Cancer prevention with Cox-2 inhibitors hampered by cardiovascular toxicity

Although Cox-2 inhibitors can prevent premalignant polyps, they lead to significantly increased risk of serious adverse cardiovascular events.

Issue: December 1, 2006

Published results from two large randomized trials of cyclooxygenase-2 inhibitors used to prevent colon cancer failed to find enough benefit to outweigh the cardiovascular risk conferred by the drugs.

The trials examined celecoxib’s (Celebrex, Pfizer) effect on colorectal adenoma prevention. The final results of the Adenoma Prevention with Celecoxib (APC) and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials were both published in The New England Journal of Medicine. They showed that treatment with celecoxib led to a pronounced reduction in the risk of metachronous adenomas and advanced adenomas when compared with placebo.

But in both trials, celecoxib use was associated with an increased risk of cardiovascular events. Researchers wrote that although celecoxib was effective in preventing such adenomas, they could not recommend its use because of the potential for serious cardiovascular events.

“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,” Bruce M. Psaty, MD, PhD, professor of medicine and epidemiology in the Cardiovascular Health Research Unit at the University of Washington in Seattle, wrote in an accompanying editorial.

“The cardiovascular risks outweigh even optimistic projections of the benefits on colorectal cancer incidence,” he told HemOnc Today.

A third trial, the APPROVe (Adenomatous Polyp Prevention on Vioxx) study, was conducted by Merck Research Laboratories to assess the effect of rofecoxib (Vioxx, Merck) on preventing colorectal polyps under close colonoscopic surveillance. This study also found a chemopreventive effect on premalignant polyps in conjunction with an increased risk for serious cardiovascular events.

The APC trial

The APC trial was a randomized, placebo-controlled study to determine whether celecoxib reduced the occurrence of endoscopically-detected colorectal adenomas. Researchers led by Monica Bertagnolli, MD, associate professor of surgery at Harvard Medical School’s Brigham and Women’s Hospital in Boston, enrolled 2,035 patients at 91 clinical sites throughout the United States, Australia, Canada and the United Kingdom.

Patients received either 200 mg of celecoxib twice daily, 400 mg twice daily or placebo. The randomization was stratified on the basis of low-dose aspirin use (325 mg or less every other day or 162.5 mg or less every day) and clinical site.

Celecoxib therapy was associated with a reduced number of advanced adenomas during the three-year period. Only 35 patients in the group receiving 400 mg of celecoxib twice daily and 44 patients in the group receiving 200 mg of celecoxib twice daily had one or more advanced adenomas compared with 99 patients in the placebo group.

The estimated cumulative incidence of advanced adenomas was 17.2% for patients receiving placebo, 7.8% for those treated with 200 mg of celecoxib twice daily, and 6.3% for those treated with 400 mg of celecoxib twice daily, according to Bertagnolli and colleagues.

The study results also indicated an increased risk of serious cardiovascular complications (ie, death from cardiovascular causes, nonfatal myocardial infarction, stroke or heart failure) among those receiving celecoxib. There was a risk ratio of 2.6 (95% CI, 1.1-6.1) for the lower dosage group and 3.4 (95% CI, 1.5-7.9) for the higher dosage group. Also, blood pressure increased with the use of celecoxib, suggesting that changes in vascular tone may predispose patients to cardiovascular events, according to researchers.

Bertagnolli and colleagues wrote that this trial documented that celecoxib could prevent premalignant adenomas; however, it was not designed to assess the effectiveness of the drug for the prevention of colorectal cancer.

If future study of celecoxib for the chemoprevention of colorectal cancer is pursued, the potential addition of this drug to an optimal endoscopic surveillance program must be weighed against the known risk of serious cardiovascular events, the researchers wrote.

PreSAP trial

The PreSAP trial was a randomized, placebo-controlled, double-blind study of celecoxib given daily in a single 400 mg dose. Lead researcher Nadir Arber, MD, MSc, head of Integrated Cancer Prevention at Tel Aviv Sourasky Medical Center in Israel, and colleagues enrolled 1,561 patients who had had adenomas removed before enrollment. Patients were randomized to receive celecoxib (n=933) or placebo (n=628) and were stratified according to low-dose aspirin use. The primary outcome was the colonoscopic detection of adenomas at either one year or three years.

