BackgroundPrevious studies have shown that in-beam magnetic resonance imaging (MRI) can be used to visualize a proton beam during the irradiation of liquid-filled phantoms. The beam energy- and current-dependent local image contrast observed in water was identified to be predominantly caused by beam-induced buoyant convection and associated flow effects. Besides this flow dependency, the MR signal change was found to be characterized by a change in the T1${\rm T}_{1}$ relaxation time of water, hinting at a radiochemical contribution, which was hypothesized to lie in oxygen depletion-evoked T1${\rm T}_{1}$ relaxation time lengthening. The elucidation of the underlying contrast mechanism is required to enable the further assessment of the application potential of MRI-based proton beam visualization in tissue.PurposeThe underlying radiochemical cause of the observed local beam-induced change in the T1${\rm T}_{1}$ relaxation time of water should be identified in beam visualization experiments testing the hypothesis of beam-induced oxygen depletion-evoked T1${\rm T}_{1}$ relaxation time lengthening.MethodsCombined irradiation and imaging experiments were performed using static proton pencil beam irradiation, background-nulled inversion recovery (IR) MRI and a range of flow-restricted phantoms differing in initial oxygen concentration and homogeneity. The similarity of the irradiation-induced MRI contrast to the proton pencil beam dose distribution acquired on radiochromic film, the expected dose dependence and temporal stability, the TR dependence as well as the dependence on the initial oxygen concentration and the oxygen consumption rate were tested. Moreover, the feasibility of oxygen depletion-based beam visualization in tissue-mimicking phantoms was assessed. The levels of irradiation-induced oxygen depletion and T1${\rm T}_{1}$ relaxation time lengthening were estimated based on the measured temperatures and initial oxygen concentrations of the phantoms, the experimentally determined inversion times required for phantom background signal nulling and dosimetric measurements.ResultsThe proton irradiation-induced contrast in background-nulled IR images of well oxygenated phantoms was found similar to the proton pencil beam dose distribution and showed the characteristics expected for oxygen depletion-induced MRI contrast. No beam-induced contrast was observed in the poorly oxygenated, inhomogeneous tissue-mimicking phantoms.ConclusionsProton beam-induced radiochemical oxygen depletion can be visualized using T1${\rm T}_{1}$ relaxation time contrast-based IR MRI and represents the first identified flow-independent contrast mechanism in MRI-based proton beam visualization in real-time. Beam detection in tissue, however, will be complicated by the increased T1${\rm T}_{1}$ relaxation time inhomogeneity and the lowered levels of initial oxygen concentration compared to in liquids at atmospheric equilibrium and requires further assessment.

PURPOSE:To investigate the current practice patterns in image-guided particle therapy (IGPT) for cranio-spinal irradiation (CSI). METHODS:A multi-institutional survey was distributed to European particle therapy centres to analyse all aspects of IGPT. Based on the survey results, a Delphi consensus analysis was developed to define minimum requirements and optimal workflow for clinical practice. The centres participating in the institutional survey were invited to join the Delphi process. RESULTS:Eleven centres participated in the survey. Imaging for treatment planning was rather similar among the centres with Computed Tomography (CT) being the main modality. For positioning verification, 2D IGPT was more commonly used than 3D IGPT. Two centres performed routinely imaging for plan adaptation, by the rest ad hoc. Eight centres participated in the Delphi consensus analysis. The full consensus was reached on the use of CT imaging without contrast for treatment planning and the role of magnetic resonance imaging (MRI) in target and organs-at-risk delineation. There was an agreement on the necessity to perform patient position verification and correction before each isocentre. The most important outcome was the clear need for standardization and harmonization of the workflow. CONCLUSION:There were differences in CSI IGPT clinical practice among the European particle therapy centres. Moreover, the optimal workflow as identified by experts was not yet reached. There is a strong need for consensus guidelines. The state-of-the-art imaging technology and protocols need to be implemented into clinical practice to improve the quality of IGPT for CSI.

