224 - Attenuation of Lung Fibrosis by Multifield Fractionated Rasterscanning FLASH Carbon Ion Radiotherapy
Presenter(s)
M. Moustafa1,2, M. Akbarpour1,2, H. Hassan1,2, J. Furkel1,2, M. Knoll1,2, S. Brons3, J. Verrelle4, C. A. Assenmacher4, E. Radaelli4, J. Debus1,2, and A. Abdollahi1,2; 1Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany, 2Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, 3Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany, 4Comparative Pathology Core (CPC), Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
Purpose/Objective(s): Lateral scattering of light particles like protons limits multifield FLASH irradiation. Moreover, the impact of fractionation on FLASH sparing effect remains elusive. Here we aimed to overcome these hurdles by utilizing the unique biophysical characteristics of carbon ion radiotherapy (CIRT) and radiation induced lung fibrosis (RILF) as a paradigmatic endpoint for FLASH sparing.
Materials/Methods: Whole thoracic irradiation (WTI) of C57BL/6 mice with standard dose rate (SDR, 0.2 Gy/s) and ultra-high dose rate (FLASH, 60 Gy/s) rasterscanning CIRT was conducted at Heidelberg Ion-Beam Therapy Center (HIT). Clockwise irradiation of whole thorax was performed in 4sec (interspill) intervals using four fields (81 spots each in ~170 msec each) at the plateau region (LET ~15 keV/µm). Three fractions in consecutive days with 7.5Gy and 10Gy WTI was prescribed. The degree of RILF was quantitatively assessed by computed tomography (CT) 20 weeks after CIRT using mean lung density (LD) and volume (LV) as well as a well-established radiomics feature (the fibrosis index, FI) as surrogates. Radiological features were correlated with blood gas and clinical chemistry parameters (ipH, BE, HCO3, SvO2% and PCO2) and detailed quantitative histopathological examination (lung architecture, ECM deposition and macrophage influx/polarization). Gene expression changes were analyzed by bulk RNA sequencing (RNA-seq). Transcriptome analysis was further detailed at single cell resolution (scRNAseq, 10x) using single cell suspensions from irradiated lungs and age-matched reference lungs.
Results: A significant decrease of the parenchymal LD, preserved LV and reduced FI was found after FLASH vs. SDR CIRT 20 weeks post irradiation for both dose levels (p< 0.05). These data correlated with clinical blood gas and chemistry as well as histopathological readouts. IHC examination showed less expression of TGFß, senescence AECII and AECI in FLASH irradiated lungs as compared with SDR. These data correlated with single cell transcriptome data indicating a reduction of M2-polarized lipofibroblasts (COME2ChiL population) in FLASH vs. SDR treated lungs.
Conclusion: This is to our knowledge the first report of FLASH sparing effect of multifield fractionated CIRT for the endpoint RILF as an important step towards clinical translation of this novel therapeutic modality.