Of the 557 patients in the placebo group and the 840 patients in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, had one or more adenomas at year one, year three, or both.

A reduced risk was apparent at the first follow-up colonoscopy and persisted at the second, according to researchers. The cumulative rate of adenomas detected through year three was 33.6% in the celecoxib group and 49.3% in the placebo group (RR=0.64; 95% CI, 0.56-0.75). For advanced adenomas detected through year three, the cumulative rate was 5.3% in the celecoxib group and 10.4% in the placebo group (RR=0.49, 95% CI, 0.33-0.73).

Thirty-five patients either died of cardiovascular causes or suffered myocardial infarction, stroke or congestive heart failure adjudicated by the study’s cardiovascular safety committee. These events occurred in 2.5% of the celecoxib group (n=23) and 1.9% of the placebo group (n=12), with estimated rates of 9.4 events per 1,000 patient-years for celecoxib, and 7.2 events for the placebo group.

Of the total study population, 1,363 patients had no history of cardiovascular or cerebrovascular events. Twenty-three of these patients experienced a serious cardiovascular event. Of the 198 patients with a history of such events, 12 experienced one while enrolled in the PreSAP trial. Arber and colleagues said that there was no significant difference in relative risk between patients with and those without a history of cardiovascular events.

Contrary to the APC trial finding, once-daily celecoxib was not associated with an increase in mean blood pressure.

The significant increase of cardiovascular events prompted the suspension of the administration of celecoxib in both the APC and PreSAP trials. Arber and colleagues wrote that the PreSAP trial data show that celecoxib significantly reduced the risk of colorectal adenomas, which is consistent with other evidence indicating that selective inhibition of Cox-2 may reduce colorectal tumorigenesis. However, specific recommendations for the clinical use of this treatment approach require further investigation.

The PreSAP trial was supported by Pfizer.

The APPROVe trial

Results of the APPROVe study showed that rofecoxib reduced the risk of colorectal adenomas, but also led to serious toxicity. The study was a randomized, placebo-controlled, double-blind trial that enrolled 2,587 patients at 108 sites. All patients had a recent history of confirmed colorectal adenomas. After removal of all polyps, the participants were randomized to receive placebo or 25 mg rofecoxib on a daily basis. The primary endpoint was to analyze all adenomas diagnosed during the three-year treatment period based on colonoscopies conducted at one year and three years after baseline.

An extension to the study was conducted to assess recurrence of adenomas by a colonoscopy in the fourth year. Researchers said that although previous randomized studies have shown that Cox-2 inhibitors can lower the risk of polyps in patients with a rare genetic syndrome, this study was the first to illustrate the effect of the drug in the broad population of people at risk for colorectal cancer.

Researchers found that patients taking rofecoxib had a lower recurrence rate (44%) of adenomas than those taking placebo (55%; RR=0.76, 95% CI, 0.69-0.83).

“These are exciting findings,” said John Baron, MD, senior researcher of the APPROVe study and a professor at Dartmouth Medical School in Hanover, N.H. “They show once again the potential for [non-steroidal antiinflammatory drugs] to interfere with the development of cancer in the colon and rectum.”

Rofecoxib was also found to reduce the risk of advanced adenomas. The chemopreventive effect was larger in the first year than in the subsequent two years. Over the entire length of the trial, patients taking rofecoxib experienced a reduction in the risk of any adenoma.

Silver lining

According to Baron, although the toxicity of the currently available Cox-2 inhibitors may be problematic, the demonstration of efficacy implies that other agents may be suitable for long-term use.

“Because both celecoxib and rofecoxib increase risk of cardiovascular disease, and because there are alternative agents that have similar effects on adenomas (aspirin, sulindac), I don’t think it is likely that the currently available Cox-2 inhibitors will be very widely used for chemoprevention,” Baron said in an interview. “However, these studies solidify the conclusion that NSAIDs inhibit carcinogens in the large bowel. The next steps are continued trials that will inch toward meaningful efficacy with less toxicity. I’m optimistic that we will find an agent that is both safe and effective.”

For more information:

Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885-895.

Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873-884.

Psaty BM and Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas. N Engl J Med. 2006;355:950-952.

Robertson DJ, Greenberg ER, Beach M, et al. Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology. 2005;129:34-41.