Spread-out Bragg Peak Research Articles

On the spectral characterization of radiochromic films irradiated with clinical proton beams

Radiochromic films have been widely studied for clinical dosimetry in conventional external beam radiation therapy. With an increase in practice of proton therapy, such films are being conveniently used; however, their spectroscopic characterization for this modality is lacking. This work investigated the response of the EBT3 radiochromic films irradiated in a Mevion S250™ clinical proton beam. Dose, dose rate, inter-batch, sensitivity, and linear energy transfer (LET) dependencies of the films were studied. Pieces of the radiochromic films from different batches were irradiated using a spread-out Bragg peak (SOBP) proton beam at dose levels between 0.1–15 Gy. Absorption spectra were measured in the wavelength range of 400–800 nm with 2.5 nm resolution. For comparison, the optical density of the films was measured using a flatbed scanner.The net absorbance spectra showed two characteristic absorption bands centered at 636 nm and 585 nm. However, a saturation effect, manifested as broadening/splitting appearance, was observed in the 636 nm band for doses beyond a certain batch-dependent level ~4–10 Gy, in the three different film batches studied. The differences in the spectral shape led to dose-response curves with variable sensitivity. In general a high spectral sensitivity was observed in 0.1–6 Gy range for the three film batches. For a given dose, no significant change in the spectra was observed with change in the dose rate. No significant dependency on the LET was observed for the EBT3 films irradiated with proton beams with dose-averaged LETs ranging from 1.14–6.50 keV µm−1 studied in this work. However, at a given dose, ~5% lower spectral response was observed in the films irradiated with protons compared to their counterparts irradiated with photon beams.

Physical and biological impacts of collimator-scattered protons in spot-scanning proton therapy.

To improve the penumbra of low‐energy beams used in spot‐scanning proton therapy, various collimation systems have been proposed and used in clinics. In this paper, focused on patient‐specific brass collimators, the collimator‐scattered protons' physical and biological effects were investigated. The Geant4 Monte Carlo code was used to model the collimators mounted on the scanning nozzle of the Hokkaido University Hospital. A systematic survey was performed in water phantom with various‐sized rectangular targets; range (5–20 cm), spread‐out Bragg peak (SOBP) (5–10 cm), and field size (2 × 2–16 × 16 cm2). It revealed that both the range and SOBP dependences of the physical dose increase had similar trends to passive scattering methods, that is, it increased largely with the range and slightly with the SOBP. The physical impact was maximized at the surface (3%–22% for the tested geometries) and decreased with depth. In contrast, the field size (FS) dependence differed from that observed in passive scattering: the increase was high for both small and large FSs. This may be attributed to the different phase‐space shapes at the target boundary between the two dose delivery methods. Next, the biological impact was estimated based on the increase in dose‐averaged linear energy transfer (LET d) and relative biological effectiveness (RBE). The LET d of the collimator‐scattered protons were several keV/μm higher than that of unscattered ones; however, since this large increase was observed only at the positions receiving a small scattered dose, the overall LET d increase was negligible. As a consequence, the RBE increase did not exceed 0.05. Finally, the effects on patient geometries were estimated by testing two patient plans, and a negligible RBE increase (0.9% at most in the critical organs at surface) was observed in both cases. Therefore, the impact of collimator‐scattered protons is almost entirely attributed to the physical dose increase, while the RBE increase is negligible.

Aspects of linear energy transfer (LET) and relative biological effectiveness (RBE) in radiation therapy with positively charged particles and the role of electron capture

