Proton Linear Energy Transfer Research Articles

937: Prediction of the dose-averaged proton linear energy transfer using convolutional neural networks

937: Prediction of the dose-averaged proton linear energy transfer using convolutional neural networks

Feasibility study for the development of multilayered solar cells for proton linear energy transfer depth profile measurement.

Previous study proposed a method to measure linear energy transfer (LET) at specific points using the quenching magnitude of thin film solar cells. This study was conducted to propose a more advanced method for measuring the LET distribution. This study focuses on evaluating the feasibility of estimating the proton LET distribution in proton therapy. The feasibility of measuring the proton LET and dose distribution simultaneously using a single-channel configuration comprising two solar cells with distinct quenching constants is investigated with the objective of paving the way for enhanced proton therapy dosimetry. Two solar cells with different quenching constants were used to estimate the proton LET distribution. Detector characteristics (e.g., dose linearity and dose-rate dependency) of the solar cells were evaluated to assess their suitability for dosimetry applications. First, using a reference beam condition, the quenching constants of the two solar cells were determined according to the modified Birks equation. The signal ratios of the two solar cells were then evaluated according to proton LET in relation to the estimated quenching constants. The proton LET distributions of six test beams were obtained by measuring the signal ratios of the two solar cells at each depth, and the ratios were evaluated by comparing them with those calculated by Monte Carlo simulation. The detector characterization of the two solar cells including dose linearity and dose-rate dependence affirmed their suitability for use in dosimetry applications. The maximum difference between the LET measured using the two solar cells and that calculated by Monte Carlo simulation was 2.34keV/µm. In the case of the dose distribution measured using the method proposed in this study, the maximum difference between range measured using the proposed method and that measured using a multilayered ionization chamber was 0.7mm. The expected accuracy of simultaneous LET and dose distribution measurement using the method proposed in this study were estimated to be 3.82%. The signal ratios of the two solar cells, which are related to quenching constants, demonstrated the feasibility of measuring LET and dose distribution simultaneously. The feasibility of measuring proton LET and dose distribution simultaneously using two solar cells with different quenching constants was demonstrated. Although the method proposed in this study was evaluated using a single channel by varying the measuring depth, the results suggest that the proton LET and dose distribution can be simultaneously measured if the detector is configured in a multichannel form. We believe that the results presented in this study provide the envisioned transition to a multichannel configuration, with the promise of substantially advancing proton therapy's accuracy and efficacy in cancer treatment.

Technical note: Determination of proton linear energy transfer from the integral depth dose.

Proton linear energy transfer (LET) is associated with the relative biological effectiveness of radiation on tissues. Monte Carlo (MC) simulations have been known to be the preferred method to calculate LET. Detectors have also been built to measure LET, but they need to be calibrated with MC simulations. To propose and test a MC-free method for determining LET from the measured integral depth dose (LFI) of the protons of interest. LFI consists of three steps: (1) IDD measurements, (2) extraction of energy spectrum (ES) from the IDD, and (3) LET determination from the extracted ES and the stopping power of each energy. To validate the accuracy of the extraction of ES, we use Gaussian ES to synthesize IDD, extract ES from the synthesized IDD, and then compare the original (ground truth) and extracted ES. LETs calculated from the original and extracted ES are also compared. To obtain the LET of protons of interest, we measure IDDs by a large-area plane-parallel ionization chamber in water. Finally, TOPAS MC is employed to simulate IDDs, ES, and LETs. From the simulated IDD, the extracted ES and LET are compared with the simulations from TOPAS MC. From the synthesized IDDs, the LETs agreed excellently when the peak energies ≥10 and 1.25 MeV with depth resolutions 0.1and 0.01mm, respectively. For energy<1.25 MeV, even higher depth resolution than 0.01mm is required. From the MC simulated IDDs, our track-averaged LET excellently agreed with MC simulation, but not the LETd. Our LETd was smaller than MC simulated LETd in the shallow region but larger in the distal Bragg peak region. LET can be accurately determined from the IDD. This method can be used in the clinic to commission or validate LETs from other measurement methods or a treatment planning system.

