk before it can be recommended for prevention of colorectal cancer.

In the NCI-sponsored Adenoma Prevention with Celecoxib (APC) trial (abstract CP-3), 2,035 patients with prior polyps were randomized to receive placebo or 200 mg or 400 mg of celecoxib, each given twice daily. The groups had similar risk factors for colorectal cancer and CV disease, and patients were stratified according to low-dose aspirin use. After the first year, colonoscopy was performed in 89% of patients and after 3 years, in 76%.

Colonoscopy detected adenomas in 60.6% of patients on placebo, reported Monica Bertagnolli, MD, associate professor of surgery, Harvard Medical School. The risk of adenoma recurrence was 45% lower among those receiving 400 mg of celecoxib and 33% lower in the 200-mg group.

More advanced tumors—1 cm or greater in diameter, tubulovillous or villous histology, high-grade dysplasia, intramucosal carcinoma or invasive carcinoma—were reduced by 66% with 400 mg of celecoxib. Dr. Bertagnolli noted that for those patients who did have a recurrence, the adenomas were significantly fewer in number and smaller in size, compared with recurrences that developed in the placebo patients. The incidence of CV events overall was 1% with placebo, 2.5% with 200 mg of celecoxib, and 3.4% with 400 mg. For those with no CV history, the percentages were smaller: 0.7% for placebo and 2% for either celecoxib dosage.

PreSAP Trial

The Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) Trial, sponsored by Pfizer, maker of celecoxib, randomized 1,561 subjects who had polypectomy within 90 days of enrollment, in a 3 to 2 ratio, to receive 400 mg of celecoxib once daily or placebo (abstract CP-4). As in the APC trial, risk factors were similar between groups, and participants were stratified according to low-dose aspirin use. Colonoscopies were performed at year 1 (88.7% of patients) and year 3 (79.2% of patients).

The incidence of adenomas at year 3 was 49.3% with placebo and 33.6% with celecoxib, a reduction of about 34%.

Occurrence of more advanced lesions was reduced by 51%, reported principal investigator Nadir Arber, MD, of Tel-Aviv Sourasky Medical Center, Israel.

The researchers stopped celecoxib when the APC study showed an increase in serious CV events among those taking the drug. PreSAP data at that point showed that patients on celecoxib had a 7.5% incidence of CV events vs 4.6% for placebo (hazard ratio 1.3). Dr. Arber pointed out the low number of patients involved: 23 on celecoxib and 12 on placebo, keeping in mind the 3-to-2 randomization. The hazard ratio was lower (1.1) for patients with no CV history.

The PreSAP data, like the APC findings, offer a proof of concept, Dr. Arber said. "In the future, risk-benefit assessment will depend on enhanced patient characterizations and molecular profiling of adenomas," he said.