LET Distributions Research Articles

Secondary cancer risk in six anatomical sites when using PAT, IMPT, and VMAT/IMRT radiotherapy

Background and purposeCompared to intensity modulated proton therapy (IMPT), proton arc therapy (PAT) is expected to improve dose conformality, delivery efficiency, and provide a more favorable LET distribution. Alternatively, the low-dose bath is potentially spread over larger volumes, which could impact the likelihood of developing a radiation-induced, secondary cancer (SC). The goal of this study was to evaluate this risk in several anatomical sites using newly developed commercial tools. Materials and methodsTreatment plans encompassing six anatomical sites, five patients per site, and three techniques per patient were created using RayStation. Techniques included PAT and IMPT for protons, and either volumetrically modulated radiotherapy (VMAT) or intensity modulated radiotherapy (IMRT) for photons. Risk estimates were based on the organ-equivalent dose (OED) concept using both Schneider’s mechanistic dose–response model for carcinoma induction and a linear dose–response model. ResultsWith few exceptions, mean and integral dose were lowest with PAT. For protons, the factor OEDIMPT/OEDPAT ranged from 0.7 to 1.8 with both the mechanistic and linear model, while for photons OEDphoton/OEDPAT ranged from 1.5 to 10 using the mechanistic model and 1.3 to using the linear model. A strong correlation was found between mean dose and OED for organs with significant repopulation/repair (high R value) and less cell death from single hit interactions (low α value). ConclusionBased on results from both mechanistic and linear risk models, the transition from IMPT to PAT should not substantially affect SC risk in patients treated with proton therapy. Additionally, when using Schneider’s model, the shapes of the dose–response curves can be used as a good predictor of how SC risk will respond to shifts from intermediate dose to low dose as anticipated when moving from IMPT to PAT.

Optically stimulated luminescence dosimeters for simultaneous measurement of point dose and dose-weighted LET in an adaptive proton therapy workflow.

To demonstrate the suitability of optically stimulated luminescence detectors (OSLDs) for accurate simultaneous measurement of the absolute point dose and dose-weighted linear energy transfer (LETD) in an anthropomorphic phantom for experimental validation of daily adaptive proton therapy. A clinically realistic intensity-modulated proton therapy (IMPT) treatment plan was created based on a CT of an anthropomorphic head-and-neck phantom made of tissue-equivalent material. The IMPT plan was optimized with three fields to deliver a uniform dose to the target volume covering the OSLDs. Different scenarios representing inter-fractional anatomical changes were created by modifying the phantom. An online adaptive proton therapy workflow was used to recover the daily dose distribution and account for the applied geometry changes. To validate the adaptive workflow, measurements were performed by irradiating Al2O3:C OSLDs inside the phantom. In addition to the measurements, retrospective Monte Carlo simulations were performed to compare the absolute dose and dose-averaged LET (LETD) delivered to the OSLDs. The online adaptive proton therapy workflow was shown to recover significant degradation in dose conformity resulting from large anatomical and positioning deviations from the reference plan. The Monte Carlo simulations were in close agreement with the OSLD measurements, with an average relative error of 1.4% for doses and 3.2% for LETD. The use of OSLDs for LET determination allowed for a correction for the ionization quenched response. The OSLDs appear to be an excellent detector for simultaneously assessing dose and LET distributions in proton irradiation of an anthropomorphic phantom. The OSLDs can be cut to almost any size and shape, making them ideal for in-phantom measurements to probe the radiation quality and dose in a predefined region of interest. Although we have presented the results obtained in the experimental validation of an adaptive proton therapy workflow, the same approach can be generalized and used for a variety of clinical innovations and workflow developments that require accurate assessment of point dose and/or average LET.

Effects of nuclear interaction corrections and trichrome fragment spectra modelling on dose and linear energy transfer distributions in carbon ion radiotherapy

