Characterization of a novel time-resolved, real-time scintillation dosimetry system for ultra-high dose rate radiation therapy applications.

Background: Scintillation dosimetry has promising qualities for ultra-high dose rate (UHDR) radiotherapy (RT), but no system has shown compatibility with mean dose rates (DR-) above 100 Gy/s and doses per pulse (Dp) exceeding 1.5 Gy typical of UHDR (FLASH)-RT. The aim of this study was to characterize a novel scintillator dosimetry system with the potential of accommodating UHDRs. Methods and Materials: A thorough dosimetric characterization of the system was performed on an UHDR electron beamline. The system's response as a function of dose, DR-,Dp, and the pulse dose rate DRp was investigated, together with the system's dose sensitivity (signal per unit dose) as a function of dose history. The capabilities of the system for time-resolved dosimetric readout were also evaluated. Results: Within a tolerance of ±3%, the system exhibited dose linearity and was independent of DR- and Dp within the tested ranges of 1.8-1341 Gy/s and 0.005-7.68 Gy, respectively. A 6% reduction in the signal per unit dose was observed as DRp was increased from 8.9e4-1.8e6 Gy/s. Additionally, the dose delivered per integration window of the continuously sampling photodetector had to remain between 0.028 and 11.64 Gy to preserve a stable signal response per unit dose. The system accurately measured Dp of individual pulses delivered at up to 120 Hz. The day-to-day variation of the signal per unit dose at a reference setup varied by up to ±13% but remained consistent (<±2%) within each day of measurements and showed no signal loss as a function of dose history. Conclusions: With daily calibrations and DRp specific correction factors, the system reliably provides real-time, millisecond-resolved dosimetric measurements of pulsed conventional and UHDR beams from typical electron linacs, marking an important advancement in UHDR dosimetry and offering diverse applications to FLASH-RT and related fields.

In Vivo Microbeam Radiation Therapy at a Conventional Small Animal Irradiator.

Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γH2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT.

Proton-FLASH: effects of ultra-high dose rate irradiation on an in-vivo mouse ear model.

FLASH-radiotherapy may provide significant sparing of healthy tissue through ultra-high dose rates in protons, electrons, and x-rays while maintaining the tumor control. Key factors for the FLASH effect might be oxygen depletion, the immune system, and the irradiated blood volume, but none could be fully confirmed yet. Therefore, further investigations are necessary. We investigated the protective (tissue sparing) effect of FLASH in proton treatment using an in-vivo mouse ear model. The right ears of Balb/c mice were irradiated with 20 MeV protons at the ion microprobe SNAKE in Garching near Munich by using three dose rates (Conv = 0.06 Gy/s, Flash9 = 9.3 Gy/s and Flash930 = 930 Gy/s) at a total dose of 23 Gy or 33 Gy. The ear thickness, desquamation, and erythema combined in an inflammation score were measured for 180 days. The cytokines TGF-ß1, TNF-α, IL1α, and IL1ß were analyzed in the blood sampled in the first 4 weeks and at termination day. No differences in inflammation reactions were visible in the 23 Gy group for the different dose rates. In the 33 Gy group, the ear swelling and the inflammation score for Flash9 was reduced by (57 ± 12) % and (67 ± 17) % and for Flash930 by (40 ± 13) % and (50 ± 17) % compared to the Conv dose rate. No changes in the cytokines in the blood could be measured. However, an estimation of the irradiated blood volume demonstrates, that 100-times more blood is irradiated when using Conv compared to using Flash9 or Flash930. This indicates that blood might play a role in the underlying mechanisms in the protective effect of FLASH.

A novel electron source for a compact x-ray tube for microbeam radiotherapy with very high dose rates.

Microbeam radiotherapy (MRT) is a novel concept in radiation oncology with arrays of alternating micrometer-wide high-dose peaks and low-dose valleys. Preclinical experiments have shown a lower normal tissue toxicity for MRT with similar tumor control rates compared to conventional radiotherapy. A promising candidate for the demanded compact radiation source is the line-focus x-ray tube. Here, we present the setup of a prototype for an electron accelerator being able to provide a suitable x-ray beam for the tube. Several beam dynamic calculations and simulations were performed concerning particle tracking, thermal and electrostatic properties of the electron source, resulting in a proper beamline, including the cathode, the pierce electrode (PE) and the focusing magnets. These parts are discussed separately. The simulations showed that a rectangular cathode with a small width of 0.4mm is mandatory. To quickly shut down the electron beam, an additional voltage of -600V must be applied to the PE. Moreover, the electric field inside the vacuum chamber stays below 10MVm-1 to minimize the risk of field emission. The thermal simulation validates a small displacement of 0.1mm of the heated cathode with respect to the PE, which must be considered during manufacturing of the cathode-PE assembly. The simulations lead to an adequate choice of cathode, electrodes and beamline to achieve the required focal spot of 0.05×20mm2 with a beam current of 0.3A and an electron energy of 300keV. With this setup first MRT experiments with high dose rates up to 10Gys-1 can be executed.

Good Timing Matters: The Spatially Fractionated High Dose Rate Boost Should Come First.

Monoplanar microbeam irradiation (MBI) and pencilbeam irradiation (PBI) are two new concepts of high dose rate radiotherapy, combined with spatial dose fractionation at the micrometre range. In a small animal model, we have explored the concept of integrating MBI or PBI as a simultaneously integrated boost (SIB), either at the beginning or at the end of a conventional, low-dose rate schedule of 5x4 Gy broad beam (BB) whole brain radiotherapy (WBRT). MBI was administered as array of 50 µm wide, quasi-parallel microbeams. For PBI, the target was covered with an array of 50 µm × 50 µm pencilbeams. In both techniques, the centre-to-centre distance was 400 µm. To assure that the entire brain received a dose of at least 4 Gy in all irradiated animals, the peak doses were calculated based on the daily BB fraction to approximate the valley dose. The results of our study have shown that the sequence of the BB irradiation fractions and the microbeam SIB is important to limit the risk of acute adverse effects, including epileptic seizures and death. The microbeam SIB should be integrated early rather than late in the irradiation schedule.

A matter of space: how the spatial heterogeneity in energy deposition determines the biological outcome of radiation exposure.

The outcome of the exposure of living organisms to ionizing radiation is determined by the distribution of the associated energy deposition at different spatial scales. Radiation proceeds through ionizations and excitations of hit molecules with an ~ nm spacing. Approaches such as nanodosimetry/microdosimetry and Monte Carlo track-structure simulations have been successfully adopted to investigate radiation quality effects: they allow to explore correlations between the spatial clustering of such energy depositions at the scales of DNA or chromosome domains and their biological consequences at the cellular level. Physical features alone, however, are not enough to assess the entity and complexity of radiation-induced DNA damage: this latter is the result of an interplay between radiation track structure and the spatial architecture of chromatin, and further depends on the chromatin dynamic response, affecting the activation and efficiency of the repair machinery. The heterogeneity of radiation energy depositions at the single-cell level affects the trade-off between cell inactivation and induction of viable mutations and hence influences radiation-induced carcinogenesis. In radiation therapy, where the goal is cancer cell inactivation, the delivery of a homogenous dose to the tumour has been the traditional approach in clinical practice. However, evidence is accumulating that introducing heterogeneity with spatially fractionated beams (mini- and microbeam therapy) can lead to significant advantages, particularly in sparing normal tissues. Such findings cannot be explained in merely physical terms, and their interpretation requires considering the scales at play in the underlying biological mechanisms, suggesting a systemic response to radiation.

Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol.

Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible.

The effect of non-ionizing excitations on the diffusion of ion species and inter-track correlations in FLASH ultra-high dose rate radiotherapy.

