Les systèmes de planification de traitement dédiés à la radiothérapie par les rayonnements synchrotron (MRT)

International audience35èmesJournées des L.A.R.D., Clermont-Ferrand, 1 et 2 Avril 2019Revue étudesLes systèmesde planification de traitement dédiés à la radiothérapie par les rayonnements synchrotron (MRT)Sarvenaz KESHMIRI1, Raphaël SERDUC1, Jean-François ADAM11Inserm UA7, Université Grenoble Alpes, STROBE, Grenoble, France.RésuméLe but de la radiothérapie estadministrer une dose létaleà la tumeur, tout en épargnant les tissus normaux voisins. Uneréponse extraordinairede la parte des tissus sains auxfaisceaux de rayons X très fractionnés spatialement a été explorée depuis plus de25 ans[1, 2]. La radiothérapiepar microfaisceaux(MRT) est une nouvelle approchede la radiothérapie qui utilise des réseaux de quelques dizaines faisceaux planairesde micromètres de largeur etespacés de 100 μm avec des doses extrêmement élevées aux régions de doseélevées et des doses inférieures au niveau detolérance entre les faisceaux[3]. Cesmicrofaisceauxsont produits par uncollimateur multi slits(MSLC)[4], qui lesfractionne dans la direction horizontale. Le spectre final du faisceau de photons à la position du patient présente une distribution continue dans une plage de 27 keV à 600 keV avecune énergie moyenne d’environ 100 keV[5, 6]. La dose centrale entre deux microfaisceaux est appelée dose de vallée, tandis que la dose au centre du microfaisceau est la dose de pic. Le rapport entre les doses de pics et les doses reçues dans lesvalléess'appelle le rapport de dose de pic à la vallée (PVDR) et cette valeur joue un rôle important dans la réponse biologique[7].L'évaluation de la dose déposée dans la direction du faisceau est un aspect crucial de la MRT, car elle détermine l'efficacité de traitement. Le calcul précis de la dose est une condition préalable importante pour l’application clinique future de la MRT en tant que modalité de traitement. Le calcul de la dose en TRM implique des défis supplémentaires par rapport aux calculs de dose en radiothérapie conventionnelle, tels que la détermination de la dose en grille micrométrique, une plage dynamique vaste et l’invalidité du théorèmede mise à l'échelle de la dosed’O’Connor[5, 6]. En générale, nous avons trois catégories de méthode de calcul de la dose dans la MRT: lesméthodesde Monte Carlo pures[8, 9, 10], lesméthodesbasées sur la convolution et lesméthodeshybrides[11].L'objectif de cette revueest d'étudier les avantages et les inconvénients des méthodes existantes et de proposer une méthode qui donne la dose avec une grande précision dans un temps de calcul compatible avec les utilisations cliniques.References[1]Martínez-Rovira, G.Fois, Y.Prezado. Dosimetic evaluation of new approaches in GRID therapy using non-conventional radiation sources.Med Phys. 42(2):685-93, 2015.[2]J.Meyer, J.Eley, TE.Schmid, SE. Combs, R.Dendale, Y.Prezado. Spatially fractionated proton minibeams. Br.J.Radiol; 92(1095):20180466, 2019.[3]E.Bräuer-Krisch, R.Serduc,E.A.Siegbahn,G.Le Duc,Y.Prezado,A.Bravin,H.Blattmann,J.A.Laissue.Effects of pulsed, spatially fractionated, microscopic synchrotron X-ray beams on normal and tumoral brain tissue.Mutation Research, 704: 160-6, 2010.[4]I.Martínez-Rovira, J. Sempau, S.Bartzsch. Development and commissioning of a Monte Carlo photon beam model for the forthcoming clinical trials in microbeam radiation therapy.Med Phys. 39(1):119-31, 2012.[5]C.Debus, U.Oelfke, Y. Prezado. A point kernel algorithm for microbeam radiation therapy.Phys. Med. Biol.62,8341–8359, 2017.[6]S.Bartzsch, U.Oelfke. A new concept of pencil beam dose calculation for 40–200 keV photons using analyticaldose kernels. Med Phys. 40(11):111714, 2013.[7]Martínez-Rovira, J. Sempau, S.Bartzsch. Monte Carlo-based treatment planning system calculation enginefor microbeam radiation therapy. Med Phys. 39(5):2829-38, 2012.[8]J. Spiga, E. A. Siegbahn and E.Bräuer-Krisch, P. Randaccio, A. Bravin.The GEANT4 toolkit for microdosimetry calculations: Application to microbeam radiation therapy (MRT).Med Phys. 34(11):4322-30, 2007.[9]A. Boudou, J. Balosso, F.Estève and H.Elleaume. Monte Carlo dosimetry for synchrotron stereotactic radiotherapy of brain tumours.Phys Med Biol.50(20):4841-51, 2005.[10]M.De Felici, R. Felici , M. Sanchez del Rio, C. Ferrero , T.Bacarian , FA. Dilmanian . Dosedistribution from x-ray microbeam arrays applied to radiation therapy: an EGS4 Monte Carlo study.Med Phys.32(8):2455-63, 2005.[11]M.Donzelli, E.Bräuer-Krisch, U.Oelfke, J.J.Wilkens and S.Bartzsch. Hybrid dose calculation: a dose calculation algorithm for microbeam radiation therapy.Phys Med Biol. 63(4):045013, 201