In radiotherapy, dose-effect relations induced by Co60 serve as a reference of the LET and RBE in normal and tumor tissue, which are usually handled by the linear-quadratic model S (LQ) with the parameters α and β, i.e. S = exp (-α·D-β·D2), working excellently up to the shoulder domain. In particle therapy, we have strictly to differ between RBE in the initial plateau and environment of the Bragg peak. Thus for protons LET and RBE of the initial plateau agree with Co60, whereas in the Bragg peak domain both properties are increased, but RBE of SOBP (spread out Bragg peak) only varies between 1.1 and 1.17; the RBE of carbon ions is increased once again. Their dose-effect curves are much steeper with a rather small shoulder domain due to dense ionizing radiation. Protons are also dense ionizing in the Bragg peak region, but their magnitude is rather smaller compared to carbon ions. A generalization of the LQ-model based on the nonlinear reaction-diffusion model is proposed to include LET and RBE of dense ionizing particles, which accounts for intra-cellular properties, too. The linear term of the reaction diffusion formula describes destroy of cells, the nonlinear term is related to repair. The diffusion term accounts for the density of the radiation damages. Based on dose-effect properties of Co60 the parameters of dense ionizing particles can be determined and compared with measurement data. However, a rigorously theoretical access starting with neglect of energy straggling and lateral scatter must account for electron capture of positively charged particles. By mathematical descriptions local dense of radiation effects and their consequences in dose-effect curves are interpreted providing a key to understanding modern therapy planning with different modalities and properties of intracellular processes.

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.

TOPAS Monte Carlo simulation for double scattering proton therapy and dosimetric evaluation

PurposeTo construct and commission a double scattering (DS) proton beam model in TOPAS Monte Carlo (MC) code. Dose comparisons of MC calculations to the measured and treatment planning system (TPS) calculated dose were performed. MethodsThe TOPAS nozzle model was based on the manufacturer blueprints. Nozzle set-up and beam current modulations were calculated using room-specific calibration data. This model was implemented to reproduce pristine peaks, spread-out Bragg peaks (SOBP) and lateral profiles. A stair-shaped target plan in water phantom was calculated and compared to measured data to verify range compensator (RC) modeling. ResultsTOPAS calculated pristine peaks agreed well with measurements, with accuracies of 0.03 cm for range R90 and 0.05 cm for distal dose fall-off (DDF). The calculated SOBP range, modulation width and DDF differences between MC calculations and measurements were within 0.05 cm, 0.5 cm and 0.03 cm respectively. MC calculated lateral penumbra agreed well with measured data, with difference less than 0.05 cm. For RC calculation, TPS underestimated the additional depth dose tail due to the nuclear halo effect. Lateral doses by TPS were 10% lower than measurement outside the target, while maximum difference of MC calculation was within 2%. At deeper depths inside the target volume, TPS overestimated doses by up to 25% while TOPAS predicted the dose to within 5% of measurements. ConclusionWe have successfully developed and commissioned a MC based DS nozzle model. The performance of dose accuracy by TOPAS was superior to TPS, especially for highly inhomogeneous compensator.

Вычисление глубинной зависимости ОБЭ клинических пучков протонов

Purpose: Accurate establishing the value of relative biological effectiveness (RBE) for high energy protons is one of the main challenges of modern radiotherapy. The purpose of the study is to calculate the depth dependence of RBE for proton beams forming a spread-out Bragg peak.
 Material and methods: Spatial distributions of absorbed dose and dose-average linear energy transfer (LET) for 50-100 MeV (0.5 MeV energy step) monochromatic proton beams were obtained by Monte-Carlo computer simulation using Geant4 software. A linear dependence of RBE on the dose-average LET was used. Absorbed dose distributions were obtained in a water phantom for monochromatic pencil proton beams of 2.5 mm radius. The absorbed dose and the dose-average LET values were calculated in voxels with dimensions of 2×2×0.2 mm.
 Results: Calculations of depth dependencies of absorbed dose and dose-average LET for 50–100 MeV monochromatic proton beams were performed. Depth dependencies of RBE for these beams were established. The weighing coefficients values allowing to generate uniformspread-out Bragg peak (SOBP) were determined. Depth distribution of “RBE-weighted” dose and RBE values for SOBP were found.
 Conclusion: The impact of the initial beam energy step on the degree of homogeneity of the modified Bragg curve was investigated. It was shown that a step up to 1.5 MeV is acceptable for generate a smooth Bragg curve. The depth dependence of the average RBE value is a complex function, which rapidly changes especially at the far end of the SOBP. RBE may vary up to 10-30 % compared to current clinical value. The linear model of RBE-LET dependence shown in the study can be easily used in dosimetric planning systems, that may will significantly improve the quality of proton radiotherapy.

Comparing 2 Monte Carlo Systems in Use for Proton Therapy Research.