Abstract Introduction The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). Methods In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. Discussion This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. Trial registration Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Purpose: Radiation pneumonitis (RP) remains a major complication in non-small cell lung cancer (NSCLC) patients undergoing radiochemotherapy (RCHT). Traditionally, the mean lung dose (MLD) and the volume of the total lung receiving at least 20 Gy (V-20Gy) are used to predict RP in patients treated with normo-fractionated photon therapy. However, other models, including the actual dose-distribution in the lungs using the effective alpha/beta model or a combination of radiation doses to the lungs and heart, have been proposed for predicting RP. Moreover, the models established for photons may not hold for patients treated with passively-scattered proton therapy (PSPT). Therefore, we here tested and validated novel predictive parameters for RP in NSCLC patient treated with PSPT. Methods: Data on the occurrence of RP, structure files and dose-volume histogram parameters for lungs and heart of 96 NSCLC patients, treated with PSPT and concurrent chemotherapy, was retrospectively retrieved from prospective clinical studies of two international centers. Data was randomly split into a training set (64 patients) and a validation set (32 patients). Statistical analyses were performed using binomial logistic regression. Results: The biologically effective dose (BED) of the 'lungs - GTV' significantly predicted RP = grade 2 in the training-set using both a univariate model (p = 0.019, AUC(train) = 0.72) and a multivariate model in combination with the effective alpha/beta parameter of the heart (p(BED) = 0.006, p(alpha/beta eff) = 0.043, AUC(train) = 0.74). However, these results did not hold in the validation-set (AUC(val) = 0.52 andAUC(val) = 0.50, respectively). Moreover, these models were found to neither outperform a model built with the MLD (p = 0.015, AUC(train) = 0.73, AUC(val) = 0.51), nor a multivariate model additionally including the V-20Gy of the heart (p(MLD) = 0.039, p(V20Gy,heart) = 0.58, AUC(trai)n = 0.74, AUCval = 0.53). Conclusion: Using the effective alpha/beta parameter of the lungs and heart we achieved similar performance to commonly used models built for photon therapy, such as MLD, in predicting RP >= grade 2. Therefore, prediction models developed for photon RCHT still hold for patients treated with PSPT.

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.

Background and purpose:Motion mitigation is of crucial importance in particle therapy (PT) of patients with abdominal tumors to ensure high-precision irradiation. Magnetic resonance imaging (MRI) is an excellent modality for target volume delineation and motion estimation of mobile soft-tissue tumors. Thus, the aims of this study were to develop an MRI- and PT-compatible abdominal compression device, to investigate its effect on pancreas motion reduction, and to evaluate patient tolerability and acceptance.Materials and methods:In a prospective clinical study, 16 patients with abdominal tumors received an individualized polyethylene-based abdominal corset. Pancreas motion was analyzed using time- and phase resolved MRI scans (orthogonal 2D-cine and 4D MRI) with and without compression by the corset. The pancreas was manually segmented in each MRI data set and the population-averaged center-of-mass motion in inferior-superior (IS), anterior-posterior (AP) and left-right (LR) directions was determined. A questionnaire was developed to investigate the level of patient acceptance of the corset, which the patients completed after acquisition of the planning computed tomography (CT) and MRI scans.Results:The corset was found to reduce pancreas motion predominantly in IS direction by on average 47 % - 51 % as found in the 2D-cine and 4D MRI data, respectively, while motion in the AP and LR direction was not significantly reduced. Most patients reported no discomfort when wearing the corset.Conclusion:An MRI- and PT-compatible individualized abdominal corset was presented, which substantially reduced breathing-induced pancreas motion and can be safely applied with no additional discomfort for the patients. The corset has been successfully integrated into our in-house clinical workflow for PT of tumors of the upper abdomen.

MRI-based proton beam visualisation in water has proven feasible in exploratory irradiation experiments performed on a first research prototype in-beam MRI system. Beam-induced convection was hypothesised to be implicated into MR signal loss observed within the beam volume. In this study, this hypothesis was tested in liquid water-filled phantoms by suppression of convection-induced motion using mechanical barriers and temperature control of water expansivity. In absence of convection-induced motion, no beam-induced signal changes occurred, supporting the hypothesis that convection triggers local MR signal loss during proton beam irradiation. The elucidation of the exact mechanism of convection-induced signal loss requires further investigation.

