Inflammatory Cytokines Associated Symptom Burden in NSCLC Patients Receiving CXRT

描述(申请人提供)：拟议研究的目的是检验与标准同期放化疗(三维适形放射治疗或3DCRT)相比，调强放射治疗(IMRT)是否会导致非小细胞肺癌(NSCLC)患者细胞因子驱动的症状负担减少。目的1：比较三维适形放射治疗与调强适形放射治疗在非小细胞肺癌患者多症状发展及血清炎症细胞因子水平方面的差异。我们的工作假设是，在一项针对NSCLC患者的双臂随机适应性临床试验中，在两个手臂的大体肿瘤体积(GTV)、放射剂量(66GY)和同时进行化疗的情况下，与标准的3DCRT手臂相比，组织保护性IMRT手臂中的患者将出现不那么严重的非特异性症状(例如疲倦、睡眠不佳、食欲不振、疼痛和喉咙痛)和较低水平的炎症细胞因子(主要是IL-6和可溶性肿瘤坏死因子受体I型(sTNF-RI))。特定目的2：建立非小细胞肺癌放化疗患者的正常组织保留参数与血清炎性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，在接受调强放疗或三维适形放射治疗的患者中，化疗期间血清促炎细胞因子水平的显著降低将与症状严重程度的显著降低和正常肺体积的中位数减少(通过放射剂量-体积直方图(DVH)和平均肺剂量(MLD)来证明)相关。这项研究的独特之处在于：(A)我们的描述性研究证明，在非小细胞肺癌化疗期间，使用一种有效的工具可以同时、重复地测量细胞因子和症状负担；(B)使用全面的统计建模方法分析纵向数据；(C)在随机试验中，比较组织保护性放射治疗对症状的减轻和预防与标准放射治疗。验证炎症作为治疗诱发症状群的病理生理机制的作用，可能为侵袭性癌症治疗的发展提供途径，在不影响肿瘤控制的情况下将症状负担降至最低，并将通过改善侵袭性癌症治疗的耐受性来提高生存率。与公共卫生相关：接受放化疗的患者会出现多种症状，包括疲劳、疼痛、睡眠障碍、食欲不振和悲伤，这些症状通常没有通过共同的毒性标准进行监测，但可能会导致严重的痛苦，并限制了治疗的耐受性。因此，有必要更好地了解症状负担的潜在机制。这项拟议的研究旨在调查与标准放化疗相比，改进的正常组织对调强放射治疗(IMRT)的保留是否可以降低血清细胞因子，从而控制甚至预防治疗相关症状。许多接受根治性侵袭性癌症治疗的患者，如化疗和放射治疗，找到减轻症状负担和改善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.