Purpose. We present a microscopic mechanism that accounts for the outward burst of 'cold' ion species (IS) in a high-energy particle track due to coupling with 'hot' non-ion species (NIS). IS refers to radiolysis products of ionized molecules, whereas NIS refers to non-ionized excitations of molecules in a medium. The interaction is mediated by a quantized field of acoustic phonons, a channel that allows conversion of thermal energy of NIS to kinetic energy of IS, a flow of heat from the outer to the inner core of the track structure.Methods. We perform step-by-step Monte Carlo (MC) simulations of ionizing radiation track structures in water to score the spatial coordinates and energy depositions that form IS and NIS at atto-second time scales. We subsequently calculate the resulting temperature profiles of the tracks with MC track structure simulations and verify the results analytically using the Rutherford scattering formulation. These temperature profiles are then used as boundary conditions in a series of multi-scale atomistic molecular dynamic (MD) simulations that describe the sudden expansion and enhanced diffusive broadening of tracks initiated by the non-equilibrium spectrum of high-energy IS. We derive a stochastic coarse-grained Langevin equation of motion for IS from first-principle MD to describe the irreversible femto-second flow of thermal energy pumping from NIS to IS, mediated by quantized fields of acoustic phonons. A pair-wise Lennard-Jones potential implemented in a classical MD is then employed to validate the results calculated from the Langevin equation.Results. We demonstrate the coexistence of 'hot' NIS with 'cold' IS in the radiation track structures right after their generation. NIS, concentrated within nano-scale volumes wrapping around IS, are the main source of intensive heat-waves and the outward burst of IS due to femto-second time scale IS-NIS coupling. By comparing the transport of IS coupled to NIS with identical configurations of non-interacting IS in thermal equilibrium at room temperature, we demonstrate that the energy gain of IS due to the surrounding hot nanoscopic volumes of NIS significantly increases their effective diffusion constants. Comparing the average track separation and the time scale calculated for a deposited dose of 10 Gy and a dose rate of 40 Gy s-1, typical values used in FLASH ultra high dose rate (UHDR) experiments, we find that the sudden expansion of tracks and ballistic transport proposed in this work strengthens the hypothesis of inter-track correlations recently introduced to interpret mitigation of the biological responses at the FLASH-UHDR (Abolfathet al2020Med. Phys.47, 6551-6561).Conclusions. The much higher diffusion constants predicted in the present model suggest higher inter-track chemical reaction rates at FLASH-UHDR, as well as lower intra-track reaction rates. This study explains why research groups relying on the current Monte Carlo frameworks have reported negligible inter-track overlaps, simply because of underestimation of the diffusion constants. We recommend incorporation of the IS-NIS coupling and heat exchange in all MC codes to enable these tool-kits to appropriately model reaction-diffusion rates at FLASH-UHDR.Novelty. To introduce a hypothetical pathway of outward burst of radiolysis products driven by highly localized thermal spikes wrapping around them and to investigate the interplay of the non-equilibrium spatio-temporal distribution of the chemical activities of diffusive high-energy particle tracks on inter-track correlations at FLASH-UHDR.

Heat management of a compact x-ray source for microbeam radiotherapy and FLASH treatments.

BACKGROUND: Microbeam and x-ray FLASH radiation therapy are innovative concepts that promise reduced normal tissue toxicity in radiation oncology without compromising tumor control. However, currently only large third-generation synchrotrons deliver acceptable x-ray beam qualities and there is a need for compact, hospital-based radiation sources to facilitate clinical translation of these novel treatment strategies. PURPOSE: We are currently setting up the first prototype of a line-focus x-ray tube (LFxT), a promising technology that may deliver ultra-high dose rates (UHDRs) of more than 100 Gy/s from a table-top source. The operation of the source in the heat capacity limit allows very high dose rates with micrometer-sized focal spot widths. Here, we investigate concepts of effective heat management for the LFxT, a prerequisite for the performance of the source. METHODS: For different focal spot widths, we investigated the temperature increase numerically with Monte Carlo simulations and finite element analysis (FEA). We benchmarked the temperature and thermal stresses at the focal spot against a commercial x-ray tube with similar power characteristics. We assessed thermal loads at the vacuum chamber housing caused by scattering electrons in Monte Carlo simulations and FEA. Further, we discuss active cooling strategies and present a design of the rotating target. RESULTS: Conventional focal spot widths led to a temperature increase dominated by heat conduction, while very narrow focal spots led to a temperature increase dominated by the heat capacity of the target material. Due to operation in the heat capacity limit, the temperature increase at the focal spot was lower than for the investigated commercial x-ray tube. Hence, the thermal stress at the focal spot of the LFxT was considered uncritical. The target shaft and the vacuum chamber housing require active cooling to withstand the high heat loads. CONCLUSIONS: The heat capacity limit allows very high power densities at the focal spot of the LFxT and thus facilitates very high dose rates. Numerical simulations demonstrated that the heat load imparted by scattering electrons requires active cooling.

Treatment Planning Study for Microbeam Radiotherapy Using Clinical Patient Data.

