Microdosimetry calculations in situ for clinically relevant photon sources and their correlation with the early DNA damage response

M Dumancic and J Kalinowski and VD Diaz-Martinez and JN Li and B Behmand and JM Decunha and SA Enger, MEDICAL PHYSICS, 52, e17979 (2025).

DOI: 10.1002/mp.17979

Background Radiobiological data suggests variations in relative biological effectiveness (RBE) between clinically used photon-based sources. A microdosimetric formalism using Monte Carlo (MC) methods can mechanistically describe the photon RBE. Experimentally derived RBE based on DNA double-strand breaks (RBEDSB$\mathrmRBE_DSB$) has been shown to scale with the microdosimetry quantity dose-mean lineal energy (yD$\mathrmy_D$).Purpose To calculate microdosimetric spectra for clinically relevant photon sources, spanning from soft x-rays produced by a 50 kVp x-ray source through various brachytherapy sources up to a 6 MV medical linac. Furthermore, we investigated the correlation between RBEDSB$\mathrmRBE_DSB$ and yD$\mathrmy_D$ of different photon sources.Methods Photon sources simulated include low-energy x-rays (50 kVp), orthovoltage x-rays (225 kVp), high-dose-rate brachytherapy sources (75Se, 192Ir and 60Co), and a 6 MV medical linac. Secondary electron spectra at the cellular level were calculated for in vitro cell irradiation setups using Geant4 MC-based packages, RapidBrachyMCTPS and RapidExternalBeam. The obtained spectra were used in MicroDose, a microdosimetry simulation software, to obtain microdosimetric quantities, including single-event lineal energy (y$y$) and specific energy (z$z$) spectra, and dose-mean and frequency-mean quantities (yF$\mathrmy_F$, yD$\mathrmy_D$, zFs$\mathrmz_F<^>s$, zDs$\mathrmz_D<^>s$). Uniform spherical targets (1-14 mu m$\mu \rm m$ radius) and realistic HeLa and PC3 cell nucleus models were simulated using cell size data obtained from literature and nuclei size data from confocal microscopy imaging. Radiobiological experiments using gamma H2AX$\gamma\textH2AX$ foci quantified DNA double-strand breaks for HeLa and PC3 cells after irradiations with 50 and 225 kVp, 192Ir, and 6 MV linac, and RBEDSB$\mathrmRBE_DSB$ was determined using 225 kVp as the reference.Results The calculated yD$\mathrmy_D$ (yF$\mathrmy_F$) is within the 3.5-1.2 keV/mu m$\mu \rm m$ range (1.8-0.2 keV/mu m$\mu\rm m$) for 1 mu m$\mu \rm m$ simulated target size between the lowest energy 50 kVp x-ray source and the highest energy 6 MV linac source, respectively. For the HeLa and PC3 cell nuclei models based on microscopy data, yD$\mathrmy_D$ (yF$\mathrmy_F$) spans from 1.6 to 0.6 keV/mu m$\mu \rm m$ (0.7 to 0.2 keV/mu m$\mu\rm m$). When compared between different target sizes, yD$\mathrmy_D$ (yF$\mathrmy_F$) ranges from 3.5 to 1.0 (1.8-0.4) keV/mu m$\mu \rm m$ between 1 and 10 mu m$\mu \rm m$ radius targets for the 50 kVp x-ray source. A smaller change is observed for 6 MV linac, ranging from 1.2 to 0.5 keV/mu m$\mu \rm m$ and 0.23 to 0.22 keV/mu m$\mu \rm m$ for yD$\mathrmy_D$ and yF$\mathrmy_F$, respectively. For the simulated 75Se source currently under investigation, the calculated yD$\mathrmy_D$ values are 11%-24% higher relative to those of 192Ir in the range of target sizes between 1 and 14 mu m$\mu \rm m$ in radius. RBEDSB$\mathrmRBE_DSB$ for HeLa cells was 1.4 +/-$\pm$0.7 for 50 kVp x-rays, 0.5 +/-$\pm$0.2 for 192Ir, and 0.7 +/-$\pm$0.4 for 6 MV linac irradiations. For PC3 cells, RBEDSB$\mathrmRBE_DSB$ was 1.3 +/-$\pm$0.6, 0.8 +/-$\pm$0.4 and 0.5 +/-$\pm$0.3 for 50 kVp, 192Ir and 6 MV linac, respectively. Measured RBEDSB$\mathrmRBE_DSB$ values are consistent with yD$\mathrmy_D$ ratios of the corresponding photon sources for HeLa and PC3 nucleus models. Conclusions Microdosimetric spectra strongly depend on the simulated energy of photon sources and target size, with yD$\mathrmy_D$ and zDs$\mathrmz_D<^>s$ decreasing by a factor of approximate to$\approx$2-3 between diagnostic 50 kVp and 6 MV therapeutic x-rays for target sizes from 1-14 mu m$\mu \rm m$ in radius. The early damage RBEDSB$\mathrmRBE_DSB$ indicates this stochastic change in energy density between various photon sources as the yields of gamma H2AX$\gamma \textH2AX$ foci per nucleus scale with yD$\mathrmy_D$ of the source.

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