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  ORAL 36 - Translational Science/Radiation (ID 151)

  • Event: WCLC 2015
  • Type: Oral Session
  • Track: Treatment of Locoregional Disease – NSCLC
  • Presentations: 1
  • Moderators:E. Vokes, B. Kavanagh
  • Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c

  • 15845

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    ORAL36.04 - Nintedanib Safely Reduces Late Radiation-Induced Lung Damage: A Preclinical Study with a High Precision Image-Guided Small Animal Irradiator (ID 1456)

    17:17 - 17:28  |  Author(s): L. Dubois
    • Abstract
    • Presentation
    • Slides

    Background:
    The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.
    
    Methods:
    266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.
    
    Results:
    Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.
    
    Conclusion:
    Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.
    
    

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