BIOCHEMOPREVENTION THERAPY IN ADVANCED LARYNGEAL DYSPLAS

描述：（申请人的描述） 这是一项前瞻性随机临床试验，旨在研究 联合生物化学预防治疗逆转的生物学效应 和芬维A胺维持治疗对喉发育不良的影响 保持或获得进一步的响应。 在上呼吸消化道 晚期癌前病变携带大量的遗传变化， 单独用类维生素A有效地逆转。 13-顺式 维甲酸（13 cRA）、α-生育酚和α-干扰素产生了 大多数喉发育不良病变的戏剧性逆转 在目前正在进行的研究中治疗，但某些遗传变化持续存在 尽管完全响应。 这一建议的基本假设是： 喉上皮的中度至重度发育不良是由慢性炎症引起的。 致癌物暴露，可作为开发化学预防的模型 战略布局 B）生物标志物可用于定义分子和细胞生物标志物。 与场和多步骤癌变相关的变化以及癌症 风险评估 （c）生物化学预防治疗将有效， 逆转中度至重度喉发育不良，并将改变生物标志物 表情 d）芬瑞林将有效维持反应， 维持生物标志物调节，毒性低于诱导 这将比安慰剂更有效。 e）芬维A胺将 逆转持续性病变，并将进一步调节和可能逆转 基因型和表型改变尚未被调节或逆转 诱导疗法 提出了以下目标：（a）确认 联合生化预防12个月的疗效和毒性， 中度至重度喉发育不良患者。 B）比较 芬维A胺在维持或实现进一步反应中的功效 安慰剂对照并测定其毒性。 （三）评估影响 对遗传生物标志物（染色体）表达的生物化学预防 多体性，染色体9 p、3 p和17 p、p53、p16杂合性丢失 和细胞周期蛋白D1基因状态和蛋白质表达），表型变化 生物标志物（增殖：Ki-67）和核维甲酸受体 表情 d）评价维持治疗在维持 逆转和/或逆转持续的基因型和表型异常。 所有患者（目标样本量为100）将接受联合治疗 生物化学预防治疗12个月，和那些显示反应或 病情稳定的患者将随机接受芬维A胺维持治疗， 24个月 对于生物标志物研究，石蜡包埋活检 将使用基线、12个月和36个月时的样本。 我们将 通过染色体原位杂交分析遗传不稳定性; 9 p的洛缺失， 3 p和17 p的微卫星分析; 免疫组织化学和直接测序分析;以及 免疫组化检测Ki-67、p16和cyclin D1表达。 研究 生物标志物将增强我们对致癌作用的理解， 干预的行动机制;而且，它将提高我们的能力 进行风险评估。 这项研究最终将指导未来的研究。 癌前病变的干预试验，不仅在喉部， 在上皮癌发生中的作用。

DESCRIPTION: (Applicant's Description) This is a prospective randomized clinical trial designed to study the biologic effects of combination biochemopreventive therapy in the reversal of laryngeal dysplasia and the effects of fenretinide maintenance therapy in maintaining or obtaining further response. In the upper aerodigestive tract advanced premalignant lesions harboring substantial genetic changes are not effectively reversed with retinoids alone. The combination of 13-cis retinoic acid (13cRA), alpha tocopherol, and alpha-interferon has produced dramatic reversal of the majority of the laryngeal dysplastic lesions treated in a currently ongoing study, but certain genetic changes persisted despite complete response. The hypotheses underlying this proposal are: a) Moderate to severe dysplasia in laryngeal epithelium results from chronic carcinogen exposure and may serve as a model for developing chemoprevention strategies. b) Biomarkers may be used to define the molecular and cellular changes associated with field and multistep carcinogenesis and for cancer risk assessment. c) Biochemopreventive therapy will be effective in reversing moderate to severe laryngeal dysplasia and will alter biomarker expression. d) Fenretinde will be effective in response maintenance and in maintenance of biomarker modulation with less toxicity than induction therapy and will be more effective than placebo. e) Fenretinide will reverse persistent lesions and will further modulate and possibly reverse genotypic and phenotypic alterations not already modulated or reversed by induction therapy. The following objectives are proposed: a) To confirm the efficacy and toxicity of combination biochemoprevention for 12 months in patients with moderate to severe laryngeal dysplasia. b) To compare the efficacy of fenretinide in maintaining or achieving further response with a placebo control and determine its toxicity. c) Evaluate the effects of biochemoprevention on the expression of genetic biomarkers (chromosome polysomy, loss of heterotozygosity at chromosomes 9p, 3p and 17p, p53, p16 and cyclin Dl gene status and protein expression), phenotypic change biomarkers (proliferation: Ki-67), and nuclear retinoic acid receptor expression. d) Evaluate the efficacy of maintenance therapy in maintaining reversal and or reversing persistent genotypic and phenotypic abnormalities. All patients (a target sample size of 100) will receive combination biochemopreventive therapy for 12 months, and those showing response or stable disease will be randomized to fenretinide maintenance versus placebo for 24 months. For the biomarker studies, paraffin-embedded biopsy specimens at baseline, 12 months, and 36 months will he used. We will analyze genetic instability by chromosome in situ hybridization; LOH of 9p, 3p, and 17p by microsatellite analysis; p53 alterations by immunohistochemistry and direct sequencing analysis; and alterations in ki-67, p16, and cyclin Dl expression by immunohistochemistry. The study of biomarkers will enhance our understanding of carcinogenesis and of mechanisms of action of the intervention; and, it will improve our ability for risk assessment. The proposed research will eventually direct future intervention trials in premalignancy, not only in the laryngeal setting but in epithelial carcinogenesis in general.