The TOPAS Monte Carlo (MC) system is used in radiation therapy and medical imaging research, having played a significant role in making Monte Carlo simulations widely available for proton therapy ...related research. While TOPAS provides detailed simulations of patient scale properties, the fundamental unit of the biological response to radiation is a cell. Thus, our goal was to develop TOPAS-nBio, an extension of TOPAS dedicated to advance understanding of radiobiological effects at the (sub-)cellular, (i.e., the cellular and sub-cellular) scale. TOPAS-nBio was designed as a set of open source classes that extends TOPAS to model radiobiological experiments. TOPAS-nBio is based on and extends Geant4-DNA, which extends the Geant4 toolkit, the basis of TOPAS, to include very low-energy interactions of particles down to vibrational energies, explicitly simulates every particle interaction (i.e., without using condensed histories) and propagates radiolysis products. To further facilitate the use of TOPAS-nBio, a graphical user interface was developed. TOPAS-nBio offers full track-structure Monte Carlo simulations, integration of chemical reactions within the first millisecond, an extensive catalogue of specialized cell geometries as well as sub-cellular structures such as DNA and mitochondria, and interfaces to mechanistic models of DNA repair kinetics. We compared TOPAS-nBio simulations to measured and published data of energy deposition patterns and chemical reaction rates (G values). Our simulations agreed well within the experimental uncertainties. Additionally, we expanded the chemical reactions and species provided in Geant4-DNA and developed a new method based on independent reaction times (IRT), including a total of 72 reactions classified into 6 types between neutral and charged species. Chemical stage simulations using IRT were a factor of 145 faster than with step-by-step tracking. Finally, we applied the geometric/chemical modeling to obtain initial yields of double-strand breaks (DSBs) in DNA fibers for proton irradiations of 3 and 50 MeV and compared the effect of including chemical reactions on the number and complexity of DSB induction. Over half of the DSBs were found to include chemical reactions with approximately 5% of DSBs caused only by chemical reactions. In conclusion, the TOPAS-nBio extension to the TOPAS MC application offers access to accurate and detailed multiscale simulations, from a macroscopic description of the radiation field to microscopic description of biological outcome for selected cells. TOPAS-nBio offers detailed physics and chemistry simulations of radiobiological experiments on cells simulating the initially induced damage and links to models of DNA repair kinetics.
Purpose:
Magnetic resonance imaging (MRI) is a prime candidate for image‐guided radiotherapy. This study was designed to assess the feasibility of real‐time MRI‐guided proton therapy by quantifying ...the dosimetric effects induced by the magnetic field in patients’ plans and identifying the associated clinical consequences.
Methods:
Monte Carlo dose calculation was performed for nine patients of various treatment sites (lung, liver, prostate, brain, skull‐base, and spine) and tissue homogeneities, in the presence of 0.5 and 1.5 T magnetic fields. Dose volume histogram (DVH) parameters such as D95, D5, and V20 as well as equivalent uniform dose were compared for the target and organs at risk, before and after applying the magnetic field. The authors further assessed whether the plans affected by clinically relevant dose distortions could be corrected independent of the planning system.
Results:
By comparing the resulting dose distributions and analyzing the respective DVHs, it was determined that despite the observed lateral beam deflection, for magnetic fields of up to 0.5 T, neither was the target coverage jeopardized nor was the dose to the nearby organs increased in all cases except for prostate. However, for a 1.5 T magnetic field, the dose distortions were more pronounced and of clinical concern in all cases except for spine. In such circumstances, the target was severely underdosed, as indicated by a decrease in D95 of up to 41% of the prescribed dose compared to the nominal situation (no magnetic field). Sites such as liver and spine were less affected due to higher tissue homogeneity, typically smaller beam range, and the choice of beam directions. Simulations revealed that small modifications to certain plan parameters such as beam isocenter (up to 19 mm) and gantry angle (up to 10°) are sufficient to compensate for the magnetic field‐induced dose disturbances. The authors’ observations indicate that the degree of required corrections strongly depends on the beam range and direction relative to the magnetic field. This method was also applicable to more heterogeneous scenarios such as skull‐base tumors.
