2863 - Surprising Dose Dependent Sparing Effects of Fractionated FLASH Electrons in Experimental Radiation Induced Lung Fibrosis Model

M. Moustafa^1,2, M. Akbarpour^2,3, H. Hassan^2,3, J. Furkel^2,3, M. Knoll^2,3, M. Gerlad^2,3, C. Zhou^2,3, K. Petersson⁴, A. J. Giaccia⁵, J. Verrelle⁶, C. A. Assenmacher⁶, E. Radaelli⁶, J. Debus^2,3, and A. Abdollahi^1,3; ¹Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, ²CCU Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany, ³Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg University Hospital (UKHD), Heidelberg, Germany, ⁴Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom, ⁵CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom, ⁶Comparative Pathology Core (CPC), Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA

Purpose/Objective(s): Amelioration of radiation induced lung fibrosis (RILF) by relatively high single dose electron radiotherapy (RT) at ultra-high dose-rates provided one of the first clear evidences for FLASH sparing effect. The requirement of single high dose of e.g. >15Gy on the other side will compromise the benefit of normal tissue sparing by standard fractionation schemes. Therefore, we sought to systematically investigate the impact of dose per fraction on FLASH sparing effect in the paradigmatic RILF model. Materials/

Methods: Whole thoracic electron RT at standard dose rate (SDR, 0.3 Gy/s) and FLASH (120 Gy/s) was performed in C57BL6 mice using the FLASH Mobetron system. Total doses of 15, 20, 35 and 40 in five consecutive fractions, i.e., 3 vs. 4, 6 and 8 Gy each of both SDR and FLASH quality were evaluated. The degree of fibrosis was assessed 24 weeks post RT by computed tomography (CT-scans) using lung density, volume and radiomics features (fibrosis index, FI) as surrogates. Radiological features were correlated with blood gases and clinical chemistry parameters (ipH, BE, HCO3, SvO2%, and PCO2) as well as detailed quantitative histopathological examination (lung architecture, ECM-deposition and Macrophage influx/polarization).
Results: After a follow-up time of 24 weeks, the dose–response curve revealed a narrow FLASH sparing window for only 5x6Gy with significant decrease of the parenchymal lung density (LD), preserved lung volume (LV) and reduced FI (p< 0.01) as compared with SDR. These data correlated with clinical chemistry and histopathological readouts. While at lower doses <6Gy per Fx no significant difference was seen at standard 24 weeks continued monitoring of 5x3Gy and 5x4Gy FLASH cohorts showed significant sparing of moderate RILF levels vs. SDR at > 48 Weeks post RT.
Conclusion: This is to our knowledge the first report of RILF sparing window of FLASH electron RT in fractionated scheme demonstrating a narrow benefit at doses >4 and <8 Gy per fraction for the endpoint RILF at standard 24 weeks post RT. Surprisingly, moderate level of RILF sparing by FLASH at late stage > 48 weeks post RT were found at relatively low < 4Gy per fraction.