Multislit Collimator Research Articles

Preclinical photon minibeam radiotherapy using a custom collimator: Dosimetry characterization and preliminary in-vivo results on a glioma model

PurposeThe purpose of this study is to investigate the dosimetric characteristics of a collimator for minibeam radiotherapy (MBRT) with film dosimetry and Monte Carlo (MC) simulations. The outcome of MBRT with respect to conventional RT using a glioma preclinical model was also evaluated. MethodsA multi-slit collimator was designed to be used with commercial small animal irradiator. The collimator was built by aligning 0.6 mm wide and 5 mm thick parallel lead leaves at 0.4 mm intervals. Dosimetry characteristics were evaluated by Gafchromic (CG) films and TOPAS Monte Carlo (MC) code.An in vivo experiment was performed using a glioma preclinical model by injecting two million GL261cells subcutaneously and treating with 25 Gy, single fraction, with MBRT and conventional RT. Survival curves and acute radiation damage were measured to compare both treatments. ResultsA satisfactory agreement between experimental results and MC simulations were obtained, the measured FWHM and distance between the peaks were respectively 0.431 and 1.098 mm.In vivo results show that MBRT can provide local tumor control for three weeks after RT treatment and a similar survival fraction of open beam radiotherapy. No severe acute effects were seen for the MBRT group. ConclusionsWe developed a minibeam collimator and presented its dosimetric features. Satisfactory agreement between MC and GC films was found with differences consistent with uncertainties due to fabrication and set-up errors. The survival curves of MBRT and open field RT are similar while atoxicity is dramatically lower with MBRT, preliminarily confirming the expected effect.

Tuning spatially fractionated radiotherapy dose profiles using the moiré effect

Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document} to 50∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document} we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator’s (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.Our study illuminates the dual MSC system’s potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.

Towards Clinical Proton Minibeam Radiation Therapy (pMBRT): Development of Clinical pMBRT System Prototype and pMBRT-Specific Treatment Planning Method

Proton minibeam radiation therapy (pMBRT) is an emerging spatially fractionated RT (SFRT) modality that can provide very high therapeutic index compared to conventional radiotherapy methods and clinically-available SFRT methods (GRID and LATTICE). The biological data collected thus far encourage the preparation of clinical trials in pMBRT. This work is to facilitate the clinical translation of pMBRT by developing (1) the first clinical pMBRT system prototype worldwide, readily available for both small-animal biology studies and large-animal pMBRT trials; (2) pMBRT-specific treatment planning method with peak-valley dose ratio (PVDR) optimization capability for large animal and patient pMBRT trials, which is currently unavailable. The pMBRT system is based on clinically-used pencil-beam-scanning proton machine equipped with large-field clinical-size pMBRT collimator, pMBRT-dedicated treatment planning system, and KV/CBCT imaging guidance. The multi-slit brass collimator has 10 × 10 cm field size, 0.4mm width per slit and 4 mm center-to-center distance. The divergence of slits is tailed to the divergence of the proton beam. A unique universal collimator design is implemented, so that we can keep the outer fitting to the snout and conveniently inter-change collimators as needed. The pMBRT-specific treatment planning method jointly optimizes PVDR and dose objectives, to meet a minimal PVDR threshold and maximize PVDR, to avoid the situations where meeting dose objectives can compromise PVDR when PVDR were not optimized. In addition, the survival fraction for organs at risk is also optimized. The dose calculation engine is based on the Monte Carlo method using TOPAS. The optimization algorithm utilizes total variation and L1 sparsity regularization to maximize PVDR and iterative convex relaxation method to solve the optimization problem. Monte Carlo simulations via TOPAS were performed to design this large-field multi-slit collimator, using the beam structure and the beam data specific to our proton system, with mean dose rate of 8 Gy/min under clinical condition with the collimator in place. The feasibility of using this pMBRT system for small-animal studies has been demonstrated, with customized 3D printed holder for immobilizing small animals, on-board KV imaging system for accurate small-animal positioning, and the GAFchromic film for verifying radiation dose and PVDR. On the other hand, the efficacy of pMBRT-specific treatment planning method (with PVDR optimization capability) to improve PVDR has been demonstrated using retrospective patient planning studies in comparison with standard proton treatment planning method (without PVDR optimization capability). The initial development of a clinical pMBRT system prototype and pMBRT-specific treatment planning method of PVDR optimization capability has been completed with ongoing efforts to make this system ready for large-animal pMBRT studies.

