Proton Dose Research Articles

Beam mask and sliding window-facilitated deep learning-based accurate and efficient dose prediction for pencil beam scanning proton therapy.

Accurate and efficient dose calculation is essential for on-line adaptive planning in proton therapy. Deep learning (DL) has shown promising dose prediction results in photon therapy. However, there is a scarcity of DL-based dose prediction methods specifically designed for proton therapy. Successful dose prediction method for proton therapy should account for more challenging dose prediction problems in pencil beam scanning proton therapy (PBSPT) due to its sensitivity to heterogeneities. To develop a DL-based PBSPT dose prediction workflow with high accuracy and balanced complexity to support on-line adaptive proton therapy clinical decision and subsequent replanning. PBSPT plans of 103 prostate cancer patients (93 for training and the other 10 for independent testing) and 83 lung cancer patients (73 for training and the other 10 for independent testing) previously treated at our institution were included in the study, each with computed tomography scans (CTs), structure sets, and plan doses calculated by the in-house developed Monte-Carlo dose engine (considered as the ground truth in the model training and testing). For the ablation study, we designed three experiments corresponding to the following three methods: (1) Experiment 1, the conventional region of interest (ROI) (composed of targets and organs-at-risk [OARs]) method. (2) Experiment 2, the beam mask (generated by raytracing of proton beams) method to improve proton dose prediction. (3) Experiment 3, the sliding window method for the model to focus on local details to further improve proton dose prediction. A fully connected 3D-Unet was adopted as the backbone. Dose volume histogram (DVH) indices, 3D Gamma passing rates with a criterion of 3%/3mm/10%, and dice coefficients for the structures enclosed by the iso-dose lines between the predicted and the ground truth doses were used as the evaluation metrics. The calculation time for each proton dose prediction was recorded to evaluate the method's efficiency. Compared to the conventional ROI method, the beam mask method improved the agreement of DVH indices for both targets and OARs and the sliding window method further improved the agreement of the DVH indices (for lung cancer, CTV D98 absolute deviation: 0.74 ± 0.18 vs. 0.57 ± 0.21 vs. 0.54 ± 0.15 Gy[RBE], ROI vs. beam mask vs. sliding window methods, respectively). For the 3D Gamma passing rates in the target, OARs, and BODY (outside target and OARs), the beam mask method improved the passing rates in these regions and the sliding window method further improved them (for prostate cancer, targets: 96.93% ± 0.53% vs. 98.88% ± 0.49% vs. 99.97% ± 0.07%, BODY: 86.88% ± 0.74% vs. 93.21% ± 0.56% vs. 95.17% ± 0.59%). A similar trend was also observed for the dice coefficients. This trend was especially remarkable for relatively low prescription isodose lines (for lung cancer, 10% isodose line dice: 0.871 ± 0.027 vs. 0.911 ± 0.023 vs. 0.927 ± 0.017). The dose predictions for all the testing cases were completed within 0.25s. An accurate and efficient deep learning-augmented proton dose prediction framework has been developed for PBSPT, which can predict accurate dose distributions not only inside but also outside ROI efficiently. The framework can potentially further reduce the initial planning and adaptive replanning workload in PBSPT.

Influence of proton irradiation on the magnetic properties of two-dimensional Ni(II) molecular magnet

The influence of 1.9 MeV proton irradiation on structural and magnetic properties has been explored in the two-dimensional (2D) NiSO4(1,3-phenylenediamine)2 coordination ferrimagnet. The X-ray powder diffraction and IR spectroscopy revealed that the octahedrons with Ni ion in the center remain unchanged regardless of the fluence a sample received. In contrast, proton irradiation greatly influences the hydrogen bonds in the flexible parts in which the 1,3-phenylenediamine is involved. Dc magnetic measurements revealed that several magnetic properties were modified with proton irradiation. The isothermal magnetization measured at T = 2.0 K varied with the proton dose, achieving a 50% increase in magnetization in the highest measured field µ0Hdc = 7 T or a 25% decrease in remanence. The most significant change was observed for the coercive field, which was reduced by 90% compared to the non-irradiated sample. The observed results are accounted for the increased freedom of magnetic moments rotation and the modification of intralayer exchange couplings.

