SAN DIEGO — Celecoxib reduced the incidence of advanced colorectal adenomas by 41% at 5 years in high-risk patients who took the controversial COX-2 inhibitor for 3 years in a cancer prevention trial before stopping it because of cardiovascular safety concerns.
“Even 2 years after we discontinued treatment with celecoxib, our patients still derived a considerable chemoprotective benefit,” Dr. Monica Bertagnolli of Brigham and Women's Hospital, Boston, said at the annual meeting of the American Association for Cancer Research.
Just as notably, Dr. Bertagnolli reported celecoxib (Celebrex) was shown to be safe in patients who had no underlying risk factors for cardiovascular disease when they entered the study.
Dr. Bertagnolli led the Adenoma Prevention With Celecoxib (APC) trial, which began enrolling patients in 1999 and was planned to run for a total of 5 years of drug treatment. Sponsored by Pfizer Inc., the study was designed to test the efficacy and safety of two doses of celecoxib in preventing colorectal adenomas in 2,035 individuals at high risk for colon cancer.
Patients who had adenomas removed before study entry were assigned to placebo (679 patients), 200 mg twice a day of celecoxib (685), or 400 mg twice a day (671) of celecoxib. They were followed with colonoscopies performed at 1 and 3 years. Just as the last patients completed 3 years of the study, the investigators recognized increased cardiovascular toxicity with celecoxib and discontinued the drug in all patients.
“At the time we began our study, the cardiovascular toxicity of celecoxib was not known. In fact, this study was the first to unveil cardiovascular disease risk with the drug. So we did not screen any of our study population for cardiovascular risk factors. Most of our patients—84%—whose median age was 60 at the time of study entry, had at least one risk factor,” Dr. Bertagnolli explained in an interview.
The efficacy results at the 3-year point were impressive, she said. Sixty percent of the placebo group had new adenomas, compared with 43% of patients receiving 200 mg of celecoxib twice a day, and 38% of those in the high-dose group receiving 400 mg of celecoxib twice a day The reduction in the rate of new advanced adenomas was even more striking at this point, with a 64% reduction at the lower dose and a 55% reduction at the higher dose of celecoxib, she noted.
Although the patients discontinued celecoxib, Dr. Bertagnolli and her colleagues decided to continue the trial as an observational study. Approximately one-third of the original randomized cohort had a colonoscopy at 5 years as planned, she said. “We kept the study going, and I'm glad we did, because now we have interesting new data,” she said.
At 5 years, with no drug on board for 1.5-2 years, the reduction in advanced lesions was 41% in the cohort who received the lower dose of celecoxib and 26% in patients who received the higher dose. There was no rebound effect—that is, lesions did not suddenly appear when the drug was stopped, Dr Bertagnolli said.
“Interestingly, the lower dose of celecoxib was the most effective at the 5-year end point,” Dr. Bertagnolli commented.
The investigators also analyzed safety, looking at any event that occurred after patients took the first dose of celecoxib up until 30 days after they took the last dose.
Cardiovascular events (myocardial infarction, stroke, peripheral vascular disease, and vascular therapeutic procedure) rose with the dose of celecoxib, occurring in 3.8% of the patients on placebo, in 6.0% of patients on the low dose of celecoxib, and in 7.5% of patients on the high dose of celecoxib.
The data showed that patients with preexisting risk factors, defined as smoking, hypertension, diabetes, hyperlipidemia, atherosclerotic heart disease, and age over 65 years, had the greatest risk:
PIFor patients with no cardiovascular risk factors before using celecoxib, the rate of cardiovascular adverse events was 0.9% in the placebo group, 3.9% in the 200-mg b.i.d. group, and 1.9% in the 400-mg b.i.d. group.
PIIf a patient had one risk factor, the rate was 2.2% in the placebo group, 3.7% in the 200-mg b.i.d. group, and 4.9% in the 400-mg b.i.d. group.
PIAmong patients who had two or more cardiovascular risk factors at the time they entered the study, those on placebo had a cardiovascular adverse event rate of 5.9%; those on 200 mg b.i.d., 8.2%; and those on 400 mg b.i.d., 11.2%.
This risk needs to be balanced with the benefit patients derived from celecoxib, Dr. Bertagnolli said. “These patients were at very high risk for colorectal adenomas. Twenty-two percent of patients on placebo got advanced adenomas during the 5 years, and over 70% of patients had adenomas that recurred if they were on placebo. So this is a very high-risk group.”