Dose Profile Modulation of Proton Minibeam for Clinical Application.

Simple SummaryProton minibeam radiation therapy (pMBRT) using multislit collimator (MSC) and scatterers has been proposed to spare healthy tissues and organs on the beam path and beyond the Bragg peak. An MSC that was much thicker than the maximum range of the proton beam could provide a sufficiently high peak-to-valley dose ratio at the patient’s skin, and the scatterers could actively convert the spatially fractionated proton beam to a uniform and broad beam in tumors by changing their thickness. The combination of the MSC and the scatterers can be a good solution for implementing pMBRT in clinical proton therapy facilities.The feasibility of proton minibeam radiation therapy (pMBRT) using a multislit collimator (MSC) and a scattering device was evaluated for clinical use at a clinical proton therapy facility. We fabricated, through Monte Carlo (MC) simulations, not only an MSC with a high peak-to-valley dose ratio (PVDR) at the entrance of the proton beam, to prevent radiation toxicity, but also a scattering device to modulate the PVDR in depth. The slit width and center-to-center distance of the diverging MSC were 2.5 mm and 5.0 mm at the large end, respectively, and its thickness and available field size were 100 mm and 76 × 77.5 mm2, respectively. Spatially fractionated dose distributions were measured at various depths using radiochromic EBT3 films and also tested on bacterial cells. MC simulation showed that the thicker the MSC, the higher the PVDR at the phantom surface. Dosimetric evaluations showed that lateral dose profiles varied according to the scatterer’s thickness, and the depths satisfying PVDR = 1.1 moved toward the surface as their thickness increased. The response of the bacterial cells to the proton minibeams’ depth was also established, in a manner similar to the dosimetric pattern. Conclusively, these results strongly suggest that pMBRT can be implemented in clinical centers by using MSC and scatterers.

Preliminary results of a single photon emission computed tomography (SPECT) detector for inspection of spent fuel assembly

SPECT systems are being used by international safeguards organizations for the measurement for structural evaluation of spent fuel assemblies. However, the low sensitivity still limits the verification of spent fuel assemblies within a short measurement time (1–2 h per assembly). In this study, the SPECT detector was optimized and evaluated to identify the structure of spent fuel. The detector module consists of 64 one-dimensional (1-D) multi-slit collimators and 1-D pixelated scintillators coupled to SiPMs. We evaluated and optimized the light collection efficiency and energy resolution according to the shape of scintillator (Trapezoid, Rectangular), and reflector materials (Paint, Teflon tape, BaSO4) by Geant4 Application for Tomographic Emission (GATE) simulation and experiment. As a result, the trapezoidal scintillator coated with BaSO4 showed the highest light collection efficiency among the six models in GATE simulation and in experiments. The spent fuel rods were imaged using trapezoidal scintillator coated with BaSO4, and 1-D projections and line profiles were obtained in order to distinguish the source location. In this study, the scintillator structure and reflector material variables were optimized using Monte Carlo simulation to measure 662 keV gamma-ray of 137Cs for inspection of spent fuel assembly using the SPECT system. In order to confirm the imaging potential of the spent fuel assembly, the detector performance was evaluated using unused fuel rods for testing. The performance of the detector for fuel rod identification has been proven, and we expect that the optimized detector module will contribute to the rapid verification of the spent fuel assembly compared to conventional systems.