Background and PurposeNuclear interaction correction (NIC) and trichrome fragment spectra modelling improve relative biological effectiveness-weighted dose (DRBE) and dose-averaged linear energy transfer (LETd) calculation for carbon ions. The effect of those novel approaches on the clinical dose and LET distributions was investigated. Materials and MethodsThe effect of the NIC and trichrome algorithm was assessed, creating single beam plans for a virtual water phantom with standard settings and NIC + trichrome corrections. Reference DRBE and LETd distributions were simulated using FLUKA version 2021.2.9. Thirty clinically applied scanned carbon ion treatment plans were recalculated applying NIC, trichrome and NIC + trichrome corrections, using the LEM low dose approximation and compared to clinical plans (base RS). Four treatment sites were analysed: six prostate adenocarcinoma, ten head and neck, nine locally advanced pancreatic adenocarcinoma and five sacral chordoma. The FLUKA and clinical plans were compared in terms of DRBE deviations for D98%, D50%, D2% for the clinical target volume (CTV) and D50% in ring-like dose regions retrieved from isodose curves in base RS plans. Additionally, region-based median LETd deviations and global gamma parameters were evaluated. ResultsDose deviations comparing baseRS and evaluation plans were within ± 1% supported by γ-pass rates over 97% for all cases. No significant LETd deviations were reported in the CTV, but significant median LETd deviations were up to 80% for very low dose regions. ConclusionOur results showed improved accuracy of the predicted DRBE and LETd. Considering clinically relevant constraints, no significant modifications of clinical protocols are expected with the introduction of NIC + trichrome.

Planning Strategy to Optimize the Dose-Averaged LET Distribution in Large Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

To improve outcomes in large sarcomas/chordomas treated with CIRT, there has been recent interest in LET optimization. We evaluated 22 pelvic sarcoma/chordoma patients treated with CIRT [large: HD-CTV ≥ 250 cm3 (n = 9), small: HD-CTV < 250 cm3 (n = 13)], DRBE|LEM-I = 73.6 (70.4-73.6) Gy (RBE)/16 fractions, using the local effect model-I (LEM-I) optimization and modified-microdosimetric kinetic model (mMKM) recomputation. We observed that to improve high-LETd distribution in large tumors, at least 27 cm3 (low-LETd region) of HD-CTV should receive LETd of ≥33 keV/µm (p < 0.05). Hence, LETd optimization using 'distal patching' was explored in a treatment planning setting (not implemented clinically yet). Distal-patching structures were created to stop beams 1-2 cm beyond the HD-PTV-midplane. These plans were reoptimized and DRBE|LEM-I, DRBE|mMKM, and LETd were recomputed. Distal patching increased (a) LETd50% in HD-CTV (from 38 ± 3.4 keV/µm to 47 ± 8.1 keV/µm), (b) LETdmin in low-LETd regions of the HD-CTV (from 32 ± 2.3 keV/µm to 36.2 ± 3.6 keV/µm), (c) the GTV fraction receiving LETd of ≥50 keV/µm, (from <10% to >50%) and (d) the high-LETd component in the central region of the GTV, without significant compromise in DRBE distribution. However, distal patching is sensitive to setup/range uncertainties, and efforts to ascertain robustness are underway, before routine clinical implementation.

Proton LET Optimization Via Iterative Convex Relaxation Method

If not optimized, the LET distribution can greatly impact normal tissue toxicity near tumor targets, because the LET often peaks at the distal edge of Bragg peak. LET optimization can account for biological effectiveness of protons during treatment planning, for minimizing biological proton dose and hot spots to normal tissues. However, the LET optimization is nonlinear and nonconvex to solve, which poses a great challenge in optimization. This work will develop an effective LET optimization method via iterative convex relaxation (ICR). In contrast to the generic nonlinear optimization method, such as Quasi-Newton (QN) method, that does not account for specific characteristics of LET optimization, ICR is tailored to LET modeling and optimization in order to effectively and efficiently solve the LET problem. Specifically, nonlinear dose-averaged LET term is iteratively linearized and becomes convex during ICR, while nonconvex dose-volume constraint and minimum-monitor-unit constraint are also handled by ICR, so that the solution for LET optimization is obtained by solving a sequence of convex and linearized convex subproblems. Since the high LET mostly occurs near the target, a 1cm normal-tissue expansion of clinical target volume (CTV) (excluding CTV), i.e., CTV1cm, is defined to as an auxiliary structure during treatment planning, where LET is minimized. ICR was validated in comparison with QN for abdomen, lung, and head-and-neck (HN) cases. ICR was effective for LET optimization, as ICR substantially reduced the LET and biological dose in CTV1cm the ring, with preserved dose conformality to CTV. Compared to QN, ICR had smaller LET, physical and biological dose in CTV1cm, and higher conformity index values; ICR was also computationally more efficient, which was about 3 times faster than QN. A lung case is presented in the table, where the quantities from top to bottom are computational time T (unit: second); total objective F, dose objective Fd and LET objective FL (unit: 10-3); conformity index for physical dose CId and biological dose CIb; mean LET L (unit: keV/μm), mean physical dose d and mean biological dose b (in ratio to prescription dose) for CTV1cm; mean LET L (unit: keV/μm), mean physical dose d and mean biological dose b (in ratio to prescription dose; unit: 10-1) for the heart. A LET-specific optimization method based on ICR has been developed for solving proton LET optimization, which has been shown to be more computationally efficient than generic nonlinear optimizer via QN, with better plan quality in terms of LET, biological and physical dose conformality.