Microbeam radiotherapy (MRT) is a novel, still preclinical dose delivery technique. MRT has shown reduced normal tissue effects at equal tumor control rates compared to conventional radiotherapy. Treatment planning studies are required to permit clinical application. The aim of this study was to establish a dose comparison between MRT and conventional radiotherapy and to identify suitable clinical scenarios for future applications of MRT. We simulated MRT treatment scenarios for clinical patient data using an inhouse developed planning algorithm based on a hybrid Monte Carlo dose calculation and implemented the concept of equivalent uniform dose (EUD) for MRT dose evaluation. The investigated clinical scenarios comprised fractionated radiotherapy of a glioblastoma resection cavity, a lung stereotactic body radiotherapy (SBRT), palliative bone metastasis irradiation, brain metastasis radiosurgery and hypofractionated breast cancer radiotherapy. Clinically acceptable treatment plans were achieved for most analyzed parameters. Lung SBRT seemed the most challenging treatment scenario. Major limitations comprised treatment plan optimization and dose calculation considering the tissue microstructure. This study presents an important step of the development towards clinical MRT. For clinical treatment scenarios using a sophisticated dose comparison concept based on EUD and EQD2, we demonstrated the capability of MRT to achieve clinically acceptable dose distributions.

X-Ray Phase Contrast 3D Virtual Histology: Evaluation of Lung Alterations After Microbeam Irradiation.

PURPOSE: This study provides the first experimental application of multiscale 3-dimensional (3D) x-ray phase contrast imaging computed tomography (XPCI-CT) virtual histology for the inspection and quantitative assessment of the late-stage effects of radio-induced lesions on lungs in a small animal model. METHODS AND MATERIALS: Healthy male Fischer rats were irradiated with x-ray standard broad beams and microbeam radiation therapy, a high-dose rate (14 kGy/s), FLASH spatially fractionated x-ray therapy to avoid beamlet smearing owing to cardiosynchronous movements of the organs during the irradiation. After organ dissection, ex vivo XPCI-CT was applied to all the samples and the results were quantitatively analyzed and correlated to histologic data. RESULTS: XPCI-CT enables the 3D visualization of lung tissues with unprecedented contrast and sensitivity, allowing alveoli, vessel, and bronchi hierarchical visualization. XPCI-CT discriminates in 3D radio-induced lesions such as fibrotic scars and Ca/Fe deposits and allows full-organ accurate quantification of the fibrotic tissue within the irradiated organs. The radiation-induced fibrotic tissue content is less than 10% of the analyzed volume for all microbeam radiation therapy-treated organs and reaches 34% in the case of irradiations with 50 Gy using a broad beam. CONCLUSIONS: XPCI-CT is an effective imaging technique able to provide detailed 3D information for the assessment of lung pathology and treatment efficacy in a small animal model.

Tolerance of Normal Rabbit Facial Bones and Teeth to Synchrotron X-Ray Microbeam Irradiation.

Microbeam radiation therapy, an alternative radiosurgical treatment under preclinical investigation, aims to safely treat muzzle tumors in pet animals. This will require data on the largely unknown radiation toxicity of microbeam arrays for bones and teeth. To this end, the muzzle of six young adult New Zealand rabbits was irradiated by a lateral array of microplanar beamlets with peak entrance doses of 200, 330 or 500 Gy. The muzzles were examined 431 days postirradiation by computed microtomographic imaging (micro-CT) ex vivo, and extensive histopathology. The boundaries of the radiation field were identified histologically by microbeam tracks in cartilage and other tissues. There was no radionecrosis of facial bones in any rabbit. Conversely, normal incisor teeth exposed to peak entrance doses of 330 Gy or 500 Gy developed marked caries-like damage, whereas the incisors of the two rabbits exposed to 200 Gy remained unscathed. A single, unidirectional array of microbeams with a peak entrance dose ≤200 Gy (valley dose14 Gy) did not damage normal bone, teeth and soft tissues of the muzzle of normal rabbits longer than one year after irradiation. Because of that, Microbeam radiation therapy of muzzle tumors in pet animals is unlikely to cause sizeable damage to normal teeth, bone and soft tissues, if a single array as used here delivers a limited entrance dose of 200 Gy and a valley dose of ≤14 Gy.

A Multi-Scale and Multi-Technique Approach for the Characterization of the Effects of Spatially Fractionated X-ray Radiation Therapies in a Preclinical Model.