Conclusions:
This study confirmed the dosimetric feasibility of real‐time MRI‐guided proton therapy and delivering a clinically acceptable dose to patients with various tumor locations within magnetic fields of up to 1.5 T. This work could serve as a guide and encouragement for further efforts toward clinical implementation of hybrid MRI–proton gantry systems.
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The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential ...of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries.
FLASH radiotherapy delivers a high dose (≥10 Gy) at a high rate (≥40 Gy/s). In this way, particles are delivered in pulses as short as a few nanoseconds. At that rate, intertrack reactions between ...chemical species produced within the same pulse may affect the heterogeneous chemistry stage of water radiolysis. This stochastic process suits the capabilities of the Monte Carlo method, which can model intertrack effects to aid in radiobiology research, including the design and interpretation of experiments. In this work, the TOPAS-nBio Monte Carlo track-structure code was expanded to allow simulations of intertrack effects in the chemical stage of water radiolysis. Simulation of the behavior of radiolytic yields over a long period of time (up to 50 s) was verified by simulating radiolysis in a Fricke dosimeter irradiated by 60Co γ rays. In addition, LET-dependent G values of protons delivered in single squared pulses of widths, 1 ns, 1 µs and 10 µs, were obtained and compared to simulations using no intertrack considerations. The Fricke simulation for the calculated G value of Fe3+ ion at 50 s was within 0.4% of the accepted value from ICRU Report 34. For LET-dependent G values at the end of the chemical stage, intertrack effects were significant at LET values below 2 keV/µm. Above 2 keV/µm the reaction kinetics remained limited locally within each track and thus, effects of intertrack reactions remained low. Therefore, when track structure simulations are used to investigate the biological damage of FLASH irradiation, these intertrack reactions should be considered. The TOPAS-nBio framework with the expansion to intertrack chemistry simulation provides a useful tool to assist in this task.
. To commission a proton, double-scattering FLASH beamline by maximizing efficiency and field size, enabling higher-linear energy transfer FLASH radiotherapy to cells and small animals using a ...spread-out Bragg peak (SOBP) treatment configuration. We further aim to provide a configuration guide for the design of future FLASH proton double-scattering (DS) beamlines.
. Beam spot size and spread were measured with film and implemented into TOol for PArticle Simulation (TOPAS). Monte Carlo simulations were optimized to verify the ideal positioning, dimensions, and material of scattering foils, secondary scatterers, ridge filters, range compensators, and apertures. A ridge filter with three discrete heights was used to create a spread-out Bragg peak (SOBP) and was experimentally verified using our in-house experimental FLASH beamline. The increase in dose rate was compared to nominal shoot-through techniques.
. The configuration and scatterer distance producing the largest field size of acceptable flatness, without drastically compromising dose rate was determined to be an elliptical field of 2 cm × 1.5 cm (25% larger than a previous configuration). SOBP testing yielded three distinct but connected spikes in dose with flatness under 5%. Reducing the thickness of the (first) scattering foil by a factor of two was found to increase efficiency by 50%. The new settings increased the field size, provided a Bragg peak treatment option, and increased the maximum available dose rate by 85%, as compared to the previous, shoot through method.
. Beam line updates established FLASH dose rates of over 135 Gy s
(potentially higher) at our double-scattering beamline, increased the efficiency and field size, and enabled SOBP treatments by incorporating an optimized ridge filter. Based on our simulations we provide parametric suggestions when commissioning a new proton DS beamline. This enhanced FLASH beamline for SOBP irradiations with higher dose rates and larger field sizes will enable a wider variety of experimentation in future studies.
