Sectored single-energy volumetric-modulated proton arc therapy (VPAT): A preliminary multi-disease-site concept study.

PURPOSE: To explore the feasibility of a novel intensity-modulated proton arc technique that uses a single-energy beam from the cyclotron. The beam energy is externally modulated at each gantry angle by a tertiary energy modulator (EM). We hypothesize that irradiating in an arc without requiring an energy change from the cyclotron will achieve a faster delivery (main advantage of our technique) while keeping clinically desirable dosimetric results. METHODS: In a retrospective cohort of four patients with female pelvis, prostate, lung, and brain cancers, we investigated our volumetric-modulated proton arc therapy (VPAT) technique. Arcs were simulated by sectors of 1°-spaced static beams. Keeping the energy requested from the cyclotron the same for each entire arc was supported by a predesigned EM placed in front of the nozzle. As a feasibility measure, EM thicknesses were calculated. Delivery times and doses to targets and organs at risk (OARs) were compared to those of the clinical plans. RESULTS: VPAT plans were comparable to their clinical counterparts in achieving target dose conformity, being robust to uncertainties, and meeting clinical dose-volume constraints. Cyclotron energies for the four cases were within 159-220 MeV, and energy modulation range was 69-100 MeV, equivalent to 13-19 cm of water-equivalent thickness (WET). Plan delivery times were reduced from > 5 min in our clinical practice to < 3.5 min in VPAT. CONCLUSION: For the evaluated plans, the novel VPAT approach achieved shorter delivery times without sacrificing robustness, OAR sparing or target coverage. VPAT's EMs had WETs implementable in a clinical setup.

ESTRO-EPTN radiation dosimetry guidelines for the acquisition of proton pencil beam modelling data.

Proton therapy (PT) is an advancing radiotherapy modality increasingly integrated into clinical settings, transitioning from research facilities to hospital environments. A critical aspect of the commissioning of a proton pencil beam scanning delivery system is the acquisition of experimental beam data for accurate beam modelling within the treatment planning system (TPS). These guidelines describe in detail the acquisition of proton pencil beam modelling data. First, it outlines the intrinsic characteristics of a proton pencil beam-energy distribution, angular-spatial distribution and particle number. Then, it lists the input data typically requested by TPSs. Finally, it describes in detail the set of experimental measurements recommended for the acquisition of proton pencil beam modelling data-integrated depth-dose curves, spot maps in air, and reference dosimetry. The rigorous characterization of these beam parameters is essential for ensuring the safe and precise delivery of proton therapy treatments.

Proton Therapy Adaptation of Perisinusoidal and Brain Areas in the Cyclotron Centre Bronowice in Krakow: A Dosimetric Analysis.

Applying a proton beam in radiotherapy enables precise irradiation of the tumor volume, but only for continuous assessment of changes in patient anatomy. Proton beam range uncertainties in the treatment process may originate not only from physical beam properties but also from patient-specific factors such as tumor shrinkage, edema formation and sinus filling, which are not incorporated in tumor volume safety margins. In this paper, we evaluated variations in dose distribution in proton therapy resulting from the differences observed in the control tomographic images and the dosimetric influence of applied adaptive treatment. The data from weekly computed tomography (CT) control scans of 21 patients, which serve as the basis for adaptive radiotherapy, were used for this study. Dosimetric analysis of adaptive proton therapy (APT) was performed on patients with head and neck (H&N) area tumors who were divided into two groups: patients with tumors in the sinus/nasal area and patients with tumors in the brain area. For this analysis, the reference treatment plans were forward-calculated using weekly control CT scans. A comparative evaluation of organ at risk (OAR) dose-volume histogram (DVH) parameters, as well as conformity and homogeneity indices, was conducted between the initial and recalculated dose distributions to assess the necessity of the adaptation process in terms of dosimetric parameters. Changes in PTV volume after replanning were observed in seventeen patient cases, showing a discrepancy of over 1 cm3 in ten cases. In these cases, tumor progression occurred in 30% of patients, while regression was observed in 70%. The statistical analysis indicates that the use of the adaptive planning procedure results in a statistically significant improvement in dose distribution, particularly in the PTV area. The findings led to the conclusion that the adaptive procedure provides significant advantages in terms of dose distribution within the treated volume. However, when considering the entire patient group, APT did not result in a statistically significant dose reduction in OARs (α = 0.05).

