Characterizing Proton-Induced Biological Effects in a Mouse Spinal Cord Model: A Comparison of Bragg Peak and Entrance Beam Response in Single and Fractionated Exposures.

PURPOSE: Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. METHODS AND MATERIALS: Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/µm) and BP (LET = 6.9 keV/µm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBEENT/BP) were performed. RESULTS: Single-fraction RBEENT/BP for 50% effect probability (tolerance dose (TD50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. CONCLUSIONS: The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBEENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects.

Nano X Image Guidance in radiation therapy: feasibility study protocol for cone beam computed tomography imaging with gravity-induced motion.

BACKGROUND: This paper describes the protocol for the Nano X Image Guidance (Nano X IG) trial, a single-institution, clinical imaging study. The Nano X is a prototype fixed-beam radiotherapy system developed to investigate the feasibility of a low-cost, compact radiotherapy system to increase global access to radiation therapy. This study aims to assess the feasibility of volumetric image guidance with cone beam computed tomography (CBCT) acquired during horizontal patient rotation on the Nano X radiotherapy system. METHODS: In the Nano X IG study, we will determine whether radiotherapy image guidance can be performed with the Nano X radiotherapy system where the patient is horizontally rotated while scan projections are acquired. We will acquire both conventional CBCT scans and Nano X CBCT scans for 30 patients aged 18 and above and receiving radiotherapy for head/neck or upper abdomen cancers. For each patient, a panel of experts will assess the image quality of Nano X CBCT scans against conventional CBCT scans. Each patient will receive two Nano X CBCT scans to determine the image quality reproducibility, the extent and reproducibility of patient motion and assess patient tolerance. DISCUSSION: Fixed-beam radiotherapy systems have the potential to help ease the current shortfall and increase global access to radiotherapy treatment. Advances in image guidance could facilitate fixed-beam radiotherapy using horizontal patient rotation. The efficacy of this radiotherapy approach is dependent on our ability to image and adapt to motion due to rotation and for patients to tolerate rotation during treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04488224. Registered on 27 July 2020.

The adaptation and investigation of cone-beam CT reconstruction algorithms for horizontal rotation fixed-gantry scans of rabbits.

Fixed-gantry radiation therapy has been proposed as a low-cost alternative to the conventional rotating-gantry radiation therapy, that may help meet the rising global treatment demand. Fixed-gantry systems require gravitational motion compensated reconstruction algorithms to produce cone-beam CT (CBCT) images of sufficient quality for image guidance. The aim of this work was to adapt and investigate five CBCT reconstruction algorithms for fixed-gantry CBCT images. The five algorithms investigated were Feldkamp-Davis-Kress (FDK), prior image constrained compressed sensing (PICCS), gravitational motion compensated FDK (GMCFDK), motion compensated PICCS (MCPICCS) (a novel CBCT reconstruction algorithm) and simultaneous motion estimation and iterative reconstruction (SMEIR). Fixed-gantry and rotating-gantry CBCT scans were acquired of 3 rabbits, with the rotating-gantry scans used as a reference. Projections were sorted into rotation bins, based on the angle of rotation of the rabbit during image acquisition. The algorithms were compared using the structural similarity index measure root mean square error, and reconstruction time. Evaluation of the reconstructed volumes showed that, when compared with the reference rotating-gantry volume, the conventional FDK algorithm did not accurately reconstruct fixed-gantry CBCT scans. Whilst the PICCS reconstruction algorithm reduced some motion artefacts, the motion estimation reconstruction methods (GMCFDK, MCPICCS and SMEIR) were able to greatly reduce the effect of motion artefacts on the reconstructed volumes. This finding was verified quantitatively, with GMCFDK, MCPICCS and SMEIR reconstructions having RMSE 17%-19% lower and SSIM 1% higher than a conventional FDK. However, all motion compensated fixed-gantry CBCT reconstructions had a 56%-61% higher RMSE and 1.5% lower SSIM than FDK reconstructions of conventional rotating-gantry CBCT scans. The results show that motion compensation is required to reduce motion artefacts for fixed-gantry CBCT reconstructions. This paper further demonstrates the feasibility of fixed-gantry CBCT scans, and the ability of CBCT reconstruction algorithms to compensate for motion due to horizontal rotation.

Dosimetric Assessment of a High Precision System for Mouse Proton Irradiation to Assess Spinal Cord Toxicity.

