Modification of the Langendorff system of the isolated beating heart for experimental radiotherapy at a synchrotron: 4000†Gy in a heart beat.

Microbeam radiotherapy could help to cure malignant tumours which are currently still considered therapy-resistant. With an irradiation target in the thoracic cavity, the heart would be one of the most important organs at risk. To assess the acute adverse effects of microbeam irradiation in the heart, a powerful ex vivo tool was created by combining the Langendorff model of the isolated beating mammalian heart with X-Tream dosimetry. In a first pilot experiment conducted at the Biomedical and Imaging Beamline of the Australian Synchrotron, the system was tested at a microbeam peak dose approximately ten times higher than the anticipated future microbeam irradiation treatment doses. The entire heart was irradiated with a dose of 4000 Gy at a dose rate of >6000 Gy s-1, using an array of 50 µm-wide microbeams spaced at a centre-to-centre distance of 400 µm. Although temporary arrhythmias were seen, they reverted spontaneously to a stable rhythm and no cardiac arrest occurred. This amazing preservation of cardiac function is promising for future therapeutic approaches.

A retrospective analysis of setup and intrafraction positional variation in stereotactic radiotherapy treatments.

PURPOSE: The aim of this study was to provide a comprehensive assessment of patient intrafraction motion in linac-based frameless stereotactic radiosurgery (SRS) and radiotherapy (SRT). METHODS: A retrospective review was performed on 101 intracranial SRS/SRT patients immobilized with the Klarity stereotactic thermoplastic mask (compatible with the Brainlab frameless stereotactic system) and aligned on a 6 Degree of Freedom (DoF) couch with the Brainlab ExacTrac image guidance system. Both pretreatment and intrafraction correction data are provided as observed by the ExacTrac system. The effects of couch angle and treatment duration on positioning outcomes are also explored. RESULTS: Initial setup data for patients is shown to vary by up to ±4.18 mm, ±2.97°, but when corrected with a single x-ray image set with ExacTrac, patient positions are corrected to within ±2.11 mm, ±2.27°. Intrafraction patient motion is shown to be uniformly random and independent of both time and couch angle. Patient motion was also limited to within approximately 3 mm, 3° by the thermoplastic mask. CONCLUSIONS: Our results indicate that since patient intrafraction motion is unrelated to couch rotation and treatment duration, intrafraction patient monitoring in 6 DoF is required to minimize intracranial SRS/SRT margins.

Characterization of selected additive manufacturing materials for synchrotron monochromatic imaging and broad-beam radiotherapy at the Australian synchrotron-imaging and medical beamline.

Objective.This study aims to characterize radiological properties of selected additive manufacturing (AM) materials utilizing both material extrusion and vat photopolymerization technologies. Monochromatic synchrotron x-ray images and synchrotron treatment beam dosimetry were acquired at the hutch 3B and 2B of the Australian Synchrotron-Imaging and Medical Beamline.Approach.Eight energies from 30 keV up to 65 keV were used to acquire the attenuation coefficients of the AM materials. Comparison of theoretical, and experimental attenuation data of AM materials and standard solid water for MV linac was performed. Broad-beam dosimetry experiment through attenuated dose measurement and a Geant4 Monte Carlo simulation were done for the studied materials to investigate its attenuation properties specific for a 4 tesla wiggler field with varying synchrotron radiation beam qualities.Main results.Polylactic acid (PLA) plus matches attenuation coefficients of both soft tissue and brain tissue, while acrylonitrile butadiene styrene, Acrylonitrile styrene acrylate, and Draft resin have close equivalence to adipose tissue. Lastly, PLA, co-polyester plus, thermoplastic polyurethane, and White resins are promising substitute materials for breast tissue. For broad-beam experiment and simulation, many of the studied materials were able to simulate RMI457 Solid Water and bolus within ±10% for the three synchrotron beam qualities. These results are useful in fabricating phantoms for synchrotron and other related medical radiation applications such as orthovoltage treatments.Significance and conclusion.These 3D printing materials were studied as potential substitutes for selected tissues such as breast tissue, adipose tissue, soft-tissue, and brain tissue useful in fabricating 3D printed phantoms for synchrotron imaging, therapy, and orthovoltage applications. Fabricating customizable heterogeneous anthropomorphic phantoms (e.g. breast, head, thorax) and pre-clinical animal phantoms (e.g. rodents, canine) for synchrotron imaging and radiotherapy using AM can be done based on the results of this study.

Multi-institutional investigation into the robustness of intra-cranial multi-target stereotactic radiosurgery plans to patient setup errors.