Variable RBE in proton radiotherapy: a comparative study with the predictive Mayo Clinic Florida microdosimetric kinetic model and phenomenological models of cell survival

Objectives. (1) To examine to what extent the cell- and exposure- specific information neglected in the phenomenological proton relative biological effectiveness (RBE) models could influence the computed RBE in proton therapy. (2) To explore similarities and differences in the formalism and the results between the linear energy transfer (LET)-based phenomenological proton RBE models and the microdosimetry-based Mayo Clinic Florida microdosimetric kinetic model (MCF MKM). (3) To investigate how the relationship between the RBE and the dose-mean proton LET is affected by the proton energy spectrum and the secondary fragments. Approach. We systematically compared six selected phenomenological proton RBE models with the MCF MKM in track-segment simulations, monoenergetic proton beams in a water phantom, and two spread-out Bragg peaks. A representative comparison with in vitro data for human glioblastoma cells (U87 cell line) is also included. Main results. Marked differences were observed between the results of the phenomenological proton RBE models, as reported in previous studies. The dispersion of these models’ results was found to be comparable to the spread in the MCF MKM results obtained by varying the cell-specific parameters neglected in the phenomenological models. Furthermore, while single cell-specific correlation between RBE and the dose-mean proton LET seems reasonable above 2 keV μm−1, caution is necessary at lower LET values due to the relevant contribution of secondary fragments. The comparison with in vitro data demonstrates comparable agreement between the MCF MKM predictions and the results of the phenomenological models. Significance. The study highlights the importance of considering cell-specific characteristics and detailed radiation quality information for accurate RBE calculations in proton therapy. Furthermore, these results provide confidence in the use of the MCF MKM for clonogenic survival RBE calculations in proton therapy, offering a more mechanistic approach compared to phenomenological models.

Dosimetric response of Gafchromic™ EBT-XD film to therapeutic protons.

EBT-XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared to its predecessor models. This characteristic has made EBT-XD films suitable for high-dose applications such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra-high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT-XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot-scanning proton beam was used to study LET dependence at three dose-averaged LET (LETd) values of 1.0 keV/µm, 3.6 keV/µm, and 7.6 keV/µm. A research proton beamline was used to study dose rate dependence at 150 Gy/second in the FLASH mode and 0.3 Gy/second in the non-FLASH mode. Film response data from LETd values of 0.9 keV/µm and 9.0 keV/µm of the proton FLASH beam were also compared. Film response data from a clinical 6 MV photon beam were used as a reference. Both gray value method and optical density (OD) method were used in film calibration. Calibration results using a specific OD calculation method and a generic OD calculation method were compared. The four-parameter NIH Rodbard function and three-parameter rational function were compared in fitting the calibration curves. Experimental results showed that the response of EBT-XD film is proton LET dependent but independent of dose rate. Goodness-of-fit analysis showed that using the NIH Rodbard function is superior for both protons and photons. Using the "specific OD + NIH Rodbard function" method for EBT-XD film calibration is recommended.

An iterative convex relaxation method for proton LET optimization

Objective: A constant relative biological effectiveness of 1.1 in current clinical practice of proton radiotherapy (RT) is a crude approximation and may severely underestimate the biological dose from proton RT to normal tissues, especially near the treatment target at the end of Bragg peaks that exhibits high linear energy transfer (LET). LET optimization can account for biological effectiveness of protons during treatment planning, for minimizing biological proton dose and hot spots to normal tissues. However, the LET optimization is usually nonlinear and nonconvex to solve, for which this work will develop an effective optimization method based on iterative convex relaxation (ICR). Approach: In contrast to the generic nonlinear optimization method, such as Quasi-Newton (QN) method, that does not account for specific characteristics of LET optimization, ICR is tailored to LET modeling and optimization in order to effectively and efficiently solve the LET problem. Specifically, nonlinear dose-averaged LET term is iteratively linearized and becomes convex during ICR, while nonconvex dose-volume constraint and minimum-monitor-unit constraint are also handled by ICR, so that the solution for LET optimization is obtained by solving a sequence of convex and linearized convex subproblems. Since the high LET mostly occurs near the target, a 1 cm normal-tissue expansion of clinical target volume (CTV) (excluding CTV), i.e. CTV1cm, is defined to as an auxiliary structure during treatment planning, where LET is minimized. Main results: ICR was validated in comparison with QN for abdomen, lung, and head-and-neck cases. ICR was effective for LET optimization, as ICR substantially reduced the LET and biological dose in CTV1cm the ring, with preserved dose conformality to CTV. Compared to QN, ICR had smaller LET, physical and biological dose in CTV1cm, and higher conformity index values; ICR was also computationally more efficient, which was about 3 times faster than QN. Significance: A LET-specific optimization method based on ICR has been developed for solving proton LET optimization, which has been shown to be more computationally efficient than generic nonlinear optimizer via QN, with better plan quality in terms of LET, biological and physical dose conformality.

