Case Study III Chemoprevention Studies of Retinoids and Second Primary Cancers of the Upper Aerodigestive Tract

One of the first definitive proofs of principle for chemoprevention came from the translational studies of Kim and Hong and colleagues, who have studied retinoids and other chemo-preventive agents in upper aerodigestive tract cancers since the early 1980s. Clinical, epidemiologic, and animal studies in the 1970s and 1980s had suggested that vitamin A could positively influence epithelial cell differentiation and thus, retinoids may be effective agents for preventing epithelial cancers in the upper aerodigestive tract.37

Chemoprevention Trials of Upper Aerodigestive Tract Cancers by Retinoids

As summarized in Table 23.3, Hong et al. established that high-dose 13-cis retinoic acid (13-CRA) is more effective than placebo in reversing oral premalignant lesions (OPLs)38 and later showed that low-dose 13-CRA is more effective than b-carotene and less toxic than high-dose 13-CRA.39,40 These studies demonstrate that retinoids can indeed be used to reverse OPLs, as suggested by several reports in animal models.41-43 Further explorations of less toxic and more effective agents and regimens were accomplished by incorporating multidisciplinary studies of biomarkers into their trials and the development of statistical methodologies for analyzing multiple biomarkers for the prediction of cancer development in patients with OPLs,44 Studies by Hong and colleagues demonstrate the importance of conducting parallel basic and translational studies. They observed that the synthetic retinoid fenretinide induces apoptosis through retinoic acid receptor-independent mechanisms and induces cell death in cell lines resistant to all-trans retinoic acid, 13-CRA, 9-CRA, and other nuclear receptor-dependent retinoids.45 These findings have led to an ongoing trial of fenretinide in patients with retinoid-resistant OPLs and to the characterization of several novel retinoids with even more potent apoptosis-inducing effects than fenretinide.46 Further studies are needed to determine whether these agents reduce mortality after treatment is completed.

The Hong group, along with many groups studying chemoprevention of OPLs, are currently moving away from retinoids toward less toxic agents, including bioactive food components, such as vitamin E and green tea polyphenols, or pharmacologic agents that target specific pathways, such as inhibitors of farnesyl transferase, cyclooxygenase 2, or the epidermal growth factor receptor. However, these initial studies of retinoids were critical to establish the feasibility of developing a translational chemoprevention strategy.

These translational research findings also led to new combination approaches to preventing OPLs. Retinoid resistance was shown to be associated with higher levels of genetic instability and mutant p53 expression.47 Combination regimens of 13-CRA, a-tocopherol, and interferon-g have been very effective in reversing laryngeal premalignant lesions but not OPLs,48 probably because some, but not all, of the p53-mutated OPL clones can be eliminated, suggesting that some genotypically altered clones can regrow and manifest as phe-notypic lesions after treatment is discontinued.49,50

TABLE 23.3. Prevention trials evaluating chemoprevention of upper aerodigestive tract cancers by retinoids.

Reference

Sample Size

Design

Intervention

Primary results

Papadimitrakopoulou48

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