Calculation of Spatial Response of a Collimated Segmented HPGe Detector for Gamma Emission Tomography by MCNP Simulations

We have proposed a planar electronically segmented high-purity germanium (HPGe) detector concept in combination with a multislit collimator for gamma emission tomography. In this work, the spatial resolution achievable using the collimated segmented HPGe detector was evaluated, prior to the manufacture and operation of the detector. The spatial response of a collimated segmented HPGe detector concept was evaluated using simulations performed with Monte Carlo N-Particle (MCNP) transport code MCNP6. The full detector and multislit collimator system were modeled, and for the quantification of the spatial response, the modulation transfer function (MTF) was chosen as a performance metric. The MTF curve was obtained through the calculation of the line spread function (LSF) by analyzing the simulated projection data. In addition, tomographic reconstructions of the simulated simplified test objects were made to demonstrate the performance of the segmented HPGe detector in planned application. For 662-keV photons, the spatial resolution obtained was approximately the same as the collimator slit width for both the 100- and 150-mm-long collimators. The corresponding spatial resolution at 1596-keV photon energy was almost twice the slit width for the 100-mm collimator, due to the partial penetration of the high-energy gamma rays through the collimator bulk. For a 150-mm-long collimator, an improved resolution was obtained.

Simulation Study of a 3-D Multislit Prompt Gamma Imaging System for Proton Therapy Monitoring

The Bragg peak phenomenon empowers proton therapy in targeted dose delivery in principle and also critically demands high accuracy of proton beam’s dispatch track in practice. To ensure the accuracy, prompt gamma imaging (PGI) systems were studied for monitoring the delivery of proton beams in real time. In this work, a dual-head PGI system was proposed and optimized with multislit collimators and BGO scintillators. The dual-head system was then assessed through a contrast recovery coefficient (CRC)-variance approach to identify a preferred setup. The performance of the PGI system was evaluated in terms of detection efficiency, spatial resolution, and positioning accuracy through a series of Monte Carlo simulations. Simulation results show that the detection efficiency of the system is 0.53% at the center of the FOV for 4.44 MeV prompt gamma, and the spatial resolution is better than 2 mm across the FOV. The positioning accuracy defined as the most distal edge position (MDEP) error is less than 2 mm along the beam incident direction at a relatively low number of detected events ( <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$5 \times 10^{4}$ </tex-math></inline-formula> ) in the dual-head system corresponding to a beam spot of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$10 ^{8}$ </tex-math></inline-formula> incident protons. The system design is feasible for the real-time proton therapy monitoring.

Converging Proton Minibeams with Magnetic Fields for Optimized Radiation Therapy: A Proof of Concept.

Simple SummaryHealthy tissue tolerance to radiation is one of the main limitations in radiotherapy treatment. To broaden the therapeutic index, innovative approaches using non-conventional spatial and temporal beam structure are currently being investigated. Among them, proton minibeam radiation therapy is a promising solution that has already shown a remarkable increase in healthy tissue tolerance in various preclinical models. The purpose of this study is to propose potential strategies to further optimize proton minibeam spatial modulation with the use of magnetic fields. By generating a converging minibeam pattern with dipole magnetic fields, we show that spatial modulation can be improved at shallow depth for the same dose distribution at the tumor location. This indicates that proton minibeam radiation therapy could be efficiently combined with magnetic fields to further increase healthy tissue tolerance.Proton MiniBeam Radiation Therapy (pMBRT) is a novel strategy that combines the benefits of minibeam radiation therapy with the more precise ballistics of protons to further optimize the dose distribution and reduce radiation side effects. The aim of this study is to investigate possible strategies to couple pMBRT with dipole magnetic fields to generate a converging minibeam pattern and increase the center-to-center distance between minibeams. Magnetic field optimization was performed so as to obtain the same transverse dose profile at the Bragg peak position as in a reference configuration with no magnetic field. Monte Carlo simulations reproducing realistic pencil beam scanning settings were used to compute the dose in a water phantom. We analyzed different minibeam generation techniques, such as the use of a static multislit collimator or a dynamic aperture, and different magnetic field positions, i.e., before or within the water phantom. The best results were obtained using a dynamic aperture coupled with a magnetic field within the water phantom. For a center-to-center distance increase from 4 mm to 6 mm, we obtained an increase of peak-to-valley dose ratio and decrease of valley dose above 50%. The results indicate that magnetic fields can be effectively used to improve the spatial modulation at shallow depth for enhanced healthy tissue sparing.