An optimized framework for cone-beam computed tomography-based online evaluation for proton therapy.

Clinical evidence has demonstrated that proton therapy can achieve comparable tumor control probabilities compared to conventional photon therapy but with the added benefit of sparing healthy tissues. However, proton therapy is sensitive to inter-fractional anatomy changes. Online pre-fraction evaluation can effectively verify proton dose before delivery to patients, butthere is a lack of guidelines for implementing this workflow. The purpose of this study is to develop a cone-beam CT-based (CBCT) online evaluation framework for proton therapy that enables knowledge transparency and evaluates the efficiency and accuracy of each essential component. Twenty-three patients with various lesion sites were included to conduct a retrospective study of implementing the proposed CBCT evaluation framework for the clinic. The framework was implemented on the RayStation 11B Research platform. Two synthetic CT (sCT) methods, corrected CBCT (cCBCT), and virtual CT (vCT), were used, and the ground truth images were acquired from the same-day deformed quality assurance CT (dQACT) for the comparisons. The evaluation metrics for the framework include time efficiency, dose-difference distributions (gamma passing rates), and water equivalent thickness (WET) distributions. The mean online CBCT evaluation times were 1.6±0.3min and 1.9±0.4min using cCBCT and vCT, respectively. The dose calculation and deformable image registration dominated the evaluation efficiency, and accounted for 33% and 30% of the total evaluation time, respectively. The sCT generation took another 19% of the total time. Gamma passing rates were greater than 91% and 97% using 1%/1mm and 2%/2mm criteria, respectively. When the appropriate sCT was chosen, the target mean WET difference from the reference were less than 0.5mm. The appropriate sCT method choice determined the uncertainty for the framework, with the cCBCT being superior for head-and-neck patient evaluation and vCT being better for lung patient evaluation. An online CBCT evaluation framework was proposed to identify the use of the optimal sCT algorithm regarding efficiency and dosimetry accuracy. The framework is extendable to adopt advanced imaging methods and has the potential to support online adaptive radiotherapy to enhance patient benefits.It could be implemented into clinical use in the future.

A simulation study of in-beam visualization system for proton therapy by monitoring scattered protons.

Recently, in-beam positron emission tomography (PET) has been actively researched for reducing biological washout effects and dose monitoring during irradiation. However, the positron distribution does not precisely reflect the dose distribution since positron production and ionization are completely different physical processes. Thus, a novel in-beam system was proposed to determine proton dose range by measuring scattered protons with dozens of scintillation detectors surrounding the body surface. While previous studies conducted a preliminary experiment with a simple phantom, we simulated more complex situations in this paper. Especially, we conducted three stepwise simulation studies to demonstrate the feasibility of the proposed method. First, a simple rectangular phantom was reproduced on simulation and irradiated with protons for obtaining current values and Monte Carlo (MC) dose. Next, we trained a deep learning model to estimate 2-dimensional-dose range (2D-DL dose) from measured current values for simulation (A). We simulated plastic scintillators as detectors to measure the scattered protons. Second, a rectangular phantom with an air layer was used, and 3D-DL dose was estimated in simulation (B). Finally, a cylindrical phantom that mimics the human body was used for confirming the estimation quality of the simulation (C). Consequently, the position of the Bragg peak was estimated with an error of 1.0 mm in simulation (A). In addition, the position of the air layer, as well as the verifying peak position with an error of 2.1 mm, was successfully estimated in simulation (B). Although the estimation error of the peak position was 12.6 mm in simulation (C), the quality was successfully further improved to 9.3 mm by incorporating the mass density distribution obtained from the computed tomography (CT). These simulation results demonstrated the potential of the as-proposed verification system. Additionally, the effectiveness of CT utilization for estimating the DL dose was also indicated.

Investigation on the proton range uncertainty with spectral CT-based virtual monoenergetic images.

