This is a prospective, non-randomized clinical and laboratory feasibility trial to study adjuvant biologic therapy for stage III/IV head and neck cancer in conjunction with the biomarker study. Adjuvant therapy in advanced H&N cancer after definitive local therapy has not been established, although the survival rate is still detrimental because of the high incidence of recurrence and second primary tumor development. The applicant proposes this study in an adjuvant setting using 13-cis-retinoic acid (13 cRA), alpha-tocopherol, and alpha-interferon to prevent both recurrence and second primary tumors. Biomarker studies have been incorporated to enhance the understanding of pathobiology for tumor development and biological risk assessment for patterns of treatment failure. The hypotheses underlying this application are: (1) head and neck cancer development is derived from the carcinogen exposed field in a multistep process where genomic instability is ongoing, which may lead to the development of primary and/or second primary tumors; (2) adjuvant therapy using 13cRA, alpha tocopherol, and alpha-IFN, will be effective in the prevention of recurrence and/or second primary tumors; and (3) biomarkers may be used to define the molecular and cellular changes associated with field cancerization and multistep carcinogenesis and to identify individuals at an increased risk for recurrence and second primary tumors. With these working hypotheses, the applicant proposes the following specific aims: (1) to determine the efficacy and toxicity of adjuvant therapy with 13cRA, alpha-tocopherol and alpha-IFN in preventing recurrence and second primary tumor development in patients with stage III/IV head and neck squamous cell carcinoma following definitive local therapy; (2) to evaluate the overall and disease free survival; (3) to evaluate the alterations of biomarkers (p53 alterations, chromosomal changes, retinoic acid receptor-beta, expression of interferon inducible genes, and the interferon signal transduction pathway) in adjacent premalignant lesions and tumor tissue at baseline and at time of either recurrence or second primary tumor development and to determine whether alterations of these biomarkers are related to the patterns of treatment failure. To achieve these goals, 45 patients will receive 13cRA, alpha-tocopherol, and alpha-IFN for 12 months. For the biomarker studies, p53 expression/mutations by immunohistochemistry and PCR-SSCP sequencing analysis, retinoic acid receptors by RNA in situ hybridization, and interferon responsiveness by interferon receptor analysis and 2',5' oligoadenylate synthetase assay will be performed. This translational research of integration of biomarker studies into an adjuvant clinical trial will promote a unique opportunity to improve the pathobiologic understanding of tumorigenesis and biologic basis of patterns of treatment failure to the proposed therapy. Furthermore, this feasibility study will be a good basis for the future randomized adjuvant trial after definitive local therapy.
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| Shin, D M; Donato, N J; Perez-Soler, R et al. (2001) Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7:1204-13 |
| Tae, K; El-Naggar, A K; Yoo, E et al. (2000) Expression of vascular endothelial growth factor and microvessel density in head and neck tumorigenesis. Clin Cancer Res 6:2821-8 |
| Shin, D M; Mao, L; Papadimitrakopoulou, V M et al. (2000) Biochemopreventive therapy for patients with premalignant lesions of the head and neck and p53 gene expression. J Natl Cancer Inst 92:69-73 |
