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.