Overview of chemoprevention strategies for head and neck cancer.

CS02-03 Head and neck squamous cell carcinoma (HNSCC), the most common epithelial malignancy arising in the upper aerodigestive tract, is an important public health problem HNSCC is clearly associated with the widely accepted risk factors of tobacco smoking and alcohol use and is the result of a multiyear, multipath disease process of progressive genetic and associated tissue damage. A brief historical perspective on intervention trials of active agents points out two areas of focus: reversal of premalignant lesions and prevention of second primary tumors (SPTs). Retinoids have an established efficacy in reversing early premalignant lesions but are associated with mucocutaneous toxicity. After Hong et al. demonstrated in their 1986 randomized trial that high-dose 13-cRA for three months had a 67% response rate versus 10% for placebo (P = 0.002), several other trials confirmed retinoid and vitamin A activity in oral premalignant lesions. Building on the single-agent retinoid experience showing that one retinoid is not sufficient to reverse moderately and severely dysplastic lesions (which are more prone to transform than are hyperplastic lesions), a combination of interferon-α, α-tocopherol, and 13-cRA was evaluated. This combination was active in preventing the progression of laryngeal lesions, leading to a study in laryngeal lesions that revealed persistent genetic abnormalities despite response. However, the realizations that carcinogenesis is multifocal and multiclonal, even within the same lesion, that not all IEN progresses to cancer or can be readily detected and measured, and that no specific drug can target all genetic changes have made it increasingly clear more precise definitions of risk ( versus risk defined by histologic IEN only) are necessary in order to proceed with rational chemoprevention trials with novel chemopreventive agents. LOH studies of specific loci in the genome harboring tumor suppressor genes have pointed out the power of LOH at these loci as predictors of oral cancer development. Specifically, LOH at 3p and 9p is not only frequent but also a predictor of progression to invasive cancer and of a second oral malignancy at previously treated oral cancer sites. Moreover, the concept of field cancerization has been genetically confirmed by LOH findings showing the clonal relationship of transformed cells in large areas of mucosa. Microsatellite analysis at the 9p, 3p, 17p, 8p, 13q, and 18q chromosomal regions and mutation analysis for p53 have shown that genetically altered mucosa remains after treatment in a significant proportion of HNSCC patients, a finding with potentially significant clinical implications. Retinoid prevention studies have highlighted the predictive power of polymorphisms of the cyclin D1 gene, which is often used as a marker of resistance and a predictor of shorter time cancer development. Retinoid-dependent cyclin D1 proteolysis has been suggested as a candidate intermediate marker for effective retinoid chemoprevention. EGFR overexpression occurs frequently in HNSCC, is a poor prognostic factor, and is detected early during head and neck carcinogenesis, constituting a potential target. Multiple lines of evidence suggest that COX-2 has a significant role in head and neck carcinogenesis; recent findings suggest that COX-2 is overexpressed in the oral mucosa of active smokers through tobacco-smoke stimulated EGFR tyrosine kinase activity. Current prevention studies in the settings of oral IEN and SPT prevention involve intervention targeted toward p53 abnormalities, as well selective COX-2 and EGFR tyrosine kinase inhibitors and the epigallocatechin gallate (EGCG) component of green tea. SPTs in curatively treated patients occur with an annual rate ranging from 1.2% to 4.7% in retrospective studies and from 4% to 7% in prospective studies. Initial studies in this setting suggested the potential effect of high-dose retinoids. SPTs developed in significantly fewer 13-cRA-treated patients (4%) than in patients receiving placebo (24%) (P = 0.005). Although the overall annual decrease in SPTs has lessened over time since the one-year intervention was completed, the reduction has persisted for the subset of SPTs within the high-risk tobacco-exposed field of the head and neck, lung, and esophagus. These results have not been confirmed by studies with different retinoids such as etretinate and retinyl palmitate (with N -acetylcysteine) within the EUROSCAN trial or in the NCI C91-002 trial, where patients were prospectively randomized to low-dose 13-cRA for three years versus placebo. Retinoid-associated toxicity and the need for long-term targeted prevention strongly point to the need for developing other classes of agents. Defining risk models is a critically important area of head and neck cancer prevention. At least for trials planned in the near future, information such as LOH at critical loci should be included in trial screening or stratification criteria, along with more standard criteria such as the presence of a preneoplastic lesion or prior cancer. New studies should integrate exploratory analyses of both risk markers, ideally target-specific, and pharmacodynamic markers of efficacy and/or resistance to the intervention and integrate novel technology to construct molecularly based risk models.