Circulating Cytokine Levels Predictive Of Grade >= 3 Radiation Pneumonitis: Preliminary Secondary Analysis Of A Randomized Controlled Trial Of Definitive Chemoradiation In Locally Advanced Nsclc

Abstract PURPOSE: Host immune activation is believed to be a major player of radiation pneumonitis (RP). Several cytokine and angiogenic factors (CAFs) have been studied as correlative markers and therapeutic targets for RP; however, studies are sparse in the setting of prospective trials and high-grade toxicity (Grade≥3) endpoints. We examined the predictive value of several CAFs in combination with clinical factors for RP in the context of a Phase II, prospective randomized study of intensity modulated RT (IMRT) versus proton therapy for locally advanced NSCLC (n=178) as well as a prospective laboratory cohort (n=43). METHODS: From July 2009 to April 2014, 221 patients were treated with proton therapy or IMRT to doses of 60-74 Gy equivalents with concurrent platinum-doublet chemotherapy. Primary endpoints were symptomatic RP (Grade≥2) and RP requiring intervention (Grade≥3). Plasma circulating levels of IL-6, IL-10, IL-8, IL-17, IL-2, IL-1β, and IL-1α were measured at baseline and post-treatment (median time 48 days post-RT) by multiplex electrochemiluminescence immunoassay. Clinical characteristics were evaluated for associations with Grade≥3 RP: histology, age, smoking status, mean lung dose (MLD), chemotherapy, stage, performance status, and RT technique. CAFs with >50% undetectable samples were removed from analysis, and samples below the lower limit of quantitation (LLQ) were transformed to the mean of zero and the LLQ. Predictive values of clinical and cytokine factors were evaluated in univariate and multivariate analyses via Cox proportional hazards modeling. RESULTS: Of the 221 patients, 42 (19.0%) developed Grade 2 RP, and 22 (9.95%) developed Grade≥3 RP. Both IL-1α and IL-1β had >50% of undetectable samples and were removed from analysis. Pre-treatment level of IL-6 ≥4.00 pg/mL was associated with Grade≥3 RP (HR 2.487; p=.048), as was post-treatment level of IL-10 ≥0.50 pg/mL (HR 2.931; p=.020). On multivariate analysis, the factors associated with Grade≥3 RP development were post-treatment level of IL-10 ≥0.50 pg/mL (HR 3.332; p=.015) and MLD ≥20 Gy (HR 5.864; p<.001). CONCLUSIONS: In this preliminary analysis of prospectively collected CAFs, post-radiation IL-10 level was significantly associated with Grade≥3 RP and, if validated, may serve as a predictor of this toxicity in combination with MLD. IL-10 plays an important role in the inflammatory response and is potentially targetable, warranting further investigation. Citation Format: Matthew S. Ning, Ting Xu, Daniel Gomez, Hai T. Tran, Ritsuko Komaki, Xiong Wei, Steven H. Lin, Stephen Hahn, Eric Prado, Jianjun Zhang, John V. Heymach, Zhongxing Liao. Circulating cytokine levels predictive of Grade≥3 radiation pneumonitis: Preliminary secondary analysis of a randomized controlled trial of definitive chemoradiation in locally advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2017-4745