Proton linear energy transfer and variable relative biological effectiveness for adolescent patients with Hodgkin lymphoma.

Proton therapy has a theoretical dosimetric advantage due to the Bragg peak, but the linear energy transfer (LET), and therefore the relative biological effectiveness (RBE), increase at the end of range. For patients with Hodgkin lymphoma, the distal edge of beam is often located within or close to the heart, where elevated RBE would be of potential concern. The purpose of this study was to investigate the impact of RBE and the choice of beam arrangement for adolescent patients with mediastinal Hodgkin lymphoma. For three previously treated adolescent patients, proton plans with 1-3 fields were created to a prescribed dose of 19.8 Gy (RBE) in 11 fractions (Varian Eclipse v13.7), assuming an RBE of 1.1. Plans were recalculated using Monte-Carlo (Geant4 v10.3.3/Gate v8.1) to calculate dose-averaged LET. Variable RBE-weighted dose was calculated using the McNamara model, assuming an α/β ratio of 2 Gy for organs-at-risk. Although the LET decreased as the number of fields increased, the difference in RBE-weighted dose (Δdose) to organs-at-risk did not consistently decrease. Δdose values varied by patient and organ and were mostly of the order of 0-3 Gy (RBE), with a worst-case of 4.75 Gy (RBE) in near-maximum dose to the left atrium for one plan. RBE-weighted doses to organs-at-risk are sensitive to the choice of RBE model, which is of particular concern for the heart. There is a need to remain cautious when evaluating proton plans for Hodgkin lymphoma, especially when near-maximum doses to organs-at-risk are considered.

Determination of the proton LET using thin film solar cells coated with scintillating powder.

The amount of luminescent light detected in a scintillator is reduced with increased proton linear energy transfer (LET) despite receiving the same proton dose, through a phenomenon called quenching. This study evaluated the ability of a solar cell coated with scintillating powder (SC-SP) to measure therapeutic proton LET by measuring the quenching effect of the scintillating powder using a solar cell while simultaneously measuring the dose of the proton beam. SC-SP was composed of a flexible thin film solar cell and scintillating powder. The LET and dose of the pristine Bragg peak in the 14 cm range were calculated using a validated Monte Carlo model of a double scattering proton beam nozzle. The SC-SP was evaluated by measuring the proton beam under the same conditions at specific depths using SC-SP and Markus chamber. Finally, the 10 and 20 cm range pristine Bragg peaks and 5 cm spread-out Bragg peak (SOBP) in the 14 cm range were measured using the SC-SP and the Markus chamber. LETs measured using the SC-SP were compared with those calculated using Monte Carlo simulations. The quenching factors of the SC-SP and solar cell alone, which were slopes of linear fit obtained from quenching correction factors according to LET, were 0.027 and 0.070 µm/keV (R2 : 0.974 and 0.975). For pristine Bragg peaks in the 10 and 20 cm ranges, the maximum differences between LETs measured using the SC-SP and calculated using Monte Carlo simulations were 0.5 keV/µm (15.7%) and 1.2 keV/µm (12.0%), respectively. For a 5 cm SOBP proton beam, the LET measured using the SC-SP and calculated using Monte Carlo simulations differed by up to 1.9 keV/µm (18.7%). Comparisons of LETs for pristine Bragg peaks and SOBP between measured using the SC-SP and calculated using Monte Carlo simulations indicated that the solar cell-based system could simultaneously measure both LET and dose in real-time and is cost-effective.

