Cancer is associated with systemic inflammation driven by multiple pro-inflammatory cytokines . The network of pro-inflammatory cytokines such as regulated upon activation normal T-cell expressed and secreted (RANTES), interleukin (IL)-10, and IL-8 have been proposed as mediators of cancer development [1, 2]. Pro-inflammatory cytokines play roles in catabolism, gluconeogenesis, and acute-phase protein production . They also play protective roles during the first stages of inflammation; however, persistent continuation has deleterious effects.
Gefitinib and erlotinib are orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) used for the treatment of non–small-cell lung cancer (NSCLC) in patients with activated mutations of the EGFR gene [3–6]. Unlike treatment with cytotoxic agents, EGFR-TKIs are associated with excellent response rates, prolonged survival, low numbers of adverse hematological events, and improved quality of life. EGFR signaling is triggered by the binding of EGF and EGF-like growth factors, resulting in the homodimerization of EGFR molecules or heterodimerization of EGFR with other closely related receptors such as c-erbB2 . EGF-stimulated EGFR phosphorylation  promotes cancer cell proliferation through the downstream phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways . PI3K/Akt and ERK1/2 pathways are activated in lung cancer  and are closely associated with cancer cell proliferation [11, 12].
RANTES is a known chemotactic cytokine that is produced by many cell types, including T-lymphocytes, monocytes, platelets, eosinophils, epithelial cells, dendritic cells, and mast cells . RANTES, which is transcribed and secreted not only by T cells, other inflammatory cells, and stromal cells, but also tumor cells and nonmalignant bronchial epithelium, is involved in immunoregulatory and inflammatory processes . RANTES has been used as a prognostic indicator in both breast and cervical cancers and high levels of RANTES in these malignancies correlates with a poor outcome [14, 15]. RANTES in breast carcinoma is associated with invasion, metastasis, and poor clinical survival [16, 17]. Protein kinases C (PKC) α and β have been shown to affect tumor progression and malignant phenotype [18, 19]. PKCα plays an obligatory role in EGFR transactivation and signaling to ERK1/2 activation [20–22]. PKCα-dependent EGFR transactivation may contribute to the development and maintenance of the androgen-refractory phenotype in advanced prostate cancer . PKCα/β activator 12-O-tetradecanoylphorbol-13-acetate (TPA) only induces IL-8 expression, whereas both inhibit tumor necrosis factor (TNF)-α induced RANTES expression .
IL-10, an immunoregulatory component in the cytokine network, is mainly expressed by monocytes, macrophages, T cells, and normal and neoplastic B cells . IL-10 is associated with tumor malignancy via immune escape. IL-10 promotes tumor malignancy by promoting T cell apoptosis and tumor cell survival . Marked decrease in plasma IL-10 levels accompanies marked increase in RANTES levels in patients with severe, treatment-resistant atopic dermatitis . Previous reports have shown that IL-10 has different prognostic significance in early and late stage lung cancer patients . Absence of IL-10 expression is associated with poor outcome in stage I NSCLC, whereas presence of IL-10 positive macrophages in late stage NSCLC is an indicator of poor prognostic outcome. Moreover, persistence of EGFR and IL-10 in the blood of colorectal cancer patients after surgery indicates a high risk of relapse in patients .
IL-8 is a cytokine of the CXC chemokine family and acts as a ligand for 2 G-protein coupled receptors . In addition to its role in neutrophil recruitment and activation, IL-8 is thought to be involved in a wide variety of other processes such as angiogenesis and the formation of metastases in lung cancer [27, 28]. EGF has been demonstrated to initiate the release of IL-8 from bronchial epithelial and lung cancer cells [9, 29, 30]. ERK phosphorylation is associated with IL-8 expression in airway epithelium cells [31, 32]. An in vitro study has shown that the ability of IL-8 to increase cell proliferation is blocked by an inhibitor of EGFR tyrosine kinase . IL-8 is positively regulated by EGFR signaling, whereas EGFR inhibitors block IL-8 expression . In the nude mice model, treatment with monoclonal antibody C225, directed against the EGFR, inhibits mRNA and protein production of IL-8 .
EGFR-TKIs are thought to partially affect these cancer related pro-inflammatory cytokine networks. To test this hypothesis, we investigated the correlation between plasma pro-inflammatory cytokine levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs.