Spread-out Bragg Peak Research Articles

Microdosimetric study for helium-ion beam using fully 3D silicon microdosimeters

In this study, the survival fraction of pancreatic cancer cells exposed to a spread-out Bragg peak (SOBP) helium-ion beam are estimated using the microdosimetric method with the microdosimetric kinetic (MK) model, by measuring the specific energy with a microdosimeter. To measure the microdosimetric spectra, a 3D mushroom microdosimeter was used by mounting it on silicon-on-insulator (SOI) substrates. At different positions of the Bragg curve of a pristine helium-ion beam of 166 MeV/u, microdosimetric spectra were measured via a scanning beam port in the National Institute of Radiological Sciences. The MK parameters were determined such that the survival fraction (SF) calculated by the MK model predicts the previously reported in vitro data. For a cuboid target of 10×10×6 cm3, a treatment plan that utilised helium-ion beam was designed from the in-house treatment planning software (TPS) to achieve a 10% SF of pancreatic cancer cells throughout the target. The physical doses and microdosimetric spectra were measured for different depths by irradiating the scanning-SOBP helium-ion beam; consequently, the SF at each position of the SOBP was predicted. The predicted SFs from measured physical dose and microdosimetric spectra were in good agreement with the planned SF from TPS.

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.

A machine learning framework with anatomical prior for online dose verification using positron emitters and PET in proton therapy

We developed a machine learning framework in order to establish the correlation between dose and activity distributions in proton therapy. A recurrent neural network was used to predict dose distribution in three dimensions based on the information of proton-induced positron emitters. Hounsfield Unit (HU) information from CT images and analytically derived stopping power (SP) information were incorporated as auxiliary inputs. Four different scenarios were investigated: Activity only, Activity + HU, Activity + SP and Activity + HU + SP. The performance was quantitatively studied in terms of mean absolute error (MAE) and mean relative error (MRE), under different signal-to-noise ratios (SNRs). In addition to the first dataset of mono-energetic beams, three additional datasets were validated to help evaluate the generalization capability of our proposed model: a dataset of a lower SNR, five reconstructed PET images, and a dataset of spread-out Bragg peaks. Good verification accuracy of dose verification in three dimensions is demonstrated. The inclusion of anatomical information improves both accuracy and generalization. For an activity profile with an SNR of 4 (the mono-energetic case), the framework is able to obtain an MRE of ∼ 0.99% over the whole range and a range uncertainty of ∼ 0.27 mm. The machine learning-based framework may emerge as a useful tool to allow for online dose verification and quality assurance in proton therapy.

Development of a Monte Carlo beam model for raster scanning proton beams and dosimetric comparison

Purpose To develop a Monte Carlo (MC) beam model for raster scanning proton beams for dose verification purposes. Methods and materials MC program FLUKA was used in the model. The nominal energy, momentum spread and beam angular distribution in the model were determined by matching the simulation profiles with the measured integral depth dose (IDD) and in air spot size. Dosimetric comparison was done by comparing the measured and simulated dose distributions. The 1 D dose profile of cubic Spread Out Bragg Peak (SOBP) plans, and the 2 D dose distribution of previously treated breast cancer patients’ clinical plans were measured by using Pinpoint chambers and 2 D array ionization chambers, respectively. Corresponding DICOM plan information was utilized for MC simulation. Results The MC results showed good agreement with measurements for the SOBP plans. The absolute comparison of the absorbed dose difference between the MC and the measurement was 0.93%±0.88%. For the patient plans, the overall passing rate of the gamma index analysis (γ-PR) between the MC simulation and measurement with the 2%-2 mm criteria was 97.78%, and only 1 case had a γ-PR less than 90%. With the 3%-3 mm criteria, γ-PR was never below 99% for all cases with and without the range shifter. Conclusions This work described a method for adapting a MC simulation model for a raster scanning proton beam. The good concordance between the simulations and measurements shows that the MC model is an accurate and reliable method. It has the potential to be used for patient specific quality assurance (PSQA) to reduce the beam time for the measurements in water.

Preliminary Dosimetric Study of Proton Minibeam Radiation Therapy for the Treatment of Choroidal Melanoma

This study aimed to evaluate dosimetrically the feasibility of saving both the lens and the ciliary body in the treatment of a choroidal melanoma by using spatially fractionated proton minibeams. A multi-slit brass collimator was designed by using Monte Carlo simulation data and was fabricated with a 0.4-mm beam opening and a 1.1-mm center-to-center distance. A phantom was also fabricated for proton beam dosimetry, involving five polymethylmethacrylate (PMMA) plates of 2 mm and 8 mm thicknesses, respectively. The peak-to-valley dose ratio (PVDR) of the proton minibeams was used to validate the feasibility of lens and ciliary body sparing. The typical single-scattered proton beam for treating a patient with a choroidal melanoma was delivered to Gafchromic EBT3 films in the phantom after having passed through the multi-slit: the energy of proton beam was 60 MeV, and its depth dose profile was a full spread-out Bragg peak (SOBP). The average dose at mid-depth of the SOBP was approximately 3 CGE with ±3% of ripple. Dosimetric evaluation showed the PVDR depended on the air gap strongly. It varied from 3.4 to 1.1 in the air gap range from 2 mm to 62 mm. The PVDR values at PMMA depths of 2, 12, 22, and 32 mm were 2.0, 1.5, 1.1, and 1.06, respectively. This result shows that a spatially fractionated proton beam might save the lens and ciliary body seated at a shallow depth in the eye ball when a choroidal melanoma is treated using proton minibeam radiotherapy.

Initial Validation of Proton Dose Calculations on SPR Images from DECT in Treatment Planning System.

PurposeTo investigate and quantify the potential benefits associated with the use of stopping-power-ratio (SPR) images created from dual-energy computed tomography (DECT) images for proton dose calculation in a clinical proton treatment planning system (TPS).Materials and MethodsThe DECT and single-energy computed tomography (SECT) scans obtained for 26 plastic tissue surrogate plugs were placed individually in a tissue-equivalent plastic phantom. Relative-electron density (ρe) and effective atomic number (Zeff) images were reconstructed from the DECT scans and used to create an SPR image set for each plug. Next, the SPR for each plug was measured in a clinical proton beam for comparison of the calculated values in the SPR images. The SPR images and SECTs were then imported into a clinical TPS, and treatment plans were developed consisting of a single field delivering a 10 × 10 × 10-cm3 spread-out Bragg peak to a clinical target volume that contained the plugs. To verify the accuracy of the TPS dose calculated from the SPR images and SECTs, treatment plans were delivered to the phantom containing each plug, and comparisons of point-dose measurements and 2-dimensional γ-analysis were performed.ResultsFor all 26 plugs considered in this study, SPR values for each plug from the SPR images were within 2% agreement with measurements. Additionally, treatment plans developed with the SPR images agreed with the measured point dose to within 2%, whereas a 3% agreement was observed for SECT-based plans. γ-Index pass rates were > 90% for all SECT plans and > 97% for all SPR image–based plans.ConclusionTreatment plans created in a TPS with SPR images obtained from DECT scans are accurate to within guidelines set for validation of clinical treatment plans at our center. The calculated doses from the SPR image–based treatment plans showed better agreement to measured doses than identical plans created with standard SECT scans.

Feasibility study of patient-specific dose verification in proton therapy utilizing positron emission tomography (PET) and generative adversarial network (GAN).