Characterization and quenching correction for a 2D real time radioluminescent system in therapeutic proton and carbon charged beams

Two dimensional radioluminescence (RL) films were investigated for application in proton and carbon therapy dosimetry. The films are made of Al 2 O 3 :C,Mg micro powder in two sizes (38 µm and 7 µm) mixed with a water-equivalent binder. The films were irradiated behind different thicknesses of solid slabs and behind wedge shaped plastic absorbers. Bragg curves presented quenching effect attributed to the non-linear response of the RL signal as a function of proton linear energy transfer (LET). Experimental data and Monte Carlo simulations were utilized to acquire a quenching correction method, adapted from Birks’ formula, to restore the linear dose response for particle therapy beams. The method for quenching correction was applied, reaching an agreement at the Bragg peak of 3 % for films with 38 µm median grain size phosphor and 1.5 % for films with 7 µm median grain size phosphor for the proton beams; and 2 % for films with 38 µm median grain size phosphor and 3 % for films with 7 µm median grain size phosphor for the carbon charged particles. • Radioluminescence Al2O3:C,Mg films and a scientific camera. • Real time two-dimensional RL characterization along proton and carbon Bragg curves. • Films were irradiated behind different thicknesses of solid slabs and behind wedge shaped plastic absorbers. • The films present quenching with high LET. • A quenching correction was applied, good agreement along the Bragg curve.

An empirical model of proton RBE based on the linear correlation between x-ray and proton radiosensitivity.

Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and β vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE=1.1. Here, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters. We performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x-rays and 1.2, 2.6, or 9.9keV/µm protons, and combined our measurements with published survival data (n=397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF% , (the dose required to achieve survival fraction [SF], e.g., D10% ) varied with proton LET, and calculated the Bayesian information criteria associated with different LET-dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six-parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting. Our analyses of the trends in the data show that DSF% is linearly correlated between x-rays and protons, regardless of the choice of the survival level (e.g., D10% , D37% , or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%-30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE-weighted doses than the other empirical models, with RBE-weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE-weighted doses (RBE=1.1) to the tumor. We established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams.

Impact of a spatially dependent dose delivery time structure on the biological effectiveness of scanning proton therapy.

In the scanning beam delivery of protons, different portions of the target are irradiated with different linear energy transfer protons with various time intervals and irradiation times. This research aimed to evaluate the spatially dependent biological effectiveness of protracted irradiation in scanning proton therapy. One and two parallel opposed fields plans were created in water phantom with the prescribed dose of 2 Gy. Three scenarios (instantaneous, continuous, and layered scans) were used with the corresponding beam delivery models. The biological dose (physical dose × relative biological effectiveness) was calculated using the linear quadratic model and the theory of dual radiation action to quantitatively evaluate the dose delivery time effect. In addition, simulations using clinical plans (postoperative seminoma and prostate tumor cases) were conducted to assess the impact of the effects on the dose volume histogram parameters and homogeneity coefficient (HC) in targets. In a single-field plan of water phantom, when the treatment time was 19 min, the layered-scan scenario showed a decrease of<0.2% (almost 3.3%) in the biological dose from the plan on the distal (proximal) side because of the high (low) dose rate. This is in contrast to the continuous scenario, where the biological dose was almost uniformly decreased over the target by approximately 3.3%. The simulation with clinical geometry showed that the decrease rates in D99% were 0.9% and 1.5% for every 10 min of treatment time prolongation for postoperative seminoma and prostate tumor cases, respectively, whereas the increase rates in HC were 0.7% and 0.2%. In protracted irradiation in scanning proton therapy, the spatially dependent dose delivery time structure in scanning beam delivery can be an important factor for accurate evaluation of biological effectiveness.

