This is a prospective, non-randomized clinical trial designed to study the biologic effects of combination biochemopreventive therapy for the reversal of advanced premalignant lesions including moderate and severe dysplasia in the upper aerodigestive tract. Chemopreventive therapy using retinoids alone has not been effective for the advanced premalignant lesions that will imminently develop into invasive cancer. Therefore, we propose a more aggressive regimen including 13-cis-retinoic acid (13cRA), alpha-tocopherol, and interferon-alpha for these advanced premalignant lesions. Biomarker studies have been incorporated to enhance understanding of pathophysiology for the tumor development and risk assessment, and as """"""""intermediate endpoints"""""""" in the chemoprevention trial. The hypotheses underlying this proposal are: 1) advanced premalignant lesions in the epithelium of the upper aerodigestive tract result from chronic carcinogen exposure and may serve as a model for developing chemoprevention studies; 2) biomarkers may be used to define the molecular and cellular changes of field and multistep carcinogenesis, and to identify individuals at increased risk for the development of cancer; and 3) biochemopreventive therapy will be effective in reversing advanced premalignant lesions, and will modulate a panel of the expression of biomarkers. With these working hypotheses, we propose the following specific objectives: 1) to determine the efficacy and toxicity of biochemopreventive therapy in patients with advanced premalignant lesions; 2) to evaluate the effect of this combination in modulating the expression of biomarkers of carcinogenesis, including genetic markers (chromosomal changes, p53 expression/mutation), phenotypic changes (proliferating cell nuclear antigen, epidermal growth factor receptor), and nuclear retinoic acid receptors; and 3) to evaluate the measurement of cell apoptosis and interferon response as biological phenomenon of the effect of biochemopreventive therapy, including in situ end-labeling assay and interferon receptor analysis. To achieve these goals, all patients will receive interferon-alpha, 13cRA and alpha-tocopherol for 6 months, then will be evaluated for response. The responders will continue on therapy for 6 more months, and nonresponders will be taken offstudy and followed for up to 1 more year for all patients. Target sample size for this protocol will be 35 patients by the Simon's two- stage phase II trial. For the biomarker studies, we will utilize the paraffin-embedded biopsied specimens at baseline, 6 months, and 12 months of therapy. Using biopsied specimens, we will analyze genetic instability by chromosome in situ hybridization, p53 alterations by immunohistochemistry and PCR-SSCP/sequencing analysis, phenotypic alterations of PCNA and EGFR by immunohistochemistry, retinoic acid receptors by RNA in situ hybridization, and cell apoptosis and interferon response by in situ end labeling assay and interferon receptor analysis. This integration of biomarker studies into the chemoprevention trial will provide a unique opportunity to improve our pathobiological basis of understanding of tumorigenesis and responsiveness to the proposed therapy. This proposed translational research will eventually direct future intervention trials of premalignant lesions, not only in the upper aerodigestive tract, but also in other human epithelial malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA068089-01
Application #
2111940
Study Section
Special Emphasis Panel (SRC (26))
Project Start
1995-09-14
Project End
1998-08-31
Budget Start
1995-09-14
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Izzo, Julie G; Papadimitrakopoulou, Vassiliki A; Liu, Diane D et al. (2003) Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 95:198-205
Papadimitrakopoulou, Vassiliki A; Liu, Diane D; Mao, Li et al. (2002) Biologic correlates of a biochemoprevention trial in advanced upper aerodigestive tract premalignant lesions. Cancer Epidemiol Biomarkers Prev 11:1605-10
Papadimitrakopoulou, V A; Izzo, J; Mao, L et al. (2001) Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development. Clin Cancer Res 7:3127-34
Hittelman, W N (2001) Genetic instability in epithelial tissues at risk for cancer. Ann N Y Acad Sci 952:1-12
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
Mao, L; El-Naggar, A K; Papadimitrakopoulou, V et al. (1998) Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 90:1545-51