Correlation between local instantaneous dose rate and oxygen pressure reduction during proton pencil beam scanning irradiation.

Background and purpose: Oxygen dynamics may be important for the tissue-sparing effect observed at ultra-high dose rates (FLASH sparing effect). This study investigated the correlation between local instantaneous dose rate and radiation-induced oxygen pressure reduction during proton pencil beam scanning (PBS) irradiations of a sample and quantified the oxygen consumption g-value. Materials and methods: A 0.2 ml phosphorescent sample (1 µM PtG4 Oxyphor probe in saline) was irradiated with a 244 MeV proton PBS beam. Four irradiations were performed with variations of a PBS spot pattern with 5 × 7 spots. During irradiation, the partial oxygen pressure (pO2) was measured with 4.5 Hz temporal resolution with a phosphorometer (Oxyled) that optically excited the probe and recorded the subsequently emitted light. A calibration was performed to calculate the pO2 level from the measured phosphorescence lifetime. A fiber-coupled scintillator simultaneously measured the instantaneous dose rate in the sample with 50 kHz sampling rate. The oxygen consumption g-value was determined on a spot-by-spot level and using the total pO2 change for full spot pattern irradiation. Results: A high correlation was found between the local instantaneous dose rate and pO2 reduction rate, with a correlation coefficient of 0.96-0.99. The g-vales were 0.18 ± 0.01 mmHg/Gy on a spot-by-spot level and 0.17 ± 0.01 mmHg/Gy for full spot pattern irradiation. Conclusions: The pO2 reduction rate was directly related to the local instantaneous dose rate per delivered spot in PBS deliveries. The methodology presented here can be applied to irradiation at ultra-high dose rates with modifications in the experimental setup.

Robust IMPT and follow-up toxicity in skull base chordoma and chondrosarcoma-a single-institution clinical experience.

BACKGROUND: Chordomas and chondrosarcomas of the skull base are rare, slowly growing malignant bone neoplasms. Despite their radioresistant properties, proton therapy has been successfully used as an adjunct to resection or as a definitive treatment. Herewith, we present our experience with robustly optimized intensity-modulated proton therapy (IMPT) and related toxicities in skull base chordoma and chondrosarcoma patients treated at HollandPTC, Delft, the Netherlands. METHODS: Clinical data, treatment plans, and acute toxicities of patients treated between July 2019 and August 2021 were reviewed. CT and 3.0T MRI scans for treatment planning were performed in supine position in a thermoplastic mold. In total, 21 dose optimization and 28 dose evaluation scenarios were simulated. Acute toxicity was scored weekly before and during the treatment according to the CTCAE v4.0. Median follow-up was 35 months (range 12-36 months). RESULTS: Overall, 9 chordoma and 3 chondrosarcoma patients with 1-3 resections prior to IMPT were included; 4 patients had titanium implants. Brainstem core and surface and spinal cord core and surface were used for nominal plan robust optimization in 11, 10, 8, and 7 patients, respectively. Middle ear inflammation, dry mouth, radiation dermatitis, taste disorder, and/or alopecia of grades 1-3 were noted at the end of treatment among 6 patients without similar complaints at inclusion; symptoms disappeared 3 months following the treatment. CONCLUSION: Robustly optimized IMPT is clinically feasible as a postoperative treatment for skull base chordoma and chondrosarcoma patients. We observed acceptable early toxicities (grade 1-3) that disappeared within the first 3 months after irradiation.

Online MR-guided proton and ion beam radiotherapy: investigation of image quality.