PURPOSE: This study aimed to analyse correlations between planning factors including plan geometry and plan complexity with robustness to patient setup errors. METHODS: Multiple-target brain stereotactic radiosurgery (SRS) plans were obtained through the Trans-Tasman Radiation Oncology Group (TROG) international treatment planning challenge (2018). The challenge dataset consisted of five intra-cranial targets with a 20 Gy prescription. Setup error was simulated using an in-house tool. Dose to targets was assessed via dose covering 99 % (D99 %) of gross tumour volume (GTV) and 98 % of planning target volume (PTV). Dose to organs at risk was assessed using volume of normal brain receiving 12 Gy and maximum dose covering 0.03 cc of brainstem. Plan complexity was assessed via edge metric, modulation complexity score, mean multi-leaf collimator (MLC) gap, mean MLC speed and plan modulation. RESULTS: Even for small (0.5 mm/°) errors, GTV D99 % was reduced by up to 20 %. The strongest correlation was found between lower complexity plans (larger mean MLC gap and lower edge metric) and higher robustness to setup error. Lower complexity plans had 1 %-20 % fewer targets/scenarios with GTV D99 % falling below the specified tolerance threshold. These complexity metrics correlated with 100 % isodose volume sphericity and dose conformity, though similar conformity was achievable with a range of complexities. CONCLUSIONS: A higher level of importance should be directed towards plan complexity when considering plan robustness. It is recommended when planning multi-target SRS, larger MLC gaps and lower MLC aperture irregularity be considered during plan optimisation due to higher robustness should patient positioning errors occur.

Design, construction, and dosimetry of 3D printed heterogeneous phantoms for synchrotron brain cancer radiation therapy quality assurance.

Objective.This study aims to design, manufacture, and test 3D printed quality assurance (QA) dosimetry phantoms for synchrotron brain cancer radiation therapy at the Australian synchrotron.Approach.Fabricated 3D printed phantoms from simple slab phantoms, a preclinical rat phantom, and an anthropomorphic head phantom were fabricated and characterized. Attenuation measurements of various polymers, ceramics and metals were acquired using synchrotron monochromatic micro-computed tomography (CT) imaging. Polylactic acid plus, VeroClear, Durable resin, and tricalcium phosphate were used in constructing the phantoms. Furthermore, 3D printed bone equivalent materials were compared relative to ICRU bone and hemihydrate plaster. Homogeneous and heterogeneous rat phantoms were designed and fabricated using tissue-equivalent materials. Geometric accuracy, CT imaging, and consistency were considered. Moreover, synchrotron broad-beam x-rays were delivered using a 3 Tesla superconducting multipole wiggler field for four sets of synchrotron radiation beam qualities. Dose measurements were acquired using a PinPoint ionization chamber and compared relative to a water phantom and a RMI457 Solid Water phantom. Experimental depth doses were compared relative to calculated doses using a Geant4 Monte Carlo simulation.Main results.Polylactic acid (PLA+) shows to have a good match with the attenuation coefficient of ICRU water, while both tricalcium phosphate and hydroxyapatite have good attenuation similarity with ICRU bone cortical. PLA+ material can be used as substitute to RMI457 slabs for reference dosimetry with a maximum difference of 1.84%. Percent depth dose measurement also shows that PLA+ has the best match with water and RMI457 within ±2.2% and ±1.6%, respectively. Overall, PLA+ phantoms match with RMI457 phantoms within ±3%.Significance and conclusion.The fabricated phantoms are excellent tissue equivalent equipment for synchrotron radiation dosimetry QA measurement. Both the rat and the anthropomorphic head phantoms are useful in synchrotron brain cancer radiotherapy dosimetry, experiments, and future clinical translation of synchrotron radiotherapy and imaging.

The design and characterization of a novel dynamic collimator system for synchrotron radiotherapy applications.