The stopping power ratio (SPR) prediction error will contribute to the range uncertainty of proton therapy. Spectral CT is promising in reducing the uncertainty in SPR estimation. The purpose of this research is to determine the optimal energy pairs of SPR prediction for each tissue and to evaluate the dose distribution and range difference between the spectral CT with the optimal energy pairs method and the single energy CT (SECT) method. A new method was proposed based on image segmentation to calculate the proton dose with spectral CT images for the head and body phantom. CT number of each organ region were converted to SPR with the optimal energy pairs of each organ. The CT images were segmented into different organ parts with thresholding method. Virtual monoenergetic (VM) images from 70keV to 140keV were investigated to determine the optimal energy pairs for each organ based on Gammex 1467 phantom. The beam data of Shanghai Advanced Proton Therapy facility (SAPT) was employed in matRad (an open-source software for radiation treatment planning) for the dose calculation. The optimal energy pairs were obtained for each tissue. The dose distribution of two tumor sites (brain and lung) were calculated with the aforementioned optimal energy pairs. The maximum dose deviation between spectral CT and SECT at the target region was 2.57% and 0.84% for the lung tumor and brain tumor respectively. The range difference between spectral and SECT was significant with 1.8411mm for the lung tumor. γ passing rate was 85.95% and 95.49% for the lung tumor and brain tumor with the criterion 2%/2mm. This work presents a way to determine the optimal energy pairs for each organ and to calculate the dose distribution based on the more accurate SPR prediction.

Tailoring the Charge Carrier Lifetime Distribution of 10 kV SiC PiN Diodes by Physical Simulations

In this paper, Shockley-Read-Hall (SRH) lifetime depth profiles in the drift layer of 10 kV SiC PiN diodes are calculated after MeV proton implantation. It is assumed that the carbon vacancy will be the domination trap for charge carrier recombination and the SRH lifetime is calculated with defect parameters from the literature and proton-induced defect distributions deduced from SRIM calculations. The lifetime profiles are imported to Sentaurus TCAD and static and dynamic simulations using tailored lifetime profiles are carried out to study the electrical effect of proton implantation parameters. The results are compared to measurements, specializing on optimization of the trade off between on-state and turn-off losses, represented by the forward voltage drop, VT, and reverse recovery charge, Qrr, respectively. Both the simulated and measured IV characteristics show that increasing proton dose, or energy, has the effect on increasing forward voltage drop and on-state losses, while simultaneously, the localized SRH lifetime drop decreases the plasma level, increases the speed of recombination and decreases reverse recovery charge. Finally, TCAD simulations with different combinations of proton energies and fluences are used to optimize the trade-off between static and dynamic performances. Reverse recovery charge and forward voltage drops of these groups of diodes are plotted together, showing that a medium energy which induces the most defects in the depletion region relatively close to the anode gives the best dynamic performances, with a minimum cost of static performance.

Experimental dosimetric characterization of proton pencil beam distortion in a perpendicular magnetic field of an in-beam MR scanner.

As it promises more precise and conformal radiation treatments, magnetic resonance imaging-integrated proton therapy (MRiPT) is seen as a next step in image guidance for proton therapy. The Lorentz force, which affects the course of the proton pencil beams, presents a problem for beam delivery in the presence of a magneticfield. To investigate the influence of the 0.32-T perpendicular magnetic field of an MR scanner on the delivery of proton pencil beams inside an MRiPT prototypesystem. An MRiPT prototype comprising of a horizontal pencil beam scanning beam line and an open 0.32-T MR scanner was used to evaluate the impact of the vertical magnetic field on proton beam deflection and dose spot pattern deformation. Three different proton energies (100, 150, and 220 MeV) and two spot map sizes (15 × 15 and 30 × 20 cm2 ) at four locations along the beam path without and with magnetic field were measured. Pencil-beam dose spots were measured using EBT3 films and a 2D scintillation detector. To study the magnetic field effects, a 2D Gaussian fit was applied to each individual dose spot to determine the central position , minimum and maximum lateral standard deviation ( and ), orientation (θ), and the eccentricity (ε). The dose spots were subjected to three simultaneous effects: (a) lateral horizontal beam deflection, (b) asymmetric trapezoidal deformation of the dose spot pattern, and (c) deformation and rotation of individual dose spots. The strongest effects were observed at a proton energy of 100 MeV with a horizontal beam deflection of 14-186 mm along the beam path. Within the central imaging field of the MR scanner, the maximum relative dose spot size decreased by up to 3.66%, while increased by a maximum of 2.15%. The largest decrease and increase in the eccentricity of the dose spots were 0.08 and 0.02, respectively. The spot orientation θ was rotated by a maximum of 5.39°. At the higher proton energies, the same effects were still seen, although to a lesserdegree. The effect of an MRiPT prototype's magnetic field on the proton beam path, dose spot pattern, and dose spot form has been measured for the first time. The findings show that the impact of the MF must be appropriately recognized in a future MRiPT treatment planning system. The results emphasize the need for additional research (e.g., effect of magnetic field on proton beams with range shifters and impact of MR imaging sequences) before MRiPT applications can be employed to treat patients.

