Spread-out Bragg Peak Research Articles

Manifestation of the FLASH effect in proton irradiation of embryos

Purpose In order to study the FLASH effect using live models, this work compared proton-induced damage to embryos (nine days after fertilization) and one-day-old chicks (18 days after fertilization) from irradiated at different dose rates eggs of Japanese quail (Coturnix coturnix japónica). Materials and methods Eggs were irradiated with protons in different modes depending on the dose rate: in a conventional mode (<1 Gy/s, CONV), in a flash mode (∼100 Gy/s, FLASH) and in a single-pulse flash mode (∼105 Gy/s SPLASH). Results By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in nine-day-old embryos from eggs irradiated in the spread-out Bragg peak (SOBP) (8.5 Gy), FLASH and SPLASH modes were found to be less traumatic compared with the CONV mode. Among all irradiated embryos, the maximum body weight and length were observed in the SPLASH mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation. In chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, while chicks from eggs irradiated in the CONV mode were less active than all others. Conclusions The proton irradiation of eggs in SOBP using high dose-rate modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.

Commissioning of a commercial treatment planning system for scanned carbon-ion radiotherapy.

To commission the RayStation (RS) TPS (treatment planning system) for scanned CIRT (carbon-ion radiotherapy) utilizing pencil beam algorithms (PBv4.2). The beam model commissioning entailed employing 1D single beams and 2D monoenergetic fields to validate spot profiles with films, assess beam range using Peakfinder measurements, and evaluate fragment spectra through dose-averaged linear energy transfer (LETd) calculations. 3D dose distributions were verified in homogeneous phantoms for both absorbed and relative biological effectiveness (RBE)-weighted doses, and further assessed in double wedge and anthropomorphic phantoms for absorbed dose only. Finally, RBE-weighted dose verification and patient-specific quality assurance were conducted using 58 beams from 20 clinically treated patient plans. The results demonstrated good agreement in absolute dose distribution between TPS calculations and measurements, with mean dose discrepancies within 3%. However, deviations were slightly higher (>1%) for the cases involving the range shifter (RaShi) compared to those without the RaShi (<1%). Beam range, depth dose distribution, and lateral profiles of spread-out Bragg peaks (SOBPs) closely matched between RS TPS calculations and measurements. Some discrepancies (less than 0.5mm) were observed at field edges and in penumbra regions due to limitations in simulating asymmetrical spots, but within clinical tolerance. After model tuning, RBE-weighted dose calculations in RS TPS were in agreement with those from the clinically used TPS, except for variations exceeding 3% observed at energies exceeding 408.07 MeV/u, primarily attributed to fragment spectra differences. Overall, this study validated the RS TPS for calculating absorbed doses against measurements and RBE-weighted doses against a clinically used TPS. The results suggested that the RS TPS could be utilized for CIRT treatment planning, except for energies exceeding 408.07 MeV/u.

Proton FLASH Irradiation Using a Synchrotron Accelerator: Differences by Irradiation Positions

PurposeTo establish an ultra-high dose rate (UHDR) radiation system using a synchrotron proton beam accelerator and to compare the effects by irradiation positions on cultured cells and chick embryos. Methods and MaterialsProtons for UHDR were obtained by applying high-frequency power at much higher levels than usual to extract all protons within approximately 50 ms. Subsequently, monitoring with a Faraday cup was performed immediately after synchrotron extraction and the waveform was adjusted accordingly. Four cultured tumor lines, two normal cell lines, and chick embryos were used. Ultra-high dose-rate radiation (UHDR-RT) at 6-18 Gy (200-300 Gy/s, single exposure) and conventional dose-rate radiation (Conv-RT) at 6-18 Gy (3 Gy/s) were administered to the 1-cm spread-out Bragg peak (SOBP) and the plateau region preceding SOBP. Following irradiation, disparities in cell growth rates and cell cycle progression were assessed, and cell survival was evaluated via colony assay. Chick embryos were also examined for survival. ResultsUHDR-RT was achieved at a range of 40 to 800 Gy/s, encompassing both plateau and peak phases. In vitro studies demonstrated similar cell-killing effects between UHDR-RT and Conv-RT in cancer cells. Significant apoptotic effects and G2 arrest were observed during the cell cycle under peak UHDR-RT conditions. The FLASH effect was not observed in normal single cells under normal atmospheric conditions. Stronger cell-killing effects were noted in V79 spheroids exposed to peak UHDR-RT than peak Conv-RT. Moreover, in chick embryos, an increase in survival rate, indicative of the FLASH effect, was observed. ConclusionsThe FLASH effect was also achieved with UHDR-RT using a synchrotron proton beam accelerator in chick embryos. The cell-killing effects in cancer cells were higher with peak UHDR-RT which may be due to the higher linear energy transfer at the SOBP.

