Clinical and Translational Oncology

, Volume 18, Issue 10, pp 1003–1010 | Cite as

Stereotactic body radiation therapy and intensity modulated radiation therapy induce different plasmatic cytokine changes in non-small cell lung cancer patients: a pilot study

  • M. Trovo
  • N. Giaj-Levra
  • C. Furlan
  • M. T. Bortolin
  • E. Muraro
  • J. Polesel
  • E. Minatel
  • R. Tedeschi
  • A. R. Filippi
  • F. Alongi
  • U. Ricardi
Research Article



To assess kinetics of plasmatic cytokines during radiation therapy (RT) for locally advanced and early-stage non-small cell lung cancer (NSCLC).


This prospective study was conducted on 15 early-stage NSCLC underwent to extreme hypofractionated regimen (52 Gy in 8 fractions) with stereotactic body RT (SBRT), and 13 locally advanced NSCLC underwent to radical moderated hypofractionated regimen (60 Gy in 25 fractions) with intensity modulated RT (IMRT). For patients undergoing SBRT, peripheral blood samples were collected on the first day of SBRT (TFd), the last day (TLd) and 45 days (T45d) after the end of SBRT. For patients undergoing IMRT, blood samples were collected at: TFd, 2 weeks (T2w), 4 weeks (T4w), TLd, and T45d. The following cytokines were measured: IL-1, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17A, EGF, FGF-2, INF-γ, MIP-1α, MIP-1β, TGF-α, TNF-α, and VEGF. Cytokine levels measured in different RT time and compared.


No difference in baseline levels of cytokines was documented between patient radiation approaches (except for MIP-1α). For SBRT patients, a mean reduction of IL-10 and IL-17 plasma level was documented between TLd and TFd, respectively (p < 0.05). For IMRT patients, a statistically significant (p < 0.05) mean plasma level reduction was documented between T4w and TFd for all the following cytokines: IL-1, IL-1ra, IL-2, IL-12, FGF-2, MIP-1α, MIP-1β, TGF-α, TNF-α, VEGF.


SBRT and IMRT induce different plasmatic cytokine changes in NSCLC patients, supporting hypothesis that RT regimes of dose schedules and techniques have different impacts on the host immune response.


Non-small cell lung cancer Stereotactic ablative radiotherapy Intensity modulated radiotherapy Cytokines 


Compliance with ethical standards

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

The current study has been performed in accordance with the ethical standards laid down in the 1964 declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.

Conflict of interest

The authors have declared that no conflict of interest exists.


