Biophysical modeling of low-energy ion irradiations with NanOx.

BACKGROUND: Targeted radiotherapies with low-energy ions show interesting possibilities for the selective irradiation of tumor cells, a strategy particularly appropriate for the treatment of disseminated cancer. Two promising examples are boron neutron capture therapy (BNCT) and targeted radionuclide therapy with α $\alpha$ -particle emitters (TAT). The successful clinical translation of these radiotherapies requires the implementation of accurate radiation dosimetry approaches able to take into account the impact on treatments of the biological effectiveness of ions and the heterogeneity in the therapeutic agent distribution inside the tumor cells. To this end, biophysical models can be applied to translate the interactions of radiations with matter into biological endpoints, such as cell survival. PURPOSE: The NanOx model was initially developed for predicting the cell survival fractions resulting from irradiations with the high-energy ion beams encountered in hadrontherapy. We present in this work a new implementation of the model that extends its application to irradiations with low-energy ions, as the ones found in TAT and BNCT. METHODS: The NanOx model was adapted to consider the energy loss of primary ions within the sensitive volume (i.e., the cell nucleus). Additional assumptions were introduced to simplify the practical implementation of the model and reduce computation time. In particular, for low-energy ions the narrow-track approximation allowed to neglect the energy deposited by secondary electrons outside the sensitive volume, increasing significantly the performance of simulations. Calculations were performed to compare the original hadrontherapy implementation of the NanOx model with the present one in terms of the inactivation cross sections of human salivary gland cells as a function of the kinetic energy of incident α $\alpha$ -particles. RESULTS: The predictions of the previous and current versions of NanOx agreed for incident energies higher than 1 MeV/n. For lower energies, the new NanOx implementation predicted a decrease in the inactivation cross sections that depended on the length of the sensitive volume. CONCLUSIONS: We reported in this work an extension of the NanOx biophysical model to consider irradiations with low-energy ions, such as the ones found in TAT and BNCT. The excellent agreement observed at intermediate and high energies between the original hadrontherapy implementation and the present one showed that NanOx offers a consistent, self-integrated framework for describing the biological effects induced by ion irradiations. Future work will focus on the application of the latest version of NanOx to cases closer to the clinical setting.

Determination of the ion collection efficiency of the Razor Nano Chamber for ultra-high dose-rate electron beams.

BACKGROUND: Ultra-high dose-rate (UHDR) irradiations (>40 Gy/s) have recently garnered interest in radiotherapy (RT) as they can trigger the so-called "FLASH" effect, namely a higher tolerance of normal tissues in comparison with conventional dose rates when a sufficiently high dose is delivered to the tissue. To transfer this to clinical RT treatments, adapted methods and practical tools for online dosimetry need to be developed. Ionization chambers remain the gold standards in RT but the charge recombination effects may be very significant at such high dose rates, limiting the use of some of these dosimeters. The reduction of the sensitive volume size can be an interesting characteristic to reduce such effects. PURPOSE: In that context, we have investigated the charge collection behavior of the recent IBA Razor™ Nano Chamber (RNC) in UHDR pulses to evaluate its potential interest for FLASH RT. METHODS: In order to quantify the RNC ion collection efficiency (ICE), simultaneous dose measurements were performed under UHDR electron beams with dose-rate-independent Gafchromic™ EBT3 films that were used as the dose reference. A dose-per-pulse range from 0.01 to 30 Gy was investigated, varying the source-to-surface distance, the pulse duration (1 and 3 µs investigated) and the LINAC gun grid tension as irradiation parameters. In addition, the RNC measurements were corrected from the inherent beam shot-to-shot variations using an independent current transformer. An empirical logistic model was used to fit the RNC collection efficiency measurements and the results were compared with the Advanced Markus plane parallel ion chamber. RESULTS: The RNC ICE was found to decrease as the dose-per-pulse increases, starting from doses above 0.2 Gy/pulse and down to 40% of efficiency at 30 Gy/pulse. The RNC resulted in a higher ICE for a given dose-per-pulse in comparison with the Markus chamber, with a measured efficiency found higher than 85 and 55% for 1 and 10 Gy/pulse, respectively, whereas the Markus ICE was of 60 and 25% for the same doses. However, the RNC shows a higher sensitivity to the pulse duration than the Advanced Markus chamber, with a lower efficiency found at 1 µs than at 3 µs, suggesting that this chamber could be more sensitive to the dose rate within the pulse. CONCLUSIONS: The results confirmed that the small sensitive volume of the RNC ensures higher ICE compared with larger chambers. The RNC was thus found to be a promising online dosimetry tool for FLASH RT and we proposed an ion recombination model to correct its response up to extreme dose-per-pulses of 30 Gy.

Dosimetry and radioprotection evaluations of very high energy electron beams.

Very high energy electrons (VHEEs) represent a promising alternative for the treatment of deep-seated tumors over conventional radiotherapy (RT), owing to their favourable dosimetric characteristics. Given the high energy of the electrons, one of the concerns has been the production of photoneutrons. In this article we explore the consequence, in terms of neutron yield in a water phantom, of using a typical electron applicator in conjunction with a 2 GeV and 200 MeV VHEE beam. Additionally, we evaluate the resulting ambient neutron dose equivalent at various locations between the phantom and a concrete wall. Through Monte Carlo (MC) simulations it was found that an applicator acts to reduce the depth of the dose build-up region, giving rise to lower exit doses but higher entrance doses. Furthermore, neutrons are injected into the entrance region of the phantom. The highest dose equivalent found was approximately 1.7 mSv/Gy in the vicinity of the concrete wall. Nevertheless, we concluded that configurations of VHEEs studied in this article are similar to conventional proton therapy treatments in terms of their neutron yield and ambient dose equivalent. Therefore, a clinical implementation of VHEEs would likely not warrant additional radioprotection safeguards compared to conventional RT treatments.

