Paolo Pellicioli

Développement d'un protocole de film dosimétrie pour la radiothérapie par microfaisceaux synchrotron: But de l’étude:La radiothérapie par microfaisceaux (Microbeam Radiation Therapy: MRT) est une nouvelle approche de la radiothérapie pour le traitement du cancer et de certaines maladies neurologiques basée sur des champs spatialement fractionnés à l'échelle micrométrique. La MRT est réalisée avec des rayons X d’orthovoltage, les faisceaux sont classiquement des faisceaux plans de 50 µm de large espacés de 400 µm. La MRT permet de mieux ménager les tissus sains et de mieux contrôler les tumeurs par rapport à la radiothérapie conventionnelle basée sur des irradiations homogènes. Des protocoles de dosimétrie fiables et robustes constituent la base de toute radiothérapie, car une définition précise de la dose est indispensable pour la mise en œuvre de toute radiothérapie. La dosimétrie en MRT est difficile en raison des conditions extrêmes dans lesquelles elle est effectuée. Les différences entre les doses simulées et mesurées en MRT sont généralement bien supérieures à la limite de 3% utilisée en radiothérapie conventionnelle. Des améliorations de la dosimétrie en MRT sont nécessaires sur les plans méthodologique, expérimental et de simulation informatique, afin de rendre cette technique de radiothérapie innovante disponible en clinique.Méthodes:Les films radiochromiques ont plusieurs propriétés utiles pour la dosimétrie en MRT et un protocole de lecture pour leur analyse à l'échelle micrométrique a été développé en utilisant un microscope optique. La détermination des facteurs critiques influençant la dosimétrie sur film et, plus généralement, la dosimétrie en MRT a été réalisée. Les simulations de transport de rayonnement de Monte Carlo (MC), mises en œuvre avec le code Geant4, ont été utilisées pour améliorer les modèles de dosimétrie en MRT. Lorsque des films sont placés entre les plaques de plastique d'un fantôme afin de les irradier avec un ensemble de microfaisceaux, la présence d'espaces d'air entre le film et le plastique peut influencer la distribution de la dose et ce facteur a été quantifié. L’interaction des rayons X avec un collimateur à plusieurs lames (MultiSlit Collimator : MSC) est l’un des éléments les plus critiques pour la description correcte du profil de dose de l’ensemble des microfaisceaux. La réflexion du rayonnement à partir de la surface interne du MSC a été étudiée. En outre, la fuite de rayonnement à travers les sections métalliques du MSC a été étudiée. Tous ces facteurs ont été pris en compte pour comparer la simulation Monte Carlo à la dosimétrie sur film pour l’évaluation de la dose.Résultats:La caractérisation des composants du microscope optique et du protocole de traitement d'image a fourni une incertitude totale (2σ) pour la lecture du film de 3,8%. La présence d'espaces d'air entre les plaques du fantôme utilisé dégrade la distribution de la dose déposée par les microfaisceaux: ainsi des espaces d'air de 30 µm augmentent la dose dans la vallée jusqu’à 12%. L’étude de l’interaction photon - MSC montre que la réflexion du rayonnement peut amener entre 5% et 15% de dose supplémentaire. La fuite de rayonnement à travers le MSC est un autre facteur important, en augmentant les doses de 5% à 30%.Compte tenu de tous ces facteurs dans la dosimétrie en MRT, la concordance entre les simulations MC et la dosimétrie sur film a été significativement améliorée par rapport à la plage de 10-30% obtenue jusqu'à présent. Les différences entre les doses calculées et mesurées sont désormais inférieures à 5% pour la dosimétrie dans un fantôme équivalent eau.Conclusion:Ce travail a amélioré la dosimétrie des MRT en établissant un protocole robuste et fiable pour la dosimétrie sur film radiochromique à l'échelle micrométrique, à l'aide d'un microscope optique. Plusieurs problèmes de dosimétrie en MRT ont été résolus et la concordance entre les doses simulées et mesurées est maintenant proche des exigences de la radiothérapie en médecine, rapprochant ainsi la MRT de ses potentielles applications cliniques.