  1. 1.
    Bradley JD, El Naqua I, Drzymala RE, Trovò M, Jones G, Denning MD. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: the pattern of failure is distant. Int J Radiat Oncol Biol Phys. 2010;77:1146–50.CrossRefPubMedGoogle Scholar
  2. 2.
    National Comprehensive Cancer Network. 2015. Accessed 24 Nov 2015.
  3. 3.
    Ricardi U, Frezza G, Filippi AR, et al. Stereotactic ablative radiotherapy for stage I hisologically proven non-small cell lung cancer: an Italian multicenter observational study. Lung Cancer. 2014;84:248–53.CrossRefPubMedGoogle Scholar
  4. 4.
    Curran W, Paulus R, Langer C, Komaki R, Lee JD, Hauser S, et al. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–60.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bearz A, Minatel E, Rumeileh IA, et al. Concurrent chemoradiotherapy with tomotherapy in locally advanced non-small cell lung cancer: a phase I, docetaxel dose-escalation study, with hypofractionated radiation regimen. BMC Cancer. 2013;13:513.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Faivre-Finn C. Dose escalation in lung cancer: have we gone full circle? Lancet Oncol. 2015;16:125–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Trovo M, Linda A, El Naqua I, Javidan-Nejad C, Bradley J. Early and late radiographic injurie following stereotactic body radiation therapy (SBRT). Lung Cancer. 2010;69:77–85.CrossRefPubMedGoogle Scholar
  8. 8.
    Linda A, Trovo M, Bradley JD. Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes. Eur J Radiol. 2011;79:147–54.CrossRefPubMedGoogle Scholar
  9. 9.
    McBride WH, Chiang CS, Olson JL, Wang CC, Hong JH, Pajonk F, et al. A sense of danger from radiation. Radiat Res. 2004;162:1–19.CrossRefPubMedGoogle Scholar
  10. 10.
    Barcellos-Hoff MH, Park C, Wright EG. Radiation and the microenvironment—tumorigenesis and therapy. Nat Rev Cancer. 2005;5:867–75.CrossRefPubMedGoogle Scholar
  11. 11.
    Rübe CE, Wilfert F, Uthe D, König J, Liu L, Schuck A, et al. Increased expression of pro-inflammatory cytokines as a cause of lung toxicity after combined treatment with gemcitabine and thoracic irradiation. Radiother Oncol. 2004;72:231–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Chen Y, Williams J, Ding I, Hernady E, Liu W, Smudzin T, et al. Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol. 2002;12(1 suppl 1):26–33.CrossRefPubMedGoogle Scholar
  13. 13.
    Hong ZY, Song KH, Yoon JH, Cho J, Story MD. An experimental model-based exploration of cytokines in ablative radiation-induced lung injury in vivo and in vitro. Lung. 2015;193:409–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Yang X, Walton W, Cook DN, Hua X, Tilley S, Haskell CA, et al. The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;45:127–35.CrossRefPubMedGoogle Scholar
  15. 15.
    van Tinteren H, Hoekstra OS, Smit EF, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet. 2002;359(9315):1388–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Ansher MS, Kong FM, Andrews K, Clough R, Marks LB, Bentel G, et al. Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1998;41:1029–35.CrossRefGoogle Scholar
  17. 17.
    Ansher MS, Marks LB, Shafman TD, Clough R, Huang H, Tisch A, et al. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:988–95.CrossRefGoogle Scholar
  18. 18.
    Chen Y, Rubin P, William J, Hernady E, Smudzin T, Okunieff P. Circulating IL-6 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2001;49:641–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Bright RK. Immunology of lung cancer. In: Pass HI, Mitchel IB, Johnson DH, et al., editors. Lung cancer. Philadelphia: Lippincott W&W; 2000. p. 304–18.Google Scholar
  20. 20.
    Witz IP. Tumor-microenvironment interactions: the selectin-selectin ligand axis in tumor-endothelium cross talk. Cancer Treat Res. 2006;130:125–40.CrossRefPubMedGoogle Scholar
  21. 21.
    Travès PG, Luque A, Hortelano S. Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game. Mediators Inflamm. 2012;2012:568783.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kong FM, Washington MK, Jirtle RL, Anscher MS. Plasma transforming growth factor-beta 1 reflects disease status in patients with lung cancer after radiotherapy: a possible tumor marker. Lung Cancer. 1996;16:47–59.CrossRefPubMedGoogle Scholar
  23. 23.
    Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–42.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8alpha+ dendritic cells. J Exp Med. 2011;208(10):2005–16.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–52.CrossRefPubMedGoogle Scholar
  26. 26.
    Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28.CrossRefPubMedGoogle Scholar
  27. 27.
