Nouvelles approches en Radiothérapie

Publications de l’équipe

Année de publication : 2020

P Lansonneur, H Mammar, C Nauraye, A Patriarca, E Hierso, R Dendale, Y Prezado, L De Marzi (2020 Apr 29)

First proton minibeam radiation therapy treatment plan evaluation.

Scientific reports : 7025 : DOI : 10.1038/s41598-020-63975-9 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

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Alejandro Mazal, Yolanda Prezado, Carme Ares, Ludovic de Marzi, Annalisa Patriarca, Raymond Miralbell, Vincent Favaudon (2020 Feb 1)

FLASH and minibeams in radiation therapy: the effect of microstructures on time and space and their potential application to protontherapy.

The British journal of radiology : 20190807 : DOI : 10.1259/bjr.20190807 En savoir plus
Résumé

After years of lethargy, studies on two non-conventional microstructures in time and space of the beams used in radiation therapy are enjoying a huge revival. The first effect called « FLASH » is based on very high dose-rate irradiation (pulse amplitude ≥10 Gy/s), short beam-on times (≤100 ms) and large single doses (≥10 Gy) as experimental parameters established so far to give biological and potential clinical effects. The second effect relies on the use of arrays of minibeams ( 0.5-1 mm, spaced 1-3.5 mm). Both approaches have been shown to protect healthy tissues as an endpoint that must be clearly specified and could be combined with each other ( minibeams under FLASH conditions). FLASH depends on the presence of oxygen and could proceed from the chemistry of peroxyradicals and a reduced incidence on DNA and membrane damage. Minibeams action could be based on abscopal effects, cell signalling and/or migration of cells between « valleys and hills » present in the non-uniform irradiation field as well as faster repair of vascular damage. Both effects are expected to maintain intact the tumour control probability and might even preserve antitumoural immunological reactions. FLASH experiments involving Zebrafish, mice, pig and cats have been done with electron beams, while minibeams are an intermediate approach between X-GRID and synchrotron X-ray microbeams radiation. Both have an excellent rationale to converge and be applied with proton beams, combining focusing properties and high dose rates in the beam path of pencil beams, and the inherent advantage of a controlled limited range. A first treatment with electron FLASH (cutaneous lymphoma) has recently been achieved, but clinical trials have neither been presented for FLASH with protons, nor under the minibeam conditions. Better understanding of physical, chemical and biological mechanisms of both effects is essential to optimize the technical developments and devise clinical trials.

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Tim Schneider, Ludovic De Marzi, Annalisa Patriarca, Yolanda Prezado (2020 Jan 30)

Advancing proton minibeam radiation therapy: magnetically focussed proton minibeams at a clinical centre.

Scientific reports : 1384 : DOI : 10.1038/s41598-020-58052-0 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that has proven to significantly increase dose tolerances and sparing of normal tissue. It uses very narrow proton beams (diameter ≤1 mm), roughly one order of magnitude smaller than state-of-the-art pencil beams. The current implementation of pMBRT with mechanical collimators is suboptimal as it is inflexible, decreases efficiency and produces additional secondary neutrons. As a potential solution, we explore in this article minibeam generation through magnetic focussing and investigate possibilities for the integration of such a technique at existing clinical centres. For this, a model of the pencil beam scanning (PBS) nozzle and beam at the Orsay Proton Therapy Centre was established and Monte Carlo simulations were performed to determine its focussing capabilities. Moreover, various modifications of the nozzle geometry were considered. It was found that the PBS nozzle in its current state is not suitable for magnetic minibeam generation. Instead, a new, optimised nozzle design has been proposed and conditions necessary for minibeam generation were benchmarked. In addition, dose simulations in a water phantom were performed which showed improved dose distributions compared to those obtained with mechanical collimators.

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W González, M Dos Santos, C Guardiola, R Delorme, C Lamirault, M Juchaux, M Le Dudal, G Jouvion, Y Prezado (2020 Jan 10)

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation.

Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB) : 256-261 : DOI : S1120-1797(19)30537-X En savoir plus
Résumé

Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator.

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M Dos Santos, R Delorme, R Salmon, Y Prezado (2020 Jan 5)

Minibeam radiation therapy: A micro- and nano-dosimetry Monte Carlo study.

Medical physics : 1379-1390 : DOI : 10.1002/mp.14009 En savoir plus
Résumé

Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro- and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations.

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Année de publication : 2019

Consuelo Guardiola, Ludovic De Marzi, Yolanda Prezado (2019 Dec 24)

Verification of a Monte Carlo dose calculation engine in proton minibeam radiotherapy in a passive scattering beamline for preclinical trials.

The British journal of radiology : 20190578 : DOI : 10.1259/bjr.20190578 En savoir plus
Résumé

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that combines the benefits of proton therapy with the remarkable normal tissue preservation observed with the use of submillimetric spatially fractionated beams. This promising technique has been implemented at the Institut Curie-Proton therapy centre (ICPO) using a first prototype of a multislit collimator. The purpose of this work was to develop a Monte Carlo-based dose calculation engine to reliably guide preclinical studies at ICPO.

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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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