Spread-out Bragg Peak Beam Research Articles

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


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.
Main results:
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.

Calculation of biological effectiveness of SOBP proton beams: a TOPAS Monte Carlo study

Objective. This study aims to investigate the biological effectiveness of Spread-Out Bragg-Peak (SOBP) proton beams with initial kinetic energies 50–250 MeV at different depths in water using TOPAS Monte Carlo code. Approach. The study modelled SOBP proton beams using TOPAS time feature. Various LET-based models and Repair-Misrepair-Fixation model were employed to calculate Relative Biological Effectiveness (RBE) for V79 cell lines at different on-axis depths based on TOPAS. Microdosimetric Kinetic Model and biological weighting function-based models, which utilize microdosimetric distributions, were also used to estimate the RBE. A phase-space-based method was adopted for calculating microdosimetric distributions. Main results. The trend of variation of RBE with depth is similar in all the RBE models, but the absolute RBE values vary based on the calculation models. RBE sharply increases at the distal edge of SOBP proton beams. In the entrance region of all the proton beams, RBE values at 4 Gy i.e. RBE(4 Gy) resulting from different models are in the range of 1.04–1.07, comparable to clinically used generic RBE of 1.1. Moving from the proximal to distal end of the SOBP, RBE(4 Gy) is in the range of 1.15–1.33, 1.13–1.21, 1.11–1.17, 1.13–1.18 and 1.17–1.21, respectively for 50, 100, 150, 200 and 250 MeV SOBP beams, whereas at the distal dose fall-off region, these values are 1.68, 1.53, 1.44, 1.42 and 1.40, respectively. Significance. The study emphasises application of depth-, dose- and energy- dependent RBE values in clinical application of proton beams.

Effects of cellular radioresponse on therapeutic helium-, carbon-, oxygen-, and neon-ion beams: a simulation study

Objective. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges. Approach. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams. Main results. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases. Significance. From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.

Microdosimetric analysis of the radiation quality of two different proton beams in the distal edge of the depth-dose profile.

Proton-therapy exploits the advantageous depth-dose profile of protons to induce the highest damage to tumoral cells in the last millimetres of their range in sharp Bragg Peak. To cover the whole tumoral volume, beams of different energies are combined to create the Spread Out Bragg Peak (SOBP). In passive modulated beams, the energy spread is created with modulators in which the highest energy beam is degraded through different thicknesses of calibrated plastic materials. The highest energy is chosen depending on the deepest point that needs to be treated. This study aims to investigate differences in the radiation quality in the distal edge of SOBP beams with different initial energy and modulation techniques based on microdosimetric measurements with mini Tissue-Equivalent Proportional Counters. The beams investigated are the 62MeV proton SOBP of the clinical facility of CATANA and the 148MeV proton SOBP of the research beam line of the proton-therapy centre of Trento.

The impact of DNA double-strand break repair pathways throughout the carbon ion spread-out Bragg peak beam.

Following carbon ion beam irradiation in mammalian cells, such as used in carbon ion radiotherapy (CIRT), it has been suggested that the balance between whether nonhomologous end joining (NHEJ) or homologous recombination (HR) is utilized depends on the DNA double-strand break (DSB) complexity. Here, we quantified DSB distribution and identified the importance of each DSB repair pathway at increasing depths within the carbon ion spread-out Bragg peak (SOBP) beam range. Chinese hamster ovary (CHO) cell lines were irradiated in a single biological system capable of incorporating the full carbon ion SOBP beam range. Cytotoxicity and DSB distribution/repair kinetics were examined at increasing beam depths using cell survival as an endpoint and γ-H2AX as a surrogate marker for DSBs. We observed that proximal SOBP had the highest number of total foci/cell and lowest survival, while distal SOBP had the most dense tracks. Both NHEJ- and HR-deficient CHO cells portrayed an increase in radiosensitivity throughout the full carbon beam range, although NHEJ-deficient cells were the most radiosensitive cell line from beam entrance up to proximal SOBP and demonstrated a dose-dependent decrease in ability to repair DSBs. In contrast, HR-deficient cells had the greatest ratio of survival fraction at entrance depth to the lowest survival fraction within the SOBP and demonstrated a linear energy transfer (LET)-dependent decrease in ability to repair DSBs. Collectively, our results provide insight into treatment planning and potential targets to inhibit, as HR was a more beneficial pathway to inhibit than NHEJ to enhance the cell killing effect of CIRT in targeted tumor cells within the SOBP while maintaining limited unwanted damage to surrounding healthy cells.

