Impact of Celecoxib and Inflammation on Survival in Stage III Colon Cancer

描述（申请人提供）：流行病学和科学研究表明，饮食、生活方式和其他可变因素对结直肠癌（CRC）的发生风险有显著影响。然而，这些干预措施对已确诊CRC患者生存率的影响仍知之甚少。虽然随机临床试验（RCT）证明接受基于氟尿嘧啶的辅助化疗的III期结肠癌患者具有显著的生存优势，但接受当前辅助化疗的III期患者中仍有35-40%发生癌症复发。患者经常试图了解什么，如果有任何饮食，生活方式或补充剂会降低癌症复发的机会。此外，饮食和生活方式如何影响预后可能部分取决于特定的患者特征 以及肿瘤中的分子变化。我们建议在NCI申办的大型、双盲、安慰剂对照RCT中解决这些知识空白，该RCT评估塞来昔布对同时接受标准辅助化疗的III期结肠癌患者生存率的影响（CALGB 80702）。除了直接讨论考克斯抑制的作用外，该试验还提供了a）两项关于饮食、药物使用和生活习惯的纵向前瞻性评估; B）肿瘤标本，以检查外源性因素如何与特定分子改变相互作用; c）前瞻性收集的血液和生殖系DNA;以及d）关于癌症复发、死亡率和治疗相关毒性的广泛数据。由于在本试验中仔细定义了病理分期、体能状态、术后治疗和随访，因此应尽量减少疾病和治疗特征的残留混杂。在本申请中，我们建议检查塞来昔布和炎症（目标1）的影响，以及相关的效应调节途径（目标2）对癌症复发，死亡率和治疗相关毒性的风险。每个目标都扩展了这些领域的现有知识。除了上述假设，这一组将允许快速检查未来的假设，因为他们出现。最终，拟议的工作旨在提高我们对CRC生物学的理解，确定可以提高患者生存率的干预措施，并利用广泛的临床病理学，基因组和生物标志物数据进行分析，告知临床医生如何最大限度地利用这些干预措施来改善临床护理。

DESCRIPTION (provided by applicant): Epidemiologic and scientific research indicates that diet, lifestyle, and other modifiable factors have a significant influence on the risk of developin colorectal cancer (CRC). However, the influence of these interventions on the survival of patients with established CRC remains poorly understood. While randomized clinical trials (RCTs) demonstrate a significant survival advantage for stage III colon cancer patients who receive adjuvant fluorouracil-based chemotherapy, 35-40% of stage III patients receiving current adjuvant chemotherapy still develop cancer recurrence. Patients often seek to understand what, if any diet, lifestyle or supplement will reduce their chances of cancer recurrence. Moreover, how diet and lifestyle influence prognosis may depend, in part, on specific patient characteristics as well as molecular alterations in the tumor. We propose to address these gaps in knowledge within a NCI-sponsored, large, double-blind, placebo- controlled RCT assessing the influence of celecoxib on survival in stage III colon cancer patients who are concurrently receiving standard adjuvant chemotherapy (CALGB 80702). Beyond directly addressing the role of COX inhibition, the trial provides a) two longitudinal prospective assessments of diet, medication usage, and lifestyle habits; b) tumor specimens to examine how exogenous factors interact with specific molecular alterations; c) prospectively collected blood and germline DNA; and d) extensive data on cancer recurrence, mortality, and treated-related toxicity. Since pathologic stage, performance status, post-operative therapy and follow-up are carefully defined in this trial, residual confounding by disease and treatment characteristics should be minimized. In this application, we propose to examine the influence celecoxib and inflammation (Aim 1), and relevant effect modifying pathways (Aim 2) on the risk of cancer recurrence, mortality, and treatment-related toxicity. Each aim extends current knowledge in these areas. Beyond the aforementioned hypotheses, this cohort will allow for the rapid examination of future hypotheses as they emerge. Ultimately, the proposed work seeks to improve our understanding of CRC biology, identify interventions that can improve patient survival, and, with the extensive clinical pathologic, genomic, and biomarker data available for analysis, inform clinicians how to maximally utilize these interventions to improve clinical care.