In a previous trial, we found that combined
13-cis-retinoic acid, IFN-alpha, and
alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that
cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with
cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and
protein expression, in association with
cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined
13-cis-retinoic acid daily, alpha-IFN twice weekly, and
alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance
fenretinide or placebo for 2 years. During induction, two patients had
pathologic complete responses, six had partial responses (30% overall response rate), and five developed
laryngeal cancer. There were no significant differences between maintenance
fenretinide and placebo in response or
cancer rates. Ten patients developed
cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1
protein expression. Consistent with our earlier report, shorter
cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse
cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and
protein expression as important risk markers for
laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.