Inflammatory Cytokines Associated Symptom Burden in NSCLC Patients Receiving CXRT

描述（由申请方提供）：拟定研究的目的是检查与标准同步放化疗（三维适形放疗，或3DCRT）相比，强度调制放射治疗（IMRT）（调节给予正常组织的放射强度）是否会导致非小细胞肺癌（NSCLC）患者的细胞因子驱动症状负荷减少。具体目标1：目的比较3DCRT和IMRT放化疗对非小细胞肺癌（NSCLC）患者多种症状的发生及血清炎性细胞因子水平的影响。我们的工作假设是，在一项2组、II期随机适应性NSCLC患者临床试验中，两组患者的大体肿瘤体积（GTV）、放射剂量（66戈伊）和同时化疗相同，疲劳、睡眠不佳、食欲不振、疼痛和咽喉痛）以及炎性细胞因子水平降低（主要是IL-6和可溶性TNF受体I型（sTNF-RI））将在组织保护性IMRT组中的患者中比在标准3DCRT组中发生。为了建立正常的参数之间的关联-接受放化疗的NSCLC患者的组织保留和炎性细胞因子的血清水平以及症状严重程度。我们的工作假设是，显着降低血清中的促炎细胞因子水平在放化疗将与显着降低症状严重程度和减少正常肺被照射的体积中位数（由辐射剂量-体积直方图（DVH）和平均肺剂量（MLD）证明）在接受调强放疗或3DCRT治疗的患者。本研究的独特之处在于：（a）我们的描述性研究证明，使用有效的工具对NSCLC放化疗时间内的细胞因子和症状负荷进行同步、重复测量;（B）使用综合统计建模方法分析纵向数据;（c）在随机试验中比较组织保护性放疗与标准放疗在症状减轻和预防方面的效果。验证炎症作为治疗诱导的症状群的病理生理机制的作用可能为开发侵袭性癌症治疗提供途径，该治疗在不影响肿瘤控制的情况下最大限度地减少症状负担，并通过改善侵袭性癌症治疗的耐受性来提高生存率。公共卫生相关性：接受放化疗的患者患有多种症状，包括疲劳、疼痛、睡眠障碍、食欲不振和悲伤，这些症状通常不受常见毒性标准的监测，但可能导致严重的痛苦并限制治疗的耐受性。因此，有必要更好地了解潜在的症状负担的机制。该研究旨在调查与标准化放疗相比，调强放疗（IMRT）中改善的正常组织保留是否可以降低血清细胞因子，从而控制甚至可能预防治疗相关症状。寻找减轻症状负担和改善许多接受根治性侵袭性癌症治疗（如放化疗）的患者的功能的机制具有巨大的公共卫生意义。

DESCRIPTION (provided by applicant): The objective of the proposed study is to examine whether the Intensity-Modulated Radiation Therapy (IMRT), which modulates the intensity of radiation administered to normal tissue, will result in less cytokine- driven symptom burden in patients with non-small cell lung cancer (NSCLC) compared with standard concurrent chemoradiation therapy (3-Dimensional Conformal Radiation Therapy, or 3DCRT). SPECIFIC AIM 1: To identify the difference between 3DCRT and IMRT chemoradiation therapy in the development of multiple symptoms and serum levels of inflammatory cytokines in patients with NSCLC. Our working hypothesis is that, in a 2-arm, phase II randomized adaptive clinical trial of patients with NSCLC and with the same gross tumor volume (GTV), radiation dose (66 Gy), and concurrent chemotherapy in each arm, less-severe nonspecific symptoms (e.g., fatigue, poor sleep, poor appetite, pain, and sore throat) and lower levels of inflammatory cytokines (mainly IL-6 and soluble TNF receptor type I (sTNF-RI)) will occur in patients in the tissue-protective IMRT arm than in the standard 3DCRT arm. SPECIFIC AIM 2: To establish the association between the parameters for normal-tissue sparing and the serum levels of inflammatory cytokines and symptom severity in patients with NSCLC undergoing chemoradiation. Our working hypothesis is that significantly reduced serum levels of proinflammatory cytokines during chemoradiation will be associated with both significantly decreased symptom severity and reduced median volumes of normal lung being irradiated (evidenced by radiation dose-volume histogram (DVH) and mean lung dose (MLD)) in patients treated with either IMRT or 3DCRT. The unique features of this study are: (a) use of a valid tool to make simultaneous, repeated measurements of cytokines and symptom burden over time of chemoradiation for NSCLC, demonstrated by our descriptive study; (b) use of comprehensive statistical modeling methods to analyze longitudinal data; and (c) comparison of tissue-protective radiotherapy for symptom reduction and prevention with standard radiotherapy in a randomized trial. Validating the role of inflammation as a pathophysiologic mechanism of treatment-induced symptom clusters may suggest avenues for development of aggressive cancer treatment that minimizes symptom burden without compromising tumor control, and will enhance survival by improving the tolerability of aggressive cancer treatments. PUBLIC HEALTH RELEVANCE: Patients undergoing chemoradiation suffer from multiple symptoms, including fatigue, pain, disturbed sleep, poor appetite, and sadness, that often are not monitored by common toxicity criteria yet may cause severe distress and limit the tolerability of the treatment. There is therefore a need for better understanding of the mechanisms underlying symptom burden. The proposed study aims to investigate whether improved normal-tissue sparing from Intensity-Modulated Radiation Therapy (IMRT) may lower serum cytokines and thus control and possibly even prevent treatment-related symptoms, compared with standard chemoradiation treatment. Finding mechanisms to relieve symptom burden and improve the function of the many patients undergoing curative aggressive cancer treatment such as chemoradiation has immense public health significance.