The uncertainty associated with the relative biological effectiveness (RBE) in proton therapy, particularly near the Bragg peak (BP), has led to the shift towards biological-based treatment planning. Proton RBE uncertainty has recently been reported as a possible cause for brainstem necrosis in pediatric patients treated with proton therapy. Despite this, in vivo studies have been limited due to the complexity of accurate delivery and absolute dosimetry. The purpose of this investigation was to create a precise and efficient method of treating the mouse spinal cord with various portions of the proton Bragg curve and to quantify associated uncertainties for the characterization of proton RBE. Mice were restrained in 3D printed acrylic boxes, shaped to their external contour, with a silicone insert extending down to mold around the mouse. Brass collimators were designed for parallel opposed beams to treat the spinal cord while shielding the brain and upper extremities of the animal. Up to six animals may be accommodated for simultaneous treatment within the restraint system. Two plans were generated targeting the cervical spinal cord, with either the entrance (ENT) or the BP portion of the beam. Dosimetric uncertainty was measured using EBT3 radiochromic film with a dose-averaged linear energy transfer (LETd) correction. Positional uncertainty was assessed by collecting a library of live mouse scans (n = 6 mice, two independent scans per mouse) and comparing the following dosimetric statistics from the mouse cervical spinal cord: Volume receiving 90% of the prescription dose (V90); mean dose to the spinal cord; and LETd. Film analysis results showed the dosimetric uncertainty to be ±1.2% and ±5.4% for the ENT and BP plans, respectively. Preliminary results from the mouse library showed the V90 to be 96.3 ± 4.8% for the BP plan. Positional uncertainty of the ENT plan was not measured due to the inherent robustness of that treatment plan. The proposed high-throughput mouse proton irradiation setup resulted in accurate dose delivery to mouse spinal cords positioned along the ENT and BP. Future directions include adapting the setup to account for weight fluctuations in mice undergoing fractionated irradiation.

Pre-treatment and real-time image guidance for a fixed-beam radiotherapy system.

PURPOSE: A radiotherapy system with a fixed treatment beam and a rotating patient positioning system could be smaller, more robust and more cost effective compared to conventional rotating gantry systems. However, patient rotation could cause anatomical deformation and compromise treatment delivery. In this work, we demonstrate an image-guided treatment workflow with a fixed beam prototype system that accounts for deformation during rotation to maintain dosimetric accuracy. METHODS: The prototype system consists of an Elekta Synergy linac with the therapy beam orientated downward and a custom-built patient rotation system (PRS). A phantom that deforms with rotation was constructed and rotated within the PRS to quantify the performance of two image guidance techniques: motion compensated cone-beam CT (CBCT) for pre-treatment volumetric imaging and kilovoltage infraction monitoring (KIM) for real-time image guidance. The phantom was irradiated with a 3D conformal beam to evaluate the dosimetric accuracy of the workflow. RESULTS: The motion compensated CBCT was used to verify pre-treatment position and the average calculated position was within -0.3 ± 1.1 mm of the phantom's ground truth position at 0°. KIM tracked the position of the target in real-time as the phantom was rotated and the average calculated position was within -0.2 ± 0.8 mm of the phantom's ground truth position. A 3D conformal treatment delivered on the prototype system with image guidance had a 3%/2 mm gamma pass rate of 96.3% compared to 98.6% delivered using a conventional rotating gantry linac. CONCLUSIONS: In this work, we have shown that image guidance can be used with fixed-beam treatment systems to measure and account for changes in target position in order to maintain dosimetric coverage during horizontal rotation. This treatment modality could provide a viable treatment option when there insufficient space for a conventional linear accelerator or where the cost is prohibitive.

A High-Precision Method for In Vitro Proton Irradiation.

PURPOSE: Although proton therapy has become a well-established radiation modality, continued efforts are needed to improve our understanding of the molecular and cellular mechanisms occurring during treatment. Such studies are challenging, requiring many resources. The purpose of this study was to create a phantom that would allow multiple in vitro experiments to be irradiated simultaneously with a spot-scanning proton beam. MATERIALS AND METHODS: The setup included a modified patient-couch top coupled with a high-precision robotic arm for positioning. An acrylic phantom was created to hold 4 6-well cell-culture plates at 2 different positions along the Bragg curve in a reproducible manner. The proton treatment plan consisted of 1 large field encompassing all 4 plates with a monoenergetic 76.8-MeV posterior beam. For robust delivery, a mini pyramid filter was used to broaden the Bragg peak (BP) in the depth direction. Both a Markus ionization chamber and EBT3 radiochromic film measurements were used to verify absolute dose. RESULTS: A treatment plan for the simultaneous irradiation of 2 plates irradiated with high linear energy transfer protons (BP, 7 keV/µm) and 2 plates irradiated with low linear energy transfer protons (entrance, 2.2 keV/µm) was created. Dose uncertainty was larger across the setup for cell plates positioned at the BP because of beam divergence and, subsequently, variable proton-path lengths. Markus chamber measurements resulted in uncertainty values of ±1.8% from the mean dose. Negligible differences were seen in the entrance region (<0.3%). CONCLUSION: The proposed proton irradiation setup allows 4 plates to be simultaneously irradiated with 2 different portions (entrance and BP) of a 76.8-MeV beam. Dosimetric uncertainties across the setup are within ±1.8% of the mean dose.