Several Monte Carlo transport codes are available for medical physics users. To ensure confidence in the accuracy of the codes, they must be continually cross-validated. This study provides comparisons between MC2 and Tool for Particle Simulation (TOPAS) simulations, that is, between medical physics applications for Monte Carlo N-Particle Transport Code (MCNPX) and Geant4. Monte Carlo simulations were repeated with 2 wrapper codes: TOPAS (based on Geant4) and MC2 (based on MCNPX). Simulations increased in geometrical complexity from a monoenergetic beam incident on a water phantom, to a monoenergetic beam incident on a water phantom with a bone or tissue slab at various depths, to a spread-out Bragg peak incident on a voxelized computed tomography (CT) geometry. The CT geometry cases consisted of head and neck tissue and lung tissue. The results of the simulations were compared with one another through dose or energy deposition profiles, r 90 calculations, and γ-analyses. Both codes gave very similar results with monoenergetic beams incident on a water phantom. Systematic differences were observed between MC2 and TOPAS simulations when using a lung or bone slab in a water phantom, particularly in the r 90 values, where TOPAS consistently calculated r 90 to be deeper by about 0.4%. When comparing the performance of the 2 codes in a CT geometry, the results were still very similar, exemplified by a 3-dimensional γ-analysis pass rate > 95% at the 2%-2-mm criterion for tissues from both head and neck and lung. Differences between TOPAS and MC2 were minor and were not considered clinically relevant.

Effects of modulation materials for lung dose distribution in proton therapy

Exploration of the optimal combination of range modulation materials (RMMs) for proton beam irradiation in lung heterogeneous media using Monte Carlo simulation was the focus of study. Physical and dosimetric properties of each homogenous RMM irradiated with proton beam were investigated. The water equivalent ratio (WER) and full width at half maximum (FWHM) were compared to determine the primary RMM. The optimized trade-off between the effects of thickness needed for range modulation and FWHMs for selecting optimal RMM combinations was found. The optimal 2nd RMM was determined based on figure-of-merit (FOM) analyses in the water-lung-water media irradiated by proton beams. This study created an easier approach and successfully created the spread–out Bragg peak (SOBP) in lung heterogeneous media, using statistically fitted matrix with uniformity of SOBP better than 2%. The weighting factors matrix for creating SOBP may theoretically be applied to any multiple range modulation systems. The methodology for the 150 MeV proton beams' range modulation in the lung heterogeneous media can be similarly applied to other energy of proton as well as for heavy ion therapy.

Dosimetry and characterization of a 25-MeV proton beam line for preclinical radiobiology research.

With the increase in proton therapy centers, there is a growing need to make progress in preclinical proton radiation biology to give accessible data to medical physicists and practicing radiation oncologists. A cyclotron usually producing radioisotopes with a proton beam at an energy of about 25MeV after acceleration, was used for radiobiology studies. Depleted silicon surface barrier detectors were used for the beam energy measurement. A complementary metal oxide semiconductor (CMOS) sensor and a plastic scintillator detector were used for fluence measurement, and compared to Geant4 and an in-house analytical dose modeling developed for this purpose. Also, from the energy measurement of each attenuated beam, the dose-averaged linear energy transfer (LETd ) was calculated with Geant4. The measured proton beam energy was 24.85±0.14MeV with an energy straggling of 127±22keV before scattering and extraction in air. The measured flatness was within±2.1% over 9mm in diameter. A wide range of LETd is achievable: constant between the entrance and the exit of the cancer cell sample ranging from 2.2 to 8keV/μm, beyond 20keV/μm, and an average of 2-5keV/μm in a scattering spread-out Bragg peak calculated for an example of a 6-mm-thick xenograft tumor. The dosimetry and the characterization of a 25-MeV proton beam line for preclinical radiobiology research was performed by measurements and modeling, demonstrating the feasibility of delivering a proton beam for preclinical invivo and invitro studies with LETd of clinical interest.