A Molecular Approach to Characterize the Effects of Fluence, Fluence Rate and LET on Radiation Damage

Effects of fluence, fluence rate and LET on radiation damage are not resolved using traditional methods of measuring energy deposited by ionization events. The deficiency led to the use of empirical RBE factors in the clinical applications of particle therapy. The use of ionization dosimetry is similarly challenged when applied to development of radiation treatment at ultrahigh (FLASH) dose rate. This study reports a molecular method using plasmid DNA as a more comprehensive model for radiation dosimetry than ionization measurements. Aqueous solutions of purified supercoiled plasmid DNA, pUC19 (2686 bp), were prepared at different scavenging conditions and injected into 5x5x1 mm3 wells as detector elements. Irradiated samples were analyzed using base excision repair enzymes (Nth and Fpg) and gel electrophoresis to measure yields for DNA single and double strand breaks (SSB and DSB), and clustered lesions. The low LET characteristics of conventional radiation treatment was modeled using orthovoltage 150 kVp x-rays to deliver 2-110 Gy at 90 and 0.5 Gy/s. Higher LET irradiations in the range of 2 - 14 keV/μm were facilitated by measurements in the pristine Bragg peak region using synchrotron-produced 142.2 MeV protons to deliver dose at 2 - 160 Gy at 600 and 1 Gy/s. The DNA wells were inserted into a solid water equivalent phantom for proton irradiation. Only 4 wells could be positioned in the short Bragg peak region in water (∼ 2 cm). To alleviate the uncertainties due to rapidly varying dose and LET distributions, we innovated the use of a 3% water density (i.e., Styrofoam) medium to extend the Bragg peak region from 2 cm to 20 cm, enabling the placement of 20 well containers. Quantity and quality of molecular damage in the plasmid DNA model varies with fluence, fluence rate and LET of radiation. At high fluence (> 30 Gy) of low-LET radiations, the yields of DNA SSB and non-DSB clustered lesions depend on the fluence rate. These yields decrease by two times between ultrahigh and conventional dose rate irradiation. At a given fluence and fluence rate, the yields for the formation of DNA DSB and non-DSB clustered lesions increase linearly with LET. The low-density phantom allows significant (∼ 10 folds) increase in the number of sampling points and more accurate sample positioning at specific LET compared to water-equivalent phantom. Monte-Carlo track structure simulation of yields for different DNA lesions is being developed to model the molecular damage. In parallel, approaches to improve the sensitivity of the measurements to dose are being investigated. Our results suggest that a molecular-based approach can be used to differentiate the effects of fluence, fluence rate, and LET on radiation damage. The approach demonstrates the potential to improve on the modeling of radiation effects in biological systems than using measured ionization energy. Correlation of the molecular changes to biological outcome for in vitro and in vivo systems are under investigation.

PO-1946 Measurement of LET distributions by CR-39 for a carbon ion beam in the microporous structure

PO-1946 Measurement of LET distributions by CR-39 for a carbon ion beam in the microporous structure

Modeling of dose and linear energy transfer homogeneity in cell nuclei exposed to alpha particles under various setup conditions

Purpose Different alpha exposure setups are often used to study the relation between biological responses and LET. This study aimed to estimate the dose heterogeneity and uncertainty in four exposure setups using Geant4 and PARTRAC codes. The importance of the irradiation system characteristics was shown in the context of reporting experimental results, especially in radiobiological studies at the molecular level. Materials and methods Geant4 was used to estimate the dose distributions in cells grown on a disk exposed to alpha particles penetrating from above and below. The latter setup was simulated without and with a collimator. PARTRAC was used for the validation of Geant4 simulations based on distributions of the number of alpha particles penetrating a round nucleus and the deposited energy. Results The LET distributions obtained for simulated setups excluding the collimator were wide and non-Gaussian. Using a collimator resulted in a Gaussian LET distribution, but strongly reduced dose rate and dose homogeneity. Comparison between PARTRAC and Geant4 calculations for the cell nucleus exposed to alpha radiation showed an excellent agreement. Conclusions The interpretation of results from radiobiological experiments with alpha particles should always cover the characteristics of the experimental setup, which can be done precisely with computational methods.