BACKGROUND: Novel synchrotron radiotherapy techniques are currently limited to using prefabricated beam-limiting blocks for field definition. For large experiments, a single square tungsten block is often used for every treatment since conformal blocks are both patient and field specific, and require long lead times for fabrication. Future synchrotron radiotherapy treatments would benefit from a dynamic collimator system. PURPOSE: We developed and tested a novel collimator design for use on the Imaging and Medical Beamline (IMBL) at the ANSTO Australian Synchrotron. METHODS: The maximum usable beam size on IMBL is 50-mm wide by 3-mm tall. Given the beam shape, targets must be vertically scanned through the synchrotron beam to cover the target volume. To shape the beam, a novel collimator design was developed, consisting of two semi-circular leaves made from 4-mm thick tungsten sheets, with each leaf capable of both vertical and horizontal movement. A software model was created to optimize motor trajectories and generate deliverable treatment fields. A series of geometric field shapes and clinical target volumes were delivered using the collimator and imaged with a digital imaging detector. Four similarity metrics (volumetric similarity, DICE, and the average and maximum Hausdorff distances) were used to measure differences between the input and planned fields, and the planned and delivered fields. RESULTS: Differences between input and planned fields increased with delivery speed, and were worse for rectangular and square fields compared to circular fields. However, the differences between planned and delivered fields were small, where the maximum average deviation between the fields was 0.25 mm (one pixel). Field repeatability was consistent with no difference (σ = 0 for all metrics) observed in consecutively delivered fields. CONCLUSIONS: We have successfully built and demonstrated a novel collimator for synchrotron radiotherapy applications on IMBL. Several design improvements have been highlighted and will be addressed in future revisions the collimator. However, in its current state, the collimator enables dynamically delivered conformal treatment fields to be utilized on IMBL, and is ready to support the forthcoming canine treatments on IMBL.

The Spinal Cord as Organ of Risk: Assessment for Acute and Subacute Neurological Adverse Effects after Microbeam Radiotherapy in a Rodent Model.

Microbeam radiotherapy (MRT), a high dose rate radiotherapy technique using spatial dose fractionation at the micrometre range, has shown a high therapeutic efficacy in vivo in different tumour entities, including lung cancer. We have conducted a toxicity study for the spinal cord as organ of risk during irradiation of a target in the thoracic cavity. In young adult rats, the lower thoracic spinal cord was irradiated over a length of 2 cm with an array of quasi-parallel microbeams of 50 µm width, spaced at a centre-to-centre distance of 400 µm, with MRT peak doses up to 800 Gy. No acute or subacute adverse effects were observed within the first week after irradiation up to MRT peak doses of 400 Gy. No significant differences were seen between irradiated animals and non-irradiated controls in motor function and sensitivity, open field test and somatosensory evoked potentials (SSEP). After irradiation with MRT peak doses of 450-800 Gy, dose-dependent neurologic signs occurred. Provided that long-term studies do not reveal significant morbidity due to late toxicity, an MRT dose of 400 Gy can be considered safe for the spinal cord in the tested beam geometry and field size.

Accurate and Fast Deep Learning Dose Prediction for a Preclinical Microbeam Radiation Therapy Study Using Low-Statistics Monte Carlo Simulations.

Microbeam radiation therapy (MRT) utilizes coplanar synchrotron radiation beamlets and is a proposed treatment approach for several tumor diagnoses that currently have poor clinical treatment outcomes, such as gliosarcomas. Monte Carlo (MC) simulations are one of the most used methods at the Imaging and Medical Beamline, Australian Synchrotron to calculate the dose in MRT preclinical studies. The steep dose gradients associated with the 50µm-wide coplanar beamlets present a significant challenge for precise MC simulation of the dose deposition of an MRT irradiation treatment field in a short time frame. The long computation times inhibit the ability to perform dose optimization in treatment planning or apply online image-adaptive radiotherapy techniques to MRT. Much research has been conducted on fast dose estimation methods for clinically available treatments. However, such methods, including GPU Monte Carlo implementations and machine learning (ML) models, are unavailable for novel and emerging cancer radiotherapy options such as MRT. In this work, the successful application of a fast and accurate ML dose prediction model for a preclinical MRT rodent study is presented for the first time. The ML model predicts the peak doses in the path of the microbeams and the valley doses between them, delivered to the tumor target in rat patients. A CT imaging dataset is used to generate digital phantoms for each patient. Augmented variations of the digital phantoms are used to simulate with Geant4 the energy depositions of an MRT beam inside the phantoms with 15% (high-noise) and 2% (low-noise) statistical uncertainty. The high-noise MC simulation data are used to train the ML model to predict the energy depositions in the digital phantoms. The low-noise MC simulations data are used to test the predictive power of the ML model. The predictions of the ML model show an agreement within 3% with low-noise MC simulations for at least 77.6% of all predicted voxels (at least 95.9% of voxels containing tumor) in the case of the valley dose prediction and for at least 93.9% of all predicted voxels (100.0% of voxels containing tumor) in the case of the peak dose prediction. The successful use of high-noise MC simulations for the training, which are much faster to produce, accelerates the production of the training data of the ML model and encourages transfer of the ML model to different treatment modalities for other future applications in novel radiation cancer therapies.

Microbeam Irradiation of the Beating Rodent Heart: An Ex Vivo Study of Acute and Subacute Effects on Cardiac Function.