Objective.Magnetic resonance (MR) images free of artefacts are of pivotal importance for MR-guided ion radiotherapy. This study investigates MR image quality for simultaneous irradiation in an experimental setup using phantom imaging as well asin-vivoimaging. Observed artefacts are described within the study and their cause is investigated with the goal to find conclusions and solutions for potential future hybrid devices.Approach.An open MR scanner with a field strength of 0.25 T has been installed in front of an ion beamline. Simultaneous magnetic resonance imaging and irradiation using raster scanning were performed to analyze image quality in dedicated phantoms. Magnetic field measurements were performed to assist the explanation of observed artifacts. In addition,in-vivoimages were acquired by operating the magnets for beam scanning without transporting a beam.Main Results.The additional frequency component within the isocenter caused by the fringe field of the horizontal beam scanning magnet correlates with the amplitude and frequency of the scanning magnet steering and can cause ghosting artifacts in the images. These are amplified with high currents and fast operating of the scanning magnet. Applying a real-time capable pulse sequencein-vivorevealed no ghosting artifacts despite a continuously changing current pattern and a clinical treatment plan activation scheme, suggesting that the use of fast imaging is beneficial for the aim of creating high quality in-beam MR images. This result suggests, that the influence of the scanning magnets on the MR acquisition might be of negligible importance and does not need further measures like extensive magnetic shielding of the scanning magnets.Significance.Our study delimited artefacts observed in MR images acquired during simultaneous raster scanning ion beam irradiation. The application of a fast pulse sequence showed no image artefacts and holds the potential that online MR imaging in future hybrid devices might be feasible.

Investigation of linear energy transfer (LET)-dependence behavior and dosimetric response of a flat-panel detector in pencil beam scanning proton therapy.

PURPOSE: This study aims to elucidate the dependence of the flat-panel detector's response on the linear energy transfer (LET) and evaluate the practical viability of employing flat-panel detectors in proton dosimetry applications through LET-dependent correction factors. METHODS: The study assessed the flat-panel detector's response across varying depths using solid water and distinct 100, 150, and 200 MeV proton beams by comparing the flat-panel readings against reference doses measured with an ionization chamber. A Monte Carlo code was used to derive LET values, and an LET-dependent response correction factor was determined based on the ratio of the uncorrected flat-panel dose to the ionization chamber dose. The implications of this under-response correction were validated by applying it to a measurement involving a spread-out Bragg peak (SOBP), followed by a comparative analysis against doses calculated using the Monte Carlo code and MatriXX ONE measurement. RESULTS: The association between LET and the flat-panel detector's under-response displayed a positive correlation that intensified with increasing LET values. Notably, with a 10 keV/µm LET value, the detector's under-response reached 50 %, while the measurement points in the SOBP demonstrated under-response greater than 20 %. However, post-correction, the adjusted flat-panel profile closely aligned with the Monte Carlo profile, yielding a 2-dimensional 3 %/3mm gamma passing rate of 100 % at various verification depths. CONCLUSION: This study successfully defined the link between LET and the responsiveness of flat-panel detectors for proton dosimetric measurements and established a foundational framework for integrating flat-panel detectors in clinical proton dosimetry applications.

Proton Pencil Beam Scanning Facilitates the Safe Treatment of Extended Radiation Targets for Hodgkin Lymphoma: A Report from the Proton Collaborative Group Registry.

Because proton beam therapy (PBT) can lower the dose of radiation to the heart, lungs, and breast, it is an established radiation modality for patients with Hodgkin lymphoma (HL). Pencil beam scanning (PBS) PBT facilitates the treatment of more extensive targets. This may be especially of value for lymphoma patients who require RT to both mediastinal and axillary targets, defined here as extended target RT (ETRT), given the target distribution and need to minimize the lung, heart, and breast dose. Using the Proton Collaborative Group registry, we identified patients with HL treated with PBT to both their mediastinum and axilla, for which DICOM-RT was available. All patients were treated with PBS. To evaluate the dosimetric impact of PBS, we compared delivered PBS plans with VMAT butterfly photon plans optimized to have the same target volume coverage, when feasible. Between 2016 and 2021, twelve patients (median 26 years) received PBS ETRT (median 30.6 Gy (RBE)). Despite the large superior/inferior (SI, median 22.2 cm) and left/right (LR, median 22.8 cm) extent of the ETRT targets, all patients were treated with one isocenter except for two patients (both with SI and LR > 30 cm). Most commonly, anterior beams, with or without posterior beams, were used. Compared to photons, PBS had greater target coverage, better conformity, and lower dose heterogeneity while achieving lower doses to the lungs and heart, but not to the breast. No acute grade 3+ toxicities were reported, including pneumonitis. Proton ETRT in this small cohort was safely delivered with PBS and was associated with an improved sparing of the heart and lungs compared to VMAT.

Time structures of proton pencil beam scanning delivery on a microsecond scale measured with a pixelated semiconductor detector Timepix3.

PURPOSE: The time structures of proton spot delivery in proton pencil beam scanning (PBS) radiation therapy are essential in many clinical applications. This study aims to characterize the time structures of proton PBS delivered by both synchrotron and synchrocyclotron accelerators using a non-invasive technique based on scattered particle tracking. METHODS: A pixelated semiconductor detector, AdvaPIX-Timepix3, with a temporal resolution of 1.56 ns, was employed to measure time of arrival of secondary particles generated by a proton beam. The detector was placed laterally to the high-flux area of the beam in order to allow for single particle detection and not interfere with the treatment. The detector recorded counts of radiation events, their deposited energy and the timestamp associated with the single events. Individual recorded events and their temporal characteristics were used to analyze beam time structures, including energy layer switch time, magnet switch time, spot switch time, and the scanning speeds in the x and y directions. All the measurements were repeated 30 times on three dates, reducing statistical uncertainty. RESULTS: The uncertainty of the measured energy layer switch times, magnet switch time, and the spot switch time were all within 1% of average values. The scanning speeds uncertainties were within 1.5% and are more precise than previously reported results. The measurements also revealed continuous sub-milliseconds proton spills at a low dose rate for the synchrotron accelerator and radiofrequency pulses at 7 µs and 1 ms repetition time for the synchrocyclotron accelerator. CONCLUSION: The AdvaPIX-Timepix3 detector can be used to directly measure and monitor time structures on microseconds scale of the PBS proton beam delivery. This method yielded results with high precision and is completely independent of the machine log files.

Impact of intensity-modulated proton therapy in reducing radiation-induced lymphopenia in glioma patients.

Background: Current standard management in adult grades 2-4 gliomas includes maximal safe resection followed by adjuvant radiotherapy (RT) and chemotherapy. Radiation-induced lymphopenia (RIL) has been shown to possibly affect treatment outcomes adversely. Proton beam therapy (PBT) may reduce the volume of the normal brain receiving moderate radiation doses, and consequently RIL. Our aim was to evaluate the incidence and severity of RIL during proton beam therapy (PBT). Methods: We identified patients with grades 2-4 glioma treated with PBT at our center between January 2019 and December 2021. We evaluated the incidence and severity of RIL from weekly complete blood count (CBC) data collected during PBT and compared it to the patients who were treated with photon-based RT (XRT) at our center during the same time. Results: The incidence of any degree of lymphopenia (48% in PBT, vs. 81.2% in XRT, P value = .001) and severe lymphopenia (8% in PBT, vs. 24.6% in XRT, P value = .093) were both significantly lesser in patients who received PBT. Severe RIL in patients receiving PBT was seen in only CNS WHO Gr-4 tumors. Mean whole brain V20GyE and V25GyE inversely correlated to nadir ALC and were both significantly lower with PBT. Patients with lymphopenia during PBT showed a trend toward poorer progression-free survival (P = .053) compared to those with maintained lymphocyte counts. Conclusions: Proton therapy seems to have a superior sparing of normal brain to moderate dose radiation than photon-based RT and reduces the incidence of lymphopenia. Glioma patients with lymphopenia possibly have worse outcomes than the ones with maintained lymphocyte counts.

Two-dimensional oxygen-diffusion modelling for FLASH proton therapy with pencil beam scanning-Impact of diffusive tissue properties, dose, dose rate and scan patterns.

Objective.Oxygen depletion is generally believed to play an important role in the FLASH effect-a differential reduction of the radiosensitivity of healthy tissues, relative to that of the tumour under ultra-high dose-rate (UHDR) irradiation conditions. In proton therapy (PT) with pencil-beam scanning (PBS), the deposition of dose, and, hence, the degree of (radiolytic) oxygen depletion varies both spatially and temporally. Therefore, the resulting oxygen concentration and the healthy-tissue sparing effect through radiation-induced hypoxia varies both spatially and temporally as well.Approach.We propose and numerically solve a physical oxygen diffusion model to study these effects and their dependence on tissue parameters and the scan pattern in pencil-beam delivery. Since current clinical FLASH PT (FLASH-PT) is based on 250 MeV shoot-through (transmission) beams, for which dose and dose rate (DR) hardly vary with depth compared to the variation transverse to the beam axis, we focus on the two-dimensional case. We numerically integrate the model to obtain the oxygen concentration in each voxel as a function of time and extract voxel-based and spatially and temporarily integrated metrics for oxygen (FLASH) enhanced dose. Furthermore, we evaluate the impact on oxygen enhancement of standard pencil-beam delivery patterns and patterns that were optimised on dose-rate. Our model can contribute to the identification of tissue properties and pencil-beam delivery parameters that are critical for FLASH-PT and it may be used for the optimisation of FLASH-PT treatment plans and their delivery.Main results.(i) the diffusive properties of oxygen are critical for the steady state concentration and therefore the FLASH effect, even more so in two dimensions when compared to one dimension. (ii) The FLASH effect through oxygen depletion depends primarily on dose and less on other parameters. (iii) At a fixed fraction dose there is a slight dependence on DR. (iv) Scan patterns optimised on DR slightly increase the oxygen induced FLASH effect.Significance.To our best knowledge, this is the first study assessing the impact of scan-pattern optimization (SPO) in FLASH-PT with PBS on a biological FLASH model. While the observed impact of SPO is relatively small, a larger effect is expected for larger target volumes. A better understanding of the FLASH effect and the role of oxygen (depletion) therein is essential for the further development of FLASH-PT with PBS, and SPO.

Patient-specific quality assurance of dynamically-collimated proton therapy treatment plans.

BACKGROUND: The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans. PURPOSE: To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions. METHODS: Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array. RESULTS: Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3 mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS). CONCLUSIONS: The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

Simulation and experimental benchmarking of a proton pencil beam scanning nozzle model for development of MR-integrated proton therapy.

BACKGROUND: MR-integrated proton therapy is under development. It consists of the unique challenge of integrating a proton pencil beam scanning (PBS) beam line nozzle with an magnetic resonance imaging (MRI) scanner. The magnetic interaction between these two components is deemed high risk as the MR images can be degraded if there is cross-talk during beam delivery and image acquisition. PURPOSE: To create and benchmark a self-consistent proton PBS nozzle model for empowering the next stages of MR-integrated proton therapy development, namely exploring and de-risking complete integrated prototype system designs including magnetic shielding of the PBS nozzle. MATERIALS AND METHODS: Magnetic field (COMSOL Multiphysics ${\text{Multiphysics}}$ ) and radiation transport (Geant4) models of a proton PBS nozzle located at OncoRay (Dresden, Germany) were developed according to the manufacturers specifications. Geant4 simulations of the PBS process were performed by using magnetic field data generated by the COMSOL Multiphysics ${\text{Multiphysics}}$ simulations. In total 315 spots were simulated which consisted of a 40 × 30 cm 2 $40\times 30\,{\text{cm}}^{2}$ scan pattern with 5 cm spot spacings and for proton energies of 70, 100, 150, 200, and 220 MeV. Analysis of the simulated deflection at the beam isocenter plane was performed to determine the self-consistency of the model. The magnetic fringe field from a sub selection of 24 of the 315 spot simulations were directly compared with high precision magnetometer measurements. These focused on the maximum scanning setting of ± $\pm$  20 cm beam deflection as generated from the second scanning magnet in the PBS for a proton beam energy of 220 MeV. Locations along the beam line central axis (CAX) were measured at beam isocenter and downstream of 22, 47, 72, 97, and 122 cm. Horizontal off-axis positions were measured at 22 cm downstream of isocenter ( ± $\pm$  50, ± $\pm$  100, and ± $\pm$  150 cm from CAX). RESULTS: The proton PBS simulations had good spatial agreement to the theoretical values in all 315 spots examined at the beam line isocenter plane (0-2.9 mm differences or within 1.5 % of the local spot deflection amount). Careful analysis of the experimental measurements were able to isolate the changes in magnetic fields due solely to the scanning magnet contribution, and showed 1.9  ± $\pm$  1.2 µ T $\bf{\mu} {\text{T}}$ -9.4 ± $\pm$  1.2 µ T $\bf{\mu} {\text{T}}$ changes over the range of measurement locations. Direct comparison with the equivalent simulations matched within the measurement apparatus and setup uncertainty in all but one measurement point. CONCLUSIONS: For the first time a robust, accurate and self-consistent model of a proton PBS nozzle assembly has been created and successfully benchmarked for the purposes of advancing MR-integrated proton therapy research. The model will enable confidence in further simulation based work on fully integrated designs including MRI scanners and PBS nozzle magnetic shielding in order to de-risk and realize the full potential of MR-integrated proton therapy.