In Vivo Radiobiological Investigations with the TOP-IMPLART Proton Beam on a Medulloblastoma Mouse Model.

Protons are now increasingly used to treat pediatric medulloblastoma (MB) patients. We designed and characterized a setup to deliver proton beams for in vivo radiobiology experiments at a TOP-IMPLART facility, a prototype of a proton-therapy linear accelerator developed at the ENEA Frascati Research Center, with the goal of assessing the feasibility of TOP-IMPLART for small animal proton therapy research. Mice bearing Sonic-Hedgehog (Shh)-dependent MB in the flank were irradiated with protons to test whether irradiation could be restricted to a specific depth in the tumor tissue and to compare apoptosis induced by the same dose of protons or photons. In addition, the brains of neonatal mice at postnatal day 5 (P5), representing a very small target, were irradiated with 6 Gy of protons with two different collimated Spread-Out Bragg Peaks (SOBPs). Apoptosis was visualized by immunohistochemistry for the apoptotic marker caspase-3-activated, and quantified by Western blot. Our findings proved that protons could be delivered to the upper part while sparing the deepest part of MB. In addition, a comparison of the effectiveness of protons and photons revealed a very similar increase in the expression of cleaved caspase-3. Finally, by using a very small target, the brain of P5-neonatal mice, we demonstrated that the proton irradiation field reached the desired depth in brain tissue. Using the TOP-IMPLART accelerator we established setup and procedures for proton irradiation, suitable for translational preclinical studies. This is the first example of in vivo experiments performed with a "full-linac" proton-therapy accelerator.

GPU-based cross-platform Monte Carlo proton dose calculation engine in the framework of Taichi

GPU-based cross-platform Monte Carlo proton dose calculation engine in the framework of Taichi

MO-0480 Motion-induced proton dose change measured by 3D deformable dosimeters in an anthropomorphic phantom

MO-0480 Motion-induced proton dose change measured by 3D deformable dosimeters in an anthropomorphic phantom

OC-0775 Comprehensive proton dose prediction with Bayesian LSTMs

OC-0775 Comprehensive proton dose prediction with Bayesian LSTMs

Effectiveness of CT-image guidance in proton therapy for liver cancer and the importance of daily dose monitoring for tumors and organs at risk.

It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity. We evaluated the effectiveness of computed tomography (CT)-image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image-guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated. A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n=19) or 76 GyE/20 fractions (n=19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D99% , V30GyE , and Dmax for the tumor volumes, non-tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT-based tumor registrations (hereafter, "tumor registration") by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X-ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets. In the 66 GyE/10 fractions, the daily D99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%-6% (SD), and the V30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor-dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D99% in the tumor registration was superior to that in the other registration (p<0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re-planning. For three patients, the daily Dmax increased gradually or changed randomly, resulting in an inter-fractional averaged Dmax higher than the constraints. The dose distribution would have been improved if re-planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re-planning when needed. The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment.

