Nouvelles approches en Radiothérapie

Publications de l’équipe

Année de publication : 2019

Tim Schneider, Annalisa Patriarca, Yolanda Prezado (2019 Jun 8)

Improving the dose distributions in minibeam radiation therapy: Helium ions vs protons.

Medical physics : 3640-3648 : DOI : 10.1002/mp.13646 En savoir plus
Résumé

Charged particle minibeam radiation therapy is a novel therapeutic strategy aiming at reducing the normal tissue complication probability by combining the normal tissue sparing of submillimetric, spatially fractionated beams with the improved dose deposition of ions. This may allow a safe dose escalation in the tumor and other targets. In particular, proton minibeam radiation therapy has already proven a remarkable increase of the therapeutic index for high-grade gliomas in animal experiments. The reduced multiple Coulomb scattering and nuclear fragmentation of helium ions compared to protons and heavier ions, respectively, make them a good candidate for minibeam radiation therapy (MBRT). The purpose of the present work was to perform a comprehensive dosimetric comparison between proton and helium MBRT (pMBRT and HeMBRT).

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Yolanda Prezado, Gregory Jouvion, Consuelo Guardiola, Wilfredo Gonzalez, Marjorie Juchaux, Judith Bergs, Catherine Nauraye, Dalila Labiod, Ludovic De Marzi, Frederic Pouzoulet, Annalisa Patriarca, Remi Dendale (2019 Feb 1)

Tumor Control in RG2 Glioma-Bearing Rats: A Comparison Between Proton Minibeam Therapy and Standard Proton Therapy.

International journal of radiation oncology, biology, physics : 266-271 : DOI : S0360-3016(19)30171-3 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel radiation therapy approach that exploits the synergies of proton therapy with the gain in normal tissue preservation observed upon irradiation with narrow, spatially fractionated, beams. The net gain in normal tissue sparing that has been shown by pMBRT may lead to the efficient treatment of very radioresistant tumors, which are currently mostly treated palliatively. The aim of this study was to perform an evaluation of the tumor effectiveness of proton minibeam radiation therapy for the treatment of RG2 glioma-bearing rats.

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Année de publication : 2018

Yolanda Prezado, Gregory Jouvion, Annalisa Patriarca, Catherine Nauraye, Consuelo Guardiola, Marjorie Juchaux, Charlotte Lamirault, Dalila Labiod, Laurene Jourdain, Catherine Sebrie, Remi Dendale, Wilfredo Gonzalez, Frederic Pouzoulet (2018 Nov 9)

Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas.

Scientific reports : 16479 : DOI : 10.1038/s41598-018-34796-8 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel strategy which has already shown a remarkable reduction in neurotoxicity as to compared with standard proton therapy. Here we report on the first evaluation of tumor control effectiveness in glioma bearing rats with highly spatially modulated proton beams. Whole brains (excluding the olfactory bulb) of Fischer 344 rats were irradiated. Four groups of animals were considered: a control group (RG2 tumor bearing rats), a second group of RG2 tumor-bearing rats and a third group of normal rats that received pMBRT (70 Gy peak dose in one fraction) with very heterogeneous dose distributions, and a control group of normal rats. The tumor-bearing and normal animals were followed-up for 6 months and one year, respectively. pMBRT leads to a significant tumor control and tumor eradication in 22% of the cases. No substantial brain damage which confirms the widening of the therapeutic window for high-grade gliomas offered by pMBRT. Additionally, the fact that large areas of the brain can be irradiated with pMBRT without significant side effects, would allow facing the infiltrative nature of gliomas.

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Juergen Meyer, John Eley, Thomas E Schmid, Stephanie E Combs, Remi Dendale, Yolanda Prezado (2018 Oct 26)

Spatially fractionated proton minibeams.

The British journal of radiology : 20180466 : DOI : 10.1259/bjr.20180466 En savoir plus
Résumé

Extraordinary normal tissue response to highly spatially fractionated X-ray beams has been explored for over 25 years. More recently, alternative radiation sources have been developed and utilized with the aim to evoke comparable effects. These include protons, which lend themselves well for this endeavour due to their physical depth dose characteristics as well as corresponding variable biological effectiveness. This paper addresses the motivation for using protons to generate spatially fractionated beams and reviews the technological implementations and experimental results to date. This includes simulation and feasibility studies, collimation and beam characteristics, dosimetry and biological considerations as well as the results of in vivo and in vitro studies. Experimental results are emerging indicating an extraordinary normal tissue sparing effect analogous to what has been observed for synchrotron generated X-ray microbeams. The potential for translational research and feasibility of spatially modulated proton beams in clinical settings is discussed.