FLASH Bragg-peak irradiation with a therapeutic carbon ion beam: first in vivo results

Background and purposeIn recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons or protons, is the improved normal tissue sparing, while the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei. Materials and MethodsHere we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, i.e., at high-LET in the spread-out Bragg peak (SOBP) of a 12C beam using an osteosarcoma mouse model. ResultsWe show that UHDR irradiation was less toxic in the normal tissue compared to CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. Both UHDR and CDR exposures steered the metagenome toward a balanced state. ConclusionsThese results suggest that the UHDR irradiations can improve the safety and effectiveness of heavy ion therapy, and provide a crucial benchmark for current mechanistic FLASH models. However, additional experiments are needed to validate these findings across other animal and tumor models.

Determination of RBE of 450 MeV/nucleon carbon ions using the micronucleus test and survival of mice after irradiation in different regions of the Bragg curve

Purpose Determination of the value of relative biological effectiveness (RBE) of heavy charged ions in vivo is an important task for their optimal use in particle radiotherapy. The aim of this study was to determine the RBE value of a beam of carbon ions with an energy of 450 MeV/nucleon in different regions of the Bragg curve in irradiation of mice at low, medium, and high doses in comparison with X-ray radiation. Materials and methods SHK mice (n = 330) were irradiated in three regions of the Bragg curve in the dose range of 0–1.5 Gy for cytogenetic damage detection and at a dose of 6.5 Gy for determination of 30-day survival. For irradiation of mice in the Bragg peak, two widths of a spread-out Bragg peak (SOBP) were used: 10 mm (LET ∼100 keV/µm) and 30 mm (LET ∼39 keV/µm). Results The RBE value was 0.8–0.9 before the Bragg peak (LET ∼15 keV/µm) and 0.8 after the peak (LET ∼5 keV/µm), and did not depend on the determination method, despite the differences in LET values. The RBE value determined by the micronucleus test was 1.1–1.7 for the 10-mm-wide SOBP and 1.0–1.3 for the 30-mm-wide SOBP, with the highest RBE value obtained in the low-dose region upon irradiation of mice in the 10-mm-wide Bragg peak. The RBE values in the high-dose region determined by the 30-day survival test lay in the range from 1.4 to 2.6 depending on the width of the Bragg peak and the chosen criterion for calculating the value. The RBE values in the 10-mm-wide Bragg peak (LET ∼100 keV/µm) were higher than those in the 30-mm-wide Bragg peak (LET ∼39 keV/µm) at all used criteria. Conclusions The present findings suggest that there is the complex relationship between LET and organism response to accelerated charged particle radiation, and the contribution of specific factors and mechanisms must be further considered.

Design of a compact beam transport system for laser-driven proton therapy

Abstract We put forward a new design of a compact beam transport system for intense laser-driven proton therapy, where instead of using conventional pulsed solenoids, our design relies on a helical coil irradiated by a nanosecond laser pulse to generate strong magnetic fields for focusing protons. A pair of dipole magnets and apertures are employed to further filter protons with large divergences and low energies. Our numerical studies combine particle-in-cell simulations for laser-plasma interaction to generate high-energy monoenergetic proton beams, finite element analysis for evaluating the magnetic field distribution inside the coil, and Monte-Carlo simulations for beam transport and energy deposition. Our results show that with this design, a spread-out Bragg peak in a range of several centimeters to a deep-seated tumor with a dose of approximately 16.5 cGy and fluctuation around 2% can be achieved. The instantaneous dose rate reaches up to 109 Gy/s, holding the potential for future FLASH radiotherapy research.