A 3-dimensional stationary cascade gamma-ray coincidence imager

Objective. For certain radionuclides that decay through emitting two or more gamma photons consecutively within a short time interval—called cascade gamma-rays, the location where a radiopharmaceutical molecule emits cascade gamma-rays can be identified through coincidence detection of the photons. If each cascade photon is detected through a collimation mechanism, the location of the molecule can be inferred from the intersection of the back-projections of the two photons. Approach. In this work, we report the design and evaluation of a three-dimensional stationary imager based on this concept for imaging distributions of cascade-emitting radionuclides in radiopharmaceutical therapy. The imager was composed of two gamma-ray cameras assembled in an L-shape. Both cameras were NaI(Tl) scintillator based, one with a multi-slit collimator, the other with a multi-pinhole collimator. The field of view (FOV) was 100 mm (∅) × 100 mm (L). Based on the unique characteristics of the cascade coincidence events, we used a direct back-projection algorithm to reconstruct point source images for assessing the imager’s intrinsic spatial resolution and the standard maximum likelihood expectation maximization algorithm for reconstructing phantom images. Main results. We evaluated the performance of the imager in both simulated and prototype form with radionuclide 177Lu (cascade photon emitter). On the simulated imager, the coincidence detection efficiency at the center of FOV was 3.85 × 10−6, the spatial resolution was 7.0 mm. On the prototype imager, the corresponding values were 3.20 × 10−6 and 6.7 mm, respectively. Simulated hot-rod and experimental cardiac phantom studies demonstrate the first three-dimensional cascade gamma coincidence imager is fully functional.

A scanning dynamic collimator for spot-scanning proton minibeam production

In proton minibeam radiation therapy, proton minibeams are typically produced by modulating a uniform field using a multislit collimator. Multislit collimators produce minibeams of fixed length and width, and a new collimator has to be manufactured each time a new minibeam array is required, limiting its flexibility. In this work, we propose a scanning dynamic collimator for the generation of proton minibeams arrays. The new collimator system proposed is able to produce any minibeam required on an on-line basis by modulating the pencil beam spots of modern proton therapy machines, rather than a uniform field. The new collimator is evaluated through Monte Carlo simulations and the produced proton minibeams are compared with that of a multislit collimator. Furthermore, a proof of concept experiment is conducted to demonstrate the feasibility of producing a minibeam array by repositioning (i.e. scanning) a collimator. It is concluded that besides the technical challenges, the new collimator design is producing equivalent minibeam arrays to the multislit collimator, whilst is flexible to produce any minibeam array desired.

Perspectives for microbeam irradiation at the SYRMEP beamline.

It has been shown previously both in vitro and in vivo that microbeam irradiation (MBI) can control malignant tumour cells more effectively than the clinically established concepts of broad beam irradiation. With the aim to extend the international capacity for microbeam research, the first MBI experiment atthe biomedical beamline SYRMEP of the Italian synchrotron facility ELETTRA has been conducted. Using a multislit collimator produced by the company TECOMET, arrays of quasi-parallel microbeams were successfully generated with a beam width of 50 µm and a centre-to-centre distance of 400 µm. Murine melanoma cell cultures were irradiated with a target dose of approximately 65 Gy at a mean photon energy of ∼30 keV with a dose rate of70 Gy s-1 and a peak-to-valley dose of ∼123. This work demonstrated a melanoma cell reduction of approximately 80% after MBI. It is suggested that, while a high energy is essential to achieve high dose rates in order to deposit high treatment doses in a short time in a deep-seated target, for in vitro studies and for the treatment of superficial tumours a spectrum in the lower energy range might be equally suitable or even advantageous.

Study of the X-ray radiation interaction with a multislit collimator for the creation of microbeams in radiation therapy.