PURPOSE: Microbeam radiation therapy (MRT) has shown several advantages compared with conventional broad-beam radiation therapy in small animal models, including a better preservation of normal tissue function and improved drug delivery based on a rapidly increased vascular permeability in the target region. Normal tissue tolerance is the limiting factor in clinical radiation therapy. Knowledge of the normal tissue tolerance of organs at risk is therefore a prerequisite in evaluating any new radiation therapy approach. With an irradiation target in the thoracic cavity, the heart would be the most important organ at risk. METHODS AND MATERIALS: We used the ex vivo beating rodent heart in the Langendorff perfusion system at the synchrotron to administer microbeam irradiation (MBI) with a peak dose of 40 or 400 Gy. By continuously recording the electrocardiogram, the left ventricular pressure, and the aortic pressure before, during and after MBI, we were able to assess acute and subacute effects of MBI on electrophysiological and mechanical cardiac function. In addition, we analyzed histologic and ultrastructural sequelae caused by MBI. RESULTS: There were no significant changes in heart rate, heart rate variability, systolic increase of left ventricular pressure or aortic pressure. Moreover, the changes of heart rate, left ventricular pressure and aortic pressure by adding 10-5 mol/L norepinephrine to the perfusate, were also not significant between MBI and sham experiments. However, the rate-pressure product as a surrogate marker for maximum workload after MBI was significantly lower compared with sham-irradiated controls. On the structural level, no severe membranous, sarcomeric, mitochondrial or nuclear changes caused by MBI were detected by desmin immunohistochemistry and electron microscopy. CONCLUSIONS: With respect to acute and subacute toxicity, an MBI peak dose up to 400 Gy did not result in severe changes in cardiac electrophysiology or mechanics.

Synchrotron Microbeam Radiation Therapy for the Treatment of Lung Carcinoma: A Preclinical Study.

PURPOSE: In the past 3 decades, synchrotron microbeam radiation therapy (S-MRT) has been shown to achieve both good tumor control and normal tissue sparing in a range of preclinical animal models. However, the use of S-MRT for the treatment of lung tumors has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model. METHODS AND MATERIALS: Lewis Lung carcinoma-bearing mice were irradiated with 2 cross-fired arrays of S-MRT or synchrotron broad-beam (S-BB) radiation therapy. S-MRT consisted of 17 microbeams with a width of 50 µm and center-to-center spacing of 400 µm. Each microbeam delivered a peak entrance dose of 400 Gy whereas S-BB delivered a homogeneous entrance dose of 5.16 Gy (corresponding to the S-MRT valley dose). RESULTS: Both treatments prolonged the survival of mice relative to the untreated controls. However, mice in the S-MRT group developed severe pulmonary edema around the irradiated carcinomas and did not have improved survival relative to the S-BB group. Subsequent postmortem examination of tumor size revealed that the mice in the S-MRT group had notably smaller tumor volume compared with the S-BB group, despite the presence of edema. Mice that were sham-implanted did not display any decline in health after S-MRT, experiencing only mild and transient edema between 4 days and 3 months postirradiation which disappeared after 4 months. Finally, a parallel study investigating the lungs of healthy mice showed the complete absence of radiation-induced pulmonary fibrosis 6 months after S-MRT. CONCLUSIONS: S-MRT is a promising tool for the treatment of lung carcinoma, reducing tumor size compared with mice treated with S-BB and sparing healthy lungs from pulmonary fibrosis. Future experiments should focus on optimizing S-MRT parameters to minimize pulmonary edema and maximize the therapeutic ratio.

Toward personalized synchrotron microbeam radiation therapy.

Synchrotron facilities produce ultra-high dose rate X-rays that can be used for selective cancer treatment when combined with micron-sized beams. Synchrotron microbeam radiation therapy (MRT) has been shown to inhibit cancer growth in small animals, whilst preserving healthy tissue function. However, the underlying mechanisms that produce successful MRT outcomes are not well understood, either in vitro or in vivo. This study provides new insights into the relationships between dosimetry, radiation transport simulations, in vitro cell response, and pre-clinical brain cancer survival using intracerebral gliosarcoma (9LGS) bearing rats. As part of this ground-breaking research, a new image-guided MRT technique was implemented for accurate tumor targeting combined with a pioneering assessment of tumor dose-coverage; an essential parameter for clinical radiotherapy. Based on the results of our study, we can now (for the first time) present clear and reproducible relationships between the in vitro cell response, tumor dose-volume coverage and survival post MRT irradiation of an aggressive and radioresistant brain cancer in a rodent model. Our innovative and interdisciplinary approach is illustrated by the results of the first long-term MRT pre-clinical trial in Australia. Implementing personalized synchrotron MRT for brain cancer treatment will advance this international research effort towards clinical trials.