Objective: One‐third of patients with epilepsy, particularly those with mesial temporal lobe epilepsy (MTLE), remain resistant to medication. Resective surgery, the gold standard, is highly invasive and carries significant risks. Here, using a mouse model, we explored the potential of microbeam radiation therapy (MRT), a new technique based on the spatial microfractionation of high‐flux X‐rays, as a non‐invasive alternative for treating MTLE. Methods: MTLE was modeled in male C57BL6/J mice via unilateral kainate injection in the dorsal hippocampus. Mice with magnetic resonance imaging (MRI)–validated hippocampal sclerosis (HS) were irradiated at the European Synchrotron Radiation Facility (ESRF) using MRT with either a single trajectory (peak doses = 125–500 Gy) or multiple trajectories (2 or 5 ports at a cumulated peak dose of 125 Gy at the target). Their focal seizures were then monitored with use of electroencephalography (EEG) during 8 weeks, upon which immunochemistry was performed to assess potential tissular toxicity. Results: Anteroposterior 1‐port MRT significantly reduced EEG‐recorded focal seizures at 125 and 250 Gy, in a dose‐dependent manner. However, increased mortality was observed at 500 Gy. Immunohistolabeling revealed neuronal loss (revealed by NeuN staining), microgliosis (revealed by Iba1 straining), and astrogliosis (revealed by GFAP staining) limited to the microbeam tracks at all doses in the injected hippocampus and adjacent brain structures (e.g., cortex). Five‐port MRT with a peak dose of 125 Gy at the target improved the antiepileptic effect, whereas no significant tissue alterations outside the microbeam tracks were detected by histological assessment. Significance: This proof‐of‐concept study highlights MRT as a promising non‐invasive therapy for drug‐resistant focal epilepsies with optimal peak doses of 125–250 Gy, and it suggests that distributing the dose through multiple angles optimizes the therapeutic effect. MRT could provide a safer alternative to surgery, warranting further investigations.

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

Objective. Radiation therapy requires reliable dosimetry protocols to deliver successful treatments with high accuracy and precision. In this context, accurate knowledge of the beam’s energy spectra is mandatory. The goal of this study was to validate the synchrotron x-ray spectrum of the ID17 beamline at the European Synchrotron Radiation Facility (ESRF). The modification of the synchrotron storage ring and beamline in recent years necessitates a new characterisation of the radiation spectra of the ID17 beamline. The validated spectra will be a starting point for possible future clinical applications. Approach. The half value layer method was used to measure the attenuation of the x-ray spectrum in Al and Cu. Experimental data was validated against theoretical data produced using OASYS; an in-house developed software for calculating beamline spectra. Two different spectral configurations, ‘conventional’ and ‘clinical’, were investigated. The characterised spectra were used to perform dosimetric validation of depth dose profiles measured in a water-equivalent phantom. The dose profile was measured using two different detectors and compared with calculations generated using two different Monte Carlo algorithms. Main results. The results showed good agreement between measured and predicted half value layers, with differences of less than 1% in most cases. Excellent dosimetric agreement to within 3% was obtained, an agreement that satisfies the requirements in conventional radiotherapy for approvable treatment planning. Significance. Accurate spectra have been defined and validated for the ESRF—ID17 Biomedical beamline. The validated spectra can be used as input for future dosimetric studies and treatment planning systems in the context of preclinical studies and possible future clinical trials.

Microbeam radiation therapy (MRT) is a radiotherapy technique combining spatial fractionation of the dose distribution on a micrometric scale, X-rays in the 50–500 keV range and dose rates up to 16 × 10³ Gy s⁻¹. Nowadays, in vivo dosimetry remains a challenge due to the ultra-high radiation fluxes involved and the need for high-spatial-resolution detectors. The aim here was to develop a striped diamond portal detector enabling online microbeam monitoring during synchrotron MRT treatments. The detector, a 550 µm bulk monocrystalline diamond, is an eight-strip device, of height 3 mm, width 178 µm and with 60 µm spaced strips, surrounded by a guard ring. An eight-channel ASIC circuit for charge integration and digitization has been designed and tested. Characterization tests were performed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility (ESRF). The detector measured direct and attenuated microbeams as well as interbeam fluxes with a precision level of 1%. Tests on phantoms (RW3 and anthropomorphic head phantoms) were performed and compared with simulations. Synchrotron radiation measurements were performed on an RW3 phantom for strips facing a microbeam and for strips facing an interbeam area. A 2% difference between experiments and simulations was found. In more complex geometries, a preliminary study showed that the absolute differences between simulated and recorded transmitted beams were within 2%. Obtained results showed the feasibility of performing MRT portal monitoring using a microstriped diamond detector. Online dosimetric measurements are currently ongoing during clinical veterinary trials at ESRF, and the next 153-strip detector prototype, covering the entire irradiation field, is being finalized at our institution.