The Biology Behind NSAIDs for the Chemoprevention of Oral Cancer: Promise or Pessimism? Commentary re J. L. Mulshine et al., Randomized, Double-Blind, Placebo-Controlled, Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal

Introduction Oral cancer causes considerable morbidity and is associated with a 5-year survival rate of less than 50%. It is a major problem in populations in which alcohol and tobacco use are prevalent such as in lower socioeconomic communities. Oral cancer, like cancers in many other sites, is often preceded by the development of premalignant lesions of the oral mucosa, also termed intraepithelial neoplasia. Among these premalignant lesions are leukoplakia, erythroplakia, hyperplasia, and dysplasia with leukoplakia being the most common (1). To date, there are no effective treatments documented in randomized controlled clinical trials to prevent malignant transformation of leukoplakia (2). Isotretinoin has been shown to be effective in the resolution of these lesions; however, relapses and significant adverse effects are common (3). The present treatment of choice for premalignant localized oral leukoplakia is surgical removal, but wide distribution of mucosal lesions precludes excision in many patients. Despite even aggressive mucosal resections, these lesions tend to relapse or new lesions appear. In addition, a substantial portion of oral cancers develop away from the site of the visible lesions, perhaps because of widespread abnormalities, the so-called field defect, or through lateral spread from the sentinel lesion further bolsters the appeal of chemoprevention in this clinical setting (4). Therefore, chemoprevention is an attractive approach to the treatment of leukoplakia and oral cancer prevention. Lack of effective therapy is the main rationale for studies examining the ability of a variety of agents, both natural or synthetic, to inhibit carcinogenetic events in the oral mucosa. Premalignant lesions and malignant lesions of the upper aerodigestive tract have been shown to express genotypic and phenotypic abnormalities including increased DNA index, specific chromosomal abnormalities, and an inactivating mutation of the p53 tumor suppressor gene (5–8). The dysregulation of p53 in the mucosal epithelium correlates with increased proliferative activity (9). Moreover, p53 status has been shown to be a predictor of progression of premalignant oral dysplasias to invasive cancers (10). These molecular alterations have stimulated rational chemopreventive agent selection that targets specific abnormalities detected in the cells of the oral mucosa. Several classes of agents have shown promise as chemopreventive agents including the nonsteroidal anti-inflammatory drugs (NSAIDs), which possess a valid scientific basis for the chemoprevention of multiple cancers. For those cancers in which they have demonstrated chemopreventive potential, evidence of efficacy is derived from epidemiological, animal studies in relevant model systems, and from tissue cell culture studies. In addition, recent prospective randomized controlled trials have demonstrated convincingly that aspirin prevents the development of intraepithelial neoplasia in the colon and rectum (11, 12).