Celecoxib Effective in Reducing Incidence of Colon Adenomas

Roxanne Nelson

April 16, 2008

April 16, 2008 (San Diego, California) — In patients without underlying cardiovascular disease who are at high risk for colon adenomas, chemoprevention with celecoxib appears to be safe and effective. The 5-year data from a randomized phase 3 trial, presented here at the American Association for Cancer Research 2008 Annual Meeting, found that although the COX-2 inhibitors have been associated with increased cardiovascular risk in some patients, celecoxib was highly effective in reducing adenomas.

"There were over 2000 patients enrolled in the study, with 3 treatment arms," said Monica Bertagnolli, MD, an associate professor of surgery at the Brigham and Women's Hospital, in Boston, Massachusetts, and the lead researcher on the Adenoma Prevention with Celecoxib (APC) trial. "The main end point was to evaluate the incidence of adenomas at 3 years, but we wanted to keep it going for 5 years."

The study was halted when the researchers became aware of associated cardiac toxicity. At that point, nearly all of the enrolled patients had received treatment for 3 years. The researchers decided that they would continue monitoring patients for an additional 2 years to assess safety and efficacy.

The APC study randomized 2035 patients who were at high risk for developing sporadic colon adenomas into 1 of 3 groups: celecoxib 200 mg twice daily (total, 400 mg); celecoxib 400 mg twice daily (total, 800 mg); or placebo. At the 3-year end point, patients taking 400 mg of celecoxib had 33% fewer adenomas and 57% fewer advanced lesions. Participants taking the 800 mg dose had 45% fewer adenomas and 66% fewer advanced lesions.

At the end of the study, participants were offered the opportunity to continue in a 2-year off-treatment observational study. After 5 years, the rate of adenomas was reduced by 41% in patients who took the lower dose of celecoxib, and by 25% in patients who took the higher dose. Colonoscopies were performed on 639 patients at 5 years, and results demonstrated a cumulative advanced adenoma incidence of 0.125 in patients who took 400 mg of celecoxib and 0.158 in patients who took 800 mg, compared with 0.212 in patients who took placebo.

"We had more than 400 patient-years of data," said Dr. Bertagnolli. "These patients were all at very high risk for adenomas. Twenty-two percent of patients on placebo developed advanced adenomas, and many had recurring adenomas."

She also pointed out that 84% of patients in the study had at least 1 risk factor for cardiovascular disease. "At the time we designed it, we didn't know about the cardiovascular risk, so there was no exclusion criteria for heart disease."

Overall, nonadjudicated selected cardiovascular events, as reported by trial investigators, occurred 35 times in the 676 patients taking placebo, 45 times in 683 patients taking the lower dose of celecoxib, and 46 times in 669 patients taking the higher dose.

"There are many different ways of looking at safety," said Dr. Bertagnolli. "If we look at treatment-emergent events — an event that occurs after the first dose of the drug is taken and continues until the last dose — we saw that 8.5% had some type of adverse cardiovascular event. There were more events in the 2 groups that used the drug, and there was a consistent dose response."

Patients who had at least 2 cardiovascular risk factors at study baseline were at the highest risk for cardiac complications during the course of the study. Among this subgroup, patients taking 800 mg had an 11.2% risk, those taking 400 mg had an 8.2% risk, and those taking placebo had a 5.9% risk.

One third of the patients were taking low-dose aspirin for cardiac protection, and 5-year colonoscopy data showed that this subset had an increased incidence of adenomas, suggesting the presence of more aggressive disease in individuals using aspirin.

"Celecoxib had a high rate of efficacy for reducing adenomas, and it persists even after discontinuing the drug," she concluded. "There was no benefit to the higher dose. The twice-daily 200 mg is safer than 400 mg, but we can't say that either dose is safe for a patient with cardiac risk factors."

American Association for Cancer Research (AACR) 2008 Annual Meeting: Abstract LB-141. Presented April 14, 2008.

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