A novel methodology to assess linear energy transfer and relative biological effectiveness in proton therapy using pairs of differently doped thermoluminescent detectors

A new methodology for assessing linear energy transfer (LET) and relative biological effectiveness (RBE) in proton therapy beams using thermoluminescent detectors is presented. The method is based on the different LET response of two different lithium fluoride thermoluminescent detectors (LiF:Mg,Ti and LiF:Mg,Cu,P) for measuring charged particles. The relative efficiency of the two detector types was predicted using the recently developed Microdosimetric d(z) Model in combination with the Monte Carlo code PHITS. Afterwards, the calculated ratio of the expected response of the two detector types was correlated with the fluence- and dose- mean values of the unrestricted proton LET. Using the obtained proton dose mean LET as input, the RBE was assessed using a phenomenological biophysical model of cell survival.The aforementioned methodology was benchmarked by exposing the detectors at different depths within the spread out Bragg peak (SOBP) of a clinical proton beam at iThemba LABS. The assessed LET values were found to be in good agreement with the results of radiation transport computer simulations performed using the Monte Carlo code GEANT4. Furthermore, the estimated RBE values were compared with the RBE values experimentally determined by performing colony survival measurements with Chinese Hamster Ovary (CHO) cells during the same experimental run. A very good agreement was found between the results of the proposed methodology and the results of the in vitro study.

LET response variability of Gafchromic EBT3 film from a Co calibration in clinical proton beam qualities.

To establish a method of accurate dosimetry required to quantify the expected linear energy transfer (LET) quenching effect of EBT3 film used to benchmark the dose distribution for a given treatment field and specified measurement depth. In order to facilitate this technique, a full analysis of film calibration which considers LET variability at the plane of measurement and as a function of proton beam quality is demonstrated. Additionally, the corresponding uncertainty from the process was quantified for several measurement scenarios. The net change in optical density (OD) from a single version of Gafchromic EBT3 film was measured using an Epson flatbed scanner and NIST-traceable OD filters. Film OD response was characterized with respect to the known dose to water at the point of measurement for both a NIST-traceable beam at the UWADCL and several clinical single-energy and spread-out Bragg peak (SOBP) proton beam qualities at the Northwestern Medicine Chicago Proton Center. Increasing proton LET environments were acquired by placing film at increasing depths of Gammex HE Solid Water® whose water-equivalent thickness was characterized prior to measurement. A strong LET dependence was observed near the Bragg peak (BP) consistent with previous studies performed with earlier versions of EBT3 film. The influence of range straggling on the film's LET response appears to have a uniform effect toward the BP regardless of the nominal beam energy. Proximal to this depth, the film's response decreased with decreasing energy at the same dose-average LET. The opposite trend was observed for depths past the BP. Changes in the SOBP energy modulation showed a linear relationship between the film's relative response and dose-averaged LET. Relative effectiveness factors (RE) were observed to range between 2%-7% depending on the width of the SOBP and depth of the film. Using the field-specific calibration technique, a total k=1 uncertainty in the absorbed dose to water was estimated to range from 4.68%-5.21%. While EBT3 film's strong LET dependence is a common problem in proton beam dosimetry, this work has shown that the LET dependence can be taken into account by carefully considering the depth and energy modulation across the film using field-specific corrections. RE factors were determined with a combined k=1 uncertainty of 3.57% for SOBP environments and between3.17%-4.69% for uniform, monoenergetic fields proximal to the distal 80% of the BP.

A Model for Secondary Monitor Unit Calculations of PBS Proton Therapy Treatment Plans.

Purpose:This article summarizes a volume-based method by which secondary monitor unit (MU) calculations may be performed for pencil beam scanning, single field uniform dose (SFUD) proton therapy treatment plans.Materials and Methods:Treatment planning system (TPS) simulations were performed by using the local beam model to define relationships between planning target volume (PTV) characteristics and the MUs required to deliver a uniform dose for a given beam orientation. Relevant target attributes included volume, depth (ie, beam range), range-shifter air gap, and the projected area of the target volume in the beam's eye view (BEV). The proposed model approximates the PTV as a simplified cuboid region of interest as defined by its volume and BEV projected area. Output factors (cGy/MU) were then tabulated for the idealized geometry through TPS simulations using region of interests with a range of dimensions expected to be seen clinically. Correction factors were applied that account for differences between the PTV and the idealized conditions, and MUs for each beam were then scaled according to the measured spread out Bragg peak (SOBP) dose in water.Results:Our model was applied to various treatment sites, including pelvis, brain, lung, and head and neck. Monitor units prescribed by the TPS were compared to those predicted by using the model for 78 treatment beams. The total mean percentage difference for all beams was −0.2% ± 3.8%.Conclusion:This work demonstrates the potential for reasonably accurate secondary verification of MUs in pencil beam scanning proton therapy for SFUD treatment plans with the proposed method. Required inputs are few, and are readily accessible, facilitating automation and clinical application. Further investigation will expand the current model to accommodate a broader range of potential optimization problems, and intensity-modulated proton therapy treatment plans.