Further development of spinal cord retreatment dose estimation: including radiotherapy with protons and light ions

Purpose A graphical user interface (GUI) was developed to aid in the assessment of changes in the radiation tolerance of spinal cord/similar central nervous system tissues with time between two individual treatment courses. Methods The GUI allows any combination of photons, protons (or ions) to be used as the initial, or retreatment, radiotherapy courses. Allowances for clinical circumstances, of reduced tolerance, can also be made. The radiobiological model was published previously and has been incorporated with additional checks and safety features, to be as safe to use as possible. The proton option includes use of a fixed RBE of 1.1 (set as the default), or a variable RBE, the latter depending on the proton linear energy transfer (LET) for organs at risk. This second LET-based approach can also be used for ions, by changing the LET parameters. Results GUI screenshots are used to show the input and output parameters for different clinical situations used in worked examples. The results from the GUI are in agreement with manual calculations, but the results are now rapidly available without tedious and error-prone manual computations. The software outputs provide a maximum dose limit boundary, which should not be exceeded. Clinicians may also choose to further lower the number of treatment fractions, whilst using the same dose per fraction (or conversely a lower dose per fraction but with the same number of fractions) in order to achieve the intended clinical benefit as safely as possible. Conclusions The new GUI will allow scientific-based estimations of time related radiation tolerance changes in the spinal cord and similar central nervous tissues (optic chiasm, brainstem), which can be used to guide the choice of retreatment dose fractionation schedules, with either photons, protons or ions.

DNA double-strand breaks in cancer cells as a function of proton linear energy transfer and its variation in time

Purpose The complex relationship between linear energy transfer (LET) and cellular response to radiation is not yet fully elucidated. To better characterize DNA damage after irradiations with therapeutic protons, we monitored formation and disappearance of DNA double-strand breaks (DNA DSB) as a function of LET and time. Comparisons with conventional γ-rays and high LET carbon ions were also performed. Materials and Methods In the present work, we performed immunofluorescence-based assay to determine the amount of DNA DSB induced by different LET values along the 62 MeV therapeutic proton Spread out Bragg peak (SOBP) in three cancer cell lines, i.e. HTB140 melanoma, MCF-7 breast adenocarcinoma and HTB177 non-small lung cancer cells. Time dependence of foci formation was followed as well. To determine irradiation positions, corresponding to the desired LET values, numerical simulations were carried out using Geant4 toolkit. We compared γ-H2AX foci persistence after irradiations with protons to that of γ-rays and carbon ions. Results With the rise of LET values along the therapeutic proton SOBP, the increase of γ-H2AX foci number is detected in the three cell lines up to the distal end of the SOBP, while there is a decrease on its distal fall-off part. With the prolonged incubation time, the number of foci gradually drops tending to attain the residual level. For the maximum number of DNA DSB, irradiation with protons attain higher level than that of γ-rays. Carbon ions produce more DNA DSB than protons but not substantially. The number of residual foci produced by γ-rays is significantly lower than that of protons and particularly carbon ions. Carbon ions do not produce considerably higher number of foci than protons, as it could be expected due to their physical properties. Conclusions In situ visualization of γ-H2AX foci reveal creation of more lesions in the three cell lines by clinically relevant proton SOBP than γ-rays. The lack of significant differences in the number of γ-H2AX foci between the proton and carbon ion-irradiated samples suggests an increased complexity of DNA lesions and slower repair kinetics after carbon ions compared to protons. For all three irradiation types, there is no major difference between the three cell lines shortly after irradiations, while later on, the formation of residual foci starts to express the inherent nature of tested cells, therefore increasing discrepancy between them.

Dual-storage phosphor proton therapy dosimetry: Simultaneous quantification of dose and linear energy transfer.

