A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer

PLoS One. 2014 Oct 7;9(10):e109560. doi: 10.1371/journal.pone.0109560. eCollection 2014.


Purpose: Lung 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 design: In 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.

Results: Twelve 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.

Conclusions: Inflammatory 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / radiotherapy*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / radiotherapy*
  • Chemokine CCL11 / blood
  • Chemokine CCL11 / genetics
  • Chemokine CCL2 / blood
  • Chemokine CCL2 / genetics
  • Chemokine CXCL10 / blood
  • Chemokine CXCL10 / genetics
  • Female
  • Gamma Rays / adverse effects*
  • Gene Expression
  • Humans
  • Interleukin-6 / blood
  • Interleukin-6 / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / radiotherapy*
  • Male
  • Middle Aged
  • Pneumonia / blood
  • Pneumonia / etiology
  • Pneumonia / genetics
  • Pneumonia / pathology
  • Radiation Injuries / blood*
  • Radiation Injuries / genetics
  • Radiation Injuries / pathology
  • Radiotherapy Dosage
  • Tissue Inhibitor of Metalloproteinase-1 / blood
  • Tissue Inhibitor of Metalloproteinase-1 / genetics


  • Biomarkers
  • CCL11 protein, human
  • CCL2 protein, human
  • CXCL10 protein, human
  • Chemokine CCL11
  • Chemokine CCL2
  • Chemokine CXCL10
  • IL6 protein, human
  • Interleukin-6
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1

Grant support

Dr Shankar Siva has received National Health and Medical Research Council scholarship funding for this research, APP1038399. http://www.nhmrc.gov.au/grants/apply-funding/postgraduate-scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.