    Chen X, Wan J, Liu J, Xie W, Diao X, Xu J, et al. Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer. 2010;69:348–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Fleckenstein K, Gauter-Fleckenstein B, Jackson IL, Rabbani Z, Anscher M, Vujaskovic Z. Using biological markers to predict risk of radiation injury. Semin Radiat Oncol. 2007;17:89–98.CrossRefPubMedGoogle Scholar
  29. 29.
    Han G, Zhang H, Xie CH, Zhou YF. Th2-like immune response in radiation-induced lung fibrosis. Oncol Rep. 2011;26:383–8.PubMedGoogle Scholar
  30. 30.
    Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zeng L, O’Connor C, Zhang J, Kaplan AM, Cohen DA. IL-10 promotes resistance to apoptosis and metastatic potential in lung tumor cell lines. Cytokine. 2010;49:294–302.CrossRefPubMedGoogle Scholar
  32. 32.
    De Vita F, Orditura M, Galizia G, Ciaramella F, Musicò M, Ferrigno A, et al. Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients. Chest. 2000;117:365–73.CrossRefPubMedGoogle Scholar
  33. 33.
    Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM. The dual role of IL-10. Trends Immunol. 2003;24:36–43.CrossRefPubMedGoogle Scholar
  34. 34.
    Wang YC, Sung WW, Wu TC, Wang L, Chien WP, Cheng YW, et al. Interleukin-10 haplotype may predict survival and relapse in resected non-small cell lung cancer. PLoS One. 2012;7:e39525.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Arpin D, Perol D, Blay JY, Falchero L, Claude L, Vuillermoz-Blas S, et al. Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis. J Clin Oncol. 2005;23:8748–56.CrossRefPubMedGoogle Scholar
  36. 36.
    Neurath MF, Finotto S. The emerging role of T cell cytokines in non-small cell lung cancer. Cytokine Growth Factor Rev. 2012;23:315–22.CrossRefPubMedGoogle Scholar
  37. 37.
    Li Y, Cao ZY, Sun B, Wang GY, Fu Z, Liu YM, et al. Effects of IL-17A on the occurrence of lung adenocarcinoma. Cancer Biol Ther. 2011;12:610–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Crittenden M, Gough M, Harrington K, Olivier K, Thompson J, Vile RG. Expression of inflammatory chemokines combined with local tumor destruction enhances tumor regression and long-term immunity. Cancer Res. 2003;63:5505–12.PubMedGoogle Scholar
  39. 39.
    Kono SA, Heasley LE, Doebele RC, Camidge DR. Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer. Curr Cancer Drug Targets. 2012;12:107–23.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Umekita Y, Ohi Y, Sagara Y, Yoshida H. Co-expression of epidermal growth factor receptor and transforming growth factor-alpha predicts worse prognosis in breast-cancer patients. Int J Cancer. 2000;89:484–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Arend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002;3:323–40.CrossRefGoogle Scholar
  42. 42.
    Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer Control. 2008;15:140–50.PubMedGoogle Scholar
  43. 43.
    Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy induced immunogenic cell death. Oncoimmunology. 2014;3:e28518.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front Oncol. 2012;2:153.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–95.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Klug F, Prakash H, Huber PE, et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24(5):589–602.CrossRefPubMedGoogle Scholar
  47. 47.
    Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res. 2012;177(3):311–27.CrossRefPubMedGoogle Scholar
  48. 48.
    Tsavaris N, Kosmas C, Vadiaka M, Kanelopoulos P, Boulamatsis D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer. 2002;87:21–7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Heuvers ME, Aerts JG, Cornelissen R, Groen H, Hoogsteden HC, Hegmans JP. Patient-tailored modulation of the immune system may revolutionize future lung cancer treatment. BMC Cancer. 2012;12:580.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  • M. Trovo
    • 1
  • N. Giaj-Levra
    • 2
    • 3
  • C. Furlan
    • 1
  • M. T. Bortolin
    • 4
  • E. Muraro
    • 5
  • J. Polesel
    • 6
  • E. Minatel
    • 1
    • 4
  • R. Tedeschi
    • 4
  • A. R. Filippi
    • 3
  • F. Alongi
    • 2
  • U. Ricardi
    • 3
  1. 1.Department of Radiation OncologyCentro di Riferimento Oncologico of AvianoAvianoItaly
  2. 2.Radiation OncologySacro Cuore Don Calabria HospitalVeronaItaly
  3. 3.Department of OncologyUniversity of TorinoTurinItaly
  4. 4.Department of Microbiology-Immunology and VirologyCentro di Riferimento Oncologico of AvianoAvianoItaly
  5. 5.Department of Translational ResearchCentro di Riferimento Oncologico of AvianoAvianoItaly
  6. 6.Department of Epidemiology and BiostatisticsCentro di Riferimento Oncologico of AvianoAvianoItaly

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