To investigate the feasibility of using the high Zeff storage phosphor material BaFBrI:Eu2+ in conjunction with the low Zeff storage phosphor material KCl:Eu2+ for simultaneous proton dose and linear energy transfer (LET) measurements by (a) measuring the fundamental optical and dosimetric properties of BaFBrI:Eu2+ , (b) evaluating its compatibility in being readout simultaneously with KCl:Eu2+ dosimeters, and (c) modeling and validating its LET dependence under elevated proton LET irradiation. A commercial BaFBrI:Eu2+ storage phosphor detector (Model ST-VI, Fujifilm) was characterized with energy dispersive x-ray spectroscopy (EDS) analysis to obtain its elemental composition. The dosimeters were irradiated using both a Mevion S250 proton therapy unit (at the center of a spread-out Bragg peak, SOBP) and a Varian Clinac iX linear accelerator with the latter being a low LET irradiation. The photostimulated luminescence (PSL) emission spectra, excitation spectra, and luminescent lifetimes of the detector were measured after proton and photon irradiations. Dosimetric properties including dose linearity, dose rate dependence, radiation hardness, temporal, and readout stabilities were studied using a laboratory optical reader after proton irradiations. In addition, its proton energy dependence was analytically modeled and experimentally validated by irradiating the detectors at various depths within the SOBP (Range: 15.0g/cm2 , Modulation: 10.0g/cm2 ). The active detector composition for the high Zeff storage phosphor detector was found to be BaFBr0.85 I0.15 :Eu2+ . The BaFBr0.85 I0.15 :Eu2+ material's excitation and emission spectra were in agreement under proton and photon irradiations, with peaks of 586±1nm and 400±1nm, respectively, with a full width at half maximum (FWHM) of 119±3nm and 30±2nm, respectively. As dosimeter response under photon irradiation is generally believed to be free from LET effect, these results suggest LET independence of charge storage center types resulted from ionizing radiations. There is sufficient spectral overlaps with KCl:Eu2+ dosimeters allowing both dosimeters to be readout under equivalent readout conditions, that is, 594nm stimulation and 420nm detection wavelengths. Its PSL characteristic lifetime was found to be less than 5 microseconds which would make it suitable for fast 2D readout post irradiation. Its 420nm emission band intensity was found to be linear up to 10Gy absolute proton dose under the same irradiation conditions, dose rate independent, stable in time and under multiple readouts, and with high radiation hardness under cumulative proton dose histories up to 200Gy as tested in this study. BaFBr0.85 I0.15 :Eu2+ showed significant proton energy-dependent dose under-response in regions of high LET which could be modeled by stopping power ratio calculations with an accuracy of 3% in low LET regions and a distance-to-agreement (DTA) of 1mm in high LET regions (>5keV/μm). We have proven the feasibility of dual-storage phosphor proton dosimetry for simultaneous proton dose and LET measurements. BaFBr0.85 I0.15 :Eu2+ has shown equally excellent dosimetry performance as its low Zeff complement KCl:Eu2+ with distinctive LET dependence merely as a result of its higher Zeff . These promising results pave the way for future studies involving simultaneous proton dose and LET measurements using this novel approach.

Fast neutron energy based modelling of biological effectiveness with implications for proton and ion beams

A practical neutron energy dependent RBE model has been developed, based on the relationship between a mono-energetic neutron energy and its likely recoil proton energy. Essentially, the linear energy transfer (LET) values of the most appropriate recoil proton energies are then used to modify the linear quadratic model radiosensitivities (α and β) from their reference LET radiation values to provide the RBE estimates. Experimental neutron studies published by Hall (including some mono-energetic beams ranging from 0.2 to 15 MeV), Broerse, Berry, and data from the Clatterbridge and Detroit clinical neutron beams, which all contain some data from a spectrum of neutron energies, are used to derive single effective neutron energies (NEeff) for each spectral beam. These energies yield a recoil proton spectrum, but with an effective mean proton energy (being around 50% of NEeff). The fractional increase in LET is given by the recoil proton LET divided by the proton (LETU) value which provides the highest RBE. This ratio is then used to determine the change in the linear-quadratic model α and β parameters, from those of the reference radiation, to estimate the RBE. The predicted proton recoil RBE is then reasonably close to the experimental neutron RBE values found when taking into account the variation inherent in biological experiments. The work has some important consequences. The data of Hall et al (1975 Radiat. Res. 64 245–55) shows that the highest RBE values are found with neutron energies around 0.3–0.4 MeV, but this energy cannot possibly generate recoil proton energies which are higher, as necessary for a 0.68 MeV proton with a 30.5 keV μm−1 LETU (the LET value which provides the maximum obtainable RBE for a specified ion). For 0.4 MeV neutrons with proton recoil energies of around 0.2 MeV, the latter have a LET of around 62.88 keV μm−1. This could have an impact on proton beam RBE modelling. However, this is compensated by finding that the maximum radiosensitivity for mono-energetic neutrons was around 1.7 times larger than previously suggested from experimental ion beam studies, probably due to the necessary spreading out of Bragg peaks for ion beam experimental purposes, sampling errors and particle range considerations. This semi-empirical model can be used with minimal computer support and could have applications in ionic beams and in radioprotection.

