Research Papers:

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

Ivana Dokic, Andrea Mairani, Martin Niklas, Ferdinand Zimmermann, Naved Chaudhri, Damir Krunic, Thomas Tessonnier, Alfredo Ferrari, Katia Parodi, Oliver Jäkel, Jürgen Debus, Thomas Haberer and Amir Abdollahi _

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Oncotarget. 2016; 7:56676-56689. https://doi.org/10.18632/oncotarget.10996

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Ivana Dokic1,2,3,4,*, Andrea Mairani3,5,*, Martin Niklas1,2,3,4, Ferdinand Zimmermann1,2,3,4, Naved Chaudhri3, Damir Krunic6, Thomas Tessonnier4,7, Alfredo Ferrari8, Katia Parodi3,7, Oliver Jäkel3,9, Jürgen Debus1,2,3,4, Thomas Haberer3, Amir Abdollahi1,2,3,4

1German Cancer Consortium (DKTK), Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany

2Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), Heidelberg, Germany

3Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany

4Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany

5National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy

6Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany

7Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Munich, Germany

8European Organization for Nuclear Research CERN, Geneva, Switzerland

9Division of Medical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany

*These authors equally contributed to this work

Correspondence to:

Amir Abdollahi, email: [email protected]

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


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.

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