First theoretical determination of relative biological effectiveness of very high energy electrons.

Very high energy electrons (VHEEs, E > 70 MeV) present promising clinical advantages over conventional beams due to their increased range, improved penumbra and relative insensitivity to tissue heterogeneities. They have recently garnered additional interest in their application to spatially fractionated radiotherapy or ultra-high dose rate (FLASH) therapy. However, the lack of radiobiological data limits their rapid development. This study aims to provide numerical biologically-relevant information by characterizing VHEE beams (100 and 300 MeV) against better-known beams (clinical energy electrons, photons, protons, carbon and neon ions). Their macro- and microdosimetric properties were compared, using the dose-averaged linear energy transfer ([Formula: see text]) as the macroscopic metric, and the dose-mean lineal energy [Formula: see text] and the dose-weighted lineal energy distribution, yd(y), as microscopic metrics. Finally, the modified microdosimetric kinetic model was used to calculate the respective cell survival curves and the theoretical RBE. From the macrodosimetric point of view, VHEEs presented a potential improved biological efficacy over clinical photon/electron beams due to their increased [Formula: see text]. The microdosimetric data, however, suggests no increased biological efficacy of VHEEs over clinical electron beams, resulting in RBE values of approximately 1, giving confidence to their clinical implementation. This study represents a first step to complement further radiobiological experiments.

Comparison of gadolinium nanoparticles and molecular contrast agents for radiation therapy-enhancement.

PURPOSE: Nanoparticles appear as a novel tool to enhance the effectiveness of radiotherapy in cancer treatments. Many parameters influence their efficacy, such as their size, concentration, composition, their cellular localization, as well as the photon source energy. The current Monte Carlo study aims at comparing the dose-enhancement in presence of gadolinium (Gd), either as isolated atoms or atoms clustered in nanoparticles (NPs), by investigating the role played by these physical parameters at the cellular and the nanometer scale. In parallel, in vitro assays were performed in presence of either the gadolinium contrast agent (GdCA) Magnevist® or ultrasmall gadolinium NPs (GdNPs, 3 nm) for comparison with the simulations. METHODS: PENELOPE Monte Carlo Code was used for in silico dose calculations. Monochromatic photon beams were used to calculate dose enhancements in different cell compartments and low-energy secondary electron spectra dependence with energy. Particular attention has been placed on the interplay between the X-ray beam energy, the Gd localization and its distance from cellular targets. Clonogenic assays were used to quantify F98 rat glioma cell survival after irradiation in the presence of GdNPs or GdCA, using monochromatic X-rays with energies in the 30 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. The simulations that correspond to the experimental conditions were compared with the experimental results. RESULTS: In silico, a highly heterogeneous and clustered Gd-atom distribution, a massive production of low energy electrons around GdNPs and an optimal X-ray beam energy, above the Gd K-edge, were key factors found to increase microscopic doses, which could potentially induce cell death. The different Gd localizations studied all resulted in a lower dose enhancement for the nucleus component than for cytoplasm or membrane compartments, with a maximum dose-enhancement factor (DEF) found at 65 keV and 58 keV, respectively. In vitro, radiosensitization was observed with GdNPs incubated 5 h with the cells (2.1 mg Gd/mL) at all energies. Experimental DEFs were found to be greater than computational DEFs but follow a similar trend with irradiation energy. However, an important radiosensitivity was observed experimentally with GdNPs at high energy (1.25 MeV), whereas no effect was expected from modeling. This effect was correlated with GdNPs incubation time. In vitro, GdCA provided no dose enhancement at 1.25 MeV energies, in agreement with computed data. CONCLUSIONS: These results provide a foundation on which to base optimizations of the physical parameters in Gd radiation-enhanced therapy. Strong evidence was provided that GdCA or GdNPs could both be used for radiation dose-enhancement therapy. There in vivo biological distribution, in the tumor volume and at the cellular scale, will be the key factor for providing large dose enhancements and determine their therapeutic efficacy.

Gadolinium nanoparticles and contrast agent as radiation sensitizers.

The goal of the present study was to evaluate and compare the radiosensitizing properties of gadolinium nanoparticles (NPs) with the gadolinium contrast agent (GdCA) Magnevist(®) in order to better understand the mechanisms by which they act as radiation sensitizers. This was determined following either low energy synchrotron irradiation or high energy gamma irradiation of F98 rat glioma cells exposed to ultrasmall gadolinium NPs (GdNPs, hydrodynamic diameter of 3 nm) or GdCA. Clonogenic assays were used to quantify cell survival after irradiation in the presence of Gd using monochromatic x-rays with energies in the 25 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. Radiosensitization was demonstrated with both agents in combination with X-irradiation. At the same concentration (2.1 mg mL(-1)), GdNPS had a greater effect than GdCA. The maximum sensitization-enhancement ratio at 4 Gy (SER4Gy) was observed at an energy of 65 keV for both the nanoparticles and the contrast agent (2.44 ± 0.33 and 1.50 ± 0.20, for GdNPs and GdCA, respectively). At a higher energy (1.25 MeV), radiosensitization only was observed with GdNPs (1.66 ± 0.17 and 1.01 ± 0.11, for GdNPs and GdCA, respectively). The radiation dose enhancements were highly 'energy dependent' for both agents. Secondary-electron-emission generated after photoelectric events appeared to be the primary mechanism by which Gd contrast agents functioned as radiosensitizers. On the other hand, other biological mechanisms, such as alterations in the cell cycle may explain the enhanced radiosensitizing properties of GdNPs.