Online dose verification based on proton-induced positron emitters is a promising strategy for quality assurance in proton therapy. Because of the nonlinear correlation between dose and the activity distributions, a machine learning-based approach was developed to establish their relationship. Simulations were carried out using a pencil beam scanning system and a computed tomography (CT) image-based phantom. A DiscoGAN model was developed to perform dose verification for both central and off-center lines. Besides the activity as input, HU information from CT images and stopping power (SP) prior were incorporated as auxiliary features for the model. The performance was quantitatively studied in terms of mean absolute error (MAE) and mean relative error (MRE), under different signal-to-noise ratios (SNRs). In addition to a dataset comprising monoenergetic beams, two additional datasets were generated to evaluate the model's generalization capability: five reconstructed PET images based on an in-beam PET system and a dataset comprising spread-out Bragg peaks (SOBPs). The feasibility of dose verification was successfully demonstrated for all three datasets. For the monoenergetic case (i.e., raw activity of positron emitters), the MRE is found to be <1% for the central lines and 5% for the off-center lines, respectively. The range uncertainty is found to be less than 1mm. The prediction based on five PET images, which take into account the detection of 511-keV photons and image reconstruction, yields slightly inferior performance. For the SOBP case, the MRE of the center lines is found to be <3% and the range uncertainty is <1mm. The inclusion of anatomical information (HU and SP) improves both accuracy and generalization of the DiscoGAN model. The combination of proton-induced positron emitters, in-beam PET, and machine learning may become a useful tool allowing for patient-specific online dose verification in proton therapy.

Ultra-High Dose-Rate, Pulsed (FLASH) Radiotherapy with Carbon Ions: Generation of Early, Transient, Highly Oxygenated Conditions in the Tumor Environment.

It is well known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, which is distinct from low-LET radiation wherein O2 radiolytic yield is negligible. Since O2 is a powerful radiosensitizer, this fact is of practical relevance in cancer therapy with energetic heavy ions, such as carbon ions. It has recently been discovered that large doses of ionizing radiation delivered to tumors at very high dose rates (i.e., in a few milliseconds) have remarkable benefits in sparing healthy tissue while preserving anti-tumor activity compared to radiotherapy delivered at conventional, lower dose rates. This new method is called "FLASH radiotherapy" and has been tested using low-LET radiation (i.e., electrons and photons) in various pre-clinical studies and recently in a human patient. Although the exact mechanism(s) underlying FLASH are still unclear, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion. In addition, heavy-ion radiation achieves tumor control with reduced normal tissue toxicity due to its favorable physical depth-dose profile and increased radiobiological effectiveness in the Bragg peak region. To date, however, biological research with energetic heavy ions delivered at ultra-high dose rates has not been performed and it is not known whether heavy ions are suitable for FLASH radiotherapy. Here we present the additive or even synergistic advantages of integrating the FLASH dose rates into carbon-ion therapy. These benefits result from the ability of heavy ions at high LET to generate an oxygenated microenvironment around their track due to the occurrence of multiple (mainly double) ionization of water. This oxygen is abundant immediately in the tumor region where the LET of the carbon ions is very high, near the end of the carbon-ion path (i.e., in the Bragg peak region). In contrast, in the "plateau" region of the depth-dose distribution of ions (i.e., in the normal tissue region), in which the LET is significantly lower, this generation of molecular oxygen is insignificant. Under FLASH irradiation, it is shown that this early generation of O2 extends evenly over the entire irradiated tumor volume, with concentrations estimated to be several orders of magnitude higher than the oxygen levels present in hypoxic tumor cells. Theoretically, these results indicate that FLASH radiotherapy using carbon ions would have a markedly improved therapeutic ratio with greater toxicity in the tumor due to the generation of oxygen at the spread-out Bragg peak.

