title: A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Shankar
authors.initials: S
authors.lastname: Siva
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: MacManus
authors.affiliation: Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia; Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kron
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia.
authors.forename: Nickala
authors.initials: N
authors.lastname: Best
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia.
authors.forename: Jai
authors.initials: J
authors.lastname: Smith
authors.affiliation: Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia; Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Lobachevsky
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ball
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia; Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia.
authors.forename: Olga
authors.initials: O
authors.lastname: Martin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy*; D054413:Chemokine CCL11 / Q000097:blood / Q000235:genetics; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011832:Radiation Injuries / Q000097:blood* / Q000235:genetics / Q000473:pathology; D011879:Radiotherapy Dosage; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000235:genetics
chemical_list: D015415:Biomarkers; C515456:CCL11 protein, human; C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C508600:IL6 protein, human; D015850:Interleukin-6; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1