A novel methodology to assess linear energy transfer and relative biological effectiveness in proton therapy using pairs of differently doped thermoluminescent detectors.

A new methodology for assessing linear energy transfer (LET) and relative biological effectiveness (RBE) in proton therapy beams using thermoluminescent detectors is presented. The method is based on the different LET response of two different lithium fluoride thermoluminescent detectors (LiF:Mg,Ti and LiF:Mg,Cu,P) for measuring charged particles. The relative efficiency of the two detector types was predicted using the recently developed Microdosimetric d(z) Model in combination with the Monte Carlo code PHITS. Afterwards, the calculated ratio of the expected response of the two detector types was correlated with the fluence- and dose- mean values of the unrestricted proton LET. Using the obtained proton dose mean LET as input, the RBE was assessed using a phenomenological biophysical model of cell survival. The aforementioned methodology was benchmarked by exposing the detectors at different depths within the spread out Bragg peak (SOBP) of a clinical proton beam at iThemba LABS. The assessed LET values were found to be in good agreement with the results of radiation transport computer simulations performed using the Monte Carlo code GEANT4. Furthermore, the estimated RBE values were compared with the RBE values experimentally determined by performing colony survival measurements with Chinese Hamster Ovary (CHO) cells during the same experimental run. A very good agreement was found between the results of the proposed methodology and the results of the in vitro study.

INVESTIGATING VARIABLE RBE IN A 12C MINIBEAM FIELD WITH MICRODOSIMETRY AND GEANT4.

An experimental and simulation-based study was performed on a 12C ion minibeam radiation therapy (MBRT) field produced with a clinical broad beam and a brass multi-slit collimator (MSC). Silicon-on-insulator (SOI) microdosimeters developed at the Centre for Medical Radiation Physics (CMRP) with micron sized sensitive volumes were used to measure the microdosimetric spectra at varying positions throughout the MBRT field and the corresponding dose-mean lineal energies and RBE for 10% cell survival (RBE10) were calculated using the modified Microdosimetric Kinetic Model (MKM). An increase in the average RBE10 of ∼30% and 10% was observed in the plateau region compared to broad beam for experimental and simulation values, respectively. The experimental collimator misalignment was determined to be 0.7° by comparison between measured and simulated microdosimetric spectra at varying collimator angles. The simulated dose-mean lineal energies in the valley region between minibeams were found to be higher on average than in the minibeams due to higher LET particles being produced in these regions from the MSC. This work presents the first experimental microdosimetry measurements and characterisation of the local biological effectiveness in a MBRT field.

A silicon strip detector array for energy verification and quality assurance in heavy ion therapy.

PURPOSE: The measurement of depth dose profiles for range and energy verification of heavy ion beams is an important aspect of quality assurance procedures for heavy ion therapy facilities. The steep dose gradients in the Bragg peak region of these profiles require the use of detectors with high spatial resolution. The aim of this work is to characterize a one dimensional monolithic silicon detector array called the "serial Dose Magnifying Glass" (sDMG) as an independent ion beam energy and range verification system used for quality assurance conducted for ion beams used in heavy ion therapy. METHODS: The sDMG detector consists of two linear arrays of 128 silicon sensitive volumes each with an effective size of 2mm × 50µm × 100µm fabricated on a p-type substrate at a pitch of 200 µm along a single axis of detection. The detector was characterized for beam energy and range verification by measuring the response of the detector when irradiated with a 290 MeV/u 12 C ion broad beam incident along the single axis of the detector embedded in a PMMA phantom. The energy of the 12 C ion beam incident on the detector and the residual energy of an ion beam incident on the phantom was determined from the measured Bragg peak position in the sDMG. Ad hoc Monte Carlo simulations of the experimental setup were also performed to give further insight into the detector response. RESULTS: The relative response profiles along the single axis measured with the sDMG detector were found to have good agreement between experiment and simulation with the position of the Bragg peak determined to fall within 0.2 mm or 1.1% of the range in the detector for the two cases. The energy of the beam incident on the detector was found to vary less than 1% between experiment and simulation. The beam energy incident on the phantom was determined to be (280.9 ± 0.8) MeV/u from the experimental and (280.9 ± 0.2) MeV/u from the simulated profiles. These values coincide with the expected energy of 281 MeV/u. CONCLUSIONS: The sDMG detector response was studied experimentally and characterized using a Monte Carlo simulation. The sDMG detector was found to accurately determine the 12 C beam energy and is suited for fast energy and range verification quality assurance. It is proposed that the sDMG is also applicable for verification of treatment planning systems that rely on particle range.