A High-Precision Method for In Vitro Proton Irradiation.

PurposeAlthough proton therapy has become a well-established radiation modality, continued efforts are needed to improve our understanding of the molecular and cellular mechanisms occurring during treatment. Such studies are challenging, requiring many resources. The purpose of this study was to create a phantom that would allow multiple in vitro experiments to be irradiated simultaneously with a spot-scanning proton beam.Materials and MethodsThe setup included a modified patient-couch top coupled with a high-precision robotic arm for positioning. An acrylic phantom was created to hold 4 6-well cell-culture plates at 2 different positions along the Bragg curve in a reproducible manner. The proton treatment plan consisted of 1 large field encompassing all 4 plates with a monoenergetic 76.8-MeV posterior beam. For robust delivery, a mini pyramid filter was used to broaden the Bragg peak (BP) in the depth direction. Both a Markus ionization chamber and EBT3 radiochromic film measurements were used to verify absolute dose.ResultsA treatment plan for the simultaneous irradiation of 2 plates irradiated with high linear energy transfer protons (BP, 7 keV/μm) and 2 plates irradiated with low linear energy transfer protons (entrance, 2.2 keV/μm) was created. Dose uncertainty was larger across the setup for cell plates positioned at the BP because of beam divergence and, subsequently, variable proton-path lengths. Markus chamber measurements resulted in uncertainty values of ±1.8% from the mean dose. Negligible differences were seen in the entrance region (<0.3%).ConclusionThe proposed proton irradiation setup allows 4 plates to be simultaneously irradiated with 2 different portions (entrance and BP) of a 76.8-MeV beam. Dosimetric uncertainties across the setup are within ±1.8% of the mean dose.

Dose- rather than fluence-averaged LET should be used as a single-parameter descriptor of proton beam quality for radiochromic film dosimetry.

PurposeThe dose response of Gafchromic EBT3 films exposed to proton beams depends on the dose, and additionally on the beam quality, which is often quantified with the linear energy transfer (LET) and, hence, also referred to as LET quenching. Fundamentally different methods to determine correction factors for this LET quenching effect have been reported in literature and a new method using the local proton fluence distribution differential in LET is presented. This method was exploited to investigate whether a more practical correction based on the dose‐ or fluence‐averaged LET is feasible in a variety of clinically possible beam arrangements.MethodsThe relative effectiveness (RE) was characterized within a high LET spread‐out Bragg peak (SOBP) in water made up by the six lowest available energies (62.4–67.5 MeV, configuration “b1”) resulting in one of the highest clinically feasible dose‐averaged LET distributions. Additionally, two beams were measured where a low LET proton beam (252.7 MeV) was superimposed on “b1”, which contributed either 50% of the initial particle fluence or 50% of the dose in the SOBP, referred to as configuration “b2” and “b3,” respectively. The proton LET spectrum was simulated with GATE/Geant4 at all measurement positions. The net optical density change differential in LET was integrated over the local proton spectrum to calculate the net optical density and therefrom the beam quality correction factor. The LET dependence of the film response was accounted for by an LET dependence of one of the three parameters in the calibration function and was determined from inverse optimization using measurement “b1.” This method was then validated on the measurements of “b2” and “b3” and subsequently used to calculate the RE at 900 positions in nine clinically relevant beams. The extrapolated RE set was used to derive a simple linear correction function based on dose‐averaged LET (Ld) and verify the validity in all points of the comprehensive RE set.ResultsThe uncorrected film dose deviated up to 26% from the reference dose, whereas the corrected film dose agreed within 3% in all three beams in water (“b1”, “b2” and “b3”). The LET dependence of the calibration function started to strongly increase around 5 keV/μm and flatten out around 30 keV/μm. All REs calculated from the proton fluence in the nine simulated beams could be approximated with a linear function of dose‐averaged LET (RE = 1.0258−0.0211 μm/keV Ld). However, no functional relationship of RE‐ and fluence‐averaged LET could be found encompassing all beam energies and modulations.ConclusionsThe film quenching was found to be nonlinear as a function of proton LET as well as of the dose‐averaged LET. However, the linear relation of RE on dose‐averaged LET was a good approximation in all cases. In contrast to dose‐averaged LET, fluence‐averaged LET could not describe the RE when multiple beams were applied.

