COX-2 Inhibitor, Celecoxib, May Prevent Lung Cancer

A study in the journal Cancer Prevention Research has shown evidence that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, may be a potent chemopreventive agent for lung cancer (doi: 10.1158/1940-6207. CAPR-11-0078). According to Jenny Mao, MD, the findings "strongly suggest that celecoxib can be used as a chemopreventive agent in these high-risk groups."

Space-filling model of the celecoxib molecule. Source: Ephemeronium, Wikimedia Commons

Source: David Shay, Wikimedia Commons

Dr. Mao is a professor of medicine at the University of New Mexico and section chief of pulmonary and critical care medicine at the New Mexico VA Health System. The first author and her collaborators from the David Geffen School of Medicine at University of California Los Angeles and the Division of Cancer Prevention at the National Cancer Institute (NCI) tested the COX-2 inhibitor among former smokers who quit at least 1 year prior to enrolling in the study, who had smoked more than 30 pack-years, and who were at least 45 years old.

"The oncology community does not have a good treatment for lung cancer. Unless it is caught in the earliest stages, the five-year survival is only about 15 percent," said J. Jack Lee, a professor of biostatistics at The University of Texas MD Anderson Cancer Center. "The best way is to intercept at the earliest stages and try to reverse the processes that can lead to cancer. These studies suggest celecoxib may be a tool to do that."

Study rationale

An estimated 222,520 new cases of lung cancer were diagnosed in 2010 in the United States. Lung cancer (both non–small-cell and small-cell) is the second most common cancer and the most common cause of cancer death in the United States. Approximately 157,300 people died of the disease in 2010, according to the NCI.

Many of these cases are smoking-related, and both smoking prevention and cessation are key in preventing lung cancer. While smoking cessation does not eliminate risk for lung cancer development, it does eliminate a significant risk for former smokers. The authors reasoned that chemoprevention in former-smokers would greatly aid in decreasing the risk of lung cancer in this population. According to Professor Lee at the MD Anderson Cancer Center in Texas, there are approximately 45 million former smokers and 45 million current smokers in the United States.

Previous studies have suggested that the COX-2/prostaglandin E2 (PGE2) pathway plays a key role in cancer development and that inhibition of the pathway via a COX-2 inhibitor can prevent lung cancer development. There is ample evidence from animal models that COX-2 inhibition has antineoplastic effects in the lung, and this was the rationale for examining the effect of celecoxib in preventing bronchogenic carcinoma in a randomized prospective trial. The impetus for the current phase IIb trial was a 6-month celecoxib phase IIa trial that reduced key surrogate lung biomarkers of 20 heavy active smokers.

The study design

Because active smokers generally fair poorly in chemopreventive trials and former smokers have had neutral results in chemopreventive trials with beta-carotene and retinoid, and because celecoxib had demonstrated potential in the previous IIa trial, the current randomized, double-blind trial was designed to test whether celecoxib in former smokers would reduce levels of lung carcinoma biomarkers. The primary and secondary endpoints were the level of Ki-67 LI and computed tomography and histology, respectively.

Ki-67 is a proliferative biomarker that has been causally linked to lung cancer development and is an unfavorable prognostic factor in non–small-cell lung cancer (NSCLC). The fluctuation of this biomarker can be readily measured and may preempt histopathology changes, allowing for earlier detection of carcinogenesis.

137 former smokers with an average age of 55 and ~43 cigarette pack-years were randomized 1:1 to receive either 400 mg oral celecoxib twice daily or placebo for 6 months total. Patients were evaluated monthly for health status and every 3 months for histology and biomarkers.

The results

The beneficial effect on Ki-67 LI levels was greater in patients treated with celecoxib compared with placebo (P = .0006). Celecoxib significantly reduced Ki-67 LI by an average of 34%, compared with a 3.8% reduction in those taking placebo. Decreases in Ki-67 LI were also linked with a reduction in lung nodules, a potential precursor to cancer. Reduction and changes in lung nodules were strongly correlated with decreased Ki-67 (P = .008).

Celecoxib was generally well tolerated, with the majority of exhibited adverse events categorized as grade 1. Overall, 47 study participants reported at least one adverse event, with only six grade 3 events, four of which were not thought to be drug-related.

Although a large-scale phase III trial is needed to confirm these findings, the data so far suggest that celecoxib is biologically active in lung epithelial tissue and capable of altering key biomarkers that presumably reflect the path towards carcinogenesis in the lungs.

If the biomarkers are indeed confirmed to be biologically relevant and the driver for lung cancer development, their changes would greatly facilitate early cancer detection. Using relevant biomarkers as a read-out is important, since molecular and biochemical changes often occur before detectable histological changes. This is particularly important for lung cancer, in which biopsies are often difficult.

This trial additionally emphasizes a personalized medicine approach. Identification of the molecular characteristics of a particular individual allows for better assessment of disease and more predictable treatment responses.