9cRA Shown to Reverse Premaliagnant Changes in Ex-Smokers

ORLANDO - About half of the new cases of lung cancer diagnosed each year occur in patients who have already quit smoking. Treatment with oral doses of 9-cis-retinoic acid (9cRA), a form of vitamin A, might help protect ex-smokers from previous damage done to their lungs, said Jonathan M. Kurie, MD, Thoracic and Head and Neck Medical Oncology, M.D. Anderson Cancer Center.

At the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1177), Dr. Kurie presented data from a randomized, placebo-controlled trial showing that 9cRA significantly increased expression of the retinoic acid receptor- (RAR-) in former smokers. This effect was associated with a significant decrease in the amount of squamous metaplasia in bronchial biopsies and suggests that upregulating RAR- expression can, indeed, reverse some of the lung damage that leads to cancer in former smokers.

Dr. Kurie conducted this National Cancer Institute-funded study with his colleagues at M.D. Anderson, National Cancer Center Hospital, Tokyo, and Southwestern Medical Center, Dallas.

"All chemoprevention trials in current smokers have been negative or actually harmful. Beta-carotene, for example, increases conversion of procarcinogens to carcinogens in smokers," Dr. Kurie said. "These harmful effects are not seen in nonsmokers or former smokers. Since former smokers now account for 50% of lung cancers, they are an important group for trials of potentially protective agents."

Heavy smoking reduces expression of the RAR- receptor. Such receptor loss makes cells unresponsive to normal growth regulator signals and is associated with an increased risk of preneoplastic cellular changes. Loss of RAR- expression is thought to be a useful biomarker for identifying cells likely to become cancerous.

The researchers randomized 226 ex-smokers to 3 months of treatment with one of three treatments: 9cRA, 13-cis-retinoic acid (13cRA) plus alpha-tocopherol (a synthetic form of vitamin E), or placebo. All subjects had smoked at least 20 pack-years and had stopped smoking at least 12 months before the trial.

Subjects had bronchoscopic biopsies at six predetermined sites. Biopsies were done prior to treatment, after 3 months of treatment, and 3 months after the end of treatment. Biopsies were evaluated for loss of RAR- expression and for squamous metaplasia or dysplasia.

Dr. Kurie presented data on 177 patients who had baseline and 3-month biopsies. At baseline, 69.9% of biopsies from these patients (948 of 1,357) still expressed RAR-, but 7.0% of the biopsy sites (98 of 1,398) showed metaplasia.

The primary study endpoint was reversal of RAR- loss over the first 3 months of treatment. This was quantified as the RAR- Index, defined as the percent of biopsies that expressed RAR-. After 3 months of treatment, the RAR- Index increased significantly in the 9cRA arm but decreased in the 13cRA/alpha-tocopherol arm and in the placebo arm (see Table). Metaplasia also decreased significantly in the 9cRA arm (P = .01).

Dr. Kurie concluded that 9cRA is biologically active in the lung, reverses biomarkers of bronchial preneoplasia in former smokers, and should be studied in larger groups of patients. However, he also told ONI that although upregulating expression of the RAR- receptor appears to be a promising strategy for preventing lung cancer, 9cRA (which is not commercially available) was associated with headache, skin rashes, and fatigue, and might not be the best candidate for achieving that effect.