Effects of proton irradiation-induced point defects on Shockley–Read–Hall recombination lifetimes in homoepitaxial GaN p–n junctions

This work examined the intentional generation of recombination centers in GaN p–n junctions on freestanding GaN substrates. Irradiation with a 4.2 MeV proton beam was used to create a uniform distribution of vacancies and interstitials across GaN p+/n− and p−/n+ junctions through anode electrodes. With increasing proton dose, the effective doping concentrations were found to be reduced. Because the reduction in the doping concentration was much higher than the hydrogen atom concentration, this decrease could not be attributed solely to carrier compensation resulting from interstitial hydrogen atoms. In fact, more than half of the electron and hole compensation was caused by the presence of point defects. These defects evidently served as Shockley–Read–Hall (SRH) recombination centers such that the SRH lifetimes were reduced to several picoseconds from several hundred picoseconds prior to irradiation. The compensation for holes in the p−/n+ junctions was almost double that for electrons in the p+/n− junctions. Furthermore, the SRH lifetimes associated with p−/n+ junctions were shorter than those for p+/n− junctions for a given proton dose. These differences can be explained by variations in the charge state and/or the formation energy of intrinsic point defects in the p-type and n-type GaN layers. The results of the present work indicate the asymmetry of defect formation in GaN based on the fact that intrinsic point defects in p-type GaN readily compensate for holes.

Scatter correction of 4D cone beam computed tomography to detect dosimetric effects due to anatomical changes in proton therapy for lung cancer.

The treatment of moving tumor entities is expected to have superior clinical outcomes, using image-guided adaptive intensity-modulated proton therapy (IMPT). For 21 lung cancer patients, IMPT dose calculations were performed on scatter-corrected 4D cone beam CTs (4DCBCTcor ) to evaluate their potential for triggering treatment adaptation. Additional dose calculations were performed on corresponding planning 4DCTs and day-of-treatment 4D virtual CTs (4DvCTs). A 4DCBCT correction workflow, previously validated on a phantom, generates 4DvCT (CT-to-CBCT deformable registration) and 4DCBCTcor images (projection-based correction using 4DvCT as a prior) with 10 phase bins, using day-of-treatment free-breathing CBCT projections and planning 4DCT images as input. Using a research planning system, robust IMPT plans administering eight fractions of 7.5 Gy were created on a free-breathing planning CT (pCT) contoured by a physician. The internal target volume (ITV) was overridden with muscle tissue. Robustness settings for range and setup uncertainties were 3% and 6 mm, and a Monte Carlo dose engine was used. On every phase of planning 4DCT, day-of-treatment 4DvCT, and 4DCBCTcor , the dose was recalculated. For evaluation, image analysis as well as dose analysis were performed using mean error (ME) and mean absolute error (MAE) analysis, dose-volume histogram (DVH) parameters, and 2%/2-mm gamma pass rate analysis. Action levels (1.6% ITV D98 and 90% gamma pass rate) based on our previous phantom validation study were set to determine which patients had a loss of dosimetriccoverage. Quality enhancements of 4DvCT and 4DCBCTcor over 4DCBCT were observed. ITV D98% and bronchi D2% had its largest agreement for 4DCBCTcor -4DvCT, and the largest gamma pass rates (>94%, median 98%) were found for 4DCBCTcor -4DvCT. Deviations were larger and gamma pass rates were smaller for 4DvCT-4DCT and 4DCBCTcor -4DCT. For five patients, deviations were larger than the action levels, suggesting substantial anatomical changes between pCT and CBCT projectionsacquisition. This retrospective study shows the feasibility of daily proton dose calculation on 4DCBCTcor for lung tumor patients. The applied method is of clinical interest as it generates up-to-date in-room images, accounting for breathing motion and anatomical changes. This information could be used to triggerreplanning.

Fraction optimization for hybrid proton-photon treatment planning.