Event-by-event approach to the oxygen-effect-incorporated stochastic microdosimetric kinetic model for hypofractionated multi-ion therapy.

An oxygen-effect-incorporated stochastic microdosimetric kinetic (OSMK) model was previously developed to estimate the survival fraction of cells exposed to charged-particle beams with wide dose and linear energy transfer (LET) ranges under various oxygen conditions. In the model, hypoxia-induced radioresistance was formulated based on the dose-averaged radiation quality. This approximation may cause inaccuracy in the estimation of the biological effectiveness of the radiation with wide variation in energy deposited to a sensitive volume per event, such as spread-out Bragg peak (SOBP) beams. The purpose of this study was to apply an alternative approach so as to consider the energy depositions on an event-by-event basis. The production probability of radiation-induced lesions per energy was formulated with oxygen partial pressure to account for the hypoxia-induced radioresistance. The reduction in the oxygen enhancement ratio for high-LET radiations was modeled by reducing the sensitive-volume size and increasing the saturation energy in microdosimetry. The modified OSMK model was tested against the reported survival data of three cell lines exposed to six species of ions with wide dose and LET ranges under aerobic and hypoxic conditions. The model reasonably reproduced the reported cell survival data. To evaluate the event-by-event approach, survival distributions of Chinese hamster ovary cells exposed to SOBP beams were estimated using the original and modified OSMK models. The differences in the estimated survival distributions between the models were marginal even under extreme hypoxia. The event-by-event approach improved the theoretical validity of the OSMK model. However, the original OSMK model can still provide an accurate estimation of the biological effectiveness of therapeutic radiations.

Development of a SiC semiconductor-based dosimeter for evaluating clinical dose distribution in carbon ion cancer therapy fields

Dosimeters with excellent energy resolution are required to improve quality control and assurance (QA/QC) for heavy-ion cancer therapy, in which multiple species of ions are expected to be used. The conventional ionization chamber that is widely used for QA/QC generally does not support quality discrimination for different radiation species, and several types of energy-dispersive dosimeters are being studied for this application, including silicon semiconductors on insulator devices. Other wide bandgap semiconductors with good radiation hardness, including SiC and diamond, are being studied for use in cancer therapy ion fields. In this study, a 4H-SiC Schottky barrier diode was used for energy-dispersive dosimetry in the clinical carbon therapy field at Gunma University Medical Center for Heavy Ion Beam Medicine. The relative biological effectiveness was estimated from the linear energy transfer spectra for a pristine carbon beam with an energy of 290 MeV/n and a spread-out Bragg peak beam using the linear-quadratic model. The results showed that the SiC-based dosimeter could be used in the detailed characterization of the clinical dose distribution of carbon ion cancer therapy fields.

Formation of spread-out Bragg peak for helium-ion beam using microdosimetric kinetic model

PurposeTo evaluate the applicability of microdosimetric kinetic model (MKM) to helium-ion therapy by forming a spread-out Bragg peak (SOBP) of a helium-ion beam using the MKM developed for carbon-ion radiotherapy and confirming the predictions in biological experiments. MethodsUsing a ridge filter, a 90-mm wide SOBP for a 210 MeV/u helium-ion beam was created in a broad beam delivery system. The ridge filter was designed such that a uniform biological response was achieved with a cell survival rate of 7% over the SOBP region. Biological experiments were then performed using the SOBP beam in a human salivary gland (HSG) cell line to measure the cell survival rates. ResultsThe biological responses were uniform in the SOBP region, as expected by the MKM; however, the mean of the measured cell survival rates was (11.2 ± 0.6) % in the SOBP region, which was 60% higher than the designed rate. When investigating the biological parameters of the HSG cell line used in the experiments, we found that they were altered slightly from the MKM parameters used for carbon-ion radiotherapy. The new β parameter reproduced the measured survival rates within 6.5% in the SOBP region. ConclusionWe produced biologically uniform SOBP using MKM for carbon-ion radiotherapy. The measured survival rates in the SOBP region were higher than expected, and the survival rates were reproduced by modifying the MKM parameter. This study was limited to one SOBP, and further investigations are required to prove that MKM is generally applicable to helium-ion radiotherapy.