Linear Energy Transfer and Relative Biological Effectiveness Investigation of Various Structures for a Cohort of Proton Patients With Brain Tumors

PurposeThe current knowledge on biological effects associated with proton therapy is limited. Therefore, we investigated the distributions of dose, dose-averaged linear energy transfer (LETd), and the product between dose and LETd (DLETd) for a patient cohort treated with proton therapy. Different treatment planning system features and visualization tools were explored. Methods and MaterialsFor a cohort of 24 patients with brain tumors, the LETd, DLETd, and dose was calculated for a fixed relative biological effectiveness value and 2 variable models: plan-based and phenomenological. Dose threshold levels of 0, 5, and 20 Gy were imposed for LETd visualization. The relationship between physical dose and LETd and the frequency of LETd hotspots were investigated. ResultsThe phenomenological relative biological effectiveness model presented consistently higher dose values. For lower dose thresholds, the LETd distribution was steered toward higher values related to low treatment doses. Differences up to 26.0% were found according to the threshold. Maximum LETd values were identified in the brain, periventricular space, and ventricles. An inverse relationship between LETd and dose was observed. Frequency information to the domain of dose and LETd allowed for the identification of clusters, which steer the mean LETd values, and the identification of higher, but sparse, LETd values. ConclusionsIdentifying, quantifying, and recording LET distributions in a standardized fashion is necessary, because concern exists over a link between toxicity and LET hotspots. Visualizing DLETd or dose × LETd during treatment planning could allow for clinicians to make informed decisions.

End-of-Range Radiobiology Effect on Phantosmia in Pediatric Proton Patients

<h3>Purpose/Objective(s)</h3> Reports of bad odors perceived during proton radiation delivery are common for patients receiving dose to the whole brain. Previous work has correlated the onset of the effect with the timing of dose delivery to the olfactory region. The increased LET in proton beams has been a suspected cause for some side effects observed in proton therapy. This work is examining the difference in LET distributions for whole brain fields delivered using pencil beam scanning. We investigate a potential correlation between LET in the olfactory region and the nasal cavity and incidence of phantosmia. <h3>Materials/Methods</h3> A cohort of eight patients previously treated with scanned proton beams was selected, such that half of patients reported odor during irradiation and half did not. All patients received whole brain irradiation, with varying histologies. For clinically delivered treatment plans the dose and LET distribution was computed using TOPAS. The region containing the olfactory bulb as well as the nasal cavity was contoured. LET and dose volume histograms were generated, and values computed to 95%, 50% and 2% of the structures' volume noted. The cohorts are examined for a correlation of these metrics to clinically observed symptoms. <h3>Results</h3> No statistically significant differences were found in dose or LET between the two patient cohorts for the olfactory bulb. In the nasal cavity, the differences in D95 and LET95 were statistically significant. D95 was slightly higher in patients who did report odor (16.4 +/- 5.1 cGy per fraction versus 11.7 +/- 4.4 cGy per fraction). LET95 was in fact slightly higher in the group without phantosmia (2.8 +/- 0.1 keV/micrometer versus 2.5 +/- 0.1 keV/micrometer). <h3>Conclusion</h3> Differences in all evaluated parameters are either statistically insignificant or very small. In this patient cohort we do not observe a correlation between elevated LET and phantosmia. The results indicate that treatment planning techniques modifying LET alone in an effort to alleviate the symptoms in patients may not be successful.

Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance.

Simple SummaryNormal tissue’s morbidity continues to limit the increase in the therapeutic index in radiation therapy. This study explores the potential advantages of combining proton arc therapy and proton minibeam radiation therapy, which have already individually shown a significant normal tissue’s sparing. This alliance aims to integrate the benefits of those techniques in a single approach.(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.

Compensating for beam modulation due to microscopic lung heterogeneities in carbon ion therapy treatment planning.

