Scott M. Lippman

Chemoprevention strategies for the control of cancer

High incidence and low survival rates of many epithelial cancers remain beyond the control of established preventive and therapeutic modalities. Chemoprevention is a new approach under study that involves the intervention within the premalignant process with specific chemical agents to reverse carcinogenesis and prevent the development of invasive cancer. The two biologic concepts that underlie this research are multistep carcinogenesis and field carcinogenesis. Major clinical issues include trial design and drug development in head and neck, lung, and breast cancer chemoprevention. Within the area of trial design, intermediate end point biomarkers will become very important for providing biologic insights in the short term and greater trial efficiencies in the long term. Drugs that are under the strongest investigation include retinoids and β‐carotene in the head and neck and lung, calcium in the colon, and tamoxifen in the breast. This new field has the potential to make an important contribution toward increasing our control over many deadly epithelial cancers.

Retinoid chemoprevention of aerodigestive carcinogenesis

Epithelial cancers of the upper aerodigestive tract, lung and esophagus are a significant public health problem throughout the world. Despite improvement in local treatment and decreasing cigarette consumption in developing countries, the incidence of aerodigestive cancers unfortunately continues to increase worldwide. Clearly, new directions are needed.

Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia

PURPOSE Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers. PATIENTS AND METHODS We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment. RESULTS In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke. CONCLUSION Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.