Prompt X-ray imaging during irradiation with spread-out Bragg peak (SOBP) beams of carbon ions

Prompt secondary electron bremsstrahlung X-ray (prompt X-ray) imaging using a low-energy X-ray camera is a promising method for observing a beam shape from outside the subject. However, such imaging has so far been conducted only for pencil beams without a multi-leaf collimator (MLC). The use of spread-out Bragg peak (SOBP) with an MLC may increase the scattered prompt gamma photons and decrease the contrast of the images of prompt X-rays. Consequently, we performed prompt X-ray imaging of SOBP beams formed with an MLC. This imaging was carried out in list mode during irradiation of SOBP beams to a water phantom. An X-ray camera with a 1.5-mm diameter as well as 4-mm-diameter pinhole collimators was used for the imaging. List mode data were sorted to obtain the SOBP beam images as well as energy spectra and time count rate curves. Due to the high background counts from the scattered prompt gamma photons penetrating the tungsten shield of the X-ray camera, the SOBP beam shapes were difficult to observe with a 1.5-mm-diameter pinhole collimator. With the 4-mm-diameter pinhole collimators, images of SOBP beam shapes at clinical dose levels could be obtained with the X-ray camera. The use of a 4-mm-diameter pinhole collimator attached to the X-ray camera is effective for prompt X-ray imaging with high sensitivity and low background counts. This approach makes it possible to image SOBP beams with an MLC when the counts are low and the background levels are high.

A Novel Mechanistic Cell Survival Model to Replace Linear-Quadratic Model for Relative Biological Effectiveness (RBE) in Proton Therapy

<h3>Purpose/Objective(s)</h3> Relative biological effectiveness (RBE) is important in proton therapy. Although a large amount of in vitro cell experimental data exists for various linear energy transfers (LETs) and various cell lines, it is difficult to derive a reliable RBE model from these data using the classic linear-quadratic (LQ) model, mainly because its parameters, α_LQ and β_LQ, have no clear mechanistic correlation with LET. In this study, we hypothesize that a mechanistic model with parameters directly relate to LET can be developed to replace the LQ model for cell survival description, and it would be better than the LQ model for RBE model derivation. The 2 parameters in the model are α_M, which represents the ability to generate cell damage and may linearly increase with LET, and β_M, which represents the ability to repair cell damage and may linearly decrease with LET (because higher LET generates more clustered DNA damages, which are difficult to repair). <h3>Materials/Methods</h3> We used the number of unit damages to score the severity of radiation-generated damage in a cell. Assuming that a dose of D generated an average number of α_M*D unit damages, the probability of cells having n (n = 0, 1, 2, ...m) unit damages was thus determined using the Poisson Equation, P(n) = [(α_MD)ⁿ/n!]*exp(-α_MD). We further assumed that a cell with n unit damages has a probability of β_Mⁿ to be repaired, and cells having 4 or more unit damages would not be repaired. Thus, the survival fraction of cells after a dose of D was derived as SF(D) = [1+α_Mβ_MD+(α_Mβ_MD)²/2+(α_Mβ_MD)³/6]*exp(-α_MD). A total of 47 experimental cell survival datasets for 3 cell lines in the literature were used to test this mechanistic model. Correlations of α_M and β_M with LET were determined in terms of RBE_α and RBE_β, which is the ratio of α_M (or β_M) in proton and photon. A RBE model was consequently derived. <h3>Results</h3> The mechanistic model fitted well with all experimental data, similar as the LQ model. Interestingly, for two cell lines with pristine proton beam data, both α_M and β_M were perfect linear functions of LET, with R² = 0.98∼1.0. On the other hand, the linearity was greatly degraded for the corresponding spread-out Bragg Peak (SOBP) data, with same data points deviating at same directions for 2 cell lines, suggesting that the LET values calculated in SOBP were not as accurate as pristine beam. For the 3^rd cell line with majority data points of SOBP beams, R² = 0.89∼0.91. The correlation of α_M and β_M with LET were expressed as RBE_α = 1.1+k_α*LET and RBE_β = 1.0-k_β*LET, where k_α = 0.018, 0.009 and 0.005, k_β = 0.031, 0.028, and 0.027 for 3 cell lines, respectively. A RBE model depending on LET, dose and cell type (represented by α_M and β_M in photon) was finally derived. <h3>Conclusion</h3> A mechanistic cell survival model was developed and it appeared to have advantage over the LQ model in deriving a reliable RBE model.