A novel treatment planning method via scissor beams for uniform-target-dose proton GRID with peak-valley-dose-ratio optimization.

BACKGROUND: Proton spatially fractionated RT (SFRT) can potentially synergize the unique advantages of using proton Bragg peak and SFRT peak-valley dose ratio (PVDR) to reduce the radiation-induced damage for normal tissues. Uniform-target-dose (UTD) proton GRID is a proton SFRT modality that can be clinically desirable and conveniently adopted since its UTD resembles target dose distribution in conventional proton RT (CONV). However, UTD proton GRID is not used clinically, which is likely due to the lack of an effective treatment planning method. PURPOSE: This work will develop a novel treatment planning method using scissor beams (SB) for UTD proton GRID, with the joint optimization of PVDR and dose objectives. METHODS: The SB method for spatial dose modulation in normal tissues with UTD has two steps: (1) a primary beam (PB) is halved with interleaved beamlets, to generate spatial dose modulation in normal tissues; (2) a complementary beam (CB) is added to fill in previously valley-dose positions in the target to generate UTD, while the CB is angled slightly from the PB, to maintain spatial dose modulation in normal tissues. A treatment planning method with PVDR optimization via the joint total variation and L1 (TVL1) regularization is developed to jointly optimize PVDR and dose objectives. The plan optimization solution is obtained using an iterative convex relaxation algorithm. RESULTS: The new methods SB and SB-TVL1 were validated in comparison with CONV. Compared to CONV of relatively homogeneous dose distribution, SB had modulated spatial dose pattern in normal tissues with UTD and comparable plan quality. Compared to SB, SB-TVL1 further maximized PVDR, with comparable dose-volume parameters. CONCLUSIONS: A novel SB method is proposed that can generate modulated spatial dose pattern in normal tissues to achieve UTD proton GRID. A treatment planning method with PVDR optimization capability via TVL1 regularization is developed that can jointly optimize PVDR and dose objectives for proton GRID.

Validation and reproducibility of in vivo dosimetry for pencil beam scanned FLASH proton treatment in mice.

PURPOSE: To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber. METHODS AND MATERIALS: 227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector. RESULTS: Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose. CONCLUSION: In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose.

Proton beam spot size and position measurements using a multi-strip ionization chamber.

PURPOSE: To develop and characterize a large-area multi-strip ionization chamber (MSIC) for efficient measurement of proton beam spot size and position at a synchrotron-based proton therapy facility. METHODS AND MATERIALS: A 420 mm x 320 mm MSIC was designed with 240 vertical strips and 180 horizontal strips at 1.75 mm pitch. The MSIC was characterized by irradiating a grid of proton spots across 17 energies from 73.5 MeV to 235 MeV and comparing to simultaneous measurements made with a reference Gafchromic EBT3 film. Beam profiles, spot sizes, and positions were analyzed. Short term measurement stability and sensitivity were evaluated. RESULTS: Excellent agreement was demonstrated between the MSIC and EBT3 film for both spot size and position measurements. Spot sizes agreed within ± 0.18 mm for all energies tested. Measured beam spot positions agreed within ± 0.17 mm. The detector showed good short term measurement stability and low noise performance. CONCLUSION: The large-area MSIC enables efficient and accurate proton beam spot characterization across the clinical energy range. The results indicate the MSIC is suitable for pencil beam scanning proton therapy commissioning and quality assurance applications requiring fast spot size and position quantification.

