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.

Radiobiological issues in prospective carbon ion therapy trials

“…However, oxygen ions are considered as a promising candidate to treat bulky resistant tumors due to the increased LET over the whole target volume as compared with carbon ions. Also mixed ion beam treatments have been suggested, which would result in an LET‐painting approach …”

“…Also mixed ion beam treatments have been suggested, which would result in an LET-painting approach. 110 As a general remark, the current trend is toward an optimization of CIRT that accounts for specific patient-, tissue-, and tumor-related factors. This is a development toward an individualized therapy that must, of course, be validated with clinical data.…”

Carbon ion dosimetry on a fluorescent nuclear track detector using widefield microscopy

“…The FNTDs analysed in this paper were irradiated at Heidelberg Ionenstrahl Therapiezentrum (HIT) with 0.5 Gy carbon ions at 3.5cm depth in a 3-4cm spread out bragg peak (SOBP). Irradiation setup was similar to the setup used in [15]. The irradiated FNTD was the physical compartment of the biomedical sensor Cell-Fit-HD 4D introduced in [12]: Briefly, the bottom of a conventional 6 well glass bottom dish (MatTek) was replaced by a disk-shaped FNTD (diameter: 19 mm, thickness: 100µm, Fig.1).…”

“…The FLUKA Monte Carlo version fluka.2011.2x.8 has been used. In terms of settings, the default ones employed for hadron therapy application has been used as described in [15,19]. A detailed geometry of the HIT beam-line was implemented.…”

“…In contrast, the ideal imaging setup for live cell imaging of cells growing on the FNTD is a widefield microscope (WF) combined with a high sensitivity sCMOS camera as this enables a larger number of frames to be acquired over time and using a tunable LED excitation and a live cell incubation chamber can insure minimal phototoxicity and cellular viability. The current readout process of Cell-FIT-HD for example uses two microscopes to perform in situ bio dosimetry, the imaging routine used to detect the ionizations in an irradiated FNTD makes use of a Zeiss LSM710 confocal microscope [14][15][16]. The second microscope used to image the cells growing on the FNTD was an Olympus IX83 widefield microscope with LED illumination and live cell incubation chamber is used to ensure the cells are growing at a constant 37°C and 5% CO2.…”