A linear relationship for the LET-dependence of Gafchromic EBT3 film in spot-scanning proton therapy

Radiochromic film (RCF) is a valuable dosimetric tool, primarily due to its sub-millimeter spatial resolution. For accurate proton dosimetry, the dependence of film response on linear energy transfer (LET) must be characterized and calibrated. In this work, we characterized film under-response, or ‘quenching’, as a function of dose-weighted linear energy transfer (LETd) in several proton fields and established a simple, linear relationship with LETd.We performed measurements as a function of depth in a PMMA phantom irradiated by a spot-scanning proton beam. The fields had energies of 71.3 MeV, 71.3 MeV with filter, and 159.9 MeV. At each depth (measurements taken in depth step sizes of 0.5–1 mm in the Bragg peak), we measured dose with a PTW Markus ion chamber and EBT3 RCF. EBT3 under-response was characterized by the ratio of dose measured with film to that with ion chamber. LETd values for our experimental setup were calculated using in-house clinical Monte Carlo code. Measured film under-response increased with LETd, from approximately 10% under-response for LETd = 5 keV µm−1 to approximately 20% for LETd = 8 keV µm−1. The under-response for all measurements was plotted versus LETd. A linear fit to the data was performed, yielding a function for under-response, , with respect to LETd: . Finally, the linear under-response relationship was applied to a film measurement within a spread-out Bragg peak (SOBP). Without correcting for LETd-dependence in the SOBP measurement, the discrepancy between film and Monte Carlo profiles was greater than 15% at the distal edge. With correction, the corrected film profile was within 2% and 1 mm of the Monte Carlo profile.RCF response depends on LETd, potentially under-responding by >15% in clinically-relevant scenarios. Therefore, it is insufficient to perform only a dose calibration; LET calibration is also necessary for accurate proton film dosimetry. The LETd-dependence of EBT3 can be described by a single, linear function over a range of clinically-relevant proton therapy LETd values.

Design and commissioning of the non-dedicated scanning proton beamline for ocular treatment at the synchrotron-based CNAO facility.

Only few centers worldwide treat intraocular tumors with proton therapy, all of them with a dedicated beamline, except in one case in the USA. The Italian National Center for Oncological Hadrontherapy (CNAO) is a synchrotron-based hadrontherapy facility equipped with fixed beamlines and pencil beam scanning modality. Recently, a general-purpose horizontal proton beamline was adapted to treat also ocular diseases. In this work, the conceptual design and main dosimetric properties of this new proton eyeline are presented. A 28 mm thick water-equivalent range shifter (RS) was placed along the proton beamline to shift the minimum beam penetration at shallower depths. FLUKA Monte Carlo (MC) simulations were performed to optimize the position of the RS and patient-specific collimator, in order to achieve sharp lateral dose gradients. Lateral dose profiles were then measured with radiochromic EBT3 films to evaluate the dose uniformity and lateral penumbra width at several depths. Different beam scanning patterns were tested. Discrete energy levels with 1 mm water-equivalent step within the whole ocular energy range (62.7-89.8 MeV) were used, while fine adjustment of beam range was achieved using thin polymethylmethacrylate additional sheets. Depth-dose distributions (DDDs) were measured with the Peakfinder system. Monoenergetic beam weights to achieve flat spread-out Bragg Peaks (SOBPs) were numerically determined. Absorbed dose to water under reference conditions was measured with an Advanced Markus chamber, following International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice. Neutron dose at the contralateral eye was evaluated with passive bubble dosimeters. Monte Carlo simulations and experimental results confirmed that maximizing the air gap between RS and aperture reduces the lateral dose penumbra width of the collimated beam and increases the field transversal dose homogeneity. Therefore, RS and brass collimator were placed at about 98 cm (upstream of the beam monitors) and 7 cm from the isocenter, respectively. The lateral 80%-20% penumbra at middle-SOBP ranged between 1.4 and 1.7 mm depending on field size, while 90%-10% distal fall-off of the DDDs ranged between 1.0 and 1.5 mm, as a function of range. Such values are comparable to those reported for most existing eye-dedicated facilities. Measured SOBP doses were in very good agreement with MC simulations. Mean neutron dose at the contralateral eye was 68 μSv/Gy. Beam delivery time, for 60 Gy relative biological effectiveness (RBE) prescription dose in four fractions, was around 3 min per session. Our adapted scanning proton beamline satisfied the requirements for intraocular tumor treatment. The first ocular treatment was delivered in August 2016 and more than 100 patients successfully completed their treatment in these 2 yr.

