New York, NY - Pfizer's well-known nonsteroidal anti-inflammatory drug celecoxib (Celebrex) does not have a role to play in cancer prevention, experts say. The risks of the drug continue to outweigh the benefits, and opinion leaders in a range of specialties warn that any new trials studying the well-known pain reliever in high doses would be unethical.

Dr Steven Nissen (Cleveland Clinic, OH), lead investigator of the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial, an eagerly anticipated 20 000-patient study assessing the safety of celecoxib, says his group will study a 200-mg dose. "Because of the risk of cardiovascular complications, I wouldn't have agreed to do the trial using a higher dose," Nissen said.

PRECISION is assessing the safety of key pain relievers. It is expected that the Pfizer-sponsored trial will be completed in 2012.

Nissen was among the first to highlight the potential risks of another nonsteroidal anti-inflammatory drug, rofecoxib (Vioxx, Merck), which was pulled from the market in September 2004.

I'm not sure I understand the enthusiasm of the APC trialists.

He and other experts who served on the subsequent US Food and Drug Administration panel assessing the safety of the drugs emphasized the dangers of high-dose celecoxib. Panelists recommended that doctors choose 200-mg doses.

Renewed debate has been sparked by five-year data from the Adenoma Prevention with Celecoxib (APC) trial, a randomized placebo-controlled study. Researchers presenting at the recent American Association for Cancer Research 2008 Annual Meeting showed that celecoxib was highly effective in reducing colon adenomas.

"I'm not sure I understand the enthusiasm of the APC trialists," Nissen said during an interview. "They have identified a benefit in precursor lesions—not in colon cancer itself—and, given the cardiovascular risk of the drug, it's very hard to advocate for therapy."

Editorialists agreed when the primary results of APC and another key celecoxib trial, the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP), were first published [1,2].

In the editorial [3], Drs Bruce Psaty and John Potter (University of Washington, Seattle) write: "It is reasonable to conclude that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population."

The APC trial included 2035 patients in a study of 200- or 400-mg twice-daily doses of celecoxib. The PreSAP trial included more than 1560 patients and evaluated a single 400-mg daily dose.

Psaty and Potter say the placebo-controlled trials were well-designed and well-conducted and had many features in common, including sample size, age of the patients, exclusion criteria, and duration of the run-in phase to assess adherence.

Efficacy outcomes for the two trials were similar. Treatment with celecoxib, compared with placebo, was associated with a reduction in the risk for metachronous and advanced adenomas.

The latest five-year APC data extend these results. After completing the study, patients were given the option of participating in a two-year off-treatment observational study.

Five years after treatment was initiated, colonoscopies were performed on 639 patients. 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 (p<0.0001).

As in the first report, APC investigators concluded that, because of the severity of the drug-related cardiovascular events, celecoxib could not be recommended for routine prevention of colorectal adenomas or cancer.

"This situation is especially true for patients who have access to colonoscopy with polypectomy, which is a relatively safe and highly effective method of cancer prevention," lead investigator Dr Monica Bertagnolli (Brigham and Women's Hospital, Boston, MA) reports in a Personal View published last year in Lancet Oncology [4].

However, Bertagnolli is hesitant to reject celecoxib entirely as a chemopreventive agent. "To ignore the potential benefit of chemoprevention is to continue to accept a high death rate from colorectal cancer in patient populations that are, so far, only minimally compliant with colonoscopy and polypectomy as a preventive treatment."

Nissen said that low-dose aspirin might provide the chemopreventive properties researchers are looking for, with fewer adverse effects. "More study is needed," he said.

In their editorial, Psaty and Potter develop a hypothetical risk/benefit analysis for celecoxib and low-dose aspirin over a period of three years in 1000 patients with colon adenomas.

"We were working under the assumption that adenomas lead to colorectal cancer," Psaty said during an interview. "If you do not believe these precursor lesions necessarily lead to cancer, then we have underestimated the risk, and it is even higher."

Psaty said the new five-year APC results do not change his original view. "Celecoxib doesn't have a chance," he said, "and I see no clinical application."