Hybrid proton-photon radiotherapy (RT) can provide better plan quality than proton or photon only RT, in terms of robustness of target coverage and sparing of organs-at-risk (OAR). This work develops a hybrid treatment planning method that can optimize the number of proton and photon fractions as well as proton and photon plan variables, so that the hybrid plans can be clinically delivered day-to-day using either proton or photon machine. In the new hybrid treatment planning method, the total dose distribution (sum of proton dose and photon dose) is optimized for robust target coverage and optimal OAR sparing, by jointly optimizing proton spots and photon fluences, while the target dose uniformity is also enforced individually on both proton dose and photon dose, so that the hybrid plans can be separately and robustly delivered on proton or photon machine. To ensure the target dose uniformity for proton and photon plans, the number of proton and photon fractions is explicitly modeled and optimized, so that the target dose for proton and photon dose components is constrained to be a constant fraction of the total prescription dose while the plan quality based on total dose is optimized. The feasibility of hybrid planning using the proposed method is validated with representative clinical cases including abdomen, lung, head-and-neck (HN), and brain. For all cases, hybrid plans provided better overall plan quality and OAR sparing than proton-only or photon-only plans, better target dose uniformity and robustness than proton-only plans, quantified by treatment planning objectives and dosimetric parameters. Moreover, for HN and brain cases, hybrid plans also had better target coverage than photon-only plans. We have developed a new hybrid treatment planning method that optimizes number of proton and photon fractions as well as proton spots and photon fluences, for generating hybrid plans that can be separately and robustly delivered on proton or photon machines. Preliminary results have demonstrated that hybrid plans generated by the new method have better plan quality than proton-only or photon-only plans.

Clinical 3D/4D cumulative proton dose assessment methods for thoracic tumours with large motion

PurposeDespite the anticipated clinical benefits of intensity-modulated proton therapy (IMPT), plan robustness may be compromised due to its sensitivity to patient treatment uncertainties, especially for tumours with large motion. In this study, we investigated treatment course-wise plan robustness for intra-thoracic tumours with large motion comparing a 4D pre-clinical evaluation method (4DREM) to our clinical 3D/4D dose reconstruction and accumulation methods. Materials and methodsTwenty patients with large target motion (>10 mm) were treated with five times layered rescanned IMPT. The 3D-robust optimised plans were generated on the averaged planning 4DCT. Using multiple 4DCTs, treatment plan robustness was assessed on a weekly and treatment course-wise basis through the 3D robustness evaluation method (3DREM, based on averaged 4DCTs), the 4D robustness evaluation method (4DREM, including the time structure of treatment delivery and 4DCT phases) and 4D dose reconstruction and accumulation (4DREAL, based on fraction-wise information). ResultsBaseline target motion for all patients ranged from 11–17 mm. For the offline adapted course-wise dose assessment, adequate target dose coverage was found for all patients. The target volume receiving 95% of the prescription dose was consistent between methods with 16/20 patients showing differences < 1%. 4DREAL showed the highest target coverage (99.8 ± 0.6%, p < 0.001), while no differences were observed between 3DREM and 4DREM (99.3 ± 1.3% and 99.4 ± 1.1%, respectively). ConclusionOur results show that intra-thoracic tumours can be adequately treated with IMPT in free breathing for target motion amplitudes up to 17 mm employing any of the accumulation methods. Anatomical changes, setup and range errors demonstrated a more severe impact on target coverage than motion in these patients treated with fractionated proton radiotherapy.

Investigating the potential contribution of inter-track interactions within ultra-high dose-rate proton therapy

Objective. Laser-accelerated protons offer an alternative delivery mechanism for proton therapy. This technique delivers dose-rates of ≥109 Gy s−1, many orders of magnitude greater than used clinically. Such ultra-high dose-rates reduce delivery time to nanoseconds, equivalent to the lifetime of reactive chemical species within a biological medium. This leads to the possibility of inter-track interactions between successive protons within a pulse, potentially altering the yields of damaging radicals if they are in sufficient spatial proximity. This work investigates the temporal evolution of chemical species for a range of proton energies and doses to quantify the circumstances required for inter-track interactions, and determine any relevance within ultra-high dose-rate proton therapy. Approach. The TOPAS-nBio Monte Carlo toolkit was used to investigate possible inter-track interactions. Firstly, protons between 0.5 and 100 MeV were simulated to record the radial track dimensions throughout the chemical stage from 1 ps to 1 μs. Using the track areas, the geometric probability of track overlap was calculated for various exposures and timescales. A sample of irradiations were then simulated in detail to compare any change in chemical yields for independently and instantaneously delivered tracks, and validate the analytic model. Main results. Track overlap for a clinical 2 Gy dose was negligible for biologically relevant timepoints for all energies. Overlap probability increased with time after irradiation, proton energy and dose, with a minimum 23 Gy dose required before significant track overlap occurred. Simulating chemical interactions confirmed these results with no change in radical yields seen up to 8 Gy for independently and instantaneously delivered tracks. Significance. These observations suggest that the spatial separation between incident protons is too large for physico-chemical inter-track interactions, regardless of the delivery time, indicating such interactions would not play a role in any potential changes in biological response between laser-accelerated and conventional proton therapy.