A Fast 3D Range-Modulator Delivery Approach: Validation of the FLUKA Model on a Varian ProBeam System Including a Robustness Analysis

A 3D range-modulator (RM), optimized for a single energy and a specific target shape, is a promising and viable solution for the ultra-fast dose delivery in particle therapy. The aim of this work was to investigate the impact of potential beam and modulator misalignments on the dose distribution. Moreover, the FLUKA Monte Carlo model, capable of simulating 3D RMs, was adjusted and validated for the 250 MeV single-energy proton irradiation from a Varian ProBeam system. A 3D RM was designed for a cube target shape rotated 45° around two axes using a Varian-internal research version of the Eclipse treatment planning software, and the resulting dose distribution was simulated in a water phantom. Deviations from the ideal alignment were introduced, and the dose distributions from the modified simulations were compared to the original unmodified one. Finally, the FLUKA model and the workflow were validated with base-line data measurements and dose measurements of the manufactured modulator prototype at the HollandPTC facility in Delft. The adjusted FLUKA model, optimized particularly in the scope of a single-energy FLASH irradiation with a PMMA pre-absorber, demonstrated very good agreement with the measured dose distribution resulting from the 3D RM. Dose deviations resulting from modulator-beam axis misalignments depend on the specific 3D RM and its shape, pin aspect ratio, rotation angle, rotation point, etc. A minor modulator shift was found to be more relevant for the distal dose distribution than for the spread-out Bragg Peak (SOBP) homogeneity. On the other hand, a modulator tilt (rotation away from the beam axis) substantially affected not only the depth dose profile, transforming a flat SOBP into a broad, Gaussian-like distribution with increasing rotation angle, but also shifted the lateral dose distribution considerably. This work strives to increase awareness and highlight potential pitfalls as the 3D RM method progresses from a purely research concept to pre-clinical studies and human trials. Ensuring that gantry rotation and the combined weight of RM, PMMA, and aperture do not introduce alignment issues is critical. Given all the other range and positioning uncertainties, etc., not related to the modulator, the RM must be aligned with an accuracy below 1° in order to preserve a clinically acceptable total uncertainty budget. Careful consideration of critical parameters like the pin aspect ratio and possibly a novel robust modulator geometry optimization are potential additional strategies to mitigate the impact of positioning on the resulting dose. Finally, even the rotated cube 3D modulator with high aspect ratio pin structures (~80 mm height to 3 mm pin base width) was found to be relatively robust against a slight misalignment of 0.5° rotation or a 1.5 mm shift in one dimension perpendicular to the beam axis. Given a reliable positioning and QA concept, the additional uncertainties introduced by the 3D RM can be successfully managed adopting the concept into the clinical routine.

Real-time measurement of two-dimensional LET distributions of proton beams using scintillators.

&#xD;The linear energy transfer (LET) of proton therapy beams increases rapidly from the Bragg peak to the end of the beam. Although the LET can be determined using analytical or computational methods, a technique for efficiently measuring its spatial distribution has not yet been established. Thus, the purpose of this study is to develop a technique to measure the two-dimensional LET distribution in proton therapy in real time using a combination of multiple scintillators with different quenching. Inorganic and organic scintillator sheets were layered and irradiated with proton beams. Two-color signals of the CMOS sensor were obtained from the scintillation light and calibration curves were generated using LET. LET was calculated using Monte Carlo simulations as LETt and LETd weighted by fluence and dose, respectively. The accuracy of the calibration curve was evaluated by comparing the calculated and measured LET values for the 200 MeV monoenergetic and spread-out Bragg peak (SOBP) beams. LET distributions were obtained from the calibration curves.&#xD;Main results:&#xD;The deviation between the calculated and measured LET values was evaluated. For both LETt and LETd, the deviation in the plateau region of the monoenergetic and SOBP beams tended to be larger than those in the peak region. The deviation was smaller for LETd. In the obtained LETd distribution, the deviation between the calculated and measured values agreed within 3% in the peak region, while the deviation was larger in other regions. The LET distribution can be measured with a single irradiation using two scintillator sheets. This method may be effective for verifying LET in daily clinical practice and for quality control.&#xD.