Microbeam radiation therapy (MRT) is a developing radiotherapy, based on the use of beams only a few tens of micrometres wide, generated by synchrotron X-ray sources. The spatial fractionation of the homogeneous beam into an array of microbeams is possible using a multislit collimator (MSC), i.e. a machined metal block with regular apertures. Dosimetry in MRT is challenging and previous works still show differences between calculated and experimental dose profiles of 10-30%, which are not acceptable for a clinical implementation of treatment. The interaction of the X-rays with the MSC may contribute to the observed discrepancies; the present study therefore investigates the dose contribution due to radiation interaction with the MSC inner walls and radiation leakage of the MSC. Dose distributions inside a water-equivalent phantom were evaluated for different field sizes and three typical spectra used for MRT studies at the European Synchrotron Biomedical beamline ID17. Film dosimetry was utilized to determine the contribution of radiation interaction with the MSC inner walls; Monte Carlo simulations were implemented to calculate the radiation leakage contribution. Both factors turned out to be relevant for the dose deposition, especially for small fields. Photons interacting with the MSC walls may bring up to 16% more dose in the valley regions, between the microbeams. Depending on the chosen spectrum, the radiation leakage close to the phantom surface can contribute up to 50% of the valley dose for a 5 mm × 5 mm field. The current study underlines that a detailed characterization of the MSC must be performed systematically and accurate MRT dosimetry protocols must include the contribution of radiation leakage and radiation interaction with the MSC in order to avoid significant errors in the dose evaluation at the micrometric scale.

Investigating the Dosimetric Characteristics of Microbeam Radiation Treatment.

Background:High-radiation therapeutic gain could be achieved by the modern technique of microbeam radiation treatment (MRT). The aim of this study was to investigate the dosimetric properties of MRT.Methods:The EGSnrc Monte Carlo (MC) code system was used to transport photons and electrons in MRT. The mono-energetic beams (1 cm × 1 cm array) of 50, 100, and 150 keV and the spectrum photon beam (European Synchrotron Radiation Facility [ESRF]) were modeled to transport through multislit collimators with the aperture's widths of 25 and 50 μm and the center-to-center (c-t-c) distance between two adjacent microbeams (MBs) of 200 μm. The calculated phase spaces at the upper surface of water phantom (1 cm × 1 cm) were implemented in DOSXYZnrc code to calculate the percentage depth dose (PDD), the dose profile curves (in depths of 0–1, 1–2, and 3–4 cm), and the peak-to-valley dose ratios (PVDRs).Results:The PDD, dose profile curves, and PVDRs were calculated for different effective parameters. The more flatness of lateral dose profile was obtained for the ESRF spectrum MB. With constant c-t-c distance, an increase in the MB size increased the peak and valley dose; simultaneously, the PVDR was larger for the 25 μm MB (33.5) compared to 50 μm MB (21.9) beam, due to the decreased scattering photons followed to the lower overlapping of the adjacent MBs. An increase in the depth decreased the PVDRs (i.e., 54.9 in depth of 0–1 cm).Conclusion:Our MC model of MRT successfully calculated the effect of dosimetric parameters including photon's energy, beam width, and depth to estimate the dose distribution.

A dual-domain deep learning-based reconstruction method for fully 3D sparse data helical CT

Helical CT has been widely used in clinical diagnosis. In this work, we focus on a new prototype of helical CT, equipped with sparsely spaced multidetector and multi-slit collimator (MSC) in the axis direction. This type of system can not only lower radiation dose, and suppress scattering by MSC, but also cuts down the manufacturing cost of the detector. The major problem to overcome with such a system, however, is that of insufficient data for reconstruction. Hence, we propose a deep learning-based function optimization method for this ill-posed inverse problem. By incorporating a Radon inverse operator, and disentangling each slice, we significantly simplify the complexity of our network for 3D reconstruction. The network is composed of three subnetworks. Firstly, a convolutional neural network (CNN) in the projection domain is constructed to estimate missing projection data, and to convert helical projection data to 2D fan-beam projection data. This is follwed by the deployment of an analytical linear operator to transfer the data from the projection domain to the image domain. Finally, an additional CNN in the image domain is added for further image refinement. These three steps work collectively, and can be trained end to end. The overall network is trained on a simulated CT dataset based on eight patients from the American Association of Physicists in Medicine (AAPM) Low Dose CT Grand Challenge. We evaluate the trained network on both simulated datasets and clinical datasets. Extensive experimental studies have yielded very encouraging results, based on both visual examination and quantitative evaluation. These results demonstrate the effectiveness of our method and its potential for clinical usage. The proposed method provides us with a new solution for a fully 3D ill-posed problem.