DNA damage in blood leukocytes from mice irradiated with accelerated carbon ions with an energy of 450 MeV/nucleon

Purpose The objective of the study was to estimate the DNA damage in blood leukocytes at long terms after irradiation of mice with carbon ions (450 MeV/nucleon) both before and in the Bragg peak. Materials and methods White outbred SHK male mice were exposed to whole-body irradiation with carbon ions at doses of 0.1–2 Gy in the spread-out Bragg peak and at a dose of 6 Gy before and in the Bragg peak. At different times after irradiation (1–75 days), whole blood was collected from the tail of each mouse and analyzed by the comet assay. Mice X-irradiated in the same dose range served as a positive control. The level of the expression of mRNA of CDKN1A, APEX1, BBC3, TXN2, and β-ACT genes in bone marrow cells was determined in animals irradiated with carbon ions at doses of 0.1–2 Gy using the real-time PCR. Results It was found that, 24 h after 12C-irradiation, a dose-dependent (0.1–2 Gy) increase in the DNA damage of leukocytes occurred, which was accompanied by a decrease in their concentration and an increase in the expression of the CDKN1A and BBC3 genes in bone marrow cells. The expression of the APEX1 and TXN2 genes did not change. In mice 12C-irradiated at a dose of 6 Gy before and in the Bragg peak, the level of DNA damage changed as follows: by day 3, it increased; by day 23 it returned to the control level; by day 30, it increased again; and by day 75, it fell to the control level on irradiation before the Bragg peak and was significantly higher (p < .05) than in the control after irradiation in the Bragg peak. Conclusions The dynamics of changes in the level of DNA damage in leucocytes of 12C-irradiated mice within 30 days is similar to that in mice exposed to sublethal doses of X-radiation. The retention of the high level of DNA damage by day 75 after 12C-irradiation in the Bragg peak indicates a significant injury of cells from different cell pools of the blood system. The high level of DNA damage may be related not only to complex DNA injuries but also to chronic oxidative stress.

FRoG: An independent dose and LETd prediction tool for proton therapy at ProBeam® facilities.

Particle therapy is becoming increasingly available world-wide for precise tumor targeting, its favorable depth dose deposition, and increased biological damage to tumor tissue compared to conventional photon therapy. As demand increases for improved robustness and conformality, next-generation secondary dose calculation engines are needed to verify treatment plans independently and provide estimates for clinical decision-making factors, such as dose-averaged linear energy transfer (LETd ) and relative biological effectiveness (RBE). FRoG (Fast dose Recalculation on GPU) has been installed and commissioned at the Danish Centre for Particle Therapy (DCPT). FRoG was developed for synchrotron-based facilities and has previously demonstrated good agreement with gold-standard Monte Carlo simulations and measurements. In this work, additions and modifications to FRoG's pencil beam algorithm to support the ion beam delivery with cyclotron-based technology as used at the DCPT, range shifter (RS) implementation, and robustness analysis methods are presented. FRoG dose predictions are compared to measurements and predictions of the clinical treatment planning system (TPS) Eclipse (Varian Medical Systems, Palo Alto, United States of America, CA, v.13.7.16) in both homogenous and heterogeneous scenarios using a solid-water/water and a half-head anthropomorphic phantom, respectively. Additional capabilities of FRoG are explored by performing a plan robustness analysis, analyzing dose and LETd for ten patients. Mid-target measurements in spread-out Bragg Peaks (SOBP) were on average within -0.19%±0.30% and ≤0.5% of FRoG predictions for irradiations withoutand with RS, respectively. Average 3%/2mm 3D γ-analysis passing rates were 99.1% for ~200 patient plan QA comparisons. Measurement with an anthropomorphic head-phantom yielded a γ-passing rate >98%. Overall, maximum target differences in D02% of <2% between the TPS and FRoG were observed for patient plans. The robustness analysis study accounting for range, delivery, and positioning uncertainties revealed small differences in target dose and a maximum LETd VH02% (LETd received by 2% of the volume having dose larger than 1% of maximum dose) values below 10.1keV/µm to the brain stem. We demonstrate that auxiliary dose calculation systems like FRoG can yield excellent agreement to measurements comparable to clinical beam models. Through this work, application of FRoG as a secondary engine at third party cyclotron-based particle treatment facilities is now established for dose verification as well as providing further insight on LETd and variable RBE distributions for protons, currently absent from the standard clinical TPS.

Quantitative proton radiation therapy dosimetry using the storage phosphor europium-doped potassium chloride.