Three-dimensional radiation dosimetry of carbon ion beams using surfactant hydrogels: Fundamental investigation.

In carbon ion radiotherapy, accurate measurement of the three-dimensional (3D) absorbed dose distribution is critical for effectively targeting tumors. Although micellar gel dosimeters exhibit considerable potential for measuring 3D absorbed dose distributions, few studies have focused on radiotherapy using carbon ion beams. This study investigated the applicability of the surfactant hydrogel dosimeter (SHD), a micellar gel dosimeter, to measuring a 3D dose absorbed through carbon ion beam irradiation. A cubic target region of 34mm per side was established at a depth of 46mm below the upper surface of an SHD specimen. Scanning irradiation was performed using a pencil beam of carbon ions at the Ion-beam Radiation Oncology Center in Kanagawa ("i-ROCK"), Japan, under irradiation conditions set by the treatment planning system ("Monaco for Carbon", Ver. 5.20, Elekta AB, Sweden) to create a spread-out Bragg peak within the target. The physical dose was set to 10Gy at the isocenter, situated at the center of the target. The SHD responsiveness was measured twice using optical computed tomography (CT) ("Vista 15", Modus Medical Devices, Canada) for three irradiated specimens, and six types of measured optical attenuation coefficient (OAC) were obtained. To assess whether the OAC represented the absorbed dose expected in the treatment plan, we compared the relative distribution of the OAC and that of the absorbed dose. Relative fraction (RF) was used to measure the difference between the relative value of the OAC and that of the absorbed dose. Moreover, the distribution of OH radical (•OH) concentration obtained by Monte Carlo simulation ("PHITS" ver. 3.24 JAEA, Japan) and that of the OAC were compared. In the direction of beam travel, the relative distribution of the OAC was lower than that of the absorbed dose. This discrepancy could be attributed to a decrease in the concentration of •OH produced by irradiation owing to the recombination reaction, which does not accurately reflect the absorbed dose. By contrast, the distributions in the plane perpendicular to the beam travel were consistent. The RF increased from±3% to±13% along the beam travel direction. The small RF in the plane perpendicular to the beam travel could be attributed to the constant distribution of linear energy transfer, regardless of the irradiation position, and the generation of radicals proportionally to the absorbed dose. The increase in RF along the beam travel direction was ascribed to ring artifacts in the irradiated region. The measurement of the absorbed dose distribution in the beam travel direction should be improved. The observed discrepancy is attributed to the reduced reactivity of the SHD due to a high liner energy transfer near the Bragg peak. However, the absorbed dose distribution can be effectively evaluated in the plane perpendicular to the direction of beam travel.

LET-based approximation of the microdosimetric kinetic model for proton radiotherapy.

Phenomenological relative biological effectiveness (RBE) models for proton therapy, based on the dose-averaged linear energy transfer (LET), have been developed to address the apparent RBE increase towards the end of the proton range. The results of these phenomenological models substantially differ due to varying empirical assumptions and fitting functions. In contrast, more theory-based approaches are used in carbon ion radiotherapy, such as the microdosimetric kinetic model (MKM). However, implementing microdosimetry-based models in LET-based proton therapy treatment planning systems poses challenges. This work presents a LET-based version of the MKM that is practical for clinical use in proton radiotherapy. At first, we derived an approximation of the Mayo Clinic Florida (MCF) MKM for relatively-sparsely ionizing radiation such as protons. The mathematical formalism of the proposed model is equivalent to the original MKM, but it maintains some key features of the MCF MKM, such as the determination of model parameters from measurable cell characteristics. Subsequently, we carried out Monte Carlo calculations with PHITS in different simulated scenarios to establish a heuristic correlation between microdosimetric quantities and the dose averaged LET of protons. A simple allometric function was found able to describe the relationship between the dose-averaged LET of protons and the dose-mean lineal energy, which includes the contributions of secondary particles. The LET-based MKM was used to model the in vitro clonogenic survival RBE of five human and rodent cell lines (A549, AG01522, CHO, T98G, and U87) exposed to pristine and spread-out Bragg peak (SOBP) proton beams. The results of the LET-based MKM agree well with the biological data in a comparable or better way with respect to the other models included in the study. A sensitivity analysis on the model results was also performed. The LET-based MKM integrates the predictive theoretical framework of the MCF MKM with a straightforward mathematical description of the RBE based on the dose-averaged LET, a physical quantity readily available in modern treatment planning systems for proton therapy.