Cardinality-constrained plan-quality and delivery-time optimization method for proton therapy.

BACKGROUND: While minimizing plan delivery time is beneficial for proton therapy in terms of motion management, patient comfort, and treatment throughput, it often poses a tradeoff with optimizing plan quality. A key component of plan delivery time is the energy switching time, which is approximately proportional to the number of energy layers, that is, the cardinality. PURPOSE: This work aims to develop a novel optimization method that can efficiently compute the pareto surface between plan quality and energy layer cardinality, for the planner to navigate through this quality-and-efficiency tradeoff and select the appropriate plan of a balanced tradeoff. METHODS: A new IMPT method CARD is proposed that (1) explicitly incorporates the minimization of energy layer cardinality as an optimization objective, and (2) automatically generates a set of plans sequentially with a descending order in number of energy layers. The energy layer cardinality is penalized through the l1,0-norm regularization with an upper bound, and the upper bound is monotonically decreased to compute a series of treatment plans with gradually decreased energy layer cardinality on the quality-and-efficiency pareto surface. For any given treatment plan, the plan optimality is enforced using dose-volume planning objectives and the plan deliverability is imposed through minimum-monitor-unit (MMU) constraints, with optimization solution algorithm based on iterative convex relaxation. RESULTS: The new method CARD was validated in comparison with the benchmark plan of all energy layers (P0), and a state-of-the-art method called MMSEL, using prostate, head-and-neck (HN), lung, pancreas, liver and brain cases. While labor-intensive and time-consuming manual parameter tuning was needed for MMSEL to generate plans of predefined energy layer cardinality, CARD automatically and efficiently computed all plans with sequentially decreasing predefined energy layer cardinality all at once. With the acceptable plan quality (i.e., no more than 110% of total optimization objective value from P0), CARD achieved the reduction of number of energy layers to 52% (from 77 to 40), 48% (from 135 to 65), 59% (from 85 to 50), 67% (from 52 to 35), 80% (from 50 to 40), and 30% (from 66 to 20), for prostate, HN, lung, pancreas, liver, and brain cases, respectively, compared to P0, with overall better plan quality than MMSEL. Moreover, due to the nonconvexity of the MMU constraint, CARD provided the similar or even smaller optimization objective than P0, at the same time with fewer number of energy layers, that is, 55 versus 77, 85 versus 135, 45 versus 52, and 25 versus 66 for prostate, HN, pancreas, and brain cases, respectively. CONCLUSIONS: We have developed a novel optimization algorithm CARD that can efficiently and automatically compute a series of treatment plans of any given energy layer sequentially, which allows the planner to navigate through the plan-quality and energy-layer-cardinality tradeoff and select the appropriate plan of a balanced tradeoff.

Proton therapy re-irradiation outcomes and genomic landscape of patients with recurrent head and neck cancer.

INTRODUCTION: Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is challenging. We describe clinical outcomes and toxicity of proton therapy (PT) for recurrent HNC, and report genomic alterations associated with patterns of failure. MATERIALS & METHODS: We performed a retrospective analysis of rHNC patients treated with PT. Outcomes were estimated using the Kaplan-Meier method. Univariate (UVA) and multivariate analyses (MVA) were performed to assess multiple patient factors. Next-generation sequencing and genomic analyses were performed on available samples. RESULTS: Eighty-nine patients treated with PBS-PT for rHNC with a median follow-up of 12 mo (0-71 mo) were included. The 1- and 2-y local control (LC) rates were 80.8 % (95 % CI: 70.8-90.8) and 66.2 % (95 % CI: 50.7-81.7), and 1- and 2-y distant metastasis-free survival (DMFS) were 41.0 % (95 % CI: 30.0-52.0) and 26.3 % (95 % CI: 15.7-36.9). The median overall survival (OS) was 13 mo (95 % CI: 9.3-16.7). On UVA and MVA, smaller gross tumor volume (GTV) was associated with improved OS (HR 1.002, P = 0.004), DMFS (HR 1.002, P = 0.004), and PFS (HR 1.002, P = 0.014). There were 35 late Gr3 + toxicity events (30.3 %). Patients with higher candidate gene-specific mutation burden (genes with [OR] > 2, P < 0.05) had inferior PFS. TP53, NOTCH4, and ARID1B mutations were associated with inferior DMFS (OR > 2, P < 0.05). CONCLUSIONS: PBS-PT is effective at achieving LC for rHNC with favorable toxicity. Distant metastases are common, and associated with TP53, NOTCH4, and ARID1B mutations. Inclusion of genomic alterations in the clinical decision process may be warranted.

