Potential Chemopreventive Role for Celecoxib in Lung Cancer

Roxanne Nelson

June 05, 2008

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Lead author discusses the study with Medscape Oncology

June 5, 2008 (Chicago, Illinois) — Celecoxib (Celebrex) could potentially play a role as a chemopreventive agent for lung cancer; it was able to reduce the expression of Ki-67, a biomarker associated with bronchial premalignant lesions. The study is the first reported randomized trial of celecoxib in lung cancer chemoprevention, and the findings were presented here at the American Society of Clinical Oncology 44th Annual Meeting.

"We know that smoking defines a high-risk population, but we also know that there are people who develop lung cancer who have had limited exposure to tobacco smoke, and that there smokers who never develop lung cancer," said lead author Edward S. Kim, MD, assistant professor of medicine at the University of Texas MD Anderson Cancer Center in Houston. "So we have to continue to define what we consider to be a high-risk population, and that includes not only clinical risk but also biologic characteristics. That means we have to look at biomarkers."

Although a number of large-scale chemoprevention studies have been conducted, none have yet yielded positive results. "Now we are looking at smaller groups that are more defined by their risk factors," explained Dr. Kim during a press conference. "And when we consider any sort of prevention trial, we want to make sure that the agent is safe and effective."

Cyclooxygenase-2 (COX-2) is overexpressed in bronchial premalignant tissue and enhances cell proliferation and survival. Premalignant lesions have enhanced cellular proliferation, as measured by nuclear Ki-67 expression. Ki-67 is detectable in basal and parabasal layers in the normal bronchial epithelium. The researchers speculated that celecoxib is active in the bronchial epithelium of current and former smokers, and examined the effects of celecoxib on Ki-67 levels for up to 6 months.

From November 2001 to September 2006, 204 patients (162 of whom were current smokers and 182 of whom had no cancer history) were randomized to 1 of 4 treatment groups: celecoxib then placebo; celecoxib then celecoxib; placebo then celecoxib; placebo then placebo. Celecoxib was administered at 200 mg twice daily (81 patients) and then at a higher dose of 400 mg twice daily (123 patients). All participants were required to have at least a 20 pack-year smoking history, and those with a history of cancer had to be disease-free for at least 6 months.

Patients underwent bronchoscopy with biopsies at baseline, and at 3 and 6 months, and the researchers observed that baseline Ki-67 expression in basal and parabasal layers was higher in current smokers than in former smokers (P = .001 and P = .005, respectively). Multicovariable analyses also showed that basal-layer Ki-67 expression was reduced in both current and former smokers who received the 400 mg dose, but not the 200 mg dose.

This study demonstrates the possible importance of COX-2 inhibition in the prevention of lung cancer, the researchers noted, and the fact that it might be effective in downregulating proliferation in the bronchial epithelium of high-risk patients. Celecoxib was safe and tolerable, with 3 patients reporting grade 3 toxicities on the higher dose, none of which were cardiac related. None of the study participants experienced any cardiovascular events during the course of the study.

Risk for Cardiovascular Events

Celecoxib has been evaluated for its chemopreventive potential in other cancers, but many of these trials have been halted because of a possible association with an increased risk for cardiovascular events. The MD Anderson Cancer Center voluntarily suspended this trial in December 2004, at the request of Pfizer, the manufacturer of celecoxib, and the National Cancer Institute (NCI), until the risk for cardiovascular toxicities could be more thoroughly investigated.

Advisors to the US Food and Drug Administration eventually recommended that the study of celecoxib in the treatment and prevention of cancer be continued. The NCI also supported continuing these trials, but encouraged researchers to weigh the risks and benefits of celecoxib in their particular clinical setting. The trial was reopened in May 2005.

"Certainly, there have been some changes in the way we perceive COX-2 inhibitors in certain populations," said Dr. Kim. "We can't say that everyone who uses COX-2 inhibitors is going to have a cardiac event. We know that cardiac events increase with aging; it's the number 1 risk factor. What we had to do during this trial was to add a cardiology evaluation and consultation; it was an extra layer of protection."

Dr. Kim expressed concern about the chronicity of treatment with celecoxib, in light of possible cardiac effects. "One of the study arms was 6 months, and we are not sure how long a patient should stay on a drug like this."

"I hope that if we decide to use celecoxib for longer periods of time, we are able to define patients who are at less risk for cardiac events, but that may be difficult upfront," he said. "The other way to do that is to find patients who are at a higher risk of developing lung cancer; that risk would outweigh the risk of cardiac events, and that is the balance that we have to strive for."

Balancing Risk and Benefit

"This study is an important contribution to the research in this field," Steven Dubinett, MD, professor of medicine and director of the Lung Cancer Research Program at the University of California, Los Angeles, commented in a discussion of the study. It shows an impact on a biomarker that is involved in epithelial proliferation, and it shows that intervention in the prostaglandin pathway may be important. However, he told Medscape Oncology in an interview, "this is just a place on the station to the future."

There are other ways to interfere with this pathway, and celecoxib may not be the answer; he said. It may be that interfering with prostaglandins rather than the cyclooxygenase enzyme COX-2 will yield better results. Currently, there are 2 other trials in progress, and both should be reporting results before the end of the year. One study is investigating iloprost (prostacyclin) in current and former smokers; another is looking at celecoxib in former smokers. These results will add more pieces to the puzzle, he said.

Dr. Dubinett commented that fellow oncologists have said to him that if celecoxib had chemopreventive properties, they would have surely noticed by now, considering how many people take the drug for arthritis and related conditions. However, the dose is very important, Dr. Dubinett noted. In a study his group conducted 2 years ago, in patients with established lung cancer treated with erlotinib and celecoxib, there was a 65% reduction in prostaglandin E2 with the 400 mg dose of celecoxib, but a reduction of less than 10% with the 200 mg and 300 mg doses. Thus, it is fortunate that Dr. Kim's study used the 400 mg dose, he said.

However, this higher dose has been discouraged in the general population because it carries a higher risk for cardiac toxicity. Recently, cardiologist Steven Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, in Ohio, said that the use of this higher 400 mg dose is unethical. In answer, Dr. Dubinett said that ethics depend on the setting. In a patient with terminal cancer and 6 months to live, the risk of an increase in cardiac toxicity after 1 year becomes a small consideration. "As always, it comes down to the risk–benefit ratio," he said.

The study was funded by the National Cancer Institute.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting. Abstract 1501. Presented Monday June 2, 2008.