Celebrex Shows Benefit In First-of-its-kind Lung Cancer Chemoprevention Trial

The study is the first large randomized trial of Celebrex in lung cancer prevention; the findings will be presented at the American Society for Clinical Oncology's (ASCO) upcoming annual meeting as an oral presentation.

"With this study, in principal, we've been able to demonstrate the importance of COX-2 and the implications on inflammation pathway in lung cancer development," said Edward Kim, M.D., assistant professor in M. D. Anderson's Department of Thoracic Head and Neck Medical Oncology. "We've also been able to demonstrate that this drug class is safe and tolerable for this patient population. As we move forward in lung cancer chemoprevention, the importance of this class of drugs cannot be ignored."

From November 2001 to September 2006, the M. D. Anderson study enrolled 212 individuals, all of whom were current or former smokers with at least a 20-pack-year smoking habit. Most participants did not have any history of cancer; however, patients with a history of cancer who had been disease-free for six months could participate. The median age of participants was 53. The study examined levels of KI-67, a biomarker associated with precancerous lung lesions.

Participants underwent a baseline broncoscopy in which six predetermined biopsies were performed. They then were randomized to receive Celebrex at either 200 milligrams (low dose) or 400 milligrams (high dose) twice a day or placebo. After three months, participants received a second broncoscopy, the primary endpoint of the trial. Patients had the option to continue on the trial for three more months per their prior randomized arm; for those participants, a third and final broncoscopy was conducted at six months.

"In patients who had high risk features such as smoking, especially in the current smokers, we were able to see that a higher dose of Celebrex could decrease the proliferation marker KI-67 in these patients, as seen through their bronchial epithelium," said Kim. "We are encouraged that we have a drug like Celebrex that decreases the expression of this proliferation marker."

These findings are also significant in that the study shows that serial broncoscopies are feasible, explained Kim. "Although CT scanning and other imaging techniques are important, for lung cancer, it may be vital to examine actual tissue to see what the markers are doing in the actual epithelium of the lung so as to best understand if an individual has a higher or lower risk of developing lung cancer."

Celebrex is in a class of medications known as nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin or ibuprofen, which work by blocking chemical enzymes that cause inflammation.

The COX-2 enzyme inside cancer cells is thought to control the synthesis of prostaglandins, which are substances believed to trigger cancer cell growth. Researchers believe that prostaglandins promote the growth of new blood vessels to feed tumors, and also protect new cancers from destruction by the body's immune system. Blocking the COX-2 enzyme may reduce the amount of prostaglandin available to cancer cells and thus repress tumor growth, says Kim.

In December 2004, M. D. Anderson voluntarily suspended the trial at the request of Pfizer and the National Cancer Institute, the funding source for the study, until further data on the drug's risk for cardiac toxicities, specifically heart attacks and strokes, could be investigated. Months later, advisors to the FDA recommended that Celebrex continue to be studied in the treatment and prevention of cancer, and the NCI supported the continuation of the trials, encouraging investigators to weigh the risks and benefits of the drug for their specific clinical setting.

After adding stringent guidelines to further reduce the cardiac risk to patients, the M. D. Anderson investigators then reapplied to the institution's Institutional Review Board to reactivate the trial. The study reopened in May 2005.

Kim noted that there were no adverse cardiac events in the M. D. Anderson trial. Three patients experienced grade three toxicities on the higher dose of the drug which were not cardiac related.

Lung cancer is the leading cause of cancer death in the United States, according to the American Cancer Society. In 2008, approximately 215,000 people will be diagnosed with lung cancer and approximately 114,000 people will die from the disease.

The study was funded by a five-year, $10 million POI lung grant, awarded in 2001 by the NCI to a multi-disciplinary team headed by Waun Ki Hong, M.D., head of the Division of Cancer Medicine. M. D. Anderson has been a leader in chemoprevention since the early 1990s, when Hong was the first to demonstrate that retinoids can reverse oral leukoplakia, a premalignant condition that often leads to cancer, and that 13-cis retinoic acid can prevent secondary primary tumors among patients with head and neck cancers.

"Lung cancer remains a lethal and stubborn disease with tobacco as the leading culprit for this killer," said Hong. "The Celebrex findings are exciting for the entire field of lung cancer chemoprevention."

In addition to Kim and Hong, other M. D. Anderson faculty members on the study include: Jack Lee, Ph.D., professor in the Department of Biostatistics, Li Mao, M.D. professor in the Department of Thoracic/Head and Neck Medical Oncology-Research, Rodolfo Morice, M.D., professor in the Department of Pulmonary Medicine, Diane Liu, statistical analyst in the Division of Quantitative Sciences; Georgie Eapen, M.D., assistant professor in the Department of Pulmonary Medicine; Ignacio Wistuba, M.D., associate professor in the Department of Pathology-Research and Jonathan Kurie, M.D. professor in the Department of Thoracic/Head and Neck Medical Oncology, who served as Principal Investigator on the Celebrex trial.

Updated data will be presented at ASCO on June 2 in the clinical science symposium session "Clinical Testing of Agents for Cancer Prevention: The Price of Progress."