Long-term stability of a PTW 34070 large-area parallel ionization chamber in clinical proton scanning beams.

In the modeling of beam data for proton therapy planning systems, absolute dose measurements are performed utilizing a Bragg peak chamber (BPC), which is a parallel-plate ionization chamber. The long-term stability of the BPC is crucial for ensuring accurate absolute dose measurement. The study aims to assess the long-term stability of the BPC in clinical proton pencil beam scanning delivery. The long-term stability evaluation focused on the BPC-Type 34070 (PTW Freiburg, Germany), utilizing clinical proton scanning beams from December 2022 to November 2023. Monthly investigations were conducted to evaluate the response and cross-calibration factor of the BPC and a reference chamber, employing the spread-out Bragg peak (SOBP) field. Additionally, assessments were made regarding the BPC's response to monoenergetic beams, along with an examination of the impact of polarity and ion recombination on the BPC. The response and cross-calibration factor of the BPC varied up to 1.9% and 1.8%, respectively, while the response of the reference chamber remained within a 0.5% range. The BPC's response to the mono-energetic beams varied up to 2.0% across all energies, demonstrating similar variation trends in both the SOBP field and mono-energetic beams. Furthermore, the variations in polarity and ion recombination effect remained stable within a 0.4% range throughout the year. Notably, the reproducibility of the BPC remained high for each measurement conducted, whether for the SOBP field or mono-energetic beams, with a maximum deviation observed at 0.1%. The response and cross-calibration factor of the BPC demonstrated significant variations, with maximum changes of 1.9% and 1.8%, respectively. However, the reproducibility of the BPC remained consistently high for each measurement. It is recommended that when conducting absolute dose measurements using a BPC, its response should be compared and corrected against the reference chamber for each measurement.

Investigation of linear energy transfer (LET)-dependence behavior and dosimetric response of a flat-panel detector in pencil beam scanning proton therapy

PurposeThis study aims to elucidate the dependence of the flat-panel detector’s response on the linear energy transfer (LET) and evaluate the practical viability of employing flat-panel detectors in proton dosimetry applications through LET-dependent correction factors. MethodsThe study assessed the flat-panel detector’s response across varying depths using solid water and distinct 100, 150, and 200 MeV proton beams by comparing the flat-panel readings against reference doses measured with an ionization chamber. A Monte Carlo code was used to derive LET values, and an LET-dependent response correction factor was determined based on the ratio of the uncorrected flat-panel dose to the ionization chamber dose. The implications of this under-response correction were validated by applying it to a measurement involving a spread-out Bragg peak (SOBP), followed by a comparative analysis against doses calculated using the Monte Carlo code and MatriXX ONE measurement. ResultsThe association between LET and the flat-panel detector’s under-response displayed a positive correlation that intensified with increasing LET values. Notably, with a 10 keV/µm LET value, the detector’s under-response reached 50 %, while the measurement points in the SOBP demonstrated under-response greater than 20 %. However, post-correction, the adjusted flat-panel profile closely aligned with the Monte Carlo profile, yielding a 2-dimensional 3 %/3mm gamma passing rate of 100 % at various verification depths. ConclusionThis study successfully defined the link between LET and the responsiveness of flat-panel detectors for proton dosimetric measurements and established a foundational framework for integrating flat-panel detectors in clinical proton dosimetry applications.