To (a) characterize the fundamental optical and dosimetric properties of the storage phosphor europium-doped potassium chloride for quantitative proton dosimetry, and (b) investigate if its dose radiation response can be described by an analytic radiation transport model. Cylindrical KCl:Eu2+ dosimeters with dimensions of 6mm diameter and 1mm thickness were fabricated in-house. The dosimeters were irradiated using both a Mevion S250 passive scattering proton therapy system and a Varian Clinac iX linear accelerator. Photostimulated luminescence (PSL) emission spectra, excitation spectra, and luminescence lifetimes were measured for both proton and photon irradiations. Dosimetric properties including radiation hardness, dose linearity, signal stabilization, dose rate sensitivity, and energy dependence were studied using a laboratory optical reader after irradiations. The dosimeters were modeled using physical quantities including mass stopping powers in the storage phosphor and water for a given proton beam, and mass energy absorption coefficients and massing stopping powers in detector and water for a given photon beam. KCl:Eu2+ exhibited optical emission and stimulation peaks at 421 and 560nm, respectively, for both proton and photon irradiations, enabling postirradiation readouts using a visible light source while detecting the PSL using a photomultiplier tube. KCl:Eu2+ showed a linear response from 0 to 8Gy absorbed dose-to-water, a large dynamic range up to 60Gy, dose-rate independence measured from 83 to 500MU/min, and a PSL lifetime of <5ms that is sufficiently short for supporting rapid scanning in a two-dimensional geometry. KCl:Eu2+ was highly reusable with only a slight signal decrease of ~3% at accumulated doses over 100Gy, which could be managed by a periodic recalibration. The detected PSL signal strength of the dosimeter in the proton field had been calculated accurately to a maximum discrepancy of 2% using known physical quantities along with its prior signal strength as measured in a photon field at the same dose-to-water. This discrepancy might be attributed to an under-response due to linear energy transfer (LET) effect. However, comparisons of depth-dose measurements in a spread-out Bragg peak (SOBP) field with a parallel-plate ionization chamber showed no clear evidence of LET effects. Furthermore, range measurements agreed with ionization chamber measurements to within 1mm. KCl:Eu2+ showed linear response over a large dynamic range for proton irradiations and reliably reproduced SOBP measurements as measured by ionization chambers. Its relatively low atomic number of 18 and near LET independence make it suited for quantitative proton dosimetry. In addition, its high radiation hardness means that it can be reused numerous times. Any potential measurement artifacts encountered in complex irradiation conditions should be able to be corrected for using known physical quantities.

Neutron activation of gadolinium for ion therapy: a Monte Carlo study of charged particle beams

This study investigates the photon production from thermal neutron capture in a gadolinium (Gd) infused tumor as a result of secondary neutrons from particle therapy. Gadolinium contrast agents used in MRI are distributed within the tumor volume and can act as neutron capture agents. As a result of particle therapy, secondary neutrons are produced and absorbed by Gd in the tumor providing potential enhanced localized dose in addition to a signature photon spectrum that can be used to produce an image of the Gd enriched tumor. To investigate this imaging application, Monte Carlo (MC) simulations were performed for 10 different particles using a 5–10 cm spread out-Bragg peak (SOBP) centered on an 8 cm3, 3 mg/g Gd infused tumor. For a proton beam, 1.9 × 106 neutron captures per RBE weighted Gray Equivalent dose (GyE) occurred within the Gd tumor region. Antiprotons (bar{P}), negative pions (− π), and helium (He) ion beams resulted in 10, 17 and 1.3 times larger Gd neutron captures per GyE than protons, respectively. Therefore, the characteristic photon based spectroscopic imaging and secondary Gd dose enhancement could be viable and likely beneficial for these three particles.

Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation

Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after invivo mouse pelvic GRT versus PRT. One hundred twenty-four female prepubertal mice received sham, GRT, or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1, 3, and 8 weeks after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. For ovaries beyond the SOBP, ovarian function (P = .5) and ovarian primordial follicle (OPF; P = 1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8 weeks after treatment were reduced for all groups: 1.8 Gy GRT (βAMH = -4.9 ng/mL; βOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (βAMH = -5.1 ng/mL; βOPF = -728.2/animal), 0.2 Gy GRT (βAMH = -2.5 ng/mL; βOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (βAMH = -3.0 ng/mL; βOPF = -555.4/animal) relative to sham controls (all differences P < .001). This study uses an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.

The impact of dose delivery time on biological effectiveness in proton irradiation with various biological parameters

The purpose of this study is to evaluate the sublethal damage (SLD) repair effect in prolonged proton irradiation using the biophysical model with various cell-specific parameters of (α/β)x and T1/2 (repair half time). At present, most of the model-based studies on protons have focused on acute radiation, neglecting the reduction in biological effectiveness due to SLD repair during the delivery of radiation. Nevertheless, the dose-rate dependency of biological effectiveness may become more important as advanced treatment techniques, such as hypofractionation and respiratory gating, come into clinical practice, as these techniques sometimes require long treatment times. Also, while previous research using the biophysical model revealed a large repair effect with a high physical dose, the dependence of the repair effect on cell-specific parameters has not been evaluated systematically. Biological dose [relative biological effectiveness (RBE)×physical dose] calculation with repair included was carried out using the linear energy transfer (LET)-dependent linear-quadratic (LQ) model combined with the theory of dual radiation action (TDRA). First, we extended the dose protraction factor in the LQ model for the arbitrary number of different LET proton irradiations delivered sequentially with arbitrary time lags, referring to the TDRA. Using the LQ model, the decrease in biological dose due to SLD repair was systematically evaluated for spread-out Bragg peak (SOBP) irradiation in a water phantom with the possible ranges of both (α/β)x and repair parameters ((α/β)x =1-15Gy, T1/2 =0-90min). Then, to consider more realistic irradiation conditions, clinical cases of prostate, liver, and lung tumors were examined with the cell-specific parameters for each tumor obtained from the literature. Biological D99% and biological dose homogeneity coefficient (HC) were calculated for the clinical target volumes (CTVs), assuming dose-rate structures with a total irradiation time of 0-60min. The differences in the cell-specific parameters resulted in considerable variation in the repair effect. The biological dose reduction found at the center of the SOBP with 30min of continuous irradiation varied from 1.13% to 14.4% with a T1/2 range of 1-90min when (α/β)x is fixed as 10Gy. It varied from 2.3% to 6.8% with an (α/β)x range of 1-15Gy for a fixed value of T1/2 =30min. The decrease in biological D99% per 10min was 2.6, 1.2, and 3.0% for the prostate, liver, and lung tumor cases, respectively. The value of the biological D99% reduction was neither in the order of (α/β)x nor prescribed dose, but both comparably contributed to the repair effect. The variation of HC was within the range of 0.5% for all cases; therefore, the dose distribution was not distorted. The reduction in biological dose caused by the SLD repair largely depends on the cell-specific parameters in addition to the physical dose. The parameters should be considered carefully in the evaluation of the repair effect in prolonged proton irradiation.

Monte Carlo simulations and dose measurements of 2D range-modulators for scanned particle therapy

