A Pattern of Early Radiation-Induced Inflammatory Cytokine Expression Is Associated with Lung Toxicity in Patients with Non-Small Cell Lung Cancer

Abstract

PurposeLung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity.Experimental DesignIn 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0.ResultsTwelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity.ConclusionsInflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.

Radiotherapy for Non–Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues

“…Inflammatory mediators, such as chemokines, cytokines, and prostaglandins, as well as reactive oxygen and nitrogen species mediate this effect (4,22). We have previously demonstrated a dose/volume dependence of cytokines induced in plasma within 1 hour of thoracic irradiation in patients with localised NSCLC (16). In the present study we report a statistically significant decrease of plasma MDC levels in both treatment groups.…”

“…The cytokine analysis was conducted by an external contractor as previously described (16). In brief, a commercial multiplexed sandwich ELISA-based flow cytometry array was used (Quantibody® custom array, RayBiotech, Norcross, GA, USA).…”

“…In a subset of 12 patients for whom sufficient plasma sample remained after the primary DNA damage analysis and clinical tests, TIMP-1, TNF-α) were above the limit of detection. We recently reported that early changes in levels of 5 of these factors, IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1, were associated with pulmonary toxicity after RT and chemoRT treatment (16). This toxicity in normal lung tissues occurs within or in close proximity to the irradiated volume and secondary to damage from direct or scattered irradiation.…”

Impact of single-nucleotide polymorphisms on radiation pneumonitis in cancer patients

“…Inflammation is a defensive reaction that results from tissue damage or cellular injury, and is also a key process underlying radiation-induced toxicity (8,9). Several studies have been conducted to evaluate inflammation-related biomarkers, focusing mostly on genes as described below.…”

Radiation treatment and cancer stem cells

“…In response of irradiation, many inflammatory cytokines or soluble factors are known to be secreted in tumor microenvironment (Siva et al 2014;Muller and Meineke 2007;Derradji et al 2008). Possibly, these radiation-induced secretory factors could contribute to the increase in cancer stem cell population (Fig.…”