Erratum: A deep learning method for predicting proton beam range and spread-out Bragg peak in passive scattering mode

Erratum: A deep learning method for predicting proton beam range and spread-out Bragg peak in passive scattering mode

Particle tracking, recognition and LET evaluation of out-of-field proton therapy delivered to a phantom with implants

Objective. This study aims to assess the composition of scattered particles generated in proton therapy for tumors situated proximal to some titanium (Ti) dental implants. The investigation involves decomposing the mixed field and recording Linear Energy Transfer (LET) spectra to quantify the influence of metallic dental inserts located behind the tumor. Approach. A therapeutic conformal proton beam was used to deliver the treatment plan to an anthropomorphic head phantom with two types of implants inserted in the target volume (made of Ti and plastic, respectively). The scattered radiation resulted during the irradiation was detected by a hybrid semiconductor pixel detector MiniPIX Timepix3 that was placed distal to the Spread-out Bragg peak. Visualization and field decomposition of stray radiation were generated using algorithms trained in particle recognition based on artificial intelligence neural networks (AI NN). Spectral sensitive aspects of the scattered radiation were collected using two angular positions of the detector relative to the beam direction: 0° and 60°. Results. Using AI NN, 3 classes of particles were identified: protons, electrons & photons, and ions & fast neutrons. Placing a Ti implant in the beam’s path resulted in predominantly electrons and photons, contributing 52.2% of the total number of detected particles, whereas for plastic implants, the contribution was 65.4%. Scattered protons comprised 45.5% and 31.9% with and without metal inserts, respectively. The LET spectra were derived for each group of particles identified, with values ranging from 0.01 to 7.5 keV μm−1 for Ti implants/plastic implants. The low-LET component was primarily composed of electrons and photons, while the high-LET component corresponded to protons and ions. Significance. This method, complemented by directional maps, holds the potential for evaluating and validating treatment plans involving stray radiation near organs at risk, offering precise discrimination of the mixed field, and enhancing in this way the LET calculation.

Modelling of RBE differences in selected points within similar spread-out Bragg-peaks (SOBP) placed at superficial and deep water phantom locations in passively scattered beams but not in scanned pencil beams: A hypothesis

PurposeTo model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2–1.3) were found within superficially- placed SOBP but reduced to lower values (1–1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam. MethodsThe equations used allow α and β changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/β ratios, compatible with a reduction in micro-volumetric energy transfer (the product of Fluence and LET), with commensurate reductions in RBE. The experimental depth-distances, positions within SOBP, observed dose-rates and radiosensitivity ratios were used to estimate the changes in RBE. ResultsRBE values within a 5 % tolerance limit of the experimental results for PSB were found at the deepest SOBP placement. No RBE changes were predicted for PBS beams, as in the published results. ConclusionsEnhanced proton therapy toxicity might occur with PBS when compared with PSB for deeply positioned SOBP due to the maintenance of higher RBE. Scanned pencil beam users need to be vigilant about RBE and further research is indicated.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen etal. (4). Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Mini-ridge filter designs for conformal FLASH proton therapy

The present study designed a mini-ridge filter capable of generating a 30 mm spread-out Bragg peak (SOBP) specific to the proton FLASH beamline for use in proton FLASH mouse studies. Proton FLASH therapy delivers ultra-high dose rates exceeding 40 Gy/s, necessitating instantaneous SOBP generation via static method. The TOol for PArticle Simulation (TOPAS) was used to model the FLASH beamline, which enabled accurate replication of beam characteristics identified from measurements, and ensured accurate dose calculations. Comparisons between simulated and measured peak widths and R80d values, accurate to within 1 mm, verified the accuracy and reliability of Monte Carlo code. Two mini-ridge filters of different materials were designed and optimized using MATLAB, simulated with TOPAS for SOBP verification, and fabricated using 3D-printing or computer numerical control manufacturing. The results indicated strong agreement between the simulated and measured SOBP widths for the polylactic acid mini-ridge filter but with discrepancies observed in the range and flatness measurements, which may be due to the use of 3D printing. By contrast, the aluminium alloy mini-ridge filter achieved excellent results, generating a 31.6 mm SOBP width with 0.89% flatness. Therefore, the present study validated the accuracy of our Monte Carlo code in simulating the FLASH beamline and the feasibility of our mini-ridge filters.