An iterative convex relaxation method for proton LET optimization

Objective: A constant relative biological effectiveness of 1.1 in current clinical practice of proton radiotherapy (RT) is a crude approximation and may severely underestimate the biological dose from proton RT to normal tissues, especially near the treatment target at the end of Bragg peaks that exhibits high linear energy transfer (LET). 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 usually nonlinear and nonconvex to solve, for which this work will develop an effective optimization method based on iterative convex relaxation (ICR). Approach: 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 1 cm 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. Main results: ICR was validated in comparison with QN for abdomen, lung, and head-and-neck 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. Significance: 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.

Single pulse protoacoustic range verification using a clinical synchrocyclotron

Objective. Proton therapy as the next generation radiation-based cancer therapy offers dominant advantages over conventional radiation therapy due to the utilization of the Bragg peak; however, range uncertainty in beam delivery substantially mitigates the advantages of proton therapy. This work reports using protoacoustic measurements to determine the location of proton Bragg peak deposition within a water phantom in real time during beam delivery. Approach. In protoacoustics, proton beams have a definitive range, depositing a majority of the dose at the Bragg peak; this dose is then converted to heat. The resulting thermoelastic expansion generates a 3D acoustic wave, which can be detected by acoustic detectors to localize the Bragg peak. Main results. Protoacoustic measurements were performed with a synchrocyclotron proton machine over the exhaustive energy range from 45.5 to 227.15 MeV in clinic. It was found that the amplitude of the acoustic waves is proportional to proton dose deposition, and therefore encodes dosimetric information. With the guidance of protoacoustics, each individual proton beam (7 pC/pulse) can be directly visualized with sub-millimeter (<0.7 mm) resolution using single beam pulse for the first time. Significance. The ability to localize the Bragg peak in real-time and obtain acoustic signals proportional to dose within tumors could enable precision proton therapy and hope to progress towards in vivo measurements.

Predictive Model of Liver Toxicity to Aid the Personalized Selection of Proton Versus Photon Therapy in Hepatocellular Carcinoma

Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics. Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n=117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we evaluated stability using internal bootstrap resampling and generalizability using a data set from a different institution (n=88). Finally, we implemented a class activation map method to characterize the critical DVH subregions and benchmarked the model against logistic regression and XGBoost. The models were evaluated using the area under the receiver operating characteristic curve and area under the precision-recall curve. The CNNE model showed similar internal performance and robustness compared with the benchmarks. CNNE exceeded the benchmark models in external validation, with an area under the receiver operating characteristic curve of 0.78 versus 0.55 to 0.70, and an area under the precision-recall curve of 0.6 versus 0.43 to 0.52. The model showed improved predictive power in the photon group, excellent specificity in both modalities, and high sensitivity in the photon high-risk group. Models built solely on DVHs confirm outperformance of the CNNE and indicate that the proposed structure efficiently abstracts features from both proton and photon dose distributions. The activation map method demonstrates the importance of the low-dose bath and its interaction with low liver function at baseline. We developed and externally validated a patient-specific prediction model for hepatic toxicity based on the entire DVH and clinical factors that can integrate both photon and proton therapy cohorts. This model complements the new American Society for Radiation Oncology clinical practice guidelines and could support value-driven integration of proton therapy into the management of HCC.