To predict and mitigate for the degradation in physical and biologically effective dose distributions of particle beams caused by microscopic heterogeneities in lungtissue. The TRiP98 treatment planning system was adapted to account for the beam-modulating effect of heterogeneous lung tissue in physical and biological inverse treatment planning. The implementation employs an analytical model that derives the degradation from the established "modulation power" parameter and the total water-equivalent thickness of lung parenchyma traversed by the beam. Beam modulation was reproduced through an on-the-fly convolution of the reference Bragg curve with Gaussian kernels depending on the modulation power of lung tissue (upstream). For biological doses, the degradation was determined by modulating dose-averaged , , and LET distributions. Carbon SOBP measurements behind lung substitute material were performed to validate the code. The implementation was then applied to a phantom and patientcase. Experimental results show the passage through a 20-cm Gammex LN300 slab led to a decrease in target coverage and broadening of the SOBP distal fall-off. However, dose coverage was regained through optimization. A good agreement between calculated and measured SOBPs was also found. In addition, a patient case study revealed a 3.2% decrease in D from degradation ( = 450 m), which was reduced to a 0.4% difference after optimization. Furthermore, widening of the RBE distribution beyond the target distal edge was observed. This implies an increased degradation in the biological dose, which could be harmful to healthy tissues distal to thetarget. This is the first implementation capable of compensating for lung dose perturbations, which is more effective than margin extensions. A larger patient study is needed to examine the observed modulation in the RBE distribution and judge the clinical relevance also in IMPT, where margins might prove insufficient to recover targetcoverage.

Next Evolutions in Particle Therapy: Spot-Scanning Hadron Arc (SHArc) Therapy

To develop and evaluate spot-scanning hadron arc (SHArc) therapy, the first arc delivery technique for both light and heavy ions, in different clinical scenarios.Robust treatment planning and biological optimization procedures were developed within a GPU-accelerated dose engine and treatment planning system, establishing a dedicated energy/spot/angle selection protocol for robust SHArc delivery. Initial tests were performed for three clinical particle beams (protons, helium, and carbon ions) on water-equivalent cylindrical phantoms for simple targets and clinical-like scenarios with an organ-at-risk (OAR) in proximity of the target to compare SHArc against reference conventional techniques using single and multi-field configurations. SHArc patient treatments were surveyed in various sites (head, H&N, thorax and pelvic region). Dosimetric and biological features were calculated and evaluated applying the modified microdosimetric kinetic model. To determine impact of LET variations within the tumor volume, a model for hypoxia-induced radio-resistance was developed and applied for particle therapy to investigate impact on effective dose.SHArc plans exhibited similar target coverage with unique treatment attributes and distributions compared to conventional planning, with carbon ions demonstrating the greatest potential for tumor control and normal tissue sparing among the arc techniques. All SHArc plans exhibited a low-dose bath outside the target volume with a reduced maximum dose in normal tissues compared to single and multi-field plans. Moreover, favorable LET distributions were possible with the SHArc approach with substantial increases in LETmax and volume containing high-LET components. Moreover, reductions of high-LET regions in normal tissues and OARs were observed compared to static treatment beam delivery.The first arc treatment delivery technique using helium and carbon ion beams is proposed. Evidence suggests that through arc delivery of high-LET particle beams, SHArc therapy may offer uniquely valuable clinical advantages both dosimetrical and biological. Robust SHArc treatments could potentially improve tumor control by overcoming tumor microenvironment resistance factors such as hypoxia induced radio-resistance, and reduce toxicity in critical structures by minimizing high-LET components.

FLUKA simulation of target fragmentation in proton therapy.

In proton therapy, secondary fragments are created in nuclear interactions of the beam with the target nuclei. The secondary fragments have low kinetic energies and high atomic numbers as compared to primary protons. Fragments have a high LET and deposit all their energy close to the generation point. For their characteristics, secondary fragments can alter the dose distribution and lead to an increase of RBE for the same delivered physical dose. Moreover, the radiobiological impact of target fragmentation is significant mostly in the region before the Bragg peak, where generally healthy tissues are present, and immediately after Bragg peak. Considering the high biological impact of those particles, especially in the case of healthy tissues or organs at risk, the inclusion of target fragmentation processes in the dose calculation of a treatment planning system can be relevant to improve the treatment accuracy and for this reason it is one of the major tasks of the MoVe IT project. In this study, Monte Carlo simulations were employed to fully characterize the mixed radiation field generated by target fragmentation in proton therapy. The dose averaged LET has been evaluated in case of a Spread Out Bragg Peak (SOBP). Starting from LET distribution, RBE has been evaluated with two different phenomenological models. In order to characterize the mixed radiation field, the production cross section has been evaluated by means of the FLUKA code. The future development of present work is to generate a MC database of fragments fluence to be included in TPS.