Solid state microdosimetry of a 148 MeV proton spread-out Bragg peak with a pixelated silicon telescope

A constant value of the Relative Biological Effectiveness (RBE), equal to 1.1, to weight the physical dose of proton therapy treatment planning collides with the experimental evidence of an increase of effectiveness along the depth dose profile, especially at the end of the particle range. In this context, it is desirable to develop new optimized treatment planning systems that account for a variable RBE when weighting the physical dose. In particular, due to the increasing interest on microdosimetry as a possible methodology for measuring physical quantities correlated with the biological effectiveness of the therapeutic beam, the development of new Tissue-Equivalent Proportional Counters (TEPCs) specifically designed for the clinical environment are in progress.In this framework, the silicon technology allows to produce solid state detectors of real micrometric dimensions. This is a valid alternative to the TEPC from a practical point of view, being simple, easy-of-use and more versatile. The feasibility of a solid state microdosimeter based on a monolithic double stage silicon telescope has been previously proposed and deeply investigated by comparing its response to the one obtained by reference TEPCs in various radiation fields. The device is constituted by a matrix of cylindrical elements, 2 μm in thickness and 9 μm in diameter, coupled to a single E stage, 500 μm in thickness. Each segmented ΔE stage acts as a solid state microdosimeter, while the E stage gives information on the energy of the impinging proton up to about 8 MeV.This work is dedicated to the description of the microdosimetric characterization of the 148 MeV energy-modulated proton beam at the radiobiological research line of the Trento Proton Therapy Centre by means of a pixelated silicon microdosimeter. All measurements were carried out at different positions across the spread-out Bragg peak (SOBP) and the corresponding microdosimetric distributions were derived by applying a novel extrapolation algorithm. Finally, microdosimetric assessment of Relative Biological Effectiveness was carried out by weighting the dose distribution of the lineal energy with the Loncol's biological weighting function. Benefits and possible limitations of this approach are discussed.

Diamond energy-dispersive dosimeter for measuring linear energy deposition distributions in clinical carbon beam therapy

A thin diamond membrane energy-dispersive dosimeter 50 μm thick was fabricated for estimating clinical dose distribution. In contrast to conventional semiconductors, diamond wide-bandgap semiconductors are expected to have excellent radiation tolerance and biological compatibility based on the linear relationship of stopping power ratio for clinical carbon particles. Linear energy transfer (LET) spectra were obtained along with the Bragg curve for a clinical carbon beam generated at Gunma University Heavy Ion Medical Center. The relative biological effectiveness (RBE) distributions were estimated from the LET spectra for both the mono-energy and spread-out Bragg peak irradiation configurations. The diamond detector was also used as a solid ionization chamber to obtain the radiation-induced current (RIC) distribution, which represents the physical dose distribution. The clinical dose distribution was estimated from the RIC and RBE distributions as proof of concept for the clinical carbon beam therapy field with a single-chip diamond energy-dispersive dosimeter.

Dose measurements with radiophotoluminescent glass dosimeters (GD- 352M and GD-302M) in therapeutic proton beams

Radiophotoluminescent glass dosimeters (RPLDs) are increasingly used, especially to measure the doses in therapeutic beams, but the reported data are mainly related to photon and electron beams, while the data for proton beams are limited and not always consistent.In this study, dose measurements were performed with two types of RPLDs: GD-352M and GD-302 M (Asahi Techno Glass Corporation). The dose dependence, long-term fading and response in different Spread out Bragg Peak (SOBP) configurations were evaluated. The dose dependence was measured in the middle of the SOBP for doses ranging from 1 Gy to 120 Gy and a linear dose response was shown for both types of RPLDs. The long-term fading of RPLDs irradiated with proton beams determined under normal ambient conditions over a period of one year is negligible. The GD-352M and GD-302M responses were evaluated in different configurations of the SOPB. The fluence-averaged (LETf) and dose-averaged (LETd) LET values at the positions of the dosimeters were calculated using the PHITS Monte Carlo code. GD-302 M results showed a small under-response compared to the doses provided by treatment planning system (TPS) (within 1.9 %). GD-352M showed an under-response compared to TPS doses for all investigated ranges and modulations with an average under-response of 20 %, indicating the need for correction factors. Both types showed a slight decrease in the response with an increase in the LET.