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Ludovic De Marzi, Annalisa Patriarca, Catherine Nauraye, Eric Hierso, Rémi Dendale, Consuelo Guardiola, Yolanda Prezado (2018 Oct 13)

Implementation of planar proton minibeam radiation therapy using a pencil beam scanning system: A proof of concept study.

Medical physics : 5305-5316 : DOI : 10.1002/mp.13209 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose-rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments.

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Consuelo Guardiola, Yolanda Prezado, Christophe Roulin, Judith W J Bergs (2018 Sep 14)

Effect of X-ray minibeam radiation therapy on clonogenic survival of glioma cells.

Clinical and translational radiation oncology : 7-13 : DOI : 10.1016/j.ctro.2018.07.005 En savoir plus
Résumé

The goal is to compare, the efficiency of minibeam radiotherapy (MBRT) and standard RT in inducing clonogenic cell death in glioma cell lines. With this aim, we report on the first study performed in an X-ray Small Animal Radiation Research Platform (SARRP) modified for minibeam irradiations. F98 rat and U87 human glioma cells were irradiated with either an array of minibeams (MB) or with conventional homogeneous beams (broad beam, BB). A specially designed multislit collimator was used to generate the minibeams with a with of a center-to-center distance of 1465 (±10) μm, and a PVDR value of 12.4 (±2.3) measured at 1 cm depth in a water phantom. Cells were either replated for clonogenic assay directly (immediate plating, IP) or 24 h after irradiation (delayed plating, DP) to assess the effect of potentially lethal damage repair (PLDR) on cell survival. Our hypothesis is that with MBRT, a similar level of clonogenic cell death can be reached compared to standard RT, when using equal mean radiation doses. To prove this, we performed dose escalations to determine the minimum integrated dose needed to reach a similar level of clonogenic cell death for both treatments. We show that this minimum dose can vary per cell line: in F98 cells a dose of 19 Gy was needed to obtain similar levels of clonogenic survival, whereas in U87 cells there was still a slightly increased survival with MB compared to BB 19 Gy treatment. The results suggest also an impairment of DNA damage repair in F98 cells as there is no difference in clonogenic cell survival between immediately and delayed plated cells for each dose and irradiation mode. For U87 cells, a small IP-DP effect was observed in the case of BB irradiation up to a dose of 17 Gy. However, at 19 Gy BB, as well as for the complete dose range of MB irradiation, U87 cells did not show a difference in clonogenic survival between IP and DP. We therefore speculate that MBRT might influence PLDR. The current results show that X-ray MBRT is a promising method for treatment of gliomas: future preclinical and clinical studies should aim at reaching a minimum radiation (valley) dose for effective eradication of gliomas with increased sparing of normal tissues compared to standard RT.

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Francisco Manchado de Sola, Manuel Vilches, Yolanda Prezado, Antonio M Lallena (2018 May 16)

Impact of cardiosynchronous brain pulsations on Monte Carlo calculated doses for synchrotron micro- and minibeam radiation therapy.

Medical physics : 3379-3390 : DOI : 10.1002/mp.12973 En savoir plus
Résumé

The purpose of this study was to assess the effects of brain movements induced by heartbeat on dose distributions in synchrotron micro- and minibeam radiation therapy and to develop a model to help guide decisions and planning for future clinical trials.

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Année de publication : 2017

Y Prezado, M Dos Santos, W Gonzalez, G Jouvion, C Guardiola, S Heinrich, D Labiod, M Juchaux, L Jourdain, C Sebrie, F Pouzoulet (2017 Dec 13)

Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept.

Scientific reports : 17295 : DOI : 10.1038/s41598-017-17543-3 En savoir plus
Résumé

Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.

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Yolanda Prezado, Gregory Jouvion, David Hardy, Annalisa Patriarca, Catherine Nauraye, Judith Bergs, Wilfredo González, Consuelo Guardiola, Marjorie Juchaux, Dalila Labiod, Remi Dendale, Laurène Jourdain, Catherine Sebrie, Frederic Pouzoulet (2017 Nov 2)

Proton minibeam radiation therapy spares normal rat brain: Long-Term Clinical, Radiological and Histopathological Analysis.