Impact of Multiple Beams on Plan Quality, Linear Energy Transfer Distribution, and Plan Robustness of Intensity Modulated Proton Therapy for Lung Cancer.

The increase of proton beam number might provide higher degrees of freedom in the optimization of intensity-modulated proton therapy planning. In this study, we aimed to quantitatively explore the potential benefits of the increased beam number, including dose volume histogram (DVH), linear energy transfer volume histogram, and DVH bandwidth metrics. Twelve patients with lung cancer are retrospectively selected. Four plans were created based on internal target volume (ITV) robust optimization for each patient using the RayStation treatment planning system. Four plans were generated using different numbers (three, five, seven, and nine) of evenly separated coplanar beams. The three-beam plan was considered as the reference plan. Biologically equivalent doses were calculated using both constant relative biological effectiveness (RBE) and variable RBE models, respectively. To evaluate plan quality, DVH metrics in the target [ITV: D2%, CI, HI] and organs-at-risk [Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were calculated using both RBE models. To evaluate LET distributions, LET volume histogram metrics [ITV LETmean and LET2%; Lung LETmean and LET2%; Heart LET2%; Spinal cord LET2%] were quantified. To evaluate plan robustness, the metrics using DVH bandwidth [ITV: D2%, D99%; Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were also reported. For plan quality, the increase of proton beam number resulted in fewer target hot spots, improved target dose conformity, improved target dose homogeneity, lower median-dose lung volume, and fewer hot spots in spinal cord. As to LET distributions, target mean LET increased significantly as the beam number increased to seven or more. Lung LET hot spots were significantly reduced with the increase of proton beams. With respect to plan robustness, the robustness of target dose coverage, target hot spots, and low-dose lung volume were improved, while the robustness of heart hot spots became worse as the beam number increased to nine. The robustness of cord hot spots became worse using five and seven beams compared to that using three beams. As the proton beam number increased, plan quality and LET distributions were comparable or significantly improved. The robustness of target dose coverage, target dose hot spots, and low-dose lung volume were significantly improved.

DICOM-RT Ion interface to utilize MC simulations in routine clinical workflow for proton pencil beam radiotherapy

To adopt Monte Carlo (MC) simulations as an independent dose calculation method for proton pencil beam radiotherapy, an interface that converts the plan information in DICOM format into MC components such as geometries and beam source is a crucial element. For this purpose, a DICOM-RT Ion interface (https://github.com/topasmc/dicom-interface) has been developed and integrated into the TOPAS MC code to perform such conversions on-the-fly. DICOM-RT objects utilized in this interface include Ion Plan (RTIP), Ion Beams Treatment Record (RTIBTR), CT image, and Dose. Beamline geometries, gantry and patient coordinate systems, and fluence maps are determined from RTIP and/or RTIBTR. In this interface, DICOM information is processed and delivered to a MC engine in two steps. A MC model, which consists of beamline geometries and beam source, to represent a treatment machine is created by a DICOM parser of the interface. The complexities from different DICOM types, various beamline configurations and source models are handled in this step. Next, geometry information and beam source are transferred to TOPAS on-the-fly via the developed TOPAS extensions. This interface with two treatment machines was successfully deployed into our automated MC workflow which provides simulated dose and LET distributions in a patient or a water phantom automatically when a new plan is identified. The developed interface provides novel features such as handling multiple treatment systems based on different DICOM types, DICOM conversions on-the-fly, and flexible sampling methods that significantly reduce the burden of handling DICOM based plan or treatment record information for MC simulations.