The purpose of this study is to use a multi-technique approach to detect the effects of spatially fractionated X-ray Microbeam (MRT) and Minibeam Radiation Therapy (MB) and to compare them to seamless Broad Beam (BB) irradiation. Healthy- and Glioblastoma (GBM)-bearing male Fischer rats were irradiated in-vivo on the right brain hemisphere with MRT, MB and BB delivering three different doses for each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray Phase Contrast Imaging-Computed Tomography (XPCI-CT), histology, immunohistochemistry, X-ray Fluorescence (XRF), Small- and Wide-Angle X-ray Scattering (SAXS/WAXS). XPCI-CT discriminates with high sensitivity the effects of MRT, MB and BB irradiations on both healthy and GBM-bearing brains producing a first-time 3D visualization and morphological analysis of the radio-induced lesions, MRT and MB induced tissue ablations, the presence of hyperdense deposits within specific areas of the brain and tumor evolution or regression with respect to the evaluation made few days post-irradiation with an in-vivo magnetic resonance imaging session. Histology, immunohistochemistry, SAXS/WAXS and XRF allowed identification and classification of these deposits as hydroxyapatite crystals with the coexistence of Ca, P and Fe mineralization, and the multi-technique approach enabled the realization, for the first time, of the map of the differential radiosensitivity of the different brain areas treated with MRT and MB. 3D XPCI-CT datasets enabled also the quantification of tumor volumes and Ca/Fe deposits and their full-organ visualization. The multi-scale and multi-technique approach enabled a detailed visualization and classification in 3D of the radio-induced effects on brain tissues bringing new essential information towards the clinical implementation of the MRT and MB radiation therapy techniques.

Quantification of Differential Response of Tumour and Normal Cells to Microbeam Radiation in the Absence of FLASH Effects.

Microbeam radiotherapy (MRT) is a preclinical method of delivering spatially-fractionated radiotherapy aiming to improve the therapeutic window between normal tissue complication and tumour control. Previously, MRT was limited to ultra-high dose rate synchrotron facilities. The aim of this study was to investigate in vitro effects of MRT on tumour and normal cells at conventional dose rates produced by a bench-top X-ray source. Two normal and two tumour cell lines were exposed to homogeneous broad beam (BB) radiation, MRT, or were separately irradiated with peak or valley doses before being mixed. Clonogenic survival was assessed and compared to BB-estimated surviving fractions calculated by the linear-quadratic (LQ)-model. All cell lines showed similar BB sensitivity. BB LQ-model predictions exceeded the survival of cell lines following MRT or mixed beam irradiation. This effect was stronger in tumour compared to normal cell lines. Dose mixing experiments could reproduce MRT survival. We observed a differential response of tumour and normal cells to spatially fractionated irradiations in vitro, indicating increased tumour cell sensitivity. Importantly, this was observed at dose rates precluding the presence of FLASH effects. The LQ-model did not predict cell survival when the cell population received split irradiation doses, indicating that factors other than local dose influenced survival after irradiation.

Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer.

PURPOSE: Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines. METHODS: The human pancreatic cancer cell lines, Panc-1 and MIA PaCa-2 were repeatedly exposed to radiation to generate radioresistant (RR) isogenic cell lines. The surviving cells were expanded, and their radiosensitivity was measured using colony formation assay. Tumor growth delay after irradiation was determined in a mouse pancreatic cancer xenograft model. Gene and protein expression were analyzed using RNA sequencing and Western blot, respectively. Cell cycle distribution and apoptosis (Caspase 3/7) were measured by FACS analysis. Reactive oxygen species generation and DNA damage were analyzed by detection of CM-H2DCFDA and γH2AX staining, respectively. Transwell chamber assays were used to investigate cell migration and invasion. RESULTS: The acquired radioresistance of RR cell lines was demonstrated in vitro and validated in vivo. Ingenuity pathway analysis of RNA sequencing data predicted activation of cell viability in both RR cell lines. RR cancer cell lines demonstrated greater DNA repair efficiency and lower basal and radiation-induced reactive oxygen species levels. Migration and invasion were differentially affected in RR cell lines. CONCLUSIONS: Our data indicate that repeated exposure to irradiation increases the expression of genes involved in cell viability and thereby leads to radioresistance. Mechanistically, increased DNA repair capacity and reduced oxidative stress might contribute to the radioresistant phenotype.

Deep Learning Based HPV Status Prediction for Oropharyngeal Cancer Patients.

Infection with the human papillomavirus (HPV) has been identified as a major risk factor for oropharyngeal cancer (OPC). HPV-related OPCs have been shown to be more radiosensitive and to have a reduced risk for cancer related death. Hence, the histological determination of HPV status of cancer patients depicts an essential diagnostic factor. We investigated the ability of deep learning models for imaging based HPV status detection. To overcome the problem of small medical datasets, we used a transfer learning approach. A 3D convolutional network pre-trained on sports video clips was fine-tuned, such that full 3D information in the CT images could be exploited. The video pre-trained model was able to differentiate HPV-positive from HPV-negative cases, with an area under the receiver operating characteristic curve (AUC) of 0.81 for an external test set. In comparison to a 3D convolutional neural network (CNN) trained from scratch and a 2D architecture pre-trained on ImageNet, the video pre-trained model performed best. Deep learning models are capable of CT image-based HPV status determination. Video based pre-training has the ability to improve training for 3D medical data, but further studies are needed for verification.