High-Precision Radiosurgical Dose Delivery by Interlaced Microbeam Arrays of High-Flux Low-Energy Synchrotron X-Rays

Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 µm wide, spaced 200 µm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm3 in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy

Effets de la radiothérapie par microfaisceaux synchrotron sur la microvascularisation cérébrale saine et tumorale chez la souris

La radiothérapie par microfaisceaux (MRT) est une nouvelle forme de radiochirurgie des tumeurs cérébrales utilisant les rayons X produits par un synchrotron. Elle est basée sur un fractionnemènt spatial du faisceau incident en microfaisceaux de quelques dizaines de micromètres de largeur et permet de délivrer des doses de radiation extrêmement élevées (plusieurs centaines de Gy) sans induire de dégâts tissulaires importants dans les tissus bordant la lésion. Dans ce travail, nous avons pu montrer que l'irradiation en mode microfaisceau n'induisait pas de modification des paramètres morphométriques du réseau vasculaire cérébral de la souris nude (densité de vaisseaux, volume sanguin) au cours des 3 premiers mois qui suivent une irradiation à 312 ou 1000 Gy. Le réseau vasculaire reste par ailleurs perfusé quelque soit la dose déposée. Une augmentation de la perméabilité de la barrière hémato-encéphalique a pu être mise en évidence entre la 12ème heure et le 12ème jour après une irradiation à 1000 Gy. Cependant, l'œdème cérébral détecté à la phase aigue après exposition et associé avec une augmentation significative du contenu cérébral en eau, semble être rapidement résorbé. L'absence de dommages vasculaires importants au niveau des tissus cérébraux sains assurerait un maintien de l'apport en oxygène et nutriments aux tissus irradiés et permettrait d'expliquer la résistance surprenante des tissus sains face à la l'irradiation microfaisceau. Par ailleurs nous avons montré que la MRT augmentait significativement la médiane de survie de souris nude porteuses de gliosarcomes 9L. Cependant, il semble que la MRT, dans les conditions dans lesquelles elle a été utilisée dans cette étude, n'ait qu'un effet limité sur le réseau vasculaire tumoral, puisque aucune modification du volume sanguin ou de l'index de taille des vaisseaux (mesurés par IRM) n'a pu être mise en évidence après MRT. En revanche, une augmentation de la perméabilité vasculaire tumorale, détectée 24h après irradiation, pourrait être exploitée afin de délivrer spécifiquement des chimio-agents à la lésion via le système circulatoire. Les paramètres d'irradiation devraient être optimisés afin de cibler au mieux le tissu vasculaire tumoral et d'augmenter encore l'index thérapeutique de la radiothérapie par microfaisceaux.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

PenMRT: A PENELOPE based high-resolution dose calculation engine for microbeam radiation therapy