A new facility for proton radiobiology at the Trento proton therapy centre: Design and implementation

We present a new facility dedicated to radiobiology research, which has been implemented at the Trento Proton Therapy Centre (Italy).A dual-ring double scattering system was designed to produce irradiation fields of two sizes (i.e. 6 and 16 cm diameter) starting from a fix pencil beam at 148 MeV. The modulation in depth was obtained with a custom-made range modulator, optimized to generate a 2.5 cm spread-out Bragg peak (SOBP). The resulting irradiation field was characterized in terms of lateral and depth-dose profiles. The beam characteristics and the geometry of the setup were implemented in the Geant4 Monte Carlo (MC) code. After benchmark against experimental data, the MC was used to characterize the distribution of dose-average linear energy transfer (LET) associated to the irradiation field.The results indicate that dose uniformity above 92.9% is obtained at the entrance channel as well as in the middle SOBP in the target regions for both irradiation fields. Dose rate in the range from 0.38 to 0.78 Gy/min was measured, which can be adjusted by proper selection of cyclotron output current, and eventually increased by about a factor 7. MC simulations were able to reproduce experimental data with good agreement. The characteristics of the facility are in line with the requirements of most radiobiology experiments. Importantly, the facility is also open to external users, after successful evaluation of beam proposals by the Program Advisory Committee.

Production and distribution of chromosome aberrations in human lymphocytes by particle beams with different LET

We investigated induction of chromosome aberrations (CA) in human lymphocytes when exposed to 150 MeV and spread out Bragg peak (SOBP) proton beams, and 199 MeV/u carbon beam which are currently widely used for cancer treatment and simultaneously are important components of cosmic radiation. For a comparison, the boron ions of much lower energy 22 MeV/u and a 60Co γ rays were used. Dose–effect curves as well as the distributions of CA were studied using Poisson and Neyman type A statistics. Systematics of experimentally determined parameters, their dependence on applied doses and irradiation quality are presented.

Effect of 5-fluorouracil on cellular response to proton beam in esophageal cancer cell lines according to the position of spread-out Bragg peak

Introduction: To investigate enhancement by 5-fluorouracil (5-FU) of the sensitivity of cancer cells to proton beam irradiation and clarify the differences in the responses of the 5-FU-treated cells to proton beam irradiation according to the position of the cells on the spread-out Bragg peak (SOBP).Methods: OE21 human esophageal squamous cells were irradiated with a 235-MeV proton beam at four different positions on the SOBP. The effects of the irradiation plus 5-FU treatment on the cell survival were assessed by clonogenic assays and determination of the sensitizer enhancement ratio (SER). In addition, DNA double-strand breaks were estimated by measuring phospho-histone H2AX (γH2AX) foci formation in the cells at 0.5 and 24 h after irradiation.Results: The relative biological effectiveness (RBE) of proton beam irradiation against vehicle-control cells tended to increase with an increase in the depth of the cells on the SOBP. On the other hand, the degree of enhancement of the cellular sensitivity to proton beam irradiation by 5-FU was similar across all the positions on the SOBP. Furthermore, a marked increase in the number of residual γH2AX foci at 24 h post-irradiation was observed in the cells at the distal end of the SOBP.Conclusions: Our data indicated that the degree of enhancement by 5-FU of the sensitivity of OE21 cells to 235-MeV proton beam irradiation did not differ significantly depending on the position of the cells on the SOBP. Furthermore, the degree of increase in the number of γH2AX foci at 24 h after proton beam irradiation with or without 5-FU exposure did not differ significantly according to the position on the SOBP. The effect of 5-FU in enhancing the effect of proton beam irradiation on cancer cells may be constant for all positions on the SOBP.

