Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams

// Ivana Dokic 1, 2, 3, 4, * , Andrea Mairani 3, 5, * , Martin Niklas 1, 2, 3, 4 , Ferdinand Zimmermann 1, 2, 3, 4 , Naved Chaudhri 3 , Damir Krunic 6 , Thomas Tessonnier 4, 7 , Alfredo Ferrari 8 , Katia Parodi 3, 7 , Oliver Jäkel 3, 9 , Jürgen Debus 1, 2, 3, 4 , Thomas Haberer 3 , Amir Abdollahi 1, 2, 3, 4 1 German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany 3 Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany 4 Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany 5 National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy 6 Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany 7 Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Munich, Germany 8 European Organization for Nuclear Research CERN, Geneva, Switzerland 9 Division of Medical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany * These authors equally contributed to this work Correspondence to: Amir Abdollahi, email: a.amir@dkfz.de Keywords: radiobiology, DNA-double strand breakages, complex DNA damage, monte carlo simulations, biophysical hybrid detectors Received: March 22, 2016      Accepted: July 19, 2016      Published: August 01, 2016 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.