Spread-out Bragg peak proton FLASH irradiation using a clinical synchrocyclotron: Proof of concept and ion chamber characterization.

The purpose of this work is to (a) demonstrate the feasibility of delivering a spread-out Bragg peak (SOBP) proton beam in ultra-high dose rate (FLASH) using a proton therapy synchrocyclotron as a major step toward realizing an experimental platform for preclinical studies, and (b) evaluate the response of four models of ionization chambers in such a radiation field. A clinical Mevion HYPERSCAN® synchrocyclotron was adjusted for ultra-high dose rate proton delivery. Protons with nominal energy of 230MeV were delivered in pulses with temporal width ranging from 12.5μs to 24μs spanning from conventional to FLASH dose rates. A boron carbide absorber and a range modulator block were placed in the beam path for range modulation and creating an SOBP dose profile. The radiation field was defined by a brass aperture with 11mm diameter. Two Faraday cups were used to determine the number of protons per pulse at various dose rates. The dosimetric response of two cylindrical (IBA CC04 and CC13) and two plane-parallel (IBA PPC05 and PTW Advanced Markus® ) ionization chambers were evaluated. The dose rate was measured using the plane-parallel ionization chambers. The integral depth dose (IDD) was measured with a PTW Bragg Peak® ionization chamber. The lateral beam profile was measured with EBT-XD radiochromic film. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements and as a tool for further optimization of the range modulators' design. Faraday cups measurement showed that the maximum protons per pulse is 39.9 pC at 24μs pulse width. A good agreement between the measured and simulated IDD and lateral beam profiles was observed. The cylindrical ionization chambers showed very high ion recombination and deemed not suitable for absolute dosimetry at ultra-high dose rates. The average dose rate measured using the PPC05 ionization chamber was 163Gy/s at the pristine Bragg peak and 126Gy/s at 1cm depth for the SOBP beam. The SOBP beam range and modulation were measured 24.4mm and 19mm, respectively. The pristine Bragg peak beam had 25.6mm range. Simulation results showed that the IDD and profile flatness can be improved by the cavity diameter of the range modulator and the number of scanned spots, respectively. Feasibility of delivering protons in an SOBP pattern with >100Gy/s average dose rate using a clinical synchrocyclotron was demonstrated. The dose heterogeneity can be improved through optimization of the range modulator and number of delivered spots. Plane-parallel chambers with smaller gap between electrodes are more suitable for FLASH dosimetry compared to the other ion chambers used in this work.

In-field and out-of-field microdosimetric characterisation of a 62 MeV proton beam at CATANA.

A 5 and 10 μm thin silicon on insulator (SOI) 3D mushroom microdosimeter was used to characterize both the in-field and out-of-field of a 62 MeV proton beam. The SOI mushroom microdosimeter consisted of an array of cylindrical sensitive volumes (SVs), developed by the Centre for Medical Radiation Physics, University of Wollongong, was irradiated with 62 MeV protons at the CATANA (Centro di AdroTerapia Applicazioni Nucleari Avanzate) facility in Catania, Italy, a facility dedicated to the radiation treatment of ocular melanomas. Dose mean lineal energy, ( ), values were obtained at various depths in PMMA along a pristine and spread out Bragg peak (SOBP). The measured microdosimetric spectra at each position were then used as inputs into the modified Microdosimetric Kinetic Model (MKM) to derive the RBE for absorbed dose in a middle of the SOBP 2Gy (RBED ). Microdosimetric spectra were obtained with both the 5 and 10 μm 3D SOI microdosimeters, with a focus on the distal part of the BP. The in-field and out-of-field measurement configurations along the Bragg curve were modeled in Geant4 for comparison with experimental results. Lateral out-of-field measurements were performed to study secondary particles' contribution to normal tissue's dose, up to 12 mm from the edge of the beam field, and quality factor and dose equivalent results were obtained. Comparison between experimental and simulation results showed good agreement between one another for both the pristine and SOBP beams in terms of and RBED. Though a small discrepancy between experiment and simulation was seen at the entrance of the Bragg curve, where experimental results were slightly lower than Geant4. The dose equivalent value measured 12 mm from the edge of the target volume was 1.27 ± 0.15 mSv/Gy with a value of 2.52 ± 0.30, both of which agree within uncertainty with Geant4 simulation. These results demonstrate that SOI microdosimeters are an effective tool to predict RBED in-field as well as dose equivalent monitoring out-of-field to provide insight to probability of second cancer generation.