This paper introduces the concept of a 2D range-modulator as a static device for generating spread-out Bragg peaks at very small distances to the target. The 2D range-modulator has some distinct advantages that can be highly useful for different research projects in particle therapy facilities. Most importantly, it creates an instantaneous, quasi-static irradiation field with only one energy, thus decreasing irradiation time tremendously. In addition, it can be manufactured fast and cost efficiently and its SOBP width and shape can be adjusted easily for the specific purpose/experiment. As the modulator is a static element, there is no need for rotation (e.g. like in a modulation wheel) or lateral oscillation and due to the small base structure period it can be positioned close to the target.Two different rapid prototyping manufacturing techniques were utilized. The modulation properties of one polymer and one steel modulator were investigated with both simulations and measurements. For this purpose, a sophisticated water phantom system (WERNER), that can perform fast, completely automated and high resolution dose measurements, was developed. Using WERNER, the dose distribution of a modulator can be verified quickly and reliably, both during experiments, as well as in a time constrained clinical environment.The maximum deviation between the Monte Carlo simulations and dose measurements in the spread-out Bragg peak region was 1.4% and 4% for the polymer and steel modulator respectively. They were able to create spread-out Bragg peaks with a high degree of dose homogeneity, thus validating the whole process chain, from the mathematical optimization and modulator development, to manufacturing, MC simulations and dose measurements.Combining the convenience, flexibility and cost-effectiveness of rapid prototyping with the advantages of highly customizable modulators, that can be adapted for different experiments, the 2D range-modulator is considered a very useful tool for a variety of research objectives. Moreover, we have successfully shown that the manufacturing of 2D modulators with high quality and high degree of homogeneity is possible, paving the way for the further development of the more complex 3D range-modulators, which are considered a viable option for the very fast treatment of moving targets and/or FLASH irradiation.

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

IntroductionThe increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia. MethodsThe RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO2) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO2 ranging from strongly hypoxic to normoxic (0.01–30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO2 estimated voxel-by-voxel using [18F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations. ResultsThe SOBP in water had decreasing ROWD with decreasing pO2. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE1.1-weighted doses. ConclusionWe realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO2 and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.

Ramipril reduces incidence and prolongates latency time of radiation-induced rat myelopathy after photon and carbon ion irradiation.

To test the hypothesis that the use of an angiotensin-converting enzyme inhibitor (ACEi) during radiotherapy may be ameliorative for treatment-related normal tissue damage, a pilot study was conducted with the clinically approved (ACE) inhibitor ramipril on the outcome of radiation-induced myelopathy in the rat cervical spinal cord model. Female Sprague Dawley rats were irradiated with single doses of either carbon ions (LET 45 keV/μm) at the center of a 6 cm spread-out Bragg peak (SOBP) or 6 MeV photons. The rats were randomly distributed into 4 experimental arms: (i) photons; (ii) photons + ramipril; (iii) carbon ions and (iv) carbon ions + ramipril. Ramipril administration (2 mg/kg/day) started directly after irradiation and was maintained during the entire follow-up. Complete dose-response curves were generated for the biological endpoint radiation-induced myelopathy (paresis grade II) within an observation time of 300 days. Administration of ramipril reduced the rate of paralysis at high dose levels for photons and for the first time a similar finding for high-LET particles was demonstrated, which indicates that the effect of ramipril is independent from radiation quality. The reduced rate of myelopathy is accompanied by a general prolongation of latency time for photons and for carbon ions. Although the already clinical approved drug ramipril can be considered as a mitigator of radiation-induced normal tissue toxicity in the central nervous system, further examinations of the underlying pathological mechanisms leading to radiation-induced myelopathy are necessary to increase and sustain its mitigative effectiveness.

A Monte Carlo‐based analytic model of neutron dose equivalent for a mevion gantry‐mounted passively scattered proton system for craniospinal irradiation