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 at the 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 of 70 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.

A Mouse Model for Microbeam Radiation Therapy of the Lung.

PURPOSE: Radiation therapy is an important treatment component for patients with lung cancer. However, the survival time gained with clinical radiation therapy techniques is relatively short. Data from preclinical experiments suggest that synchrotron microbeam radiation therapy could be much better suited to control malignant brain tumors than current clinical concepts of radiation therapy. Even at peak doses of several hundred gray, the extent of functional deficits is low. METHODS AND MATERIALS: We have developed the first mouse model to study the effects of microbeam irradiation in lung tissue. RESULTS: Up to peak doses of 400 Gy, no acute adverse effects were seen. CONCLUSION: This model is well suited to explore the potential of microbeam radiation therapy in the treatment of lung cancer and the response of normal lung tissue and organs at risk.

Establishment of Microbeam Radiation Therapy at a Small-Animal Irradiator.

PURPOSE: Microbeam radiation therapy is a preclinical concept in radiation oncology. It spares normal tissue more effectively than conventional radiation therapy at equal tumor control. The radiation field consists of peak regions with doses of several hundred gray, whereas doses between the peaks (valleys) are below the tissue tolerance level. Widths and distances of the beams are in the submillimeter range for microbeam radiation therapy. A similar alternative concept with beam widths and distances in the millimeter range is presented by minibeam radiation therapy. Although both methods were developed at large synchrotron facilities, compact alternative sources have been proposed recently. METHODS AND MATERIALS: A small-animal irradiator was fitted with a special 3-layered collimator that is used for preclinical research and produces microbeams of flexible width of up to 100 µm. Film dosimetry provided measurements of the dose distributions and was compared with Monte Carlo dose predictions. Moreover, the micronucleus assay in Chinese hamster CHO-K1 cells was used as a biological dosimeter. The focal spot size and beam emission angle of the x-ray tube were modified to optimize peak dose rate, peak-to-valley dose ratio (PVDR), beam shape, and field homogeneity. An equivalent collimator with slit widths of up to 500 µm produced minibeams and allowed for comparison of microbeam and minibeam field characteristics. RESULTS: The setup achieved peak entrance dose rates of 8 Gy/min and PVDRs >30 for microbeams. Agreement between Monte Carlo simulations and film dosimetry is generally better for larger beam widths; qualitative measurements validated Monte Carlo predicted results. A smaller focal spot enhances PVDRs and reduces beam penumbras but substantially reduces the dose rate. A reduction of the beam emission angle improves the PVDR, beam penumbras, and dose rate without impairing field homogeneity. Minibeams showed similar field characteristics compared with microbeams at the same ratio of beam width and distance but had better agreement with simulations. CONCLUSION: The developed setup is already in use for in vitro experiments and soon for in vivo irradiations. Deviations between Monte Carlo simulations and film dosimetry are attributed to scattering at the collimator surface and manufacturing inaccuracies and are a matter of ongoing research.

Non-conventional Ultra-High Dose Rate (FLASH) Microbeam Radiotherapy Provides Superior Normal Tissue Sparing in Rat Lung Compared to Non-conventional Ultra-High Dose Rate (FLASH) Radiotherapy.

Conventional radiotherapy is a widely used non-invasive form of treatment for many types of cancer. However, due to a low threshold in the lung for radiation-induced normal tissue damage, it is of less utility in treating lung cancer. For this reason, surgery is the preferred treatment for lung cancer, which has the detriment of being highly invasive. Non-conventional ultra-high dose rate (FLASH) radiotherapy is currently of great interest in the radiotherapy community due to demonstrations of reduced normal tissue toxicity in lung and other anatomy. This study investigates the effects of FLASH microbeam radiotherapy, which in addition to ultra-high dose rate incorporates a spatial segmentation of the radiation field, on the normal lung tissue of rats. With a focus on fibrotic damage, this work demonstrates that FLASH microbeam radiotherapy provides an order of magnitude increase in normal tissue radio-resistance compared to FLASH radiotherapy. This result suggests FLASH microbeam radiotherapy holds promise for much improved non-invasive control of lung cancer.