Is the dose-averaged LET a reliable predictor for the relative biological effectiveness?

The dose-averaged linear energy transfer (LETD ) is frequently used as representative quantity for the biological effectiveness of a radiation field. Moreover, relative biological effectiveness (RBE) values measured or calculated in mixed radiation fields are typically plotted vs the LETD . In this study, we will investigate whether the LETD is an appropriate quantity to describe the RBE of any mixed radiation field of protons and heavier ions and discuss potential limitations. To study the reliability of LETD , we investigate model predictions of RBE in monoenergetic beams under track segment conditions and pristine Bragg peaks as well as spread out Bragg peaks (SOBP) in water. Both, the pristine Bragg peaks and the SOBPs are regarded as mixed radiation fields in this analysis, that is, they are characterized by a certain width of the energy spectrum of the projectile, although the underlying energy distribution is much broader in the case of an SOBP as compared to a pristine peak. For both cases, the corresponding RBE values are compared to those of strictly monoenergetic particles under track segment conditions, characterized by a single LET value. For the planning we use the treatment planning software TRiP98 together with the Local Effect Model to predict the RBE of protons, helium, and carbon ions. We further compare our model predictions for protons with a simplistic linear RBE-LET relationship representative for the phenomenological models in literature. Regarding pristine Bragg peaks in water, the deviations in RBE compared to monoenergetic particles under track segment conditions for the same LET value are low (mostly 0-5%), except for the distal fall-off region. The situation changes in SOBPs for which we found deviations in the order of up to 25% for the lighter particles and even more pronounced deviations for heavier particles like carbon ions. The analysis showed that LETD is a sufficiently accurate predictor for RBE only in regions with comparably narrow, but not in regions with broad, LET distribution as in a single SOBP or in multiple overlapping fields. The deviations are caused by the nonlinearity of the RBE(LET) relationship in the case of track segment conditions. Thus, independent of the underlying RBE model and the particle type regarded, as long as the RBE(LET) relationship deviates from being purely linear, LETD is not a good predictor for RBE, and especially for heavier particles like carbon ions knowledge of the underlying LET distribution is mandatory to describe the RBE in mixed radiation fields.

Development of proton beam irradiation system for small animals using FFAG accelerator

To evaluate the biological effect of boron compounds on normal tissues in boron neutron capture therapy, it is necessary to compare the radiation effects of neutron irradiation and gamma ray irradiation on small animals in nonclinical studies. Neutron beams and gamma rays are difficult to collimate; thus, it is impossible to administer a dose on each part of the normal tissues of small animals. Therefore, we have developed a method to compare biological effects by irradiating neutrons and gamma rays after irradiating a proton beam to the point just before the threshold dose at which the biological effects occur. We aim to develop an irradiation field that irradiates proton beams locally using a fixed-field alternating-gradient (FFAG) accelerator and a small ridge filter.An aluminum scatterer, transmission dose monitor, ridge filter, range shifter, collimator, and a proton beam from the FFAG accelerator were used to form an irradiation field with a spread out Bragg peak (SOBP) with a length of 10 mm and a size of 10 mm2.Dose measurement was performed using a Gafchromic film and an ionization chamber. The irradiation system was simulated using the PHITS Monte Carlo simulation code, and simulation results were compared with experimental results.We succeeded in forming an irradiation field with a dose rate of 14.3 ± 0.24 Gy/min, an SOBP length of 10 mm, and a size of 10 mm2.

Modelling the Biological Beamline at HIMAC using Geant4

A Geant4 simulation modelling the passive Biological beamline at the Heavy Ion Medical Accelerator Chiba (HIMAC) is described and validated against experimental measurements for a mono-energetic and spread out Bragg peak (SOBP) 12C beam. Comparisons to experimental data showed good agreement for both lateral and depth dose profiles. It was found that simplifying the simulation model by generating a cone beam instead of using the wobbler magnets provided a good approximation for both lateral and depth dose measurements.