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RETINOID CHEMOPREVENTION OF LUNG CANCER

Waun Ki Hong, M.D., Steven E. Benner, M.D., Scott M. Lippman, M.D. Department of ThoracicMead and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston TX 77030

Lung cancer is a significant public health problem worldwide, with 153,000 deaths predicted in 1994. Despite intensive efforts in primary prevention, screening, and therapy, long-term survival rates have not improved substantially since the 1960s. One promising approach for controlling lung cancer which is currently under investigation is chemoprevention, defined as the use of selected synthetic, chemical, or natural agents to reverse or suppress the carcinogenic process.

One of the three basic concepts that supports chemoprevention is the multi-step nature of carcinogenesis. Epithelial cancers in the aerodigestive tract appear to develop in a predictable series of steps. Epithelial carcinogenesis is conceptually divided into three phases, initiation, promotion, and progression. This process has been inferred from human studies identifying clinical-histological premalignant lesions, for example, leukoplakia, metaplasia, and dysplasia, associated with malignant transformation rates up to 30-40%.

The second supporting concept for chemoprevention is that of field carcinogenesis, which proposes that repeated exposure to carcinogens such as tobacco can result in multiple neoplastic lesions of independent origin within the aerodigestive field. This is supported by the fact that patients who develop cancers of the aerodigestive tract secondary to cigarette smoke are also likely to have multiple premalignant lesions of independent origin within the carcinogen-exposed field.

The third support provided for chemoprevention is the significant activity that retinoids have already shown in preventing or suppressmg human cancers. Data from in ~itn), animal and epidemiologic studies strongly support the role of retinoids and carotenoids in the prevention of epithelial carcinogenesis. Retinoids are well-established agents for epithelial cell growth and differentiation in I~~IYI and in ~*i/m. Retinoids can suppress carcinogenesis in a variety of epithelial tissues including the skin, trachea, lung and oral mucosa Recent investigations suggest that retinoids modulate or inhibit carcinogenesis by directly modulating gene expression through mediation of nuclear retinoic acid receptors.

The theories of multi-step carcinogenesis and field carcinogenesis are strongly supported by laboratory biomarker data in many epithelial tumor systems. A number of inhibitors of the carcinogenic process have been identified through animal model systems; these include retinoids for inhibiting epithelial carcinogenesis.

Chemopreventive agents act by altering the pathway of the cells from proliferation to differentiation and acquisition of fully matured cells. A great deal has been learned recently about the mechanism of cellular differentiation, inhibition of cell proliferation, growth factors, and other cellular attributes which are involved in the progression of preneoplastic cells to neoplastic phenotypes. Based on encouragin g results of several clinical trials (i.e., the efficacy of 13-cis-retinoic acid [ I3cRA] in suppressing oral premalignant lesions and reducing incidence of second primary tumors in patients with head and neck cancer; and the efficacy of retinyl palmitate in reducing the incidence of second primary tumors in patients with lung

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cancer), coupled with a better understanding of molecular and cellular biology, chemoprevention concepts are being expanded to lung carcinogenesis. If the chemoprevention approach is shown to be effective in reversing premalignant lesions, individuals at increased risk for cancer can be protected from progression to full-blown malignancy.

Several lung chemoprevention trials have used retinoids in attempts to reverse lung premalignancies. These trials have used progressive changes in the bronchial epithelium, such as metaplasia or dysplasia, as study end points. Their results have shown that the retinoids 13cRA and etretinate have no effect on metaplasia and sputum atypia, but that the significant response of metaplasia to smoking cessation in the l3cRA trial, and its significant spontaneous variability, indicates that metaplasia may be one of the earliest stages in the carcinogenic process. Retinoids have shown activity in later stages of the carcinogenic process, and it is therefore possible that they are active in later stages of lung premalignancy. The activity of retinoids in the chemoprevention of lung cancer remains to be established in future trials using intermediate biomarkers that reflect later stages of carcinogenesis.

Retinoid chemoprevention trials are also being carried out in the prevention of second primary tumors; the lifetime risk of second primary tumors following early stage lung cancer is 20 percent to 40 percent. Ongoing trials throughout the world are testing a variety of retinoids and retinoid combinations, including low-dose 13cRA, retinyl palmitate and N- acetylcysteine, and beta-carotene and retinol.

This presentation will focus on several areas, including: the completed double-blind 13cRA trial of bronchial metaplasia in smokers; the status of the ongoing intergroup trial in preventing second primary tumors in patients with Stage I non-small cell lung cancer; the ongoing N (4-hydroxyphenyl)retinamide (4-HPR) trial in patients with bronchial metaplasia and dysplasia; and the role of nuclear retinoic acid receptors in reversing oral and bronchial premalignant lesions.

References:

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