MOSFET dose measurements for proton SOBP beam.

The aim of this work was to develop a computational scheme for the correction of the LET dependence on the MOSFET response in water phantom dose measurements for a spread-out Bragg peak (SOBP) proton beam. The LET dependence of MOSFET was attributed to the stopping power ratio of SiO2 to H2O and to the fractional hole yield in the SiO2 layer. Using literature values for the stopping powers of the continuous slowing down approximation and measured fractional hole yields vs. electric field and LET, formulas were derived for the computation of a dose-weighted correction factor of a SOBP beam. Dose-weighted correction factors were computed for a clinical 190-MeV proton SOBP beam in a high-density polyethylene phantom. By applying correction factors to the SOBP beam, which consisted of weighted monoenergetic Bragg peaks, the MOSFET outputs were predicted and agreed well with the measured MOSFET responses. By applying LET dependent correction factors to MOSFET data, quality assurance of dose verification based on MOSFET measurements becomes possible for proton therapy.

Evaluations of a flat-panel based compact daily quality assurance device for proton pencil beam scanning (PBS) system.

To evaluate the flat-panel detector quenching effect and clinical usability of a flat-panel based compact QA device for PBS daily constancy measurements. The QA device, named Sphinx Compact, is composed of a 20x20 cm2 flat-panel imager mounted on a portable frame with removable plastic modules for constancy checks of proton energy (100MeV, 150MeV, 200MeV), Spread-Out-Bragg-Peak (SOBP) profile, and machine output. The potential quenching effect of the flat-panel detector was evaluated. Daily PBS QA tests of X-ray/proton isocenter coincidence, the constancy of proton spot position and sigma as well as the energy of pristine proton beam, and the flatness of SOBP proton beam through the 'transformed' profile were performed and analyzed. Furthermore, the sensitivity of detecting energy changes of pristine proton beam was also evaluated. The quenching effect was observed at depths near the pristine peak regions. The flat-panel measured range of the distal 80% is within 0.9mm to the defined ranges of the delivered proton beams. X-ray/proton isocenter coincidence tests demonstrated maximum mismatch of 0.3mm between the two isocenters. The device can detect 0.1mm change of spot position and 0.1MeV energy changes of pristine proton beams. The measured transformed SOBP beam profile through the wedge module rendered as flat. Even though the flat-panel detector exhibited quenching effect at the Bragg peak region, the proton range can still be accurately measured. The device can fulfill the requirements of the daily QA tests recommended by the AAPM TG224 Report.

Extension of the ML-EM algorithm for dose estimation using PET in proton therapy: application to an inhomogeneous target

Positron emission tomography (PET) has been used for in vivo treatment verification, mainly for range verification, in proton therapy. Evaluating the direct dose from PET measurements remains challenging; however, it is highly desirable from a clinical perspective. In this study, a method for estimating the dose distribution from the positron emitter distributions was developed using the maximum likelihood expectation maximization algorithm. The 1D spatial relationship between positron emitter distributions and a dose distribution in an inhomogeneous target was inputted into the system matrix based on a filter framework. In contrast, spatial resolution of the PET system and total variation regularization (as prior knowledge for dose distribution) were considered in the 3D image-space. The dose estimation was demonstrated using Monte Carlo simulated PET activity distributions with substantial noise in a head and neck phantom. This mimicked the single field irradiation of the spread-out Bragg peak beams at clinical dose levels. Besides the simple implementation of the algorithm, this strategy achieved a high-speed calculation (30 s for a 3D dose estimation) and accurate dose and range estimations (less than 10% and 2 mm errors at 1-σ values, respectively). The proposed method could be key for using PET for in vivo dose monitoring.

