Particle arc therapy: Status and potential.

There is a rising interest in developing and utilizing arc delivery techniques with charged particle beams, e.g., proton, carbon or other ions, for clinical implementation. In this work, perspectives from the European Society for Radiotherapy and Oncology (ESTRO) 2022 physics workshop on particle arc therapy are reported. This outlook provides an outline and prospective vision for the path forward to clinically deliverable proton, carbon, and other ion arc treatments. Through the collaboration among industry, academic, and clinical research and development, the scientific landscape and outlook for particle arc therapy are presented here to help our community understand the physics, radiobiology, and clinical principles. The work is presented in three main sections: (i) treatment planning, (ii) treatment delivery, and (iii) clinical outlook.

Correlation of LET With MRI Changes in Brain and Potential Implications for Normal Tissue Complication Probability for Patients With Meningioma Treated With Pencil Beam Scanning Proton Therapy.

PURPOSE: This study aimed to investigate the correlation between imaging changes in brain normal tissue and the spatial distribution of linear energy transfer (LET) for a cohort of patients with meningioma treated with scanned proton beams. Then, assuming imaging changes are induced by cell lethality, we studied the correlation between normal tissue complication probability and LET. METHODS AND MATERIALS: Magnetic resonance imaging T2/fluid attenuated inversion recovery acquired at different intervals after proton radiation were coregistered with the planning computed tomography (CT) images from 26 patients with meningioma with abnormalities after proton radiation therapy. For this purpose, the T2/fluid attenuated inversion recovery areas not on the original magnetic resonance images were contoured, and the LET values for each voxel in the patient geometry were calculated to investigate the correlation between the position of imaging changes and the LET at those positions. To separate the effect of the dose as the inductor of these changes, we compared the LET in these areas with a sample of voxels matching the dose distributions across the image change areas. Patients with a higher LET in image change areas were grouped to verify whether they shared common characteristics. RESULTS: Eleven of the patients showed higher dose-averaged LET (LETd) in imaging change regions than in the group of voxels with the same dose. This group of patients had significantly shallower targets for their treatment than the other 15 and used fewer beams and angles. CONCLUSIONS: This study points toward the possibility that areas with imaging change are more likely to occur in regions with high dose or in areas with lower dose but increased LETd. The effect of LETd on imaging changes seems to be more relevant when treating superficial lesions with few nonopposed beams. However, most patients did not show a spatial correlation between their image changes and the LETd values, limiting the cases for the possible role of high LET as a toxicity inductor.

Modelling Dose Effects from Space Irradiations: Combination of High-LET and Low-LET Radiations with a Modified Microdosimetric Kinetic Model.

The Microdosimetric Kinetic Model (MKM) to predict the effects of ionizing radiation on cell colonies is studied and reformulated for the case of high-linear energy transfer (LET) radiations with a low dose. When the number of radiation events happening in a subnuclear domain follows a Poisson distribution, the MKM predicts a linear-quadratic (LQ) survival curve. We show that when few events occur, as for high-LET radiations at doses lower than the mean specific energy imparted to the nucleus, zF,n, a Poisson distribution can no longer be assumed and an initial pure linear relationship between dose and survival fraction should be observed. Predictions of survival curves for combinations of high-LET and low-LET radiations are produced under two assumptions for their comparison: independent and combined action. Survival curves from previously published articles of V79 cell colonies exposed to X-rays, α particles, Ar-ions, Fe-ions, Ne-ions and mixtures of X-rays and each one of the ions are predicted according to the modified MKM. We conclude that mixtures of high-LET and low-LET radiations may enhance the effect of individual actions due to the increase of events in domains provided by the low-LET radiation. This hypothesis is only partially validated by the analyzed experiments.

Radiobiological effectiveness difference of proton arc beams versus conventional proton and photon beams.

This paper aims to demonstrate the difference in biological effectiveness of proton monoenergetic arc therapy (PMAT) compared to intensity modulated proton therapy (IMPT) and conventional 6 MV photon therapy, and to quantify this difference when exposing cells of different radiosensitivity to the same experimental conditions for each modality. V79, H1299 and H460 cells were cultured in petri dishes placed in the central axis of a cylindrical and homogeneous solid water phantom of 20 cm in diameter. For the PMAT plan, cells were exposed to 13 mono-energetic proton beams separated every 15° over a 180° arc, designed to deliver a uniform dose of higher LET to the petri dishes. For the IMPT plans, 3 fields were used, where each field was modulated to cover the full target. Cells were also exposed to 6 MV photon beams in petri dishes to characterize their radiosensitivity. The relative biological effectiveness of the PMAT plans compared with those of IMPT was measured using clonogenic assays. Similarly, in order to study the quantity and quality of the DNA damage induced by the PMAT plans compared to that of IMPT and photons, γ-H2AX assays were conducted to study the relative amount of DNA damage induced by each modality, and their repair rate over time. The clonogenic assay revealed similar survival levels to the same dose delivered with IMPT or x-rays. However, a systematic average of up to a 43% increase in effectiveness in PMAT plans was observed when compared with IMPT. In addition, the repair kinetic assays proved that PMAT induces larger and more complex DNA damage (evidenced by a slower repair rate and a larger proportion of unrepaired DNA damage) than IMPT. The repair kinetics of IMPT and 6 MV photon therapy were similar. Mono-energetic arc beams offer the possibility of taking advantage of the enhanced LET of proton beams to increase TCP. This study presents initial results based on exposing cells with different radiosensitivity to other modalities under the same experimental conditions, but more extensive clonogenic and in-vivo studies will be required to confirm the validity of these results.