Objective. Local magnetic resonance (MR) signal loss was previously observed during proton beam irradiation of free-floating water phantoms at ambient temperature using a research prototype in-beam magnetic resonance imaging (MRI) scanner. The emergence of this MR signal loss was hypothesised to be dependent on beam-induced convection. The aim of this study was therefore to unravel whether physical conditions allowing the development of convection must prevail for the beam-induced MRI signatures to emerge. Approach. The convection dependence of MRI magnitude signal-based proton beam visualisation was investigated in combined irradiation and imaging experiments using a gradient echo (GE)-based time-of-flight (ToF) angiography pulse sequence, which was first tested for its suitability for proton beam visualisation in free-floating water phantoms at ambient temperature. Subsequently, buoyant convection was selectively suppressed in water phantoms using either mechanical barriers or temperature control of water expansivity. The underlying contrast mechanism was further assessed using sagittal imaging and variation of T1 relaxation time-weighting. Main results. In the absence of convection-driven water flow, weak beam-induced MR signal changes occurred, whereas strong changes did occur when convection was not mechanically or thermally inhibited. Moreover, the degree of signal loss was found to change with the variation of T1-weighting. Consequently, beam-induced MR signal loss in free-floating water phantoms at ambient temperature does not exclusively originate from buoyant convection, but is caused by local composite effects of beam-induced motion and radiation chemistry resulting in a local change in the water T1 relaxation time. Significance. The identification of ToF angiography sequence-based proton beam visualisation in water phantoms to result from composite effects of beam-induced motion and radiation chemistry represents the starting point for the future elucidation of the currently unexplained motion-based MRI contrast mechanism and the identification of the proton beam-induced material change causing T1 relaxation time lengthening.

BACKGROUND 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 magnetic field. PURPOSE 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 prototype system. METHODS 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 ( X , Y ) $(X,Y)$ , minimum and maximum lateral standard deviation ( σ m i n $\sigma _{min}$ and σ m a x $\sigma _{max}$ ), orientation (θ), and the eccentricity (ε). RESULTS 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 σ m a x $\sigma _{max}$ decreased by up to 3.66%, while σ m i n $\sigma _{min}$ 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 lesser degree. CONCLUSIONS 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.

PURPOSE:The low sensitivity and limitation to water phantoms of convection-dependent MRI magnitude signal-based proton beam visualization hinder its in vivo applicability in MR-integrated proton beam therapy. The purpose of the present study was, therefore, to assess possible contrast mechanisms for MRI phase signal-based proton beam visualization that can potentially be exploited to enhance the sensitivity of the method and extend its applicability to tissue materials. METHODS:To assess whether proton beam-induced magnetic field perturbations, changes in material susceptibility or convection result in detectable changes in the MRI phase signal, water phantom characteristics, experiment timing, and imaging parameters were varied in combined irradiation and imaging experiments using a time-of-flight angiography pulse sequence on a prototype in-beam MRI scanner. Velocity encoding was used to further probe and quantify beam-induced convection. RESULTS:MRI phase signal-based proton beam visualization proved feasible. The observed phase difference contrast was evoked by beam-induced buoyant convection with flow velocities in the mm/s range. Proton beam-induced magnetic field perturbations or changes in magnetic susceptibility did not influence the MRI phase signal. Velocity encoding was identified as a means to enhance the detection sensitivity. CONCLUSION:Because the MRI phase difference contrast observed during proton beam irradiation of water phantoms is caused by beam-induced convection, this method will unlikely be transferable to tightly compartmentalized tissue wherein flow effects are restricted. However, strong velocity encoded pulse sequences were identified as promising candidates for the future development of MRI-based methods for water phantom-based geometric quality assurance in MR-integrated proton beam therapy.

Proton therapy (PT) is expected to benefit from real-time MRI guidance. However, the integration of MRI and PT is challenging due to the interaction between the magnetic fringe fields of the PT beamline and the B0-field of the MR scanner. In this study, we measured the magnetic fringe field of the PT beamline. The measurement data will be used to validate a finite element model. With a match to this model, we can proceed to investigate what type of magnetic shielding solution would be needed to decouple the magnetic fields of the PT and MRI systems.

Image guidance using in-beam real-time magnetic resonance (MR) imaging is expected to improve the targeting accuracy of proton therapy for moving tumors, by reducing treatment margins, detecting interfractional and intrafractional anatomical changes and enabling beam gating. The aim of this study is to quantitatively characterize the static magnetic field and image quality of a 0.22T open MR scanner that has been integrated with a static proton research beamline. The magnetic field and image quality studies are performed using high-precision magnetometry and standardized diagnostic image quality assessment protocols, respectively. The magnetic field homogeneity was found to be typical of the scanner used (98ppm). Operation of the beamline magnets changed the central resonance frequency and magnetic field homogeneity by a maximum of 16Hz and 3ppm, respectively. It was shown that the in-beam MR scanner features sufficient image quality and influences of simultaneous irradiation on the images are restricted to a small sequence-dependent image translation (0.1–0.7mm) and a minor reduction in signal-to-noise ratio (1.3%–5.6%). Nevertheless, specific measures have to be taken to minimize these effects in order to achieve accurate and reproducible imaging which is required for a future clinical application of MR integrated proton therapy.