Fetal dose assessment in a pregnant patient with brain tumor: A comparative study of proton PBS and 3DCRT/VMAT radiation therapy techniques.

PURPOSE: The treatment of brain tumors in pregnant patients poses challenges, as the out-of-field dose exposure to the fetus can potentially be harmful. A pregnant patient with prior radiation treatment was presented with a brain tumor at our clinic. This work reports on our pre-treatment study that compared fetal dose exposure between intensity-modulated proton therapy (IMPT) using pencil beam scanning (PBS) and conventional photon 3D conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT), and the subsequent pregnant patient's radiation treatment. MATERIALS AND METHODS: Pre-treatment measurements of clinical plans, 3DCRT, VMAT, and IMPT, were conducted on a phantom. Measurements were performed using a device capable of neutron detections, closely following AAPM guidelines, TG158. For photon measurements, fetus shielding was utilized. On patient treatment days, which was determined to be proton treatment, shielding was used only during daily imaging for patient setup. Additionally, an in vivo measurement was conducted on the patient. RESULTS: Measurements showed that IMPT delivered the lowest fetal dose, considering both photon and neutron out-of-field doses to the fetus, even when shielding was implemented for photon measurements. Additionally, the proton plans demonstrated superior treatment for the mother, a reirradiation case. CONCLUSION: The patient was treated with proton therapy, and the baby was subsequently delivered at full term with no complications. This case study supports previous clinical findings and advocates for the expanded use of proton therapy in this patient population.

Beam Position Projection Algorithms in Proton Pencil Beam Scanning.

Beam position uncertainties along the beam trajectory arise from the accelerator, beamline, and scanning magnets (SMs). They can be monitored in real time, e.g., through strip ionization chambers (ICs), and treatments can be paused if needed. Delivery is more reliable and accurate if the beam position is projected from monitored nozzle parameters to the isocenter, allowing for accurate online corrections to be performed. Beam position projection algorithms are also used in post-delivery log file analyses. In this paper, we investigate the four potential algorithms that can be applied to all pencil beam scanning (PBS) nozzles. For some combinations of nozzle configurations and algorithms, however, the projection uses beam properties determined offline (e.g., through beam tuning or technical commissioning). The best algorithm minimizes either the total uncertainty (i.e., offline and online) or the total offline uncertainty in the projection. Four beam position algorithms are analyzed (A1-A4). Two nozzle lengths are used as examples: a large nozzle (1.5 m length) and a small nozzle (0.4 m length). Three nozzle configurations are considered: IC after SM, IC before SM, and ICs on both sides. Default uncertainties are selected for ion chamber measurements, nozzle entrance beam position and angle, and scanning magnet angle. The results for other uncertainties can be determined by scaling these results or repeating the error propagation. We show the propagation of errors from two locations and the SM angle to the isocenter for all the algorithms. The best choice of algorithm depends on the nozzle length and is A1 and A3 for the large and small nozzles, respectively. If the total offline uncertainty is to be minimized (a better choice if the offline uncertainty is not stable), the best choice of algorithm changes to A1 for the small nozzle for some hardware configurations. Reducing the nozzle length can help to reduce the gantry size and make proton therapy more accessible. This work is important for designing smaller nozzles and, consequently, smaller gantries. This work is also important for log file analyses.