Range optimization for mono- and bi-energetic proton modulated arc therapy with pencil beam scanning.

The development of rotational proton therapy plans based on a pencil-beam-scanning (PBS) system has been limited, among several other factors, by the energy-switching time between layers, a system-dependent parameter that ranges between a fraction of a second and several seconds. We are investigating mono- and bi-energetic rotational proton modulated arc therapy (PMAT) solutions that would not be affected by long energy switching times. In this context, a systematic selection of the optimal proton energy for each arc is vital. We present a treatment planning comparison of four different range selection methods, analyzing the dosimetric outcomes of the resulting treatment plans created with the ranges obtained. Given the patient geometry and arc definition (gantry and couch trajectories, snout elevation) our in-house treatment planning system (TPS) FoCa was used to find the maximum, medial and minimum water-equivalent thicknesses (WETs) of the target viewed from all possible field orientations. Optimal ranges were subsequently determined using four methods: (1) by dividing the max/min WET interval into equal steps, (2) by taking the average target midpoints from each field, (3) by taking the average WET of all voxels from all field orientations, and (4) by minimizing the fraction of the target which cannot be reached from any of the available angles. After the range (for mono-energetic plans) or ranges (for bi-energetic plans) were selected, the commercial clinical TPS in use in our institution (Varian Eclipse™) was used to produce the PMAT plans using multifield optimization. Linear energy transfer (LET) distributions of all plans were also calculated using FoCa and compared among the different methods. Mono- and bi-energetic PMAT plans, composed of a single 180° arc, were created for two patient geometries: a C-shaped target located in the mediastinal area of a thoracic tissue-equivalent phantom and a small brain tumor located directly above the brainstem. All plans were optimized using the same procedure to (1) achieve target coverage, (2) reduce dose to OAR and (3) limit dose hot spots in the target. Final outcomes were compared in terms of the resulting dose and LET distributions. Data shows little significant differences among the four studied methods, with superior results obtained with mono-energetic plans. A streamlined systematic method has been implemented in an in-house TPS to find the optimal range to maximize target coverage with rotational mono- or bi-energetic PBS rotational plans by minimizing the fraction of the target that cannot be reached by any direction.

Proposed linear energy transfer areal detector for protons using radiochromic film.

Radiation therapy depends on predictably and reliably delivering dose to tumors and sparing normal tissues. Protons with kinetic energy of a few hundred MeV can selectively deposit dose to deep seated tumors without an exit dose, unlike x-rays. The better dose distribution is attributed to a phenomenon known as the Bragg peak. The Bragg peak is due to relatively high energy deposition within a given distance or high Linear Energy Transfer (LET). In addition, biological response to radiation depends on the dose, dose rate, and localized energy deposition patterns or LET. At present, the LET can only be measured at a given fixed point and the LET spatial distribution can only be inferred from calculations. The goal of this study is to develop and test a method to measure LET over extended areas. Traditionally, radiochromic films are used to measure dose distribution but not for LET distribution. We report the first use of these films for measuring the spatial distribution of the LET deposited by protons. The radiochromic film sensitivity diminishes for large LET. A mathematical model correlating the film sensitivity and LET is presented to justify relating LET and radiochromic film relative sensitivity. Protons were directed parallel to radiochromic film sandwiched between solid water slabs. This study proposes the scaled-normalized difference (SND) between the Treatment Planning system (TPS) and measured dose as the metric describing the LET. The SND is correlated with a Monte Carlo (MC) calculation of the LET spatial distribution for a large range of SNDs. A polynomial fit between the SND and MC LET is generated for protons having a single range of 20 cm with narrow Bragg peak. Coefficients from these fitted polynomial fits were applied to measured proton dose distributions with a variety of ranges. An identical procedure was applied to the protons deposited from Spread Out Bragg Peak and modulated by 5 cm. Gamma analysis is a method for comparing the calculated LET with the LET measured using radiochromic film at the pixel level over extended areas. Failure rates using gamma analysis are calculated for areas in the dose distribution using parameters of 25% of MC LET and 3 mm. The processed dose distributions find 5%-10% failure rates for the narrow 12.5 and 15 cm proton ranges and 10%-15% for proton ranges of 15, 17.5, and 20 cm and modulated by 5 cm. It is found through gamma analysis that the measured proton energy deposition in radiochromic film and TPS can be used to determine LET. This modified film dosimetry provides an experimental areal LET measurement that can verify MC calculations, support LET point measurements, possibly enhance biologically based proton treatment planning, and determine the polymerization process within the radiochromic film.

Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness.

PURPOSE: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted dose (DRBE) to the target the same. METHODS AND MATERIALS: The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]). RESULTS: The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the Drbe at 90% of the volume (Drbe, 90) constant to FTP. CONCLUSIONS: LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.

Optical super-resolution imaging by high-index microspheres embedded in elastomers.

We demonstrated feasibility of super-resolution imaging through high-index microspheres embedded in transparent elastomers. We performed imaging, with resolution improvement by a factor of two, by using implanted barium titanate glass microspheres (diameters ∼30-150 µm and refractive index ∼1.9-2.1) in a thin film of polydimethylsiloxane elastomer placed over the specimen. Microsphere-assisted imaging technique is a promising candidate for applications in cancer research. As a proof-of-principle, we used microsphere-assisted imaging technique for the observation of radiation-induced γ-H2AX foci formation in U87 human glioblastoma cells irradiated by clinical proton beams.

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver.

Proton relative biological effectiveness (RBE) is known to depend on the (α/ß)x of irradiated tissues, with evidence of ∼60% variation over (α/ß)x values from 1-10 Gy. The range of (α/ß)x values reported for prostate tumors (1.2-5.0 Gy), brain tumors (10-15 Gy) and liver tumors (13-17 Gy) imply that the proton RBE for these tissues could vary significantly compared to the commonly used generic value of 1.1. Our aim is to evaluate the impact of this uncertainty on the proton dose in Gy(RBE) absorbed in normal and tumor tissues. This evaluation was performed for standard and hypofractionated regimens. RBE-weighted total dose (RWTD) distributions for 15 patients (five prostate tumors, five brain tumors and five liver tumors) were calculated using an in-house developed RBE model as a function of dose, dose-averaged linear energy transfer (LETd) and (α/ß)x. Variations of the dose-volume histograms (DVHs) for the gross tumor volume (GTV) and the organs at risk due to changes of (α/ß)x and fractionation regimen were calculated and the RWTD received by 10% and 90% of the organ volume reported. The goodness of the plan, bearing the uncertainties, was then evaluated compared to the delivered plan, which considers a constant RBE of 1.1. For standard fractionated regimens, the prostate tumors, liver tumors and all critical structures in the brain showed typically larger RBE values than 1.1. However, in hypofractionated regimens lower values of RBE than 1.1 were observed in most cases. Based on DVH analysis we found that the RBE variations were clinically significant in particular for the prostate GTV and the critical structures in the brain. Despite the uncertainties in the biological input parameters when estimating RBE values, the results show that the use of a variable RBE with dose, LETd and (α/ß)x could help to further optimize the target dose in proton treatment planning. Most importantly, this study shows that the consideration of RBE variations could influence the comparison of proton and photon treatments in clinical trials, in particular in the case of the prostate.

Range uncertainty in proton therapy due to variable biological effectiveness.

Traditionally, dose in proton radiotherapy is prescribed as Gy(RBE) by scaling up the physical dose by 10%. The relative biological effectiveness (RBE) of protons is considered to vary with dose-averaged linear energy transfer (LET(d)), dose (d) and (α/ß)(x). The increase of RBE with depth causes a shift of the falloff of the beam, i.e. a change of the beam range. The magnitude of this shift will depend on dose and (α/ß)(x). The aim of this project was to quantify the dependence of the range shift on these parameters. Three double-scattered beams of different ranges incident on a computational phantom consisting of different regions of interest (ROIs) were used. Each ROI was assigned with (α/ß)(x) values between 0.5 and 20 Gy. The distribution of LET(d) within each ROI was obtained from a Monte Carlo simulation. The LET(d) distribution depends on the beam energy and thus its nominal range. The RBE values within the ROIs were calculated for doses between 1 and 15 Gy using an in-house developed biophysical model. Dose-volume histograms of the RBE-weighted doses were extracted for each ROI for a 'fixed RBE' (RBE = 1.1) and a 'variable RBE' (RBE = f (d, α/ß, LET(d))), and the percentage difference in range was obtained from the difference of the percentage volumes at the distal 80% of the dose. Range differences in normal tissue ((α/ß)(x) = 3 Gy) of the order of 3-2 mm were obtained, respectively, for a shallow (physical range 4.8 cm) and a deep (physical range 12.8 cm) beam, when a dose of 1 Gy normalized to the mid-SOBP was delivered. As the dose increased to 15 Gy, the variable RBE decreases below 1.1 which induces ranges of about 1 mm shorter than those obtained with an RBE of 1.1. The shift in the range of an SOBP when comparing biological dose distributions obtained with a fixed or a variable RBE was quantified as a function of dose, (α/ß)(x) and physical range (as a surrogate of the initial beam energy). The shift increases with the physical range but decreases with increasing dose or (α/ß)(x). The results of our study allow a quantitative consideration of RBE-caused range uncertainties as a function of treatment site and dose in treatment planning.