We provide optimal particle split numbers for speeding up TOPAS Monte Carlo simulations of linear accelerator (linac) treatment heads while maintaining accuracy. In addition, we provide a new TOPAS ...physics module for simulating photoneutron production and transport. TOPAS simulation of a Siemens Oncor linac was used to determine the optimal number of splits for directional bremsstrahlung splitting as a function of the field size for 6MV and 18MV x-ray beams. The linac simulation was validated against published data of lateral dose profiles and percentage depth-dose curves (PDD) for the largest square field (40cm side). In separate simulations, neutron particle split and the custom TOPAS physics module was used to generate and transport photoneutrons, called "TsPhotoNeutron". Verification of accuracy was performed by comparing simulations with published measurements of: 1) neutron yields as a function of beam energy for thick targets of Al, Cu, Ta, W, Pb and concrete; and 2) photoneutron energy spectrum at 40cm laterally from the isocenter of the linac from an 18MV beam with closed jaws and MLC. The optimal number of splits obtained for directional bremsstrahlung splitting enhanced the computational efficiency by two orders of magnitude. The efficiency decreased with increasing beam energy and field size. Calculated lateral profiles in the central region agreed within 1mm/2% from measured data, PDD curves within 1 mm/1%. For the TOPAS physics module, at a split number of 146, the efficiency of computing photoneutron yields was enhanced by a 27.6 factor, whereas it improved the accuracy over existing Geant4 physics modules. This work provides simulation parameters and a new TOPAS physics module to improve the efficiency and accuracy of TOPAS simulations that involve photonuclear processes occurring in high-Z materials found in linac components, patient devices, and treatment rooms, as well as to explore new therapeutic modalities such as very-high-energy electron therapy.
Simulation of water radiolysis and the subsequent chemistry provides important information on the effect of ionizing radiation on biological material. The Geant4 Monte Carlo toolkit has added ...chemical processes via the Geant4-DNA project. The TOPAS tool simplifies the modeling of complex radiotherapy applications with Geant4 without requiring advanced computational skills, extending the pool of users. Thus, a new extension to TOPAS, TOPAS-nBio, is under development to facilitate the configuration of track-structure simulations as well as water radiolysis simulations with Geant4-DNA for radiobiological studies. In this work, radiolysis simulations were implemented in TOPAS-nBio. Users may now easily add chemical species and their reactions, and set parameters including branching ratios, dissociation schemes, diffusion coefficients, and reaction rates. In addition, parameters for the chemical stage were re-evaluated and updated from those used by default in Geant4-DNA to improve the accuracy of chemical yields. Simulation results of time-dependent and LET-dependent primary yields Gx (chemical species per 100 eV deposited) produced at neutral pH and 25 °C by short track-segments of charged particles were compared to published measurements. The LET range was 0.05-230 keV µm−1. The calculated Gx values for electrons satisfied the material balance equation within 0.3%, similar for protons albeit with long calculation time. A smaller geometry was used to speed up proton and alpha simulations, with an acceptable difference in the balance equation of 1.3%. Available experimental data of time-dependent G-values for agreed with simulated results within 7% ± 8% over the entire time range; for over the full time range within 3% ± 4%; for H2O2 from 49% ± 7% at earliest stages and 3% ± 12% at saturation. For the LET-dependent Gx, the mean ratios to the experimental data were 1.11 ± 0.98, 1.21 ± 1.11, 1.05 ± 0.52, 1.23 ± 0.59 and 1.49 ± 0.63 (1 standard deviation) for , , H2, H2O2 and , respectively. In conclusion, radiolysis and subsequent chemistry with Geant4-DNA has been successfully incorporated in TOPAS-nBio. Results are in reasonable agreement with published measured and simulated data.
Purpose: To develop a nano‐dosimetric Monte Carlo simulation package, TOPAS‐nBio, based on the TOPAS (TOol for PArticle Simulations) framework that is being developed in a collaboration between the ...Massachusetts General Hospital (MGH), the SLAC National Accelerator Laboratory and the University of California, San Francisco. The goal is to incorporate biological processes on a sub‐cell level that will provide the basis for a wide range of research in the field of radiobiology, such as bystander effects, biological dose calculations and effects of nano‐particles on radiation therapy. Methods: The TOPAS framework has been utilized to extend the functionality of this tool for particle transport to include nano‐ dosimetry. The physics lists of TOPAS have been extended to include efforts by the Geant4‐DNA group to model physics on nanometer scales, including chemical processes of the first millisecond after irradiation. TOPAS‐nBio uses the functionality of TOPAS to score energy depositions on nanometer scales. A simulation of the setup of a cell culture irradiation experiment has been used as to test the feasibility of the project. Results: Track structures for an irradiation of a cell culture experiment were successfully obtained. Delta‐electron distributions have been produced and single track delta electrons and their energy depositions were observed. Conclusions: This study is a first step in the development of TOPAS‐nBio, a tool that aims at bringing nanometer scale radiation physics and biology together and make Monte Carlo simulations accessible for all radiobiology researchers. The results presented here show a first proof of concept for the development of TOPAS‐nBio.