Preliminary Dosimetric Study of Proton Minibeam Radiation Therapy for the Treatment of Choroidal Melanoma

This study aimed to evaluate dosimetrically the feasibility of saving both the lens and the ciliary body in the treatment of a choroidal melanoma by using spatially fractionated proton minibeams. A multi-slit brass collimator was designed by using Monte Carlo simulation data and was fabricated with a 0.4-mm beam opening and a 1.1-mm center-to-center distance. A phantom was also fabricated for proton beam dosimetry, involving five polymethylmethacrylate (PMMA) plates of 2 mm and 8 mm thicknesses, respectively. The peak-to-valley dose ratio (PVDR) of the proton minibeams was used to validate the feasibility of lens and ciliary body sparing. The typical single-scattered proton beam for treating a patient with a choroidal melanoma was delivered to Gafchromic EBT3 films in the phantom after having passed through the multi-slit: the energy of proton beam was 60 MeV, and its depth dose profile was a full spread-out Bragg peak (SOBP). The average dose at mid-depth of the SOBP was approximately 3 CGE with ±3% of ripple. Dosimetric evaluation showed the PVDR depended on the air gap strongly. It varied from 3.4 to 1.1 in the air gap range from 2 mm to 62 mm. The PVDR values at PMMA depths of 2, 12, 22, and 32 mm were 2.0, 1.5, 1.1, and 1.06, respectively. This result shows that a spatially fractionated proton beam might save the lens and ciliary body seated at a shallow depth in the eye ball when a choroidal melanoma is treated using proton minibeam radiotherapy.

First proton minibeam radiation therapy treatment plan evaluation

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

Proton minibeams-a springboard for physics, biology and clinical creativity.

Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams-either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, in vitro and in vivo preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit. We outline some of the guiding principle of PMBT in this concise overview of this emerging area of preclinical and clinical research inquiry.

Verification of a Monte Carlo dose calculation engine in proton minibeam radiotherapy in a passive scattering beamline for preclinical trials.

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that combines the benefits of proton therapy with the remarkable normal tissue preservation observed with the use of submillimetric spatially fractionated beams. This promising technique has been implemented at the Institut Curie-Proton therapy centre (ICPO) using a first prototype of a multislit collimator. The purpose of this work was to develop a Monte Carlo-based dose calculation engine to reliably guide preclinical studies at ICPO. The whole "Y1"-passive beamline at the ICPO, including pMBRT implementation, was modelled using the Monte Carlo GATE v. 7.0 code. A clinically relevant proton energy (100 MeV) was used as starting point. Minibeam generation by means of the brass collimator used in the first experiments was modelled. A virtual source was modelled at the exit of the beamline nozzle and outcomes were compared with dosimetric measurements performed with EBT3 gafchromic films and a diamond detector in water. Dose distributions were recorded in a water phantom and in rat CT images (7-week-old male Fischer rats). The dose calculation engine was benchmarked against experimental data and was then used to assess dose distributions in CT images of a rat, resulting from different irradiation configurations used in several experiments. It reduced computational time by an order of magnitude. This allows us to speed up simulations for in vivo trials, where we obtained peak-to-valley dose ratios of 1.20 ± 0.05 and 6.1 ± 0.2 for proton minibeam irradiations targeting the tumour and crossing the rat head. Tumour eradication was observed in the 67 and 22% of the animals treated respectively. A Monte Carlo dose calculation engine for pMBRT implementation with mechanical collimation has been developed. This tool can be used to guide and interpret the results of in vivo trials. This is the first Monte Carlo dose engine for pMBRT that is being used to guide preclinical trials in a clinical proton therapy centre.