International audienceIn radiotherapy, the compromise between an increased tumoral control and reduced side effects is quantified as the therapeutic index. In order to increase the therapeutic index, the use of synchrotron generated x-rays spatially fractionated into microbeams is being studied. The treatment in micorbeam radiation therapy (MRT) is performed via an array of intense parallel microbeams (25-50 μm wide beams replicated with a pitch of 200-400 μm) at high dose rate to benefits from the improved healthy tissues due to the dose-volume effect and FLASH effect. The promising preclinical results of MRT[1], encourages its clinical transfer. A safe clinical transfer of MRT needs an adequate treatment planning system (TPS). The calculation core of this TPS must be able to calculate accurately the dose in human or animal patient by taking into account the MRT beam specificities (high dose gradients, spatial fractionation and polarization effect). The most advanced dose calculation engine for MRT is a hybrid algorithm which inherits photon transport from Monte-Carlo (MC) method and electron transport from convolution based methods [2]. This algorithm is remarkably fast but limited to macroscopic rendering of dose without taking into account the complexity of dose distribution in multidirectional treatments. To overcome the limitations of the existing calculation methods, a multi-scale full MC dose calculation engine called penMRT has been developed and benchmarked against an already validated main program in the PENELOPE code package

A high resolution dose calculation engine for x‐ray microbeams radiation therapy

International audienceBackgroundMicrobeam radiation therapy (MRT) is a treatment modality based on spatial fractionation of synchrotron generated x-rays into parallel, high dose, microbeams of a few microns width. MRT is still an under-development radiosurgery technique for which, promising preclinical results on brain tumors and epilepsy encourages its clinical transfer.PurposeA safe clinical transfer of MRT needs a specific treatment planning system (TPS) that provides accurate dose calculations in human patients, taking into account the MRT beams properties (high dose gradients, spatial fractionation, polarization effects). So far, the most advanced MRT treatment planning system, based on a hybrid dose calculation algorithm, is limited to a macroscopic rendering of the dose and does not account for the complex dose distribution inherent to MRT if delivered as conformal irradiations with multiple incidences. For overcoming these limitations, a multi-scale full Monte-Carlo calculation engine called penMRT has been developed and benchmarked against two general purpose Monte Carlo codes: penmain based on PENELOPE and Gate based on Geant4.MethodsPenMRT, is based on the PENELOPE (2018) Monte Carlo (MC) code, modified to take into account the voxelized geometry of the patients (CT-scans) and offering an adaptive micrometric dose calculation grid independent to the CT size, location and orientation. The implementation of the dynamic memory allocation in penMRT, makes the simulations feasible within a huge number of dose scoring bins. The possibility of using a source replication approach to simulate arrays of microbeams, and the parallelization using OpenMPI have been added to penMRT in order to increase the calculation speed for clinical usages. This engine can be implemented in a TPS as a dose calculation core.ResultsThe performance tests highlight the reliability of penMRT to be used for complex irradiation conditions in MRT. The benchmarking against a standard PENELOPE code did not show any significant difference for calculations in centimetric beams, for a single microbeam and for a microbeam array. The comparisons between penMRT and Gate as an independent MC code did not show any difference in the beam paths, whereas in valley regions, relative differences between the two codes rank from 1 to 7.5% which are probably due to the differences in physics lists that are used in these two codes. The reliability of the source replication approach has also been tested and validated with an underestimation of no more than 0.6% in low dose areas.ConclusionsGood agreements (a relative difference between 0 to 8%) were found when comparing calculated peak to valley dose ratio (PVDR) values using penMRT, for irradiations with a full microbeam array, with calculated values in the literature. The high-resolution calculated dose maps obtained with penMRT are used to extract differential and cumulative dose-volume histograms (DVHs) and analyze treatment plans with much finer metrics regarding the irradiation complexity. To our knowledge, these are the first high-resolution dose maps and associated DVHs ever obtained for cross-fired microbeams irradiation, which is bringing a significant added value to the field of treatment planning in spatially fractionated radiation therapy