To calculate in- and out-of-field neutron spectra and dose equivalent, using Monte Carlo (MC) simulation, for a Mevion gantry-mounted passively scattered proton system in craniospinal irradiation. An analytical model based on the MC calculations that estimates in- and out-of-field neutron dose equivalent from proton Craniospinal irradiation (CSI) was also developed. The MCNPX MC code was used to simulate a Mevion S250 proton therapy system. The simulated proton depth doses and profiles for pristine and spread-out Bragg peaks were benchmarked against the measured data. Previous measurements using extended-range Bonner spheres were used to verify the calculated neutron spectra and dose equivalent. Using the benchmarked results as a reference condition, a correction-based analytical model was reconstructed by fitting the data to derive model parameters at 95% confidence interval. Sensitivity analysis of brass aperture opening, thickness of the Lucite (PMMA) range compensator, and modulation width was performed to obtain correction parameters for nonreference conditions. For the neutron dose equivalent per therapeutic proton dose, the MCNPX calculated dose equivalent matched the measured values to within 8%. The benchmarked neutron dose equivalent at the isocenter was 41.2 and 20.8mSv/Gy, for cranial and spinal fields, respectively. For in- and out-of-field neutron dose calculations, the correction-based analytical model showed up to 17% discrepancy compared to the MC calculations. The correction factors may provide a conservative estimation of neutron dose, especially for depth≤5cm and regions underneath the brass aperture. The proposed analytical model can be used to estimate the contribution of the neutron dose to the overall CSI treatment dose. Moreover, the model can be employed to estimate the neutron dose to the implantable cardiac electronic devices.

Design and Optimization Based on Monte Carlo Method of a Range Shifter for Proton Therapy

A proton therapy facility based on an isochronous superconducting cyclotron is under constructed at the Proton Therapy Facility of the Huazhong University of Science and Technology. Due to the limitation of minimum energy extracted by the energy selection system in the upstream beamline, a range shifter is installed at the end of the nozzle to further decrease the proton beam energy so that the shallow-seated tumors can be treated. In this paper, the physical structure, energy degradation scheme, and material optimization selection of the range shifter are discussed and analyzed by Monte Carlo simulation software Geant4 and FLUKA. At the same time, the treatment outcome on the energy degradation process and its influence on the synthesis of spread-out Bragg peak (SOBP) in the treatment plan system after the application of the range shifter are analyzed. The results show that by using a high-density polyethylene energy-degrading plate with a thickness of 42.35 mm, combined with two 30-mm copper collimators, the range shifter can achieve a good energy-degradation effect while significantly reducing the beam horizontal penumbra at the edge of the radiation field. At the same time, the addition of the range shifter can reduce the number of the energy level required to form the SOBP and shorten the treatment time, but it will inevitably lead to a slight increase in the longitudinal penumbra.

Assessment of RBE-Weighted Dose Models for Carbon Ion Therapy Toward Modernization of Clinical Practice at HIT: In Vitro, in Vivo, and in Patients

Present-day treatment planning in carbon ion therapy is conducted with assumptions for a limited number of tissue types and models for effective dose. Here, we comprehensively assess relative biological effectiveness (RBE) in carbon ion therapy and associated models toward the modernization of current clinical practice in effective dose calculation. Using 2 human (A549, H460) and 2 mouse (B16, Renca) tumor cell lines, clonogenic cell survival assay was performed for examination of changes in RBE along the full range of clinical-like spread-out Bragg peak (SOBP) fields. Prediction power of the local effect model (LEM1 and LEM4) and the modified microdosimetric kinetic model (mMKM) was assessed. Experimentation and analysis were carried out in the frame of a multidimensional end point study for clinically relevant ranges of physical dose (D), dose-averaged linear energy transfer (LETd), and base-line photon radio-sensitivity (α/β)x. Additionally, predictions were compared against previously reported RBE measurements invivo and surveyed in patient cases. RBE model prediction performance varied among the investigated perspectives, with mMKM prediction exhibiting superior agreement with measurements both invitro and invivo across the 3 investigated end points. LEM1 and LEM4 performed their best in the highest LET conditions but yielded overestimations and underestimations in low/midrange LET conditions, respectively, as demonstrated by comparison with measurements. Additionally, the analysis of patient treatment plans revealed substantial variability across the investigated models (±20%-30% uncertainty), largely dependent on the selected model and absolute values for input tissue parameters αx and βx. RBE dependencies invitro, invivo, and in silico were investigated with respect to various clinically relevant end points in the context of tumor-specific tissue radio-sensitivity assignment and accurate RBE modeling. Discovered model trends and performances advocate upgrading current treatment planning schemes in carbon ion therapy and call for verification via clinical outcome analysis with large patient cohorts.