Validation of a Monte Carlo simulation for Microbeam Radiation Therapy on the Imaging and Medical Beamline at the Australian Synchrotron

Microbeam Radiation Therapy (MRT) is an emerging cancer treatment modality characterised by the use of high-intensity synchrotron-generated x-rays, spatially fractionated by a multi-slit collimator (MSC), to ablate target tumours. The implementation of an accurate treatment planning system, coupled with simulation tools that allow for independent verification of calculated dose distributions are required to ensure optimal treatment outcomes via reliable dose delivery. In this article we present data from the first Geant4 Monte Carlo radiation transport model of the Imaging and Medical Beamline at the Australian Synchrotron. We have developed the model for use as an independent verification tool for experiments in one of three MRT delivery rooms and therefore compare simulation results with equivalent experimental data. The normalised x-ray spectra produced by the Geant4 model and a previously validated analytical model, SPEC, showed very good agreement using wiggler magnetic field strengths of 2 and 3 T. However, the validity of absolute photon flux at the plane of the Phase Space File (PSF) for a fixed number of simulated electrons was unable to be established. This work shows a possible limitation of the G4SynchrotronRadiation process to model synchrotron radiation when using a variable magnetic field. To account for this limitation, experimentally derived normalisation factors for each wiggler field strength determined under reference conditions were implemented. Experimentally measured broadbeam and microbeam dose distributions within a Gammex RMI457 Solid Water® phantom were compared to simulated distributions generated by the Geant4 model. Simulated and measured broadbeam dose distributions agreed within 3% for all investigated configurations and measured depths. Agreement between the simulated and measured microbeam dose distributions agreed within 5% for all investigated configurations and measured depths.

First experimental measurement of the effect of cardio-synchronous brain motion on the dose distribution during microbeam radiation therapy.

Microbeam radiation therapy (MRT) is an emerging radiation oncology modality ideal for treating inoperable brain tumors. MRT employs quasi-parallel beams of low-energy x rays produced from modern synchrotrons. A tungsten carbide multislit collimator (MSC) spatially fractionates the broad beam into rectangular beams. In this study, the MSC creates beams 50μm wide ("peaks") separated by a center-to-center distance of 400μm ("valleys"). The peak to valley dose ratio (PVDR) is of critical importance to the efficacy of MRT. The underlying radiobiological advantage of MRT relies on high peak dose for tumor control and low valley dose for healthy tissue sparing. Cardio synchronous brain motion of the order 100-200μm is comparable to microbeam width and spacing. The motion can have a detrimental effect on the PVDR, full width at half maximum (FWHM) of the microbeams, and ultimately the dose distribution. We present the first experimental measurement of the effect of brain motion on MRT dose distribution. Dosimetry in MRT is difficult due to the high dose rate (up to 15-20kGy/s) and small field sizes. A real-time dosimetry system based on a single silicon strip detector (SSSD) has been developed with spatial resolution ~10μm. The SSSD was placed in a water-equivalent phantom and scanned through the microbeam distribution. A monodirectional positioning stage reproduced brain motion during the acquisition. Microbeam profiles were reconstructed from the SSSD and compared with Geant4 simulation and radiochromic HD-V2 film. The SSSD is able to reconstruct dose profiles within 2μm compared to film. When brain motion is applied the SSSD shows a two time increase in FWHM of profiles and 50% reduction in PVDR. This is confirmed by Geant4 and film data. Motion-induced misalignment and distortion of microbeams at treatment delivery will result in a reduced PVDR and increased irradiation of additional healthy tissue compromising the radiobiological effectiveness of MRT. The SSSD was able to reconstruct dose profiles under motion conditions and predict similar effects on FWHM and PVDR as by the simulation. The SSSD is a simple to setup, real-time detector which can provide time-resolved high spatial resolution dosimetry of microbeams in MRT.