Inflammatory Cytokines Associated Symptom Burden in NSCLC Patients Receiving CXRT

描述（由申请人提供）：拟议研究的目的是研究调强放疗（IMRT）是否会导致非小细胞肺癌（NSCLC）患者比标准同步放化疗（三维适形放疗，或3DCRT）更少的细胞因子驱动的症状负担，IMRT可以调节正常组织的放射强度。特异性目的1：确定3DCRT与IMRT放化疗在NSCLC患者多种症状发展和血清炎症因子水平方面的差异。我们的工作假设是，在一项两组非小细胞肺癌患者的II期随机适应性临床试验中，每组患者具有相同的总肿瘤体积（GTV）、辐射剂量（66 Gy）和同期化疗，较轻的非特异性症状(如疲劳、睡眠差、食欲差、疼痛、与标准3DCRT组相比，组织保护性IMRT组患者的炎症因子（主要是IL-6和可溶性TNF受体I型（sTNF-RI））水平会降低。特异性目的2：在接受放化疗的NSCLC患者中，建立正常组织保留参数与血清炎症细胞因子水平和症状严重程度之间的关系。我们的工作假设是，在接受IMRT或3DCRT治疗的患者中，放化疗期间血清促炎细胞因子水平的显着降低将与症状严重程度的显着降低和正常肺被照射中位数体积的减小（通过辐射剂量-体积直方图（DVH）和平均肺剂量（MLD）证明）相关。本研究的独特之处是：(a)使用一种有效的工具来同时重复测量细胞因子和随时间的非小细胞肺癌放化疗的症状负担，我们的描述性研究证明了这一点；(b)采用综合统计建模方法分析纵向数据；(c)在一项随机试验中比较组织保护放疗减轻和预防症状与标准放疗。验证炎症作为治疗诱导症状簇的病理生理机制的作用，可能为开发积极的癌症治疗提供途径，在不影响肿瘤控制的情况下，最大限度地减少症状负担，并通过提高积极的癌症治疗的耐受性来提高生存率。公共卫生相关性：接受放化疗的患者会出现多种症状，包括疲劳、疼痛、睡眠紊乱、食欲不振和悲伤，这些症状通常不受常见毒性标准的监测，但可能导致严重痛苦并限制治疗的耐受性。因此，有必要更好地了解潜在症状负担的机制。拟议的研究旨在调查与标准放化疗相比，调强放疗（IMRT）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治疗性侵袭性癌症治疗（如放化疗）的患者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.