Effect of Irradiation Time on Biological Effectiveness and Tumor Control Probability in Proton Therapy

The biological effectiveness of proton beams may decrease with irradiation time because of sublethal damage repair (SLDR). The purpose of this study is to systematically evaluate this effect in hypofractionated proton therapy for various target sizes, depths, and prescribed doses per fraction. Plans with a single spread-out Bragg peak beam were created using a constant relative biological effectiveness (RBE) of 1.1 to cover targets of 6 different sizes located at 3 different depths in water. Biological doses of 2, 3, 5, 10, and 20 Gy (RBE) were prescribed to the targets. First, to investigate the depth variation of the biological effectiveness, the biological dose in instantaneous irradiation was recalculated based on the microdosimetric kinetic model. SLDR was then taken into account in the microdosimetric kinetic model during treatments to obtain the irradiation time-dependent biological effectiveness for irradiation time T of 5 to 60 minutes and beam interruption time τ of 0 to 60 minutes. The tumor control probabilities were calculated for single-fraction proton therapy fields of different Ts and τs, and the curative doses were evaluated at a tumor control probability of 90%. The biological effectiveness decreased with longer T and τ and higher prescribed dose. The maximum decrease in the biological effectiveness was 21% with a 20 Gy (RBE) prescribed dose. In single-fraction proton therapy, the curative dose increased linearly by approximately 33% to 35% with the increase of T from 0 to 60 minutes. The biological effectiveness varies largely with T and τ because of SLDR during treatments. This effect was pronounced for high prescribed doses per fraction. Thus, the effect of SLDR needs to be considered in hypofractionated and single-fraction proton therapies in relation to size and depth of the target.

The Potential Application of Heavy Ion Beams in the Treatment of Arrhythmia: The Role of Radiation-Induced Modulation of Connexin43 and the Sympathetic Nervous System.

It has been known that heart disease-such as myocardial infarction (MI), cardiac hypertrophy, or heart failure-alters the molecular structure and function of the gap junction, which can lead to an abnormal heart rhythm. Radiation has been shown to modulate intercellular communication in the skin and lungs by increasing connexin43 (Cx43) expression. Understanding how Cx43 upregulation is induced in a diseased heart can help provide a new perspective to radiation therapy for arrhythmias. In a recent study with rabbits after MI, carbon ions were accelerated to 290 MeV/u and extracted in the air; a biologically (cell kill) uniform 6-cm spread-out Bragg peak beam was generated, and beam tissue depth was set to 30 mm with energy degraders to the depth position. Targeted heavy ion irradiation (THIR) with 15 Gy to the left ventricle increased Cx43 expression, improved conductivity, decreased the spatial heterogeneity of repolarization, and reduced the vulnerability of rabbit hearts to ventricular arrhythmias after MI. In clinically normal rabbits, THIR > = 10 Gy caused a significant dose-dependent increase of Cx43 protein and messenger RNA 2 weeks after irradiation. The left (irradiated) and right (nonirradiated) ventricles exhibited circumferential upregulation of Cx43 lasting for at least 1 year. There were no significant changes in electrocardiograms and echocardiograms, indicating no apparent injury for 1 year. A single exposure of 135 MeV/u THIR with 15 Gy to a dog heart attenuated vulnerability to ventricular arrhythmia after the induction of MI for at least 1 year through the modulation of Cx43 expression. This long-lasting remodeling effect on gap junctions may lay the groundwork to novel therapies against life-threatening ventricular arrhythmias in structural heart disease. To date, there have been few investigations into the effects of carbon-ion irradiation on electrophysiological properties in the human heart. Patients with mediastinum cancer were investigated for 5 years after treatment that included irradiation to the heart, and investigators found that carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction. Its practical application in non-cancer treatment, such as in arrhythmia treatment, is highly anticipated.

Depth Dose Measurement using a Scintillating Fiber Optic Dosimeter for Proton Therapy Beam of the Passive-Scattering Mode Having Range Modulator Wheel

To apply a scintillating fiber dosimetry system to measure the range of a proton therapy beam, a new method was proposed to correct for the quenching effect on measuring an spread out Bragg peak (SOBP) proton beam whose range is modulated by a range modulator wheel. The scintillating fiber dosimetry system was composed of a plastic scintillating fiber (BCF-12), optical fiber (SH 2001), photo multiplier tube (H7546), and data acquisition system (PXI6221 and SCC68). The proton beam was generated by a cyclotron (Proteus-235) in the National Cancer Center in Korea. It operated in the double-scattering mode and the spread out of the Bragg peak was achieved by a spinning range modulation wheel. Bragg peak beams and SOBP beams of various ranges were measured, corrected, and compared to the ion chamber data. For the Bragg peak beam, quenching equation was used to correct the quenching effect. On the proposed process of correcting SOBP beams, the measured data using a scintillating fiber were separated by the Bragg peaks that the SOBP beam contained, and then recomposed again to reconstruct an SOBP after correcting for each Bragg peak. The measured depth-dose curve for the single Bragg peak beam was well corrected by using a simple quenching equation. Correction for SOBP beam was conducted with a newly proposed method. The corrected SOBP signal was in accordance with the results measured with an ion chamber. We propose a new method to correct for the SOBP beam from the quenching effect in a scintillating fiber dosimetry system. This method can be applied to other scintillator dosimetry for radiation beams in which the quenching effect is shown in the scintillator.

