Retinoids in the management of head and neck cancer. An update

Despite smoking cessation programs and recent advances in cancer treatment, it is anticipated that head and neck cancer along with lung and esophageal cancers will still be a serious health hazard worldwide. Cancer chemoprevention represents a promising new area of intensive clinical research. Chemoprevention agents which have been considered in clinical trials with the intention of reversing the carcinogenic process include natural agents as well as synthetic retinoids. At the molecular level these agents seem to modify gene expression through the mediation of intracellular-binding proteins and nuclear receptors. In vitro, retinoids induce tumor cell differentiation, inhibit proliferation and also affect other important cell functions, such as adhesion and invasion. Clinical studies conducted in individuals with premalignant lesions, such as oral leukoplakia or laryngeal papillomatosis, have shown that retinoids have the capability to reverse the malignant process in the majority of cases. Furthermore, in patients with head and neck tumors, who became disease-free, after primary treatment, 13-cis retinoic acid (isotretinoin) significantly reduced the incidence of second primaries as compared to placebo. These exciting results urged investigators in Europe and the USA to organize confirmatory trials as well as other chemoprevention trials in order to evaluate the role of new agents. It is hoped that these trials will clarify several important aspects of chemoprevention, such as the safety and activity of new compounds, the significance of integration of retinoids with chemotherapy and/or biotherapy and the establishment of biological markers as intermediate endpoints of carcinogenesis.