Response to the Commentary from Bevelacqua et al.

This response clarifies certain misconceptions published in the commentary by Bevelacqua et al. (2019). We are pleased that our article entitled “New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation” (Acharya et al., 2019) has stimulated interesting discussions and different perspectives on what may or may not be relevant to estimating the risks of CNS dysfunction following exposure to the space radiation environment. Here we provide our response to the commentary from Bevelacqua et al. (2019). Bevelacqua et al. (2019) stated that there were a few major shortcomings with our approach, and we would like to clarify our stance regarding those statements. The first and perhaps most disconcerting statement was their assertion that we have ignored “…that in a realistic space environment, cells will be exposed to multiple low LET (linear energy transfer) protons before being traversed by intermediate and high-LET HZE (high charge and energy) particles.” The authors of Acharya et al. (2019) have conducted research at heavy ion particle accelerators around the world for more than a decade, and the implication that we might be unaware of the complexities of the radiation fields in space is misguided (Parihar et al., 2015, 2016, 2018; Lee et al., 2017). During long-term missions into deep space, astronauts will be exposed to a complex radiation field that includes high LET components from high energy, heavy ions (HZE particles) at low dose rates of ∼0.5 mGy/d for long durations. About 20% of the dose is delivered with LET >10 keV/μm. Particle accelerators are capable of simulating components of the galactic cosmic radiation (GCR) spectrum. The main impediment to performing accelerator-based experiments, which are designed to simulate exposures to …

Harnessing the Differential Immune Signature of High Versus Low Linear Energy Transfer Protons to Elicit Potent Systemic Immune Responses in Colorectal Cancer

Harnessing the Differential Immune Signature of High Versus Low Linear Energy Transfer Protons to Elicit Potent Systemic Immune Responses in Colorectal Cancer

Nonhomologous End Joining Is More Important Than Proton Linear Energy Transfer in Dictating Cell Death

This study seeks to identify biological factors that may yield a therapeutic advantage of proton therapy versus photon therapy. Specifically, we address the role of nonhomologous end-joining (NHEJ) and homologous recombination (HR) in the survival of cells in response to clinical photon and proton beams. We irradiated HT1080, M059K (DNA-PKcs+/+), and HCC1937 human cancer cell lines and their isogenic counterparts HT1080-shDNA-PKcs, HT1080-shRAD51IND, M059J (DNA-PKcs-/-), and HCC1937-BRCA1 (BRCA1 complemented) to assess cell clonogenic survival and γ-H2AX radiation-induced foci. Cells were irradiated with either clinically relevant photons or 1 of 3 proton linear energy transfer (LET) values. Our results indicate that NHEJ deficiency is more important in dictating cell survival than proton LET. Cells with disrupted HR through BRCA1 mutation showed increased radiosensitivity only for high-LET protons whereas RAD51 depletion showed increased radiosensitivity for both photons and protons. DNA double strand breaks, assessed by γ-H2AX radiation-induced foci, showed greater numbers after 24 hours in cells exposed to higher LET protons. We also observed that NHEJ-deficient cells were unable to repair the vast majority of double strand breaks after 24 hours. BRCA1 mutation significantly sensitizes cells to protons, but not photons. Loss of NHEJ renders cells hypersensitive to radiation, whereas the relative importance of HR increases with LET across several cell lines. This may be attributable to the more clustered damage induced by higher LET protons, which are harder to repair through NHEJ. This highlights the importance of tumor biology in dictating treatment modality and suggests BRCA1 as a potential biomarker for proton therapy response. Our data also support the use of pharmacologic inhibitors of DNA repair to enhance the sensitivity to different radiation types, although this raises issues for normal tissue toxicity.