Validation of the physical and RBE-weighted dose estimator based on PHITS coupled with a microdosimetric kinetic model for proton therapy.

The microdosimetric kinetic model (MKM) is widely used for estimating relative biological effectiveness (RBE)-weighted doses for various radiotherapies because it can determine the surviving fraction of irradiated cells based on only the lineal energy distribution, and it is independent of the radiation type and ion species. However, the applicability of the method to proton therapy has not yet been investigated thoroughly. In this study, we validated the RBE-weighted dose calculated by the MKM in tandem with the Monte Carlo code PHITS for proton therapy by considering the complete simulation geometry of the clinical proton beam line. The physical dose, lineal energy distribution, and RBE-weighted dose for a 155 MeV mono-energetic and spread-out Bragg peak (SOBP) beam of 60 mm width were evaluated. In estimating the physical dose, the calculated depth dose distribution by irradiating the mono-energetic beam using PHITS was consistent with the data measured by a diode detector. A maximum difference of 3.1% in the depth distribution was observed for the SOBP beam. In the RBE-weighted dose validation, the calculated lineal energy distributions generally agreed well with the published measurement data. The calculated and measured RBE-weighted doses were in excellent agreement, except at the Bragg peak region of the mono-energetic beam, where the calculation overestimated the measured data by ~15%. This research has provided a computational microdosimetric approach based on a combination of PHITS and MKM for typical clinical proton beams. The developed RBE-estimator function has potential application in the treatment planning system for various radiotherapies.

Characterization of proton pencil beam scanning and passive beam using a high spatial resolution solid-state microdosimeter.

This work aims to characterize a proton pencil beam scanning (PBS) and passive double scattering (DS) systems as well as to measure parameters relevant to the relative biological effectiveness (RBE) of the beam using a silicon on insulator (SOI) microdosimeter with well-defined 3D sensitive volumes (SV). The dose equivalent downstream and laterally outside of a clinical PBS treatment field was assessed and compared to that of a DS beam. A novel silicon microdosimeter with well-defined 3D SVs was used in this study. It was connected to low noise electronics, allowing for detection of lineal energies as low as 0.15keV/μm. The microdosimeter was placed at various depths in a water phantom along the central axis of the proton beam, and at the distal part of the spread-out Bragg peak (SOBP) in 0.5mm increments. The RBE values of the pristine Bragg peak (BP) and SOBP were derived using the measured microdosimetric lineal energy spectra as inputs to the modified microdosimetric kinetic model (MKM). Geant4 simulations were performed in order to verify the calculated depth-dose distribution from the treatment planning system (TPS) and to compare the simulated dose-mean lineal energy to the experimental results. For a 131MeV PBS spot (124.6mm R90 range in water), the measured dose-mean lineal energy yD¯ increased from 2keV/μm at the entrance to 8keV/μm in the BP, with a maximum value of 10keV/μm at the distal edge. The derived RBE distribution for the PBS beam slowly increased from 0.97±0.14 at the entrance to 1.04±0.09 proximal to the BP, then to 1.1±0.08 in the BP, and steeply rose to 1.57±0.19 at the distal part of the BP. The RBE distribution for the DS SOBP beam was approximately 0.96±0.16 to 1.01±0.16 at shallow depths, and 1.01±0.16 to 1.28±0.17 within the SOBP. The RBE significantly increased from 1.29±0.17 to 1.43±0.18 at the distal edge of the SOBP. The SOI microdosimeter with its well-defined 3D SV has applicability in characterizing proton radiation fields and can measure relevant physical parameters to model the RBE with submillimeter spatial resolution. It has been shown that for a physical dose of 1.82Gy at the BP, the derived RBE based on the MKM model increased from 1.14 to 1.6 in the BP and its distal part. Good agreement was observed between the experimental and simulation results, confirming the potential application of SOI microdosimeter with 3D SV for quality assurance in proton therapy.