A high resolution dose calculation engine for x‐ray microbeams radiation therapy

International audienceBackgroundMicrobeam radiation therapy (MRT) is a treatment modality based on spatial fractionation of synchrotron generated x-rays into parallel, high dose, microbeams of a few microns width. MRT is still an under-development radiosurgery technique for which, promising preclinical results on brain tumors and epilepsy encourages its clinical transfer.PurposeA safe clinical transfer of MRT needs a specific treatment planning system (TPS) that provides accurate dose calculations in human patients, taking into account the MRT beams properties (high dose gradients, spatial fractionation, polarization effects). So far, the most advanced MRT treatment planning system, based on a hybrid dose calculation algorithm, is limited to a macroscopic rendering of the dose and does not account for the complex dose distribution inherent to MRT if delivered as conformal irradiations with multiple incidences. For overcoming these limitations, a multi-scale full Monte-Carlo calculation engine called penMRT has been developed and benchmarked against two general purpose Monte Carlo codes: penmain based on PENELOPE and Gate based on Geant4.MethodsPenMRT, is based on the PENELOPE (2018) Monte Carlo (MC) code, modified to take into account the voxelized geometry of the patients (CT-scans) and offering an adaptive micrometric dose calculation grid independent to the CT size, location and orientation. The implementation of the dynamic memory allocation in penMRT, makes the simulations feasible within a huge number of dose scoring bins. The possibility of using a source replication approach to simulate arrays of microbeams, and the parallelization using OpenMPI have been added to penMRT in order to increase the calculation speed for clinical usages. This engine can be implemented in a TPS as a dose calculation core.ResultsThe performance tests highlight the reliability of penMRT to be used for complex irradiation conditions in MRT. The benchmarking against a standard PENELOPE code did not show any significant difference for calculations in centimetric beams, for a single microbeam and for a microbeam array. The comparisons between penMRT and Gate as an independent MC code did not show any difference in the beam paths, whereas in valley regions, relative differences between the two codes rank from 1 to 7.5% which are probably due to the differences in physics lists that are used in these two codes. The reliability of the source replication approach has also been tested and validated with an underestimation of no more than 0.6% in low dose areas.ConclusionsGood agreements (a relative difference between 0 to 8%) were found when comparing calculated peak to valley dose ratio (PVDR) values using penMRT, for irradiations with a full microbeam array, with calculated values in the literature. The high-resolution calculated dose maps obtained with penMRT are used to extract differential and cumulative dose-volume histograms (DVHs) and analyze treatment plans with much finer metrics regarding the irradiation complexity. To our knowledge, these are the first high-resolution dose maps and associated DVHs ever obtained for cross-fired microbeams irradiation, which is bringing a significant added value to the field of treatment planning in spatially fractionated radiation therapy

Hybrid dose calculation algorithm for high flux synchroton X-Rays Microbeam Radiation Therapy (MRT)

International audienceSarvenaz KESHMIRI, Alexandre Ocadiz, Raphaël Serduc, Jean-François AdamInserm UA7, Université Grenoble Alpes, STROBE, Grenoble, FranceAbstractA curative radiation therapy treatment requires high absorbed dose in a malignant area and minimizing the damages to the neighbouring normal tissues. Increased normal tissue sparing effect to highly spatially fractionated radiation therapy (SFRT) has been extensively explored for the past 25 years. Microbeam radiation therapy (MRT) is an approach based on dose-volume effect which uses spatially fractionated high flux synchrotron X-ray beams as arrays of micrometric beamlets. The zone of interest is irradiated with high doses through beams path (>100 Gy) and doses below tolerance level between the beamlets. The precilinical experiences performed at the European Synchrotron Radiation Facility (ESRF) confirmed the MRT’s higher therapeutic index compared to non-fractionated beams with the same characteristics.The biological response and in consequence the effectiveness of MRT treatments depend on beamlet dose (peak) and central dose between beamlets (valley) as well as peak to valley dose ratio (PVDR). In order to have an optimal therapeutic gain, the PVDR should be maximised and accurately calculated. The commercially available treatment planning systems (TPS) are not suitable for MRT dose planning, due to its distinct features of irradiation geometry, beam source, low energy spectrum and beam polarization compared to conventionalradiotherapy. Therefore, in pursuing the realisation of this treatment modality, it is important to have a modern treatment planning paradigm. There are three categories of dose calculation methods for MRT: pure Monte Carlo, convolution based methods and hybrid methods. The aims of this study was to investigate the reliability, the pros and cons of hybrid dose calculation algorithm and to validate this algorithm using experimental film dosimetr