Scientific reports : 14403 : DOI : 10.1038/s41598-017-14786-y En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel strategy for minimizing normal tissue damage resulting from radiotherapy treatments. This strategy partners the inherent advantages of protons for radiotherapy with the gain in normal tissue preservation observed upon irradiation with narrow, spatially fractionated beams. In this study, whole brains (excluding the olfactory bulb) of Fischer 344 rats (n = 16) were irradiated at the Orsay Proton Therapy Center. Half of the animals received standard proton irradiation, while the other half were irradiated with pMBRT at the same average dose (25 Gy in one fraction). The animals were followed-up for 6 months. A magnetic resonance imaging (MRI) study using a 7-T small-animal MRI scanner was performed along with a histological analysis. Rats treated with conventional proton irradiation exhibited severe moist desquamation, permanent epilation and substantial brain damage. In contrast, rats in the pMBRT group exhibited no skin damage, reversible epilation and significantly reduced brain damage; some brain damage was observed in only one out of the eight irradiated rats. These results demonstrate that pMBRT leads to an increase in normal tissue resistance. This net gain in normal tissue sparing can lead to the efficient treatment of very radio-resistant tumours, which are currently mostly treated palliatively.

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Immaculada Martínez-Rovira, Josep Puxeu-Vaqué, Yolanda Prezado (2017 Jul 25)

Dose evaluation of Grid Therapy using a 6 MV flattening filter-free (FFF) photon beam: A Monte Carlo study.

Medical physics : 5378-5383 : DOI : 10.1002/mp.12485 En savoir plus
Résumé

Spatially fractionated radiotherapy is a strategy to overcome the main limitation of radiotherapy, i.e., the restrained normal tissue tolerances. A well-known example is Grid Therapy, which is currently performed at some hospitals using megavoltage photon beams delivered by Linacs. Grid Therapy has been successfully used in the management of bulky abdominal tumors with low toxicity. The aim of this work was to evaluate whether an improvement in therapeutic index in Grid Therapy can be obtained by implementing it in a flattening filter-free (FFF) Linac. The rationale behind is that the removal of the flattening filter shifts the beam energy spectrum towards lower energies and increase the photon fluence. Lower energies result in a reduction of lateral scattering and thus, to higher peak-to-valley dose ratios (PVDR) in normal tissues. In addition, the gain in fluence might allow using smaller beams leading a more efficient exploitation of dose-volume effects, and consequently, a better normal tissue sparing.

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Jayde Livingstone, Jean François Adam, Jeffrey C Crosbie, Chris J Hall, Jessica E Lye, Jonathan McKinlay, Daniele Pelliccia, Frédéric Pouzoulet, Yolanda Prezado, Andrew W Stevenson, Daniel Häusermann (2017 Jul 1)

Preclinical radiotherapy at the Australian Synchrotron’s Imaging and Medical Beamline: instrumentation, dosimetry and a small-animal feasibility study.

Journal of synchrotron radiation : 854-865 : DOI : 10.1107/S1600577517006233 En savoir plus
Résumé

Therapeutic applications of synchrotron X-rays such as microbeam (MRT) and minibeam (MBRT) radiation therapy promise significant advantages over conventional clinical techniques for some diseases if successfully transferred to clinical practice. Preclinical studies show clear evidence that a number of normal tissues in animal models display a tolerance to much higher doses from MRT compared with conventional radiotherapy. However, a wide spread in the parameters studied makes it difficult to make any conclusions about the associated tumour control or normal tissue complication probabilities. To facilitate more systematic and reproducible preclinical synchrotron radiotherapy studies, a dedicated preclinical station including small-animal irradiation stage was designed and installed at the Imaging and Medical Beamline (IMBL) at the Australian Synchrotron. The stage was characterized in terms of the accuracy and reliability of the vertical scanning speed, as this is the key variable in dose delivery. The measured speed was found to be within 1% of the nominal speed for the range of speeds measured by an interferometer. Furthermore, dose measurements confirm the expected relationship between speed and dose and show that the measured dose is independent of the scan direction. Important dosimetric parameters such as peak dose, valley dose, the collimator output factor and peak-to-valley dose ratio are presented for 5 mm × 5 mm, 10 mm × 10 mm and 20 mm × 20 mm field sizes. Finally, a feasibility study on three glioma-bearing rats was performed. MRT and MBRT doses were prescribed to achieve an average dose of 65 Gy in the target, and magnetic resonance imaging follow-up was performed at various time points after irradiation to follow the tumour volume. Although it is impossible to draw conclusions on the different treatments with such a small number of animals, the feasibility of end-to-end preclinical synchrotron radiotherapy studies using the IMBL preclinical stage is demonstrated.

