title: Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams.
abstract: The growing number of particle therapy facilities worldwide landmarks a novel era of precision oncology. Implementation of robust biophysical readouts is urgently needed to assess the efficacy of different radiation qualities. This is the first report on biophysical evaluation of Monte Carlo simulated predictive models of prescribed dose for four particle qualities i.e., proton, helium-, carbon- or oxygen ions using raster-scanning technology and clinical therapy settings at HIT. A high level of agreement was found between the in silico simulations, the physical dosimetry and the clonogenic tumor cell survival. The cell fluorescence ion track hybrid detector (Cell-Fit-HD) technology was employed to detect particle traverse per cell nucleus. Across a panel of radiobiological surrogates studied such as late ROS accumulation and apoptosis (caspase 3/7 activation), the relative biological effectiveness (RBE) chiefly correlated with the radiation species-specific spatio-temporal pattern of DNA double strand break (DSB) formation and repair kinetic. The size and the number of residual nuclear γ-H2AX foci increased as a function of linear energy transfer (LET) and RBE, reminiscent of enhanced DNA-damage complexity and accumulation of non-repairable DSB. These data confirm the high relevance of complex DSB formation as a central determinant of cell fate and reliable biological surrogates for cell survival/ RBE. The multi-scale simulation, physical and radiobiological characterization of novel clinical quality beams presented here constitutes a first step towards development of high precision biologically individualized radiotherapy.
authors: German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany.|Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Ivana
authors: I
authors: Dokic
authors: Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy.
authors: Andrea
authors: A
authors: Mairani
authors: German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany.|Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Martin
authors: M
authors: Niklas
authors: German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany.|Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Ferdinand
authors: F
authors: Zimmermann
authors: Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.
authors: Naved
authors: N
authors: Chaudhri
authors: Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany.
authors: Damir
authors: D
authors: Krunic
authors: Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.|Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Munich, Germany.
authors: Thomas
authors: T
authors: Tessonnier
authors: European Organization for Nuclear Research CERN, Geneva, Switzerland.
authors: Alfredo
authors: A
authors: Ferrari
authors: Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Munich, Germany.
authors: Katia
authors: K
authors: Parodi
authors: Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Division of Medical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Jäkel
authors: German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany.|Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Jürgen
authors: J
authors: Debus
authors: Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.
authors: Thomas
authors: T
authors: Haberer
authors: German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany.|Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.|Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Amir
authors: A
authors: Abdollahi
mesh_terms: D000072283:A549 Cells; D002244:Carbon / Q000627:therapeutic use*; D019070:Cell Lineage; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D063193:Heavy Ion Radiotherapy / Q000379:methods*; D006371:Helium / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D018499:Linear Energy Transfer; D009010:Monte Carlo Method; D009369:Neoplasms / Q000532:radiotherapy*; D010100:Oxygen / Q000627:therapeutic use*; D061766:Proton Therapy / Q000379:methods*; D011874:Radiometry; D012062:Relative Biological Effectiveness; D015203:Reproducibility of Results; D012984:Software
chemical_list: C468783:H2AX protein, human; D006657:Histones; D006371:Helium; D002244:Carbon; D010100:Oxygen
keywords: DNA-double strand breakages; biophysical hybrid detectors; complex DNA damage; monte carlo simulations; radiobiology