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The chemical stage of theMonte Carlo track-structure simulation codeGeant4-DNA has been revised andvalidated. The root-mean-square (RMS) empirical parameter that dictates the displacement ...ofwatermolecules after an ionization and excitation event inGeant4-DNA has been shortened to betterfitexperimental data. The pre-defined dissociation channels and branching ratioswere notmodified, but thereaction rate coefficientsfor simulating the chemical stage ofwater radiolysiswere updated. The evaluationofGeant4-DNA was accomplishedwith TOPAS-nBio. For that,we compared predicted time-dependentGvalues in pure liquidwaterfor·OH, e–aq, and H2with published experimental data. For H2O2 and H·,simulation of added scavengers at different concentrations resulted in better agreementwithmeasurements.In addition, DNA geometry information was integratedwith chemistry simulation in TOPAS-nBio to realizereactions between radiolytic chemical species and DNA. Thiswas used in the estimation of the yield of singlestrand breaks(SSB)induced by 137Cs γ-ray radiolysis of supercoiled pUC18 plasmids dissolved in aeratedsolutions containing DMSO. The efficiency of SSB induction by reaction between radiolytic species andDNA used in the simulation was chosen to provide the best agreementwith publishedmeasurements. AnRMS displacement of 1.24 nm provided agreementwithmeasured datawithin experimental uncertaintiesfor time-dependentGvalues and under the presence of scavengers. SSB efficiencies of 24% and 0.5%for·OHand H·, respectively, led to an overall agreement of TOPAS-nBio resultswithin experimental uncertainties.The efficiencies obtained agreed with values obtainedwith published non-homogeneous kineticmodel andstep-by-stepMonte Carlo simulations but disagreed by 12%with published directmeasurements.Improvement of the spatial resolution of the DNA damagemodelmightmitigate such disagreement. Inconclusion,with these improvements,Geant4-DNA/TOPAS-nBio provides afast, accurate, and userfriendly toolfor simulating DNA damage under low linear energy transfer irradiation.
The chemical stage of the Monte Carlo track-structure (MCTS) code Geant4-DNA was extended for its use in DNA strand break (SB) simulations and compared against published experimental data. Geant4-DNA ...simulations were performed using pUC19 plasmids (2686 base pairs) in a buffered solution of DMSO irradiated by
Co or
Cs
-rays. A comprehensive evaluation of SSB yields was performed considering DMSO, DNA concentration, dose and plasmid supercoiling. The latter was measured using the super helix density value used in a Brownian dynamics plasmid generation algorithm. The Geant4-DNA implementation of the independent reaction times method (IRT), developed to simulate the reaction kinetics of radiochemical species, allowed to score the fraction of supercoiled, relaxed and linearized plasmid fractions as a function of the absorbed dose. The percentage of the number of SB after •OH + DNA and H• + DNA reactions, referred as SSB efficiency, obtained using MCTS were 13.77% and 0.74% respectively. This is in reasonable agreement with published values of 12% and 0.8%. The SSB yields as a function of DMSO concentration, DNA concentration and super helix density recreated the expected published experimental behaviors within 5%, one standard deviation. The dose response of SSB and DSB yields agreed with published measurements within 5%, one standard deviation. We demonstrated that the developed extension of IRT in Geant4-DNA, facilitated the reproduction of experimental conditions. Furthermore, its calculations were strongly in agreement with experimental data. These two facts will facilitate the use of this extension in future radiobiological applications, aiding the study of DNA damage mechanisms with a high level of detail.
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