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Immaculada Martínez-Rovira, Wilfredo González, Stephan Brons, Yolanda Prezado (2017 May 31)

Carbon and oxygen minibeam radiation therapy: An experimental dosimetric evaluation.

Medical physics : 4223-4229 : DOI : 10.1002/mp.12383 En savoir plus
Résumé

To perform dosimetric characterization of a minibeam collimator in both carbon and oxygen ion beams to guide optimal setup geometry and irradiation for future radiobiological studies.

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Wilfredo González, Cécile Peucelle, Yolanda Prezado (2017 Feb 26)

Theoretical dosimetric evaluation of carbon and oxygen minibeam radiation therapy.

Medical physics : 1921-1929 : DOI : 10.1002/mp.12175 En savoir plus
Résumé

Charged particles have several advantages over x-ray radiations, both in terms of physics and radiobiology. The combination of these advantages with those of minibeam radiation therapy (MBRT) could help enhancing the therapeutic index for some cancers with poor prognosis. Among the different ions explored for therapy, carbon ions are considered to provide the optimum physical and biological characteristics. Oxygen could be advantageous due to a reduced oxygen enhancement ratio along with a still moderate biological entrance dose. The aforementioned reasons justified an in-depth evaluation of the dosimetric features of carbon and oxygen minibeam radiation therapy to establish the interest of further explorations of this avenue.

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Asuncion Carmona, Stéphane Roudeau, Baptiste L'Homel, Frédéric Pouzoulet, Sarah Bonnet-Boissinot, Yolanda Prezado, Richard Ortega (2017 Feb 23)

Heterogeneous intratumoral distribution of gadolinium nanoparticles within U87 human glioblastoma xenografts unveiled by micro-PIXE imaging.

Analytical biochemistry : 50-57 : DOI : S0003-2697(17)30080-5 En savoir plus
Résumé

Metallic nanoparticles have great potential in cancer radiotherapy as theranostic drugs since, they serve simultaneously as contrast agents for medical imaging and as radio-therapy sensitizers. As with other anticancer drugs, intratumoral diffusion is one of the main limiting factors for therapeutic efficiency. To date, a few reports have investigated the intratumoral distribution of metallic nanoparticles. The aim of this study was to determine the quantitative distribution of gadolinium (Gd) nanoparticles after direct intratumoral injection within U87 human glioblastoma tumors grafted in mice, using micro-PIXE (Particle Induced X-ray Emission) imaging. AGuIX (Activation and Guiding of Irradiation by X-ray) 3 nm particles composed of a polysiloxane network surrounded by gadolinium chelates were used. PIXE results indicate that the direct injection of Gd nanoparticles in tumors results in their heterogeneous diffusion, probably related to variations in tumor density. All tumor regions contain Gd, but with markedly different concentrations, with a more than 250-fold difference. Also Gd can diffuse to the healthy adjacent tissue. This study highlights the usefulness of mapping the distribution of metallic nanoparticles at the intratumoral level, and proposes PIXE as an imaging modality to probe the quantitative distribution of metallic nanoparticles in tumors from experimental animal models with micrometer resolution.

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Consuelo Guardiola, Cécile Peucelle, Yolanda Prezado (2017 Jan 28)

Optimization of the mechanical collimation for minibeam generation in proton minibeam radiation therapy.

Medical physics : 1470-1478 : DOI : 10.1002/mp.12131 En savoir plus
Résumé

The dose tolerances of normal tissues continue to be the main barrier in radiation therapy. To lower it, a novel concept based on a combination of proton therapy and the use of arrays of parallel and thin beams has been recently proposed: proton minibeam radiation therapy (pMBRT). It allies the inherent advantages of protons with the remarkable normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams. Due to multiple Coulomb scattering, the tumor receives a homogeneous dose distribution, while normal tissues in the beam path benefit from the spatial fractionation of the dose. This promising technique has already been implemented at a clinical center (Proton therapy Center of Orsay) by means of a first prototype of a multislit collimator. The main goal of this work was to optimize the minibeam generation by means of a mechanical collimation.

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