A new treatment planning approach accounting for prompt gamma range verification and interfractional anatomical changes

Prompt gamma (PG) imaging is widely investigated for spot-by-spot in vivo range verification for proton therapy. Previous studies pointed out that the accuracy of prompt gamma imaging is affected by the statistics (number of protons delivered per pencil beam) of the proton beams and the conformity between prompt gamma and dose distribution (PG-dose correlation). Recently a novel approach to re-optimize conventional treatment plans by boosting a few pencil beams with good PG-dose correlation above the statistics limit for reliable PG detectability was proposed. However, up to now, only PG-dose correlation on the planning computed tomography (CT) was considered, not accounting for the fact that the robustness of the PG-dose correlation is not guaranteed in the cases of interfractional anatomical changes. In this work, this approach is further explored with respect to the robustness of the PG-dose correlation of each pencil beam in the case of interfractional anatomical changes. A research computational platform, combining Monte Carlo pre-calculated pencil beams with the analytical Matlab-based treatment planning system (TPS) CERR, is used for treatment planning. Geant4 is used for realistic simulation of the dose delivery and PG generation for all individual pencil beams in the heterogeneous patient anatomy using multiple CT images for representative patient cases (in this work, CTs of one prostate and one head and neck cancer patient are used). First, a Monte Carlo treatment plan is created using CERR. Thereby the PG emission and dose distribution for each individual spot is obtained. Second, PG-dose correlation is quantified using the originally proposed approach as well as a new indicator, which accounts for the sensitivity of individual spots to heterogeneities in the 3D dose distribution. This is accomplished by using a 2D distal surface (dose surface) derived from the 3D dose distribution for each spot. A few pencil beams are selected for each treatment field, based on their PG-dose correlation and dose surface, and then boosted in the new re-optimized treatment plan. All treatment plans are then fully re-calculated with Monte Carlo on the CT scans of the corresponding patient at three different time points. The result shows that all treatment plans are comparable in terms of dose distribution and dose averaged LET distributions. The spots recommended by our indicators maintain good PG-dose correlation in the cases of interfractional anatomical changes, thus ensuring that the proton range shift due to anatomical changes can be monitored. Compared to another proposed spots aggregation approach, our approach shows advantages in terms of the detectability and reliability of PG, especially in presence of heterogeneities.

Heavy Ion Nuclear Reaction Impact on SEE Testing: From Standard to Ultra-high Energies

We perform Monte Carlo (MC) simulations to describe heavy ion (HI) nuclear interactions in a broad energy range (4 MeV/n-150 GeV/n), focusing on the single event effect (SEE) sub-linear energy transfer (LET) impact. Previously retrieved single event latch-up (SEL) experimental data have indicated that standard energy ions (~10 MeV/n) can produce high-LET secondaries through fusion reactions which are expected to strongly influence the SEE cross section in the sub-LET region. Alternatively, interactions of higher energy ions (>100 MeV/n) yield secondaries of a similar LET distribution as from the projectile, for projectile-like fragments, and high-energy proton reactions, for target-like fragments. Hence, the factor of relevance to the sub-LET SEE cross section is correlated to low-energy.

Sensitivity analysis of Monte Carlo model of a gantry‐mounted passively scattered proton system

PurposeThis study aimed to present guidance on the correlation between treatment nozzle and proton source parameters, and dose distribution of a passive double scattering compact proton therapy unit, known as Mevion S250.MethodsAll 24 beam options were modeled using the MCNPX MC code. The calculated physical dose for pristine peak, profiles, and spread out Bragg peak (SOBP) were benchmarked with the measured data. Track‐averaged LET (LETt) and dose‐averaged LET (LETd) distributions were also calculated. For the sensitivity investigations, proton beam line parameters including Average Energy (AE), Energy Spread (ES), Spot Size (SS), Beam Angle (BA), Beam Offset (OA), and Second scatter Offset (SO) from central Axis, and also First Scatter (FS) thickness were simulated in different stages to obtain the uncertainty of the derived results on the physical dose and LET distribution in a water phantom.ResultsFor the physical dose distribution, the MCNPX MC model matched measurements data for all the options to within 2 mm and 2% criterion. The Mevion S250 was found to have a LETt between 0.46 and 8.76 keV.μm–1 and a corresponding LETd between 0.84 and 15.91 keV.μm–1. For all the options, the AE and ES had the greatest effect on the resulting depth of pristine peak and peak‐to‐plateau ratio respectively. BA, OA, and SO significantly decreased the flatness and symmetry of the profiles. The LETs were found to be sensitive to the AE, ES, and SS, especially in the peak region.ConclusionsThis study revealed the importance of considering detailed beam parameters, and identifying those that resulted in large effects on the physical dose distribution and LETs for a compact proton therapy machine.

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.