LUNG CANCER CHEMOPREVENTION WITH CELECOXIB IN EX-SMOKERS

肺癌是美国癌症死亡的主要原因，治疗肺癌的主要障碍之一是晚期表现，此时治疗的选择主要是姑息性的。 缺乏有效的治疗强调了重新评估我们目前的管理策略和探索新的治疗前沿的紧迫性，如高危人群的化学预防。 以前的研究表明，以前的重度吸烟者（等于或> 30包年），特别是那些有气流阻塞和/或有I期非小细胞肺癌（NSCLC）病史的人，他们已经进行了根治性切除术，与从不吸烟者相比，癌症风险继续显著升高。 因此，本试点方案的总体目标是评估塞来昔布（一种环氧合酶-2（考克斯-2）抑制剂）在该高危人群中预防肺癌的可行性和有效性。 为了实现这一目标，将招募180名有气流阻塞证据和/或既往I期NSCLC的既往重度吸烟者，进行双盲、安慰剂对照、交叉初步研究。 受试者将以随机顺序接受治疗，首先口服6个月塞来昔布作为化学预防剂，然后接受6个月安慰剂，反之亦然。 所有受试者将根据预定算法接受一系列检查，包括痰液分析、LIFE支气管镜检查和螺旋CT。 将评价塞来昔布对肺癌发生相关细胞和分子事件的影响：包括1）调节一组现场癌变的生物标志物（Ki-67、支气管组织病理学的表型调节、支气管肺泡灌洗液中前列腺素E2产生的改变、考克斯-2、EGFR、p27、p16、bcl-2的表达、凋亡指数、细胞周期蛋白D1和E、GST P1甲基化、GSTP 1、GSTM 1和CYP 1A 1多态性、P53多态性和p16甲基化; 2）花生四烯酸代谢的调节; 3）抗肿瘤免疫; 4）肺微环境中的血管生成。 长期使用考克斯-2抑制剂的安全性和副作用将采用改良的NCI常见毒性标准量表和系列不良反应问卷进行监测。 此外，将对系列支气管组织、痰液、口腔涂片、血液（血浆和血沉棕黄层）和尿液标本、呼吸和健康问卷进行存档，以供将来分析。 这个试验项目的发现将为未来化学预防试验的设计和实施提供重要的见解。

Lung cancer is the leading cause of cancer death in the U.S. One of the major obstacles in treating lung cancer is its late presentation, when the options for treatment are primarily palliative. The lack of effective therapy underscores the urgency to reevaluate our current management strategy and explore new frontiers of treatment such as chemoprevention in high-risk individuals. Previous studies have shown that former heavy smokers (equal to or > 30 pack years), particularly those with airflow obstruction and/or a history of stage I non-small cell lung cancer (NSCLC) who have had curative resection, continue to have significantly elevated cancer risk than never smokers. Therefore, the overall objective of this pilot proposal is to evaluate the feasibility and effectiveness of Celecoxib, a cyclooxygenase-2 (Cox-2) inhibitor, for lung cancer prevention in this high-risk population. To achieve this objective, 180 former heavy smokers, with either evidence of airflow obstruction and/or prior stage I NSCLC, will be recruited into a double blind, placebo controlled, crossover pilot study. Subjects will be treated in random order with either 6 months of oral Celecoxib as a chemopreventive agent first, followed by 6 months of placebo or vise versa. All subjects will be followed with serial tests including sputum analysis, LIFE bronchoscopy and spiral CT according to a pre- determined algorithm. Celecoxib will be evaluated for its impact on cellular and molecular events associated with lung carcinogenesis: including 1) modulation of a panel of biomarkers of field cancerization (Ki-67, phenotypic modulations of bronchial histopathology, alteration of prostaglandin E2 production in bronchoalveolar lavage fluid, expression of Cox-2, EGFR, p27,p16, bcl-2, apoptosis index, cyclin D1 and E, GSTP1 methylation, GSTP1, GSTM1 and CYP1A1 polymorphisms, P53 polymorphisms and p16 methylation; 2) regulation of arachidonic acid metabolism; 3) antitumor immunity; and 4) angiogenesis in the lung microenvironment. The safety and side effect of long term use of Cox-2 inhibition will be monitored with the modified NCI common toxicity criteria scale and serial adverse reaction questionnaire. Moreover, serial bronchial tissue, sputum, buccal smear, blood (plasma and buffy coat), and urine specimens, respiratory and health questionnaires will be archived for future analysis. The finding from this pilot project will provide important insight into the design and conduct of future chemopreventive trials.